Journal of Gynecologic Oncology

Feasibility, accuracy and acceptability of self-sampled human papillomavirus testing using careHPV in Cambodia: a cross-sectional study

Self-sampled human papillomavirus (HPV) testing is a potential option for cervical cancer screening, but research is scarce in Cambodia. We evaluated the feasibility, accuracy, and acceptability of self-sampled HPV testing using careHPV. A cross-sectional study including women aged 20-49 years attending 2 national hospitals in the capital city was conducted. Women underwent both self-sampling and clinician-sampling of specimens, and were then asked to complete an acceptability questionnaire. The paired samples were analyzed for high-risk HPV by careHPV and genotyped by polymerase chain reaction (PCR). A total of 375 women were eligible for inclusion. Based on PCR, 78.9% were negative for HPV in both self and clinician-samples, 9.9% had a complete HPV type match, and 6.1% had all HPV types in clinician-samples also detected in self-samples. In 5.1%, one or more HPV types identified in the clinician-samples were missed in self-samples. When using careHPV, the overall agreement between the 2 sampling methods was 95.7% (95% confidence interval [CI]=95.8-95.6) with good concordance (κ=0.66, 95% CI=0.56-0.76). Nearly 90% of the women preferred clinician-sampling over self-sampling, citing greater comfort, ease, and speed. Self-sampled HPV testing using careHPV could be an option for cervical cancer screening in Cambodia; however, it requires periodic quality control of handling procedures. In addition, women's health education regarding the accuracy of self-sampled HPV testing and the importance of follow-up in cases of positive results is needed.

A phase II trial evaluating the efficacy and safety of repeated high dose medroxyprogesterone acetate (MPA) therapy for patients with recurrent early-stage endometrial cancer or atypical endometrial hyperplasia: Japanese Gynecologic Oncology Group study (JGOG2051/KGOG2031, REMPA trial)

Fertility preserving therapy using medroxyprogesterone acetate (MPA) is an important option for young patients with endometrial cancer or atypical endometrial hyperplasia (AEH). However, the effectiveness and feasibility of repeated MPA therapy for patients with intrauterine recurrence following initial MPA therapy is controversial. Only a few single-institution retrospective studies have been conducted on repeated MPA therapy, therefore, multicenter prospective studies for repeated MPA therapy are highly needed. The aim of this study is to assess whether repeated MPA therapy is effective and feasible for patients with intrauterine recurrence following initial MPA therapy. This is a prospective, single-arm, a multicenter phase II trial on repeated MPA therapy for intrauterine recurrence following fertility-preserving therapy for AEH or stage IA (the International Federation of Gynecology and Obstetrics [FIGO] 2008) non-myoinvasive endometrioid carcinoma grade 1. Patients are treated with oral MPA (500-600 mg/day). Pathologically assessment via dilation and curettage will be performed every 2 months until complete response. The major inclusion criteria are 1) intrauterine recurrence of AEH or stage IA (FIGO 2008) endometrioid carcinoma grade 1 without myometrial invasion or extrauterine spread confirmed by imaging tests after complete remission with the previous MPA therapy. 2) The number of recurrences should be up to twice. 3) histologically diagnosed as AEH or endometrioid carcinoma grade 1, 4) 20-42 years of age, and 5) strong desire and consent for fertility-sparing treatment. The primary endpoint is 2-year recurrence-free survival rate. A total of 115 patients will be enrolled from multiple institutions in Japan and Korea within 4 years and followed up for 2 years. Japan Registry of Clinical Trials Identifier: jRCTs031200256.

Immunotherapy plus chemotherapy in patients with advanced endometrial cancer: a cost-effectiveness analysis

Pembrolizumab and dostarlimab are immune checkpoint inhibitors that target programmed death receptor 1 (PD-1). Combination anti-PD-1 regimens have been shown to exhibit favorable survival benefits when treating advanced endometrial cancer (EC). Which treatment was preferable will need to be confirmed by a cost-effectiveness comparison between them. Based on patient and clinical parameters from RUBY and NRG-GY018 phase III randomized controlled trials, the Markov model with a 20-year time horizon was established to evaluate the cost-effectiveness of dostarlimab plus chemotherapy (DC), pembrolizumab plus chemotherapy (PC), and chemotherapy alone (C) treatment for patients with mismatch repair-proficient microsatellite-stable (pMMR-MSS) and mismatch repair-deficient microsatellite instability-high (dMMR-MSI-H) advanced EC from the American payers' perspective. The main results include total cost, life-years (LYs), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) at a $150,000/QALY of willingness-to-pay. In the pMMR-MSS population, DC, PC, and C produced costs (QALYs) of $99,205 (3.02), $322,530 (3.25), and $421,923 (4.40), resulting in corresponding ICERs of $974,177/QALY (PC vs. C), $234,527/QALY (DC vs. C), $86,671/QALY (DC vs. PC), respectively; In the dMMR-MSI-H population, DC, PC, and C obtained costs (QALYs) of $120,177 (5.73), $691,399 (8.43), and $708,787 (11.26), yielding ICERs of $266,423/QALY (PC vs. C), $135,165/QALY (DC vs. C), $7,866/QALY (DC vs. PC), respectively. In the US, DC was a more cost-effective treatment than PC for patients with advanced EC irrespective of MMR status. However, compared to C, DC was associated with more cost-effectiveness in the dMMR-MSI-H population.

Evolving standards and future directions for systemic therapies in cervical cancer

Several groundbreaking clinical trials with the potential to transform the management paradigm of both locally advanced and persistent, recurrent, or metastatic cervical cancers have been presented in 2023. This review describes the reported data from INTERLACE and KEYNOTE-A18 in the locally advanced setting, as well as BEATcc, innovaTV 301 and DESTINY-PanTumor02 for advanced disease. The practice implications of their positive results are interpreted in the context of global health considerations, and updated treatment algorithms are proposed. Furthermore, emerging trends in drug development for cervical cancer are discussed. As the routine use of immune checkpoint inhibitors (ICIs) for curative and palliative indications increases in the foreseeable future, patients whose cervical cancers which persist, relapse or progress after prior ICI exposure will represent an area of unmet clinical need and form the key target population for next-generation trials. Future research will help shape oncologists' approaches in the optimal selection, sequencing and re-treatment or rechallenge of immuno-oncology agents and/or antibody-drug conjugates in women with cervical cancer.

Feasibility of laparoscopic diaphragmatic peritonectomy during Visceral-Peritoneal Debulking (VPD) in patients with stage IIIC-IV ovarian cancer

To describe the surgical technique and evaluate the safety, feasibility and efficacy of laparoscopic diaphragmatic peritonectomy during Visceral-Peritoneal Debulking (VPD) in patients with stage IIIC-IV ovarian cancer (OC). This report is part of a Service Evaluation Protocol (Trust number 3267) on laparoscopy in patients with OC following neo-adjuvant chemotherapy. Between April 2015 and November 2017, all patients underwent to exploratory laparoscopy and a selected court was offered laparoscopic VPD. Laparoscopic diaphragmatic surgery was considered if there was no full thickness involvement. Primary endpoints of this part of the study were the safety, feasibility and efficacy of laparoscopic diaphragmatic peritonectomy. We report the surgical technique and outcomes. Ninety-six patients underwent diaphragmatic surgery during the study period. Fifty patients (52.1%) had intra-operative exclusion criteria and/or full thickness diaphragmatic resection, 46 (47.9%) had peritonectomy and were included in the study. Laparoscopic diaphragmatic peritonectomy was performed in 21 patients (45.4%, group 1), while in 25 patients (54.6%, group 2) laparotomy was necessary. Extent of disease and complexity of surgery were similar. Reasons for conversions were disease coalescing the liver to the diaphragm preventing safe mobilization (22 patients) and accidental pleural opening (3 patients). Overall, intra- and post-operative morbidity was lower in group 1 and pulmonary specific morbidity was very low. Diaphragmatic peritonectomy can be safely accomplished by laparoscopy in almost half of the patients with OC whose disease is limited to the diaphragmatic peritoneum.

Cause-specific mortality rate of ovarian cancer in the presence of competing risks of death: a nationwide population-based cohort study

This nationwide cohort study aimed to evaluate the cause-specific mortality (probability of death by ovarian cancer, probability of death by other causes) under the competing risks of death in women with ovarian cancer. The Korea Central Cancer Registry was searched to identify women with primary ovarian cancer diagnosed between 2006 and 2016. Epithelial ovarian cancer cases were identified using the International Classification of Diseases for Oncology 3rd edition. We estimated the cause-specific mortality according to age (<65 years, ≥65 years), stage (local, regional, and distant), and histology (serous, mucinous, endometrioid, clear cell, and others) under the competing risks framework; moreover, cumulative incidences were estimated. We included 21,446 cases. Cause-specific mortality continuously increased throughout 10 year follow-up. Compared with women aged <65 years, ovarian cancer-specific mortality (5-year, 28.9% vs. 61.9%; 10-year, 39.0% vs. 68.6%, p<0.001) and other cause mortality (5-year, 1.7% vs. 4.8%; 10-year, 2.8% vs. 8.2%, p<0.001) increased in women aged ≥65 years. This trend was consistent across all the stages and histological types. There was a substantial increase in competing risks from 1.1% in women aged <65 years to 8.0% in women aged ≥65 years in patients with early-stage (p<0.001) non-serous ovarian cancer (p<0.001). Older age at diagnosis is associated with increasing ovarian cancer-specific mortality and competing risks. Given the substantial effect of competing risks on elderly patients, there is a need for assessment tools to balance the beneficial and harmful effects to provide optimal treatment.

Where is ERAS in the management of advanced ovarian cancer?: between myths and truths

Controversies in the treatment of advanced ovarian cancer in the PARP inhibitors era: a Delphi consensus

Our aim was to reach a consensus on the management of the most controversial issues of advanced ovarian cancer. Nominal group and Delphi techniques were used. A steering committee of 5 experts analyzed current management of advanced ovarian cancer, identified controversies, critically analyzed the evidence, and formulated guiding statements for clinicians. Subsequently, a panel of 15 experts was selected to test agreement with the statements through two Delphi rounds. Items were scored on a 4-point Likert scale from 1 (totally disagree) to 4 (totally agree). In the first and second rounds, consensus was considered if ≥70% of answers pertained to category 1 or category 4. Overall, 112 statements were incorporated in the following areas: 1) biomarkers and hereditary ovarian cancer; 2) first-line treatment; 3) recurrent disease when platinum might be the best option; and 4) post-poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors setting. In the first Delphi round, 37 statements reached consensus and did thus not pass to the second round. After the second round, another 18 statements reached consensus. Forty-six of the consensus were with the agreement and 9 with the disagreement. Through the methodology used, a consensus was reached in approximately half of the statements. The results of this work may be useful in addressing the most controversial issues on the management of advanced ovarian cancer.

Oncogenic pathway landscape of ovarian cancer and correlation with clinical prognosis

We aimed to identify the main oncogenic pathway by histological type of ovarian cancer based on Next-generation sequencing (NGS) test and to determine the correlation with clinical prognosis. We conducted a retrospective review of 420 patients with ovarian cancer who underwent NGS testing at Asan Medical Center from June 1, 2017, to May 31, 2021. Identified mutations were categorized into seven oncogenic pathways that are most frequently associated with ovarian cancer. The average number of oncogenic pathways involved in each cancer patient was 1.76 (range, 0-6). TP53 mutation was the primary oncogenic pathway in patients with high-grade serous carcinoma (HGSC) (92.8%) and carcinosarcoma (87.5%). MAP kinase signaling was the primary oncogenic pathway in low-grade serous carcinoma (58.3%) and mucinous carcinoma (54.5%). The involvement of more diverse oncogenic pathways has been identified in patients with endometrioid carcinoma and clear cell carcinoma and PI3K-AKT-mTOR signaling and SWI/SNF family pathways were the most common in both groups. The involvement of the DNA damage response pathway showed an association with better progression free survival (PFS), but not with overall survival (OS) in patients with HGSC. On the other hand, the involvement of the RTK signaling family pathway showed an association with better OS despite no association with PFS in patients with HGSC. The clinical prognosis may be improved by implementing targeted treatment tailored to the patient's genetic profile through NGS. Additional research is needed to determine whether the involvement of the RTK signaling family pathway is indeed associated with better OS and to identify the underlying reasons for this association.

Risk of ovarian cancer in women with pelvic inflammatory disease and homologous recombination repair gene mutations under 55: a population-based cohort study

To address the relation among pelvic inflammatory disease (PID), genetic vulnerability and ovarian cancer (OC) risk, we assessed the association between PID and OC risk, alongside the interplay with germline homologous recombination repair (gHR) mutation, utilizing the UK Biobank. We conducted a prospective cohort study in the UK Biobank by tracking OC incidences between individuals with and without a PID history. Identification of gHR mutations ( In the large prospective cohort study, the adjusted HR for OC in patients with PID was 1.45 (95% confidence interval [CI]=0.90, 2.32) compared with those with non-PID. Intriguingly, age-stratified analysis unveiled a positive association between PID history and OC risk in those aged under 55 years (HR=1.92; 95% CI=1.02, 3.63). Moreover, individuals aged younger than 55 years harboring both a history of PID and gHR mutations exhibited the highest risk of OC (HR=7.40; 95% CI=1.03, 53.10). An association between PID and OC risk emerged, notably in the subgroup aged younger than 55 years old. Individuals with both a PID history and gHR mutations exhibited the highest risk of OC. These findings imply PID as a potential precursor for OC, underscoring the importance of early intervention, particularly in the younger population with gHR mutations.

A novel technique for transdiaphragmatic latero-pericardial cardiophrenic lymph node excision using the minimally invasive surgical access procedure in patient with advanced stage ovarian cancer

This study reports the first case of transdiaphragmatic lateropericardial cardiophrenic lymph node excision using the GelPOINT™ mini access platform in a patient with advanced-stage ovarian cancer. A 69-year-old woman with high-grade serous epithelial ovarian cancer. Cardiophrenic lymph node dissection is vital in advanced ovarian cancer surgery, as enlarged nodes are linked to poor prognosis. No clear guidelines exist for operating on patients with enlarged cardiophrenic lymph nodes [1,2]. These nodes are categorized by location relative to the heart: anterior, median (lateropericardial), and posterior [3]. Cardiophrenic lymph node resection can be performed using transdiaphragmatic, transxiphoid, or transthoracic approaches with video-assisted thoracoscopic surgery [4]. In cases with suspicious nodes on imaging, removing them is essential for optimal cytoreduction and accurate staging. In this case, preoperative computed tomography revealed suspicious cardiophrenic lymph nodes measuring 16×13 mm and 10×8 mm, located near the xiphoid process and lateral pericardium. A 30 mm diaphragm incision was made 60 mm from the xiphoid process. An Alexis O-wound retractor was used, and the GelPOINT™ mini platform was introduced with three ports, including one for the camera. A 30-degree optic scope was used to excise the node with LigaSure. When we needed smoke management, we used an aspirator. With this method, we were able to access distally located cardiophrenic lymph nodes with a small incision. Transdiaphragmatic excision of the cardiophrenic lymph node using the mini access platform can be performed effectively with a smaller incision, demonstrating the feasibility and safety of this minimally invasive technique in managing such cases.

Trends in the cost of ovarian cancer across phases of care and surgical years in Korea

This study aimed to estimate the medical costs among patients with ovarian cancer across distinct phases of care and surgical years. This population-based retrospective cohort study identified newly diagnosed ovarian cancer patients who underwent surgery based on nationwide claims data from Korea (2012-2019). Medical costs were categorized into 5 phases: neoadjuvant chemotherapy, surgery, frontline chemotherapy, monitoring, and recurrence. Total and cancer-related costs were analyzed by surgical year on a per patient and per patient per month (PPPM) basis. Per patient costs were estimated for each phase, with up to one year of follow-up per phase, for patients identified between 2013 and 2016. Generalized linear models (GLMs) examined associations between surgical year and cancer-related costs. Among 10,594 patients, median cancer-related costs per patient were highest in the recurrent phase ($20,548), followed by the frontline chemotherapy ($7,005), neoadjuvant chemotherapy ($5,870), surgery ($4,965), and monitoring phases ($1,906). The median surgery phase costs per patient increased from $4,254 in 2013 to $5,676 in 2016; recurrent phase costs increased from $17,289 to $26,750. GLM analysis revealed that per patient and PPPM costs significantly increased over time, particularly in the surgery and recurrent phases. Compared with the cost per patient in 2013, the cost per patient in 2016 was 27% higher for the surgery phase and 49% higher for the recurrent phase. Ovarian cancer-related costs have significantly increased over time, especially in the surgery and recurrent phases, thus highlighting the growing economic burden and the need for cost-effective care strategies.

Impact of lymph node staging on survival in presumed early-stage ovarian cancer: a multicentric retrospective study

This study aimed to assess the impact of comprehensive staging on survival outcomes in this population. Patients who underwent surgery for epithelial ovarian cancer in one of the 14 Francogyn cancer centers between 2000 and 2020 were included in the study. The primary analysis evaluated the impact of lymphadenectomy on overall survival and recurrence-free survival. Lymph node count was analyzed as a continuous variable, and its association with survival, considered as a continuous outcome was assessed using linear regression (secondary analysis). Survival was compared using the log-rank test, and multivariate analysis was performed using a Cox model. A total of 467 patients with presumed early-stage epithelial ovarian cancer were included, of which 198 underwent complete lymphadenectomy and 266 did not. No significant association was found between lymph node staging and survival in the primary analysis, possibly due to limited statistical power and a selection bias, as patients without lymphadenectomy had more favorable disease profiles (p=0.600 and p=0.700, respectively). Complete lymphadenectomy was associated with a significantly higher risk of complications (34.5% vs. 14%, p<0.001). In secondary analysis, the number of para-aortic lymph nodes harvested was identified as an independent predictor of both overall survival and recurrence-free survival (p=0.007 and p=0.002, respectively). Histological characteristics and adjuvant chemotherapy also showed a significant correlation with improved survival outcomes. Extensive para-aortic lymphadenectomy in early-stage epithelial ovarian cancer is associated with better overall and recurrence-free survival but comes with an increased risk of complications.

The relationship between histopathological data and molecular alterations with oncological outcomes in endometrioid-type endometrial cancers and a novel POLE mutation

To identify molecular subgroups in endometrioid endometrial cancer (EEC), evaluate their association with clinicohistopathological characteristics, and define low-intermediate risk groups by integrating these parameters. This retrospective-cohort study included 1,040 patients who underwent surgery between January 2000 and June 2022. Among 900 EEC cases, 72 recurred. Patients with tumor recurrence (n=62) and those without (n=52) were matched. POLE exons 9-14 were examined using Sanger sequencing. p53 and mismatch repair (MMR) protein expression were assessed via immunohistochemistry. The molecular subgroups were POLE mutation (POLE-mut) 5%, mismatch repair-deficient (MMR-d) 43%, p53 mutation (p53-mut) 5%, and non-specific molecular profile (NSMP) 42%. 5% of cases displayed multiple molecular mutations. POLE-mut were more prevalent in high-grade tumors (p=0.026). MMR-d tumors exhibited higher rates of lymphovascular space invasion and myometrial invasion ≥50% (p=0.032, p=0.020). No recurrences occurred in POLE-mut tumors (p=0.002), while MMR-d was significantly associated with recurrence (p=0.002). Median disease-free survival (DFS) for MMR-d, p53-mut, and NSMP were 34, 49, and 107 months, respectively. Median overall survival (OS) for these groups was 128, 102, and 181 months. Multivariate Cox-regression analysis employing the Backward-Stepwise method identified stage as the strongest predictor of DFS, and grade and stage as predictors of OS. POLE mutations were linked to the most favorable molecular prognostic factor. NSMP cases showed the longest DFS and OS, while p53-mut had the shortest OS. Except for POLE, molecular features alone were insufficient for establishing risk groups, highlighting the continued importance of histopathology in EEC management.

Maintenance therapy for platinum-sensitive recurrent ovarian cancer with a history of PARPi administration

This study explored new insights into the selection criteria for maintenance therapy for platinum-sensitive recurrent ovarian cancer by comparing the efficacy of poly(ADP-ribose) polymerase inhibitors (PARPis) and bevacizumab in patients with a history of PARPi administration. Between April 2014 and December 2024, 81 patients underwent maintenance therapy with either PARPi (52 patients) or bevacizumab (29 patients) at our institution. The primary endpoint was progression-free survival (PFS) after the end of the last chemotherapy treatment. The median PFS did not differ significantly between the PARPi and bevacizumab groups (9 vs. 12 months, p=0.942). Similarly, in the propensity score-matched cohort (15 pairs), no significant difference was observed between the PARPi and bevacizumab groups (p=0.444). In the PARPi group, a history of PARPi administration was associated with a significant difference in PFS in both univariate and multivariate analyses (PARPi-naïve vs. PARPi-experienced: 12 vs. 4 months, p=0.002; hazard ratio=3.24, 95% confidence interval=1.56-6.69). In the bevacizumab group, a history of PARPi administration was not associated with a significant difference in PFS. Among patients with a history of PARPi administration, the bevacizumab group had a significantly better PFS than the PARPi group (PARPi rechallenge vs. bevacizumab: 4 vs. 12 months, p=0.042), and the proportion of patients experiencing platinum-resistant recurrence during maintenance therapy was higher in the PARPi rechallenge group (58.8%) than in the bevacizumab group (20.0%) (p=0.049). Maintenance therapy with bevacizumab may be more beneficial for patients with platinum-sensitive recurrent ovarian cancer who have a history of PARPi administration.

Clinical analysis of the impact of systematic pelvic and para-aortic lymphadenectomy on the prognosis of patients with early-stage ovarian cancer (stage IA–IIA): a propensity score matching study

The role of systematic pelvic and para-aortic lymphadenectomy (PPAL) in completion staging surgery for early-stage (stage I-IIA) ovarian cancer (EOC) remains controversial. This study evaluates the impact of PPAL on the prognosis of EOC patients. A retrospective cohort study was conducted using data from the Surveillance, Epidemiology, and End Results database. Patients with EOC (stage I-IIA) were included. Propensity score matching (PSM) was used at a 1:1 ratio based on age, marital status, race, tumor grade, histological type, FIGO stage, and postoperative adjuvant therapy. Post-matching overall survival (OS) and cancer-specific survival (CSS) were compared between the systematic PPAL group (pathological staging) and the non-lymphadenectomy group (clinical staging). After PSM, no significant differences were observed in OS (p=0.140) and CSS (p=0.066) between the two groups. Subgroup analysis showed that for tumor grade III patients, the pathological staging group had significantly higher OS (p=0.028) and CSS (p=0.010) than the clinical staging group. Multivariate Cox regression indicated that tumor grade III was an independent prognostic factor for OS (p=0.006) and CSS (p=0.020). Systematic PPAL does not significantly improve survival in EOC patients. However, for tumor grade III patients, the pathological staging group demonstrates significantly better prognosis, offering a more personalized alternative to routine staging surgery, which requires further validation through prospective trials.

Relacorilant plus nab-paclitaxel for recurrent, platinum-resistant ovarian cancer: a cost-effectiveness study

The phase 2, open-label, randomized, 3-arm study (NCT03776812) found that intermittently dosed relacorilant + nab-paclitaxel improved progression-free survival, duration of response, and overall survival compared with nab-paclitaxel monotherapy with minimal additional toxicity. This study analyzed the cost-effectiveness of intermittent relacorilant + nab-paclitaxel (IN), continuous relacorilant + nab-paclitaxel (CN) and nab-paclitaxel monotherapy (N) from the payer's perspective over a 5-year time horizon. The health outcome is expressed in quality-adjusted life years (QALYs). IN, CN and N were evaluated using QALYs and incremental cost-effectiveness ratio (ICER). The data for this model come from the NCT03776812 trial and other published literature. The impact of the variables is studied using a one-way deterministic sensitivity analysis and a probabilistic sensitivity analysis based on a second-order Monte Carlo simulation. N was the least costly strategy, at $ 4606.05, followed by IN ($22,597.75) and CN ($44,276.86). Based on a willingness-to-pay threshold of $100,000/QALY, IN was cost-effective compared with N, with an ICER of $21,418.69 per QALY gained for N, whereas CN was ruled out by extended dominance (less effective, more costly), compared with N. The incremental benefits of IN compared to CN and N were 0.72 QALYs and 0.84 QALYs. From a US health care system perspective, IN may be cost-effective compared to CN for patients with recurrent platinum-resistant ovarian cancer, and IN is also better than CN and N in terms of efficacy. Therefore, IN is a high-quality regimen for clinicians to treat patients with recurrent platinum-resistant ovarian cancer. ClinicalTrials.gov Identifier: NCT03776812.

Treatment and outcomes in undifferentiated and dedifferentiated endometrial carcinoma

Undifferentiated and dedifferentiated endometrial carcinoma is a rare type of uterine malignancy. This study assesses disease characteristics, treatment and survival outcomes in patients with undifferentiated and dedifferentiated endometrial carcinoma treated at BC Cancer. All patients diagnosed with undifferentiated and dedifferentiated endometrial carcinoma between 2000 and 2019 at BC Cancer were reviewed centrally. Clinical, pathologic, treatment and outcomes were reviewed retrospectively. The Kaplan-Meier method was used to evaluate overall survival (OS) and disease-free survival (DFS). Multivariable analysis was performed using Cox regression analysis. Fifty-two patients were included, 33% had undifferentiated carcinoma and 67% dedifferentiated carcinoma. Sixty-nine percent of those who had mismatch repair (MMR) testing of their tumor had an abnormal profile. The 5-year DFS was 80% (95% confidence interval [CI]=71%-89%) for stage I/II, 29% (95% CI=28%-40%) for stage III and 10% (95% CI 1%-19%) for stage IV. The 5-year OS was 84% (95% CI=75%-92%) for stage I/II, 38% (95% CI=26%-50%) for stage III and 12% (95% CI=1%-24%) for stage IV. Multivariate analysis showed that receiving adjuvant chemotherapy, adjuvant radiotherapy, lower stage and better Eastern Cooperative Group performance status were associated with improved DFS (p<0.05). Patients with stage I/II undifferentiated and dedifferentiated endometrial carcinoma had excellent survival outcomes, those with stage III/IV had worse outcomes, similar to previously reported. Adjuvant chemotherapy and radiotherapy were associated with improved DFS. MMR testing should be performed for these patients due to the high incidence of abnormal profiles.

Oncological safety of minimally invasive surgery in borderline ovarian tumor and ovarian cancer: a retrospective comparative study

This study aimed to evaluate the oncological safety of laparoscopic surgery for patients with benign tumors who underwent laparoscopic surgery at our facility and were subsequently diagnosed with borderline ovarian tumors or ovarian cancer. We conducted a retrospective review of 45 patients initially diagnosed with benign ovarian tumors who underwent laparoscopic surgery at our institution from January 2009 to April 2024. Postoperative pathological examination identified 32 cases of borderline ovarian tumors and 13 cases of ovarian cancer. Laparoscopic cystectomy was performed in 14 (43.8%) borderline cases and 4 (30.8%) ovarian cancer cases. Out of 14 patients with borderline ovarian tumors who underwent cystectomy, 8 subsequently underwent staging laparotomy, whereas 6 underwent only ovarian tumor cystectomy. In contrast, none of the patients with ovarian cancer completed treatment with only ovarian tumor cystectomy. Recurrent disease was observed in 9.4% of borderline tumor cases, all of which were successfully managed with further surgery. In the ovarian cancer group, recurrence occurred in 31% of patients, with 3 resulting in tumor-related mortality. Laparoscopic surgery for borderline ovarian tumors is suggested to be oncologically safe, with low recurrence rate and no adverse impact on survival. However, for ovarian cancer, particularly in cases with peritoneal dissemination, rapid disease progression remains a concern. While this study suggests that laparoscopic surgery may be a viable option for borderline ovarian tumors, further research is needed to validate these findings, particularly for ovarian cancer.

Pregnancy complications and outcomes in patients with early endometrial cancer or atypical hyperplasia after fertility-sparing treatment

To explore the characteristics of pregnancy outcomes in patients with early-stage endometrioid endometrial cancer (EEC) and endometrial atypical hyperplasia (EAH) after successful fertility-sparing treatment. This was a retrospective, single-center analysis of 481 patients with EEC/EAH who desired to conceive after successful fertility-sparing treatment from January 2015 to June 2023. Pregnancy outcomes across reproductive methods were compared. The pregnancy rate was 58.24% and the live birth rate was 48.65% in patients with EAH/EEC after successful fertility-preserving treatment. An age ≥35 years, BMI ≥25 kg/m², and hypertension were independent risk factors for failure of pregnancy. Higher pregnancy (65.77% and 63.64%) and live birth (53.08% and 48.86%) rates were achieved in the in vitro fertilization and embryo transfer (IVF-ET) and ovulation induction group than in the natural conception group (47.68% and 35.10%, respectively). The incidence of threatened abortion (56.52%), cervical insufficiency (5.58%), and placenta accrete/increta (11.15%) appeared to be numerically higher in patients with EAH/EEC than in epidemiological data. More than 5 times of hysteroscopic evaluation was an independent risk factor for placenta accreta/increta. Assisted reproductive technology including IVF-ET and ovulation induction might be preferred for patients with EEC/EAH after successful fertility-sparing treatment to achieve a relatively better pregnancy outcome, though IVF-ET has a higher incidence risk of threatened abortion, preterm birth and placenta accreta/increta. Obstetricians should be prepared for the treatment of threatened abortion, cervical insufficiency, and placenta accreta/increta in patients with EEC/EAH once they become pregnant, especially in those receiving more than 5 times of hysteroscopic evaluation.

Role of adjuvant chemotherapy in stage IC ovarian granulosa cell tumors: a systematic review and meta-analysis

This systematic review and meta-analysis aimed to assess the impact of postoperative adjuvant chemotherapy on recurrence and mortality in stage IC granulosa cell tumors (GCTs). We searched the PubMed, Embase, and Cochrane Library for studies published up to December 1, 2024, comparing the oncological outcomes of adjuvant chemotherapy with observation in stage IC GCTs. Seventy studies were identified, with 12 included in the meta-analysis. Among 695 patients, 255 (36.7%) received postoperative adjuvant chemotherapy and 440 (63.3%) received observation. The overall recurrence and mortality rates were 18.7% and 7.6%, respectively. No significant differences were observed in survival outcomes between the adjuvant chemotherapy and observation groups, including recurrence rate (odds ratio [OR]=1.32; 95% confidence interval [CI]=0.67-2.58; p=0.424; I²=33%), mortality rate (OR=0.83; 95% CI=0.44-1.57; p=0.560; I²=0%), 5-year disease free survival (OR=0.88; 95% CI=0.18-4.18; p=0.868; I²=54%) and 5-year overall survival (OR=1.28; 95% CI=0.60-2.74; p=0.519; I²=0%). Subgroup analysis revealed no significant difference in recurrence rate between adjuvant chemotherapy and observation for both adult and juvenile GCTs, or between patients who underwent fertility-sparing surgery and those who did not. Additionally, no difference was found in recurrence rate between 'bleomycin, etoposide, and cisplatin' or 'etoposide and cisplatin' and 'paclitaxel combined with carboplatin or cisplatin' regimens. Postoperative adjuvant chemotherapy did not provide additional benefits in disease recurrence or survival outcomes compared to observation in stage IC GCTs. PROSPERO Identifier: CRD42024559478.

Clinical outcome and pattern of care for isolated or incidental serous tubal intraepithelial carcinoma: a multicenter retrospective cohort study

Serous tubal intraepithelial carcinoma (STIC), a potential precursor of high-grade serous carcinoma, is associated with subsequent carcinomas development. This study aimed to identify cases of STIC and serous tubal intraepithelial lesions (STIL) and examine clinical outcomes and patterns of care in This retrospective study was conducted at six institutions to examine patients with isolated STIC/STIL. Demographic, adjuvant treatment, and follow-up data were collected from the date of implementation of Sectioning and Extensively Examining the Fimbriated end protocol, which varied from 2006 to 2015, until December 2022. We analyzed the data of 1,119 women who underwent RRSO and were carriers of While patient monitoring after STIC/STIL detection may be considered due to the minimal risk of carcinoma, excessive concern may not be necessary. Furthermore, adjuvant chemotherapy should be considered only with caution.

SPOCK2 promotes the invasion and migration of ovarian cancer cells through FAK signaling pathway

Ovarian cancer is one of the most prevalent malignancies worldwide, with the highest mortality rate among gynecological cancers. This study aims to investigate the molecular mechanisms of SPOCK2 in ovarian cancer progression and metastasis and evaluate its potential as a therapeutic target. The expression levels of SPOCK2 in ovarian cancer tissues and normal tissues were analyzed using data from The Cancer Genome Atlas (TCGA) and immunohistochemistry experiments. Functional assays, including epithelial-mesenchymal transition (EMT), invasion, and migration assays, were performed in high-grade serous ovarian cancer (HGSOC) cells to explore the role of SPOCK2. The interaction between SPOCK2 and ITGA3 and the subsequent activation of focal adhesion kinase (FAK) signaling were investigated. In vivo experiments were conducted to validate the effects of SPOCK2 knockdown on tumor metastasis and invasiveness. SPOCK2 expression was significantly upregulated in ovarian cancer tissues compared to normal tissues and was associated with poor prognosis. Functional assays demonstrated that SPOCK2 promotes EMT, invasion, and migration in HGSOC cells by interacting with ITGA3 and activating FAK signaling. In vivo experiments confirmed that SPOCK2 knockdown significantly suppressed tumor metastasis and invasiveness. This study highlights the critical role of the SPOCK2/ITGA3 axis in driving ovarian cancer progression and provides evidence for SPOCK2 as a potential molecular marker and therapeutic target. These findings offer new insights into the early diagnosis and treatment of ovarian cancer, with significant clinical implications for improving patient outcomes.

Laparoscopy-assisted laterally extended endopelvic resection and sacrectomy (beyond laterally extended endopelvic resection) for platinum-sensitive recurrent ovarian cancer

Laterally extended endopelvic resection (LEER) is a surgical option for patients with laterally recurrent gynecological malignancies to preserve sciatic nerve function [1]. However, when a laterally recurrent tumor involves the sacrum, debulking surgery is generally abandoned because the surgical excision line is outside the standard LEER. Since its technical feasibility and oncological safety have been demonstrated, sacrectomy for recurrent rectal cancer is now considered the treatment of choice [2]. Theoretically, if complete resection is deemed possible, LEER and sacrectomy (beyond-LEER) may be the treatments of choice for recurrent gynecological malignancies. However, the technical feasibility of beyond-LEER has not been reported. In this video, we demonstrate the step-by-step procedure of laparoscopy-assisted beyond-LEER in a patient with platinum-sensitive recurrent ovarian cancer. The patient, with stage IVA ovarian cancer, was in complete remission after debulking surgery and chemotherapy. At the 13-month-platinum-free interval, a solitary recurrent tumor, involving the right internal iliac vessels and infiltrating the right sacral foramen (S3), was detected. Thus, second-line chemotherapy was initially introduced. During 6 months of chemotherapy, the tumor size remained unchanged and no other metastatic lesions were detected. Therefore, surgical resection was planned. Laparoscopy-assisted beyond-LEER was performed, and complete resection without tumor exposure was accomplished. No sign of recurrence 9 months post debulking surgery has been noted. This is the first report to demonstrate the technical feasibility of laparoscopy-assisted beyond-LEER. Table 1 presents a comparison with cases wherein open total pelvic exenteration with low-sacrectomy (TPES) was performed for recurrent rectal cancer. Forty-nine cases of open TPES demonstrated operation time, 11.5 hours; blood loss volume, 2,630 mL; and length of stay, 24.5 days [3]. These results are similar to the findings in our case: operation time, 11 hours; blood loss volume, 1,700 mL; and length of stay, 35 days. We suggest that the benefit of laparoscopy cannot be demonstrated because TPES is a different procedure compared with the beyond LEER. Kimura et al. [4] demonstrated that laparoscopic TPES for recurrent rectal cancer might have a benefit of reduced blood loss. The advantages of laparoscopy during our multidirectional procedure include not only the possibility of reducing blood loss but also the quick closure of abdominal wound and ease of keeping wound clean while changing patient's position during sacrectomy. However, due to the limited case and follow up periods, further studies are required to determine the efficacy of this novel surgery and real advantage of laparoscopy. The informed consent for use of this video was taken from the patient.

Platinum free interval and clinical benefit of the second-line chemotherapy in recurrent uterine and ovarian carcinosarcoma: a retrospective cohort analysis

Uterine and ovarian carcinosarcomas (OCSs) are rare and aggressive neoplasms. We assessed whether progression free survival after initial treatment (PFS1) was associated with the clinical benefit of chemotherapy after progression, estimated as overall survival (OS) after progression/relapse. All consecutive patients treated with chemotherapy for stage I-IV uterine/OCS in Cochin University Hospital between 2010 and 2022 were included in this retrospective cohort. Association between PFS1 and OS after progressive disease (PD) was determined by Cox regression. Optimal PFS1 threshold for OS after PD prediction was determined by a time-dependent receiver operating characteristic-curve analysis. Forty patients treated for endometrial (n=32) or OCS (n=8) were included. Median PFS1 and OS after PD were 16 months 95% confidence interval (95% CI=11-not available [NA]) and 6 months (95% CI=2-15). In patients who relapsed/progressed (n=20), OS after PD was anticipated by PFS1 (Pearson r=0.61; area under the curve=0.79; 95% CI=0.6-1). At the threshold of PFS1 ≤/>9 months (n=6/n=7), median OS post PD were 2 months (0.1-NA) and 15 months (6-NA), for patients treated with platinum/anthracycline based chemotherapy in second line. Patients receiving best supportive care alone (n=7) had a median OS post PD of 8 months (1.3-NA). Our results highlight that a subgroup of carcinosarcomas patients exhibits a durable benefit from chemotherapy in the relapse settings, and suggest the use of PFS1, as a proxy of platinum-sensitivity, to select patients who might derive higher clinical benefit of a 2nd line of chemotherapy.

Developing standardized informed consent for hysterectomy and vulva cancer surgery

Informed consent is a fundamental aspect of surgical care, designed to reinforce patient autonomy, promote shared decision-making, and potentially mitigate legal conflicts by ensuring the provision of comprehensive and consistent information in clinical practice. The Korean Society of Gynecologic Oncology (KSGO) previously published detailed informed consent documents for cervical, endometrial, and ovarian cancer surgery. However, standardized consent forms remain relatively lacking for laparoscopic-robotic hysterectomy performed for non-malignant indications, as well as for vulvar cancer surgery. Hence, the KSGO subcommittee collected, reviewed, and discussed consent forms from domestic medical institutions and subsequently developed informed consent for laparoscopic-robotic hysterectomy and vulvar cancer surgery, aiming to build patient trust and understanding.

Pattern of first recurrence in advanced epithelial ovarian, fallopian tube and peritoneal cancers treated with cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy

Bevacizumab in frontline chemotherapy improved the survival outcome for advanced ovarian clear cell carcinoma: a multicenter retrospective analysis

Advanced ovarian clear cell carcinoma (OCCC) is associated with poor outcomes owing to chemoresistance. Bevacizumab (Bev) is increasingly being used to treat advanced ovarian cancer; however, its efficacy in OCCC remains unclear. This study evaluated the treatment outcomes of frontline bevacizumab chemotherapy in patients with OCCC. This retrospective multi-institutional study included patients diagnosed with advanced OCCC at eight institutions in Japan between 2008 and 2018. Patients were categorized into pre and post-market groups based on the Bev approval dates. Progression-free survival (PFS) and overall survival (OS) were analyzed using univariate and multivariate methods. Additionally, patients were classified into Bev-treated (Bev+) and non-Bev-treated (Bev-) groups, and their prognoses were compared. A total of 96 patients were in the pre-market group and 82 in the post-market group. The post-market group had a significantly higher proportion of patients with poor performance status and patients who underwent interval debulking surgery (p<0.01 and p<0.01, respectively). Univariate analysis demonstrated a better PFS in the post-market group (p=0.041). In multivariate analysis, better PFS (hazard ratio [HR]=0.52; p=0.002) and OS (HR=0.47; p=0.002) were observed in the post-market group than in the pre-market group. Bev+ patients had significantly better PFS and OS than Bev- patients in univariate (p<0.001 and p<0.001, respectively) and multivariate analyses (PFS: HR=0.36; p<0.001 and OS: HR=0.21; p=0.001, respectively). Incorporating Bev into frontline chemotherapy may improve outcomes in patients with advanced OCCC.

Gynecologic oncology in 2024: breakthrough trials and evolving treatment strategies for cervical, uterine corpus, and ovarian cancers

This review summarized the results of clinical trials in 2024 that were believed to have a significant impact on clinical practice in the field of gynecologic oncology. The SHAPE trial, INTERLACE and KEYNOTE-A18 trials, and BEATcc and COMPASSION-16 trials were included in early-stage, locally advanced, and recurrent/metastatic cervical cancer, respectively. For uterine corpus cancer, updated survival data of the four trials (NRG-GY018, RUBY, AtTEnd, DUO-E) for endometrial cancer and the first survival data of LMS-04 trial for leiomyosarcoma were described. For ovarian cancer, the final overall survival results of PRIMA study were followed by DUO-O, ATHENA-combo, and FIRST-ENGOT-OV44 trial in different disease conditions. Finally, the results of DESTINY-PanTumor02, a basket trial of trastuzumab deruxtecan, were briefly addressed.

Prophylactic salpingectomy as a preventative strategy for ovarian cancer in the general population: a systematic review and meta-analysis

The impact of prophylactic salpingectomy on the prevention of epithelial ovarian cancer (EOC) remains unclear, particularly in Asian populations where data is lacking. In this systematic review and meta-analysis study, we sought to assess whether prophylactic salpingectomy could reduce the incidence of ovarian cancer in the general population of multiple ethnicities. A systematic review and meta-analysis were conducted using PubMed/MEDLINE, EMBASE, the Cochrane Library, and Web of Science to assess the effectiveness of salpingectomy, bilateral salpingectomy (BS), and unilateral salpingectomy (US) in reducing the risk of EOC and evaluating postoperative outcomes. The final analyses included 6 eligible trials (5,747,056 patients), including 1 cohort study and 5 case-control studies. The analyses of these studies demonstrated that women who underwent salpingectomy had a significantly reduced risk of EOC compared to those who did not receive salpingectomy (odds ratio [OR]=0.63; 95% confidence interval [CI]=0.45-0.89; p=0.007). Five studies (5,746,469 patients) indicated a significant reduction in EOC risk among patients who underwent BS (OR=0.48; 95% CI=0.33-0.69; p<0.001). On the other hand, in the analysis of 4 studies (5,745,887 patients) that examined US, the association with EOC risk was not significant despite the protective trend (OR=0.82; 95% CI=0.64-1.06; p=0.12). Our results indicate BS is an effective strategy for reducing the risk of sporadic EOC, but the results did not lead to the same conclusion for patients who underwent US. When a candidate or patient is undergoing a hysterectomy or has other benign diseases, prophylactic BS may be a safe surgical procedure that carries future benefits in terms of EOC risk.

Clinical practice guidelines for ovarian cancer: an update to the Korean Society of Gynecologic Oncology guidelines

We updated the Korean Society of Gynecologic Oncology (KSGO) practice guideline for the management of ovarian cancer as version 5.1. The ovarian cancer guideline team of the KSGO published announced the fifth version (version 5.0) of its clinical practice guidelines for the management of ovarian cancer in December 2023. In version 5.0, the selection of the key questions and the systematic reviews were based on the data available up to December 2022. Therefore, we updated the guidelines version 5.0 with newly accumulated clinical data and added 5 new key questions reflecting the latest insights in the field of ovarian cancer between 2023 and 2024. For each question, recommendation was provided together with corresponding level of evidence and grade of recommendation, all established through expert consensus.

Bevacizumab combined with chemotherapy could be superior to chemotherapy alone in relapsed ovarian cancer after PARPi: evidence from a multi-center propensity score-matched analysis

A retrospective, multi-center propensity score-matched (PMS) analysis was conducted to investigate the efficacy and safety of the treatment strategy that combines bevacizumab and chemotherapy for patients with relapsed epithelial ovarian cancer (EOC) who previously received poly ADP-ribose polymerase inhibitors (PARPis). A total of 250 ovarian cancer (OC) patients relapsed after PARPi received chemotherapy with or without bevacizumab at 4 medical centers were enrolled in the study. For both treatments, Kaplan-Meier analysis and Cox regression were used to compare PFS. In the multivariable analysis of 250 patients, the incorporation of bevacizumab into chemotherapy demonstrated a significant enhancement in PFS (hazard ratio [HR]=0.49; 95% confidence interval [CI]=0.34-0.72; p<0.001). Fifty-five patients were enrolled in Group A (bevacizumab combined with chemotherapy) and 55 were enrolled in Group B (chemotherapy alone regime) after PSM analysis. A statistically significant difference in PFS was observed between the 2 regimens (HR=0.62; 95% CI=0.40-0.97; p=0.036), suggesting that the bevacizumab combined with chemotherapy regimen confers superior clinical benefits. The median PFS was 11 months in Group A and 9 months in Group B. A significant variation was noted in PFS between patients without RCRS (HR=0.50; 95% CI=0.30-0.82) and the platinum-resistant subgroup (HR=0.31; 95% CI=0.14-0.68). Adverse effects of Grade 3-4 were more prevalent in Group A than in Group B. Additionally, instances of severe hypertension and bowel perforation were reported solely within Group A. In patients diagnosed with EOC relapsed after PARPi, the regime of chemotherapy combined with bevacizumab is associated with better PFS.

Diagnostic performances of the Ovarian Adnexal Reporting and Data System, the Risk of Ovarian Malignancy Algorithm, and the Copenhagen Index in the preoperative prediction of ovarian cancer: a prospective cohort study

This study aimed to assess the diagnostic performance of the Risk of Ovarian Malignancy Algorithm (ROMA), Copenhagen Index (CPH-I), and Ovarian Adnexal Reporting and Data System (O-RADS) for the preoperative prediction of ovarian cancer (OC). A prospective cohort study was conducted on 462 patients diagnosed with ovarian tumors admitted to the Departments of Obstetrics and Gynecology, Hue University of Medicine and Pharmacy Hospital, and Hue Central Hospital from May 2020 to December 2022. ROMA and CPH-I were calculated using cancer antigen 125 (CA125), human epididymal protein 4 (HE4) levels, and patient characteristics (age and menopausal status). O-RADS criteria were applied to describe ovarian tumor characteristics from ultrasound findings. Compared with histopathological results, the predictive values of ROMA, CPH-I, and O-RADS alone or in combination with CA125/HE4 for OC were calculated. Among 462 patients, 381 had benign tumors, 11 had borderline tumors, and 50 had OC. At optimal cut-off points, ROMA's and CPH-I's areas under the curves (AUCs) were 0.880 (95% confidence interval [CI]=0.846-0.909) and 0.890 (95% CI=0.857-0.918), respectively, and ROMA and CPH-I sensitivities/specificities (Se/Sp) were 68.85%/95.01% and 77.05%/91.08%, respectively. O-RADS ≥3 yielded an AUCs of 0.949 (95% CI=0.924-0.968), with Se/Sp of 88.52%/88.98% (p<0.001). Combining O-RADS with CA125 demonstrated the highest predictive value, with AUCs of 0.969 (95% CI=0.949-0.983) and Se/Sp of 98.36%/86.09% (p<0.001). The ROMA, CPH-I, O-RADS, O-RADS + CA125, and O-RADS + HE4 models demonstrated good predictive values for OC; the combination of O-RADS and CA125 yielded the highest values.

Step-by-step demonstration of “sciatic-nerve-preserved beyond-LEER” in a Thiel-embalmed cadaver: a novel salvage surgery for recurrent gynecologic malignancies

Anticancer effect of the antipsychotic agent penfluridol on epithelial ovarian cancer

Chemoresistant-epithelial ovarian cancer (EOC) has a poor prognosis, prompting the search for new therapeutic drugs. The diphenylbutylpiperidine (DPBP) class of antipsychotic drugs used in schizophrenia has shown anticancer effects. This study aimed to investigate the preclinical efficacy of penfluridol, fluspirilene, and pimozide (DPBP) using in vitro and in vivo models of EOC. Human EOC cell lines A2780, HeyA8, SKOV3ip1, A2780-CP20, HeyA8-MDR, and SKOV3-TR were treated with penfluridol, fluspirilene, and pimozide, and cell proliferation, apoptosis, and migration were assessed. The preclinical efficacy of DPBP was also investigated using in vivo mouse models, including cell lines and patient-derived xenografts (PDX) of EOC. DPBP drugs significantly decreased cell proliferation in chemosensitive (A2780, HeyA8, and SKOV3ip1) and chemoresistant (A2780-CP20, HeyA8-MDR, and SKOV3-TR) cell lines. Among these drugs, penfluridol exerted a relatively stronger cytotoxic effect on all cell lines. Penfluridol significantly increased apoptosis and inhibited migration of EOC cells. In the cell line xenograft mouse model with HeyA8, the penfluridol group showed significantly decreased tumor weight compared with the control group. In the paclitaxel-resistant model with HeyA8-MDR, the penfluridol group had significantly decreased tumor weight compared with the paclitaxel or control groups. Penfluridol exerted anticancer effects on the PDX model. Penfluridol exerted significant anticancer effects on EOC cells and xenograft models, including PDX. Thus, penfluridol therapy, as a drug repurposing strategy, might be a potential therapeutic for EOCs.

Evaluating the specific STAT3 inhibitor YHO-1701 in ovarian cancer cell lines and patient-derived cell models: efficacy, mechanisms, and therapeutic potential

Signal transducer and activator of transcription 3 (STAT3) plays key roles in regulating cancer cell proliferation, survival, and metastasis. We aimed to determine the effects of YHO-1701, an oral STAT3 inhibitor, in ovarian cancer (OC). We evaluated the impact of YHO-1701 on cell growth in patient-derived cells (PDCs) and OC cell lines using standard cell proliferation assays. Spheroid models derived from PDCs were assessed using three-dimensional (3D) cell viability assays. Antitumor activity was performed in SKOV3 xenograft mice treated orally administrated YHO-1701 with 20 mg/kg. Changes in STAT3 signaling were analyzed by western blotting. The molecular mechanisms of STAT3 inhibition were investigated by sequencing RNA and analyzing pathways in the SKOV3 using a small interfering RNA targeting STAT3 (STAT3 siRNA) and YHO-1701. YHO-1701 inhibited the growth of OC cell lines by preventing STAT3 dimerization and decreasing the expression of its downstream signaling molecule, survivin. The growth of PDCs and spheroids obtained from patients with primary and recurrent OCs was significantly inhibited. Antitumor effect was observed in the SKOV3 xenograft mice with YHO-1701. YHO-1701 induced apoptosis in OC cells. Additionally, p53 and/or MAPK signaling pathways were upregulated in SKOV3 cells incubated with YHO-1701 and in those with STAT3 siRNA. Our results showed that YHO-1701 suppressed cell growth in PDCs of OC, accompanied by survivin inhibition, and a decrease in the number of peritoneal metastasis in the mice by YHO-1701, compared with those treated with control. Therefore, YHO-1701 could be a promising candidate agent for treating OC.

Patient-reported symptom burden and circulating cytokines undergoing chemotherapy: a pilot study in patients with ovarian cancer

To analyze the fluctuations of patient-reported outcomes (PROs) and their relationships with cytokines in the peripheral blood of patients undergoing chemotherapy for ovarian cancer (OC). PROs burden was prospectively measured by the M.D. Anderson Symptom Inventory-Ovarian Cancer (MDASI-OC) at baseline before chemotherapy, on a daily basis during and post-chemotherapy days (PCD) 7, 14, and 20. Cytokines were collected at baseline, days prior to hospital discharge and PCD 20. Pearson correlation was used to explore the associations between PROs and cytokines levels in peripheral blood. The top 8 rated symptoms were compared between the neoadjuvant chemotherapy (NACT) group (n=20) and the postoperative adjuvant chemotherapy (PAC) group (n=7). Before chemotherapy, the mean scores of fatigue and lack of appetite in the NACT group were higher than those in the PAC group. After chemotherapy, pain, nausea, vomiting, disturbed sleep, lack of appetite, and constipation increased to peak during PCD 2-6; while, fatigue and numbness or tingling remained at high levels over PCD 2-13. By PCD 20, disturbed sleep and fatigue showed a significant increase in mean scores, particularly in the NACT group; while, other symptom scores decreased and returned to baseline levels. Additionally, the longitudinal fluctuations in pain, fatigue, and lack of appetite were positively associated with circulating levels of interleukin-6 and interferon gamma (p<0.05). MDASI-OC was feasible and adaptable for demonstrating the fluctuations of symptom burden throughout chemotherapy course. Moreover, symptoms changing along with cytokines levels could provide clues for exploring mechanism underlying biochemical etiology.

Response to: Author's reply to: Lymphadenectomy in clinically early epithelial ovarian cancer and survival analysis (LILAC): a Gynecologic Oncology Research Investigators Collaboration (GORILLA-3002) retrospective study

Targeting BRAF pathway in low-grade serous ovarian cancer

Mutations in genes encoding for proteins along the RAS-RAF-MEK-ERK pathway have been detected in a variety of tumor entities including ovarian carcinomas. In the recent years, several inhibitors of this pathway have been developed, whose antitumor potential is currently being assessed in different clinical trials. Low grade serous ovarian carcinoma, is a rare gynecological tumor which shows favorable overall survival, compared to the general ovarian cancer population, but worrying resistance to conventional chemotherapies. The clinical behavior of low grade serous ovarian carcinoma reflects the different gene profile compared to high-grade serous carcinoma:

Investigation of selective glucocorticoid receptor modulation in high-grade serous ovarian cancer PDX models

In ovarian cancer (OvCa), tumor cell high glucocorticoid receptor (GR) has been associated with poor patient prognosis. In vitro, GR activation inhibits chemotherapy-induced OvCa cell death in association with transcriptional upregulation of genes encoding anti-apoptotic proteins. A recent randomized phase II study demonstrated improvement in progression-free survival (PFS) for heavily pre-treated OvCa patients randomized to receive therapy with a selective GR modulator (SGRM) plus chemotherapy compared to chemotherapy alone. We hypothesized that SGRM therapy would improve carboplatin response in OvCa patient-derived xenograft (PDX). Six high-grade serous (HGS) OvCa PDX models expressing GR mRNA ( One of the 6 GR-positive PDX models showed a significant improvement in PFS with the addition of a SGRM. Interestingly, the single model with an improved PFS was least carboplatin sensitive. Possible explanations for the modest SGRM activity include the high carboplatin sensitivity of 5 of the PDX tumors and the potential that SGRMs activate the tumor invasive immune cells in patients (absent from immunocompromised mice). The level of tumor GR protein expression alone appears insufficient for predicting SGRM response. The significant improvement in PFS shown in 1 of the 6 models after treatment with a SGRM plus chemotherapy underscores the need to determine predictive biomarkers for SGRM therapy in HGS OvCa and to better identify patient subgroups that are most likely to benefit from adding GR modulation to chemotherapy.

Clinical characteristics and status of treatment of small-cell carcinoma of the ovary, hypercalcemic type in the Chinese population: a meta-analysis

This study aimed to comprehensively analyze the clinical characteristics and treatment status of Chinese small cell carcinoma of the ovary hypercalcemic type (SCCOHT) patients, providing insights into this unique population and comparing findings with international literature. Through a meta-analysis, we collected data from published case reports and records from the Obstetrics & Gynecology Hospital of Fudan University. Demographic information, clinical presentations, tumor attributes, treatment modalities, and survival outcomes were extracted and examined alongside relevant global studies. The analysis encompassed 80 Chinese SCCOHT patients, of which 62 from 33 previously reported literatures, and the other 18 were from Obstetrics & Gynecology Hospital of Fudan University. In 62 cases with stage information, A total of 25 tumors were International Federation of Gynecology and Obstetrics stage I, 3 were stage II, 19 were stage III, and 15 were stage IV. Most patients received surgery and chemotherapy, but regimens were varied. Median follow-up was 10 months (range=4-120). Elevated carbohydrate antigen 125 and serum calcium levels were consistent findings. Recurrence rates were notable, especially among stage I patients. Platinum-based chemotherapy, paclitaxel and carboplatin (n=11, 13.4%), constituted common treatment regimens. This study observed demographic and clinical similarities with international datasets. And the findings emphasize the urgency for innovative therapeutic approaches to improve outcomes in SCCOHT patients. Continued research efforts are essential to enhance the knowledge surrounding this rare malignancy and to optimize its clinical management.

The effectiveness of CA125 and HE4 as clinical prognostic markers in epithelial ovarian cancer patients with BRCA mutation

To investigate the efficacy of cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) in predicting survival outcomes based on breast cancer gene (BRCA) mutational status in epithelial ovarian cancer. Medical records of 448 patients diagnosed with epithelial ovarian cancer at a single tertiary institution in Korea were retrospectively analyzed. Area under the curve, sensitivity, specificity, and accuracy were assessed using the CA125 and HE4 values after surgery and 3 cycles of chemotherapy to predict 1-year survival based on the BRCA mutational status. Kaplan-Meier analysis was used to obtain progression-free and overall survival to evaluate CA125 and HE4 effectiveness in predicting survival outcomes. A total of 423 patients were analyzed, including 180 (42.6%) who underwent interval debulking surgery (IDS) and 243 (57.4%) who underwent primary debulking surgery (PDS). BRCA mutations were observed in 37 (15.2%) and 44 (22.4%) patients in the PDS and IDS groups, respectively. CA125 and HE4 normalization demonstrated the highest specificity in patients with or without BRCA mutations, with specificities of 97.1% and 99.1% in the PDS group and 78.6% and 86.2% in the IDS group, respectively. Normalizing HE4 alone may be an effective prognostic marker, with an area under the curve of 0.774 and specificity of 75.0%, in patients with BRCA mutations. Normalizing both biomarkers emerged as the most effective predictive marker for the 1-year recurrence rate, regardless of BRCA mutational status. A negative HE4 value can be a useful predictor for 1-year recurrence-free survival in patients with BRCA mutations.

Mirvetuximab soravtansine in platinum-resistant recurrent ovarian cancer with high folate receptor-alpha expression: a cost-effectiveness analysis

Mirvetuximab soravtansine (MIRV), a new antibody-drug conjugate, versus the investigator's choice of chemotherapy (IC) was the first treatment to demonstrate benefits for progression-free and overall survival in platinum-resistant recurrent ovarian cancer (PROC) with high folate receptor-alpha (high-FRα) expression. Efficacy, safety, and economic effectiveness make MIRV the new standard of care for these patients. Based on patients and clinical parameters from MIRASOL (GOG 3045/ENGOT-ov55) phase III randomized controlled trials, the Markov model with a 20-year time horizon was established to evaluate the cost and efficacy of MIRV and IC for PROC with high-FRα expression, considering the bevacizumab-pretreated situation from the American healthcare system. Total cost, life-years (LYs), quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), and incremental net health benefits were the main outcome indicators and compared with willingness-to-pay threshold of $100,000/QALY. Sensitivity and scenario analyses were conducted. Compared with the IC, MIRV was associated with incremental costs of $538,251, $575,674, and $188,248 with the corresponding QALYs (LYs) increased by 0.90 (1.55), 1.09 (1.88), and 0.53 (0.79), leading to ICERs of $596,189/QALY ($347,995/LY), $530,061/QALY ($306,894/LY), and $1,011,310/QALY ($680,025/LY) in the overall, bevacizumab-naïve, and bevacizumab-pretreated patients, respectively. When MIRV is reduced by more than 75%, it may be a cost-effective treatment. At the current price, MIRV for PROC with high-FRα expression is not the cost-effective strategy in the US. However, its treatment has higher health benefits in bevacizumab-naïve patients, which is likely to be an alternative.

Modified posterior pelvic exenteration combined with ileocecal resection for locally advanced endometrial cancer

There are several retrospective studies which have suggested that optimal cytoreductive surgery for stage IV endometrial cancer improves survival [1-3]. In addition, some investigators have reported that achieving maximal cytoreduction to a visibly disease-free outcome in the abdominal cavity for endometrial cancer with distant metastases can extend patients' survival [4]. Due to the anatomic proximity of the rectosigmoid colon to the female pelvic organs and its involvement in locally advanced endometrial cancer, an en bloc resection of the uterus, adnexa, and rectosigmoid, also known as a modified posterior pelvic exenteration (MPPE), is performed to achieve optimal cytoreduction [5,6]. Additionally, if the tumor has infiltrated the ileal end and/or cecum, ileocecal resection can be added. I report the details of the technique for this surgery requiring intestinal reconstruction. We routinely placed a transanal drainage tube after a MPPE to decrease the rate of anastomotic leakage and the need for a diverting stoma [7]. No visible tumors were observed after surgery. No intraoperative or early postoperative complications occurred. The patient did not have an impediment in her postoperative bladder and bowel function. Concerning the extent of hysterectomy during surgery, the procedure was performed as described in that of a class II hysterectomy [8]. This might partly explain the preservation of these function. Subsequently, she was treated with 6 cycles of doxorubicin and cisplatin chemotherapy. Two years after surgery, she is alive with no evidence of recurrence. The patient provided informed consent for use of this video.

Study of neoadjuvant chemotherapy in advanced malignant ovarian germ cell tumors at a tertiary center in western India

To study clinical characters and outcomes in patients of malignant ovarian germ cell tumor (MOGCT) undergoing surgery following neoadjuvant chemotherapy (NACT). Retrospective study of patients undergoing surgery following NACT for MOGCT at our institute. Platinum based chemotherapy was given in all patients in NACT. Between March 2013 and February 2023, 30 patients had surgery after NACT. Patient's median age was 22 years (range, 12 to 35 years) and median follow up 42months (range, 6 to 132 months). Majority had endodermal sinus tumor (n=12), dysgerminoma (n=9) and mixed GCT (n=7). All had either International Federation of Gynecology and Obstetrics (FIGO) stage 3 (n=19) or FIGO stage 4 disease (n=11). Complete response to NACT seen in 5 patients and 23 patients had partial response. Fertility sparing surgery in 18 patients and complete surgery in 12 patients. Suboptimal surgery was seen in 4 patients. Currently, 20 of 30 patients are alive and disease free, 3 lost for follow up and 7 patients had progression after adjuvant therapy. Five patients had mortality-4 with progression and 1 with bleomycin toxicity. Fifteen of 17 eligible patients have resumed menstruation and one had successful pregnancy. Prognostic factors noted in study are stage, optimal surgery and viable tumor in histopathology. Dysgerminoma had better outcome than other histology. NACT may be a reasonable option in patients with extensive unresectable disease or in whom fertility sparing is not possible or in the poor general condition. Fertility sparing surgery can be attempted post neoadjuvant chemotherapy without adversely affecting prognosis.

Clinical and molecular biomarkers predicting response to PARP inhibitors in ovarian cancer

To determine the useful biomarker for predicting the effects of poly-(ADP ribose)-polymerase (PARP) inhibitors in Japanese patients with ovarian cancer. We collected clinical information and performed molecular biological analysis on 42 patients with ovarian, fallopian tube, and primary peritoneal carcinomas who received PARP inhibitors. Among the analyzed patients with ovarian cancer, 23.8% had germline We found that HRRm can be a useful biomarker for predicting the effects of PARP inhibitors in treating ovarian cancer and that the PFI can also be useful in recurrent ovarian cancer.

Mesothelin expression in gynecologic carcinosarcoma: clinicopathological significance and correlation with HER2 expression

This study aimed to evaluate mesothelin (MSLN) expression and determine its clinical significance and correlation with human epidermal growth factor receptor 2 (HER2) expression in gynecological carcinosarcoma. We retrospectively evaluated patients with uterine carcinosarcoma (UCS) and ovarian carcinosarcoma (OCS) who underwent surgery between 1997 and 2019. Immunohistochemical staining of formalin-fixed, paraffin-embedded specimens for MSLN (clone SP74) and HER2 (clone 4A5) was also performed. MSLN was scored using the H-score and 4-tired scoring system (0-3+). MSLN positivity was defined as any positive cell at any intensity, while high MSLN expression was defined as an intensity of ≥2+ in ≥30% of tumor cells. HER2 expression was scored according to modified 2018 American Society of Clinical Oncology/College of American Pathologists criteria. A total of 128 patients were recruited, including 119 with UCS and 9 with OCS. All cases in UCS exhibited MSLN positivity, and 33.9% showed high-MSLN expression. Clinicopathological characteristics were not significantly associated with high or low-MSLN expression. However, the high-MSLN group showed more prolonged overall survival (OS) than the low-MSLN group (not assessed vs. 36.8 months; hazard ratio=0.48, 95% confidence interval=0.26-0.89, p=0.016). HER2-high patients had higher MSLN expression than HER2-negative patients. In high-MSLN and low-MSLN expression groups, HER2 status did not affect OS. OCS showed 100% MSLN positivity, with 66.6% high-MSLN. MSLN expression is widely observed in gynecological carcinosarcomas. Moreover, high-MSLN expression is a favorable prognostic factor for UCS. MSLN could be a promising therapeutic target for UCS, even in the era of anti-HER2 therapy.

Phase II randomized study of dostarlimab alone or with bevacizumab versus non-platinum chemotherapy in recurrent gynecological clear cell carcinoma (DOVE/APGOT-OV7/ENGOT-ov80)

Recurrent gynecological clear cell carcinoma (rGCCC) has a low objective response rate (ORR) to chemotherapy. Previous preclinical and clinical data suggest a potential synergy between immune checkpoint inhibitors and bevacizumab in rGCCC. Dostarlimab, a humanized monoclonal antibody targeting programmed cell death protein 1 (PD-1), combined with the anti-angiogenic bevacizumab, presents a novel therapeutic approach. This study will investigate the efficacy of dostarlimab +/- bevacizumab in rGCCC. DOVE is a global, multicenter, international, open-label, randomized phase 2 study of dostarlimab +/- bevacizumab with standard chemotherapy in rGCCC. We will enroll 198 patients with rGCCC and assign them to one of three groups in a 1:1:1 ratio: arm A (dostarlimab monotherapy), B (dostarlimab + bevacizumab), and C (investigator's choice of chemotherapy [weekly paclitaxel, pegylated liposomal doxorubicin, doxorubicin, or gemcitabine]). Patients with disease progression in arm A or C will be allowed to cross over to arm B. Stratification factors include prior bevacizumab use, prior lines of therapy (1 vs. >1), and primary site (ovarian vs. non-ovarian). Key inclusion criteria are histologically proven recurrent or persistent clear cell carcinoma of the ovary, endometrium, cervix, vagina, or vulva; up to five prior lines of therapy; disease progression within 12 months after platinum-based chemotherapy; and measurable disease. Key exclusion criteria are prior treatment with an anti-PD-1, anti-programmed death-ligand 1, or anti-programmed death-ligand 2 agent. The primary endpoint is progression-free survival determined by investigators. Secondary endpoints are ORR, disease control rate, clinical benefit rate, progression-free survival 2, overall survival, and toxicity. Exploratory objectives include immune biomarkers. ClinicalTrials.gov Identifier: NCT06023862.

PARPis response and outcome of ovarian cancer patients with BRCA1/2 germline mutation and a history of breast cancer

The aim of this study was to determine the poly (ADP-ribose) polymerase inhibitors (PARPis) response and outcome of ovarian cancer (OC) patients with BRCA1/2 germline mutation and a history of breast cancer (BC). Thirty-nine OC patients with BRCA1/2 germline mutation and a history of BC were included. The clinicopathological characteristics, PARPis response and prognosis were analyzed. The median interval from BC to OC diagnosis was 115.3 months (range=6.4-310.1). A total of 38 patients (38/39, 97.4%) received platinum-based chemotherapy after surgical removal. The majority of these patients were reported to be platinum sensitive (92.1%, 35/38). 21 patients (53.8%) received PARPis treatment with 16 patients (76.2%) for maintenance treatment and 5 patients (5/21, 23.8%) for salvage treatment. The median duration for PARPis maintenance and salvage treatment was 14.9 months (range=2.0-56.9) and 8.2 months (range=5.2-20.7), respectively. In the entire cohort, 5-year progression-free survival (PFS) and overall survival (OS) rate was 33.1% and 78.9%, respectively. Patients with BRCA1 mutation had a non-significantly worse 5-year PFS (28.6% vs. 45.8%, p=0.346) and 5-year OS (76.9% vs. 83.3%, p=0.426) than those with BRCA2 mutation. In patients with stage III-IV (n=31), first line PARPis maintenance treatment associated with a non-significantly better PFS (median PFS: NR vs. 22.4 months; 5-year PFS: 64.3% vs. 21.9%, p=0.096). The current study shows that these patients may have a good response to platinum-based chemotherapy and a favorable survival. And these patients can benefit from PARPis treatment and will likely be suitable candidates for PARPis.

Confirmation of the utility of the CA-125 elimination rate (KELIM) as an indicator of the chemosensitivity in advanced-stage ovarian cancer in a “real-life setting”

The modeled CA-125 ELIMination rate constant K (KELIM) has been validated as a marker of response to chemotherapy in >12,000 patients with advanced epithelial ovarian carcinoma (EOC) treated in first-line setting enrolled in >12 clinical trials. Patient KELIM is calculable online https://www.biomarker-kinetics.org/presentation. The objective was to investigate the prognostic value of KELIM in a large real-life national cancer registry with non-selected patients. We investigated 4,025 EOC patients from the Netherlands Cancer Registry treated with neoadjuvant chemotherapy (NACT) ± followed by interval debulking surgery (IDS). Patient KELIM values were calculated in patients with ≥ 3 CA-125 measurements during NACT. KELIM was standardized with a pre-specified cut-off and scored as unfavorable/favorable (<1.0/≥1.0). KELIM's prognostic value regarding radiological response, completeness of IDS, progression-free survival (PFS), and overall survival (OS) was assessed using univariate/multivariate analyses. The data from 1,582 patients treated with heterogeneous chemotherapy regimens and sequences were assessable. KELIM was prognostic for radiological response and the likelihood of complete IDS after NACT (odds ratio=2.59; 95% confidence interval [CI]=2.04-3.29). Moreover, KELIM was independently associated with PFS (hazard ratio [HR]=0.76; 95% CI=0.66-0.87), and OS (HR=0.79; 95% CI=0.69-0.91). Combining KELIM with the completeness of the IDS resulted in 3 prognostic groups (satisfactory, intermediate, and poor) with significant OS differences, namely a good, intermediate, and poor survival respectively. The value of KELIM, as a pragmatic indicator of response to chemotherapy, was maintained in a large real-life population-based cohort, highlighting its applicability in routine conditions.

Clinical guidelines for ovarian cancer: the Korean Society of Gynecologic Oncology guidelines

Since the latest practice guidelines for ovarian cancer were developed by the Korean Society of Gynecologic Oncology (KSGO) in 2021, many studies have examined the efficacy and safety of various treatments for epithelial ovarian cancer (EOC). Therefore, the need to develop recommendations for EOC treatments has been raised. This study searched the literature using 4 key items and the Population, Intervention, Comparison, and Outcome: the efficacy and safety of poly-ADP ribose polymerase inhibitors in newly diagnosed advanced EOC; the efficacy and safety of intraperitoneal plus intravenous chemotherapy in optimally debulked advanced EOC; the efficacy and safety of secondary cytoreductive surgery in platinum-sensitive recurrent ovarian cancer; and the efficacy and safety of the addition of bevacizumab to platinum-based chemotherapy in first platinum-sensitive recurrent EOC patients who received prior bevacizumab. The evidence for these recommendations, according to each key question, was evaluated using a systematic review and meta-analysis. The committee of ovarian cancer of the KSGO developed updated guidelines for treatments of EOC.

Impact of adjuvant treatment on survival in patients with 2023 FIGO stage IIC endometrial cancer: a retrospective analysis from two tertiary centers in Korea and Taiwan

In early-stage endometrial cancer, aggressive histologic types (grade 3 endometrioid, serous, clear cell, carcinosarcomas, undifferentiated, mixed, and other unusual types) are associated with an increased risk of distant metastases and worse survival. However, the optimal adjuvant treatment for these patients remains controversial. The present study investigated the outcomes of different adjuvant treatments in patients with 2023 FIGO stage IIC endometrial cancer. We retrospectively identified patients with 2023 FIGO stage IIC endometrial cancer who underwent surgery followed by either adjuvant treatment or observation from 2000 to 2020 at two tertiary centers in Korea and Taiwan. Recurrence-free survival (RFS) and overall survival (OS) were evaluated using Kaplan-Meier estimates and Cox proportional-hazards models. We also analyzed recurrence patterns after different adjuvant treatments. A total of 272 patients were identified; 204 received adjuvant treatment postoperatively, whereas 68 only underwent observation. Adjuvant treatment was not associated with improved RFS or OS. Non-endometrioid histologic types (p=0.003) and presence of lymphovascular space invasion (LVSI, p=0.002) were associated with worse RFS, whereas only non-endometrioid histologic types impacted OS (p=0.004). In subgroup analyses, adjuvant treatment improved OS in patients with LVSI (p=0.020) and in patients with both LVSI and grade 3 endometrioid histologic type (p=0.007). We found no difference in locoregional and distant recurrence between patients undergoing adjuvant treatment or observation. In this study, the addition of adjuvant treatment was associated with an OS benefit for patients with LVSI, especially those with grade 3 endometrioid tumors.

Incidence and treatment outcomes of ovarian carcinosarcoma from the national cancer registry of Korea

To investigate the incidence and survival outcomes of ovarian carcinosarcoma in Korea between 1999 and 2018. Patients diagnosed with ovarian carcinosarcoma between 1999 and 2018 were identified from the Korea Central Cancer Registry (KCCR) and their information was collected. Age-standardized incidence rates (ASRs), annual percent changes (APC), and relative survival rates of ovarian carcinosarcoma were calculated and compared to those of epithelial ovarian cancer. According to the KCCR, 458 cases of ovarian carcinosarcoma were detected, and accounted for 1.5% (458/30,679) of all epithelial ovarian cancers in Korea between 1999 and 2018. The ASR of ovarian carcinosarcoma between 1999 and 2018 was 0.064 per 100,000 women. The incidence rate of ovarian carcinosarcoma increased during the study period, with an ASR of 0.029 per 100,000 in 1999 and 0.073 per 100,000 in 2018. The APC of ovarian carcinosarcoma during 1999-2018 was 5.86 (p<0.001). The median overall survival (OS) of patients with ovarian carcinosarcoma was 39 months, and the 5-year OS rate was 42.5%. Among ovarian carcinosarcomas, patients with localized stages showed better clinical outcomes than those with regional or distant stages (5-year OS, 60.8%, 57.9%, and 32.8%, respectively; p<0.001). In addition, younger (<50 years) patients showed better OS than older (≥50 years) patients (5-year OS, 52.6% vs. 40.2%; p<0.001). Our nationwide registry-based study demonstrated that the incidence of ovarian carcinosarcoma increased from 1999 to 2018 in Korea. Patients with advanced-stage disease and older age (≥50 years) had poorer survival outcomes.

Impact of peritoneal vaginoplasty combined with radical hysterectomy on the quality of sexual life for patients with early-stage cervical cancer: trial protocol for a multi-center superiority randomized controlled trial

Radical hysterectomy (RH) is commonly used to treat early-stage cervical cancer in women of childbearing age and sexual dysfunction due to postoperative vaginal shortening is a major concern. The impact of intraoperative vaginoplasty on prognosis and quality of sexual life in patients with early-stage cervical cancer remains controversial and lacks high-level evidence. However, there are few reports on vaginoplasty after RH to lengthen vagina in patients. This prospective, multi-center, randomized controlled trial aims to explore the impact of peritoneal vaginoplasty with or without ovarian transposition after laparoscopic RH on sexual dysfunction in patients with early-stage cervical cancer. Eligible patients will be randomly assigned (1:1) to receive peritoneal vaginoplasty or not. The primary evaluation indicators are female sexual function index (FSFI) and male sexual satisfaction scale. The secondary evaluation indicators include EORTC QLQ-CX24, 2-year overall survival (OS), 5-year OS, 2-year progression-free survival (PFS), 5-year PFS and surgery-related complications. The trial will enroll 368 patients from 6 hospitals in China over a 3-year period and follow up for 5 years. Chinese Clinical Trial Registry Identifier: ChiCTR2000040610.

Clinical Trial Protocol for ROSELLA: a phase 3 study of relacorilant in combination with nab-paclitaxel versus nab-paclitaxel monotherapy in advanced platinum-resistant ovarian cancer

Ovarian cancer has the highest mortality among gynecologic cancers, primarily because it typically is diagnosed at a late stage and because of the development of chemoresistance in recurrent disease. Improving outcomes in women with platinum-resistant ovarian cancer is a substantial unmet need. Activation of the glucocorticoid receptor (GR) by cortisol has been shown to suppress the apoptotic pathways used by cytotoxic agents, limiting their efficacy. Selective GR modulation may be able to counteract cortisol's antiapoptotic effects, enhancing chemotherapy's efficacy. A previous phase 2 study has shown that adding intermittently dosed relacorilant, a selective GR modulator, to nab-paclitaxel improved outcomes, including progression-free survival (PFS) and overall survival (OS), with minimal added toxicity, in women with recurrent platinum-resistant ovarian cancer. The ROSELLA study aims to confirm and expand on these findings in a larger population. ROSELLA is a phase 3, randomized, 2-arm, open-label, global multicenter study in women with recurrent, platinum-resistant, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer. Eligible participants have received 1 to 3 lines of prior systemic anticancer therapy, including ≥1 prior line of platinum therapy and prior treatment with bevacizumab, with documented progressive disease or intolerance to the most recent therapy. There is no biomarker-based requirement for participant selection. Participants are randomized 1:1 to receive intermittently dosed relacorilant in combination with nab-paclitaxel or nab-paclitaxel monotherapy. The study's primary efficacy endpoint is PFS as assessed by blinded independent central review. Secondary efficacy endpoints include OS, investigator-assessed PFS, objective response rate, best overall response, duration of response, clinical benefit rate at 24 weeks, and cancer antigen 125 response. The study is also evaluating safety and patient-reported outcomes. ClinicalTrials.gov Identifier: NCT05257408; European Union Drug Regulating Authorities Clinical Trials Database Identifier: 2022-000662-18.

CircSMAD2 accelerates endometrial cancer cell proliferation and metastasis by regulating the miR-1277-5p/MFGE8 axis

Endometrial cancer (EC) is a common gynecological malignant tumor. CircRNAs play crucial roles in cancer progression and metastasis. However, the biological functions of circRNAs in EC remain largely unknown. CircSMAD2, miR-1277-5p, MFGE8 and relative maker protein expression in EC tissues or cell lines were analyzed by quantitative real-time polymerase chain reaction and Western blot. In vitro and in vivo functional assays, including EDU, CCK8, colony formation, transwell, tube formation and tumor xenograft assays, were conduct to explore the effects of circSMAD2 on EC. Mechanism assays were conducted to confirm the binding between miR-1277-5p and circSMAD2 or MFGE8 expression. Upregulation of circSMAD2 was uncovered in both EC tissues and cell lines. Functionally, silencing of circSMAD2 apparently inhibited the proliferation, migration, invasion and angiogenesis of EC cell lines in vitro. Mechanistically, circSMAD2 sponged miR-1277-5p to upregulate MFGE8 expression. The decrease of miR-1277-5p and increase of MFGE8 were observed both in EC tissues and cell lines. Then MFGE8 knockdown or miR-1277-5p upregulation suppressed EC cell oncogenic biological behavior. Rescue experiments showed that miR-1277-5p mimics countervailed the anticancer effects of circSMAD2 silencing on EC. Besides that, MFGE8 overexpression also attenuated the inhibitory action of miR-1277-5p mimic in EC. Moreover, knockdown of circSMAD2 inhibited EC growth in vivo. CircSMAD2 functions as an oncogene in promoting the progression of EC through miR-1277-5p/MFGE8 axis.

Detailed report on the clinicopathological factors of patients with endometrial cancer in Japan: a JSOG gynecologic tumor registry-based study

In this study, we collected data over 8 years (2012-2019) from the Japan Society of Obstetrics and Gynecology (JSOG) tumor registry to determine the status of endometrial cancer in Japan, and analyzed detailed clinicopathological factors. The JSOG maintains a tumor registry that gathers information on endometrial cancer treated at the JSOG-registered institutions. Data from the patients whose endometrial cancer treatment was initiated from 2012 to 2019 were analyzed retrospectively. A total of 82,969 patients with endometrial cancer underwent treatment from 2012 to 2019. Chemotherapy alone or in combination with hormonal therapy is more common among endometrial cancer patients under 40 years compared with those over 40 years. The number of patients with endometrial cancer, treated with laparoscopic or robot-assisted surgery was observed to have increased yearly. Small cell carcinomas and undifferentiated carcinomas were more likely to be diagnosed at an advanced stage. Lymphadenectomy was most commonly performed for stage IIIC2 disease, whereas positive peritoneal washing cytology was most common for stage IVB and serous carcinoma. Multi-year summary reports provided detailed clinicopathological information regarding endometrial cancer that could not be obtained in a single year. These reports were useful in understanding treatment strategies and trends over time based on age, histology, and stage.

Sentinel node mapping in endometrial cancer

Nodal status is one of the most important prognostic factors for patients with apparent early stage endometrial cancer. The role of retroperitoneal staging in endometrial cancer is controversial. Nodal status provides useful prognostic data, and allows to tailor the need of postoperative treatments. However, two independent randomized trials showed that the execution of (pelvic) lymphadenectomy increases the risk of having surgery-related complication without improving patients' outcomes. Sentinel node mapping aims to achieve data regarding nodal status without increasing morbidity. Sentinel node mapping is the removal of first (clinically negative) lymph nodes draining the uterus. Several studies suggested that sentinel node mapping is not inferior to lymphadenectomy in identifying patients with nodal disease. More importantly, thorough ultrastaging sentinel node mapping allows the detection of low volume disease (micrometastases and isolated tumor cells), that are not always detectable via conventional pathological examination. Therefore, the adoption of sentinel node mapping guarantees a higher identification of patients with nodal disease than lymphadenectomy. Further evidence is needed to assess the value of various adjuvant strategies in patients with low volume disease and to tailor those treatments also on the basis of the molecular and genomic characterization of endometrial tumors.

Molecular profile-based recommendations for postoperative adjuvant therapy in early endometrial cancer with high-intermediate or intermediate risk: a Chinese randomized phase III trial (PROBEAT)

The use of molecular categorisation is shifting paradigm towards the use of molecular information to refine risk stratification in endometrial cancer (EC). To date, evidence to support molecular-guided therapies is limited to retrospective studies and secondary molecular analyses of patients receiving standard treatment. The PROBEAT study is the first randomized phase III trial to evaluate tailored adjuvant treatment based on WHO-endorsed molecular classification in Chinese EC patients. It is expected to provide a clinical decision-making tool for adjuvant treatment of patients with high-intermediate risk (HIR) or intermediate risk (IR) EC to better optimise and personalise patient care and increase relapse-free survival. The PROBEAT trial is a prospective, multicentre study led by Women's Hospital of Zhejiang University Gynaecologic Oncology Group. Recruitment started on January 24, 2022, and 590 patients with HIR or IR endometrioid EC are expected to be recruited from 13 clinical centres in China. All tumor tissues will be classified into four molecular subtypes ( ClinicalTrials.gov Identifier: NCT05179447.

Enrichment for the POLE mutated against p53 wild subtype using clinicopathologic factors and cyclin B1 immunohistochemistry in endometrial cancer

The value of surgery and the prognostic factors for patients with recurrent low-grade endometrial stromal sarcoma: a retrospective study of 38 patients

As an indolent malignant tumor, the long-term management of low-grade endometrial stromal sarcoma (LGESS) patients required awareness, especially the management of recurrences. Unfortunately, few studies focused on the treatment of recurrent LGESS. Our study aimed to investigate the prognostic factors and the value of recurrent surgery on recurrent LGESS. This retrospective study consecutively recruited patients with pathologically diagnosed recurrent LGESS at our center from April 1, 2004 to April 1, 2020. After a median follow-up of 137.0 months (95% confidence interval=85.4-188.6), the 5-year cumulative survival rate of the cohort of 38 patients with recurrent LGESS was 71.1%. The median overall survival (OS) and post-recurrence survival (PRS) was 156 and 89.0 months. Survival analysis showed that patients with younger age, positive estrogen receptor (ER) and optimal abdominopelvic debulking in the first recurrent surgery had better prognosis (p0.05). The prognosis of recurrent LGESS was favorable. Optimal debulking of no residual tumor in abdominal and pelvic cavity should be the first choice of treatment for recurrent patients, while preservation of ovary or fertility should not be recommended.

Effect of adjuvant treatment on survival in 2023 FIGO stage IIC endometrial cancer

Cost-effectiveness of atezolizumab plus chemotherapy for advanced/recurrent endometrial cancer

This study assessed the cost-effectiveness of atezolizumab in combination with chemotherapy for patients with advanced or recurrent endometrial cancer (EC) from the U.S. payer's perspective. A cost-effectiveness study was conducted using a Markov model based on ENGOT-en7/MaNGO/AtTEnd clinical trials. The population consisted of patients with EC, stratified by mismatch repair-deficient (dMMR) and mismatch repair-proficient (pMMR) subgroups. The model simulated patients receiving either atezolizumab plus chemotherapy or chemotherapy alone. Cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were calculated using a Willingness-to-Pay (WTP) threshold of $150,000/QALY. Sensitivity analyses were performed. Adding atezolizumab to chemotherapy in dMMR EC resulted in an incremental gain of 3.31 QALYs but at an additional cost of $855,042, leading to an ICER of $258,391.07/QALY compared to chemotherapy alone. In pMMR EC, there was a gain of 0.50 QALYs with an additional cost of $140,502, resulting in an ICER of $279,239.72/QALY. The overall ICER for EC was $216,459.34/QALY. Scenario analysis indicated that administering atezolizumab for a maximum of 2 years improved cost-effectiveness in dMMR EC, with an ICER of $70,695.96/QALY falling within the predetermined WTP threshold. For patients with advanced or recurrent EC, the combination of atezolizumab and chemotherapy may not prove cost-effective. However, administering atezolizumab for a limited period of maximum 2 years could improve cost-effectiveness in dMMR EC.

Response to: Author's reply to: Effect of adjuvant treatment on survival in 2023 FIGO stage IIC endometrial cancer

Author's reply to: Effect of adjuvant treatment on survival in 2023 FIGO stage IIC endometrial cancer

CDK1 promotes the phosphorylation of KIFC1 to regulate the tumorgenicity of endometrial carcinoma

This study aims to clarify the mechanical action of cyclin-dependent protein kinase 1 (CDK1) in the development of endometrial carcinoma (EMCA), which may be associated with the phosphorylation of kinesin family member C1 (KIFC1) and further activate the PI3K/AKT pathway. The protein and gene expression of CDK1 in EMCA tissues and tumor cell lines were evaluated by western blot, quantitative polymerase chain reaction, and immunohistochemistry staining. Next, Cell Counting Kit-8 and colony formation assay detected cell survival and proliferation. Cell migration and invasion were measured by Transwell assay. Cell apoptosis and cell cycle were tested by flow cytometry. Immunofluorescence staining of γH2AX was used to evaluate DNA damage, respectively. Subsequently, a co-immunoprecipitation assay was used to detect the interaction between CDK1 and KIFC1. The phosphorylated protein of KIFC1 and PI3K/AKT was detected by western blot. Finally, the effect of CDK1 on the tumor formation of EMCA was evaluated in a nude mouse xenograft model. CDK1 was highly expressed in EMCA tumor cell lines and tissues, which contributed to cell survival, proliferation, invasion, and migration, inhibited cell apoptosis, and induced DNA damage of EMCA cells dependent on the phosphorylation of KIFC1. Moreover, the CDK1-KIFC1 axis further activated PI3K/AKT pathway. Finally, CDK1 knockdown repressed tumor formation of EMCA in vivo. We report that increased CDK1 promotes tumor progression and identified it as a potential prognostic marker and therapeutic target of EMCA.

The new 2023 FIGO staging system for endometrial cancer: what is different from the previous 2009 FIGO staging system?

The International Federation of Gynecology and Obstetrics committee modified the endometrial cancer (EC) staging system based on the histopathological feature and molecular profile. The aim is to evaluate the clinical implications of the new 2023 system compared with the previous 2009 system. We retrospectively identified 161 patients with EC who underwent primary surgical treatment between 2014 and 2018 at Seoul National University Hospital. The droplet-digital polymerase chain reaction for The median follow-up period was 62.9 months (range, 0.3-110.9), and the median age was 57.2 years old (range, 28.0-85.9). The 5-year progression-free survival (PFS) for the 2023 system with molecular classification was 80.3% for stage I, 75.2% for stage II, 61.2% for stage III, and 22.2% for stage IV (p<0.001). Patients with the 2009 stage I and II disease were restaged using the 2023 system. In contrast, patients with stage III and IV disease were fixed in the 2009 and 2023 systems. Molecular classification downstaged 10 patients (71.4%) to IAm The 2023 staging system for EC subdivided stages I and II compared to the 2009 system. The 2023 system with molecular classification is a good predictor of survival.

Diagnostic significance and predictive efficiency of metabolic risk score for fertility-sparing treatment in patients with atypical endometrial hyperplasia and early endometrial carcinoma

This study aims to assess the impact of the metabolic risk score (MRS) on time to achieve complete remission (CR) of fertility-sparing treatments for atypical endometrial hyperplasia (AEH) and early endometrial cancer (EC) patients. Univariate and multivariate cox analyses were employed to identify independent risk factors affecting the time to CR with patients at our center. These factors were subsequently incorporated into receiver operator characteristic curve analysis and decision curve analysis to assess the predictive accuracy of time to CR. Additionally, Kaplan-Meier analysis was utilized to determine the cumulative CR rate for patients. The 173 patients who achieved CR following fertility preservation treatment (FPT) were categorized into three subgroups based on their time to CR (9 months). Body mass index (hazard ratio [HR]=0.20; 95% confidence interval [CI]=0.03, 0.38; p=0.026), MRS (HR=0.31; 95% CI=0.09, 0.52; p=0.005), insulin resistance (HR=1.83; 95% CI=0.05, 3.60; p=0.045), menstruation regularity (HR=3.77; 95% CI=1.91, 5.64; p=0.001), polycystic ovary syndrome (HR=-2.16; 95% CI=-4.03, -0.28; p=0.025), and histological type (HR=0.36; 95% CI=0.10, 0.62; p=0.005) were identified as risk factors for time to CR, with MRS being the independent risk factor (HR=0.29; 95% CI=0.02, 0.56; p=0.021). The inclusion of MRS significantly enhanced the predictive accuracy of time to CR (area under the curve [AUC]=0.789 for Model 1, AUC=0.862 for Model 2, p=0.032). Kaplan-Meier survival curves revealed significant differences in the cumulative CR rate among different risk groups. MRS emerges as a novel evaluation system that substantially enhances the predictive accuracy for the time to achieve CR in AEH and early EC patients seeking fertility preservation.

Enhancement of circular RNA 0002577 in serum exosomes in patients with endometrial cancer accelerates disease progression via general transcription factor II-I repeat domain-containing 1 (GTF2IRD1)

Uterine corpus endometrial carcinoma (UCEC) is a common gynecologic malignancy with poor prognosis in advanced stages. Circular RNA (circRNA) and exosomes have been documented as significant contributors to the advancement of tumor cells, but the specific regulatory mechanisms between them is unclear. Therefore, our study attempts to explore the mechanism between them. Firstly, we isolated and identified exosomes, and then validated their role in UCEC progression by experiments in vivo and in vitro. Secondly, a human competing endogenous RNA (ceRNA) array was used to identify the circRNA with the most significant differences in expression from serum of UCEC patient, and validated its role in UCEC progression by experiments in vitro. Then, we find the target gene of this circRNA by RNA sequencing, and further clarify the correlation between those and their role in tumor cell progression through experiments in vitro. Serum exosomes in patients with UCEC can promote the progression of UCEC. The human ceRNA array identified that circRNA 0002577 (circ_0002577) was up-regulated and was the most significantly altered circRNA. Moreover, the up-regulated circ_0002577 in exosomes derived from UCEC patients promote proliferation and migration of UCEC. Based on RNA sequencing results, general transcription factor II-I repeat domain-containing 1 ( Exosomes promote UCEC progression through circ_0002577 mediated regulation of

Timing of adjuvant radiotherapy for early-stage endometrial carcinoma: a single-center retrospective cohort study

To investigate the appropriate timing of radiotherapy (RT) after hysterectomy in women with early-stage endometrial cancer (EC). We analyzed the data of 1,062 patients with early-stage EC who underwent postoperative RT at our hospital between April 1999 and November 2020. Restricted cubic spline were used to explore the relationship between the surgery-radiotherapy interval (SRI) and local recurrence-free survival (LRFS). The maximally selected rank statistics method was used to identify the optimal threshold for SRI. The overall survival (OS), disease-free survival (DFS), LRFS, and distant metastasis-free survival (DMFS) rates were estimated using the Kaplan-Meier method. Multivariate analysis was performed using the Cox proportional hazards regression. In entire cohort, patients with SRI ≥42 days had worse survival. In multivariate analysis, SRI was an independent prognostic factor for OS (p=0.011), DFS (p=0.019), LRFS (p=0.013) and DMFS (p=0.050). However, in piecewise Cox regression, the significance of SRI for DMFS disappeared. In the subgroup analysis, the optimal cut-off value for SRI in the high-intermediate risk (HIR) and high-risk (HR) groups was 33 days. Multivariate analysis showed that SRI was an independent prognostic factor only for LRFS (p=0.033) and marginally associated with OS (p=0.055). The timing of postoperative RT is crucial in patients with early-stage EC. Adjuvant RT should be initiated as soon as the vaginal cuff is healed, while for HIR and HR patients, it should be initiated within 33 days.

Practice guidelines for management of uterine corpus cancer in Korea: a Korean Society of Gynecologic Oncology consensus statement

The Korean Society of Gynecologic Oncology (KSGO) had been making an effort to standardize and enhance the quality of domestic uterine corpus cancer treatment by developing updated clinical practice guidelines in 2021. The KSGO revised the guidelines based on a literature search using 4 key elements: Population, Intervention, Comparison, and Outcome framework. These elements include the evaluation of the efficacy and safety of immune checkpoint inhibitor treatment in recurrent/advanced endometrial cancer patients who have failed platinum-based chemotherapy, as well as the effect of combined treatment with trastuzumab in patients with HER2/neu-positive endometrial cancer. Additionally, the guideline assessed the efficacy and safety of omitting lymph node dissection in low-risk endometrial cancer patients, investigated the effect of sentinel lymph node mapping in early-stage endometrial cancer surgery, addressed the outcome of chemoradiation therapy as a postoperative treatment in patients with advanced (stage III-IVA) endometrial cancer, and explored the impact of initial treatment with immune checkpoint inhibitors on survival in patients with advanced or recurrent endometrial cancer patients.

Clinical and biological characteristics associated with loss-of-heterozygosity in endometrial cancer

Genomic instability has been identified in a subgroup of endometrial cancers (ECs) that are predominantly We conducted a retrospective analysis of EC patients from France and Singapore. All patients underwent comprehensive molecular profiling using the tumor based FoundationOne CDX panel. The degree of LOH was correlated with molecular and clinicopathologic findings. LOH-high, intermediate and low were defined as ≥14%, 4%-14%, and <4%, respectively. One hundred twelve patients were identified, including 66% Asian and 34% Caucasian. Fifty nine percent had International Federation of Gynecology and Obstetrics III/IV diseases, 34% low-grade endometrioid, 19% high-grade endometrioid, and 15% serous. The 63% and 50% of tumors expressed estrogen receptor (ER) and progesterone receptor (PR). One percent had a In this large multiethnic cohort, 17% of EC exhibited high LOH and correlated with hormone-receptor-negative tumors and poorer survival rates. LOH may serve as a tool for identifying EC cases with high genomic instability that could potentially benefit from PARP inhibitors.

Efficacy of fertility-sparing treatment with LNG-IUS is associated with different ProMisE subtypes of endometrial carcinoma or atypical endometrial hyperplasia

To determine whether proactive molecular risk classifier for endometrial cancer (ProMisE) could be used to assess the prognosis of patients with atypical endometrial hyperplasia (AEH) or early-stage endometrial cancer (EC) treated with levonorgestrel-releasing intrauterine system (LNG-IUS). A retrospective cohort study was conducted among 93 AEH or early-stage EC patients who received LNG-IUS to preserve fertility . By immunohistochemistry and gene sequencing, 4 subtypes of ProMisE were identified (p53 wild type [p53 wt], mismatch repair-deficient [MMRd], p53-abnormal, and POLE-mutated). The primary outcome was the time to complete response (CR) after LNG-IUS therapy. Secondary outcomes included the recurrence rate after CR and success rate of conception. Among the 93 patients, 15 (16.1%) were classified as MMRd, 6 (6.5%) as POLE-mutated, 5 (5.4%) as p53-abnormal, and 67 (72.0%) as p53 wt. Comparison of serum cancer antigen 125, family history of tumor, and positive rates of programmed cell death 1 ligand 1 protein and Ki67 protein in 4 groups showed statistically significant differences (p<0.05). Patients with the p53-abnormal subtype had the lowest overall CR rate (40%) and the highest recurrence rate (2/2). Patients with POLE-mutated subtype had the best prognosis, and all 6 patients achieved CR. When patients achieved complete remission, assisted reproductive technology was more likely to help them conceive than natural conception (p<0.05). Patients with early-stage EC or AEH who are more likely to benefit from fertility-sparing treatment can be identified using ProMisE classifier. Patients with POLE-mutated are suitable for fertility-sparing treatment with LNG-IUS.

Phase III double-blind randomized placebo controlled trial of atezolizumab in combination with carboplatin and paclitaxel in women with advanced/recurrent endometrial carcinoma: the Asian cohort of the AtTEnd/ENGOT-EN7 trial

This post-hoc analysis of the AtTEnd trial explored differences in the prognostic characteristics and in the efficacy of atezolizumab between Asians and non-Asians. The role of Asian race was evaluated on progression-free survival (PFS) using Cox-models and on time to appearance of new lesions using Fine and Gray models. From October 2018 to February 2022, 549 patients were randomized, of whom, 20.4% were Asian. Asians showed a better prognostic profile in terms of age, body mass index, Eastern Cooperative Oncology Group performance status, disease status and previous treatments. The prognostic impact of Asian race on PFS was confirmed in the placebo arm (adjusted hazard ratio [HR]=0.41; 95% confidence interval [CI]=0.24-0.70). In proficient mismatch repair (pMMR) tumors, the HRs for PFS comparing atezolizumab versus placebo were 0.82 (95% CI=0.63-1.05) in non-Asians, and 1.42 (95% CI=0.80-2.50) in Asians. In the pMMR population randomized to atezolizumab, the subdistribution HRs comparing Asians to non-Asians were 0.68 (95% CI=0.43-1.09) for progression with new lesions and 1.21 (95% CI=0.73-2.03) for progression without new lesions. Asians showed a higher occurrence of severe adverse events in atezolizumab compared to placebo arm (Asians: 82.1% vs. 64.3%, p=0.036; non-Asian: 63.3% vs. 63.6%, p=0.949). Race seems to affect the safety of the addition of atezolizumab and, in pMMR tumors, also its efficacy. In the atezolizumab arm, Asian patients seem to have a lower cumulative incidence of new lesions when primary tumor regrowth was considered a competing risk, and a higher cumulative incidence of primary tumor regrowth when new lesions appearance was the competing risk. ClinicalTrials.gov Identifier: NCT03603184.

Comparison of laparoscopic and robotic-assisted minimally invasive surgery with sentinel lymph node navigation in low-risk endometrial cancer: a retrospective analysis

To evaluate and compare the perioperative and oncologic outcomes of laparoscopic and robotic-assisted surgeries in patients with low-risk endometrial cancer who underwent minimally invasive surgery (MIS) for complete surgical staging, including sentinel lymph node mapping. A retrospective study included 190 patients diagnosed with low-risk endometrial cancer who underwent MIS combined with sentinel lymph node navigation surgery (SNNS) between December 2016 and December 2021. Among these patients, 66 underwent laparoscopic surgery, while 124 underwent robotic-assisted surgery. The analysis focused on patient characteristics, perioperative outcomes, and prognostic factors, including recurrence-free survival (RFS) and overall survival (OS). Statistical analysis was performed using Kaplan-Meier survival curves and appropriate comparative tests for outcome evaluation. The median operative time and estimated blood loss were significantly longer and greater in the robotic surgery group than in the laparoscopic group (209.5 vs. 157.5 min, 20 vs. 5 mL, respectively). The identification rates of sentinel nodes were 97% and 95.2% in the laparoscopic and robotic groups, respectively, with no significant difference between the 2. Recurrence was observed in two and three cases in the laparoscopic robotic surgery groups, respectively. The 3-year RFS rates were 97.6% (95% confidence interval [CI]=0.8482-0.9769) and 93.9% (95% CI=0.9277-0.9922) for the robotic and laparoscopic groups, respectively, while the 3-year OS rates were 99.2% (95% CI=0.8561-0.9902) and 96.1% (95% CI=0.9450-0.9989), respectively, with no statistically significant differences. MIS combined with SNNS is a highly effective approach for managing low-risk endometrial cancer, providing comparable oncologic outcomes to laparoscopy while enhancing the quality of life of patients.

Navigating the future of fertility preservation: advanced predictive strategies for treatment outcomes of endometrial atypical hyperplasia and carcinoma

Due to the decreasing age of onset and the postponement of childbearing, there is a growing number of patients with endometrial carcinoma (EC) and endometrial atypical hyperplasia (EAH) seeking fertility-sparing treatments. Progestogen-based therapy serves as the principal conservative approach for EC. However, the variability in treatment outcomes hampers the potential for delivering more tailored therapies in clinical practice. To better guide the treatment of patients with fertility preservation needs, we conducted a comprehensive review of existing literature to explore factors related to molecular classification, biomarkers and artificial intelligence (AI) technology that may predict fertility-sparing treatment outcomes, we also looked ahead to future research directions in this field. The pathology before and after treatment is the primary basis for assessing the effectiveness of fertility-sparing treatment for EC and EAH. However, it is challenging to predict the therapeutic outcomes based on the pathological morphology of the initial diagnosis. Traditional immunohistochemical markers, such as estrogen and progesterone receptors, are also very limited in predicting therapeutic response. In recent years, the prognosis of fertility-sparing treatment has also been considered to be correlated with the molecular classification and gene mutation markers of EC. However, there are currently few direct clinical studies available, and our focus will be on reviewing these studies and assessing their applicability. In addition, there are some studies utilizing AI to predict the molecular classification, genes and therapeutic response of EC. The integration of these features will aid in the development of advanced predictive strategies for fertility-sparing treatment of EC and EAH.

The past, present, and future of FIGO staging of endometrial cancer

The International Federation of Gynecology and Obstetrics (FIGO) staging of endometrial cancer (EC) is regarded as a crucial tool for guiding treatment, evaluating prognosis, and advancing clinical research. It is a concept of shared importance among gynecologic oncologists, pathologists, and patients with EC. In June 2023, the International Federation of Gynecology and Obstetrics released a new staging system for EC. This review aims to discuss comprehensively the developmental trajectory of FIGO staging for EC, focusing on the differences between the 2023 FIGO and earlier staging systems, and delineating the advantages and disadvantages of incorporating various pathological factors and molecular subtypes into staging. The article emphasizes the progress made with the updated 2023 FIGO version in improving prognostic prediction accuracy for patients with EC. However, as the staging categories expand, their complexity becomes increasingly apparent, potentially impacting health care professionals' accurate understanding and application of staging. Moreover, unresolved issues persist regarding histological types and grading, lymphovascular space invasion, and molecular subtypes, as well as distinguishing between low-grade endometrioid carcinomas confined to the uterus and ovaries, which may affect the personalized management of patients with EC. In the future, these issues still require extensive clinical research and specific data for validation or confirmation, presenting a challenge shared by gynecologic oncologists and pathologists.

Modifying surgical extents in patients with preoperatively presumed early-stage endometrial cancer based on ProMisE classification: a retrospective, single-center study

This study aimed to explore differences in disease extent based on the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) classification and to establish personalized staging surgery strategies in patients with preoperatively presumed uterus-confined endometrial cancer. In this retrospective, single-center study, we reviewed the medical records of patients with endometrial cancer. These patients were classified according to the ProMisE classification based on tissue samples obtained from dilation and curettage or staging surgeries, and the disease extent was analyzed based on pathologic reports. A total of 345 patients were clinically estimated to be in stage 1/2 before staging surgery, with immunohistochemistry (IHC) results available. This cohort included 332 patients (96.2%) with clinical stage 1 and 13 patients (3.8%) with stage 2 based on the 2009 FIGO staging system. Among these, 81 patients (23.5%) were assigned to an mismatch repair deficient group (MMRd), 33 (9.6%) to an abnormal p53 group, and 123 (71.1%) to a no specific molecular profile (NSMP) group. Overall, 13 patients had nodal metastasis, with a higher rate observed in the abnormal p53 group (1.2%, 12.1%, and 2.2% for the MMRd, abnormal p53, and NSMP groups, respectively, p=0.013). One patient (0.3%) had parametrial metastasis and four (1.1%) had peritoneal metastasis. Patients with abnormal p53 IHC results exhibited a higher likelihood of lymph node metastasis, even when initially presumed to be at an early stage. For the abnormal p53 group, proactive lymphadenectomy surgery appears beneficial for accurate staging and establishing a subsequent treatment plan.

Trends in the incidence and survival outcomes of endometrial cancer in Korea: a nationwide population-based cohort study

To evaluate trends in the incidence and survival outcomes of endometrial cancer (EC) based on the year of diagnosis, stage, age, and histologic types. Women with primary EC diagnosed between 1999 and 2018, and who were followed up with until 2019, were identified from the Korea Central Cancer Registry using the International Classification of Diseases, 10th revision. The age-standardized rates (ASRs) of incidence, annual percent changes (APCs), and survival were estimated according to age, stage, histology, and year of diagnosis. The ASR for EC increased from 2.38 per 100,000 in 1999 to 7.29 per 100,000 in 2018 across all histologic types (APCs of 9.82, 15.97, and 7.73 for endometrioid, serous, and clear cell, respectively, p<0.001). There were significant differences in the 5-year survival rates based on histology (90.9%, 55.0%, and 68.5% for endometrioid, serous, and clear cell, respectively, p<0.001), stage (93.4%, 77.0%, and 31.0% for localized, regional, and distant, respectively, p<0.001), and age (93.0% for <50 years and 80.6% for ≥50 years, p<0.001). The 5-year survival was significantly better in the group diagnosed between 2000 and 2018 (85.9%) than that in the 1999-2008 group (83.3%) (p<0.001). This trend was only observed for endometrioid cancer (p<0.001). The incidence of EC increased across the all 3 subtypes. Survival of patients with endometrioid histology improved over the past two decades, but remained static for serous or clear cell histology. Healthcare strategies to prevent EC incidence in at-risk populations and apply effective treatments for high-risk histology are needed.

Prognostic significance of heterologous component in carcinosarcoma of the gynecologic organs: a systematic review and meta-analysis

The aim of this study is to determine the histologic presence of heterologous component as a prognostic factor in gynecologic carcinosarcoma through a systematic review and meta-analysis. PubMed, Web of Science, and Embase were searched for publications. Studies that evaluated survival effect of sarcomatous component based on histology in human ovarian or uterine carcinosarcoma were included. Two authors independently reviewed the references based on eligibility criteria and extracted the data including primary tumor site, survival outcome, type of survival outcome, and proportion of each sarcomatous differentiation. The quality of each eligible study was assessed with Newcastle-Ottawa scale. Meta-analysis was conducted using a random-effects model to estimate hazard ratio (HR) and 95% confidence intervals (CIs) of survival outcome for carcinosarcoma with or without heterologous component. Eight studies including 1,594 patients were identified. Overall proportion of carcinosarcoma with heterologous component was 43.3%. Presence of heterologous component was associated with worse overall survival (HR=1.81; 95% CI=1.15-2.85) but not with pooled recurrence-free survival and disease-free survival (HR=1.79; 95% CI=0.85-3.77). Removing multivariate analysis studies, early-stage studies, ovarian tumor study, or studies with large number of patient samples did not affect the significance between heterologous component and overall survival. Gynecologic carcinosarcoma is histologically a biphasic tumor which comprise of epithelial and mesenchymal components. Our study emphasizes pathologic evaluation of heterologous component as a prognostic factor in gynecologic carcinosarcoma when all stages were considered. PROSPERO Identifier: CRD42022298871.

Missing a chance to prevent: disparities in completion of genetic evaluation in high-risk patients with endometrial cancer

The primary goal of this study is to examine disparities in high-risk endometrial cancer (EC) patients in relation to rates of genetic referrals (GR), testing (GT), and counseling (GC). This is a retrospective analysis of patients with newly diagnosed EC between January 1, 2014 and September 1, 2020 at a single institution. Patients were defined as high-risk EC patients when they were 1) diagnosed at 50 years or younger, 2) had a positive family history for cancer or 3) had evidence of loss of mismatch repair protein expression on tumor immunohistochemistry. Rates of GR, GT and GC were analyzed based on race, ethnicity, primary language and insurance status. During the study period, 674 patients were diagnosed with EC and 249 (36.9%) were considered high-risk EC patients. Among high-risk patients, 128 (51.2%) were referred to GT and GC. Of those referred, 103 (80.5%) underwent GT and 85 (66.4%) completed GC. Out of all high-risk patients, 20 (18.4%) were positive for LS on GT and 29 (28.2%) had VUS results. In multivariate analysis, the odds of GT and GC referral were lower among patients who identified as Hispanic (OR=0.40; 95% CI=0.19-0.87; p=0.020). Patients who identified as black were less likely to receive GC when compared to patients of other races (p=0.030). It is our hope that through this data we will increase awareness around existing disparities in genetic evaluation for patients with EC and ultimately create strategies to improve equitable access to care for all patients.

PLIN2: a potential prognostic markers of early-stage atypical endometrial hyperplasia

In the background of endometrial hyperplasia triggered by obesity and estrogen, could the perilipin 2 (PLIN2) serve as a possible prognostic marker for early atypical endometrial hyperplasia (AEH)? A retrospective study examined blood lipid levels in endometrial cancer (EC) or AEH patients. An AEH mice model was established administrating with estradiol and/or high-fat (HF) diet. Hematoxylin and eosin staining were employed to assess pathological changes in the endometrium. Immunohistochemical staining were employed to evaluate the expression of adipose metabolism and endometrial hyperplasia proteins. The Cell Counting Kit-8 assay, cell colony-forming assays, and western blotting were utilized to verify the impact of oleic acid (OA) on HEC-1A cells. The retrospective study revealed elevated blood lipid levels among patients with EC or AEH. Prolonged HF diet stimulated the endometrium to exhibit features of complex atypical hyperplasia. In the early stage, PLIN2 (p=0.006) expression significantly increased with endometrial glandular hyperplasia. Both PLIN2 (p=0.008) and progesterone receptor (PR; p=0.019) exhibited elevated expression concurrent with simple endometrial hyperplasia. When AEH occurred, there were notable rise in the expression of PLIN2 (p<0.001), PR (p=0.044), and estrogen receptor (p=0.045). The atypical hyperplasia glands demonstrated notably elevated PLIN2 expression in comparison to surrounding normal glands in AEH lesions. OA was found to enhance the proliferation and clonal formation of HEC-1A cells. HEC-1A cells induced by OA demonstrated elevated autophagy levels accompanied by enhanced expression of PLIN2. PLIN2 may potentially serve as a biomarker for early development of AEH and EC, facilitating diagnosis and intervention and contributing to the determination of prognosis.

Evaluation of the role of liver metastasectomy in the treatment of stage IV endometrial cancer

Hepatic metastasectomy for gynecologic cancers remains controversial. Management of advanced endometrial cancer (EC) is complex. The purpose of this study is to analyze the efficacy of liver metastasectomy (LM) in the treatment of metastatic EC. The National Cancer Database was used to create a retrospective cohort of adult women with EC metastatic to the liver between 2010 and 2016. Overall survival and all-cause mortality were estimated with inverse probability of treatment weighting (IPTW) curves and IPTW Cox proportional hazard regression, respectively. Among 999 EC patients with oligometastatic disease to the liver, 162 (16.2%) underwent LM, 614 (61.5%) received chemotherapy, and 129 (12.9%) had chemotherapy and LM. Those who underwent chemotherapy, 1-, 2-, and 3-year survival for chemotherapy + LM versus chemotherapy alone were 67.8 versus 56.5%, 44.9 versus 33.4%, and 35.1 versus 23.1%, respectively. In unadjusted analysis, chemotherapy + LM group had reduced mortality risk (hazard ratio [HR]=0.68; 95% confidence interval [CI]=0.54-0.86) with longer median survival time (20.1 vs. 14.6 months, p=0.011) compared to chemotherapy alone. Adjusting for demographics and treatment characteristics, a possible reduction in mortality was associated with chemotherapy + LM (HR=0.74; 95% CI=0.55-1.01) compared to chemotherapy alone. This study of LM for EC suggests LM in addition to chemotherapy may be associated with improved outcomes for patients with EC.

Adjuvant hormone therapy and overall survival among low-grade and apparent early-stage endometrial stromal sarcoma patients

Surgery is the mainstay of treatment for low-grade endometrial stromal sarcoma (LG-ESS). While adjuvant hormone therapy is recommended for patients with advanced/recurrent disease, no consensus regarding its use among early-stage patients exists. We aimed to identify correlates of adjuvant hormone therapy use and associations of adjuvant hormone therapy and overall survival (OS) in stage I LG-ESS patients. Retrospective cohort study of patients with stage I LG-ESS who underwent hysterectomy from 2004-2019 using data from the National Cancer Database. Categorical data were compared using χ² tests. Kaplan-Meier estimates and log-rank tests were used to compare OS according to adjuvant hormone use. Hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between adjuvant hormone use and OS were estimated using Cox proportional hazards regression. Of 2,386 patients included, 20.2% were treated with adjuvant hormonal therapy. Use of hormone therapy increased over time, with rates approximately doubling from 2004 to 2019 (12.6% to 24.6%). Age, tumor size, lymphovascular space invasion and adjuvant radiation were associated with adjuvant hormone therapy use. There was no association between adjuvant hormone therapy and OS (log-rank p=0.73; HR=1.05; 95% CI=0.76-1.46) for patients with LG-ESS. Use of adjuvant hormone therapy for stage I LG-ESS has increased over time though is not associated with OS in this cohort of patients. Additional evaluation is needed to understand the impact of adjuvant hormone therapy on recurrence rates, progression rates, and quality of life to fully understand its value.

Comparison of the effect of oral megestrol acetate with or without levonorgestrel-intrauterine system on fertility-preserving treatment in patients with early-stage endometrial cancer: a prospective, open-label, randomized controlled phase II trial (ClinicalTrials.gov NCT03241914)

To evaluate the effect of levonorgestrel-releasing intrauterine system (LNG-IUS) plus oral megestrol acetate (MA) as fertility-preserving treatment in patients with early-stage endometrial cancer (EEC). In this single-center, phase II study with open-label, randomized and controlled design, young patients (18-45 years) diagnosed with primary EEC were screened, who strongly required fertility-preserving treatment. Patients were randomly assigned (1:1) into MA group (160 mg oral daily) or MA (160 mg oral daily) plus LNG-IUS group. Pathologic evaluation on endometrium retrieved by hysteroscopy was performed every 3 months. The primary endpoint was complete response (CR) rate within 16 weeks of treatment. The secondary endpoints were CR rate within 32 weeks of treatment, adverse events, recurrent and pregnancy rate. Between July 2017 and June 2020, 63 patients were enrolled and randomly assigned. Totally 56 patients (26 in MA group; 28 in MA + LNG-IUS group) were included into primary-endpoint analyses. The median follow-up was 31.6 months (range, 3.1-94.0). No significant difference in 16-week CR rate were found between MA and MA + LNG-IUS groups (19.2% vs. 25.0%, p=0.610; odds ratio=1.40; 95% confidence interval=0.38-5.12), while the 32-week CR rates were also similar (57.1% and 61.5%, p=0.743), accordingly. More women in MA + LNG-IUS group experienced vaginal hemorrhage (46.4% vs. 16.1%; p=0.012) compared with MA group. No intergroup difference was found regarding recurrence or pregnancy rate. Compared with MA alone, the addition of LNG-IUS may not improve the early CR rate for EEC, and may produce more adverse events instead. ClinicalTrials.gov Identifier: NCT03241914.

The prognostic significance and role of adjuvant therapy for low-volume nodal metastasis in apparent early stage endometrial cancer: an updated systematic review and meta-analysis

Sentinel lymph node biopsy (SLNB) has improved detection of low-volume node metastasis (LVNM) in endometrial cancer (EC), but its prognostic significance and the need for adjuvant therapy (AT) remain unclear. A comprehensive search was performed until August 31, 2024 in multiple databases and sources. From 21 studies, 65,228 apparent early-stage EC patients were identified: 370 with macrometastases (MAC), 526 with micrometastases (MM), 2,138 with isolated tumor cells (ITCs), and 62,194 with negative nodes. Findings indicated: 1) The MM group had a lower risk of recurrence or progression (R/P) than the MAC group (risk ratio [RR]=0.49; 95% confidence interval [CI]=0.31-0.78; p=0.002), higher risk than the negative nodes group (RR=2.07; 95% CI=1.59-2.68; p<0.001), and similar risk to the ITC group (RR=0.67; 95% CI=0.44-1.02; p=0.060). 2) The MM group had higher 3-year progression-free survival (PFS) (RR=1.36; 95% CI=1.21-1.52; p<0.001) and overall survival (OS) (RR=1.22; 95% CI=1.09-1.37; p<0.001) than the MAC group, similar to the ITC and negative nodes groups. 3) The ITC group had a lower R/P risk and higher 3-year PFS/OS than the MAC group, similar to the negative nodes group. 4) AT reduced the R/P risk in the MM group (RR=0.41; 95% CI=0.22-0.76; p=0.005) and increased 3-year OS in the ITC group (RR=1.06; 95% CI=1.04-1.08; p<0.001). Early-stage EC with LVNM had better prognostic outcomes than MAC, and AT may improve outcomes of LVNM patients. More evidence from prospective randomized controlled trials is needed to confirm these findings due to the inherent biases of retrospective studies. PROSPERO Identifier: CRD42022364536.

Clinical practice guidelines for uterine corpus cancer: an update to the Korean Society of Gynecologic Oncology guidelines

The Korean Society of Gynecologic Oncology has updated its clinical practice guidelines for endometrial cancer to incorporate advancements in recent high-quality randomized controlled trials. These guidelines address evolving treatment paradigms, and are tailored to the Korean medical context. Key updates include a strong recommendation for doxorubicin/trabectedin combination therapy in metastatic or recurrent unresectable leiomyosarcoma based on the significant survival benefits demonstrated in a randomized controlled trial. For advanced or recurrent endometrial cancer, immune checkpoint inhibitors combined with chemotherapy have received strong recommendations, owing to their proven efficacy and increased accessibility in Korea. Conditional recommendations were made for combination therapies involving durvalumab and olaparib, reflecting their potential benefits, but acknowledging regulatory and accessibility constraints. These guidelines aim to provide evidence-based, practical strategies to optimize care for patients with endometrial cancer while addressing unmet clinical needs and adapting global advancements to Korea's healthcare environment.

Role of systematic lymphadenectomy in patients with intermediate to high-risk early stage endometrial cancer

To determine the clinical significance of systematic lymph node dissection (LND) and to better define the relevant extent of LND in intermediate- to high-risk early stage endometrial cancer (EC). Patients who received surgery as a primary treatment of histologically confirmed EC and preoperatively considered as uterus-confined early stage disease were included in the study population. The rates of lymph node metastasis (LNM) according to the risk groups and anatomic sites were assessed. Univariate and multivariate analyses were performed to evaluate risk factors for recurrence. A total of 804 patients were included in the study analysis. The rates of LNM were significantly different according to the risk group; 1.2% in low-risk, 20.1% in intermediate-risk, and 30.0% in high-risk group. When assessing the rates of LNM in individual anatomic sites, positive LNs were evenly distributed throughout the pelvic and para-aortic regions. In the intermediate to high-risk EC cases, the rates of para-aortic LNM below and above inferior mesenteric artery (IMA) were 11.1% and 12.5%, respectively. On multivariate analysis, LNM was the only independent risk factor for recurrence in the intermediate to high-risk EC (hazard ratio=2.63, 95% confidence interval=1.01-6.82, p=0.047). LNM was frequently observed in intermediate- and high-risk early stage EC and it served as an independent risk factor for recurrence. When considering the similar rates of LNM between below and above IMA, nodal assessment needs to be performed up to the infra-renal level, especially for the staging purpose in high-risk EC.

Fertility-sparing treatment outcomes using immune checkpoint inhibitors in endometrial cancer patients with Lynch syndrome

To evaluate the efficacy of immune checkpoint inhibitors (ICIs) for fertility-sparing treatment in Lynch syndrome-associated endometrial cancer (LS-EC). Four LS-EC cases received programmed cell death protein 1 (PD-1) inhibitors for fertility preservation at the Obstetrics and Gynecology Hospital of Fudan University from 2017 to 2023. The clinical data and long-term outcomes were retrospectively reviewed. Case 1, carrying germline ICIs might be an effective choice for LS-EC patients desiring fertility preservation.

Is presumed clinical stage I endometrial cancer using PET-CT and MRI accurate in predicting surgical staging?

To evaluate upstaging, lymph node (LN) metastasis, and recurrence in patients with presumed stage I endometrial cancer using preoperative magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT). Retrospective review of 422 patients with presumed clinical stage I endometrial cancer diagnosed via MRI and PET-CT (July 2014-June 2023). Surgical staging included pelvic lymph nodes (PLNs) and para-aortic lymph nodes (PALNs), classifying patients as low/intermediate- or high-risk groups. Post-operative upstaging rate was 14.5% (8.8% low/intermediate-risk vs. 22.8% high-risk, p2 cm on MRI (OR=2.9; 95% CI=0.8-9.9) increased LN metastasis risk. Median 48.5-month follow-up showed an 8.1% overall recurrence rate (4.0% low/intermediate-risk vs. 14.0% high-risk, p<0.001), with 2.4% nodal recurrences (1.2% low/intermediate-risk vs. 4.1% high-risk). High-risk patients had significant upstaging, LN metastasis, and recurrence rates. Even in low/intermediate-risk groups, some patients exhibited LN metastasis and nodal recurrence, underscoring the importance of comprehensive surgical staging, including PALN evaluation, for precise diagnosis and treatment.

Functions, interactions and prognostic role of POLE: a bioinformatics analysis

To describe We retrieved reported mutations for Thirty mutations in POLE were retrieved, most reported mutations were p.P286R, p.V411L and p.A456P, these mutations were likely to be pathogenic. Network analysis of POLE showed interaction of this protein in biological processes such as DNA repair, the cell proliferation cycle, and mechanisms of resistance to platinum. Immune infiltration analysis showed that T cell CD8+, T cell memory activated CD4+, T cell follicular helper, T cell gamma delta and macrophage M1 were more infiltrated in EC Mutations in POLE might affect DNA polymerase epsilon function. These mutations also affect interactions with other proteins like proteins involved in different DNA repairing mechanisms.

A phase II study of induction PD-1 blockade (nivolumab) in patients with surgically completely resectable mismatch repair deficient endometrial cancer (NIVEC)

Mismatch repair deficient (MMRd) tumors are known to be highly immunogenic and of great interest for immune checkpoint inhibitor. However, there is no data about the complete response (CR) rate of programmed cell death protein 1 (PD-1) blockade and surgery in subjects with MMRd surgically resectable endometrial cancer. In this regard, we suggest a window of opportunity study of induction PD-1 blockade (nivolumab) in patients with surgically resectable MMRd endometrial cancer. This is a multicenter, single-arm phase II trial. A total of 30 surgically resectable MMRd endometrial cancer patients will be enrolled. Inclusion criteria include clinical stage I-IIIC2, tumor specimen that demonstrates MMRd by immunohistochemistry or microsatellite instability. Exclusion criteria include multiple primary cancers, residual adverse effects of prior therapy or effects of surgery. Patients are treated with nivolumab 480 mg intravenously every 4 weeks up to 6 months followed by standard surgery and/or adjuvant treatment. The primary endpoint of the study is clinical CR rate or pathological CR rate after treatment of nivolumab. Secondary endpoints include objective response rate, progression-free survival, overall survival, and adverse events. Correlative studies include genomic characterization of tumors, assessment of immune infiltration of tumor microenvironment, and serial circulating cell-free DNA and immune biomarkers. ClinicalTrials.gov Identifier: NCT05795244.

Risk factors for lower extremity lymphedema after surgery in cervical and endometrial cancer

Lower extremity lymphedema (LEL) is a well-known adverse effect related to cervical and endometrial cancer (CEC); however, very few studies have elucidated the clinicopathologic risk factors related to LEL. We investigated the incidence and risk factors in patients who received primary surgery and/or adjuvant radiotherapy (RT) or chemotherapy for CEC. We retrospectively reviewed 2,565 patients who underwent primary surgery following CEC diagnosis between January 2007 and December 2020. LEL diagnosis was based on objective and subjective assessments by experts. We identified important predictors of LEL to construct a nomogram predicting individual risks of LEL. For internal validation of the nomogram, the original data were separated using the split-sample method in a 7:3 ratio of training data and test data. Overall, 858 patients (33.5%) received RT, 586 received external beam RT (EBRT), and 630 received intracavitary RT. During follow-up period, LEL developed in 331 patients, with an overall cumulative 5-year incidence of 13.3%. In multivariate analysis, age at primary treatment, use of docetaxel-based chemotherapy, type of hysterectomy, type of surgical pelvic lymph node (LN) assessment, number of dissected pelvic and para-aortic LNs, and EBRT field were the independent predictors of LEL. We subsequently developed the nomogram showing excellent predictive power for LEL. LEL is associated with various treatment modalities, and their interactions may increase the possibility of occurrences. De-escalation strategies for treatment modalities should be considered to reduce LEL in patients with CEC.

Prognostic impact of peritoneal cytology on treating endometrial cancer using data from the Japan Society of Obstetrics and Gynecology cancer registry

The prognostic value and clinical usage of peritoneal cytology in endometrial cancer are uncertain. This study aimed to determine whether positive cytology is associated with the prognosis for endometrial cancer. A Japanese nationwide retrospective registry study was conducted between 2012 and 2019. Clinicopathological data were analyzed for patients who were registered in the Japan Society of Obstetrics and Gynecology (JSOG) gynecological tumor registry and underwent initial treatment for endometrial cancer. In total, 83,027 patients who met the inclusion criteria were identified. Data on peritoneal cytology status and overall survival (OS) were available for 74,984 and 36,995 patients, respectively. Positive peritoneal cytology was found in 11,536 (15.4%) patients. A higher proportion of patients who had positive peritoneal cytology were related to advanced stages, high-grade histology, deep myometrial invasion, lymph node (LN) metastasis, and poor risk of recurrence. After controlling for age, stage, myometrial invasion, LN metastasis, distant metastasis, and risk of recurrence, positive peritoneal cytology was associated with poor prognosis (p<0.001). Multivariate Cox regression analysis revealed that clinicopathological factors (i.e., age, International Federation of Gynecology and Obstetrics stage, histological type, myometrial invasion, LN metastasis, distant metastasis, and peritoneal cytology), including positive peritoneal cytology, were also significant prognostic factors for OS. Positive peritoneal cytology was a prognostic factor for endometrial cancer for the JSOG gynecological tumor registry.

Planning and performing simultaneous bariatric surgery and robotic hysterectomy in a super-obese patient with endometrial cancer

Endometrial cancer (EC) is the most common gynecological malignancy in developed countries, and endometrial intraepithelial neoplasia (EIN) is the defined precancerous lesion. Obesity is considered a risk factor for both EC and EIN. On the other hand, mortality is often attributed to obesity-related conditions in patients with early-stage EC. Bariatric surgery has been shown to improve oncological outcomes and obesity-related morbidity and mortality in patients with EC. Therefore, combination surgery addressing both uterine disease and obesity is a very recent point of interest. Here, we present a video article to demonstrate the crucial surgical steps for a simultaneous robotic-assisted total laparoscopic hysterectomy and sleeve gastrectomy in a patient with super obesity and EIN. A patient in her 40s with a body mass index of 62.4 kg/m² and a diagnosis of EIN was scheduled for combo surgery. The operation started with sleeve gastrectomy in the reverse Trendelenburg position. The da Vinci Xi Surgical System™ (Intuitive Surgical Inc., Sunnyvale, CA, USA) with left-side docking was used for surgery. After the mobilization of the stomach, gastric resection was performed using a stapler. Following sleeve gastrectomy, the patient was positioned in the Trendelenburg position, and the robotic system was positioned for hysterectomy. Hysterectomy and salpingectomy were performed. The excised stomach and hysterectomy material were removed through the vagina. A frozen examination revealed EC below 2 cm with superficial invasion, and bilateral oophorectomy was performed. The whole surgery took approximately 4 hours. No postoperative complications occurred, and the patient was discharged on the 3rd day.

Evaluation of autophagy related ATG4B gene, protein and miR-655-3p expression levels in endometrial cancer and hyperplasia

The pathogenesis of endometrial cancer (EC) and hyperplasia is complex and poorly understood. Autophagy has emerged as a crucial aspect of this process. This study examines the role of autophagy in the pathogenesis of EC and hyperplasia by investigating the expression of the autophagy-related 4B cysteine peptidase (ATG4B) gene, protein, and miR-665-3p levels in patients compared to a control group. This cross-sectional case control study analyzed 90 endometrial tissues, including 30 tumors, 30 normal controls, and 30 hyperplasia, using quantitative reverse transcription polymerase chain reaction and Western blot to assess ATG4B gene and protein levels. Higher ATG4B gene expression levels were found in the endometrial tissue of EC patients than in hyperplasia patients and controls. Furthermore, protein levels of ATG4B were also higher in EC and hyperplasia patients than in controls. ATG4B gene expression and protein levels were positively correlated in EC patients. However, in EC patients, miR-655-3p showed a significant negative correlation with the ATG4B gene and protein levels. ATG4B gene and protein expression is elevated in EC tissue, suggesting their role as a tumor promoter. Evaluating their levels could serve as markers for monitoring EC progression and prognosis.

Nomogram for predicting pathology upstaging in patients with EIN: is sentinel lymph node assessment useful in these patients?

The objective of this study was to identify the risk factors for postoperative pathological escalation of endometrial cancer in patients with a pathologic diagnosis of endometrial intraepithelial neoplasia (EIN) before surgery. Some of the clues from the preoperative assessment were used to build a nomogram to predict the likely pathological escalation after surgery, and to explore the feasibility of sentinel lymph node biopsy in these patients with possible pathological escalation. This was a retrospective analysis of patients who underwent surgical treatment for EIN diagnosed before surgery between 2018 and 2023 in The Obstetrics and Gynecology Hospital of Fudan University. parameters including clinical, radiological and histopathological factors were analyzed by univariate and multivariate logistic regression to determine the correlation with pathology upstaging. A nomogram based on the multivariate results was developed to predict the probability of pathology upstaging. A total of 729 patients were included, divided into training set and validation set. 484 patients were used to build the model. This nomogram was subsequently validated using 245 patients. Upstaging to endometrial carcinoma occurred in 115 (23.8 percent) of 484 women treated between 2018 and 2023 in training set. A lager endometrial thickness (at least 15 mm), menopause, hypertension, HE4, and endometrial blood were significantly associated with upstaging. A nomogram developed using these factors demonstrated good predictive performance (area under the receiver operating characteristic curve (AUC)=0.6808; 95% confidence interval [CI]=0.6246-0.7369). The nomogram showed similar predictive performance in the validation data set, based on another 245 women (AUC=0.7821; 95% CI=0.7076-0.8567). This study developed a novel nomogram based on the 5 most important factors, which can accurately predict invasive cancer. It is common for women with preoperative diagnosis of EIN to experience pathological progression to endometrial cancer. For some patients with postoperative pathological escalation, we found lymph node metastasis. This nomogram may be useful to help doctor decide whether to perform sentinel lymph node biopsy for surgical staging in these EIN patients. According to the nomogram, simultaneous sentinel lymph node biopsy in patients with high probability of postoperative pathological upgrading can provide better guidance for postoperative adjuvant treatment of endometrial cancer and avoid the occurrence of secondary surgery.

Outcomes of extended progestin therapy in atypical endometrial hyperplasia patients without an initial response to progestin: a retrospective study from two tertiary centers in Korea and Taiwan

In this study, we evaluated the role of prolonged progestin treatment on atypical endometrial hyperplasia (AEH) patients who did not achieve complete regression (CR) after at least 3 months of progestin treatment. Possible prognostic factors predicting disease regression and recurrence were also assessed. We retrospectively identified patients who had histologically confirmed persistent disease after at least 3 months of progestin treatment at two tertiary centers in Korea and Taiwan. Clinicopathologic factors and clinical outcomes were obtained from medical records. Logistic regression was used to analyze the relationship between covariates and the probability of CR and relapse. Fifty-two patients were included. Thirty-seven of 52 patients (71.2%) achieved CR after prolonged progestin treatment. Median time from starting progestin treatment to CR was 12.0 months. Daily administration of medroxyprogesterone acetate ≥200 mg or megestrol acetate ≥80 mg was associated with higher probability of regression. Nineteen of 37 patients (51.4%) experienced recurrence, with median time from CR to relapse of 15.0 months. Body mass index ≥27 was associated with higher relapse probability. Twelve of 16 patients with disease progression to endometrial carcinoma underwent surgery. The 12 cases had stage I tumors and lived without disease. Extension of progestin treatment course is feasible for AEH patients without an initial response to progestin. Higher daily progestin dosage was associated with higher probability of CR, and obesity was associated with higher risk of relapse. The patients without an initial response to progestins and whose AEH progressed to endometrial carcinoma had good prognoses.

Adjuvant carboplatin and paclitaxel with “sandwich” method radiotherapy for stage III or IV endometrial cancer: long-term follow-up at a single-institution

To evaluate disease-free survival (DFS) and overall survival (OS) associated with adjuvant carboplatin and paclitaxel chemotherapy interposed with radiation for advanced endometrial cancer. This is a cohort study of adult women with stage III or IV endometrial cancer treated at a single institution, between April 2002 and October 2017. Tumor and treatment characteristics were recorded. Treatment consisted of 4 cycles of intravenous paclitaxel and carboplatin every 3 weeks, followed by external beam radiotherapy to the pelvis (45-50 Gy), and another 2 cycles of chemotherapy. One cohort of patients were prospectively enrolled from 2002 through 2006 and an additional cohort from 2007 to 2017, which was retrospectively analyzed. Primary endpoints for this study were DFS and OS rates which were calculated using Cox regression models. Eighty-two patients with a median age of 66.5 years (range, 35-83 years) were included. Median follow-up was 46 months (range, 9-196 months). Most patients had stage IIIC disease (62.2%) and serous carcinoma histology (46.3%). Median OS was 146 months and median DFS was 71 months. A 5-year OS and DFS were 64.9% and 55.7%, respectively. Age >60 years subgroup was at a significantly higher risk of DFS event or death. Histological subtype, location of positive nodes, and cancer stage (IIIa vs. higher stage) did not correlate to a higher risk of recurrence or death. Long term follow-up and a larger population confirm that the chemoradiotherapy sandwich method yields favorable outcomes in patients with high-risk endometrial cancer.

Identification of the prognostic immune subtype in copy-number high endometrial cancer

The TCGA molecular subtype of endometrial cancer (EC) is widely applied, among which the copy-number high (CNH) subtype has the poorest prognosis. However, the heterogeneity of this subtype remains elusive. In this study, we aimed to identify heterogeneous immune subtypes in CNH EC and explore their prognostic significance. We collected 60 CNH EC cases in the TCGA database and performed unsupervised cluster analysis based on the enrichment scores of immune-related gene signatures to identify immune subtypes. We described their immune characteristics and prognoses and conducted differential gene analysis and lasso regression to identify a prognostic biomarker, GZMM. For experimental validation, we performed immunohistochemical staining of GZMM in 39 p53-positive EC surgical samples. We defined two immune subtypes, immune-hot (IH) and immune-cold (IC), which differed in immune cell infiltration, cytokine and chemokine expression and prognosis. The IH subtype has significantly stronger immune activation than the IC subtype, showing a significant infiltration of immune effector cells and high expression of relevant chemokines, with better prognosis. Moreover, the immunohistochemical staining of GZMM in a cohort of 39 p53-positive EC surgical samples confirmed GZMM as a unique prognostic biomarker, with high expression in both tumor cells and lymphocytes predicting a better prognosis. Our study revealed heterogeneous immune subtypes in CNH EC and identified GZMM as a prognostic biomarker. The stratified classification strategy combining molecular and immune subtypes provides valuable insights for future clinical practice.

Comparison of immediate germline sequencing and multi-step screening for Lynch syndrome detection in high-risk endometrial and colorectal cancer patients

Lynch syndrome (LS) is a hereditary cancer predisposition syndrome with a significantly increased risk of colorectal and endometrial cancers. Current standard practice involves universal screening for LS in patients with newly diagnosed colorectal or endometrial cancer using a multi-step screening protocol (MSP). However, MSP may not always accurately identify LS cases. To address this limitation, we compared the diagnostic performance of immediate germline sequencing (IGS) with MSP in a high-risk group. A total of 31 Taiwanese women with synchronous or metachronous endometrial and colorectal malignancies underwent MSP which included immunohistochemical staining of DNA mismatch repair (MMR) proteins, Our findings indicate that IGS surpassed MSP in terms of diagnostic yield (29.0% vs. 19.4%, respectively) and sensitivity (90% vs. 60%, respectively). Specifically, IGS successfully identified nine LS cases, which is 50% more than the number detected through MSP. Additionally, germline methylation analysis revealed one more LS case with constitutional Our study suggests that IGS may potentially offer a more effective approach compared to MSP in identifying LS among high-risk patients. This advantage is evident when patients have been pre-selected utilizing specific clinical criteria.

FIGO staging of endometrial cancer: 2023

Many advances in the understanding of the pathologic and molecular features of endometrial cancer have occurred since the FIGO staging was last updated in 2009. Substantially more outcome and biological behavior data are now available regarding the several histological types. Molecular and genetic findings have accelerated since the publication of The Cancer Genome Atlas (TCGA) data and provide improved clarity on the diverse biological nature of this collection of endometrial cancers and their differing prognostic outcomes. The goals of the new staging system are to better define these prognostic groups and create substages that indicate more appropriate surgical, radiation, and systemic therapies. The FIGO Women's Cancer Committee appointed a Subcommittee on Endometrial Cancer Staging in October 2021, represented by the authors. Since then, the committee members have met frequently and reviewed new and established evidence on the treatment, prognosis, and survival of endometrial cancer. Based on these data, opportunities for improvements in the categorization and stratification of these factors were identified in each of the four stages. Data and analyses from the molecular and histological classifications performed and published in the recently developed ESGO/ESTRO/ESP guidelines were used as a template for adding the new subclassifications to the proposed molecular and histological staging system. Based on the existing evidence, the substages were defined as follows: The updated 2023 staging of endometrial cancer includes the various histological types, tumor patterns, and molecular classification to better reflect the improved understanding of the complex nature of the several types of endometrial carcinoma and their underlying biologic behavior. The changes incorporated in the 2023 staging system should provide a more evidence-based context for treatment recommendations and for the more refined future collection of outcome and survival data.

Lymphocyte activation gene (LAG)-3 is a potential immunotherapeutic target for microsatellite stable, programmed death-ligand 1 (PD-L1)-positive endometrioid endometrial cancer

Immune checkpoint inhibitors have been widely used in the treatment of endometrial cancer (EC) with microsatellite instability-hypermutated (MSI-H). However, there is an unmet need for microsatellite stable (MSS) EC because of their modest activity. This study aimed to identify potential immune-related biomarkers in MSS EC. One hundred and twenty-three patients with EC who underwent hysterectomy were enrolled. MSI status was determined using MSI analysis and/or immunohistochemical staining for mismatch repair proteins. Immunohistochemical analysis of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), PD-L2, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), cluster of differentiation 3 (CD3), CD8, lymphocyte activation gene-3 (LAG-3), indoleamine 2,3-dioxygenase 1 (IDO1), phosphatase and tensin homolog (PTEN), p53, AT-rich interactive domain-containing protein 1A (ARID1A), and β-catenin was performed using tissue microarray blocks. Among 123 patients, 95 (77.2%) were classified as having MSS. Within EC with MSS, PD-L1 positivity was significantly associated with positive PD-1 (p<0.001), CTLA-4 (p<0.001), CD3 (p=0.002), CD8 (p<0.001), and LAG-3 (p<0.001). In the univariate analysis, positive PD-1 (odds ratio [OR]=9.281; 95% confidence interval [CI]=2.560-33.653; p<0.001), CTLA-4 (OR=5.33; 95% CI=1.418-19.307; p=0.005), CD3 (OR=5.571; 95% CI=1.746-17.775; p=0.004), CD8 (OR=6.909; 95% CI=2.647-18.037; p<0.001), and LAG-3 (OR=9.75; 95% CI=1.947-48.828; p=0.005) were significantly associated with PD-L1 positivity in MSS EC. In the multivariate analysis, LAG-3 demonstrated a significant association with positive PD-L1 expression in MSS EC (OR=5.061; 95% CI=1.534-16.693; p=0.023). In patients with MSS EC harboring PD-L1, LAG-3 may be a potential immunotherapeutic target. Clinical trials investigating the role of anti-LAG-3 antibodies, alone or in combination with other immunotherapies, are warranted.

Comparison of progression-free survival outcome of sentinel node biopsy without ultrastaging versus lymphadenectomy in endometrial cancer: a propensity-matched analysis

We aimed to investigate the oncologic outcomes of patients with endometrial cancer who underwent sentinel lymph node (SLN) biopsy without ultrastaging compared with that of those who underwent lymphadenectomy (LND). Patients with endometrial cancer who underwent staging with SLN biopsy or LND during 2006 - 2021 were analyzed using propensity score matching (PSM). SLN metastasis was examined using hematoxylin and eosin staining, without ultrastaging. Progression-free survival (PFS) was compared between the two groups before and after PSM using age, histology, and stage as covariates. Clinical variables such as recurrence patterns and lymphatic complications, were assessed. After excluding 213 patients who underwent validation LND with SLN biopsy, 902 were identified. The demographics of the remaining patients differed according to histology, myometrial invasion depth, and stage. Lymph node metastasis was less frequent in the SLN group than in the LND group (9.4% vs. 3.8%, p=0.004). The recurrence rates within 2 years were lower in the SLN group. The SLN group exhibited significantly superior 2-year and overall PFS than the LND group. Among patients with uterus-confined disease, overall PFS was favorable for SLN biopsy. After matching, differences in PFS were no longer observed, although the lymphocele and lymphedema rates were significantly lower in the SLN group. In patients with endometrial cancer, SLN biopsy without ultrastaging did not compromise survival outcomes and was associated with significantly reduced lymphatic complication rates compared with LND. Therefore, SLN biopsy can be recommended for patients with endometrial cancer without definitive preoperative evidence of distant metastasis.

Development and validation of a prognostic model based on metabolic risk score to predict overall survival of endometrial cancer in Chinese patients

Metabolic syndrome (MetS) is closely related to the increased risk and poor prognosis of endometrial cancer (EC). The purpose of this study was to analyze the relationship between metabolic risk score (MRS) and EC, and establish a predictive model to predict the prognosis of EC. A retrospective study was designed of 834 patients admitted between January 2004 to December 2019. Univariate and multivariate Cox analysis were performed to screen independent prognostic factors for overall survival (OS). A predictive nomogram is built based on independent risk factors for OS. Consistency index (C-index), calibration plots and receiver operating characteristic curve were used to evaluate the predictive accuracy of the nomogram. The patients were randomly divided into training cohort (n=556) and validation cohort (n=278). The MRS of EC patients, ranging from -8 to 15, was calculated. Univariate and multivariate Cox analysis indicated that age, MRS, FIGO stage, and tumor grade were independent risk factors for OS (p<0.05). The Kaplan-Meier analysis demonstrated that EC patients with low score showed a better prognosis in OS. Then, a nomogram was established and validated based on the above four variables. The C-index of nomogram were 0.819 and 0.829 in the training and validation cohorts, respectively. Patients with high-risk score had a worse OS according to the nomogram. We constructed and validated a prognostic model based on MRS and clinical prognostic factors to predict the OS of EC patients accurately, which may help clinicians personalize prognostic assessments and effective clinical decisions.

Surgical technique of two-step pelvic and para-aortic sentinel lymph node mapping in early-stage endometrial cancer: laparoscopic, robotic, and open method

Since sentinel lymph node mapping in endometrial cancer is becoming more widely used, the need of standardizing surgical technique is growing [1, 2]. The objective of this surgical video is to describe the procedure of two-step pelvic and para-aortic sentinel lymph node mapping using indocyanine green and fluorescent camera in endometrial cancer, in three versions of surgical modality of laparoscopic, robotic, and open laparotomy. The patients in the surgical video are diagnosed with biopsy-proven endometrial cancer in its early stage determined by the preoperative imaging study. After collecting washing cytology, bilateral salpinges were clamped with Endo Clip™ to minimize tumor spillage. Gauze packing in posterior cul-de-sac was done to minimize the spillage of indocyanine green dye during paraaortic sentinel lymph node mapping. Indocyanine green dye was injected in bilateral uterine fundus, to detect isolated paraaortic sentinel lymph node pathway. After bilateral paraaortic sentinel lymph node was sampled, cervical injection of Indocyanine green dye was done in 3 o'clock and 9 o'clock directions, both superficially and deeply, 2 mL in each side. After dissecting off the obliterated umbilical ligament, para-vesical and para-rectal spaces were developed. The ureter, uterine artery, and internal and external iliac vessels were identified before bilateral pelvic sentinel lymph nodes were sampled. Asan Medical Center's Institutional Review Board exempted this project. Sentinel paraaortic and pelvic lymph nodes were successfully harvested by two-step method of sentinel lymph node mapping through laparoscopic, robotic, and open laparotomy methods. This surgical video provides specific steps of pelvic and para-aortic sentinel lymph node mapping.

PTEN mutation predicts unfavorable fertility preserving treatment outcome in the young patients with endometrioid endometrial cancer and atypical hyperplasia

This study aimed to investigate the impact of molecular classification and PTEN, KRAS and PIK3CA gene mutation on the outcome of fertility-preserving treatment in the patients with endometrioid endometrial cancer (EEC) and endometrial atypical hyperplasia (EAH). This is a single-center retrospective study. A total of 135 patients with EEC and EAH receiving fertility-preserving treatment and molecular classification were reviewed. The distribution of the four types of molecular classification was described. The impact of non-specific molecular profile (NSMP), mismatch repair-deficiency (MMRd), and PTEN, KRAS and PIK3CA gene mutation on the outcome of fertility-preserving treatment was analyzed. Of the patients analyzed, 86.7% (117/136) were classified as having NSMP; 14 (10.4%), MMRd; 1 (0.7%), POLEmut EAH; and 3 (2.2%), p53abn EEC. The patients having NSMP and MMRd achieved similar 16-, 32-, and 48-week complete response rates. The patients harboring tier I and tier II PTEN mutations (PTENmut-Clin) achieved lower cumulative 32-week CR rates than those with PTEN-others (without PTENmut-Clin) (22/47, 46.8% vs. 50/74, 67.6%; p=0.023; odds ratio=0.422; 95% confidence interval [CI]=0.199-0.896). Insulin-resistance (hazard ratio [HR]=0.435; 95% CI=0.269-0.702; p=0.001) and PTENmut-Clin (HR=0.535; 95% CI=0.324-0.885; p=0.015) were independent negative predictors for lower 32-week CR rates. PTENmut-Clin is an independent risk factor for unfavorable fertility-preserving treatment outcomes in the patients with EEC and EAH. The patients with MMRd receiving fertility-preserving treatment achieved outcomes similar to those of the patients with NSMP. The molecular profiles might guide fertility-preserving treatment in the prognosis and clinical decisions.

Pattern of practice for postoperative management of endometrial cancer in Korea: a survey by the Korean Gynecologic Oncology Group and the Korean Radiation Oncology Group (KGOG 2028-KROG 2104)

This study aimed to investigate the current status of postoperative management of uterine endometrial cancer (EC) in Korea. A mail survey was administered to members of the Korean Gynecologic Oncology Group and Korean Radiation Oncology Group. A total of 38 gynecologic cancer surgeons (GYNs) and 31 radiation oncologists (RO) in 43 institutions was responded. The questionnaire consisted of general questions for clinical decision and clinical case questions. The GYN and RO responses were compared using chi-square statistics. The 2 expert groups had similar responses for clinical decision based on the results of the Gynecologic Oncology Group (GOG)-249 and Postoperative Radiation Therapy for Endometrial Carcinoma-III trials in the early-stage EC. In contrast, the responses based on GOG-258 results differed, as GYNs most frequently opted for sequential chemotherapy (CTx) and radiotherapy (RT), while ROs preferred concurrent chemoradiotherapy in locally advanced stage (p<0.05). Based on the GOG-258, GYNs preferred CTx alone for adjuvant treatment of serous or clear cell adenocarcinoma histology, whereas ROs advocated for combined CTx and RT (sequential or concurrent). Among the clinical case questions, GYNs were more likely than ROs to choose CTx alone rather than the combination of CTx and RT (sequential or concurrent) as the answers to case questions representing patients with locally advanced stage or unfavorable histology (all p<0.05). The present study showed several different opinions of GYNs and ROs regarding adjuvant treatment for EC, particularly for adjuvant RT in advanced stage or unfavorable histology.

Trend and characteristics of minimally invasive surgery for patients with endometrial cancer in Japan

Owing to the potential benefits of minimally invasive hysterectomy for endometrial cancer, the practice pattern has recently shifted in Japan. This study examined the trends in minimally invasive surgery (MIS) in patients with endometrial cancer in Japan. This retrospective observational study examined the Japan Society of Obstetrics and Gynecology Tumor Registry database between 2015-2019. This study examined the time-specific proportion change and predictors of MIS use in initial endometrial cancer treatment in Japan, and compared it with the use of abdominal surgery. Additionally, the association between hospital surgical treatment volume and MIS use was examined. A total of 14,059 patients (26.5%) underwent minimally invasive hysterectomy, and 39,070 patients (73.5%) underwent abdominal hysterectomy in the study period. Patients who underwent MIS were more likely to be treated at high-volume centers, younger, central, or western Japan residents, registered in recent years, and had a tumor with stage I disease, type 1 histology, and less myometrial invasion (all adjusted p<0.05). The proportion of MIS treatments increased from 19.1% in 2015 to 34.3% in 2019 (p<0.001). On multivariable analysis, treatment at high-volume centers was a contributing factor for MIS (adjusted odds ratio=3.85; 95% confidence interval=3.44-4.30). MIS at high-volume centers increased significantly from 24.8% to 41.0% (p<0.001) during the study period, whereas MIS at low-volume centers remained at median 8.8%. MIS has increased significantly in recent years, accounting for nearly 34% of surgical management of endometrial cancer in Japan. High-volume treatment centers take the lead in performing MIS.

Effects of a fertility-sparing re-treatment for recurrent atypical endometrial hyperplasia and endometrial cancer: a systematic literature review

To examine the effectiveness of progestin re-treatment for recurrent endometrial intraepithelial neoplasia (EIN), atypical endometrial hyperplasia (AH) and endometrial cancer (EC) following initial fertility-sparing treatment. A comprehensive systematic review and meta-analysis were conducted by an Expert Panel of the Japan Society of Gynecologic Oncology Endometrial Cancer Committee. Multiple search engines, including PubMed/MEDLINE and the Cochrane Database, were searched in December 2021 using the keywords "Endometrial neoplasms," "Endometrial hyperplasia," "Endometrial intraepithelial neoplasia," "Fertility preservation," "Progestins," AND "Recurrence." Cases describing progestin re-treatment for recurrent EIN, AH and EC were compared with cases that underwent conventional hysterectomy. The primary outcomes were survival and disease recurrence, and the secondary outcome was pregnancy. After screening 238 studies, 32 with results for recurrent treatment were identified. These studies included 365 patients (270 received progestin re-treatment and 95 underwent hysterectomy). Most progestin re-treatment involved medroxyprogesterone acetate or megestrol acetate (94.5%). Complete remission (CR) following progestin re-treatment was achieved in 219 (81.1%) cases, with 3-, 6- and 9-month cumulative CR rates of 22.8%, 51.7% and 82.6%, respectively. Progestin re-treatment was associated with higher risk of disease recurrence than conventional hysterectomy was (odds ratio [OR]=6.78; 95% confidence interval [CI]=1.99-23.10), and one patient (0.4%) died of disease. Fifty-one (14.0%) women became pregnant after recurrence, and progestin re-treatment demonstrated a possibility of pregnancy (OR=2.48; 95% CI=0.94-6.58). This meta-analysis suggests that repeat progestin therapy is an effective option for women with recurrent EIN, AH and EC, who wish to retain their fertility.

Alternative splicing of PSMD13 mediated by genetic variants is significantly associated with endometrial cancer risk

Accumulating evidence has shown that aberrant alternative splicing events are closely associated with the onset and development of cancer. However, whether genetic variants-associated alternative splicing is linked to risk of endometrial cancer remains largely uncertain. We identified single nucleotide polymorphisms (SNPs) locates in the splicing number trait locus (sQTL) of endometrial cancer using the CancerSplicing QTL database. In parallel with bioinformatics analysis, we conducted a case-control study comprising 2,000 cases and 2,013 controls to assess the association between identified SNP which possesses mRNA splicing function and endometrial cancer susceptibility. Furthermore, we used the Kaplan-Meier Plotter, The Human Protein Atlas, SPNR, and Spliceman2 databases for sQTL and differential gene expression analyses to identify the genetic variant which most potentially influence the risk of endometrial cancer through alternative splicing to reveal the potential mechanism by which candidate SNPs regulate the risk of endometrial cancer. The results indicated that SNP rs7128029 A<G was significantly associated with an increased risk of endometrial cancer (odds ratio=1.384; 95% confidence interval=1.038-1.964). Moreover, the carcinogenic effect of SNP rs7128029 A<G was consistently revealed by propensity matching analysis, an additive model, and a dominant model. Importantly, sQTL analysis showed that SNP rs7128029 could affect the transcriptional modification of These findings suggest that SNP rs7128029-mediated alternative splicing events in

Malignant germ cells tumor of the ovary

Malignant ovarian germ cell tumors are rare and diverse malignancies, accounting for approximately 5% of all ovarian cancers. Primarily affecting young women, these tumors present unique challenges, particularly in balancing effective treatment with fertility preservation. Early diagnosis is common due to the rapid tumor growth and symptoms such as abdominal pain and distension, leading to favorable prognoses when combined with the high chemosensitivity of platinum-based regimens. Fertility-sparing surgery is the cornerstone of treatment for stage I disease, often followed by close surveillance to minimize the long-term toxicities of chemotherapy. Pathology is pivotal for diagnosis, incorporating immunohistochemical markers to differentiate malignant ovarian germ cell tumors subtypes, including dysgerminomas, yolk sac tumors, and immature teratomas. Advanced imaging modalities like ultrasound, magnetic resonance imaging, and computed tomography are essential for staging, monitoring treatment response, and detecting recurrences. Despite high cure rates, long-term follow-up is crucial to manage late toxicities, such as gonadal dysfunction and secondary malignancies. Recurrent malignant ovarian germ cell tumors present significant therapeutic challenges. High-dose chemotherapy with stem-cell transplantation offers promise in select cases, while the role of secondary cytoreductive surgery and radiotherapy is limited to specific indications. Emerging targeted therapies and novel approaches, such as KIT inhibitors for dysgerminomas with KIT mutations, remain experimental, with limited success reported so far. The rarity and heterogeneity of malignant ovarian germ cell tumors impede large-scale research efforts, underscoring the need for greater understanding of their molecular and genetic landscape to develop more effective and personalized therapies.

Randomized comparison between sentinel lymph node mapping using indocyanine green plus a fluorescent camera versus lymph node dissection in clinical stage I-II endometrial cancer: a Korean Gynecologic Oncology Group trial (KGOG2029/SELYE)

Sentinel lymph node (SLN) mapping has been suggested as an alternative surgical technique to full lymphadenectomy for early-stage endometrial cancer. However, the survival outcomes of SLN mapping compared with lymphadenectomy have not been established via a prospective study. A multi-center, single-blind, randomized controlled trial has been designed to determine the prognostic value of SLN mapping alone compared with conventional lymphadenectomy for patients with clinical stage I-II endometrial cancer. Eligible participants will be randomly assigned in a 1:1 ratio between the group to undergo SLN mapping using indocyanine green and the conventional lymph node dissection group. A high-risk group will undergo a 2-step SLN mapping procedure. The primary endpoint is the 3-year disease-free survival (DFS). The secondary endpoints are 3-year overall survival (OS), 5-year DFS, 5-year OS after surgery, pattern of recurrence, immediate surgical outcomes, success rate of SLN mapping, postoperative lymph-related complications, postoperative quality of life, and postoperative cost effectiveness. The role of pathologic ultrastaging of SLNs will also be assessed. ClinicalTrials.gov Identifier (NCT number): NCT04845828.

Prognostication of early-onset endometrioid endometrial cancer based on genome-wide DNA methylation profiles

The aim of this study was to establish criteria that would indicate whether fertility preservation therapy would likely be safe for patients aged 40 years or less with endometrioid endometrial cancer based on their DNA methylation profile. Forty-nine fresh-frozen tissue samples from patients with endometrial cancer from an initial cohort and 31 formalin-fixed paraffin-embedded tissue samples from a second cohort were subjected to genome-wide DNA methylation analysis using the Infinium MethylationEPIC BeadChip. Epigenomic clustering of early-onset endometrial cancer was correlated with the widely used recurrence risk classification. Genes showing differences in DNA methylation levels between the low-recurrence-risk category and intermediate- and high-risk categories were accumulated in pathways related to fibroblast growth factor and nuclear factor-κB signaling. DNA hypomethylation and overexpression of DNA methylation diagnostics criteria using up to 6 of 8 CpG sites for

Substantial lymph-vascular space invasion (LVSI) as predictor of distant relapse and poor prognosis in low-risk early-stage endometrial cancer

The aim of this study is to analyze the prognostic role of lymph-vascular space invasion (LVSI), evaluated in a semi-quantitative fashion on prognosis of early stage, low risk endometrial cancer (EC). We enrolled patients who underwent surgery for endometrial cancer between 2003 and 2018 in two referral cancer center. All patients had endometrioid EC, G1-G2, with myometrial invasion <50%, and no lymph-node involvement. LVSI was analyzed in a semi-quantitative way, according to a 3-tiered scoring system in absent, focal and substantial. Among 524 patients, any positive LVSI was found in 57 patients (10.9%) with focal LVSI (n=35, 6.7%) and substantial LVSI (n=22, 4.2%). Substantial LVSI was associated to higher rate of G2 (p<0.001), myometrial infiltration (p=0.002) and greater tumor dimensions (p=0.014). Patients with substantial LVSI were more likely to receive adjuvant treatment (6.6% vs. 52.6%, p<0.001). The 5-year OS was 99.5% in patients with absent LVSI and 70.6% in those with substantial LVSI (p<0.001). The 5-year disease free survival (DFS) was 93.6% in patients with absent LVSI and 56.5% in those with substantial LVSI (p<0.001). The rate of distant failures increased from 1.8% for absent LVSI to 22.7% for substantial LVSI (p=0.002). In univariate analysis substantial LVSI was the strongest predictor of poor overall survival (hazard ratio [HR]=11.9, p=0.001). Multivariate analysis showed that substantial LVSI was an independent predictive factor of both recurrence (HR=5.88, p=0.001) and distant failure (HR=10.6, p=0.006). Substantial LVSI represents the strongest independent risk factor for decreased survival and distant relapse, indicating a role for potential hematogenous dissemination.

Associations between obesity, metabolic syndrome, and endometrial cancer risk in East Asian women

This study investigated the associations between obesity, metabolic syndrome (MetS), the combination of these two components as a metabolic obesity phenotype, and endometrial cancer risk in East Asian women. A total of 6,097,686 cancer-free women aged 40-74 years who underwent the National Health Insurance Service health examination between 2009 and 2010 were included. Cancer incidence was identified using the healthcare utilization database. Associations between baseline obesity (body mass index <23 kg/m², 23-24.9 kg/m², ≥25 kg/m²), MetS, each component of MetS, MetS stratified by obesity status, combination of obesity and MetS, and endometrial cancer risk were investigated using hazard ratios (HRs). Obesity, each component of MetS, and MetS increased the endometrial cancer risk. After these factors were mutually adjusted for, the association did not change. When stratified by obesity, MetS and MetS components were not associated with endometrial cancer in normal-weight or overweight women. However, in obese women, MetS and MetS components increased the risk of endometrial cancer (HR=1.29; 95% confidence interval [CI]=1.20-1.39). Compared with normal-weight women without MetS, endometrial cancer risk was not increased in normal-weight women with MetS. Overweight women showed an increased risk of endometrial cancer irrespective of the presence of MetS (HR=1.37 and 1.38, respectively). The HR of obese women with MetS was higher than that of obese women without MetS (HR=2.18 and 1.75). The association between MetS and endometrial cancer was most prominent in obese women, suggesting that obese women with MetS would be more vulnerable to endometrial cancer.

Laparoscopic resection surgery for malignant transformation of extragonadal endometriosis by the “pincer” approach

Up to 1% of women with endometriosis develop endometriosis-associated neoplasms [1]. Most endometriosis-associated malignant tumors develop from the ovarian endometriomas, whereas those developing from extragonadal lesions are extremely rare, estimated at 0.2% [2]. Because they are uncommon, a treatment protocol for the malignant transformation of extragonadal endometriosis lesions has not been clearly defined. When the lesion is confined to the site of origin and R0 resection is achieved, the 5-year survival rate is between 82% and 100%; therefore, complete resection should be performed [3]. The patient in this video had previously undergone hysterectomy, bilateral salpingo-oophorectomy, left nephrectomy, and low-anterior resection of the rectum due to severe endometriosis. Ten years after the surgery, the patient had a 6 cm endometrioid adenocarcinoma developing from the residual endometriosis lesion at the left uterosacral ligament that involved the bladder, left ureter, and rectum. In this case, the tumor was attached to the pelvis due to infiltration of the left sacrospinous ligament. To completely remove the tumor, we used laterally extended endopelvic resection with abdominoperineal resection of the rectum. We used the laparoscopic-perineal-laparoscopic approach (pincer approach) because improved visualization of the left sacrospinous ligament increases the probability of achieving complete resection [4]. Pathological R0 resection was achieved without intraoperative or postoperative complications. Thus, for tumors that are firmly attached to the pelvic floor, the pincer approach can be useful for achieving R0 resection. The informed consent for use of this video was taken from the patient.

Genomic landscape of advanced endometrial cancer analyzed by targeted next-generation sequencing and the cancer genome atlas (TCGA) dataset

Recent studies have detailed the genomic landscape of endometrial cancer (EC); however, no study has focused on genetic alterations in advanced EC. We performed genomic profiling of patients with advanced EC using targeted next-generation sequencing (NGS). Archival tissue samples from 21 patients diagnosed with stage III and IV EC were obtained and subjected to NGS. Our data and the cancer genome atlas dataset were combined, and somatic mutation patterns were analyzed and compared according to the stage and histological type. Additionally, survival effects of specific mutated genes were analyzed. Somatic mutation patterns of 38 genes were identified in 263 EC samples, and the most commonly mutated genes were

A prospective comparison of the diagnostic accuracies of ultrasound and magnetic resonance imaging in preoperative staging of endometrial cancer

To compare the diagnostic accuracies of ultrasound and magnetic resonance imaging (MRI) for deep (≥50%) myometrial invasion (DMI) and cervical stromal invasion (CSI) in women with endometrial cancer. This was a prospective study at a gynecology clinic for women with postmenopausal bleeding. Between October 2015-October 2018, consecutive women with suspected endometrial cancer based on ultrasound subjective pattern recognition were simultaneously assessed for DMI and CSI on ultrasound. Subsequently, they also underwent preoperative MRI. We compared the diagnostic accuracies of ultrasound and MRI in predicting DMI and CSI with the final histology as the gold standard. We included 51 women. The prevalence of DMI and CSI were 22/51 (43%) and 7/51 (14%), respectively. The majority of malignancies were of endometrioid histological subtype (38/51, 75%) and FIGO stage 1 or 2 (40/51, 78%). Ultrasound diagnosed more cases of DMI compared to MRI (19/22 vs. 17/22), however, the difference was not statistically significant. The sensitivities and specificities of ultrasound and MRI for DMI were 86% vs. 77% and 66% vs. 76%, respectively. For CSI, ultrasound and MRI correctly diagnosed the same number of cases (5/7, 71%); their respective false-positive rates were low, 0/44 (0%) and 1/44 (2%). Ultrasound and MRI had a moderate agreement for DMI (ƙ=0.49; 95% confidence interval [CI]=0.26-0.73), whereas the agreement for CSI was substantial (ƙ=0.69; 95% CI=0.36-1.00). Endometrial cancer can be simultaneously diagnosed and staged at women's initial ultrasound assessment. The accuracies of ultrasound for DMI and CSI are comparable to MRI. ISRCTN Identifier: ISRCTN24363390.

Clinicopathologic and protein markers distinguishing the “polymerase epsilon exonuclease” from the “copy number low” subtype of endometrial cancer

The need to perform genetic sequencing to diagnose the polymerase epsilon exonuclease ( Ninety-one samples (15 Body mass index (BMI) and tumor grade were significantly associated with the BMI and expression of cyclin B1, caspase 8, and XBP1 are candidate markers distinguishing the

One-step nucleic acid amplification (OSNA) assay for detecting lymph node metastasis in cervical and endometrial cancer: a preliminary study

To evaluate the accuracy of the one-step nucleic acid amplification (OSNA) assay for the diagnosis of lymph node (LN) metastasis in uterine cancer. A total of 116 LNs from 30 patients with cervical and endometrial cancer, enrolled in this prospective study, were used. Excised LNs were cut into 4 to 6 blocks at 2 mm intervals, and nonadjacent blocks were alternately subjected to either histological examination or the OSNA assay. The concordance rate between histological examination and the OSNA assay in cervical cancer and in endometrial cancer was 95.9% and 95.2%, respectively. The sensitivity, specificity, and negative predictive value of the OSNA assay were 80%, 97.7%, and 97.7% in cervical cancer, and 85.7%, 93.3%, and 98.2% in endometrial cancer, respectively. In cervical cancer, discordant results were observed in 2 out of 49 LNs (4.1%); 1 was OSNA assay-positive and histological examination-negative, and 1 was OSNA assay-negative and histological examination-positive. In endometrial cancer, discordant results were observed in 5 out of 67 LNs (7.5%); 4 were OSNA assay-positive and histological examination-negative, and 1 was OSNA assay-negative and histological examination-positive. The OSNA assay showed high concordance rate with histological examination, sensitivity, and specificity in uterine cancer, suggesting that it could enhance the accuracy of conventional pathological examination for the detection of LN metastasis by reducing false negative rate.

MLH1 promoter hypermethylation predicts poorer prognosis in mismatch repair deficiency endometrial carcinomas

The antitumor effects of anti-PD-1 antibody against mismatch repair deficiency (MMR-D)-associated cancers have been reported. MMR-D is found in approximately 20%-30% of endometrial carcinomas (ECs) and frequently occurs due to Immunohistochemistry of MMR proteins (MLH1, MSH2, MSH6, and PMS2) was performed on specimens from 527 ECs treated at our university hospital from 2003 to 2018. Accordingly, 419 (79.5%), 65 (12.3%), and 43 (8.2%) cases were categorized as "MMR-proficient," "suspected-LS," and "met-EC," respectively. Significantly, "met-EC" had a lower proportion of grade 1 tumors (37.5%) and a higher proportion of stage III/IV tumors (37.2%) than the other groups. The overall and progression-free survival of "met-EC" were significantly worse than those of "suspected-LS" in all cases. In ECs with MMR-D, "met-ECs" were a subgroup with a poorer prognosis than "suspected-LS." "Met-ECs" would be the main target for anti-PD-1 antibody treatment, and its clinical susceptibility should be verified individually.

What is the prognostic importance of lymphovascular space invasion in the absence of lymph node metastasis for early-stage endometrial cancer?

Does polycystic ovary syndrome independently affect oncologic and reproductive outcomes in patients with endometrial cancer receiving fertility-sparing treatment?

Author's reply to: What is the prognostic importance of lymphovascular space invasion in the absence of lymph node metastasis for early-stage endometrial cancer?

Cancer field surgery in endometrial cancer: peritoneal mesometrial resection and targeted compartmental lymphadenectomy for locoregional control

Peritoneal mesometrial resection (PMMR) plus targeted compartmental lymphadenectomy (TCL) aims at removal of the locoregional cancer field in endometrial cancer (EC). Optimal locoregional control without adjuvant radiotherapy and acceptable surgical morbidity should be achieved concomitantly sparing systematic lymphadenectomy (LNE) for most of the patients. We evaluated data from 132 patients treated for EC. Out of these, between January 2017 and June 2020 we performed robotic PMMR and TCL on 51 women. We present the first data of feasibility and safety of the procedure as well as preliminary oncological results. The 51 patients treated with robotic PMMR and TCL showed comparable morbidity to classic laparoscopic hysterectomy or PMMR without LNE. One intraoperative complication occurred. Postoperative complications grade 3 and higher occurred in 2 cases (3.9%). One of these (85 years old) experienced grade 5 following pulmonary embolism with lysis therapy. Fifteen patients (29.4%) could be spared complete LNE. The rate of adjuvant radiotherapy was 3.9% in our collective (n=2), compared to 39.2% of patients (n=20) eligible for irradiation according to international guidelines. In a mean follow-up time of 15 months (0-41), no locoregional recurrences were observed, although three patients showed distant relapse. Our data suggest that robotic PMMR and pelvic TCL can be performed regardless of BMI and comorbidities without a relevant increase in surgical morbidity. Moreover, despite a relevant reduction of adjuvant radiotherapy, first follow-up data hint at a favorable locoregional recurrence rate in the reported cohort.

Fertility-preserving treatment outcome in endometrial cancer or atypical hyperplasia patients with polycystic ovary syndrome

This study aimed to investigate the impact of polycystic ovary syndrome (PCOS) on fertility-sparing treatment in young patients with atypical endometrial hyperplasia (AEH) or endometrioid endometrial cancer (EEC). A total of 285 patients with EEC (n=76, FIGO stage IA, without myometrium invasion) or AEH (n=209) who received progestin-based fertility-sparing treatment were evaluated retrospectively. Among the 285 patients, 103 (36.1%), including 70 AEH cases and 33 EEC cases, were diagnosed with PCOS. General characteristics, cumulative 16- and 32-week complete response (CR) rate, pregnancy outcome and recurrence were compared between patients with or without PCOS. The cumulative 16-week CR rate was lower in the PCOS group than in the non-PCOS group (18.4% vs. 33.8%, p=0.006). Patients with PCOS took longer treatment duration to achieve CR (7.0 months vs. 5.4 months, p=0.006) and shorter time to relapse after CR (9.6 months vs. 17.6 months, p=0.040) compared with non-PCOS group. After adjusting for patient age, body mass index, PCOS, homeostasis model assessment-insulin resistance index, and serum testosterone levels, we found that body mass index ≥25 kg/m² (HR=0.583; 95% CI=0.365-0.932; p=0.024) and PCOS (HR=0.545; 95% CI=0.324-0.917; p=0.022) were significantly correlated with lower 16-week CR rate. PCOS was associated with lower 16-week CR rate, longer treatment duration and shorter recurrence interval in patients with AEH or EEC receiving fertility-preserving treatment.

Characteristics of progestin-insensitive early stage endometrial cancer and atypical hyperplasia patients receiving second-line fertility-sparing treatment

This study investigated the characteristics of progestin-insensitive endometrioid endometrial cancer (EEC) and atypical endometrial hyperplasia (AEH) patients receiving fertility-sparing treatments and assessed the therapeutic effects of second-line fertility-preserving treatments. Three hundred and thirty-eight patients with EEC (n=75) or AEH (n=263) receiving fertility-preserving treatment were retrospectively analyzed. 'Progestin-insensitive' was defined as meeting one of the following criteria: 1) presented with progressed disease at any time during conservative treatment, 2) remained with stable disease after 7 months of treatment, and/or 3) did not achieve complete response (CR) after 10 months of treatment. Clinical characteristics and treatment results of progestin-insensitive patients receiving second-line treatment and those of progestin-sensitive patients were compared. Eight-two patients (59 AEH and 23 EEC) were defined as progestin-insensitive and 256 as progestin-sensitive. In multivariate analysis, body mass index ≥28.0 kg/m² (odds ratio [OR]=1.898) and lesion size >2 cm (OR=2.077) were independent predictors of progestin-insensitive status. Compared to AEH patients, progestin-insensitive EEC patients had poorer second-line treatment responses (28-week cumulative CR rate after changing second-line treatment, 56.3% vs. 85.4%, p=0.011). No statistical difference was found in CR rate among different second-line treatments. Obesity and larger lesion size were independent risk factors associated with progestin-insensitive status. In progestin-insensitive patients receiving second-line treatment, EEC patients had lower CR rate comparing with AEH patients. Further study with larger sample size is needed to evaluate efficacy of different second-line treatments for progestin insensitive patients.

Sentinel lymph Node mapping versus systematic pelvic lymphadenectomy on the prognosis for patients with intermediate-high-risk Endometrial Cancer confined to the uterus before surgery: trial protocol for a non-inferiority randomized controlled trial (SNEC trial)

Sentinel lymph node (SLN) mapping has been recommended as an alternative staging approach to lymphadenectomy for apparent uterine-confined endometrial cancer (EC). However, the prognostic value of SLN mapping alone instead of systematic lymphadenectomy on EC patients remains unclear. A multi-center, open label, non-inferiority randomized controlled trial has been designed to identify if SLN mapping alone is not inferior to pelvic lymphadenectomy on prognosis of patients with intermediate-high-risk EC clinically confined to uterus. Eligible patients will be 1:1 randomly assigned to accept SLN mapping or pelvic lymphadenectomy. The primary endpoint is the 2-year progression-free survival (PFS). The second points are the 5-year PFS, 5-year overall survival, surgery-related adverse events and life quality. A total of 780 patients will be enrolled from 6 hospitals in China within 3-year period and followed up for 5 years. ClinicalTrials.gov Identifier: NCT04276532.

A phase II, open-labeled, single-arm study of dose-dense paclitaxel plus carboplatin in advanced or recurrent uterine endometrial cancer treatment: a KCOG-G1303, DOENCA trial

To determine the safety and efficacy of dose-dense (dd) paclitaxel (PTX) and carboplatin (CBDCA) in treating advanced or recurrent endometrial cancer. Women aged 20-75 years with histologically confirmed endometrial cancer, the International Federation of Gynecology and Obstetrics (FIGO) stage III disease with some residual tumor, FIGO stage IV disease, recurrence after front-line curative treatment, or recurrence after second-line chemotherapy or radiotherapy were enrolled in this study. PTX (80 mg/m²) was administered intravenously (IV) to every participant on days 1, 8, and 15, and CBDCA (area under the curve of 5) was administered IV on day 1 once every 3 weeks until the disease progressed, unacceptable adverse events occurred, or consent was withdrawn. The primary endpoint was the response rate (RR), while the secondary endpoints were progression-free survival, overall survival, and adverse effects. Forty-eight participants were enrolled, and 46 were eligible to receive treatment. The patients' median age was 61 years (range, 43-76 years). Twenty-two participants had experienced recurrence, and the remaining patients had primary advanced endometrial cancer. There were 10 cases of serous carcinoma, 3 cases of endometrioid carcinoma G3, 2 cases of carcinosarcoma, and 2 cases of clear-cell carcinoma according to histology. Twenty-nine participants (63.0%) received ≥6 cycles of chemotherapy. The RR (complete, 13 cases; partial, 20 cases) was 71.3% (95% confidence interval: 59.0%-84.5%). The dd PTX with CBDCA is feasible and available as a treatment option for advanced or recurrent endometrial cancer. UMIN Clinical Trials Registry Identifier: UMIN000017138.

Relevance of pathologic features in risk stratification for early-stage endometrial cancer

Vaginal cancer as a late complication of radiotherapy for endometrial cancer and ileo-perineal fistula after total pelvic exenteration

Pelvic exenteration is a highly morbid operation and remains one of the most catastrophic surgical procedures in gynecological oncology. We would like to present the case of total pelvic exenteration for vaginal cancer after radiotherapy for endometrial cancer as a secondary cancer. A 62-year-old woman, whose gravida: 3, parity: 2, body mass index: 35.9 kg/m², presented with complaints of vaginal bleeding. She had undergone a surgery because of a stage IB grade 2 endometrioid-type adenocarcinoma seventeen years previously. Following the surgery, she had external pelvic radiotherapy and brachytherapy. A palpable, solid and ulcerative mass was detected extending from the vaginal cuff area to the vestibulum vagina on the left postero-lateral wall of the vagina. The 5-cm vaginal mass was seen at vaginal examination. A punch biopsy from a pathological examination of the tumoral lesion was reported as a squamous cell carcinoma. Pelvic exenteration was performed and ileo-perineal fistula occurred after six months this surgery. In conclusion, we considered that this malignancy was a secondary malignancy induced by radiotherapy.

How to perform sentinel node detection in high-risk endometrial cancer: one step forward

Poor accuracy of endometrial sampling in patients with uterine carcinosarcomas: a nationwide analysis

To determine the accuracy of aspiration biopsy (AB), hysteroscopic biopsy (HB), and dilatation & curettage (D&C) in detecting uterine carcinosarcoma (UCS). Pathology reports were retrieved from the Dutch Nationwide Pathology Databank PALGA for patients with a certain or suggested diagnosis of UCS in pre- and/or postoperative histology between 2001 and 2021. Patients without available pre- or postoperative pathology reports were excluded. The accuracy measures sensitivity, positive predictive value (PPV), accuracy, and concordance using Cohen's kappa were calculated for AB, D&C, and HB, using postoperative histology as the reference. This was analyzed for 2 scenarios: Analysis A compared samples with a certain or suggested diagnosis of UCS vs. no mention of UCS. Analysis B compared samples with a certain diagnosis of UCS vs those without UCS. The study included 1,481 patients, totaling 1,685 samples. Sensitivity was similar for AB and HB (52.4% and 50.5%, respectively, for analysis A; 45.1% and 42.2% for analysis B). D&C showed the highest sensitivity (70.8% and 64.9% for analysis A and B, respectively). AB had the highest PPV (85.3% and 90.9% for analysis A and B, respectively), HB had the lowest PPV (79.7% and 80.9%, respectively). Accuracy was highest for D&C (44.4%) compared to AB (32.8%) and HB (29.5%). All Cohen's kappa values were below 0.20, indicating poor correlation between preoperative and postoperative diagnoses. The study reveals low accuracy measures across all conventional endometrial sampling techniques, highlighting the need for research to identify markers or tools to diagnose UCS.

Paraaortic sentinel lymph node detection in intermediate and high-risk endometrial cancer by transvaginal ultrasound-guided myometrial injection of radiotracer (TUMIR)

We aimed to evaluate the accuracy of sentinel lymph node (SLN) mapping with transvaginal ultrasound-guided myometrial injection of radiotracer (TUMIR) to detect lymph node (LN) metastases, in patients with intermediate and high-risk endometrial cancer (EC), focusing on its performance to detect paraaortic involvement. Prospective study including women with preoperative intermediate or high-risk EC, according to ESMO-ESGO-ESTRO consensus, who underwent SLN mapping using the TUMIR approach. SLNs were preoperatively localized by planar and single photon emission computed tomography/computed tomography images, and intraoperatively by gamma-probe. Immediately after SLN excision, all women underwent systematic pelvic and paraaortic lymphadenectomy by laparoscopy. The study included 102 patients. The intraoperative SLN detection rate was 79.4% (81/102). Pelvic and paraaortic drainage was observed in 92.6% (75/81) and 45.7% (37/81) women, respectively, being exclusively paraaortic in 7.4% (6/81). After systematic lymphadenectomy, LN metastases were identified in 19.6% (20/102) patients, with 45.0% (9/20) showing paraaortic involvement, which was exclusive in 15.0% (3/20). The overall sensitivity and negative predictive value (NPV) of SLNs by the TUMIR approach to detect lymphatic involvement were 87.5% and 97.0%, respectively; and 83.3% and 96.9%, for paraaortic metastases. After applying the MSKCC SLN mapping algorithm, the sensitivity and NPV were 93.8% and 98.5%, respectively. The TUMIR method provides valuable information of endometrial drainage in patients at higher risk of paraaortic LN involvement. The TUMIR approach showed a detection rate of paraaortic SLNs greater than 45% and a high sensitivity and NPV for paraaortic metastases in women with intermediate and high-risk EC.

International cost-effectiveness analysis of chemoradiotherapy plus pembrolizumab for locally advanced cervical cancer

Pembrolizumab administration can improve concurrent chemoradiotherapy (CCRT) efficacy in newly diagnosed, high-risk, locally advanced cervical cancer (LACC). Given the importance of balancing the costs of innovative therapeutics against their efficacy, this study was developed to assess the cost-effectiveness from the perspective of payers in Americas, Europe, and Asia. The main survival and other relevant parameters of 1,060 LACC patients from the KEYNOTE-A18 trial were collected to establish a lifetime 3-state Markov model to evaluate the cost and effectiveness of pembrolizumab-CCRT and placebo-CCRT. Primary outcome measures included total cost, life-years (LYs), quality-adjusted LYs (QALYs), incremental cost-effectiveness ratio (ICER), incremental net monetary benefit, and incremental net health benefits (INHBs) at countries' traditional willingness-to-pay (WTP) thresholds. Model stability was also examined through sensitivity analyses. The USA, Italy, and China are selected as representative countries for each of the 3 continents, assuming that their WTP thresholds were $150,000, $43,749, and $37,766 per QALY. The increased efficacy and costs of pembrolizumab-CCRT versus placebo-CCRT were 2.52 QALYs (3.11 LYs) and $346,479, 2.30 QALYs (2.81 LYs) and $236,776, 1.79 QALYs (2.12 LYs) and $29,027, calculating the ICER for the 3 countries as $137,500/QALY ($111,499/LY), $102,758/QALY ($84,192/LY), and $16,217/QALY ($13,726/LY), respectively. The respective INHBs were 0.21 QALY, -3.11 QALY, and 1.02 QALY, and pembrolizumab-CCRT was exhibited cost-effectiveness opportunities of 62.68%, 12.53%, and 75.23% at the selected WTP threshold, respectively. At current prices, pembrolizumab-CCRT represents a cost-effective alternative for patients with LACC in the USA and China, but not in Italy.

Laparoscopic vs. robotic-assisted laparoscopy in endometrial cancer staging: large retrospective single-institution study

The aim of this study is to analyze and draw the potential differences between the robotic-assisted surgery (RS) and the laparoscopy (LPS) in endometrial cancer staging. In this single-institution retrospective study we enrolled 1,221 consecutive clinical stage I-III endometrial cancer patients undergone minimally invasive surgical staging. We compared patients treated by LPS and by RS, on the basis of perioperative and oncological outcomes (disease-free survival [DFS] and overall survival [OS]). A sub-analysis of the high-risk endometrial cancer population was performed in the 2 cohorts. The 2 cohorts (766 treated by LPS and 455 by RS) were homogeneous in terms of perioperative and pathological data. We recorded differences in number of relapse/progression (11.7% in LPS vs. 7% in RS, p=0.008) and in number of deaths (9.8% in LPS vs. 4.8% in RS, p=0.002). Whereas, univariate and multivariate analyses according to DFS and OS confirmed that the surgical approach did not influence the DFS or the OS. In the multivariable analysis the association of the age and grading was significant for DFS and OS. In the sub-analysis of the 426 high risk EC patients (280 in LPS and 146 in RS) the univariate and the multivariate confirmed the influence of the age in DFS and OS, independently of the minimally invasive approach. In our large retrospective analysis, we confirmed that the RS and LPS have similar efficacy and safety for endometrial cancer staging also for the high-risk endometrial cancer patients.

Lumping and splitting: The need for precision medicine and “personomics” in endometrial cancer

Identification of an immune-related risk signature and nomogram predicting the overall survival in patients with endometrial cancer

Aimed to construct an immune-related risk signature and nomogram predicting endometrial cancer (EC) prognosis. An immune-related risk signature in EC was constructed using the least absolute shrinkage and selection operator regression analysis based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A nomogram integrating the immune-related genes and the clinicopathological characteristics was established and validated using the Kaplan-Meier survival curve and receiver operating characteristic (ROC) curve to predict the overall survival (OS) of EC patients. The Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) R tool was used to explore the immune and stromal scores. CCL17, CTLA4, GPI, HDGF, HFE2, ICOS, IFNG, IL21R, KAL1, NR3C1, S100A2, and S100A9 were used in developing an immune-related risk signature evaluation model. The Kaplan-Meier curve indicated that patients in the low-risk group had better OS (p<0.001). The area under the ROC curve (AUC) values of this model were 0.737, 0.764, and 0.782 for the 3-, 5-, and 7-year OS, respectively. A nomogram integrating the immune-related risk model and clinical features could accurately predict the OS (AUC=0.772, 0.786, and 0.817 at 3-, 5-, and 7-year OS, respectively). The 4 immune cell scores were lower in the high-risk group. Forkhead box P3 (FOXP3) and basic leucine zipper ATF-like transcription factor (BATF) showed a potential significant role in the immune-related risk signature. Twelve immune-related genes signature and nomogram for assessing the OS of patients with EC had a good practical value.

Evaluation of the optimal sequence of adjuvant chemotherapy and radiation therapy in the treatment of advanced endometrial cancer

The optimal sequence of adjuvant chemoradiation in the treatment of advanced endometrial carcinoma (EC) remains unclear. We sought to evaluate the outcomes of patients treated with chemoradiation in sandwich fashion (chemotherapy-radiotherapy-chemotherapy; CRC), versus those treated sequentially (chemotherapy-radiotherapy; CR) (radiotherapy-chemotherapy; RC), to determine if there is a survival advantaged associated with a particular treatment sequence. A multicenter retrospective analysis of patients with stage III and IV EC from 2000-2018 was conducted. Inclusion criteria were patients who had undergone comprehensive surgical staging/tumor debulking; followed by adjuvant chemoradiation. Differences in the frequencies of adverse events were evaluated using Pearson's χ² test. Progression free survival (PFS) and overall survival (OS) rates were calculated using Kaplan-Meier estimates. Final analysis included 152 patients; 36.8% (n=56) CRC, 28.9% (n=44) CR, and 34.2% (n=52) RC. Histology included 44.0% endometrioid, 47.5% serous and 8.5% clear cell tumors. There was no difference in the frequency of histology (p=0.973), stage (p=0.143), cytoreduction status (p=0.932), or treatment delays (p=0.571) between adjuvant therapy sequences. The most frequent location of disease recurrence was abdomen. The median PFS favored CRC versus CR or RC (36-months vs. 22-months and 24-months, respectively) (p=0.038), as did the median OS (48-months vs. 28-months and 34-months, respectively) (p=0.003). CRC demonstrated superiority over CR and RC sequencing in terms 3-year PFS (55% vs. 34% and 37%, respectively) and 3-year OS (71% vs. 50% and 52%, respectively). Adjuvant chemoradiation delivered in CRC sequence was associated with improvements in both PFS and OS compared to alternant therapy sequencing.

Management of stage II endometrial cancer and subsequent oncologic outcomes: a National Cancer Database study

The management of stage II endometrial cancer (EC) is challenging due to the wide variation in surgical practice and adjuvant treatment recommendations. We sought to describe the treatment patterns for patients with stage II EC and to evaluate the association between surgical management and adjuvant therapy on survival outcomes in a large cohort of patients with stage II EC. Using data from the National Cancer Database, we identified 9,690 women with stage II EC. We used logistic regression to identify association of sociodemographic and tumor characteristics with surgery type and receipt of adjuvant therapy. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between adjuvant therapy, hysterectomy type, and overall survival. Almost 11% of the cohort underwent radical hysterectomy; however, there was no difference in survival between surgical types even when adjusted for adjuvant therapy (HR=0.94; 95% CI=0.82-1.07). Compared to no adjuvant treatment, radiation only (HR=0.66; 95% CI=0.61-0.73) and combination radiation and chemotherapy (HR=0.53; 95% CI=0.45-0.62) were associated with lower risk of death. There was no survival benefit of chemotherapy alone even when separated by histologic subtype (HR range, 0.55-1.46). Women with stage II EC do not appear to benefit from routine radical hysterectomy though all patients appear to benefit from receipt of radiation therapy (RT), regardless of modality. Additionally, there may be an added survival benefit with the combination of computed tomography and RT in patients with non-endometrioid, high-risk histologies.

Comments on: Fertility-sparing treatment for intramucous, moderately differentiated, endometrioid endometrial cancer: a Gynecologic Cancer Inter-Group (GCIG) study

Pushing the envelope: expanding fertility sparing treatment of endometrial cancer

Stage III uterine serous carcinoma: modern trends in multimodality treatment

To examine outcomes in a modern treatment era for stage III uterine serous carcinoma (USC). Fifty women were retrospectively identified as 2009 International Federation of Gynecology and Obstetrics stage III USC patients who received radiotherapy (RT) at our institution between 1/2003-5/2018. The patients were divided into 2 cohorts: 20 in the early era (2003-2010) and 30 in the modern era (2011-2018). Patient characteristics were compared using χ² tests for categorical variables and t-tests for continuous variables. Recurrence free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards. The modern era differed from the early era in the increased use of volume-directed external beam RT (EBRT) as opposed to vaginal brachytherapy (VB) alone (33.3% vs 5.0%, p=0.048), minimally invasive surgery (56.7% vs. 25%, p=0.027), sentinel node sampling (26.7% vs. 0%, p=0.012), computed tomography imaging in the perioperative period (63.3% vs. 30%, p=0.044), and human epidermal growth factor receptor 2/ Modern era treatment was associated with improved RFS and OS in patients with stage III USC. Regional nodal recurrences were significantly reduced in patients who received EBRT.

Stage II endometrial cancer requires stratification according to uterine risk factor and sentinel lymph node sampling

Survival and recurrence in stage II endometrial cancers in relation to uterine risk stratification after introduction of lymph node resection and omission of postoperative radiotherapy: a Danish Gynecological Cancer Group Study

To evaluate survival and recurrence in stage II endometrial cancer in relation to uterine risk stratification. Outcome for stage II was compared before and after the introduction of lymph node (LN) resection and omission of all postoperative radiotherapy. The cohort consisted of 4,380 endometrial carcinoma patients radically operated (no visual tumor, all distant metastasis removed) (2005-2012) including 461 stage II. Adjusted Cox regression was used to compare survival and actuarial recurrence rates. Uterine risk factors (low-, intermediate-, and high-) were the strongest predictors of survival and recurrence in stage II. Stage II low-risk having a prognosis comparable to low-risk stage I (grade 1-2, <50% myometrial invasion), whereas cervical invasion significantly increased the risk of recurrence and decreased cancer-specific survival in intermediate- and high-risk compared to the corresponding stage I risk groups. In 355 cases of 708 with cervical stromal invasion, LN-resection showed 27.9% with LN metastasis and upstaged 18.1% from stage II to IIIC resulting in longer survival and lower recurrence in LN-resected compared to non-LN resected stage II. Radical as compared to simple hysterectomy did not alter survival. Treatment with external beam radiotherapy decreased local recurrence without affecting survival. Uterine risk groups are the strongest predictors for survival and recurrence in stage II patients and should be considered when advising adjuvant therapy. LN-resected stage II had increased survival and decreased recurrence. Omitting radiotherapy increase vaginal recurrence without affecting survival.

Prognostic significance of lymphovascular space invasion in patients with endometrioid endometrial cancer: a retrospective study from a single center

This study aims to analyze factors associated with lymphovascular space invasion (LVSI) and evaluate the prognostic significance of LVSI in Chinese endometrioid endometrial cancer (EEC) patients. Five-hundred eighty-four EEC patients undergoing surgery in our center from 2006 to 2016 were selected for analysis. Univariate analysis and multivariate logistic regression were used to examine relevant factors of LVSI. To evaluate the prognostic role of LVSI, survival analyses were conducted. In survival analyses, both multivariate Cox regression and propensity score matching were used to control the confounders. The incidence of LVSI was 12.16% (71/584). Diabetes history (p=0.021), lymph node metastasis (p=0.005), deep myometrial invasion (p<0.001) and negative PR expression (p=0.007) were independently associated with LVSI. Both Kaplan-Meier method and univariate Cox regressions showed LVSI negative and positive cases had similar tumor-specific survival (TSS) and disease-free survival (DFS). After adjusting for the influence of adjuvant therapy and other clinicopathological factors with multivariate Cox regressions, LVSI still could not bring additional survival risk to the patients (p=0.280 and p=0.650 for TSS and DFS, respectively). This result was verified by Kaplan-Meier survival analyses after propensity score matching (p=0.234 and p=0.765 for TSS and DFS, respectively). LVSI does not significantly compromise the survival outcome of Chinese EEC patients.

Survival benefit of radiation in high-risk, early-stage endometrioid carcinoma

To better delineate optimal management of high-risk, early-stage endometrial cancer, as national guidelines permit substantial practice variations. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB grade 3 and stage II endometrioid carcinoma who underwent at least total hysterectomy were identified in SEER-Medicare. Adjuvant treatments were brachytherapy (BT), external beam radiation therapy (EBRT), and chemotherapy. Death from endometrial cancer (cancer-specific mortality [CSM]) and local recurrence were analyzed using Gray's test and Fine-Gray regression. In total, 1,095 patients were identified: 52% received BT, 56% received EBRT, 16% received chemotherapy, and 29% received no adjuvant treatment. Survival outcomes were significantly worse for stage IB grade 3 and stage II grade 3 relative to stage II grades 1-2 (5-year CSM: 18% and 23% vs. 10%; p<0.001 and p=0.003, respectively), while there was no difference between stage IB grade 3 and stage II grade 3 (p=0.618). BT had a local control benefit across all patients (p<0.001) that translated into a survival benefit in stage IB grade 3 (adjusted hazard ratio [HR] for CSM=0.47, p=0.003). EBRT had a survival benefit in stage II grade 3 (adjusted HR for CSM=0.36; p=0.031), as did lymph node dissection (p=0.015). Chemotherapy was not significantly correlated with CSM. High-risk, early-stage endometrioid carcinoma is a heterogeneous population. BT was associated with a survival benefit in stage IB grade 3, whereas regional treatment with EBRT and lymphadenectomy was associated with a survival benefit in stage II grade 3.

Sensitizing endometrial cancer to ionizing radiation by multi-tyrosine kinase inhibition

Endometrial carcinoma is the most frequent gynecological cancer. About 15% of these cancers are of high risk and radiotherapy still remains the most suitable treatment. In this context, agents able to promote radiosensitization are of great interest. Here, we describe for the first time the radiosensitization ability of sunitinib in endometrial carcinoma. Four endometrial carcinoma cell lines were used for the study. The activation of apoptosis signalling pathways and tyrosine kinase receptors were analysed by Western blot, luciferase assays and Immunoprecipitation. Radiosensitization effects were assessed using clonogenic assays. p65 and phosphatase and tensin homolog (PTEN) were upregulated by lentiviral transduction. We discovered that ionizing radiation activates the pro-oncogenic proteins and signalling pathways KIT, protein kinase B (AKT), and nuclear factor kappa B (NF-κB) and these activations were abrogated by sunitinib, resulting in a radiosensitization effect. We found out that AKT pathway is greatly involved in this process as PTEN restoration in the PTEN-deficient cell line RL95-2 is sufficient to inhibit AKT, rendering these cells more susceptible to ionizing radiation and sunitinib-induced radiosensitization. In Ishikawa 3-H-12 cells, radiosensitization effects and inhibition of AKT were achieved by PTEN restoration plus treatment with the phosphoinositide-3-kinase inhibitor LY294002. This suggests that endometrial tumors could have different sensitivity degree to radiotherapy and susceptibility to sunitinib-induced radiosensitization depending on their AKT activation levels. Our results provide the rationale of using sunitinib as neoadjuvant treatment prior radiotherapy which could be a starting point for the implementation of sunitinib and radiotherapy in the clinic for the treatment of recalcitrant endometrial cancers.

A retrospective study for investigating the relationship between old and new staging systems with prognosis in ovarian cancer using gynecologic cancer registry of Japan Society of Obstetrics and Gynecology (JSOG): disparity between serous carcinoma and clear cell carcinoma

International Federation of Gynecology and Obstetrics (FIGO) staging for ovarian, fallopian tube, and peritoneal cancers was revised in 2014. The aim of this study is to clarify whether the revised FIGO2014 staging reflects the prognosis of patients with ovarian cancer by histological type in Japan. We extracted 9,747 patients who were diagnosed with ovarian cancer since 2004 until 2008 and who could be classified into appropriate stages from the Gynecologic Cancer Registry of Japan Society of Obstetrics and Gynecology. These cases were analyzed after revision to FIGO2014 based on the pTNM classification. Among stage I, the 5-year overall survival rate (5y-OS) in FIGO2014 was 94.9% in stage IA, 92.3% in stage IC1, 86.1% in IC2, and 84.9% in IC3 with significant differences between stages IA and IC1 (p=0.012), IC1 and IC2 (p<0.001). There was a significant difference between stages IA and IC1 in clear cell and mucinous carcinoma but not in serous and endometrioid carcinoma. Among stage III, the 5y-OS was 75.6% in stage IIIA1, 68.9% in IIIA2, 58.6% in IIIB, and 44.4% in IIIC, with significant differences between stages IIIA2 and IIIB (p=0.009), IIIB and IIIC (p<0.001). Among stage IV, the 5y-OS was 43.1% in stage IVA* and 32.1% in IVB with a significant difference (p=0.002). The results suggest that changes in classification for stage III and stage IV are appropriate, but the subclassification for stage IC might be too detailed. There was a discrepancy of prognosis by histological type between stage IA and IC1.

Incidence trends for epithelial peritoneal, ovarian, and fallopian tube cancer during 1999–2016: a retrospective study based on the Korean National Cancer Incidence Database

Primary peritoneal cancer (PPC), ovarian cancer (OC), and fallopian tube cancer (FTC) are considered as a single disease group. As knowledge of the pathogenesis and clinical presentation of peritoneal, ovarian, and fallopian tube (POFT) cancer grows, the tendencies in OC diagnosis are changing. We investigate the incidence and clinical characteristics of epithelial POFT based on cancer site and histologic type. Data from the Korea Central Cancer Registry for the period between 1999 and 2016 were analyzed. The incidence rates and annual percent changes (APCs) for each tumor site were reported. Among 27,768 women with cancer, 1,086 (3.91%) had PPC, 25,847 (93.08%) had OC, and 835 (3.01%) had FTC. Age-standardized rates increased from 0.05 to 0.24, 3.51 to 5.48, and 0.04 to 0.28 in PPC, OC, and FTC, respectively. The proportion of PPC and FTC among all the POFT cases increased consistently during the study period (from, respectively, 1.48 and 1.06 in 1999 to 4.52 and 4.76 in 2016). The APC of PPC, OC, and FTC during 1999-2016 was 9.3%, 2.7%, and 8.6%, respectively. The incidence of PPC, OC, and FTC was highest among patients in the 65-69, 50-54, and 55-59 years age group, respectively. The overall incidence of PPC, OC, and FTC cancer has steadily increased. The relative increase of PPC and FTC has been significant. In this study, OC incidence had a relatively young peak age, in contrast to FTC and PPC, which had an older peak age.

Peritoneal dissemination of high-grade serous ovarian cancer: pivotal roles of chromosomal instability and epigenetic dynamics

Epithelial ovarian cancer remains the lethal gynecological malignancy in women. The representative histotype is high-grade serous carcinoma (HGSC), and most patients with HGSC present at advanced stages with peritoneal dissemination. Since the peritoneal dissemination is the most important factor for poor prognosis of the patients, complete exploration for its molecular mechanisms is mandatory. In this narrative review, being based on the clinical, pathologic, and genomic findings of HGSC, chromosomal instability and epigenetic dynamics have been discussed as the potential drivers for cancer development in the fallopian tube, acquisition of cancer stem cell (CSC)-like properties, and peritoneal metastasis of HGSC. The natural history of carcinogenesis with clonal evolution, and adaptation to microenvironment of peritoneal dissemination of HGSC should be targeted in the novel development of strategies for prevention, early detection, and precision treatment for patients with HGSC.

Updated clinical practice guidelines for human papillomavirus vaccination: the Korean Society of Gynecologic Oncology recommendations

The Korean Society of Gynecologic Oncology (KSGO) first developed clinical guidelines for the appropriate administration of human papillomavirus (HPV) vaccines tailored to the Korean context in 2016. In 2019, additional guidelines were introduced following the development of the nonavalent HPV vaccine. The 2021 revision included recommendations for vaccination in middle-aged women and men, as well as the potential benefits of vaccination following conization. In this latest revision, the guidelines focus on the necessity of HPV vaccination in middle-aged men, the Society's position on the single-dose schedule recently recommended by the World Health Organization to expand global vaccine coverage, recommendations regarding additional 9-valent vaccination for those previously vaccinated with bivalent or quadrivalent vaccines, and updated scientific evidence supporting the two-dose schedule for adolescents aged 9 to 14 years.

The situation of gynecological cancers in Thailand: incidence, histopathology, and survival outcomes from national cancer registry data

Cervical, uterine, and ovarian cancers are the 3 main cancers of the female reproductive system. Analyzing data from the cancer registry database will help understand the situation and trends of these diseases. This study utilized data from Thailand's population-based cancer registries covering 16 provinces across 5 geographic regions between 2019 and 2021. Data collection included demographic characteristics, cancer incidence, histopathology, disease stage, and survival outcomes. Incidence rates were calculated using age-standardized rates (ASRs) per 100,000 population, and 5-year survival outcomes were compared across 2 time periods (2013-2017 vs. 2018-2022). During 2019-2021, Thailand recorded a mean annual ASR of 132.9 for females, with cervical cancer remaining the most common gynecologic cancer. The incidence of cervical cancer decreased from 19.5 per 100,000 in 1995-2000 to 10.3 per 100,000 in 2019-2021. Uterine cancer demonstrated a rising trend, from 3.6 per 100,000 in 2004-2006 to 6.1 per 100,000 in 2019-2021, while ovarian cancer incidence remained relatively stable at 5.9 per 100,000. Five-year survival rates improved significantly across all gynecologic cancers in 2018-2022 compared with 2013-2017. The hazard ratios for overall survival by stage ranged from 0.57 to 0.81 for cervical, 0.53 to 0.82 for uterine, and 0.57 to 0.81 for ovarian cancers (all p<0.05). The incidence of cervical cancer in Thailand has declined over the past 2 decades, while the burdens of uterine and ovarian cancers are increasing. Five-year survival rates have significantly improved across all gynecologic cancer types.

Is restaging surgery quintessential in suspected early-stage epithelial ovarian cancer? An ancillary study of the Gynecologic Oncology Research Investigators coLLaborAtion study (GORILLA-3002)

To assess the necessity of restaging surgery for patients with suspected International Federation of Gynecology and Obstetrics (FIGO) stage I-II epithelial ovarian cancer (EOC) following incomplete surgical staging. This multicenter retrospective study evaluated patients with early-stage EOC referred for restaging. These patients were diagnosed with suspected FIGO stage I-II EOC between January 2007 and November 2022 after incomplete surgical staging, and no residual region was confirmed by radiological evaluation. Progression-free survival (PFS) and overall survival (OS) were examined. Among the 173 patients included in the study, 56 were assigned to the no restaging surgery group, and 117 to the restaging surgery group. After restaging, 23 were upstaged to other main stage. However, PFS and OS were not significantly different between the groups, also, dividing the groups into 4 groups who underwent chemotherapy and those who did not also did not show significant differences. In multivariate analysis, histologic grade independently influenced PFS outcomes. While restaging surgery resulted in upstaging in some patients, it was not associated with significant differences in PFS or OS in this retrospective analysis. However, the omission of any additional treatment warrants careful consideration and further discussion. Nevertheless, the observation that patients who did not undergo restaging surgery but received adjuvant chemotherapy did not show significantly different prognoses highlights the need for further research to establish appropriate treatment strategies tailored to diverse patient contexts.

Risk factors associated with overall survival in patients with cervical cancer: a prospective cohort study in Western China comparing random survival forest and Cox proportional hazards models

Cervical cancer (CCa) significantly affects female fertility and quality of life. This study aimed to construct and validate a random survival forest (RSF) model to identify the factors that affect the overall survival (OS) in patients with CCa in China and compare its performance with that of the Cox proportional hazards model (Cox model). Data on CCa patients were collected from Chongqing University Cancer Hospital. The performance and discrimination ability of the models were evaluated via the C-index, integrated Brier score (IBS), accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). The Kaplan-Meier (K-M) survival curve was used to analyze the difference in OS between patients with high and low risk predicted by RSF model. A total of 3,982 patients were included in this study. Comparing to Cox model, the RSF model ranked important variables and identified radiotherapy (RT) as an important treatment measure. A comprehensive analysis of the evaluation indices confirmed that the RSF model outperformed the Cox model (IBS: 0.152 vs. 0.162, C-index: 0.863 vs. 0.764). The RSF model metrics for the validation cohort (VC) were as follows: 1-, 3-, and 5-year AUC (0.908, 0.884, and 0.869), sensitivity (0.746), specificity (0.825), and accuracy (0.808). The OS of low-risk patients predicted by RSF was greater than that of high-risk patients. The RSF model demonstrated excellent discrimination, calibrated predictions, and stratified risk for CCa patients. Furthermore, it outperformed the Cox model in predicting risks, thus enabling the delivery of personalised treatment and follow-up strategies.

Management for perioperative complications of diaphragmatic surgery in ovarian cancer at a Chinese tertiary cancer center

Diaphragm is the common site of metastasis in advanced ovarian cancer. Diaphragmatic surgery is necessary to achieve complete resection. Relative complications also pose challenges to perioperative management. This study aims to explore the influencing factors and management strategies for perioperative complications of diaphragm surgery. This study retrospectively included 396 patients who underwent diaphragmatic surgery for advanced ovarian cancer at Fudan University Shanghai Cancer Center from July 2015 to June 2022. Diaphragm surgical methods were classified, and perioperative complications were regarded according to Memorial Sloan Kettering Cancer Center criteria. Clinical characteristics and perioperative complications were analyzed to find correlations to establish the nomogram. Among the 396 patients, 163 patients (41.2%) suffered from perioperative complications. Pleural effusion (33.1%) and pneumothorax (5.3%) were the most commonly reported. Patients with longer surgery duration (>3 hours) (p=0.003) and who underwent diaphragmatic incision surgery (p=0.004) had a higher incidence of postoperative complications. The incidence of postoperative pleural effusion was significantly higher in patients who underwent diaphragm full-thickness resection (49.3%) than diaphragmatic stripping (29.5%) (p=0.001), and patients who underwent diaphragm full-thickness resection are more likely to require drainage (p=0.001). Multi-variate analyses showed that stage IV tumor, long operation time, and diaphragm full-thickness resection are associated with postoperative pleural effusion. Pleural effusion is the most common complication of diaphragmatic surgery in patients with ovarian cancer. Routine placement of prophylactic chest tubes is not appropriate for all patients undergoing diaphragmatic surgery. Our nomogram could help to predict its risk and indicate prophylactic management.

Practice guideline for management of endometrial cancer in Thailand: a Thai Gynecologic Cancer Society consensus statement

The Thai Gynecologic Cancer Society (TGCS) continues its efforts to elevate the standard of practice of gynecologic oncologists across all regions of Thailand. A key initiative involves collaborating with the Royal Thai College of Obstetricians and Gynaecologists and the National Cancer Institute, Thailand to regularly update and release clinical practice guidelines (CPGs) for gynecologic cancer. The TGCS released the first CPG for endometrial cancer (EMC) in 2011. Following significant advancements in disease understanding and the major revision of EMC staging by the International Federation of Gynecology and Obstetrics in 2023, national experts collaborated to update the guideline for EMC. The key components of the CPG for EMC covered screening, diagnostic indications and methods, primary treatment including surgical approaches and procedures, pathological processes, adjuvant therapies, and the management of recurrent and advanced diseases through medical or surgical means. The guideline was based on scientific evidence, recommendations from international organizations, and the unique healthcare context of Thailand. The final version reflects a consensus reached through extensive discussions among TGCS members. To share our work with international organizations and healthcare professionals, an English version of the CPG was developed. While it mirrors the content of the Thai version, it differs in length and level of detail. The English version additionally included the level of evidence and a recommendation summary for each section, reflecting common domestic practices, available resources, and coverage under health reimbursement systems.

Prognostic values of tumor size and location in early stage endometrial cancer patients who received radiotherapy

To investigate the correlation between tumor size, tumor location, and prognosis in patients with early-stage endometrial cancer (EC) receiving adjuvant radiotherapy. Data of patients who had been treated for stage I-II EC from March 1999 to September 2017 in 13 tertiary hospitals in China was screened. Cox regression analysis was performed to investigate associations between tumor size, tumor location, and other clinical or pathological factors with cancer-specific survival (CSS) and distant metastasis failure-free survival (DMFS). The relationship between tumor size as a continuous variable and prognosis was demonstrated by restricted cubic splines. Prognostic models were constructed as nomograms and evaluated by Harrell's C-index, calibration curves and receiver operating characteristic (ROC) curves. The study cohort comprised 805 patients with a median follow-up of 61 months and a median tumor size of 3.0 cm (range 0.2-15.0 cm). Lower uterine segment involvement (LUSI) was found in 243 patients (30.2%). Tumor size and LUSI were identified to be independent prognostic factors for CSS. Further, tumor size was an independent predictor of DMFS. A broadly positive relationship between poor survival and tumor size as a continuous variable was visualized in terms of hazard ratios. Nomograms constructed and evaluated for CSS and DMFS had satisfactory calibration curves and C-indexes of 0.847 and 0.716, respectively. The area under the ROC curves for 3- and 5-year ROC ranged from 0.718 to 0.890. Tumor size and LUSI are independent prognostic factors in early-stage EC patients who have received radiotherapy. Integrating these variables into prognostic models would improve predictive ability.

FOLR1 as a therapeutic target in platinum-resistant ovarian carcinoma: unique expression patterns across ovarian carcinoma histotypes and molecular subtypes of low-grade serous carcinoma

With the development of novel antibody-drug conjugates (ADCs), folate receptor alpha (FOLR1) is a promising therapeutic target for the treatment of platinum-resistant tubo-ovarian carcinomas. The main aims of this study were to assess FOLR1 protein expression in a large cohort of ovarian carcinoma histotypes. To inform future clinical trial design we identified molecular correlates of FOLR1 expression in low-grade serous carcinoma (LGSC). One thousand five hundred forty-seven ovarian carcinoma samples from 5 different Canadian cohorts were successfully evaluated by immunohistochemistry for FOLR1 expression using the PS2+ system. Statistical analyses with clinicopathological parameters, LGSC molecular subtypes, and overall survival (OS) were performed. High FOLR1 expression was detected in 44% of high-grade serous carcinomas, and in 30% LGSC, 8% clear cell, 6% endometrioid, and 0% mucinous and/or mesonephric-type adenocarcinomas. In 160 LGSC cases, FOLR1 expression was more frequent in cases with normal MAPK pathway status (37% MAPK wild type vs. 14% canonical MAPK pathway mutations; p=0.002), low progesterone receptor (PR) expression (41%) vs. 23% (Allred score >2; p A significant proportion of LGSC express high FOLR1 levels supporting the development of clinical trials to investigate ADCs targeting FOLR1 as novel agents for treating this disease. In LGSC, high FOLR1 expression was associated with fewer MAPK pathway alterations, low PR expression, and p16 loss.

Current peritonectomy practice during debulking surgery in patients with newly diagnosed advanced ovarian cancer: a Korean Gynecologic Oncology Group Study (KGOG 4004)

Because of the possible therapeutic benefit of removing occult tumor cells, a source of recurrence and chemoresistance, total parietal peritonectomy (TPP) is an alternative treatment for advanced epithelial ovarian/fallopian tube/primary peritoneal cancer. Interventional studies comparing TPP with selective parietal peritonectomy (SPP) are in progress. Since surgeons skilled in TPP are essential for such trials to be conducted, this nationwide survey aimed to examine current peritonectomy practice among gynecologic oncologists in Korea. A 17-item questionnaire, developed by a surgery committee and reviewed by the scientific review board of the Korean Gynecology Oncology Group (KGOG), was distributed to 144 KGOG members. The questionnaire was divided into 3 categories: respondent demographics, peritonectomy practice during primary debulking surgery (PDS), and peritonectomy practice during interval debulking surgery (IDS). We received 88 (61.1%) valid responses. Of the valid respondents, 98.9% and 93.8% performed SPP during PDS and IDS, respectively. Only 4.9% of the respondents performed TPP during IDS. Most respondents performed peritonectomy in cases where optimal postoperative outcomes were expected. Approximately 50.6% of the respondents had performed peritonectomy independently, while the others did so in cooperation with non-gynecologic surgeons. The primary reasons for not performing TPP were concerns about morbidity and uncertainty about the clinical benefits of the procedure. SPP is the predominant technique used in both PDS and IDS in Korea. A small percentage (4.9%) of gynecologic oncologists have performed TPP during IDS. Accordingly, a study regarding the feasibility of TPP should be conducted before proceeding with a prospective clinical trial.

Cost-effectiveness of HPV catch-up vaccination program in women aged 13–24 years in a middle income country

This study evaluated the cost-effectiveness of expanding the current routine human papillomavirus (HPV) vaccination program to women aged 13-24 years in Thailand. A Markov model of HPV infection and cervical cancer was adapted. We compared catch-up cohorts of 13- to 24-year-old women vaccinated with (1) bivalent HPV vaccine (Cervarix Compared to no vaccination, the catch-up vaccination programs decreased the incidence of cervical cancer cases and cancer-related deaths 44.8%-63.4% over a lifetime. Vaccinating with 2vHPV (Cervarix All catch-up vaccination programs for women aged 13 to 24 years produce additional health benefits and reduce healthcare costs. Vaccination with 9vHPV was considered the most cost-effective option.

A novel non-invasive mRNA-lncRNA biomarker panel for accurate prediction of cervical squamous cell carcinoma and adenocarcinoma

Squamous cell carcinoma (SCC) and adenocarcinoma (ADC) represent predominant histological subtypes of cervical cancer. To improve screening efficacy, we leveraged RNA sequencing data from 4 cervical SCC samples, 4 cervical ADC samples, and 8 normal cervix samples and conducted a comprehensive mRNA and long noncoding RNA (lncRNA) profiling analysis followed with a multi-phase study comprising 556 samples. Validating the RNA sequencing data in a clinical sample set comprising 45 normal cervix tissues, 45 SCC tissues, and 45 ADC tissues, we identified 9 mRNAs (SMC1B, OTX1, GRP, CELSR3, HOXC6, ITGB6, WDR62, SEPT3, and KLHL34) and 4 lncRNAs (FEZF1-AS1, LINC01305, LINC00857, and LINC00673) differentially expressed in both SCC and ADC samples. Utilizing quantitative reverse transcription polymerase chain reaction analysis and receiver operating characteristic (ROC) curve analysis in a training set (45 normal, 126 SCC, and 82 ADC tissues), we refined a novel mRNA-lncRNA-based panel (SMC1B/CELSR3/FEZF1-AS1/LINC01305). Employing logistic regression model and ROC analysis, this panel exhibited significant distinctions and promising area under the curve (AUC) values in both SCC (AUC=0.9520, p<0.0001) and ADC (AUC=0.9748, p<0.0001) tissues. Subsequent validation in an independent set (11 normal, 32 SCC, and 20 ADC tissues) demonstrated its diagnostic accuracy in both SCC (AUC=0.9659, p<0.0001) and ADC (AUC=0.9636, p<0.0001) patients. Notably, this tissue-based biomarker panel robustly discriminated precancerous lesion and cervical cancer patients from non-disease controls in a blood-based validation set (30 normal, 25 HSIL and 50 cervical cancer) with an AUC value of 0.9320. This study presents a non-invasive, efficient diagnostic panel for cervical cancer screening.

Efficacy and safety of immune checkpoint inhibitors with chemoradiotherapy/chemotherapy in locally advanced cervical cancer patients: a systematic review and single-arm meta-analysis

Recent advancements highlight promising outcomes with immune checkpoint inhibitors (ICIs) when combined with concurrent chemoradiotherapy (CCRT) or chemotherapy in the treatment of locally advanced cervical cancer (LACC). This systematic review and meta-analysis aimed to assess the efficacy and safety of ICIs combined with CCRT/chemotherapy in patients with LACC. We searched PubMed, Embase, Cochrane and ClinicalTrials.gov for randomized controlled trials (RCTs) and non-RCTs assessing the efficacy and safety of ICIs plus CCRT/chemotherapy in patients with LACC. All analyses were performed in R software (v.4.4.0). Our systematic review and meta-analysis included 3 RCTs and 4 observational studies, corresponding to 1,250 patients. The 1-year progression-free survival (PFS) was 78% (95% confidence interval [CI]=75-80, I²=0%), while the 1-year overall survival (OS) reached 93% (95% CI=89-95, I²=50%). The objective response rates were 88% (95% CI=74-95, I²=74%). We performed a comparative analysis of PFS and OS using data from the 2 RCTs. The results indicated that the ICI plus CCRT group had a significantly lower risk of disease progression or death compared to the CCRT group alone (PFS: hazard ratio [HR]=0.76, 95% CI=0.64-0.91, I²=4%; OS: HR=0.76, 95% CI=0.58-0.98, I²=0%), representing an approximate 25% reduction in risk. The analysis of grade ≥3 adverse events revealed the low incidences, with none exceeding 15%. Our findings suggest that ICIs are effective and safe to use with CCRT/chemotherapy in LACC patients. Further RCTs are needed to confirm these findings. International Prospective Register of Systematic Reviews Identifier: CRD42024576145.

SLAMF7 predicts prognosis and correlates with immune infiltration in serous ovarian carcinoma

Signaling lymphocytic activation molecule family members (SLAMFs) play a critical role in immune regulation of malignancies. This study aims to investigate the prognostic value and function of SLAMFs in ovarian cancer (OC). The expression analysis of SLAMFs was conducted based on The Cancer Genome Atlas Ovarian Cancer Collection (TCGA-OV) and Gene Expression Omnibus (GEO) databases. Immunohistochemistry (IHC) was further performed on tissue arrays (n=98) to determine the expression of SLAMF7. Kaplan-Meier plotter and multivariate Cox regression model were used to evaluate the correlation of SLAMF7 expression with survival outcomes of patients. The molecular function of SLAMF7 in OC was further investigated using Gene Set Enrichment Analysis (GSEA). SLAMF7 mRNA expression were significantly upregulated in OC tumor tissue compared to normal tissue. IHC revealed that SLAMF7 expression was located in the interstitial parts of tumor tissue, and higher SLAMF7 expression was associated with favorable survival outcomes. GSEA demonstrated that SLAMF7 is involved immune-related pathways. Further analysis showed that SLAMF7 had a strong correlation with the T cell-specific biomarker (CD3) but not with the B cell (CD19, CD22, and CD23) and natural killer cell-specific biomarkers (CD85C, CD336, and CD337). Furthermore, IHC analysis confirmed that SLAMF7 was expressed in tumor-infiltrating T cells, and the IHC score of SLAMF7 was positively correlated with CD3 (r=0.85, p<0.001). SLAMF7 is expressed in the interstitial components of clinical OC tissue, and higher SLAMF7 expression indicated a favorable prognosis for patients with OC. Additionally, SLAMF7 is involved in T-cell immune infiltration in OC.

Comparison of carboplatin-based chemotherapy versus cisplatin-based chemotherapy in the treatment of malignant gonadal germ cell tumor: a systematic review and meta-analysis

To evaluate the role of carboplatin-based chemotherapy in patients diagnosed with malignant gonadal germ cell tumors (GCTs), we conducted a systematic review and meta-analysis. We searched PubMed, MEDLINE, Embase, Cochrane library, and Web of Science. Randomized controlled trials or cohort studies on gonadal GCTs between January 1, 1970 and April 26, 2023 were enrolled. The treatment failure rate and mortality rate were the primary outcomes. Subgroup analysis based on the primary tumor site and dose of carboplatin was also conducted. In total, 8 studies with 1,409 patients were included. Compared to cisplatin-based chemotherapy, carboplatin-based chemotherapy had an increased treatment failure rate (odds ratio [OR]=2.23; 95% confidence interval [CI]=1.61-3.08; p<0.001), but similar overall survival outcomes (OR=1.68; 95% CI=0.61-4.61; p=0.315). Subgroup analysis revealed that carboplatin-based chemotherapy did not increase the risk of treatment failure and death in ovarian GCT, while a higher risk of treatment failure and a similar risk of death were observed in testicular GCT. Patients treated with high-dose carboplatin calculated 400 or 600 mg/m² (area under the curve=7.9) obtained similar failure-free survival to the cisplatin group (OR=0.84; 95% CI=0.40-1.73; p=0.629). Compared to the cisplatin group, milder nausea and vomiting, nephrotoxicity, ototoxicity, and more severe myelosuppression were observed in the carboplatin group. In conclusion, carboplatin-based chemotherapy achieves a comparable overall survival outcome to cisplatin-based chemotherapy in gonadal GCT patients, suggesting that carboplatin is a candidate substitute for cisplatin. The efficacy of carboplatin is dose-dependent. High-dose carboplatin can obtain better therapeutic effects with more tolerable toxicities than cisplatin.

Ovarian squamous cell carcinoma: clinicopathological features, prognosis and immunotherapy outcomes

To explore the characteristics and survival outcomes of ovarian squamous cell carcinoma (SCC) and the treatment effectiveness of immune checkpoint inhibitors (ICIs). Patients diagnosed with ovarian SCC at Peking Union Medical College Hospital between January 2000 and September 2023 were included. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method. Univariate and multivariate analysis of OS were performed using the Cox proportional hazards model. A total of 42 patients were included, with a median age of 51.5 years (range, 23-74). The majority had SCC arising from teratomas (54.8%), followed by endometriosis (14.3%) and Brenner's tumor (2.4%). Patients undergoing molecular testing exhibited a median tumor mutation burden (TMB) of 10.00 mutations/Mb (range, 7.28-46.86), predominantly featuring The prognosis for ovarian SCC remains unfavorable. The stage and age were prognostic predictors for survival. ICIs may be beneficial for patients with ovarian SCC, particularly those with a high TMB.

UPF1 inhibits cervical cancer cell migration and invasion by regulating nonsense-mediated decay of BMP6 and lncRNA WAKMAR2

Up-frameshift protein 1 (UPF1) can contribute to the progression of a variety of cancers. Currently, there is limited research on UPF1 in cervical cancer, and further investigation is necessary to understand its regulatory mechanisms in cervical cancer. mRNA expression was detected by quantitative real-time polymerase chain reaction, while protein expression was quantified by western blotting assay. Cell function was assessed by cell counting kit-8 assay, Transwell assay and wound-healing assay. A xenograft mouse model assay was performed to analyze the effect of UPF1 silencing on tumor formation. Differentially expressed genes in cell samples were screened using the R Bioconductor package DESeq2. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis was performed to determine the functional categories of the differentially expressed genes. UPF1 expression was downregulated in cervical cancer tissues and cells. Additionally, UPF1 silencing promoted invasion and migration of cervical cancer cells and tumor formation. There were a total of 188 upregulated genes in the SiHa cells after UPF1 silencing. Biological analysis showed that these upregulated genes were enriched in pathways related to regulation of cell proliferation, positive regulation of gene expression, cell adhesion, and Hippo signaling pathway. Additionally, UPF1 depletion promoted SiHa cell proliferation, invasion and migration, whereas the effects were attenuated after silencing of bone morphogenetic protein 6 ( UPF1 inhibited cervical cancer cell migration and invasion through the regulation of nonsense-mediated decay of

The activity of immune checkpoint inhibitors in patients with recurrent cervical cancer developed in previously irradiated field: clinical and immunohistochemical investigations

We aimed to 1) evaluate the efficacy of immune checkpoint inhibitors (ICIs) in cervical cancer patients according to the site of disease, 2) investigate the mechanism responsible for differential ICIs sensitivities with focuses on CD8⁺ T lymphocytes and programmed death-ligand 1 (PD-L1) expression. We retrospectively reviewed clinical data from patients with recurrent or metastatic cervical cancer treated with pembrolizumab or cemiplimab between January 2019 and January 2024 (clinical cohort). Target diseases were classified according to the site of diseases: within previously irradiated field (in-field diseases), out-of-field diseases, and both. Immunohistochemical investigations were performed using paired tumor samples (i.e. initial cervical tumor and locally-recurrent tumor developed after definitive radiotherapy: Immunohistochemical cohort). Survival rates were estimated using the Kaplan-Meier method and compared using the log-rank test. Fifty patients treated with pembrolizumab-containing chemotherapies (n=39) or cemiplimab (n=11) were assessed. Of these, six patients (12.0%) had in-field diseases alone, twenty-eight patients (56.0%) had out-of-field diseases, and the remaining sixteen (32%) patients had both types of diseases. In-field diseases demonstrated a significantly lower response rate compared to out-of-field diseases (36.3% vs. 72.7%, p=0.004). Patients with in-field diseases demonstrated significantly shorter progression-free survival (p=0.003) and overall survival (p=0.003) than those with out-of-field diseases. In-field diseases were associated with decreased tumor-infiltrating CD8⁺ T lymphocytes and PD-L1 expression. In-field cervical cancer recurrence was associated with decreased sensitivity to ICIs-containing chemotherapies when compared to out-of-field diseases. Decreased tumor-infiltrating CD8⁺ T lymphocytes and PD-L1 expression are possible reasons for this differential sensitivity to ICI-containing chemotherapies.

Suppressor of TCR signaling 2 (Sts-2) as a potential immunotherapy target and prognostic biomarker in cervical cancer

More efficient immune targets are needed for the treatment of cervical cancer. This study aimed to identify potential targets for immunotherapy and prediction in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) by conducting bioinformatics analysis and verifying the results with clinical tissue samples. A retrospective analysis of RNA sequencing data from 304 patients sourced from The Cancer Genome Atlas (TCGA) and another 300 patients from the Gene Expression Omnibus (GEO) was performed to investigate the correlation between suppressor of TCR signaling 2 (Sts-2) expression and clinical parameters in cervical cancer. To authenticate our findings, we utilized a combination of immunohistochemistry, quantitative polymerase chain reaction, and western blotting techniques in a separate cohort consisting of 6 cervical cancer tissue samples. The Sts-2 gene was discovered to be substantially co-expressed with a multitude of immune checkpoint molecules, including programmed cell death protein 1 (r=0.8, p<0.001), TIGIT (r=0.87, p<0.001), LAG3 (r=0.71, p<0.001), and CTLA4 (r=0.74, p<0.001), in CESC patients. Both the TCGA and GEO datasets have independently validated that Sts-2 expression levels significantly correlate with overall survival rates, thus demonstrating its prognostic importance. A single-gene Gene Set Enrichment Analysis indicated that Sts-2 was highly enriched in T cell-related immune pathways. Moreover, using the Tumor Immune Dysfunction and Exclusion algorithm, it was suggested that high Sts-2 expression might predict a more favorable response to immunotherapy. The heightened expression of Sts-2 serves as a dual indicator of elevated T cell content and a favorable prognosis in cervical cancer.

Relationship between the lateral dissection lines of various radical hysterectomies and anatomical structures in the female pelvis: an educational video from the Sapporo Cadaver Surgical Workshop

Radical hysterectomy with pelvic lymph node dissection is the treatment of choice for cervical cancer. All gynecologic oncologists should master this technique. The surgical procedure requires a wide dissection of the female pelvis. Performing radical hysterectomy without a thorough knowledge of the anatomy of the female pelvis can lead to serious complications. For novice surgeons to safely perform radical hysterectomy, mastering the 3-dimensional anatomy of the pelvis and aligning the dissection lines of radical hysterectomy to the female pelvic anatomy is crucial. Educational materials that demonstrate the anatomical relationship between dissection lines in radical hysterectomy and the surrounding pelvic structures are lacking. We aimed to create educational material to overcome these problems. Laparoscopic nerve sparing, non-nerve sparing, and super-radical hysterectomies, exposing pivotal pelvic anatomical structures, were performed on a Thiel-embalmed cadaver. Nerve sparing, non-nerve sparing, and super-radical hysterectomies were laparoscopically performed in the right hemi-pelvis of the cadaver. We exposed the external and internal iliac vessels; obturator, sciatic, femoral, hypogastric, and pelvic splanchnic nerves and the pelvic nerve plexus; internal obturator, piriform, and coccygeal muscles; sacrospinous ligament; and ischial spine. Thus, we demonstrated where the dissection lines of the various radical hysterectomies are in a female pelvis. Using a Thiel-embalmed cadaver, we demonstrated the relationship between the dissection lines of various radical hysterectomies and pivotal sidewall anatomical structures in a female pelvis. The anatomical detail shown in the video captured during this procedure may assist surgeons to safely perform various radical hysterectomies.

Comparison of outcomes of laparotomic and minimally invasive radical hysterectomy in women with early-stage cervical cancer

This study compared the outcomes of laparotomic radical hysterectomy (LRH) and minimally invasive radical hysterectomy (MISRH) in patients with early-stage cervical cancer. The clinical data of patients with early-stage cervical cancer who underwent LRH or MISRH (laparoscopic/robotic) at Chang Gung Memorial Hospital, Linkou Branch, from 2002 to 2017 were retrospectively reviewed. The surgical safety (operation time, blood loss, blood transfusion rate, length of postoperative stay, and perioperative complications), overall survival (OS), disease-free survival (DFS), and recurrence pattern were analyzed. Propensity score matching (PSM) at a 3:1 ratio was performed to balance prognostic variables. Of the 760 patients (entire cohort), 614 underwent LRH and 146 underwent MISRH. After PSM, 394 and 140 patients were included in the LRH and MISRH groups, respectively. The 5-year OS rate was significantly lower in the MISRH group than in the LRH group (85.6% vs. 93.2%, p=0.043), and the 5-year DFS rate (p=0.21) did not differ significantly. After PSM, the 5-year OS rates did not differ significantly between the MISRH and LRH groups (87.1% vs. 92.1%, p=0.393). The MISRH group had a significantly shorter operation time (p<0.001), lower intraoperative blood loss (p<0.001), lower blood transfusion rate (p<0.001), and shorter postoperative stay (p<0.001) but a significantly higher rate of intraoperative bladder injury (p<0.001) than the LRH group. After PSM, MISRH is associated with nonsignificantly lower OS but a significantly higher risk of intraoperative urological complications than LRH.

Safety and efficacy of radical hysterectomy based on embryo development-originated in the treatment of early cervical cancer: a single-arm meta-analysis

Cervical cancer is the leading malignancy in terms of both incidence and mortality among cancers of the female reproductive system, and initial surgical treatment is still one of the main treatments. However, for many years, radical hysterectomy based on traditional anatomical principles has failed to substantially improve oncological outcomes for cervical cancer patients or reduce the incidence of perioperative complications. In recent years, radical surgery grounded in the membrane anatomy concept of embryonic development has demonstrated promising oncological outcomes in colorectal cancer surgery. Research in the field of cervical cancer, however, remains in its early stages, although it is steadily garnering increased attention. Consequently, this meta-analysis seeks to systematically assess the safety and efficacy of radical hysterectomy, rooted in embryonic developmental principles, for the treatment of early-stage cervical cancer. This study systematically searched PubMed, Embase, Cochrane Library, Web of Science, Wanfang, and CNKI databases for relevant studies published from their inception to October 2024. Data on 5-year recurrence-free survival (RFS), overall survival (OS), and surgical complications were collected for further analysis. Eight studies involving 1,226 patients were included in the meta-analysis. The surgical complication rate was 35.2%. Two studies reported a 5-year RFS of 86% and an OS of 88%. Radical hysterectomy based on embryo development-originated shows good safety and efficacy in treating early-stage cervical cancer. PROSPERO Identifier: CRD42024602098.

The necessity of adjuvant surgery for patients with high-risk chemorefractory or relapsed gestational choriocarcinoma with complete remission after anti-PD-1 therapy

Anti-programmed cell death protein 1 (PD-1) therapy has demonstrated favorable therapeutic responses in patients with chemorefractory gestational trophoblastic neoplasia. The need for combined surgery to remove resistant foci in patients treated with anti-PD-1 therapy after complete remission (CR), however, has not been investigated. We therefore compared the prognosis of patients with high-risk chemorefractory or relapsed choriocarcinoma who underwent anti-PD-1 therapy with or without surgery. Patients with high-risk chemorefractory or relapsed choriocarcinoma who experienced CR following immunotherapy in conjunction with either surgical or non-surgical interventions were selected at Peking Union Medical College Hospital (PUMCH) between August 2018 and December 2023. Study endpoints included progression-free survival (PFS) and overall survival (OS). The results were analyzed using Mann-Whitney U tests and Kaplan-Meier analysis. Forty-three patients who received andi-PD-1 therapy were enrolled in this study, including 18 patients with surgery and 25 without. Most of the foci in the surgery group were solitary (77.8%). The median maximum diameters of resistant foci before immunotherapy were 2.9 (0.7-7.3) cm and 1.4 (0.8-11.2) cm in the surgery and non-surgery groups, respectively (p=0.184). The 2-year PFS rate was both 91.5% in the non-surgery group and 90.9% in the surgery group. The 2-year and 3-year OS rates were 100.0% in both groups. There was no significant difference in PFS (p=0.849) or OS (p=0.371) between the 2 groups. These results suggest that surgical resection of drug-resistant lesions may not be necessary in patients with high-risk chemorefractory or relapsed choriocarcinoma who achieve CR after anti-PD-1 therapy.

Prevalence of high-risk human papillomavirus genotypes among women in Uzbekistan, 2021–2023

Cervical cancer remains a significant global health concern. Extensive research has established a critical link between human papillomavirus (HPV) infection and the development of cervical cancer. As a result, high-risk HPV (Hr-HPV) testing has emerged as a promising screening method. This study aimed to retrospectively analyze the prevalence of Hr-HPV genotypes among women in three regions of Uzbekistan. Between 2021 and 2023, the Research Institute of Virology of Uzbekistan and the Korea Foundation for International Healthcare conducted a comprehensive population-based study in Tashkent, Andijan, and Samarkand. The study targeted 43,921 women aged 20 and above, utilizing real-time polymerase chain reaction to investigate the prevalence of 12 Hr-HPV genotypes. The analysis included an examination of the distribution of these genotypes based on age, region, and various demographic factors. The overall prevalence of Hr-HPV among women aged 20 and above in Uzbekistan was 7.4%. Regional variations were observed and Hr-HPV prevalence was higher in individuals in their 20s than in other age groups in all 3 regions (p<0.001). The proportion of HPV 16 and 18 was 32.5% and 6.4% in the single infections, 41.9% and 14.7% in the double infections, and 59.3% and 20.0% in the multiple infections. There were also significant differences in prevalence across demographic factors, such as marital status, parity, current smoking, and contraceptive method (p<0.005). The findings emphasize the importance of early screening and educational initiatives, particularly targeting young and co-infected women. This foundational data aims to improve women's health strategies in Uzbekistan.

Adherence of PARP inhibitor for frontline maintenance therapy in primary epithelial ovarian cancer: a cross-sectional survey

To identify the adherence rate to poly (ADP-ribose) polymerase (PARP) inhibitors and identify factors contributing to the deterioration of adherence at our institution. The adherence rate to PARP inhibitors was calculated using self-reported Adherence to Refills and Medications Scale questionnaires from a cross-sectional survey. Multivariable logistic regression analysis was performed to identify the factors that affected adherence. Of the 131 respondents, 32 (24.4%) showed non-adherence to PARP inhibitors. In the multivariable logistic regression analysis, unemployed or retired status (odds ratio [OR]=4.878; 95% confidence interval [CI]=1.528-15.572; p=0.008), patients receiving niraparib (OR=3.387; 95% CI=1.283-8.940; p=0.014), and a lower score on the quality-of-life assessment (EORTC-QLQ-OV28), which reflects a better quality of life (QOC) with a lower symptom burden (OR=1.056; 95% CI=1.027-1.086; p<0.001) were associated with high adherence to PARP inhibitors. Approximately one-fourth of patients with ovarian cancer are non-adherent to PARP inhibitors as maintenance treatment for newly diagnosed advanced ovarian cancer. The occupational status, type of PARP inhibitor, and QOC may affect adherence to PARP inhibitors.

Pan-cancer analysis of ARNT2 and its oncogenic role in cervical cancer

This study aims to elucidate the role of aryl hydrocarbon receptor nuclear transporter 2 (ARNT2) in cervical cancer (CC) and explore the potential mechanism by which ARNT2 promotes the progression of CC through the protein phosphatase 2A (PP2A)/Akt signaling pathway. Bioinformatics tools were used to analyze the expression level of ARNT2 in cancer and its correlation with cancer prognosis. Western Blot and immunohistochemistry staining were used to detect the expression of ARNT2 protein in CC tissues and cells. ARNT2 was knocked down in SiHa and HeLa cells, respectively. Cell Counting Kit-8 assay and colony formation assay were used to detect changes in cell proliferation. Transwell assay and plate scratch assay were used to detect changes in cell migration and invasion. Western Blot assay was used to detect changes in the expression of PP2A/Akt signaling pathway after ARNT2 expression was downregulated. Finally, a CC xenograft tumor model was constructed to evaluate the effect of ARNT2 on SiHa cell tumorigenesis in vivo. ARNT2 is highly expressed in tumor tissues and cell lines. ARNT2 knockdown can significantly inhibit the proliferation, invasion and migration of SiHa and HeLa cells in vitro and in xenograft models. Further studies have shown that ARNT2 may promote tumor formation by regulating the PP2A/Akt pathway. ARNT2 promotes the malignant biological behavior of CC cells through the PP2A/Akt signaling pathway, confirming its potential as a prognostic marker for CC.

Application value of personalized 3D printing vaginal model for the Image-guided adaptive brachytherapy of cervical cancer

To explore the application value of using 3-dimensional (3D) printing (3DP) technology to create individualized vaginal molds for brachytherapy (BT) in high-dose-rate 3D cervical cancer through reverse engineering of needle placement. Prospectively, 11 patients with cervical cancer were treated with 3DP-intracavitary/interstitial (IC/IS) BT using 3DP to create individualized vaginal molds. All patients were performed BT after completion of external beam radiotherapy (EBRT). Each patient was treated with BT 5 times, the prescription dose was 600 cGy/F, which was performed once or twice a week, 2 of them were freehand IC/IS BT, and 3 were 3DP-IC/IS BT. The relevant planning parameters (bladder, rectum, sigmoid colon, and small intestine) and target conformity index (CI) for high-risk clinical target volume (HR-CTV) and organs at risk (OARs) were compared between the groups. There were significant advantages in the 3DP-IC/IS BT group compared with the freehand IC/IS BT group: HR-CTV D Compared with IC/IS BT, 3DP-IC/IS BT has apparent advantages with simple operation and high safety. In addition, individualized mold helps to improve the tumor target area's radiation dose while meeting the dose-limiting requirements for organs at risk and reduces the clinical proficiency requirements for operating physicians.

Molecular subtypes and quantitative analysis of PD-L1 and tumor-associated immune cells in uterine carcinosarcoma

In the present study, molecular subtypes were determined, programmed death-ligand 1 (PD-L1) and tumor-associated immune cells (TAICs) were quantitatively detected, and their effect on prognosis in uterine carcinosarcoma (UCS) was analyzed. The study included 65 UCS cases. Direct sequencing of POLE exonuclease domain and immunohistochemistry of mismatch repair (MMR) deficiency proteins and p53 were used to stratify molecular subtypes. QuPath was used for quantitative immunohistochemical detection of PD-L1 and TAICs. The chi square test was used to determine the association between molecular subtypes and expression of PD-L1 and TAICs. The Kaplan-Meier method and Cox proportional hazards regression were used for plotting and survival analysis. In 65 UCS cases, 1 case (1.5%) was POLE ultramutated (POLEmut) subtype, 11 cases (16.9%) were deficient MMR (dMMR) subtype, 32 cases (49.3%) were p53 mutant (p53mut) subtype, and 21 cases (32.3%) were nonspecific molecular profile (NSMP) subtype. The positive density of PD-L1 in tumor (p=0.022), CD8 in stroma (p=0.036), and CD163 in stroma (p=0.025) were significantly associated with molecular subtypes. The patients with POLEmut and dMMR subtypes had a relatively better prognosis trend than patients with NSMP and p53mut subtypes. The patients with high positive density of PD-L1 in tumor had significantly better prognosis; however, high positive density of CD163 in stroma showed significantly worse prognosis. UCS could be classified into four molecular subtypes associated with prognosis. PD-L1 and M2 macrophages could effectively predict the prognosis of patients with UCS.

Oncologic outcome of metachronous oligometastatic recurrence in advanced cervical cancer patients after primary radio-chemotherapy

Systemic chemotherapy in recurrent cervical cancer is a palliative treatment approach with limited oncologic outcome. As emerging evidence supports favorable prognosis following radical local treatment strategies for oligometastatic recurrence in gynecologic malignancies, there is an unmet clinical need to define prognostic implications of surgical metastasectomy in recurrent cervical cancer. Data of 139 consecutive cervical cancer patients, who underwent primary external-beam radiotherapy with concomitant chemotherapy, followed by magnetic resonance image-guided adaptive brachytherapy between 2015 and 2019, was analyzed. Oncologic outcomes of recurrence patterns, defined according to the European Society for Radiotherapy and Oncology (ESTRO) and the American Society for Radiation Oncology (ASTRO) consensus, was assessed according to the type of recurrence therapy. Of 54 patients (38.8%) with metachronous disease recurrence, 21 (38.8%) classified as metastatic and 22 (40.7%) as oligometastatic. Oligometastatic recurrence was associated with improved progression-free survival after recurrence (PFS2; hazard ratio [HR]=2.95; 95% confidence interval [CI]=1.23-7.08; p=0.015) and disease-specific survival after recurrence (HR=3.28; 95% CI=1.40-7.70; p=0.006) irrespective of the type of recurrence therapy. An exploratory subgroup analysis of oligometastatic patients undergoing surgical resection ± adjuvant therapy (n=12) suggested reduced risk of second disease recurrence (odds ratio=0.15; 95% CI=0.02-0.92; p=0.020) and improved PFS2 (HR=0.24; 95% CI=0.06-0.99; p=0.048) as compared to palliative systemic treatment (n=7). A relevant number of recurrences qualifies as oligometastatic according to the ESTRO-ASTRO consensus, which associate with improved prognosis irrespective of the type of recurrence therapy. Patients experiencing oligometastatic recurrence should be carefully evaluated for potentially curative treatment approaches.

Risk of CIN2+ in women aged &gt;60 years with abnormal cervical cancer screening: a multicenter retrospective cohort study from the Thai Gynecologic Cancer Society research group

To study patterns of abnormal cervical cancer screening in women aged >60 years and explore the risk and predictors of cervical intraepithelial neoplasia grade 2 or worse (CIN2+). This retrospective cohort study examined 1,596 women aged >60 years with abnormal cervical cancer screening results from eight Thai cancer centers. Those who underwent hysterectomy were excluded. Patient characteristics, previous and current cervical cancer screening results, and histopathology data were collected and analyzed. Mean age was 68.2±7.2 years. The abnormal screening results were normal cytology with positive high-risk human papillomavirus (0.9%), atypical squamous cells of undetermined significance (37.7%), low-grade squamous intraepithelial lesion (12%), atypical squamous cell cannot exclude high-grade lesion (11.7%), high-grade squamous intraepithelial lesion (12.7%), atypical glandular cell (20.1%), squamous cell carcinoma (4.3%), and adenocarcinoma (0.7%). Risk of CIN2+ in women with abnormal screening was 17.9% (95% confidence interval [CI]=16.1-19.8); among those with available histopathology, the risk was 28.8% (95% CI=26.1-31.7). Univariable logistic regression showed that age >70 years, sexual activity within 1 year, previous abnormal/no screening, previous CIN2+ pathology, presence of symptoms, and high-grade cytology were significant predictors of CIN2+. In the multivariable analysis, lack of previous screening (adjusted odds ratio=4.05; 95% CI=1.91-8.60; p60 years should be individualized based on their risk factors, particularly for those who have never been screened.

The impact of bladder volume on dosimetric outcomes in VMAT for cervical cancer patients after surgery

This study aimed to investigate the impact of bladder volume on dosimetric outcomes of organs at risk (OARs) in postoperative volumetric-modulated arc therapy (VMAT) for patients with cervical cancer. The study included 71 cervical cancer patients who received radical hysterectomy and postoperative VMAT between January 2020 and January 2023. Patients were divided into 3 groups according to average bladder volume observed in computed tomography simulation positioning images: Group A (<300 mL), Group B (300-500 mL), and Group C (≥500 mL). The study compared dosimetric parameters(V₃₀, V₄₀, V₄₅, and D The median follow-up of the cohort was 33 months, with a median patient age of 48 years. Group A demonstrated the highest V₄₀ and V₄₅ values for the bladder (p<0.05). Conversely, Group C displayed the highest values for the V₄₀ and V₄₅ of the rectum, as well as the V₄₅ and D Bladder volume significantly affects dosimetry of the bladder, rectum, and sigmoid colon in postoperative VMAT for cervical cancer patients. A recommended bladder volume of 300-500 mL helps reduce radiation-induced cystitis and proctitis.

Significance of HPV status on tumor response and treatment outcomes in endocervical adenocarcinoma treated with definitive chemoradiotherapy: a retrospective study

We aimed to compare tumor response and treatment outcomes between human papillomavirus (HPV)-associated (HPVA) and HPV-independent (HPVI) endocervical adenocarcinomas (ADCs) treated with definitive concurrent chemoradiotherapy (CCRT) and to identify prognostic factors. We conducted a retrospective review of 40 patients with endocervical ADCs treated with definitive CCRT (stages I-IVA) between 2011 and 2022. Based on pathological review the cases were categorized as HPVA or HPVI ADCs. Statistical analyses were performed to compare the characteristics, complete response (CR) rates, and survival outcomes. Of 40 patients, 22 (55.0%) had HPVA and 18 (45.0%) had HPVI ADCs. HPVI patients had significantly higher rates of parametrial invasion (94.4% vs. 45.5%, p=0.001). CR was achieved in 57.5% of patients and was significantly more common in the HPVA group (81.8% vs. 27.8%, p=0.001). Patients with HPVI had higher recurrence rates (88.9% vs. 50.0%, p=0.016) and lower 3-year progression-free survival (PFS, 16.7% vs. 49.8%, p=0.001), distant metastasis-free survival (DMFS, 38.1% vs. 80.8%, p=0.001), and overall survival (OS, 42.3% vs. 90.7%, p=0.002) rates. HPVA remained a significant factor for PFS (hazard ratio [HR]=3.44; 95% confidence interval [CI]=1.09-10.81; p=0.035) and OS rates (HR=6.83; 95% CI=1.17-39.80; p=0.033) in multivariate analysis. HPVI ADC was associated with a lower response to definitive CCRT and worse prognosis than HPVA ADC. These findings suggest the need for tailored treatment strategies based on the HPV status.

Lymphadenectomy in clinically early epithelial ovarian cancer and survival analysis (LILAC): a Gynecologic Oncology Research Investigators Collaboration (GORILLA-3002) retrospective study

This study aimed to evaluate the therapeutic role of lymphadenectomy in patients surgically treated for clinically early-stage epithelial ovarian cancer (EOC). This retrospective, multicenter study included patients with clinically early-stage EOC based on preoperative abdominal-pelvic computed tomography or magnetic resonance imaging findings between 2007 and 2021. Oncologic outcomes and perioperative complications were compared between the lymphadenectomy and non-lymphadenectomy groups. Independent prognostic factors were determined using Cox regression analysis. Disease-free survival (DFS) was the primary outcome. Overall survival (OS) and perioperative outcomes were the secondary outcomes. In total, 586 patients (lymphadenectomy group, n=453 [77.3%]; non-lymphadenectomy groups, n=133 [22.7%]) were eligible. After surgical staging, upstaging was identified based on the presence of lymph node metastasis in 14 (3.1%) of 453 patients. No significant difference was found in the 5-year DFS (88.9% vs. 83.4%, p=0.203) and 5-year OS (97.2% vs. 97.7%, p=0.895) between the two groups. Using multivariable analysis, lymphadenectomy was not significantly associated with DFS or OS. However, using subgroup analysis, the lymphadenectomy group with serous histology had higher 5-year DFS rates than did the non-lymphadenectomy group (86.5% vs. 74.4%, p=0.048; adjusted hazard ratio=0.281; 95% confidence interval=0.107-0.735; p=0.010). The lymphadenectomy group had longer operating time (p<0.001), higher estimated blood loss (p<0.001), and higher perioperative complication rate (p=0.004) than did the non-lymphadenectomy group. In patients with clinically early-stage EOC with serous histology, lymphadenectomy was associated with survival benefits. Considering its potential harm, lymphadenectomy should be performed according to histologic subtype and subsequent chemotherapy in patients with clinically early-stage EOC. Clinical Research Information Service Identifier: KCT0007309.

Adjuvant chemotherapy after radical hysterectomy yields comparable outcomes to chemoradiation for stage IB2-IIB and IIIC1-2 cervical cancer: a single-center retrospective study

This study aimed to evaluate and compare recurrence-free survival (RFS) between radical hysterectomy followed by adjuvant chemotherapy and initial chemoradiotherapy for cervical cancer at our institution. In this retrospective study, we enrolled patients diagnosed with stage IB2-IIB cervical cancer according to the International Federation of Gynecology and Obstetrics 2018 staging system, who underwent either radical hysterectomy with pelvic lymphadenectomy followed by adjuvant chemotherapy or initial concurrent chemoradiation at our institution between 2009 and 2022. Among these patients, 74 and 110 underwent radical hysterectomy and chemoradiation, respectively. The radical hysterectomy group exhibited significantly improved RFS compared with the chemoradiation group; however, no significant difference was observed in overall survival between the groups. Cox hazard analysis for RFS showed that, among the clinical risk factors identified before the initial treatment, only parametrial invasion was statistically significant. No significant difference in RFS was observed between the radical hysterectomy group and chemoradiation group. Regarding recurrence patterns, para-aortic lymph node recurrence occurred significantly more frequently in the chemoradiation group than in the radical hysterectomy group. Postoperative ureteral injury was reported in once case and postoperative ureteral stenosis in 2 cases in the radical hysterectomy group. In contrast, vesicovaginal fistula and rectovaginal fistula were reported in one case each in the chemoradiation group. Radical hysterectomy followed by adjuvant chemotherapy provided RFS outcomes comparable to those achieved with initial chemoradiotherapy for stage IB2-IIB and IIIC1-2 cervical cancer. These findings suggest that both approaches are viable, although further prospective studies are needed.

Increased cardiovascular disease risk among adolescent and young adult survivors of cervical cancer

To investigate the incidence and risk factors of cardiovascular disease (CVD) in adolescent and young adult survivors of cervical cancer. This retrospective cohort study used data from the Korean National Health Insurance Service. Adolescent and young adult (AYA) cervical cancer survivors (n=7,803) were matched with non-cancer controls (n=23,327) using 1:3 propensity score matching, and hazard ratios (HRs) for CVD were determined using Cox regression models. Multivariable Cox regressions were used to assess CVD incidence according to cancer treatment and identify risk factors. A total of 7,803 AYA survivors with cervical cancer were analyzed in this study during a median 8.9 years of follow-up. They developed any CVD with an adjusted HR of 1.47 (95% confidence interval [CI]=1.33-1.62) compared with the non-cancer controls. Those who underwent concurrent chemoradiotherapy had markedly elevated risks of heart failure (subHR=2.66; 95% CI=1.24-5.72), ischemic heart disease (subHR=1.78, 95% CI=1.11-2.86), deep vein thrombosis (subHR=15.32; 95% CI=9.16-25.63), and pulmonary embolism (subHR=14.99; 95% CI=6.31-35.62). Diabetes, hypertension and chemoradiation therapy were identified as potential risk factors that increase the risk of CVD by 1.55-fold, 1.62-fold and 2.64-fold, respectively. These findings indicate a need to pay increased attention to cardiovascular health management in adolescent and young adult cervical cancer survivors, particularly those treated with chemoradiotherapy.

A multimodal intervention program to improve sexual health and self-perceived quality of life in patients treated for cervical cancer: a randomized prospective study (PROVIDENCE trial)

Patients with cervical cancer treatment experience an impairment of sexual function and quality of life. This issue is usually underreported and undertreated, and evidence-based interventions are lacking. Prevention of sexual dysfunction is a crucial pillar in improving the quality of life of these patients. The primary objective of this trial is to evaluate the impact of a multimodal intervention, encompassing prevention of vaginal dysfunction and patient education, on sexual function and quality of life in cervical cancer survivors utilizing patient-reported outcome measurements. Multi-institutional, randomized clinical trial where patients will be randomized 1:2 at diagnosis of initial or locally advanced cervical cancer to control arm or intervention arm. After treatment, control arm patients will undergo standard follow-up by their referring physician. The multimodal intervention for patients in the intervention group includes application of vaginal estrogens plus hyaluronic-acid cream along with use of vaginal vibrator, systematic evaluation of the need of systemic hormone replacement therapy and treatment if needed, and access to online content about sexuality, nutrition, sports and lifestyle habits. Through 4 appointments (at diagnosis, 1, 6, and 12 months after treatment), sexual health, vaginal trophism and self-perceived quality of life of patients in both arms will be assessed with validated questionnaires as female sexual function index (FSFI), European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30, and Cx-24, Cervantes Scale, vaginal health index and vaginal thickness assessed by ultrasound. The major inclusion criteria will be patients aged ≥18 years with the International Federation of Gynecology and Obstetrics stage I-III cervical cancer treated with surgery and/or radiotherapy. The primary endpoint will be FSFI score 12 months after treatment, which will be compared between groups. Uni- and multivariate analysis will be performed to identify factors influencing sexual function recovery after treatment. The sample size will be of 120 eligible patients, who will be randomized to detect an improvement of 5.2 points in FSFI score. Complete accrual is estimated in March 2026. To date, the present study has no external funding. ClinicalTrials.gov Identifier: NCT06031493.

Salvage hysterectomy for persistent residual cervical cancer: assessment of prognostic factors

In this multicenter retrospective cohort study of 99 patients who underwent salvage hysterectomy for residual disease in the uterine cervix following the completion of definitive radiotherapy for cervical cancer across 25 Japan Clinical Oncology Group-affiliated centers from 2005-2014, (i) time duration from the completion of definitive radiotherapy to the diagnosis of residual disease in the uterine cervix, (ii) salvage hysterectomy surgical margin status, and (iii) extent of residual disease, were independently associated with progression-free survival (PFS). Specifically, (i) time duration to identify residual disease of >62 days was associated with decreased PFS compared to ≤62 days (4-year rates 21.8% vs. 55.0%, adjusted-hazard ratio [aHR]=2.69, 95% confidence interval [CI]=1.55-4.67); (ii) presence of tumor in the surgical margin of hysterectomy specimen was associated with 4 times increased risk of disease progression compared to tumor-free surgical margin (4-year PFS rates 0% vs. 45.3%, aHR=4.27, 95% CI=2.20-8.29); and (iii) hazards of disease progression was 4.5-fold increased when the residual disease extended beyond the uterine cervix compared to residual disease within the uterine cervix only (4-year PFS rates 11.1% vs. 50.6%, aHR=4.54, 95% CI=2.60-7.95). In the absence of these 3 prognostic factors, 4-year PFS rate reached nearly 80% (78.6%, SAL-HYS criteria). In sum, these data suggested that early detection of persistent, residual disease following definitive radiotherapy for cervical cancer may be the key to improve survival if salvage hysterectomy is considered as a tailored treatment option. Ideal surgical candidate would be uterine cervix-contained disease and assurance of adequate tumor-free surgical margin.

Clinical practice guidelines for cervical cancer: an update of the Korean Society of Gynecologic Oncology Guidelines

We describe the updated Korean Society of Gynecologic Oncology (KSGO) practice guideline for the management of cervical cancer, version 5.1. The KSGO announced the fifth version of its clinical practice guidelines for the management of cervical cancer in March 2024. The selection of the key questions and the systematic reviews were based on data available up to December 2022. Between 2023 and 2024, substantial findings from large-scale clinical trials and new advancements in cervical cancer research remarkably emerged. Therefore, based on the existing version 5.0, we updated the guidelines with newly accumulated clinical data and added 4 new key questions reflecting the latest insights in the field of cervical cancer. For each question, recommendation was formulated with corresponding level of evidence and grade of recommendation, all established through expert consensus.

Efficacy and safety of 3-dimensional printing noncoplanar template (3D-PNCT)-assisted high-dose-rate interstitial brachytherapy (HDR-ISBT) for reirradiation of recurrent cervical cancer: a prospective cohort

This study aimed to investigate the efficacy and safety of 3-dimensional printing noncoplanar template (3D-PNCT)-assisted computed tomography (CT)-guided high-dose-rate interstitial brachytherapy (HDR-ISBT) for reirradiation of pelvic recurrent cervical carcinoma after external beam radiotherapy. From January 2019 to August 2023, 45 eligible patients were enrolled in this prospective cohort. All patients underwent 3D-PNCT-assisted CT-guided HDR-ISBT with a prescribed dose of 4-7 Gy/fraction to the high-risk clinical target volume (HR-CTV) over 3-8 fractions, either for curative or palliative purposes. The primary endpoints were local progression-free survival (LPFS) and tumor response rate (TRR). The secondary outcome measures included overall survival (OS), toxicities, and symptom resolution. Forty-five patients received 261 fractions of 3D-PNCT-assisted HDR-ISBT. Twenty-nine patients had isolated pelvic recurrence, and 16 patients had simultaneous extra-pelvic or distant recurrences. The TRR was 66.7%. The 2- and 5-year LPFS rates were 30.0% and 25.7%, respectively. The median OS was 23.2 months, and 2- and 5-year OS rates were 49.5% and 34.0%, respectively. The multivariate analysis indicated that squamous cell carcinoma, radical surgery, recurrence-free interval≥12 months, tumor diameter, pelvic recurrence type, and HR-CTV D₉₀≥45 Gy were independent factors influencing LPFS (all p<0.05). D₁₀₀≥21 Gy, V₁₀₀≥83%, and V₁₅₀≥45% were associated with better LPFS (all p<0.05). Tumor diameter and metastasis were independent predictive factors for OS (all p<0.05). The pain relief rate was 66.7% (10/15). Grade 3-4 toxicities occurred in 20.0% of patients. 3D-PNCT-assisted HDR-ISBT for reirradiation of recurrent cervical cancer proved to be an effective and safe alternative to radical surgery.

Toripalimab combined with bevacizumab plus chemotherapy as first-line treatment for refractory recurrent or metastatic cervical cancer: a single-arm, open-label, phase II study (JS001-ISS-CO214)

To evaluate the efficacy and safety of adding toripalimab to bevacizumab and platinum-based chemotherapy as first-line treatment for refractory recurrent or metastatic (R/M) cervical cancer (CC). Patients were administered toripalimab (240 mg) + bevacizumab (7.5 mg/kg) combined with platinum-based chemotherapy once every three weeks for six cycles, followed by the maintenance therapy involving toripalimab + bevacizumab once every 3 weeks for 12 months or when disease progression or intolerable toxicity occurred. The primary endpoint was the objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints were safety profiles, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Twenty-four patients were enrolled in this study and in the final analysis. The median follow-up duration was 18.6 (range, 3.3-28.5) months. The ORR was 83.3% (95% confidence interval [CI]=62.6-95.3) and the DCR was 95.8% (95% CI=78.9-99.9); 9 (37.5%) patients achieved complete response, 11 (45.8%) achieved partial response, and 3 (12.5%) had stable disease. The median PFS was 22.6 (95% CI=10.4-34.7) months and the median OS was not reached. The most common grade 3 treatment-related adverse events (AEs) were neutropenia (41.7%) and leukopenia (16.7%). The most common immune-related AEs (irAEs) were thyroid dysfunction (37.5%) and increased adrenocorticotropic hormone (37.5%) and serum cortisol levels (33.3%). No grade ≥3 irAEs were observed. Toripalimab combined with bevacizumab and platinum-based chemotherapy show promising clinical efficacy and favorable safety profile, providing an alternative first-line treatment option for patients with R/M CC. ClinicalTrials.gov Identifier: NCT04973904.

Clinical trial comparing the use of Orcellex® Brush versus Cervex-Brush® on vaginal vault smear cytology adequacy rate in patients treated with radiotherapy for cervical cancer

This study aims to evaluate and compare the Cervex-Brush A randomized crossover trial was conducted at a gynecological oncology center in Hong Kong to compare the Cervex-Brush One hundred sixty cervical cancer patients treated with primary radiotherapy and undergoing follow-up surveillance by vaginal vault cytology were recruited. The smear adequacy rate was 90.6% for Cervex-Brush There was no difference between the Orcellex ClinicalTrials.gov Identifier: NCT04461574.

Diagnostic accuracy of intraoperative frozen section at radical abdominal trachelectomy for early-stage cervical cancer

Intraoperative frozen section examination is crucial for confirming the oncological safety of radical abdominal trachelectomy (RAT) for early-stage cervical cancer. This study evaluated the diagnostic accuracy of frozen section during RAT at our institution. We retrospectively identified patients with International Federation of Gynecology and Obstetrics 2008 stage IA1-IB1 (tumor size ≤2 cm) cervical cancer treated between 2002 and 2021. In performing RAT, frozen section analysis was routinely performed on uterine surgical margins and grossly enlarged lymph nodes, and was confirmed to be negative. Medical records were reviewed to compare the frozen section diagnoses with the final pathology. Among the 326 patients initially planned to undergo RAT, 298 (91.4%) underwent RAT, while 28 (8.6%) were converted to radical hysterectomy. The histological types were squamous cell carcinoma in 251 (77.0%) patients and adenocarcinoma in 67 (20.6%). Of 361 frozen section for surgical margins, 4 false negatives were identified. Discrepancies were due to freezing artifacts, staining quality on frozen sections, and slight differences in cross-sections between frozen and paraffin-embedded sections. Among 446 intraoperative lymph-node biopsies, one false-negative was recorded. Sensitivities of frozen section examination were 93.5% (58/62) for surgical margins and 94.1% (16/17) for lymph nodes. Lymph-node metastases were identified in systematic lymphadenectomy specimens of 21/326 (6.4%) patients planned to undergo RAT, with 10/21 (47.6%) detected intraoperatively. Lymph-node metastases were found in 7/112 (6.3%) patients without lymph-node biopsy. Frozen section examination during RAT provides satisfactory diagnostic performance, although biopsy of grossly enlarged lymph nodes is an unreliable method.

Preoperative laboratory parameters associated with deep vein thrombosis in patients with ovarian cancer: retrospective analysis of 3,147 patients in a single institute

Patients with ovarian cancer have a high risk of developing thrombosis. We aimed to investigate laboratory parameters associated with deep vein thrombosis (DVT) in patients treated for ovarian cancer. We retrospectively analyzed pre-operation laboratory data of patients with ovarian cancer for DVT at the National Cancer Center, Korea, between January 2000 and February 2021. The test items were white blood cell count, absolute neutrophil count (ANC), hemoglobin, platelets, monocytes, serum glucose, CA125, D-dimer, fibrinogen, prothrombin time (PT), activated partial thromboplastin time (aPTT), and body mass index (BMI). Differences between patients with and without DVT were compared with Wilcoxon rank-sum test. We analyzed the variables using logistic regression. Items with significant odds ratios were included in multivariate logistic regression. Significant variables were selected using backward elimination. Items were further categorized based on reference ranges. Univariate and multivariate analyses were performed to identify items with abnormal values associated with DVT. From 3,147 patient samples analyzed, 286 (9.1%) patients with DVT were selected. Differences between patients with vs without DVT were statistically significant for hemoglobin, monocyte, serum glucose, CA125, PT, aPTT, fibrinogen, D-dimer, and BMI. After univariate and multivariate analysis, monocyte, glucose, and PT remained significant. Among the categorical variables, low hemoglobin, high monocyte, high CA125, prolonged PT, and high BMI remained significant after univariate and multivariate analysis. Pre-operation laboratory data of low hemoglobin, high monocyte percentage, high serum glucose, high CA125, prolonged PT, and high BMI were associated with DVT.

Correspondence on: The risk of lymph node metastasis in the new FIGO 2018 stage IA cervical cancer with &gt;7 mm diameter by Nicolai et al.

Role of HPV E7/miR-143-3p/SH2D3A pathway in regulating the occurrence and development of cervical cancer

This study aims to explore the role of SH2D3A in cervical cancer, as well as its potential interaction with human papillomavirus (HPV) E7 and microRNA (miRNA). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry were used to compare the expressions of SH2D3A in tissues. To assess the effects of SH2D3A on cervical cancer cell phenotypes, SH2D3A was knocked down in SiHa and HeLa cells, followed by cell proliferation (Cell Counting Kit-8 assay), apoptosis (flow cytometry), and invasion (Transwell assay) analyses. A transplantation tumor model was established to compare the tumorigenic ability of cervical cancer cells before and after SH2D3A silencing. Bioinformatics analysis predicted and dual-luciferase reporter assays verified the sponge adsorption effect of SH2D3A on miRNA. Western blot and qRT-PCR analyses were conducted to examine the impact on target genes following the downregulation of HPV E7 and SH2D3A. SH2D3A expression was significantly elevated in cervical cancer tissues. SH2D3A silencing inhibited cell proliferation and invasion, induced apoptosis, and reduced tumorigenesis in nude mice. Bioinformatics tools identified a binding relationship between SH2D3A and miR-143-3p, confirmed by the luciferase reporter assays. Western blot analysis revealed that SH2D3A knockdown led to decreased levels of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3) proteins. Additionally, qRT-PCR showed that SH2D3A mRNA levels decreased after HPV E7 silencing, whereas miR-143-3p levels significantly increased. HPV E7 influences SH2D3A expression through miR-143-3p, thereby regulating the JAK1/STAT3 pathway. This mechanism promotes the occurrence and development of cervical cancer.

Supragastric lesser sac: an insidious site for surgical exploration during the debulking surgery in advanced ovarian cancer

Metastases in the supragastric lesser sac (SGLS) are not only occult but are also barriers to complete resection of ovarian cancer. We describe a cohort of patients with SGLS disease undergoing debulking surgery. We identified all patients who underwent evaluation and eventual resection of SGLS disease as part of cytoreductive surgery for stage IIIC-IVB high-grade epithelial ovarian cancer at our institution from January 2018 to August 2022. Thirty-three of 286 patients (11.5%) underwent resection of SGLS disease. Metastases in the SGLS were identified by preoperative imaging in 4 of 33 patients (12.1%). The median peritoneal cancer index score was 22 (range, 9-33). Through surgical exploration, metastases were frequently seen in the right diaphragm (100%), hepatorenal recess (97%), lesser omentum (81.8%), left diaphragm (78.8%), supracolic omentum (75.8%), anterior transverse mesocolon (72.7%), splenic hilum (63.6%), ligamentum teres hepatis (60.6%), and gallbladder fossa (51.5%). The lesser omentum was normal in 6 of 33 (18.2%) patients, despite metastases within the SGLS. A total of 54.5% of patients underwent complex surgery (surgical complexity scores; median, 8; range, 3-14). Complete resections were achieved in 19 (57.6%) patients. No complications were related to the resection of SGLS disease. The median length of progression-free survival was 24.8 months (95% confidence interval=16.6-32.9). Metastases to the SGLS are not uncommon in advanced ovarian cancer, particularly those with widely disseminated disease. Disease in this recess is rarely identified by preoperative imaging and deserves systematic surgical exploration to attain complete cytoreduction.

Evaluation of secondary cytoreduction surgery in platinum-resistant ovarian cancer patients within three-line recurrent: a multicenter, randomized controlled study

Epithelial ovarian cancer is the leading cause of death among gynecological malignancies. Platinum resistance remains a dilemma and bottleneck in treatment, and salvage chemotherapy has limited effectiveness. Recently, the role of secondary cytoreductive surgery (SCS) in patients with platinum-resistant recurrent ovarian cancer (ROC) has caused attention especially in patients with oligometastases. However, there is neither high-quality evidence-based evidence nor standardized criteria for selecting SCS for patients with platinum-resistant ROC until now. This multicenter, randomized, controlled clinical trial is to evaluate the value of SCS and to clarify reliable criteria of utilizing SCS in women with ROC, which is led by Gynecologic Oncology Group, Women's Hospital, Zhejiang University School of Medicine. Recruitment has started on January 1st, 2023, and is scheduled to end in December 2026. One hundred and forty participants with platinum-resistant ROC who meet the "RSCS criteria" will be randomized assigned at a ratio of 1:1 to either the experimental arm or the standard arm. Patients in the experimental arm will receive SCS followed by non-platinum single agent chemotherapy (paclitaxel, gemcitabine or liposomal adriamycin) for at least 4 cycles while patients in the standard arm will be provided with only non-platinum single agent chemotherapy. The primary outcome is progression-free survival. The secondary outcomes are overall survival, adverse events and health-related cancer-specific quality of life. ClinicalTrials.gov Identifier: NCT05633199.

The role of radiomics for predicting of lymph-vascular space invasion in cervical cancer patients based on artificial intelligence: a systematic review and meta-analysis

The primary aim of this study was to conduct a methodical examination and assessment of the prognostic efficacy exhibited by magnetic resonance imaging (MRI)-derived radiomic models concerning the preoperative prediction of lymph-vascular space infiltration (LVSI) in cervical cancer cases. A comprehensive and thorough exploration of pertinent academic literature was undertaken by two investigators, employing the resources of the Embase, PubMed, Web of Science, and Cochrane Library databases. The scope of this research was bounded by a publication cutoff date of May 15, 2023. The inclusion criteria encompassed studies that utilized radiomic models based on MRI to prognosticate the accuracy of preoperative LVSI estimation in instances of cervical cancer. The Diagnostic Accuracy Studies-2 framework and the Radiomic Quality Score metric were employed. This investigation included nine distinct research studies, enrolling a total of 1,406 patients. The diagnostic performance metrics of MRI-based radiomic models in the prediction of preoperative LVSI among cervical cancer patients were determined as follows: sensitivity of 83% (95% confidence interval [CI]=77%-87%), specificity of 74% (95% CI=69%-79%), and a corresponding AUC of summary receiver operating characteristic measuring 0.86 (95% CI=0.82-0.88). The results of the synthesized meta-analysis did not reveal substantial heterogeneity.This meta-analysis suggests the robust diagnostic proficiency of the MRI-based radiomic model in the prognostication of preoperative LVSI within the cohort of cervical cancer patients. In the future, radiomics holds the potential to emerge as a widely applicable noninvasive modality for the early detection of LVSI in the context of cervical cancer.

Durvalumab plus carboplatin/paclitaxel followed by durvalumab with or without olaparib as first-line treatment for newly diagnosed advanced or recurrent endometrial cancer: Japan subset from the phase III DUO-E trial

DUO-E/GOG-3041/ENGOT-EN10 (NCT04269200) demonstrated statistically significant and clinically meaningful progression-free survival (PFS) improvement with durvalumab plus carboplatin/paclitaxel, followed by durvalumab with or without olaparib, vs. carboplatin/paclitaxel alone (intention-to-treat [ITT] population) in patients with newly diagnosed advanced or recurrent endometrial cancer. We evaluated efficacy and safety in the Japan subset of DUO-E. Patients with newly diagnosed International Federation of Gynecology and Obstetrics stage III/IV or recurrent endometrial cancer were randomized 1:1:1 to control arm (carboplatin/paclitaxel + durvalumab placebo [6 cycles] followed by durvalumab placebo + olaparib placebo), durvalumab arm (carboplatin/paclitaxel + durvalumab [1,120 mg every 3 weeks] [6 cycles] followed by durvalumab [1,500 mg every 4 weeks] + olaparib placebo), or durvalumab + olaparib arm (carboplatin/paclitaxel + durvalumab [6 cycles] followed by durvalumab + olaparib [300 mg twice a day]). Dual primary endpoints were investigator-assessed PFS for durvalumab and durvalumab + olaparib arms vs. control. This prespecified exploratory analysis evaluated PFS and safety in the Japan subset. In the Japan subset (n=88) PFS favored durvalumab (hazard ratio=0.61, 95% confidence interval [CI]=0.32-1.12) and durvalumab + olaparib (0.44, 95% CI=0.22-0.85) vs. control; median PFS was 9.9 and 15.1 vs. 9.5 months, and the 18-month PFS rate was 37.0% and 42.1% vs. 22.2%, respectively. The safety profile in the Japan subset was generally consistent with the full safety analysis set and the established profiles of the individual agents. Efficacy and safety in the Japan subset were generally consistent with outcomes in the DUO-E ITT population. This Japanese subset analysis of DUO-E supports carboplatin/paclitaxel + durvalumab followed by durvalumab with or without olaparib as new treatment options in patients with advanced or recurrent endometrial cancer and is the first to report on these regimens in Japanese patients alone.

Early prediction and risk stratification of ovarian cancer based on clinical data using machine learning approaches

Our study was aimed to construct a predictive model to advance ovarian cancer diagnosis by machine learning. A retrospective analysis of patients with pelvic/adnexal/ovarian mass was performed. Potential features related to ovarian cancer were obtained as many as possible. The optimal machine learning algorithm was selected among six candidates through 5-fold cross validation. Top 20 features having the most powerful predictive significance were ranked by Shapley Additive Interpretation (Shap) method. Clinical validation was further performed to confirm whether our model could advance diagnosis of ovarian cancer. A total of 9,799 patients were collected. The inclusion criteria included age >18 years old, the first diagnosis being pelvic/adnexal/ovarian mass of undetermined significance, and pathological report indispensable. Four hundred and thirty-eight dimensional features were obtained after filtration. LightGBM showed the best performance with accuracy 88%. Among the top 20 features, 55% belonged to laboratory test report, 35% came from imaging examination report, and 10% were attributed to basic demographics and main symptom. Age, CA125, and risk of ovarian malignancy algorithm were the top three. Our predictive model performed stably in testing and clinical validation datasets, and was found to advance the diagnosis of ovarian cancer about 17 days before clinical pathological examination. LightGBM was the optimal algorithm for our predictive model with accuracy of 88%. Laboratory test and imaging examination played essential roles in diagnosing ovarian cancer. Our model could advance the diagnosis of ovarian cancer before clinical pathological examination.

Niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer: final results of a multicenter phase 2 study

To evaluate the long-term efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer. This was the follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with homologous recombination-deficient, platinum-sensitive, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of chemotherapy and were poly(ADP-ribose) polymerase inhibitor naïve. Participants received niraparib (starting dose, 300 mg) once daily in continuous 28-day cycles until objective disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was confirmed objective response rate (ORR), as assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Safety evaluations included treatment-emergent adverse events (TEAEs). 20 patients were enrolled in the study and included in both efficacy and safety analyses. Median total study duration was 759.5 days. Median dose intensity was 201.3 mg/day. Confirmed ORR was 60.0% (90% confidence interval [CI]=39.4-78.3); 2 patients had complete response and 10 patients had partial response. Median duration of response was 9.9 months (95% CI=3.9-26.9) and the disease control rate was 90.0% (95% CI=68.3-98.8). The most common TEAEs were anemia (n=15), nausea (n=12), and decreased platelet count (n=11). TEAEs leading to study drug dose reduction, interruption, or discontinuation were reported in 16 (80.0%), 15 (75.0%), and 2 patients (10.0%), respectively. The long-term efficacy and safety profile of niraparib was consistent with previous findings in the equivalent population in non-Japanese patients. No new safety signals were identified. ClinicalTrials.gov Identifier: NCT03759600.

A retrospective study of dose-dense paclitaxel and carboplatin plus bevacizumab as first-line treatment of advanced epithelial ovarian cancer

This study compared the effectiveness, safety, and tolerability of dose-dense paclitaxel and carboplatin plus bevacizumab (ddTC+Bev) with ddTC for advanced ovarian cancer. We retrospectively analyzed the clinical records of 134 patients who received ddTC+Bev or ddTC as first-line chemotherapy for stage III-IV ovarian cancer. Progression-free survival as primary endpoint of this study was compared using the log-rank test. Cox proportional hazards model and propensity score matching (PSM) were used to analyze prognostic factors, and the frequency of adverse events was examined using the χ² test. We categorized 134 patients in the ddTC+Bev (n=57) and ddTC (n=77) groups who started treatment at four related institutions from November 2013 to December 2017. No patients used poly (ADP-ribose) polymerase inhibitors as the first line maintenance therapy. The progression-free survival (PFS) of the ddTC+Bev group had a significantly better prognosis than that of the ddTC group (hazard ratio [HR]=0.50; 95% confidence interval [CI]=0.32-0.79; p<0.003). Multivariate analysis showed that ddTC+Bev regimen was a prognostic factor. However, intergroup comparison using PSM revealed that the PFS of the ddTC+Bev group had a nonsignificantly better prognosis than that of the ddTC group (HR=0.70; 95% CI=0.41-1.20; p=0.189). Few adverse events above G3 were noted for ddTC+Bev, which were sufficiently tolerable. This study could not demonstrate that adding Bev to ddTC improves prognosis. Further studies with more cases are warranted.

Cost-effectiveness analysis of hospital treatment volume and survival outcomes in endometrial cancer in Japan

Hospital treatment volume affects survival in patients with endometrial cancer; notably, initial treatment at high-volume centers improves survival outcomes. Our study assessed the effect of hospital treatment volume on cost-effectiveness and survival outcomes in patients with endometrial cancer in Japan. A decision-analytic model was evaluated using the following variables and their impact on cost-effectiveness: 1) hospital treatment volume (low-, intermediate-, and high-volume centers) and 2) postoperative recurrent risk factors based on pathological findings (high- and intermediate-risk or low-risk). Data were obtained from the Japan Society of Obstetrics and Gynecology database, systematic literature searches, and the Japanese Diagnosis Procedure Combination database. Quality-adjusted life years (QALY) was used as a measure of effectiveness. The model was built from a public healthcare perspective and the impact of uncertainty was assessed using sensitivity analyses. A base-case analysis showed that the incremental cost-effectiveness ratio at high-volume centers was below a willingness-to-pay (WTP) threshold of ¥5,000,000 with a maximum of ¥3,777,830/4.28 QALY for the high- and intermediate-risk group, and ¥2,316,695/4.57 QALY for the low-risk group. Treatment at the high-volume centers showed better efficiency and cost-effectiveness in both strategies compared to intermediate- or low-volume centers. Sensitivity analyses showed that the model outcome was robust to changes in input values. With the WTP threshold, treatment at high-volume centers remained cost-effective in at least 73.6% and 78.2% of iterations for high- and intermediate-risk, and low-risk groups, respectively. Treatment at high-volume centers is the most cost-effective strategy for guiding treatment centralization in patients with endometrial cancer.

Genetic analysis of cervical cancer with lymph node metastasis

To find out the differences in gene characteristics between cervical cancer patients with and without lymph node metastasis, and to provide reference for therapy. From January 2018 to June 2022, recurrent cervical cancer patients 39 cases with lymph node metastasis and 73 cases without lymph node metastasis underwent testing of 1,021 cancer-related genes by next-generation sequencing. Maftools software was used to analyze somatic single nucleotide/insertion-deletion variation mutation, co-occurring mutation, cosmic mutation characteristics, oncogenic signaling pathways. EP300 and FBXW7 were significantly enriched in lymph node-positive patients. Lymph node-positive patients with EP300 or FBXW7 mutations had lower overall survival (OS) after recurrence. Both lymph node-positive and -negative patients had plenty of co-occurring mutations but few mutually exclusive mutations. Lymph node-positive co-occurring mutation number ≥6 had lower OS, while lymph node-negative co-occurring mutation number ≥3 had lower OS after recurrence. The etiology of SBS3 was defects in DNA double strand break repair by homologous recombination, which exclusively exist in lymph node-positive patients. There was no difference in median tumor mutation burden (TMB) between positive and negative lymph nodes, but TMB was significantly associated with PIK3CA mutation. The somatic SNV/Indels of EP300 and FBXW7, SBS3 homologous recombination-mediated DNA repair defect were enriched in lymph node-positive patients. For lymph node-positive patients, EP300 or FBXW7 mutations predicted poor prognosis. No matter lymph node-positive or negative, more co-occurring mutation number predicted poor prognosis. PIK3CA mutation may account for the higher TMB and help identify patients who benefit from immunotherapy.

Olaparib plus bevacizumab as a first-line maintenance treatment for patients with advanced ovarian cancer by molecular status: an updated PAOLA-1 based cost-effectiveness analysis

The PAOLA-1 trial (NCT02477644) reported final survival benefit associated with olaparib plus bevacizumab maintenance treatment of patients with advanced ovarian cancer (AOC) based on molecular status. Our aimed to compare the cost-effectiveness of olaparib plus bevacizumab for overall patients, patients with a breast cancer susceptibility genes (BRCA) mutation, homologous recombination deficiency (HRD), or HRD without BRCA mutations AOC from the context of the American healthcare system. Analysis of health outcomes in life-years (LYs), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) in various molecular status-based AOC patient at a $150,000/QALY of willingness-to-pay was performed using a state-transitioned Markov model with a 20-year time horizon. Meanwhile, sensitivity analyses assessments were also used to gauge the model's stability. The ICERs of olaparib plus bevacizumab versus bevacizumab alone were $487,428 ($374,758), $249,579 ($191,649), $258,859 ($198,739), and $270,736 ($206,640) per QALY (LY) in the overall patients, patients with BRCA mutations, patients with HRD, and patients with HRD without BRCA mutations AOC, respectively, which indicated that The ICERs was higher than $150,000/QALY in the US. Progression-free survival (PFS) value and olaparib cost emerged as the primary influencing factors of these findings in the sensitivity analysis. At current cost levels, olaparib plus bevacizumab treatment is not a cost-effective treatment for patients with AOC regardless of their molecular status in the US. However, this maintenance treatment may be more favorable health advantages for patients with BRAC mutations AOC.

Prehabilitation for medically frail patients undergoing surgery for epithelial ovarian cancer: a cost-effectiveness analysis

To assess the potential cost-effectiveness of prehabilitation in medically frail patients undergoing surgery for epithelial ovarian cancer (EOC). We created a cost-effectiveness model evaluating the impact of prehabilitation on a cohort of medically frail women undergoing primary surgical intervention for EOC. Cost was assessed from the healthcare system perspective via (1) inpatient charges from 2018-2019 institutional Diagnostic Related Grouping data for surgeries with and without major complications; (2) nursing facility costs from published market surveys. Major complication and non-home discharge rates were estimated from the literature. Based on published pilot studies, prehabilitation was determined to decrease these rates. Incremental cost-effectiveness ratio for cost per life year saved utilized a willingness-to-pay threshold of $100,000/life year. Modeling was performed with TreeAge software. In a cohort of 4,415 women, prehabilitation would cost $371.1 Million (M) versus $404.9 M for usual care, a cost saving of $33.8 M/year. Cost of care per patient with prehabilitation was $84,053; usual care was $91,713. When analyzed for cost-effectiveness, usual care was dominated by prehabilitation, indicating prehabilitation was associated with both increased effectiveness and decreased cost compared with usual care. Sensitivity analysis showed prehabilitation was more cost effective up to a cost of intervention of $9,418/patient. Prehabilitation appears to be a cost-saving method to decrease healthcare system costs via two improved outcomes: lower complication rates and decreased care facility requirements. It represents a novel strategy to optimize healthcare efficiency. Prospective studies should be performed to better characterize these interventions in medically frail patients with EOC.

Simple hysterectomy SHAPE-ing up to be the treatment of choice for early cervical cancer under 2 cm

A new technique of laparoscopic para-aortic lymphadenectomy optimizes perioperative outcome

The aim of the present study was to introduce a new technique for laparoscopic para-aortic lymphadenectomy (PAL): an invented retroperitoneum suspension needle combined with modified trocar placement. This prospective pilot study randomly categorized women with cervical cancer of stage I-II into 2 groups. The patients in the study group would have laparoscopic PAL with our new technique, while those in the control group with control method. Patients' characteristics and perioperative outcomes were compared between the 2 groups. A total of 37 patients were included in our study, of which 20 cases in the study group and 17 cases in the control group. As a result, the mean number of para-aortic lymph nodes (PALNs) resected in the study group was significantly more than that in the control group (p<0.001). The time for resecting PALNs (p<0.001) and total operative time (p<0.001) in the study group decreased significantly than those in the control group. For laparoscopic PAL, this new technique was effective and practical.

Quality of life outcomes from the randomized trial of hyperthermic intraperitoneal chemotherapy following cytoreductive surgery for primary ovarian cancer (KOV-HIPEC-01)

To investigate the health-related quality of life (HRQOL) related to hyperthermic intraperitoneal chemotherapy (HIPEC) following primary or interval cytoreductive surgery for primary ovarian cancer. Between 2010 and 2016, a total of 184 patients were randomly assigned to receive cytoreductive surgery with HIPEC (n=92) or without HIPEC (n=92). Quality of life (QOL) assessment was evaluated at baseline (before surgery); on postoperative day 7; after the 3rd and 6th cycle of adjuvant chemotherapy; and at 3, 6, 9, and 12 months after randomization. Patient-reported QOL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (EORTC-QLQ-C30), ovarian cancer questionnaire modules (QLQ-OV28), and the MD Anderson Symptoms Inventory (MDASI). Of the 184 patients enrolled, 165 (83/92 in the HIPEC group and 82/92 in the control group) participated in the baseline QOL assessment. There were no statistically significant differences in functional scales and symptom scales in QLQ-C30; symptom scales, including gastrointestinal symptoms QLQ-OV28; and severity and impact score in MDASI between the 2 treatment groups until 12 months after randomization. HIPEC with cytoreductive surgery showed no statistically significant difference in HRQOL outcomes. Thus, implementation of HIPEC during either primary or interval cytoreductive surgery does not impair HRQOL. ClinicalTrials.gov Identifier: NCT01091636.

Evaluation of perioperative management of advanced ovarian (tubal/peritoneal) cancer patients: a survey from MITO-MaNGO Groups

The European Society of Gynaecological Oncology (ESGO)-quality indicators (QIs) for advanced ovarian cancer (AOC) have been assessed only by few Italian centers, and data are not available on the proportion of centers reaching the score considered for a satisfactory surgical management. There is great consensus that the Enhanced Recovery After Surgery (ERAS) approach is beneficial, but there is paucity of data concerning its application in AOC. This survey was aimed at gathering detailed information on perioperative management of AOC patients within MITO-MaNGO Groups. A 66-item questionnaire, covering ESGO-QIs for AOC and ERAS items, was sent to MITO/MaNGO centers reporting to operate >20 AOC/year. Thirty/34 questionnaires were analyzed. The median ESGO-QIs score was 31.5, with 50% of centers resulting with a score ≥32 which provides satisfactory surgical management. The rates of concordance with ERAS guidelines were 46.6%, 74.1%, and 60.7%, respectively, for pre-operative, intra-operative, and post-operative items. The proportion of overall agreement was 61.3%, and with strong recommendations was 63.1%. Pre-operative diet, fasting/bowel preparation, correction of anaemia, post-operative feeding and early mobilization were the most controversial. A significant positive correlation was found between ESGO-QIs score and adherence to ERAS recommendations. This survey reveals a satisfactory surgical management in only half of the centers, and an at least sufficient adherence to ERAS recommendations. Higher the ESGO-QIs score stronger the adherence to ERAS recommendations, underlining the correlations between case volume, appropriate peri-operative management and quality of surgery. The present study is a first step to build a structured platform for harmonization within MITO-MaNGO networks.

Should indications for laterally extended endopelvic resection (LEER) exclude patients with sciatica?

Previously, indications for laterally extended endopelvic resection (LEER) have excluded patients with sciatica because R0 resection has not been deemed possible [1]. Because laparoscopy optimizes visualization and thus provides for meticulous dissection, we hypothesized that R0 resection can be achieved by means of laparoscopic LEER in patients with sciatica. This video article aimed to clarify the technical feasibility of laparoscopic LEER performed for laterally recurrent previously irradiated cervical cancer with concomitant sciatica. We investigated technical feasibility of laparoscopic LEER performed as a salvage therapy following abdominal radical hysterectomy and concurrent chemoradiotherapy in a patient suffering laterally recurrent cervical carcinoma with concomitant sciatica. The recurrent tumor involved the right external and internal iliac artery and vein, ileocecum, rectosigmoid colon, right ureter, right obturator nerve, and right sciatic nerve, with a resulting fistula between the tumor and the rectosigmoid colon, and severe sciatica. Resection of all these structures was essential for achievement of R0 status, and such resection means concomitant femoral bypass with prosthetic graft interposition and gastrointestinal/urinary tract resection. Laparoscopic LEER with femoral-femoral artery bypass could be conducted without any postoperative complications. Pathological R0 resection could be achieved, and local recurrence could have been controlled. However, the patient died from liver and lung metastasis at 1 year after this resection surgery. Laparoscopic LEER for a laterally recurrent previously irradiated cervical cancer with concomitant sciatica was technically feasible, however, further study involving a greater number of patients and longer follow-up period is warranted to determine the stringent indications.

Quantitative analysis of proteins related to chemoresistance to paclitaxel and carboplatin in human SiHa cervical cancer cells via iTRAQ

This study aimed to identify proteins related to paclitaxel and carboplatin chemoresistance in cervical cancer. Quantitative proteomic analysis was performed on normal SiHa cells and those treated with paclitaxel and carboplatin for 14 days, with isobaric tags for relative and absolute quantitation (iTRAQ) analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to identify related processes and differentially expressed proteins. A total of 67 and 96 differentially expressed proteins were identified in the paclitaxel- and carboplatin- treated groups, respectively. GO and KEGG enrichment analyses identified 53 (43 upregulated and 10 downregulated) and 85 differentially expressed proteins (70 upregulated and 15 downregulated) in the paclitaxel- and carboplatin-treated groups, respectively. The cell counting kit-8 results revealed that APOA1 was overexpressed in both the paclitaxel- and carboplatin- resistant SiHa cells compared with the control cells. Immunohistochemistry showed that APOA1 was highly expressed in the paclitaxel- and carboplatin- resistant squamous cell carcinoma of the cervix. This study is the first to use iTRAQ to identify paclitaxel- and carboplatin- resistance proteins in cervical cells. We identified several proteins previously unassociated with paclitaxel and carboplatin resistance in cervical cancer, thereby expanding our understanding of paclitaxel and carboplatin resistance mechanisms. Moreover, these findings indicate that the APOA1 protein could serve as a potential marker for monitoring and predicting paclitaxel and carboplatin resistance levels.

Effect of Pap smear screening on cervical cancer stage at diagnosis: results from the Korean National Cancer Screening Program

We aimed to determine the differences in stage at diagnosis of cervical cancer among Korean women according to screening history. Using linkage data from the Korean Central Cancer Registry and Korean National Cancer Screening Program (KNCSP), we included 18,388 women older than 30 years who were newly diagnosed with cervical cancer between 2013 and 2014 and examined their screening history. Between individuals, age group and socioeconomic status were matched to control for potential confounders. Significantly more cases of carcinoma in situ (CIS) were diagnosed in the ever-screened (71.77%) group than in the never-screened group (54.78%), while localized, regional, distant, and unknown stage were more frequent in the never-screened group. Women in the ever-screened group were most likely to be diagnosed with CIS than with invasive cervical cancer (adjusted odds ratio [aOR]=2.40; 95% confidence interval [CI]=2.18-2.65). The aOR for being diagnosed with CIS was highest among women who were screened 3 times or more (aOR=5.10; 95% CI=4.03-6.45). The ORs were highest for women screened within 24 months of diagnosis and tended to decrease with an increasing time since last screening (p-trend <0.01). The KNCSP for cervical cancer was found to be positively associated with diagnosis of cervical cancers at earlier stages among women aged 30 years or older. The benefit of screening according to time was highest for women screened within 24 months of diagnosis.

Chemotherapy response score no longer predicts survival outcomes in high-grade serous ovarian cancer patients with BRCA mutation and/or maintenance therapy

We aimed to revalidate the chemotherapy response score (CRS) system as a prognostic factor for ovarian cancer patients with breast cancer gene ( A retrospective analysis was performed using medical records of patients with high-grade serous carcinoma who received neoadjuvant chemotherapy followed by interval debulking surgery between January 2007 and December 2021 at 5 tertiary medical institutions in South Korea. At each hospital, pathologists independently assessed each slide of omental tissues obtained from surgery using the CRS system. Progression-free survival (PFS) and overall survival (OS) values were obtained using Kaplan-Meier analysis to evaluate the effect of Of 466 patients, CRS may not be a prognostic factor in patients with

Volume over location: prioritizing case volume over regional distribution in ovarian cancer treatment

The aim of this study was to examine the impact of hospital surgical volume and hospital region on overall survival (OS) in patients with ovarian cancer. This retrospective cohort study utilized nationwide claims data from Korea (2012-2020) to analyze ovarian cancer patients who underwent surgery. Hospitals were classified as high-volume (≥20) or low-volume (<20) based on the annual volume of upfront ovarian cancer surgeries. Propensity score matching (PSM) (1:1) addressed confounder imbalances between the groups. OS was assessed via Kaplan-Meier analysis, log-rank tests, and Cox regression, with subgroup analyses by cancer stage. A total of 11,510 patients were included in the cohort (high-volume: 8,241; low-volume: 3,269), with 3,236 matched pairs identified through PSM. Compared with low-volume hospitals, treatment at high-volume hospitals was associated with a 21% reduction in mortality risk (adjusted hazard ratio [aHR]=0.79; 95% confidence interval [CI]=0.70-0.89). This survival advantage persisted across localized/regional (aHR=0.77; 95% CI=0.63-0.95) and distant-stage disease (aHR=0.81; 95% CI=0.71-0.92). In contrast, hospital location (capital vs. noncapital) was not significantly associated with OS in the entire cohort (aHR=1.09; 95% CI=0.97-1.21) or in stage-specific analyses. These findings highlight that instead of simply distributing hospitals geographically, establishing high-volume surgical centers is crucial to improving survival outcomes for patients with ovarian cancer.

Clinical practice guidelines for cervical cancer: the Korean Society of Gynecologic Oncology guidelines

This fifth revised version of the Korean Society of Gynecologic Oncology practice guidelines for the management of cervical cancer incorporates recent research findings and changes in treatment strategies based on version 4.0 released in 2020. Each key question was developed by focusing on recent notable insights and crucial contemporary issues in the field of cervical cancer. These questions were evaluated for their significance and impact on the current treatment and were finalized through voting by the development committee. The selected key questions were as follows: the efficacy and safety of immune checkpoint inhibitors as first- or second-line treatment for recurrent or metastatic cervical cancer; the oncologic safety of minimally invasive radical hysterectomy in early stage cervical cancer; the efficacy and safety of adjuvant systemic treatment after concurrent chemoradiotherapy in locally advanced cervical cancer; and the oncologic safety of sentinel lymph node mapping compared to pelvic lymph node dissection. The recommendations, directions, and strengths of this guideline were based on systematic reviews and meta-analyses, and were finally confirmed through public hearings and external reviews. In this study, we describe the revised practice guidelines for the management of cervical cancer.

The pathologic and clinical outcomes of risk-reducing salpingo-oophorectomy in asymptomatic carriers of homologous recombination repair gene mutation

To investigate the prevalence of pathological findings and clinical outcomes of risk-reducing salpingo-oophorectomy (RRSO) in asymptomatic carriers with germline homologous recombination repair (HRR) gene pathogenic/likely pathogenic variants (PV/LPV). This retrospective study enrolled asymptomatic carriers with germline HR gene PV/LPV who underwent RRSO between 2006 and 2022 at the National Cancer Center in Korea. Clinical characteristics, including history of breast cancer, family history of ovarian/breast cancer, parity, and oral contraceptive use, were analyzed. Of the 255 women who underwent RRSO, 129 (50.6%) had PV/LPV in Women with HRR gene mutations PV/LPV who undergo RRSO are at a risk of detecting occult neoplasms, with a of 3.5%. Even in the absence of precursor lesions during RRSO, there was a cumulative risk of peritoneal carcinomatosis development, emphasizing the need for continued surveillance.

Major clinical research advances in gynecologic cancer in 2023: a tumultuous year for endometrial cancer

In the 2023 series, we summarized the major clinical research advances in gynecologic oncology based on communications at the conference of Asian Society of Gynecologic Oncology Review Course. The review consisted of 1) Endometrial cancer: immune checkpoint inhibitor, antibody drug conjugates (ADCs), selective inhibitor of nuclear export, CDK4/6 inhibitors WEE1 inhibitor, poly (ADP-ribose) polymerase (PARP) inhibitors. 2) Cervical cancer: surgery in low-risk early-stage cervical cancer, therapy for locally advanced stage and advanced, metastatic, or recurrent setting; and 3) Ovarian cancer: immunotherapy, triplet therapies using immune checkpoint inhibitors along with antiangiogenic agents and PARP inhibitors, and ADCs. In 2023, the field of endometrial cancer treatment witnessed a landmark year, marked by several practice-changing outcomes with immune checkpoint inhibitors and the reliable efficacy of PARP inhibitors and ADCs.

Adjuvant treatment algorithm based on recent ESGO/ESTRO/ESP guidelines for early endometrial carcinoma according to prognostic risk groups

The incidence of endometrial cancer (EC) is unfortunately increasing. Often diagnosis is made at an early stage and surgery is the curative treatment. Nevertheless, adjuvant treatment is proposed to reduce the risk of relapse. This treatment is tailored based on the extent of the disease, such as the presence of distant metastasis, the extent of involvement of adjacent organs or lymph nodes. However, histological parameters such as myometrial invasion, substantial lymphovascular space invasion, invasion of the cervical stroma or tumor grade are also key to selecting adjuvant treatment. The Cancer Genome Atlas (TCGA) project has demonstrated the superiority of molecular classification over histological evaluation in EC to determine the prognosis. The International Federation of Gynecology and Obstetrics 2023 staging for EC is the first staging system that has incorporated molecular biomarkers on top of morpho-histological classification. Currently, all patients should have a molecular profile of their tumor and a lymph node assessment. The landmark treatment of stage I-III ECs is surgery followed by radiotherapy. The European guidelines updated in 2025 has divided EC in 4 risk categories with specific adjuvant treatment. For clinicians, it is seen as a complex landscape from surveillance to chemo-radiotherapy. Therefore, we propose here a practical pocket guideline for adjuvant treatment of early-stage EC patients based on a review of the different clinical trials in the adjuvant setting and on existing guidelines. This pocket guideline may also serve as a base for incorporation of new clinical trials under the RAINBO umbrella research program.

Cancer-field surgery for endometrial cancer by robotic peritoneal mesometrial resection and targeted compartmental lymphadenectomy (PMMR+TCL)

Cancer-field surgery by peritoneal mesometrial resection and targeted compartmental lymphadenectomy (PMMR+TCL) for the treatment of endometrial cancer (EC) aims at optimal locoregional tumor control without the need for adjuvant radiotherapy. In a previous publication we could demonstrate the feasibility of the method and presented encouraging first oncologic data. Following up our 2021 publication, we present data on the treatment of EC by PMMR+TCL in much larger cohort and with longer follow-up. One hundred and thirty-five patients with EC International Federation of Gynecology and Obstetrics (FIGO) I-IV (75.6% FIGO I) underwent cancer field surgery via PMMR+TCL for EC in the years 2016-2023. Mean follow-up in our cohort was 27.5 months (0, 83; 19.7). The procedure was feasible and safe with favorable intra-and postoperative complication rates. Even though 50.4% of patients had an indication for postoperative radiotherapy following national and international guidelines, the rate of postoperative irradiation administered was 10.4%. The overall recurrence rate was 8.1% and we observed 2 (1.5%) isolated locoregional recurrences. Our results confirm the feasibility and safety of PMMR+TCL in EC patients. Oncologic data are very encouraging and hint at a superior locoregional control without adjuvant irradiation. Larger studies with longer follow-up will be needed to confirm these results.

Japan Society of Gynecologic Oncology 2022 guidelines for uterine cervical neoplasm treatment

The Japan Society of Gynecologic Oncology (JSGO) Guidelines 2022 for the Treatment of Uterine Cervical Cancer are revised from the 2017 guideline. This guideline aimed to provide standard care for cervical cancer, indicate appropriate current treatment methods for cervical cancer, minimize variances in treatment methods among institutions, improve disease prognosis and treatment safety, reduce the economic and psychosomatic burden of patients by promoting the performance of appropriate treatment, and enhance mutual understanding between patients and healthcare professionals. The guidelines were prepared through the consensus of the JSGO Guideline Committee, based on a careful review of evidence gathered through the literature searches and the medical health insurance system and actual clinical practice situations in Japan. The guidelines comprise seven chapters and 5 algorithms. The main features of the 2022 revision are as follows: 1) added discussed points at the final consensus meeting; 2) revised the treatment methods based on the International Federation of Gynecology and Obstetrics 2018 staging system; 3) examined minimally invasive surgery based on Laparoscopic Approach to Cervical Cancer trial; 4) added clinical question (CQ) for treatments of rare histological types, gastric type, and small-cell neuroendocrine carcinoma; 5) added CQ for intensity-modulated radiation therapy; 6) added CQ for cancer genomic profiling test; and 7) added CQ for cancer survivorship. Each recommendation is accompanied by a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here, we present the English version of the JSGO Guidelines 2022 for the Treatment of Uterine Cervical Cancer.

Efficacy and prognosis of robotic surgery with sentinel node navigation surgery in endometrial cancer

This study aimed to validate the surgical and oncologic outcomes of robotic surgery with sentinel node navigation surgery (SNNS) in endometrial cancer. This study included 130 patients with endometrial cancer, who underwent robotic surgery, including hysterectomy, bilateral salpingo-oophorectomy, and pelvic SNNS at the Department of Obstetrics and Gynecology of Kagoshima University Hospital. Pelvic sentinel lymph nodes (SLNs) were identified using the uterine cervix 99m Technetium-labeled phytate and indocyanine green injections. Surgery-related and survival outcomes were also evaluated. The median operative and console times and volume of blood loss were 204 (range: 101-555) minutes, 152 (range: 70-453) minutes, and 20 (range: 2-620) mL, respectively. The bilateral and unilateral pelvic SLN detection rates were 90.0% (117/130) and 5.4% (7/130), respectively, and the identification rate (the rate at which at least one SLN could be identified on either side) was 95% (124/130). Lower extremity lymphedema occurred in only 1 patient (0.8%), and no pelvic lymphocele occurred. Recurrence occurred in 3 patients (2.3%), and the recurrence site was the abdominal cavity, with dissemination in 2 patients and vaginal stump in one. The 3-year recurrence-free survival and 3-year overall survival rates were 97.1% and 98.9%, respectively. Robotic surgery with SNNS for endometrial cancer showed a high SLN identification rate, low occurrence rates of lower extremity lymphedema and pelvic lymphocele, and excellent oncologic outcomes.

Circ_0075960 targets the miR-202-5p/CTNND1 axis to promote the growth and migration of endometrial carcinoma cells via regulating Wnt/β-catenin signaling activity

Endometrial carcinoma (EC) is one of the most common malignant tumors of the female reproductive tract, involving multiple molecular alterations. Circular RNA (circRNA) dysregulation is frequently observed in EC tissues, suggesting the involvement of circRNA in EC development. We aimed to investigate the role of circ_0075960 in EC. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot assays were applied for expression analysis. CCK-8, EdU, colony formation, flow cytometry and wound healing assays were employed for functional analysis. The predicted binding relationship between miR-202-5p and circ_0075960 or CTNND1 was validated by dual-luciferase reporter experiment. Circ_0075960 and CTNND1 were upregulated, while miR-202-5p was downregulated in EC. Knockdown of circ_0075960 induced EC cell apoptosis, suppressed cell proliferation and migration, and repressed tumor growth in animal models. MiR-202-5p was targeted by circ_0075960 and it directly bound to CTNND1 3'UTR. The inhibition of circ_0075960 knockdown or miR-202-5p enrichment on EC cell proliferation and migration was reversed by miR-202-5p depletion or CTNND1 overexpression, respectively. Circ_0075960 targeted miR-202-5p to positively regulate CTNND1 expression. Moreover, circ_0075960 knockdown weakened the activity of Wnt/β-catenin signaling via targeting the miR-202-5p/CTNND1 axis. Circ_0075960 targets the miR-202-5p/CTNND1 axis to modulate Wnt/β-catenin signaling activity, thus contributing to the malignant development of EC.

Levonorgestrel-releasing intrauterine system-based therapies for early-stage endometrial cancer: a systematic review and meta-analysis

To conduct a systematic review and meta-analysis of studies evaluating the oncological and fertility outcomes of early-stage endometrial cancer (EC) treated with the levonorgestrel-releasing intrauterine system (LIUS)-based regimens. The Meta-analyses Of Observational Studies in Epidemiology statement for meta-analyses was followed. Searches were conducted on MEDLINE, Embase, PubMed, Preprints, and the Cochrane Central Register of Controlled Trials from January 1990 to August 4, 2022. The Joanna Briggs Institute Critical Appraisal Checklist was used for quality assessment. The primary endpoint was the complete response (CR) rate and the secondary endpoints were relapse, pregnancy, and live birth rate. A total of 25 studies (821 women) were included. The CR rate of LIUS-based regimens was 63.4% (95% confidence interval [CI]=52.3%-73.2%), with 29.6% (95% CI=23.3%-36.8%) of cases experiencing recurrence during follow-up. In sensitivity analyses, patients younger than 45 years of age with a body mass index <30 kg/m² who were treated with LIUS-based regimens achieved a high CR rate of 84.6% (95% CI=80.3%-88.1%) over a median follow-up of more than 24 months. Overall pregnancy and live birth rates were 37.9% (95% CI=24.1%-53.9%) and 39.3% (95% CI=24.0%-57.0%), respectively. No statistical differences were apparent in CR or relapse rates among the LIUS+GnRH agonist, LIUS+oral progesterone, or hysteroscopic resection followed by LIUS subgroups. LIUS-based therapies are viable for the conservative management of early-stage endometrioid EC on CR and fertility outcome. PROSPERO Identifier: CRD42022352890.

Elucidation of genomic origin of synchronous endometrial and ovarian cancer (SEO) by genomic and microsatellite analysis

Elucidation of clonal origin of synchronous endometrial and ovarian cancers (SEOs). We reviewed 852 patients who diagnosed endometrial and/or ovarian cancer. Forty-five (5.3%) patients were diagnosed as SEOs. We evaluated blood and tissue samples from 17 patients. We analyzed the clonal origins of 41 samples from 17 patients by gene sequencing, mismatch microsatellite instability (MSI) polymerase chain reaction assay and immunohistochemical (IHC) staining of 4 repair genes. Sixteen of 17 patients had at least 2 or more trunk mutations shared between endometrial and ovarian cancer suggesting the identical clonal origins. The shared trunk mutation are frequently found in endometrial cancer of the uterus, suggesting the uterine primary. Four out of 17 (24%) SEOs had mismatch repair (MMR) protein deficiency and MSI-high (MSI-H) states. One case was an endometrial carcinoma with local loss of MSH6 protein expression by IHC staining, and the result of MSI analysis using the whole formalin-fixed, paraffin-embedded specimen was microsatellite stable. In contrast, ovarian tissue was deficient MMR and MSI-H in the whole specimen. This indicated that MMR protein deficiency could occur during the progression of disease. Most SEOs are likely to be a single tumor with metastasis instead of double primaries, and their origin could be endometrium. In addition, SEOs have a high frequency of MMR gene abnormalities. These findings not only can support the notion of uterine primary, but also can help to expect the benefit for patients with SEOs by immuno-oncology treatment.

Recurrence risk factors in stage IA grade 1 endometrial cancer

Patients with early-stage endometrial cancers (EC) with disease recurrences have worse survival outcomes. The purpose of this study was to identify clinical and pathologic factors that predict for all recurrences in stage IA grade 1 (IAG1) EC. Records from patients diagnosed with EC were retrospectively reviewed. Baseline characteristics of 222 patients with IAG1 EC who underwent surgical resection were analyzed. Cox proportional hazard analysis was used to identify univariate and multivariate risk factors that predict for recurrence. Seventeen (7.65%) patients had recurrences. The 3-year cumulative incidence of recurrence were significantly higher for patients with time from biopsy to surgery ≥6 months (54% vs. 8%, p=0.003), simple hysterectomy with ovarian preservation vs. total hysterectomy and bilateral salpingo-oophorectomy (31% vs. 9%, p=0.032), any myometrial invasion vs. no invasion (18% vs. 2%, p=0.004), and tumor size ≥2 cm (15% vs. 2%, p=0.021). On, multivariate analysis, any myometrial invasion, increasing time from biopsy to surgery, and larger tumor size were independent predictors of any recurrence. Patients with recurrences had worse outcomes than those without (5-year overall survival [OS]=60%; 95% confidence interval [CI]=16%-86% vs. 5-year OS=95%; 95% CI=87%-99%, respectively, p=0.003). Time from biopsy to surgery, larger tumors, and myometrial invasion are the most important predictors of recurrence. Though the recurrence rates are generally low in IAG1 EC, the survival rate for the patients with recurrences was worse than those without. Identification of additional recurrence risk factors can help select patients who may benefit from adjuvant treatment.

Conditional relative survival of patients with endometrial cancer: a Korean National Cancer Registry study

The purpose of this study was to estimate 5-year conditional relative survival (5Y CRS) rates of endometrial cancer (EC) in Korea accounting for time already survived. Subgroup-specific estimates stratified by various patient characteristics were also presented. Using the data from the Korean Central Cancer Registry, 5Y CRS rates were calculated in patients who were diagnosed with EC between 1998 and 2017. The CRS rates were presented by year of diagnosis, age at diagnosis, histology, cancer stage, and treatment received. The 5-year relative survival rate at the time of diagnosis was 89.0% for all cases. The probability of surviving an additional 5 years (i.e., 5Y CRS), if the patient survived 1, 2, 3, 4, and 5 years after diagnosis was 91.8%, 94.1%, 95.6%, 96.5%, and 97.3%, respectively. Patients with poor initial prognoses, i.e., those who were older, had non-endometrioid histology, and high stage, showed the largest improvements in 5Y CRS, reaching >90% for most subgroups, except those with serous histology (88.4%) and distant stage (77.7%). Patients aged ≥70 years had the highest probability of death in the 1st and 2nd years after diagnosis (13.8 and 11.0%), but the conditional probability of death in the 3rd, 4th, and 5th years declined rapidly to 7.3%, 4.5%, and 3.7%, respectively. The CRS rates for patients with EC improved with increased time elapsed from diagnosis. The greatest improvements in 5Y CRS were observed among patients who were older, those with non-endometrioid histology, and those with more advanced disease.

Clinical evaluation of a droplet digital PCR assay for detecting POLE mutations and molecular classification of endometrial cancer

We evaluated droplet digital polymerase chain reaction (ddPCR) method for detecting We reviewed 240 EC specimens from our hospital database. A ddPCR assay was used to identify The ddPCR assay identified Hotspot

Reclassification of BRCA1 and BRCA2 variants found in ovarian epithelial, fallopian tube, and primary peritoneal cancers

We investigated the proportions of and reclassified Data from 805 patients who underwent genetic testing for A Approximately 33.3% (36/108) of the specific

Real world effectiveness and safety of pegylated liposomal doxorubicin in platinum-sensitive recurrent ovarian, fallopian, or primary peritoneal cancer: a Korean multicenter retrospective cohort study

To evaluate the effectiveness and safety of the combination of pegylated liposomal doxorubicin with carboplatin (CD) compared with those of carboplatin and paclitaxel (CP) for platinum-sensitive recurrent ovarian, fallopian, or primary peritoneal cancer in a real-world setting in Korea. We enrolled relevant patients from 9 institutions. All patients received CD or CP as the second- or third-line chemotherapy in routine clinical practice during 2013-2018. The primary endpoints were progression-free survival (PFS) and toxicity. The secondary endpoint included the objective response rate (ORR). Overall, 432 patients (224 and 208 in the CD and CP groups, respectively) were included. With a median follow-up of 18.9 months, the median PFS was not different between the groups (12.7 vs. 13.6 months; hazard ratio, 1.161; 95% confidence interval, 0.923-1.460; p=0.202). The ORR was 74.6% and 80.1% in the CD and CP group, respectively (p=0.556). Age and surgery at relapse were independent prognostic factors. More patients in the CD group significantly experienced a grade 3 to 4 hematologic toxicity and hand-foot syndrome (13.8% vs. 6.3%), whereas grade 2 or more alopecia (6.2% vs. 36.1%), peripheral neuropathy (4.4% vs. 11.4%), and allergic/hypersensitivity reaction (0.4% vs. 8.5%) developed more often in the CP group. The safety and effectiveness of chemotherapy with CD in a real-world setting were consistent with the results from a randomized controlled study. The different toxicity profiles between the 2 chemotherapy (CD and CP) regimens should be considered in the clinical practice. ClinicalTrials.gov Identifier: NCT03562533.

Postoperative conventional versus hypofractionated intensity-modulated radiation therapy with concurrent chemotherapy in cervical cancer: a prospective multicenter randomized phase III trial (POHIM_P3 trial)

For patients with high-risk factors such as pelvic lymph node metastasis, positive surgical margins, or parametrial involvement, concurrent chemoradiotherapy (CCRT) with whole-pelvic radiotherapy significantly improves survival outcomes. Hypofractionated radiation therapy, which delivers higher radiation doses over fewer sessions, enhances tumor control but raises concerns about increased normal tissue toxicity. A recent Korean phase II study (POHIM-CCRT) evaluated the safety of hypofractionated intensity-modulated radiation therapy (IMRT), delivering 40 Gy in 16 fractions with weekly cisplatin following radical surgery. The results showed minimal acute toxicity. Based on these findings, the present study was designed to assess the oncologic efficacy of hypofractionated CCRT compared to conventional treatment strategies in high-risk cervical cancer patients after radical surgery. The POHIM-P3 trial is a phase 3, randomized, multicenter study designed for women with cervical cancer requiring adjuvant CCRT after radical hysterectomy. Participants in the experimental arm receive hypofractionated IMRT to whole pelvis, delivering a total dose of 40 Gy in 16 fractions, and the control arm receive conventional radiotherapy with a total dose of 45-50.4 Gy in 25-28 fractions in combination with weekly cisplatin. The primary endpoint of the study is the 3-year disease-free survival and the secondary endpoints included acute and late side-effects, local control rates, and overall survival rates. ClinicalTrials.gov Identifier: NCT06509724.

HER2-negative or low expression as an unfavorable prognostic factor in patients with stage I/II uterine carcinosarcoma

Uterine carcinosarcoma (UCS) is uncommon high-grade endometrial cancer with limited treatment options. We evaluated the prognostic significance of human epidermal growth factor receptor 2 (HER2) expression and HER2 gene amplification within large cohorts of UCS, and clarify clinicopathologic characteristics of HER2-low UCS. We examined HER2 protein expression in 148 patients of UCS using in vivo diagnostic HER2 immunohistochemistry (IHC) kits and HER2 gene amplification using fluorescence in situ hybridization (FISH) in 72 patients. HER2 IHC score was evaluated according to the latest American Society of Clinical Oncology/College of American Pathologists criteria for gastric cancer, which was negative in 41 patients, low expression of 1+ was observed in 57 patients, and HER2 high expression was observed in 50 patients (2+ in 38 and 3+ in 12 patients). There was no significant statistical difference in clinicopathological characteristics based on HER2 protein expression status. HER2 negative and low expression compared to high expression revealed poor overall survival in stage I/ II. The concordance between IHC and FISH results were relatively low compared to other cancer types (HER2 IHC score 1+, 2+, and 3+ were 5%, 15%, and 50%), and combining these results was not efficient as a prognostic factor in UCS. In contrast, the HER2 IHC score alone was a prognostic factor in stage I/II UCS. HER2 low group did not show specific clinicopathologic features. Since the HER2 IHC score low in advanced UCS is a predictive factor, stratification of UCS using HER2 IHC score for HER2 IHC score low group and developing adjuvant therapy may be proposed in the near future.

Cisplatin-induced PANDAR-Chemo-EVs contribute to a more aggressive and chemoresistant ovarian cancer phenotype through the SRSF9-SIRT4/SIRT6 axis

We previously elucidated that long non-coding RNA Promoter of CDKN1A Antisense DNA damage Activated RNA (PANDAR) as a p53-dependent oncogene to promote cisplatin resistance in ovarian cancer (OC). Intriguingly, high level of p53-independent PANDAR was found in cisplatin-resistant patients with p53 mutation. Here, our study probed the new roles and the underlying mechanisms of PANDAR in p53-mutant OC cisplatin-resistance. A2780 and A2780-DDP cells were served as OC cisplatin-sensitive and cisplatin-resistant cells. HO-8910PM cells were subjected to construct chemotherapy-induced extracellular vesicles (Chemo-EVs). Transmission electron microscopy (TEM) and nanoparticle tracking analysis were employed to evaluate Chemo-EVs. Cell viability was assessed using cell counting kit-8 and colony formation assays. Cell apoptosis was assessed using Annexin V and propidium iodide staining. The relationships between PANDAR, serine and arginine-rich pre-mRNA splicing factor 9 (SRSF9) were verified by RNA immunoprecipitation and fluorescence in situ hybridization. Tumor xenograft experiment was employed to evaluate the effects of PANDAR-Chemo-EVs on OC cisplatin-resistance in vivo. Immunofluorescent staining and immunohistochemistry were performed in tumor tissue. PANDAR level increased in OC patients with p53-mutation. PANDAR efflux enacted via exosomes under cisplatin conditions. Additionally, exosomes from OC cell lines carried PANDAR, which significantly increased cell survival and chemoresistance in vitro and tumor progression and metastasis in vivo. During cisplatin-induced stress, SRSF9 was recruited to nuclear bodies by increased PANDAR and muted apoptosis in response to cisplatin. Besides, SRSF9 significantly increased the ratio of SIRT4/SIRT6 mRNA in OC. Cisplatin-induced exosomes transfer PANDAR and lead to a rapid adaptation of OC cell survival through accumulating SRSF9 following cisplatin stress exposure.

Cost-effectiveness of tisotumab vedotin as a second- or third-line therapy for cervical cancer

To evaluate the cost-effectiveness of tisotumab vedotin to treat recurrent or metastatic cervical cancer in second- or third-line from the U.S. payer perspective. A Markov model with three-state was employed to simulate recurrent or metastatic cervical cancer patients who were administered either tisotumab vedotin or investigator's choice of chemotherapy based on the phase III, open-labeled innovaTV 301 randomized clinical trial. The data on cost and health preferences were collected from the literature. Tisotumab vedotin generated an additional 0.25 quality-adjusted life-years (QALYs) compared to chemotherapy, but at an additional cost of $206,779. This results in incremental cost-effectiveness ratios of $839,107.88 per QALY. The results of the univariate sensitivity analysis indicated that cost of tisotumab vedotin, utility of progressive disease and progression-free survival had the greatest impacts on the outcomes. Probability sensitivity analysis showed that tisotumab vedotin had a 0% chance of being considered cost-effective. Tisotumab vedotin was unlikely cost-effective compared to chemotherapy for recurrent or metastatic cervical cancer patients at a willingness-to-pay threshold of $150,000/QALY from the perspective of a U.S. payer. Lowering the prices of tisotumab vedotin could potentially enhance its cost-effectiveness.

HPV vaccination status and effectiveness in Korean women with HPV16/18 infection (2010–2021): a retrospective study

To evaluate human papillomavirus (HPV) vaccine effectiveness in a cohort of Korean women infected with HPV. From 2010 to 2021, Korean women aged 20-60 years who diagnosed HPV-positive atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion were recruited from 6 hospitals. HPV vaccine effectiveness was estimated by observing the differences in pathological and clinical information and experimental results-prevalence, viral load (VL), physical state (PS), and HPV16/18 infection duration-between the vaccinated and unvaccinated groups. HPV16/18 prevalence declined from 18.5% to 11.8% as vaccination rates increased from 14.3% to 60.7% in the 1,757 registered cohort women. DNA analysis from 96 samples collected from the participants, indicated that HPV vaccination reduced HPV16 VL by 6 times and increased E2/E6 ratio for both HPV16 and HPV18 by 1.4 and 5 times, respectively. The HPV16 infection rate-lasting more than 18 months from 31.0% to 21.6%-and the HPV18 infection rate-lasting more than 12 and less than 24 months from 35.5% to 21.1%-were reduced by vaccination. We found VL and the infection duration to be directly proportional. Moreover, HPV vaccination reduced not only the VL to 1/4 in both the persistence and clearance groups but also the persistence rate from 90% (27/30) to 70.6% (12/17) in HPV16. HPV vaccination reduced the prevalence and duration of infection and kept the PS in an episomal form for both HPV16 and HPV18. The tendency of persistence VL to be higher than clearance in the unvaccinated group implies that the vaccine's effect of reducing VL in HPV16 may lower the risk of progression to cervical cancer by shortening the infection duration.

A phase 1/2a, dose-escalation, safety, and preliminary efficacy study of the RKP00156 vaginal tablet in healthy women and patients with cervical intraepithelial neoplasia 2

This study aimed to determine the safety and efficacy of the RKP00156 vaginal tablet, a CDK9 inhibitor, in healthy women and patients with cervical intraepithelial neoplasia grade 2 (CIN2). We conducted a phase 1/2a clinical trial of RKP00156. In step 1, RKP00156 at a dose of 10, 25, or 50 mg or a placebo tablet was administered transvaginally to 24 healthy women. In step 2, RKP00156 at a dose of 10, 25, or 50 mg or a placebo tablet was administered once daily for 4 weeks in 62 patients with CIN2. The primary endpoints of this trial were the safety of RKP00156 and the change in the human papillomavirus (HPV) viral load. A total of 86 patients were enrolled and randomized. RKP00156 administration did not cause serious drug-associated adverse events (AEs). Although no significant difference in the HPV viral load was found between the experimental and placebo groups, a reduction in the HPV viral load was observed in the 25 mg-dose group (-98.61%; 95% confidence interval=-99.83%, 4.52%; p=0.046) after treatment completion in patients with a high HPV viral load, despite a lack of statistical power. No differences in histologic regression and HPV clearance were observed. The safety of RKP00156 was proved with no serious AEs. Although the study did not show any significance in histologic regression and HPV clearance, our findings indicate that RKP00156 may have a possibility of short-term inhibitory effect on HPV replication in patients with higher viral loads. ClinicalTrials.gov Identifier: NCT02139267.

Anti-cancer effect of fenbendazole-incorporated PLGA nanoparticles in ovarian cancer

Fenbendazole (FZ) has potential anti-cancer effects, but its poor water solubility limits its use for cancer therapy. In this study, we investigated the anti-cancer effect of FZ with different drug delivery methods on epithelial ovarian cancer (EOC) in both in vitro and in vivo models. EOC cell lines were treated with FZ and cell proliferation was assessed. The effect of FZ on tumor growth in cell line xenograft mouse model of EOC was examined according to the delivery route, including oral and intraperitoneal administration. To improve the systemic delivery of FZ by converting fat-soluble drugs to hydrophilic, we prepared FZ-encapsulated poly(D,L-lactide-co-glycolide) acid (PLGA) nanoparticles (FZ-PLGA-NPs). We investigated the preclinical efficacy of FZ-PLGA-NPs by analyzing cell proliferation, apoptosis, and in vivo models including cell lines and patient-derived xenograft (PDX) of EOC. FZ significantly decreased cell proliferation of both chemosensitive and chemoresistant EOC cells. However, in cell line xenograft mouse models, there was no effect of oral FZ treatment on tumor reduction. When administered intraperitoneally, FZ was not absorbed but aggregated in the intraperitoneal space. We synthesized FZ-PLGA-NPs to obtain water solubility and enhance drug absorption. FZ-PLGA-NPs significantly decreased cell proliferation in EOC cell lines. Intravenous injection of FZ-PLGA-NP in xenograft mouse models with HeyA8 and HeyA8-MDR significantly reduced tumor weight compared to the control group. FZ-PLGA-NPs showed anti-cancer effects in PDX model as well. FZ-incorporated PLGA nanoparticles exerted significant anti-cancer effects in EOC cells and xenograft models including PDX. These results warrant further investigation in clinical trials.

Diverse genetic spectrum among patients who met the criteria of hereditary breast, ovarian and pancreatic cancer syndrome

Genetic high-risk assessment combines hereditary breast, ovarian and pancreatic cancer into one syndrome. However, there is a lack of data for comparing the germline mutational spectrum of the cancer predisposing genes between these three cancers. Patients who met the criteria of the hereditary breast, ovarian and pancreatic cancer were enrolled and received multi-gene sequencing. We enrolled 730 probands: 418 developed breast cancer, 185 had ovarian cancer, and 145 had pancreatic cancer. Out of the 18 patients who had two types of cancer, 16 had breast and ovarian cancer and 2 had breast and pancreatic cancer. A total of 167 (22.9%) patients had 170 mutations. Mutation frequency in breast, ovarian and pancreatic cancer was 22.3%, 33.5% and 17.2%, respectively. The mutation rate was significantly higher in patients with double cancers than those with a single cancer (p<0.001). The mutation spectrum varies across the three cancer types and family histories. Our analysis provides guidance for physicians, counsellors, and counselees on the offer and uptake of genetic counseling.

An attempt to establish real-world databases of poly(ADP-ribose) polymerase inhibitors for advanced or recurrent epithelial ovarian cancer: the Japanese Gynecologic Oncology Group

The development of new treatments for gynecological malignancies has been conducted mainly through collaborative international phase III trials led by the United States and Europe. The survival outcomes of many gynecological malignancies have greatly improved as a result. Recent large-scale genome-wide association studies have revealed that drug efficacy and adverse event profiles are not always uniform. Thus, it is important to validate new treatment options in each country to safely and efficiently provide newly developed treatment options to patients with gynecological malignancies. The Japanese Gynecologic Oncology Group (JGOG) is conducting 5 cohort studies (JGOG 3026, 3027, 3028, 3030, and 3031) to establish real-world data (RWD) of poly(ADP-ribose) polymerase (PARP) inhibitor use in patients with advanced or recurrent epithelial ovarian cancer. The RWD constructed will be used to provide newly developed PARP inhibitors for women with advanced or recurrent ovarian cancer in a safer and more efficient manner as well as to develop further treatment options. In 2022, The JGOG, Korean Gynecologic Oncology Group, Chinese Gynecologic Cancer Society, and Taiwanese Gynecologic Oncology Group established the East Asian Gynecologic Oncology Trial Group to collaborate with East Asian countries in clinical research on gynecologic malignancies and disseminate new knowledge on gynecologic malignancies from Asia. The JGOG will conduct a collaborative integrated analysis of the RWD generated from Asian countries and disseminate real-world clinical knowledge regarding new treatment options that have been clinically implemented.

Major clinical research advances in gynecologic cancer in 2022: highlight on late-line PARP inhibitor withdrawal in ovarian cancer, the impact of ARIEL-4, and SOLO-3

In the 2022 series, we summarized the major clinical research advances in gynecologic oncology based on communications at the conference of Asian Society of Gynecologic Oncology Review Course. The review consisted of 1) Ovarian cancer: long-term follow-up data, new poly (ADP-ribose) polymerase (PARP) inhibitors, overall survival (OS) issues with PARP inhibitor monotherapy, hyperthermic intraperitoneal chemotherapy, immunotherapy, and antibody-drug conjugate; 2) Cervical cancer: surgery in early stage disease, therapy for locally advanced stage and advanced, metastatic, or recurrent setting; and 3) Corpus cancer: follow-up regimen, immune checkpoint inhibitor, WEE1 inhibitor, selective inhibitor of nuclear export. A special note was made on the withdrawal of PARP inhibitor from the market for heavily pretreated ovarian cancer patients based on the final OS results of ARIEL-4 and SOLO-3 due to concerns of increased risk of death.

Recent breakthroughs in the management of locally advanced and recurrent/metastatic cervical cancer

Cervical cancer continues to be a global threat affecting individuals in resource poor communities disproportionately. The treatment paradigm for this disease is ever evolving with recent innovations propelling oncologic outcomes to a new frontier offering survival benefits for patients struggling with locally advanced disease and metastatic/recurrent carcinoma. Immunologic checkpoint inhibitors and anti-body drug conjugates represent two novel drug classes that have demonstrable activity in this disease, particularly in the first-line and second-line treatment paradigm for recurrence. The tolerability of these novel medicines and associated durable responses underscore regulatory approval by the U.S. Food and Drug Administrations and their implementation in clinic.

Histopathological subtyping of high-grade serous ovarian cancer using whole slide imaging

We have established 4 histopathologic subtyping of high-grade serous ovarian cancer (HGSOC) and reported that the mesenchymal transition (MT) type has a worse prognosis than the other subtypes. In this study, we modified the histopathologic subtyping algorithm to achieve high interobserver agreement in whole slide imaging (WSI) and to characterize the tumor biology of MT type for treatment individualization. Four observers performed histopathological subtyping using WSI of HGSOC in The Cancer Genome Atlas data. As a validation set, cases from Kindai and Kyoto Universities were independently evaluated by the 4 observers to determine concordance rates. In addition, genes highly expressed in MT type were examined by gene ontology term analysis. Immunohistochemistry was also performed to validate the pathway analysis. After algorithm modification, the kappa coefficient, which indicates interobserver agreement, was greater than 0.5 (moderate agreement) for the 4 classifications and greater than 0.7 (substantial agreement) for the 2 classifications (MT vs. non-MT). Gene expression analysis showed that gene ontology terms related to angiogenesis and immune response were enriched in the genes highly expressed in the MT type. CD31 positive microvessel density was higher in the MT type compared to the non-MT type, and tumor groups with high infiltration of CD8/CD103 positive immune cells were observed in the MT type. We developed an algorithm for reproducible histopathologic subtyping classification of HGSOC using WSI. The results of this study may be useful for treatment individualization of HGSOC, including angiogenesis inhibitors and immunotherapy.

Effectiveness and safety of nab-paclitaxel and platinum as first-line chemotherapy for ovarian cancer: a retrospective study

To evaluate the effectiveness and safety of nab-paclitaxel plus platinum as first-line chemotherapy for ovarian cancer (OC). Patients administered platinum combined with nab-paclitaxel as first-line chemotherapy for epithelial OC, fallopian tube cancer, or primary peritoneal cancer from July 2018 to December 2021 were retrospectively evaluated. The primary outcome was progression-free survival (PFS). Adverse events (AEs) were examined. Subgroup analysis was performed. Seventy-two patients (median age, 54.5 years; range, 20.0-79.0 years) were evaluated, including 12 and 60 administered neoadjuvant therapy and primary surgery with subsequent chemotherapy, respectively. The median follow-up duration was 25.6 months, and the median PFS was 26.7 (95% confidence interval [CI]=24.0-29.3) months in the whole patient population. In the neoadjuvant subgroup, the median PFS was 26.7 (95% CI=22.9-30.5) months vs. 30.1 (95% CI=23.1-37.1) months in the primary surgery subgroup. Twenty-seven patients were administered nab-paclitaxel plus carboplatin and had a median PFS of 30.3 (95% CI=not available [NA]-NA) months. The commonest grade 3-4 AEs included anemia (15.3%), white blood cell decreased (11.1%), and neutrophil count decreased (20.8%). No drug-related hypersensitivity reactions occurred. Nab-paclitaxel plus platinum as first-line treatment in OC was associated with a favorable prognosis and was tolerable in patients with OC.

RAD51/geminin/γH2AX immunohistochemical expression predicts platinum-based chemotherapy response in ovarian high-grade serous carcinoma

The RAD51 assay is a recently developed functional assay for homologous recombination deficiency (HRD) that reflects real-time HRD status. We aimed to identify the applicability and predictive value of RAD51 immunohistochemical expression in pre- and post-neoadjuvant chemotherapy (NAC) samples of ovarian high-grade serous carcinoma (HGSC). We evaluated the immunohistochemical expression of RAD51/geminin/γH2AX in ovarian HGSC before and after NAC. In pre-NAC tumors (n=51), 74.5% (39/51) showed at least 25% of γH2AX-positive tumor cells, suggesting endogenous DNA damage. The RAD51-high group (41.0%, 16/39) showed significantly worse progression-free survival (PFS) compared to the RAD51-low group (51.3%, 20/39) (p High RAD51 expression was significantly associated with worse PFS in HGSC, and post-NAC RAD51 status showed higher association than pre-NAC RAD51 status. Moreover, RAD51 status can be evaluated in a significant proportion of treatment-naïve HGSC samples. As RAD51 status dynamically changes, sequential follow-up of RAD51 status might reflect the biological behavior of HGSCs.

Reconstruction of the diaphragm with autologous fascia lata during cytoreduction in patients with advanced ovarian cancer

Cytoreductive surgery for patients with advanced ovarian cancer often requires full-thickness resection of the diaphragm [1]. In most cases, the diaphragm can be closed directly; however, when the defect is wide and simple closure is difficult, reconstruction using a synthetic mesh is usually performed [2]. However, the use of this type of mesh is contraindicated in the presence of concomitant intestinal resections because of the risk of bacterial contamination [3]. Autologous tissue shows a higher resistance to infection than artificial materials [4]; thus, we introduce diaphragm reconstruction using autologous fascia lata during cytoreduction for advanced ovarian cancer. A patient with advanced ovarian cancer underwent right diaphragmatic full-thickness resection with concomitant resection of the rectosigmoid colon, and complete resection was achieved. The defect of the right diaphragm measured 12×8 cm, and direct closure was impossible. A section of the right fascia lata measuring 10×5 cm was harvested and sutured to the diaphragmatic defect with a 2-0 proline continuous suture. The harvesting of the fascia lata required only 20 minutes, with little blood loss. No intraoperative or postoperative complications were experienced, and adjuvant chemotherapy was initiated without any delay. Diaphragm reconstruction with the fascia lata is a safe and simple method, and we propose this reconstruction technique especially for patients with advanced ovarian cancer who undergo concomitant intestinal resections. The informed consent for use of this video was taken from the patient.

Improved bladder function in radical hysterectomy without worsening oncologic outcome: resection of the posterior layer of the vesicouterine ligament with the procedure limited to the vesical veins

The classic Okabayashi nerve-sparing radical hysterectomy involves complete resection of the posterior leaf of the vesicouterine ligament, whereas in the simplified nerve-sparing radical hysterectomy, only the vesical veins and some connective tissue of the posterior layer of the vesicouterine ligament are resected. This study aimed to compare bladder function and cervical carcinoma relapse-free survival between these two techniques. We conducted a retrospective, historical control study. All female patients aged >20 years who were diagnosed with cervical cancer stage IB1-IIB and underwent radical hysterectomy with pelvic lymphadenectomy between 2009 and 2022 were enrolled. Patients who had a history of other cancers and those who were treated with non-surgical approaches or non-radical hysterectomy were excluded. The primary outcome was relapse-free survival during the follow-up period. A total of 114 patients who underwent curative-intent radical hysterectomy were included in this study. The median follow-up duration was 60 months. No significant difference was observed in relapse-free survival between the two surgical procedures. The simplified nerve-sparing radical hysterectomy was superior in terms of both motor and sensory bladder function outcomes. Resection of the posterior layer of the vesicouterine ligament, with the procedure limited to the vesical veins, is an effective and safe method for radical hysterectomy. It may be more useful for preserving the bladder function, without leading to unfavorable oncologic outcomes.

The value of PET/CT for cytoreductive surgery selection in recurrent ovarian carcinoma

To evaluate the value of positron emission tomography/computed tomography (PET/CT) in predicting no residual disease (NRD) after secondary cytoreductive surgery (SCS) compared with MSK criteria, the iMODEL, and the AGO score. We analyzed 112 patients with platinum-sensitive ovarian carcinoma who underwent SCS. We excluded patients for whom PET/CT was not performed, those without sufficient data, and who received chemotherapy before SCS. Ultimately, 69 patients were included. Variables that correlated with NRD were peritoneal carcinomatosis index (odds ratio [OR]=0.91; 95% confidence interval [CI]=0.83-0.99; p=0.044), European Cooperative Oncology Group Performance Status (ECOG) 0 (OR=8.0; 95% CI=1.34-47.5; p=0.022), and ≤2 lesions by PET/CT (OR=4.36; 95% CI=1.07-17.7; p=0.039). Of the patients with ≤2 lesions by PET/CT, 48 (92.3%) underwent complete SCS. The sensitivity, positive predictive value, negative predictive value, and accuracy of PET/CT for NRD were 85.7%, 92.3%, 33.3%, and 81.2%, respectively. NRD was achieved after fulfilling the MSK criteria, iMODEL and AGO Score in 89.1%, 88.1% and 85.9%, respectively. The accuracy of the MSK criteria, iMODEL, and AGO score in predicting NRD was 87%, 83.3%, and 77.3%, respectively. The PET/CT findings agreed well with the AGO score and iMODEL. The addition of PET/CT to these models increased the NRD rates (92.2%, 91.8%, and 89.4% for MSK+PET/CT, iMODEL+PET/CT, and AGO+PET/CT, respectively), but lowered their accuracy. We observed NRD in 92.3% of patients with ≤2 lesions by PET/CT, with an accuracy of 81.2%. PET/CT did not increase the accuracy of the MSK criteria, iMODEL, or AGO score models.

Can surgery boost the survival benefit of chemoradiotherapy in T1b1-T2a1 stage cervical cancer with lymph node metastasis? A population-based study

This study aimed to determine whether surgery followed by adjuvant chemoradiotherapy has superior survival outcomes for node-positive patients with T1b1-T2a1 stage cervical cancer compared with those who undergo chemoradiation. We investigated the Surveillance, Epidemiology, and End Results database for 12,701 patients diagnosed between 2000 and 2018. Patients were stratified according to different T stages and different treatment strategies. Surgery included radical hysterectomy (RH) or total hysterectomy (TH). Radiotherapy (RT) included adjuvant chemoradiation or chemoradiation alone. Cox analyses were performed to select the clinically important factors of survival outcomes. Survival analysis was used to compare those who received different treatment methods. A total of 12,701 International Federation of Gynecology and Obstetrics 2018 stage IIIC cervical cancer patients were identified. The risk of overall survival (OS) was significantly different between patients who received and did not receive chemoradiotherapy in the T categories. In the propensity-score matched dataset, early-T stage (T1b1 and T1b2) and node-positive patients in the "RH+RT" and "TH+RT" groups had better disease-specific survival (DSS) than those in the RT group. No difference in DSS was observed between the "surgery following RT" group and the RT group in locally advanced stage (T1b3 and T2a1, node positive) patients. Regarding T1b1-T2a1 node-positive patients, the RH+RT group had a similar survival outcome to that in the TH+RT group. We showed that surgery following RT benefits early-T stage (T1b1 and T1b2) cervical cancer patients with lymph node metastasis. For locally advanced stages (T1b3 and T2a1), surgery and RT had similar survival outcomes.

Development and validation of a novel scoring system to predict the risk of uterine perforation during intracavitary brachytherapy for cervical cancer

To develop and validate a novel scoring system for predicting the risk of uterine perforation during brachytherapy (BT) in cervical cancer patients and to stratify patients based on this score to guide the use of ultrasound guidance during BT. Fifty patients with uterine perforation during BT between January 2018 and December 2020 were included. Common reasons for perforation were identified and a scoring system was developed. This was then applied to a cohort of 50 patients without perforation. The 2 cohorts were compared using the χ² test. To validate the scoring system, all newly diagnosed patients who underwent BT in 2021 were scored, and analysed using χ² test and receiver operator characteristic curves. The mean score in the test cohort was 10.16 (range=7-14) and 5.92 (range=5-8) for patients with and without perforation. In the validation cohort, the mean score was 6.9 (range=5-10) and 9.33 (range=7-11) for those with and without perforation. Patients with a score <8 were classified as low risk, while those with a score ≥8 were classified as high risk. Among the criteria evaluated for validation, response to external beam radiotherapy, uterine position, cervico-uterine angle (uterine flexion), identification of cervical os at BT assessment, and the total score were significant predictors, while previous history of perforation, uterine length, and additional uterine anomaly were not. The novel scoring system is an effective predictor of perforation risk during BT. Implementing this during BT assessment can optimize the need for ultrasound guidance during the procedure.

Implementation rate and related factors of confirmatory tests following an abnormal Pap smear: a nationwide study from the National Health Insurance

This study aims to investigate the implementation rate and influencing factors of confirmatory tests for women with abnormal cervical cytology results in the Korean nationwide cervical cancer screening program. The National Health Insurance Service (NHIS) database was utilized to identify all Korean women who have participated in the Korean nationwide cervical cancer screening program from January 2011 and December 2021 using the NHIS database. Multiple logistic regression analysis was performed to estimate the multivariate odds ratio and evaluate the patients' characteristics. The rate of abnormal Papanicolaou (Pap) smears showed an initial increase from 2011 to 2015 and subsequently reached a plateau after 2016. When examining specific subcategories, cases of atypical squamous cells of undetermined significance (ASC-US) increased from 28,546 cases (1.1%) in 2011 to 62,850 cases (1.7%) in 2021. In contrast, cases of HSIL and SCC declined from 3,535 cases (0.14%) to 2,763 cases (0.07%) and from 383 cases (0.01%) to 179 cases (0.005%), respectively. Furthermore, the implementation rate of confirmatory tests for women with abnormal cytology increased from 8,865 cases (21.0%) in 2011 to 39,045 cases (51.2%) in 2021. Regarding the specific subcategory of ASC-US, the number of confirmatory tests exhibited a substantial increase from 4,101 cases (14.4%) in 2011 to 30,482 cases (48.5%) in 2021. For SCC, there was no significant change, with 216 cases (56.4%) in 2011 and 102 cases (57.0%) in 2021. The implementation rate of confirmatory tests was found to be significantly associated with results of abnormal Pap smear, age, and residence. Notably, economic status did not emerge as a significant factor affecting the likelihood of undergoing confirmatory tests. The severity of abnormal Pap smear results is a reliable indicator of the probability of undergoing a confirmatory test. Additional endeavors are required to improve the implementation rate among women who have received abnormal Pap smear results.

Revision of quality indicators for cervical cancer and trend analysis of existing indicators in Japan

Cervical cancer rates in Japan (16.0/100,000) exceed the global average rate (11.3/100,000, according to the High/Very-High Human Development Index in 2020). This necessitates the evaluation of care quality and the quality indicators (QIs) for cervical cancer that were developed in 2013 to serve this purpose. This study updated these indicators using current evidence and consensus while longitudinally examining trends in practice patterns. The revision involved reviewing existing QIs and patterns of care indicators and incorporating new indicators using the modified Delphi method. Adherence to these indicators was assessed using a linked hospital-based cancer registry-based diagnostic procedure combination database covering approximately 70% of patients with cancer in Japan. The longitudinal trends of the existing indicators were evaluated using the linear probability model. Seven new indicators were added to the existing twelve. Two of the new indicators mainly focused on early-stage surgical intervention, while one focused on advanced-stage bevacizumab combination therapy, with adherence rates of 81.7%, 0.8%, and 45.9%. Longitudinal analyses revealed significant improvements with the use of cisplatin in concurrent chemoradiotherapy for advanced-stage cervical cancer (+1%/year), oral anticancer agents as maintenance therapy after primary treatment for early-stage cervical cancer (-0.8%/year), and hysterectomy for adenocarcinoma in situ in patients above 44 years old (-2%/year). The QIs for cervical cancer in Japan have been revised based on 2022 evidence. The existing and new indicators should be continually evaluated to correspond to the latest knowledge. This will facilitate the standardization and promotion of bottom-up improvements in cervical cancer care.

Cost-effectiveness of pembrolizumab plus chemotherapy for advanced endometrial cancer

To assess the cost-effectiveness of pembrolizumab in combination with chemotherapy compared to chemotherapy alone, based on the results of the NRG-GY018 trial, in patients with advanced or recurrent endometrial cancer (EC), stratified by mismatch repair-deficient (dMMR) and mismatch repair-proficient (pMMR) subgroups. A Markov model was used to simulate patients receiving either pembrolizumab plus chemotherapy or chemotherapy alone. Lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were calculated using a willingness-to-pay (WTP) threshold of $150,000/QALY. Univariate and probabilistic sensitivity analyses were conducted to assess the robustness of our findings. The addition of pembrolizumab to chemotherapy led to an incremental gain of 4.05 QALYs at an additional cost of $167,224, resulting in an ICER of $41,305.09/QALY compared to chemotherapy alone in dMMR EC. Additionally, there were 0.93 additional QALYs at an additional cost of $83,661, which resulted in an ICER of $90,284.80/QALY in pMMR EC. Sensitivity analyses indicated that the cost of pembrolizumab, utility of progressed disease, and utility of progression-free survival had the greatest impact on the results. Probabilistic sensitivity analysis showed that pembrolizumab was considered cost-effective at a 100% probability at a WTP threshold of $150,000 per QALY. Pembrolizumab, when combined with chemotherapy, was found to be cost-effective compared to chemotherapy alone both for patients with advanced or recurrent dMMR and pMMR EC from the perspective of a payer in the United States.

Comments on: Peripheral blood BRCA1 methylation profiling to predict familial ovarian cancer

Current treatment strategies for ovarian cancer in the East Asian Gynecologic Oncology Trial Group (EAGOT)

Ovarian cancer, notable for its severe prognosis among gynecologic cancers, has seen substantial progress in treatment approaches recently. Enhanced protocols in chemotherapy and the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors for maintenance therapy have markedly improved outcomes for patients with specific genetic profiles, such as those positive for BRCA mutations or exhibiting homologous recombination deficiency (HRD). Additionally, the method of intraperitoneal chemotherapy administration has emerged as a valuable alternative to traditional transvenous routes, showing promise for wider clinical adoption. The field of surgery has also evolved, with increasing exploration into the benefits and feasibility of laparoscopic methods over more invasive traditional surgeries, aiming for complete tumor removal but with reduced patient impact. The hereditary nature of ovarian cancer underscores the importance of genetic testing, which has become integral in tailoring treatment strategies, particularly in determining suitability for PARP inhibitors. The formation of the East Asian Gynecologic Oncology Trial Group (EAGOT) aims to optimize treatment across Japan, Korea, China, and Taiwan. The ovarian cancer committee of EAGOT shared the current policies, focusing on 5 topics: 1) strategies for maintenance therapy after initial surgery and chemotherapy, 2) drug regimens for platinum-sensitive and platinum-resistant recurrence, 3) intraperitoneal chemotherapy, 4) laparoscopic surgery as an alternative to laparotomy, and 5) current status of genetic testing (BRCA, HRD, and panel tests) for ovarian cancer and its prospects. EAGOT's multi-national trials aim to harmonize these evolving treatment strategies, ensuring that the latest and most effective protocols are accessible across the region, thereby significantly impacting patient outcomes in East Asia.

Clinical practice guideline for high-risk human papillomavirus testing in cervical cancer screening: a consensus statement from the Korean Society of Gynecologic Oncology

High-risk human papillomavirus (hrHPV) is a necessary cause of cervical cancer, and hrHPV testing has increasingly been recognized as an effective screening tool that overcomes the limitations of cytology-based screening. However, standardized clinical guidance for the use of hrHPV testing in cervical cancer screening has been limited in Korea, resulting in variability in clinical practice. This consensus-based clinical practice guideline was developed under the auspices of the Korean Society of Gynecologic Oncology through multidisciplinary collaboration involving experts in gynecology, pathology, laboratory medicine, and public health. Relevant domestic and international evidence was systematically reviewed, and input from diverse clinical settings was incorporated through four public hearings. Final recommendations were established through expert consensus. The guideline presents four key recommendations: hrHPV testing may be considered for women aged 25 years or older, with a recommended screening interval of 3 to <5 years; screening assays should differentiate HPV genotypes 16 and 18 and detect other high-risk types, with preference given to clinically validated tests; testing should be performed in appropriately equipped settings with standardized specimen handling and reporting, including documentation of HPV 16/18 status in positive cases; and hrHPV testing should be conducted under rigorous internal and external quality control systems. This guideline aims to support consistent and rational implementation of hrHPV testing in cervical cancer screening in Korea.

A machine learning-based prediction model of pelvic lymph node metastasis in women with early-stage cervical cancer

To develop a novel machine learning-based preoperative prediction model for pelvic lymph node metastasis (PLNM) in early-stage cervical cancer by combining the clinical findings and preoperative computerized tomography (CT) of the whole abdomen and pelvis. Patients diagnosed with International Federation of Gynecology and Obstetrics stage IA2-IIA1 squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma of the cervix who had primary radical surgery with bilateral pelvic lymphadenectomy from January 1, 2003 to December 31, 2020, were included. Seven supervised machine learning algorithms, including logistic regression, random forest, support vector machine, adaptive boosting, gradient boosting, extreme gradient boosting, and category boosting, were used to evaluate the risk of PLNM. PLNM was found in 199 (23.9%) of 832 patients included. Younger age, larger tumor size, higher stage, no prior conization, tumor appearance, adenosquamous histology, and vaginal metastasis as well as the CT findings of larger tumor size, parametrial metastasis, pelvic lymph node enlargement, and vaginal metastasis, were significantly associated with PLNM. The models' predictive performance, including accuracy (89.1%-90.6%), area under the receiver operating characteristics curve (86.9%-91.0%), sensitivity (77.4%-82.4%), specificity (92.1%-94.3%), positive predictive value (77.0%-81.7%), and negative predictive value (93.0%-94.4%), appeared satisfactory and comparable among all the algorithms. After optimizing the model's decision threshold to enhance the sensitivity to at least 95%, the 'highly sensitive' model was obtained with a 2.5%-4.4% false-negative rate of PLNM prediction. We developed prediction models for PLNM in early-stage cervical cancer with promising prediction performance in our setting. Further external validation in other populations is needed with potential clinical applications.

Cervical screening among Chinese females in the era of HPV vaccination: a population-based survey on screening uptake and regular screening following an 18-year organized screening program

China has a substantial disease burden of cervical cancer. To further understand preventive measures for reducing cervical cancer in China, this study aimed to correlate screening attendance and regular screening with human papillomavirus (HPV) vaccination among Chinese females. This prospective questionnaire-based survey recruited Chinese females aged 25 or above in Hong Kong by random digit dialing telephone interviews in 2022. The survey studied women's practice of cervical screening and adherence to regular screening. Variables including HPV vaccination status and attendance of physical check-ups were involved in the questionnaire. Screening uptake and screening adherence were the main outcomes, which were measured as the proportion of women who reported having attended a cervical screening and screened regularly, respectively. Out of 906 valid respondents, the reported cervical screening uptake was over 70% among females aged 30 or above and particularly over 80% among women aged 35-59; however, the uptake was only 46% among those aged 25-29. Adherence to regular screening was 50%-60% across ages 25-59 years and dropped to approximately 40% for women older than 60 years. Both screening uptake and adherence were associated with HPV vaccination, with adjusted odds ratios of 2.37 and 2.23, respectively. A large proportion of regularly screened women may be overscreened for screening more frequently than recommended. Responded Chinese females showed good cervical screening uptake but were moderately adherent to regular screening. Policymakers should emphasize the importance of regular screening and the recommended screening frequency by HPV vaccination status for better healthcare resource use.

Regularity of cervical cancer screening in Korea: analysis using national public data for 12 years

To assess the frequency of regular uptake of national cervical cancer screening (CCS) program and identify associated factors among Korean women. This study is a fundamental investigation that employs openly accessible public data of Korea through secondary data analysis. A cohort of 4,663 women from the 2007-2012 Korean National Health and Nutrition Examination Survey, was followed up for up to 12 years (2007-2018) to obtain the frequency of national CCS. Compliance level with CCS was categorized, and an ordinal logistic regression model was employed to investigate the contributing factors. The regular uptake of CCS in South Korea was low at 18.9%. The trend of regular screening showed significant association with various factors, including age (40-59 years), household income (100%-150% bracket), occupation (service workers), place of residence (small to medium sized cities), education level (middle school graduates), marital status (married), and possession of private insurance. Moreover, individuals with a history of non-cervical cancer or carcinoma in situ of the cervix, a family history of cervical cancer, or a higher frequency of general check-ups demonstrated a stronger adherence to regular CCS uptake. Our findings revealed that regular participation in CCS in Korea was lower than anticipated, with factors such as socioeconomic status, personal history of gynecologic issue, and frequency of general health check-ups playing influential roles. However, further research, including an exploration of unexamined psychological barriers to screening, is necessary to gain a better understanding the reasons behind the reduced rates of regular CCS among Korean women.

Improving the efficacy and safety of concurrent chemoradiotherapy by neoadjuvant chemotherapy: a randomized controlled study of locally advanced cervical cancer with a large tumor

To compare the efficacy and safety of neoadjuvant chemotherapy combined with concurrent chemoradiotherapy (NACT+CCRT) vs. concurrent chemoradiotherapy (CCRT) in locally advanced cervical cancer (LACC) patients with large tumor masses. LACC patients with localized tumor diameter >4 cm, were randomly allocated in an unblinded 1:1 ratio to NACT+CCRT or CCRT groups. Patients in the NACT+CCRT group were given paclitaxel combined with cisplatin (TP) NACT every 3 weeks for 2 cycles, followed by CCRT, with the chemotherapy regimen the same as for NACT. CCRT group were given CCRT with the same as for NACT. From March 1, 2019, to June 30, 2021, 146 patients were included in the final analysis. Sixty-eight (93.2%) patients in the NACT+CCRT group and 66 (90.4%) patients in the CCRT group completed the expected treatment course. The complete response (CR) rate in the NACT+CCRT group was significantly higher than in the CCRT group (87.7% vs. 67.6%, χ²=54.540, p=0.000). In the NACT+CCRT group, the 1- and 2-year overall survival (OS) rates were significantly higher than those in the CCRT group (96% vs. 89% and 89% vs. 79%, χ²=5.737, p=0.017). Additionally, the rate of recurrences and distant metastases was significantly lower in the NACT+CCRT group than in the CCRT group (4.11% vs. 7.35%, χ²=4.059, p=0.021). Most treatment-related adverse events in both groups were grade 3. Compared to CCRT, NACT+CCRT might improve the treatment completion rate, increase CR rate and 1- and 2-year OS rates, and reduce distant metastases rate for LACC patients with large tumor masses.

Comparison of survival outcomes between robotic and laparoscopic radical hysterectomies for early-stage cervical cancer: a systemic review and meta-analysis

Survival outcomes of robotic radical hysterectomy (RRH) remain controversial. Therefore, we performed a meta-analysis to evaluate survival outcomes between RRH) and laparoscopic radical hysterectomy (LRH) in patients with early-stage cervical cancer. Studies comparing between RRH and LRH published up to November 2022 were systemically searched in the PubMed, Cochrane Library, Web of Science, ScienceDirect, and Google Scholar databases. Manual searches of related articles and relevant bibliographies of the published studies were also performed. Two researchers independently extracted data. Studies with information on recurrence and death after minimally invasive radical hysterectomy were also included. The extracted data were analyzed using the Stata MP software package version 17.0. Twenty eligible clinical trials were included in the meta-analysis. When all studies were pooled, the odds ratios of RRH for recurrence and death were 1.19 (95% confidence interval [CI]=0.91-1.55; p=0.613; I²=0.0%) and 0.96 (95% CI=0.65-1.42; p=0.558; I²=0.0%), respectively. In a subgroup analysis, the quality of study methodology, study size, country where the study was conducted, and publication year were not associated with survival outcomes between RRH and LRH. This meta-analysis demonstrates that the survival outcomes are comparable between RRH and LRH. International Prospective Register of Systematic Reviews Identifier: CRD42023387916.

RAIDS atlas of significant genetic and protein biomarkers in cervical cancer

Loss of function in epigenetic acting genes together with driver alterations in the PIK3CA pathway have been shown significantly associated with poor outcome in cervical squamous cell cancer. More recently, a CoxBoost analysis identified 16 gene alterations and 30 high level activated proteins to be of high interest, due to their association with either good or bad outcome, in the context of treatment received by chemoradiation. The objectives here were to review and confirm the significance of these molecular alterations as suggested by literature reports and to pinpoint alternate treatments options for poor-responders to chemoradiation.

Closing the gap for cervical cancer research in Vietnam: current perspectives and future opportunities: a report from the 5th Gynecologic Cancer InterGroup (GCIG) Cervical Cancer Research Network (CCRN) Education Symposium

East Asian Gynecologic Oncology Trial Group (EAGOT): founding history and future perspective

Racial and regional differences exist in morbidity, histology, drug response, toxicity, and prognosis of gynecologic cancer. However, most large-scale phase III studies have been conducted in Western countries, and these data on Asians, who account for more than half of the world's population, are limited. To build a global clinical trial network in Asia, four clinical trial groups with high expertise and international competitiveness in East Asia, namely the Japanese Gynecologic Oncology Group in Japan, the Korean Gynecologic Oncology Group in Korea, the Taiwanese Gynecologic Oncology Group in Taiwan, and the Chinese Gynecologic Cancer Society in the People's Republic of China, established a new group called the East Asia Gynecologic Oncology Trial Group (EAGOT) on November 19, 2021. It includes four committees: the Cervical Cancer Committee, Uterine Corpus Cancer Committee, Ovarian Cancer Committee, and Translational Research Committee. The purpose of EAGOT is to conduct international clinical trials in an effort to provide the best treatments for Asian women affected by gynecologic cancer. Discussions on new collaborative clinical trials have already begun. The first Annual EAGOT Meeting was held on May 25-27, 2023 in Niigata, Japan. EAGOT, the largest healthcare/investigational innovation network in Asia in the area of gynecologic cancers, will become a platform for establishing standards of care and lead to guidelines for Asian women suffering from gynecologic cancer. The harmonization of regulatory/investigator-initiated clinical trials, simultaneous approval of unapproved drugs in the four countries under a common protocol, and expansion of indications will improve the prognosis of gynecologic cancers in Asia in the near future.

The risk of lymph node metastasis in the new FIGO 2018 stage IA cervical cancer with &gt;7 mm diameter

In the 2018 FIGO staging system, cervical cancers with ≤5 mm depth of invasion (DOI) and a diameter of >7 mm, first classified as stage IB, are classified as stage IA. In this group, it is unclear what the risk of lymph node metastasis (LNM) is. This retrospective cohort study aims to determine the incidence of LNM and to study the association between disease-related characteristics and LNM. Women diagnosed with FIGO 2009 IB cervical cancer, with ≤5 mm DOI and a diameter >7 mm, treated with a radical hysterectomy and pelvic lymphadenectomy between 1985 and 2020 were selected from the databases of the Amsterdam University Medical Center and the University Medical Center Groningen. The specimens of patients with LNM were revised by expert pathologists. The incidence of LNM was calculated. The associations between LNM and DOI, diameter, histological type, clinical visibility and lymphovascular space invasion (LVSI) were evaluated by calculating odds ratios using logistic regression. Of the 389 patients included, 10 had pathologically confirmed LNM (2.6%, 95% confidence interval=1.3%-4.5%). In case of LVSI, univariate analysis showed an increased risk of LNM (p=0.003 and p=0.012, respectively). No difference in LNM was found between lesions diagnosed by microscopy and clinically visible lesions. No LNM were found in patients without LVSI and a DOI of ≤3 mm. For patients with stage IA cervical cancer with a diameter >7 mm, we recommend considering a pelvic lymph node assessment in case of DOI >3 mm and/or presence of LVSI.

Pneumovaginoscopy-assisted radical hysterectomy for early-stage cervical cancer: a novel bidirectional approach for tumor spillage prevention and R0 resection

This study evaluated the feasibility and outcomes of pneumovaginoscopy-assisted radical hysterectomy (PVRH) for cervical cancer up to stage IIA using a bidirectional fascia-oriented and nerve-sparing surgical approach. This retrospective observational cohort study examined the operative outcomes and prognoses of patients who underwent PVRH (n=59) for up to stage IIA cervical cancer. The basic procedure was Kyoto B2 (Viper Type II nerve-sparing) radical hysterectomy and pelvic lymphadenectomy through simultaneous vaginal and abdominal (open or laparoscopic) approaches. In all cases, pneumovaginoscopy (PV) was used to create a vaginal cuff and dissect the paracolpium and paracervical endopelvic fascia to minimize nerve damage. Thirty-eight (64.4%) patients had stage IB1 cancer. Seven (11.9%) had vaginal invasion (stage IIA1, n=4; IIA2, n=3). The abdominal approach was open in 38 cases and laparoscopic in 21. Adjuvant therapy was administered to 24 patients (41%); one patient received concurrent chemoradiotherapy for gastric-type adenocarcinoma. There were three (6.1%) intraoperative complications (CO PVRH is a new fascia-oriented and nerve-sparing surgery for early-stage cervical cancer. Further, it has favorable operative outcomes and good prognoses, similar to those of adjacent pelvic surgery such as trans-anal total mesorectal excision and radical prostatectomy.

A comparison of concurrent chemoradiotherapy and radical surgery in patients with specific locally advanced cervical cancer (stage IB3, IIA2, IIICr): trial protocol for a randomized controlled study (C-CRAL trial)

At present, clinical dilemma remains to be solved in terms of therapy-choices for specific locally advanced cervical cancer (LACC) patients: 1) Although concurrent chemoradiotherapy (CCRT) is recommended as the first choice for them, many patients, influenced by the Chinese culture, prefer to choose radical surgery (RS) as their primary treatment. The difference between the 2 therapies in improving patient prognosis is still unknown. 2) Laparoscopy has been questioned since the noted Laparoscopic Approach to Cervical Cancer trial. Nevertheless, clinical research on laparoscopic surgery under the strict tumor-free principle is still underway globally, therefore whether laparoscopic surgery can be used for specific LACC is also an urgent issue to be explored. A multi-center, randomized controlled study is designed to investigate the effect of different treatment strategies on the prognosis and quality of life (QoL) in patients with specific locally LACC. A total of 402 patients will be enrolled over a period of 3 years. Eligible patients will be randomized (3:1) to either RS group or CCRT group. Patients assigned to RS group will be randomized (1:2) to the abdominal RS group or laparoscopic RS group. All patients will then be followed-up for 5 years. The primary end point is the 2-year progression-free survival (PFS). The secondary end points include 5-year PFS, 2-year overall survival (OS), 5-year OS, adverse events caused by RS or CCRT and QoL. Chinese Clinical Trial Registry Identifier: ChiCTR2000041315.

Interleukin-34 cancels anti-tumor immunity by PARP inhibitor

Breast cancer susceptibility gene 1 (BRCA1)-associated ovarian cancer patients have been treated with A poly (ADP-ribose) polymerase (PARP) inhibitor, extending the progression-free survival; however, they finally acquire therapeutic resistance. Interleukin (IL)-34 has been reported as a poor prognostic factor in several cancers, including ovarian cancer, and it contributes to the therapeutic resistance of chemotherapies. IL-34 may affect the therapeutic effect of PARP inhibitor through the regulation of tumor microenvironment (TME). In this study, The Cancer Genome Atlas (TCGA) data set was used to evaluate the prognosis of IL-34 and human ovarian serous carcinoma. We also used CRISPR-Cas9 genome editing technology in a mouse model to evaluate the efficacy of PARP inhibitor therapy in the presence or absence of IL-34. We found that These results suggest that tumor-derived IL-34 benefits tumors by creating an immunosuppressive TME and conferring PARP inhibitor therapeutic resistance. Thus, we showed the pathological effect of IL-34 and the need for it as a therapeutic target in ovarian cancer.

Ovarian cancer risk score predicts chemo-response and outcome in epithelial ovarian carcinoma patients

Cytoreductive surgery followed by adjuvant chemotherapy is a standard frontline treatment for epithelial ovarian cancer (EOC). We aimed to develop an ovarian cancer risk score (OVRS) based on the expression of 10 ovarian-cancer-related genes to predict the chemoresistance, and outcomes of EOC patients. We designed a case-control study with total 149 EOC women including 75 chemosensitives and 74 chemoresistants. Gene expression was measured using the quantitative real-time polymerase chain reaction. We tested for correlation between the OVRS and chemosensitivity or chemoresistance, disease-free survival (DFS), and overall survival (OS), and validated the OVRS by analyzing patients from the TCGA database. The chemosensitive group had lower OVRS than the chemoresistant group (5 vs. 15, p≤0.001, Mann-Whitney U test). Patients with disease relapse (13 vs. 5, p60 months) of patients with OVRS ≥10 were significantly shorter than those of patients with OVRS <10). The high OVRS group also had significantly shorter median OS than the low OVRS group in 255 patients in the TCGA database (39 vs. 49 months, p=0.046). Specific genes panel can be clinically applied in predicting the chemoresistance and outcome, and decision-making of epithelial ovarian cancer.

Why was GOG-0213 a negative trial?

The role of secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer: what do the trials tell us?

Suppression of ARID1A associated with decreased CD8 T cells improves cell survival of ovarian clear cell carcinoma

AT-rich interactive domain 1A (ARID1A) plays an important role as a tumor suppressor gene in ovarian clear cell carcinoma (OCCC), but the clinical application of ARID1A remains unclear. The aim of this study was to analyze clinicopathological parameters, molecular interactions and immune-infiltration in patients with low ARID1A expression and to provide candidate target drugs. We investigated the clinicopathologic parameters, specific gene sets/genes, and immunological relevance according to ARID1A expression in 998 OCCC patients from 12 eligible studies (using meta-analyses); 30 OCCC patients from the Hanyang University Guri Hospital (HYGH) cohort; and 52 OCCC patients from gene set enrichment (GSE) 65986 (25 patients), 63885 (9 patients), and 54809 (6 patients and 12 healthy people) of the Gene Expression Omnibus (GEO). We analyzed network-based pathways based on gene set enrichment analysis (GSEA) and performed in vitro drug screening. Low ARID1A expression was associated with poor survival in OCCC from the meta-analysis, HYGH cohort and GEO data. In GSEA, low ARID1A expression was related to the tumor invasion process as well as a low immune-infiltration. In silico cytometry showed that CD8 T cells were decreased with low ARID1A expression. In pathway analysis, ARID1A was associated with angiogenic endothelial cell signaling. In vitro drug screening revealed that cabozantinib and bicalutamide effectively inhibited specific hub genes, such as vascular endothelial growth factor-A and androgen receptor, in OCCC cells with low ARID1A expression. Therapeutic strategies making use of low ARID1A could contribute to better clinical management/research for patients with OCCC.

Robot-assisted extraperitoneal para-aortic lymphadenectomy (RAePAL) performed with the bipolar cutting method

In comparison with laparoscopic transperitoneal para-aortic lymphadenectomy, the advantages of laparoscopic extraperitoneal para-aortic lymphadenectomy (ePAL) are that the operative field is not obstructed by bowel and the Trendelenburg position is not required [1]. The ePAL technique has been adopted to the robotic surgery with the da Vinci Xi. There are only a few reports demonstrating the technical feasibility of robot-assisted ePAL (RAePAL) [2 3]. This report describes the new surgical technique of RAePAL with the bipolar cutting method. The patient was a 53-year-old woman diagnosed as ovarian clear cell carcinoma (CCC) after left salpingo-oophorectomy. As the re-staging surgery, robot-assisted right salpingo-oophorectomy, hysterectomy, omentectomy, and pelvic lymphadenectomy were planned following ePAL. The patient was placed in the supine position and tilted 5 degrees to the right. Three da Vinci arms were docked at the patient's left side (Fig. 1). The bipolar cutting method was performed by with the surgeon's right hand. An AirSeal® port (ConMed, Utica, NY, USA) was placed on the side near the assistant. After the para-aortic space was expanded, lymphadenectomy was performed up to the renal veins with the bipolar cutting method. The PAL operative time was 155 minutes, estimated blood loss was 25 mL. The patient developed no perioperative complications, and the postoperative diagnosis was stage IC1 ovarian CCC with no pelvic (n=0/42) and para-aortic lymph nodes (n=0/59) metastasis. RAePAL with the bipolar cutting method was technically feasible. Performing lymphadenectomy between the aorta and the vena cava was facilitated by the articulated robotic arm.

High expression of maternal embryonic leucine-zipper kinase (MELK) impacts clinical outcomes in patients with ovarian cancer and its inhibition suppresses ovarian cancer cells growth ex vivo

Maternal embryonic leucine zipper kinase (MELK) is receiving an attention as a therapeutic target in various types of cancers. In this study, we aimed to evaluate the prognostic significance of Expression levels of MELK in 11 ovarian cancer cell lines were confirmed by western blotting. Inhibitory concentration of OTS167 was determined by colorimetric assay. We demonstrated MELK as both a prognostic marker and a therapeutic target for ovarian cancer using clinical ovarian cancer samples. MELK inhibition by OTS167 may be an effective approach to treat ovarian cancer patients.

Feasibility and safety of fertility-sparing surgery in epithelial ovarian cancer with dense adhesion: a long-term result from a single institution

We investigated the feasibility and safety of fertility-sparing surgery (FSS) in patients with epithelial ovarian cancer (EOC) with dense adhesions. Patients were divided into cases with and without dense adhesions in this retrospective study. Of the 95 eligible patients, 29 patients had dense adhesions. Mean age, proportion of staging procedure, distribution of histologic type, and co-presence of endometriosis were different (p=0.003, 0.033, 0.011, and 0.011, respectively). The median follow-up period was 57.8 (0.4-230.0) months. There were no differences in the rates of recurrence (21.2% vs. 20.7%, p=1.000) or death (16.7% vs. 6.9%, p=0.332) between the 2 groups. There was no difference in the pattern of recurrence or in disease-free survival (DFS) and overall survival (OS) between the 2 groups. In multivariate analysis, pretreatment cancer antigen-125 >35 U/mL and International Federation of Gynecology and Obstetrics stage IC were significant factors of worse DFS and OS, while dense adhesion was not a prognostic factor for both DFS (hazard ratio [HR]=0.9; 95% confidence interval [CI]=0.3-2.7; p=0.792) and OS (HR=0.2; 95% CI=0.1-1.8; p=0.142), nor were age, proportion of staging procedure, histologic type, and co-presence of endometriosis. Moreover, the distribution of those 2 significant prognostic factors was not different between the 2 groups. Dense adhesions were subgrouped into non-tumor and tumor associated dense adhesions for further analysis and the results were same. FSS is feasible and safe in EOC, regardless of the presence of dense adhesions.

Olaparib and bevacizumab in front-line maintenance of ovarian cancer: an over reliance in unpowered subgroup analysis of the PAOLA-1 trial?

Circulating exosomal circFoxp1 confers cisplatin resistance in epithelial ovarian cancer cells

Early detection and treatment are particularly important to epithelial ovarian cancer (EOC). Studies have shown that circular RNA (circRNA) dysregulation is associated with the proliferation and metastasis of ovarian cancer cells. This study focused on the role of serum exosomal circular forkhead box protein P1 (circFoxp1) on survival outcome and cisplatin (DDP) resistance in patients with EOC. Quantitative polymerase chain reaction, 5-ethynyl-2'-deoxyuridine (EdU) staining, CCK-8, luciferase reporter assay, RNA immunoprecipitation, tumor xenograft in nude mice, and bioinformatic analysis were performed. Circulating exosomal circFoxp1 was significantly increased in patients with EOC, especially in DDP-resistant EOC patients. circFoxp1 expression was positively associated with International Federation of Gynecology and Obstetrics stage, primary tumor size, lymphatic metastasis, distant metastasis, residual tumor diameter, and clinical response. Exosomal circFoxp1 also was an independent factor predicting survival and disease recurrence in patients with EOC. Overexpression of circFoxp1 could promote cell proliferation and confer DDP resistance, while knockdown of circFoxp1 could inhibit cell proliferation and enhance DDP sensitivity in vitro and in vivo. In addition, miR-22 and miR-150-3p mimic treatment attenuated circFoxp1-meadiated DDP resistance, while miR-22 and miR-150-3p inhibitor treatment enhanced DDP resistance that mitigated by circFoxp1 knockdown. Furthermore, circFoxp1 positively regulated the expression of CCAAT enhancer binding protein gamma (CEBPG) and formin like 3 (FMNL3) through miR-22 and miR-150-3p. circFoxp1 is an oncogene in EOC cells and can confer DDP resistance to EOC cells. Circulating exosomal circFoxp1 can be used as a biomarker and potential therapeutic target for EOC.

Incidence and predictors of peritoneal metastases of gynecological origin: a population-based study in the Netherlands

Peritoneal metastases (PM) are a challenge in gynecological cancers, but its appearance has never been described in a population-based study. Therefore, we describe the incidence of PM and identify predictors that increase the probability of peritoneal spread. All ovarian, endometrial and cervical cancer patients diagnosed in the Netherlands between 1989 and 2015 were identified from the Netherlands Cancer Registry and stratified for PM. Crude and age-adjusted incidence over time was calculated. Independent predictors for PM were identified using uni- and multivariable analyses. The 94,981 patients were diagnosed with ovarian, endometrial or cervical cancer and respectively 61%, 2% and 1% presented with PM. Predictors for PM in ovarian cancer were: age between 50 and 74 years (odds ratio [OR]=1.19; 95% confidence interval [CI]=1.08-1.32), other distant metastases (OR=1.25; 95% CI=1.10-1.41), poor differentiation grade (OR=2.00; 95% CI=1.73-2.32) and serous histology. Predictors in endometrial cancer were lymph node metastases (OR=2.32; 95% CI=1.65-3.26), other distant metastases (OR=1.38; 95% CI=1.08-1.77), high-grade tumors (OR=1.95; 95% CI=1.38-2.76) and clear cell (OR=1.49; 95% CI=1.04-2.13) or serous histology (OR=2.71; 95% CI=2.15-3.42). In cervical cancer, the risk is higher in adenocarcinoma than in squamous cell carcinoma (OR=4.92; 95% CI=3.11-7.79). PM are frequently seen in patients with ovarian cancer. In endometrial and cervical cancer PM are rare. Histological subtype was the strongest predictive factor for PM in all 3 cancers. Better understanding of predictive factors for PM and thus the biological behavior is of paramount importance.

Lymphadenectomy for primary ovarian cancer: a systematic review and meta-analysis

To assess the effectiveness of lymphadenectomy at primary debulking surgery (PDS) on the survival of patients with epithelial ovarian cancer (EOC). We searched PubMed, Ichushi, and the Cochrane Library. Randomized controlled trials (RCTs) and retrospective cohort studies comparing survival of women with EOC undergoing lymphadenectomy at PDS with that of women without lymphadenectomy were included. We performed a meta-analysis of overall survival (OS), progression-free survival (PFS), and adverse events. For advanced-stage EOC, 2 RCTs including 1,074 women and 7 cohort studies comprising 3,161 women were evaluated. Meta-analysis revealed that lymphadenectomy was associated with improved OS (hazard ratio [HR]=0.80; 95% confidence interval [CI]=0.70-0.90). However, meta-analysis of 2 RCTs revealed no significant difference in OS between the lymphadenectomy and no-lymphadenectomy groups (OS: HR=1.02; 95% CI=0.85-1.22). For early-stage EOC, 1 RCT comprising 268 women and 4 cohort studies comprising 14,228 women were evaluated. Meta-analysis showed that lymphadenectomy was associated with improved OS (HR=0.75; 95% CI=0.68-0.82). A RCT of early-stage EOC reported that lymphadenectomy was not associated with improved OS (HR=0.85; 95% CI=0.49-1.47). Surgery-related deaths were similar in both groups (risk ratio [RR]=1.00; 95% CI=0.99-1.01); however, blood transfusion was required less frequently in the no-lymphadenectomy group (RR=0.74; 95% CI=0.63-0.86). Meta-analysis of RCTs and observational studies suggest that lymphadenectomy was associated with improved OS in advanced- and early-stage EOC. However, results from RCTs demonstrate that lymphadenectomy was not associated with improved OS in advanced- and early-stage EOC.

Major clinical research advances in gynecologic cancer in 2019

In 2019, 12 topics were selected as the major research advances in gynecologic oncology. Herein, we first opted to introduce the significant clinical activity of pembrolizumab in women with advanced cervical cancer based on the results of the phase 2 KEYNOTE-158 trial. Thereafter, we reviewed 5 topics, including systemic lymphadenectomy in the advanced stage with no gross residual tumor, secondary cytoreductive surgery in recurrent ovarian cancer according to the results of Gynecologic Oncology Group-213 trial, dose-dense weekly paclitaxel scheduling as first-line chemotherapy, the utility of intraperitoneal therapy in the advanced stage, and an update on poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer. Additionally, we conducted a thorough review of emerging data from several clinical trials on PARP inhibitors according to drug, target population, and combined usage. For uterine corpus cancer, we reviewed adjuvant therapy for high-risk disease and chemotherapy in advanced/recurrent disease. For the field of radiation oncology, we discussed the utility of neoadjuvant chemotherapy added to chemoradiotherapy and the treatment of radiation-induced cystitis using hyperbaric oxygen. Finally, we discussed the use of individualized therapy with humanized monoclonal antibodies (trastuzumab emtansine and sacituzumab govitecan-hziy) and combination therapy (fulvestrant plus alpesilib, fulvestrant plus anastrozole, and ribociclib plus endocrine therapy) for women with advanced breast cancer.

Management of ovarian cancer patients in affected areas during COVID-19 pandemic: Japan and Korea

A phase II trial of cytoreductive surgery combined with niraparib maintenance in platinum-sensitive, secondary recurrent ovarian cancer: SGOG SOC-3 study

In China, secondary cytoreductive surgery (SCR) has been widely used in ovarian cancer (OC) over the past two decades. Although Gynecologic Oncology Group-0213 trial did not show its overall survival benefit in first relapsed patients, the questions on patient selection and effect of subsequent targeting therapy are still open. The preliminary data from our pre-SOC1 phase II study showed that selected patients with second relapse who never received SCR at recurrence may still benefit from surgery. Moreover, poly(ADP-ribose) polymerase inhibitors (PARPi) maintenance now has been a standard care for platinum sensitive relapsed OC. To our knowledge, no published or ongoing trial is trying to answer the question if patient can benefit from a potentially complete resection combined with PARPi maintenance in OC patients with secondary recurrence. SOC-3 is a multi-center, open, randomized, controlled, phase II trial of SCR followed by chemotherapy and niraparib maintenance vs chemotherapy and niraparib maintenance in patients with platinum-sensitive second relapsed OC who never received SCR at recurrence. To guarantee surgical quality, if the sites had no experience of participating in any OC-related surgical trials, the number of recurrent lesions evaluated by central-reviewed positron emission tomography-computed tomography image shouldn't be more than 3. Eligible patients are randomly assigned in a 1:1 ratio to receive either SCR followed by 6 cycles of platinum-based chemotherapy and niraparib maintenance or 6 cycles of platinum-based chemotherapy and niraparib maintenance alone. Patients who undergo at least 4 cycles of chemotherapy and must be, in the opinion of the investigator, without disease progression, will be assigned niraparib maintenance. Major inclusion criteria are secondary relapsed OC with a platinum-free interval of no less than 6 months and a possibly complete resection. Major exclusion criteria are borderline tumors and non-epithelial ovarian malignancies, received debulking surgery at recurrence and impossible to complete resection. The sample size is 96 patients. Primary endpoint is 12-month non-progression rate. ClinicalTrials.gov Identifier: NCT03983226.

SURF4 maintains stem-like properties via BIRC3 in ovarian cancer cells

As cancer stem cells (CSCs) are considered as the origin of tumor development, recurrence, and drug resistance, we aimed to explore the mechanism related to modulating stemness in CSCs, thus facilitating to search for new therapeutic strategy for ovarian cancer. In this study, ovarian cancer stem cells (OCSCs) induced from cell line 3AO and A2780 were enriched in serum-free medium (SFM). The effect of SURF4 on CSC-like properties was evaluated by sphere-forming assays, re-differentiation assays, quantitative real-time polymerase chain reaction, flow cytometry, Western blotting, cell viability assays and in vivo xenograft experiments. The downstream molecule participating in SURF4 maintaining stemness was screened by RNA-sequencing and identified by the experiments of gene function. SURF4 was upregulated expressed in OCSCs. Knockdown of SURF4 reduced the expression of the related stem markers (SOX2 and c-MYC), inhibited self-renewal ability, and improved the sensitivity to chemotherapeutic drugs (paclitaxel and cisplatin) in OCSCs. SURF4 knockdown also inhibited tumorigenesis in nonobese diabetic/severe combined immunodeficiency mice. BIRC3 expression was controlled by SURF4, and BIRC3 showed the similar effect as SURF4 did, and BIRC3 overexpression partially recovered stem-like properties abolished by SURF4 knockdown. Our findings suggest that SURF4 possesses the ability to maintain stemness of OCSCs via BIRC3, and may serve as a potential target in stem cell-targeted therapy for ovarian cancer.

Risk factors for early death among ovarian cancer patients: a nationwide cohort study

To characterize ovarian cancer patients who die within 6 months of diagnosis and to identify prognostic factors for these early deaths. A nationwide cohort study covering ovarian cancer in Denmark in 2005-2016. Tumor and patient characteristics including comorbidity and socioeconomic factors were obtained from the comprehensive Danish national registers. A total of 5,570 patients were included in the study. Three months after ovarian cancer diagnosis 456 (8.2%) had died and 664 (11.9%) died within 6 months of diagnosis. Adjusted for age and comorbidity, patients who died early were admitted to hospital significantly more often in a 6-month period before the diagnosis (odds ratio [OR]=1.61 [1.29-2.00], and OR=1.47 [1.21-1.78]), for patients who died within 3 and 6 months respectively). Low educational level (OR=2.11), low income (OR=2.50) and singlehood (OR=1.90) were factors significantly associated with higher risk of early death. The discriminative ability of risk factors in identifying early death was assessed by cross-validated area under the receiver operating characteristic curve (AUC). The AUC was found to be 0.91 (0.88-0.93) and 0.90 (0.87-0.92) for death within 3 and 6 months, respectively. Despite several admissions to hospital, the ovarian cancer diagnosis is delayed for a subgroup of patients, who end up dying early, probably due to physical deterioration in the ineffective waiting time. Up to 90% of high-risk patients might be identified significantly earlier to improve the prognosis. The admittance of the patients having risk symptoms should include fast track investigation for ovarian cancer.

Tozzi classification of diaphragmatic surgery in patients with stage IIIC–IV ovarian cancer based on surgical findings and complexity

To introduce a systematic classification of diaphragmatic surgery in patients with ovarian cancer based on disease spread and surgical complexity. For all consecutive patients who underwent diaphragmatic surgery during Visceral-Peritoneal debulking (VPD) in the period 2009-2017, we extracted: initial surgical finding, extent of liver mobilization and type of procedure. Combining these features, we aimed to classify the surgical procedures necessary to tackle different presentation of diaphragmatic disease. We also report histology, intra- and post-operative specific complication rate based on the classification. A total of 170 patients were included in this study, 110 (64.7%) had a peritonectomy, while 60 (35.3%) had a full thickness resection with pleurectomy. We identified 3 types of surgical procedures. Type I treated 28 out of 170 patients (16.5%) who only had anterior diaphragm disease, needed no liver mobilization, included peritonectomy and had no morbidity recorded. Type II pertained to 105 out of 170 patients (61.7%) who had anterior and posterior disease, needed partial and sometimes full liver mobilization, had a mix of peritonectomy and full thickness resection, and experienced 10% specific morbidity. Type III included 37 out of 170 patients (21.7%) who needed full mobilization of the liver, always had full thickness resection, and suffered 30% specific morbidity. Diaphragmatic surgery can be classified in 3 types. The adoption of this classification can facilitate standardization of the surgery, comparison of data and define the expertise required. Finally, this classification can be a benchmark to establish the training required to treat diaphragmatic disease.

Efficacy and safety of neoadjuvant chemotherapy versus primary debulking surgery in patients with ovarian cancer: a meta-analysis

Neoadjuvant chemotherapy (NACT) for the treatment of epithelial ovarian cancer (EOC) has remained controversial. This meta-analysis was performed to systematically assess the efficacy and safety of NACT versus primary debulking surgery (PDS) in patients with EOC. PubMed, Embase, ClinicalTrials.gov, and Cochrane Library were queried to assess the therapeutic value of NACT versus PDS in EOC. Electronic databases were queried by using the keywords "ovarian cancer/neoplasms", "primary debulking surgery", and "neoadjuvant chemotherapy". The available trials were pooled, and hazard ratios (HRs), relative risk ratios (RRs) and associated 95% confidence intervals (95% CIs) were determined. Sixteen trials involving 57,450 participants with EOC (NACT, 9,475; PDS, 47,975) were evaluated. We found that NACT resulted in markedly decreased overall survival than PDS in patients with EOC (HR=1.30; 95% CI=1.13-1.49; heterogeneity: p<0.001, I²=82.7%). Furthermore, our results demonstrated that the NACT group displayed increased completeness of debulking removal (RR=1.69, 95% CI=1.32-2.17; heterogeneity: p<0.001, I²=81.9%), and reduced risk of postsurgical death (RR=0.18, 95% CI=0.06-0.51; heterogeneity: p=0.698, I²=0%) and major infection (RR=0.29, 95% CI=0.17-0.51; heterogeneity: p=0.777, I²=0%) compared with patients administered PDS. This meta-analysis indicated that NACT results in increased completeness of debulking removal, and reduced risk of postsurgical death and major infection compared with PDS, while PDS is associated with improved survival in comparison with NACT in EOC patients. PROSPERO Identifier: CRD42019120625.

BRCA1/2mutation status in patients with metachronous breast and ovarian malignancies: clues towards the implementation of genetic counseling

The characteristics of patients with metachronous breast and ovarian malignancies and the pathogenic role of We retrospectively retrieved consecutive clinical records of Taiwanese patients who presented with these malignancies to our hospital between 2001 and 2017. We also collected information from the Data Science Center of the Taiwan Cancer Registry (TCR) between 2007 and 2015. Next-generation sequencing and multiplex ligation-dependent probe amplification were used to identify A total of 12,769 patients with breast cancer and 1,537 with ovarian cancer were retrieved from our hospital records. Of them, 28 had metachronous breast and ovarian malignancies. We also identified 113 cases from the TCR dataset. Eighteen hospital-based cases underwent Our results provide pilot evidence that

Comparison between weekly versus 3-weekly paclitaxel in combination with carboplatin as neoadjuvant chemotherapy in advanced ovarian cancer

To compare the efficacy and toxicity of dose-dense weekly paclitaxel and 3-weekly carboplatin (ddPC) as neoadjuvant chemotherapy (NAC) with the standard 3-weekly regimen. A retrospective study of patients diagnosed with stage IIIc and IV ovarian cancer who received at least one cycle of NAC followed by interval debulking surgery between August 2015 and January 2018 was conducted. Patient characteristics, clinical and pathological response to NAC, surgical and survival outcome, and adverse event were compared. A total of 23 patients in the ddPC group and 50 patients in the standard group received a median of 3 cycles of NAC. Rate of grade ≥3 neutropenia was significantly higher in the ddPC group than the standard (82.6% vs. 22.0%, p<0.001). Patients in the ddPC group underwent dose-reduction more frequently (34.8% vs. 4.00%, p=0.001). Normalization of cancer antigen-125 post-NAC occurred more frequently in the ddPC group (73.9% vs. 46.0%, p=0.030). No residual disease rate (43.5% vs. 60.0%, p=0.188) and chemotherapy response score of 3 (34.8% vs. 26.0%, p=0.441) were not statistically different between two groups. There was no statistical difference in progression free survival (PFS) at 2 years (36.3% vs. 28.4%, p=0.454). Cox proportional hazard model showed that ddPC was not a significant determinant of PFS (p=0.816). There was no difference between both regimens in terms of NAC response and survival outcomes. However, ddPC group showed higher hematologic toxicity requiring dose reduction.

Characteristics and survival of ovarian cancer patients treated with neoadjuvant chemotherapy but not undergoing interval debulking surgery

Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) confers similar outcomes as primary debulking surgery and chemotherapy. Little is known about patients who receive NACT but do not undergo debulking surgery. Our aim was to characterize these patients. We prospectively identified patients with newly diagnosed stage III/IV ovarian cancer treated with NACT from 7/1/15-12/1/17. Fisher exact and Wilcoxon rank-sum tests were used to compare clinical characteristics by surgical status. The Kaplan-Meier method was used to estimate survival outcomes. Log-rank test and Cox proportional hazards model were applied to assess the relationship of covariates to outcome, and time-dependent covariates were applied to variables collected after diagnosis. Of 224 women who received NACT, 162 (72%) underwent IDS and 62 (28%) did not undergo surgery. The non-surgical group was older (p<0.001), had higher Charlson comorbidity index (CCI; p<0.001), lower albumin levels (p=0.007), lower Karnofsky performance scores (p<0.001), and were more likely to have dose reductions in NACT (p<0.001). Reasons for no surgery included poor response to NACT (39%), death (15%), comorbidities (24%), patient preference (16%), and loss to follow-up (6%). The no surgery group had significantly worse overall survival (OS) than the surgery group (hazard ratio=3.34; 95% confidence interval=1.66-6.72; p<0.001), after adjustment for age, CCI, and dose reductions. A significant proportion of women treated with NACT do not undergo IDS, and these women are older, frailer, and have worse OS. More studies are needed to find optimal therapies to maximize outcomes in this high-risk, elderly population.

Well-trained gynecologic oncologists can perform bowel resection and upper abdominal surgery safely

This study was performed to examine the safety of bowel resection and upper abdominal surgery in patients with advanced ovarian cancer performed by gynecologic oncologists after training in a monodisciplinary surgical team. We implemented a monodisciplinary surgical team consisting of specialized gynecologic oncologist for advanced ovarian cancer. In the initial learning period in 65 patients with International Federation of Gynecology and Obstetrics (FIGO) III/IV, a gynecologic oncologist who had a certification as a general surgeon trained 2 other gynecologic oncologists in bowel resection and upper abdominal surgery for 4 years. After the initial learning period, the trained gynecologic oncologists performed surgeries without the certificated general surgeon in 195 patients with FIGO III/IV. The surgical outcomes and perioperative complications during the 2 periods were evaluated. The rates of achieving no gross disease after cytoreductive surgery were 80.0% in the initial learning period and 83.6% in the post-learning period (p=0.560). The incidence of anastomotic leakage after rectosigmoid resection, symptomatic pleural effusion or pneumothorax after right diaphragm resection, and pancreatic fistula after splenectomy with distal pancreatectomy in the 2 periods were 2 of 34 (6.0%), 1 of 33 (3.0%), and 3 of 15 (20.0%) patients in the initial learning period, and 12 of 147 (8.2%), 1 of 118 (0.8%), and 11 of 84 (13.1%) patients in the post-learning period, respectively. There were no significant differences between the 2 groups (p=0.270, p=0.440, p=0.520, respectively). Bowel resection and upper abdominal surgery can be performed safely by gynecologic oncologists.

ToleRability of BevacizUmab in elderly Ovarian cancer patients (TURBO study): a case-control study of a real-life experience

Bevacizumab maintenance following platinum-based chemotherapy is an effective treatment for epithelial ovarian cancer (EOC), both in primary and recurrent disease. Our aim was to identify criteria to select elderly patients who can safely benefit from bevacizumab addition. This is a case-control study on patients with primary or recurrent EOC who received platinum-based chemotherapy plus bevacizumab, between January 2015 and December 2016. Patient characteristics, treatment details and adverse events were reviewed and analyzed in 2 settings: younger (1.1 g/dL, estimated glomerular filtration rate (eGFR) ≤60 mL/min, ≥3 comorbidities were independently associated with a higher severe toxicity. Elderly patients with EOC can safely be treated with bevacizumab; factors other than age, as higher creatinine serum levels, eGFR and number of comorbidities should be considered to better estimate bevacizumab-related toxicity risk.

How to predict treatment failure in frail patients with advanced epithelial ovarian cancer: strategies to personalize surgical effort

Bispecific immunotherapy MEDI5752 or volrustomig and cervical cancer

MEDI5752 is a monovalent bispecific immunotherapy and is strategically unique as it combines both anti programmed cell death 1 and anti cytotoxic T-lymphocyte-associated protein 4 action. This is one of the first of this kind of molecule. The development of this molecule had been very interesting which is not usually described in regular clinical oncology journals thus losing an important piece of history of an upcoming subject. Only some phase I results in such development is published so far and no full report on this is available till now. This effort will try to record the facts and chain of events which actually occurred in inventing and bringing it in phase III trial.

Comparisons of survival outcomes between bevacizumab and olaparib inBRCA-mutated, platinum-sensitive relapsed ovarian cancer: a Korean Gynecologic Oncology Group study (KGOG 3052)

To compare survival outcomes between bevacizumab (BEV) and olaparib (OLA) maintenance therapy in From 10 institutions, we identified HGSOC patients with germline and/or somatic Overall, OLA users showed significantly better progression-free survival (PFS) than BEV users (median, 23.8 vs. 17.4 months; p=0.004). Before matching, PFS improved in the OLA intent group but marginal statistical significance (p=0.057). After matching, multivariate analyses adjusting confounders identified intention-to-treat OLA as an independent favorable prognostic factor for PFS in the OLA 65P (adjusted hazard ratio [aHR]=0.505; 95% confidence interval [CI]=0.280-0.911; p=0.023) to OLA 100P (aHR=0.348; 95% CI=0.184-0.658; p=0.001) datasets. The aHR of intention-to-treat OLA for recurrence decreased with increasing proportions of OLA users. No differences in overall survival were observed between the BEV and OLA intent groups, and between the BEV and OLA users. Compared to BEV, intention-to-treat OLA and actual use of OLA maintenance therapy were significantly associated with decreased disease recurrence risk in patients with

The 2020 Japan Society of Gynecologic Oncology guidelines for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer

The fifth edition of the Japan Society of Gynecologic Oncology guidelines for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer was published in 2020. The guidelines contain 6 chapters-namely, (1) overview of the guidelines; (2) epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (3) recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (4) borderline epithelial tumors of the ovary; (5) malignant germ cell tumors of the ovary; and (6) malignant sex cord-stromal tumors. Furthermore, the guidelines comprise 5 algorithms-namely, (1) initial treatment for ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (2) treatment for recurrent ovarian cancer, fallopian tube cancer, and primary peritoneal cancer; (3) initial treatment for borderline epithelial ovarian tumor; (4) treatment for malignant germ cell tumor; and (5) treatment for sex cord-stromal tumor. Major changes in the new edition include the following: (1) revision of the title to "guidelines for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer"; (2) involvement of patients and general (male/female) participants in addition to physicians, pharmacists, and nurses; (3) clinical questions (CQs) in the PICO format; (4) change in the expression of grades of recommendation and level of evidence in accordance with the GRADE system; (5) introduction of the idea of a body of evidence; (6) categorization of references according to research design; (7) performance of systematic reviews and meta-analysis for three CQs; and (8) voting for each CQ/recommendation and description of the consensus.

Clinical implications of the superficial uterine vein pattern for the dissection of the anterior layer of the vesicouterine ligament in radical hysterectomy

To describe anatomic patterns of the superficial uterine vein (sUV) and assess their association with aspects of the dissection procedure of the anterior layer of the vesicouterine ligament (aVUL) by retrospectively reviewing surgical videos. We analyzed patients who underwent laparoscopic radical hysterectomy for early-stage cervical cancer from 2014 to 2019. The primary endpoint was the time required for aVUL dissection. Multiple linear regression analyses were performed to identify factors influencing the time required for aVUL dissection. Fifty-three Japanese patients were included. Two sUV configurations were observed: type 1 (the vein ran ventral to the ureter along the uterine artery) and type 2 (the vein did not run along the usual ventral course; it ran dorsal to the ureter or was absent). Approximately 30% of the sUVs were type 2. The total time for dissection of both sides of the aVUL was significantly shorter for type 2 sUVs than for type 1 sUVs. The number of hemostatic interventions during dissection of each side of the aVUL was significantly lower for type 2 sUVs than for type 1 sUVs. In the multivariate analysis, the sUV configuration was the factor significantly influencing the duration of aVUL dissection on each side (right side: β=-143.4; left side, β=-160.4). We demonstrated that the sUV had 2 types of courses, ventral and others, and its course affected the time required for dissection and the number of hemostatic interventions. Our results provide information supportive of improved radical hysterectomy outcomes.

Cerebral infarction caused by Trousseau syndrome associated with cervical cancer

The combination of cancer and hypercoagulable states is often called Trousseau syndrome. In particular, cerebral infarction caused by Trousseau syndrome is reported to have a poor prognosis. In gynecology, there are many reports of ovarian cancer and a few of uterine cancer. Since there has been no comprehensive report of Trousseau syndrome in cervical cancer, we aimed to summarize Trousseau syndrome in cervical cancer. Cerebral infarction caused by cancer-related arterial thrombosis was defined as Trousseau syndrome. Patients with cervical cancer diagnosed at our hospital between January 2014 and December 2021 were retrospectively reviewed using the hospital's medical records. A total of 1,432 patients were included in the study. Trousseau syndrome occurred in 6 patients (0.4%). The mean age of patients with Trousseau syndrome was 63 years (range: 53-78 years). Of the 6 patients who developed Trousseau's syndrome, 4 patients had it before or during initial treatment, and 2 during recurrent/relapsed disease treatment. The 4 patients who developed the syndrome before or during initial treatment had advanced disease: 1 in stage IIIC and 3 in stage IVB. In all cases, the disease was associated with progressive distant metastasis. The median survival time from the onset of Trousseau syndrome was 1 month (range: 0-6 months). Cervical cancer causes Trousseau syndrome in cases of advanced disease with a short time between the onset of the syndrome and mortality.

Major clinical advances in gynecologic cancer in 2025: from de-escalation strategies to precision therapies beyond BRCA

The landscape of gynecologic cancer management has continued to evolve substantially in 2025, driven by major clinical advances spanning surgical, radiation, and systemic therapies. Recent progress in precision oncology has expanded therapeutic options beyond the

Long-term survival outcomes of female genital tract rhabdomyosarcoma in children, adolescents and young adults at a national rare disease diagnosis and treatment center in China

Rhabdomyosarcoma (RMS) is a rare soft-tissue sarcoma mainly affecting children and adolescents. The genitourinary tract is the second common site involved by RMS. We report the therapeutic effects and long-term survival outcomes of female genital tract RMS. Patients diagnosed with female genital RMS and younger than 25 years old from Peking Union Medical College Hospital between January 1996 and December 2023 were identified. Clinical features, treatment modalities, and survival outcomes were documented. Patient prognosis evaluation was re-evaluated according to the Children's Oncology Group (COG) risk stratification system. A total of 26 patients were included, with a mean age of 8.1 years. The median follow-up duration was 59.3 months. Primary tumor sites were distributed as follows: vagina (n=12), cervix (n=8), vulva (n=2), pelvic region (n=2), uterus (n=1), and subcutaneous perineum (n=1). The COG Risk Stratification System classified 15 patients as low-risk subset 1, 8 as low-risk subset 2, 2 as intermediate-risk, and 1 as high-risk. Nine patients (34.62%) experienced disease recurrence with a median progression free survival of 15.3 months. The disease-specific mortality rate was 26.92% (7/26). Six patients (66.7% of recurrent cases) succumbed to the disease following recurrence, while one stage 4 patient died during initial treatment. Patients diagnosed as RMS in female genital tract in early stage can have relatively good prognosis. Advanced stage and nonstandard primary treatment were related with increased risk of recurrence. Patients with disease recurrence tend to have poor prognoses and higher mortality rates.

Quality indicators for endometrial cancer care in Japan

The incidence and mortality rates of endometrial cancer are increasing globally, including in Japan. Quality of cancer care is promoted through guideline adherence. This study aimed to establish quality indicators (QIs) for endometrial cancer and explore the factors contributing to treatment nonadherence. QIs and pattern-of-care indicators (PCIs) were developed using the Research and Development/University of California Los Angeles modified Delphi method. QIs reflect desirable healthcare patterns, whereas PCIs address treatment areas with lacking evidence. Data from the Hospital-Based Cancer Registry and Diagnosis Procedure Combination Survey were used. Patients diagnosed or treated between January 1 and December 31, 2020 were included. The reasons for nonadherence were collected. Logistic regression was used to analyze the factors influencing adherence, including age, body mass index, comorbidities, facilities, and recurrence risk. Of the 35 proposed QI candidates, 8 QIs and 9 PCIs were selected, predominantly focusing on surgical aspects. Adherence rates varied, with peritoneal lavage cytology being the highest (93.1%), and postoperative hormone replacement therapy (HRT) for patients aged <45 years being the lowest (30.9%), when focusing on process indicators. Reasons for nonadherence included patient preference and medical comorbidities as significant factors. Multivariate analysis highlighted age, clinical stage, and Barthel index as significant contributors to nonadherence. We developed QIs to comprehensively assess endometrial cancer treatment. Adherence rates are favorable; however, HRT has a low adherence rate. Factors leading to nonadherence include advanced age and incomplete activities of daily living, particularly in advanced stages.

Prognostic significance of para-aortic node metastasis in endometrial cancer: Japanese Gynecologic Oncology Group Study JGOG2043 post hoc analysis

This study aimed to assess the prognostic significance of para-aortic lymphadenectomy (PALX) and para-aortic lymph node metastasis in endometrial cancer (EC) patients at risk of post-operative recurrence. Japanese Gynecologic Oncology Group (JGOG) 2043 was a randomized controlled trial assessing the efficacy of adjuvant chemotherapy in EC patients at risk for post-operative recurrence. A retrospective analysis included patients who underwent pelvic lymphadenectomy (PLX) alone or both PLX and PALX in JGOG2043. Data on positive lymph nodes and other clinicopathological risk factors were collected. PLX and PALX were performed on 402 patients, while PLX alone was conducted on 250 patients. Evaluating the effect of PALX on survival was challenging through a comparison of the outcomes of the 2 cohorts since PALX was predominantly administered to higher-risk patients. Patients with 2 or more metastases in para-aortic nodes exhibited significantly poorer overall survival than those with no or 1 metastasis, respectively (p<0.001, p=0.031). Multivariate analysis revealed that 2 or more metastases in para-aortic nodes is independent risk factors for disease-free survival (hazard ratio [HR]=1.72; 95% confidence interval [CI]=1.10-2.72; p=0.019) and are marginally significant for overall survival (HR=1.58; 95% CI=0.92-2.72; p=0.096) compared to no or a single metastasis. The clinical relevance of PALX was challenging to evaluate in the JGOG2043 cohort; however, the presence of 2 or more para-aortic node metastases was identified as an independent unfavorable prognostic factor in EC patients at risk of recurrence.

Current status and challenges in training the next generation of gynecologic cancer care providers in Asia

Gynecologic oncology is undergoing rapid development with continuous advances in treatment strategies, surgical techniques, and clinical research. Training programs must keep pace by providing future specialists with the necessary surgical skills and a solid understanding of evolving practices. This study aimed to examine the current state of gynecologic oncology training in Asia and to identify key challenges and opportunities for improvement. A descriptive survey was conducted in October 2023 under the leadership of the Education Committee of the Asian Society of Gynecologic Oncology (ASGO). Key stakeholders involved in clinical training and policy-making from eight countries and regions (China, Hong Kong SAR, India, Japan, the Philippines, South Korea, Taiwan, and Thailand) responded to an online questionnaire assessing the structure and quality of their national training programs. Six of the eight countries/regions have official gynecologic oncology societies. Training duration was three years or more in five regions and two years in the remaining three. Seven reported conducting formal assessments of surgical skills. While five programs offered adequate exposure to minimally invasive surgery, three noted limitations. Satisfaction with research opportunities and overall training quality also varied. The most frequently cited concern was the lack of standardized curricula. This regional overview reveals notable differences in training approaches across Asia. Standardizing educational frameworks and expanding collaborative initiatives - such as virtual tumor boards, elective rotations, and skills-based workshops - may help address current gaps and strengthen gynecologic oncology training in the region.

Quantifying the impact of bladder complications following gynecological cancer treatment: systematic review and meta-regression

Gynecological cancer treatments, including radiotherapy (RT) and chemotherapy, leads to various bladder complications. The anatomical proximity of the treatment site to the urinary bladder primarily explains the complications following RT, while chemotherapy contribute to bladder dysfunction through systemic mechanisms. This study systematically reviews the nature, extent, and prevalence of bladder complications among women treated for these malignancies, underscoring the influence of treatment modalities on bladder function. A comprehensive search of databases including Embase, Scopus, PubMed/MEDLINE, CINAHL, and the Cochrane Library was conducted, focusing on women undergoing RT, chemotherapy, or both for gynecological cancers. Meta-regression was performed to quantify the effects of treatments on bladder function, using random-effect models. From 15,081 citations, 12 studies with a total of 12,469 participants were included. Our analysis revealed a broad spectrum of bladder complications, with urinary incontinence (UI) and overactive bladder symptoms being common, alongside with radiation cystitis and anatomical defects formation. The prevalence of these complications varied, reflecting the complexity of treatment modalities, cancer types, and patient characteristics. Specifically, UI rates ranged from 2.6% to 84%, while the incidence of fistula formation and ureteral stenosis remained relatively low but clinically significant. Urodynamic findings showed reduced bladder capacity and increased detrusor overactivity in up to 44% of evaluated patients, highlighting treatment's impact on bladder function. Bladder complications are prevalent among gynecological cancer survivors, with notable occurrences associated with chemotherapy and RT treatments. Integrated care focusing on both oncological and urological health is essential for enhancing survivors' quality of life. PROSPERO Identifier: CRD42023467123.

Major clinical research advances in gynecologic cancer in 2020

In 2020 series, we summarized the major clinical research advances in gynecologic oncology with providing representative figures of the most influential study for 1 of each 3 gynecologic cancers: cervix, ovary, and uterine corpus. Review for cervical cancer covered targeted agents and immune checkpoint inhibitors, adjuvant radiation therapy or concurrent/sequential chemoradiation therapy after radical hysterectomy in early cervical cancer, radical surgery in early cervical cancer; and prevention and screening. Ovarian cancer research included studies of various combinations of poly (ADP-ribose) polymerase inhibitors with chemotherapy, immune checkpoint inhibitors, and/or vascular endothelial growth factor inhibitors according to the clinical setting. For uterine corpus cancer, molecular classification upon which the decision of adjuvant treatments might be based, World Health Organization recommendation of 2-tier grading system (low grade vs. high grade), sentinel lymph node assessment and ovarian preservation in clinically early-stage endometrial cancer were reviewed. Molecular targeted agents including immune checkpoint inhibitors which showed promising anti-tumor activities in advanced/recurrent endometrial cancer were also included in this review.

FUS-stabilized USP7 facilitates the bevacizumab resistance of ovarian cancer through deubiquitinating PTK2

The emergence of drug resistance brings new challenges to the clinical management of ovarian cancer (OC) patients. This study aimed to explore the role and mechanism of ubiquitin-specific peptidase 7 (USP7) on the bevacizumab resistance of OC. The mRNA levels of USP7 and protein tyrosine kinase 2 (PTK2) were measured using quantitative real-time polymerase chain reaction. Western blot analysis was used for detecting the protein levels of USP7, PTK2 and fused in sarcoma (FUS). Cell resistance, proliferation, apoptosis, invasion and angiogenesis were determined by cell counting kit 8 assay, colony formation assay, flow cytometry, transwell assay and tube formation assay. Glucose consumption, lactate production, and ATP/ADP ratio were used to evaluate glycolysis. The interactions between USP7 and PTK2/FUS were detected by co-immunoprecipitation assay. Mice xenograft model was also constructed to explore USP7 roles in vivo. USP7 was upregulated in OC tissues and bevacizumab-resistant cells. USP7 knockdown or its inhibitor P22077 inhibited the bevacizumab resistance of OC cells via suppressing cell growth, metastasis, angiogenesis and glycolysis. USP7 stabilized PTK2 protein expression via deubiquitinating. PTK2 overexpression reversed the effect of USP7 knockdown on the bevacizumab resistance of OC cells. Besides, FUS stabilized USP7 mRNA to regulate its protein level, and it could affect PTK2 expression by mediating USP7. USP7 knockdown enhanced the sensitivity of OC tumors to bevacizumab in vivo. FUS-stabilized USP7 enhanced the bevacizumab resistance of OC by deubiquitinating PTK2, providing a new idea for overcoming bevacizumab resistance in OC.

Molecular classification of endometrial cancer: entering an era of precision medicine

Global burden of uterine cancer in 204 countries and territories and its predicted level in 15 years, from 1990 to 2021

Uterine cancer (UC) is a major cause of cancer-related deaths among women. This study assesses the global burden of UC from 1990 to 2021. Data from the Global Burden of Disease 2021 study were used to analyze UC incidence, mortality, and disability-adjusted life years (DALYs) across 204 countries. Age-standardized rates were evaluated by age and Socio-Demographic Index (SDI), with trends forecasted to 2036 using Bayesian models. In 2021, the global incidence of UC reached 473,614 cases (95% uncertainty interval [UI]=4,29916-5,13667), with an age-standardized incidence rate of 5.41 per 100,000 (95% UI=4.90-5.87), showing an upward trend since 1990, particularly in high-SDI regions. However, the mortality rate in high SDI regions exhibited a declining trend, with an estimated annual percentage change (EAPC) of -0.25 (95% confidence interval=-0.42 to -0.08). Although the number of deaths globally has increased, the age-standardized mortality rate has decreased compared to 1990 (EAPC: -0.85). The global age-standardized DALYs also show a downward trend, except in high SDI and low-middle SDI regions. The highest incidence was observed among individuals aged 70-74 in 2021. By 2036, new cases are projected to rise, though incidence, mortality, and DALYs are expected to decline. Regional disparities in the global UC burden highlight the need for tailored strategies, especially in low-income countries, to reduce its impact.

Significance of PD-L1 expression in carbon-ion radiotherapy for uterine cervical adeno/adenosquamous carcinoma

Programmed cell death-ligand 1 (PD-L1) is expressed in tumor cells and has been shown to predict clinical outcomes of several types of malignancies. The aim of this study was to investigate the effects of carbon-ion (C-ion) beam irradiation on PD-L1 expression in human uterine cervical adeno/adenosquamous carcinoma (UCAA) cells and clinical samples and to identify the prognostic factors for outcomes after C-ion radiotherapy (CIRT). The effects of C-ion irradiation on PD-L1 expression in human UCAA and cervical squamous cell carcinoma cells were examined by flow cytometry. We examined PD-L1 expression in UCAA biopsy specimens from 33 patients before CIRT started (pre-CIRT) and after 12 Gy (relative biological effectiveness [RBE]) irradiation (post-12Gy-C) in 4 fractions of CIRT to investigate the correlation between PD-L1 status and clinical outcomes. The PD-L1 expression was upregulated by C-ion beam in a dose-dependent manner in HeLa and SiHa cells through phosphorylated Chk1. The overall frequencies of pre-CIRT and post-12Gy-C PD-L1 positivity were 45% (15/33) and 67% (22/33), respectively. The post-12Gy-C PD-L1 expression was significantly elevated compared to the pre-CIRT PD-L1 expression. There was no significant relationship between the pre-CIRT PD-L1 status and clinical outcomes, such as local control (LC), progression-free survival (PFS), and overall survival (OS). However, the post-12Gy-C PD-L1 expression had better correlation with PFS, but not with LC and OS. CIRT can induce PD-L1 expression in UCAA and we propose that PD-L1 expression after starting CIRT may become as a predictive prognostic marker in CIRT for UCAA.

Cost-effectiveness analysis of reflex p16/Ki-67 dual-stained cytology in HPV partial genotyping screening in Singapore

Triage testing is an integral part of high-risk human papillomavirus (HPV)-based cervical screening programs. This study assesses, from a healthcare payer perspective in Singapore, the cost-effectiveness of p16/Ki-67 dual-stained cytology (DS) compared to current standard of care (SOC). A decision-analytic Markov microsimulation model with a lifetime horizon was built to simulate the outcomes from HPV screening in Singaporean women aged 30-65 years. The intervention (primary testing with HPV genotyping followed by DS reflex test) was compared to current SOC (HPV genotyping followed by cytology) according to Singaporean clinical management guidelines. The progression through health states and associated costs and health outcomes were based on local clinical care data in Singapore. Screening impact was assessed by cost saving, number of colposcopy and quality-adjusted life years (QALYs). Compared to SOC, implementation of HPV genotyping + DS was estimated to decrease the number of screening test (-2.02 times per patient) and colposcopy (-0.16 times per patient), and reduce the overall costs to the Singaporean healthcare system by S$225.59 per patient (95% confidence interval [CI]=S$199.05 to S$249.99). The total QALYs estimates for the 2 approaches were similar (-0.0003; 95% CI=-0.0031 to 0.0022). Sensitivity analyses confirmed the robustness of expected cost-savings and that the full value of avoided colposcopies may be larger than projected in the current analysis. This economic modelling analysis projected that using DS instead of conventional cytology as the reflex test for positive test with non-HPV-16/18 subtypes significantly reduced the financial costs of cervical cancer screening in Singapore.

The prognosis impact of NACT-IDS and PDS in advanced ovarian cancer: a systematic review and meta-analysis

We aimed to explore the prognostic implications of neoadjuvant chemotherapy and interval debulking surgery (NACT-IDS) compared to primary debulking surgery (PDS) in patients diagnosed with advanced ovarian cancer by meta-analysis. The search was conducted across PubMed, Web of Science, Cochrane, Wanfang Data, China National Knowledge Infrastructure, and the Chinese BioMedical Literature Database to identify pertinent studies examining the prognostic implications of NACT-IDS versus PDS in patients with advanced ovarian cancer. As of September 11, 2023, a total of 29 articles were ultimately included, encompassing 12,916 patients with advanced ovarian cancer in this meta-analysis. NACT-IDS groups exhibited a higher satisfactory tumor reduction rate (odds ratio [OR]=2.06; 95% confidence interval [CI]=1.53 to 2.76; p<0.001). NACT-IDS effectively reduced the risk of adverse cardiac events (OR=0.36; 95% CI=0.17 to 0.80; p=0.012), surgical site infections (OR=0.42; 95% CI=0.29 to 0.60; p<0.001), and embolic complications (OR=0.43; 95% CI=0.24 to 0.75; p=0.003) in patients with advanced ovarian cancer. Compared to NACT-IDS therapy for International Federation of Gynecology and Obstetrics (FIGO) III-IV ovarian cancer patients (OR=1.66; 95% CI=1.24 to 2.23; p=0.009), NACT-IDS groups exhibited a higher satisfactory tumor reduction rate for FIGO IIIC-IV (OR=2.35; 95% CI=1.50 to 3.70; p<0.001). NACT-IDS effectively enhances the satisfactory tumor reduction rate, especially for patients with stage IIIC and IV, and decreases postoperative complications among patients with advanced ovarian cancer.

Mutations in homologous recombination repair genes in patients with metastatic endometrial cancer: association with clinical characteristics and prognosis

To evaluate the mutation rates of homologous recombination repair (HRR) genes and the impact of these mutations on the clinical characteristics of metastatic endometrial cancer (EC). Somatic DNA from 895 patients with metastatic EC in the Memorial Sloan Kettering-Metastatic Events and Tropisms cohort was assessed for mutations in 10 HRR genes ( Somatic mutations in HRR genes were detected in 106 (11.8%) patients with metastatic EC. Compared with nonmutation carriers, a greater proportion of carriers had endometrioid carcinoma (76.4% vs. 50.3%, p<0.001). Regarding the TCGA classification, the proportions of the Somatic HRR mutations are detected in 11.8% of metastatic EC. Compared with noncarriers, HRR mutation carriers in metastatic EC have higher proportions of endometrioid carcinoma,

Comparison of oncologic outcome of preoveratively presumed low-risk endometrial cancer patients who underwent only bilateral pelvic sentinel lymph node (SLN) removal and those who underwent pelvic lymphadenectomy in addition to bilateral pelvic SLN removal: Turkish Gynecologic Oncology Group (TRSGO-SLN-009)

We aimed to compare the oncological outcomes of patients with bilateral sentinel lymph nodes (SLNs) detection and removed with those who underwent pelvic lymphadenectomy (PLA) in addition to bilateral SLNs removal. This multicenter, retrospective study included cases of endometrioid type, grade I-II endometrial cancer, in which bilateral SLNs were detected and removed. Patients who had only bilateral SLNs detected and removed (group I) and patients who had bilateral SLNs detected and removed and subsequent additional bilateral PLA (group II) were included in the evaluation. In group I (n=216), SLN metastasis rate was 5.5% and in group II (n=251), it was 10.3%. The low-volume disease detection rate was 4.6% in group I and 4.8% in group II. In group II, in patients with SLN macrometastasis had also 28.6% non-SLN macrometastasis. No false-negative results occurred in group II. Recurrence was detected 1.8% in group I and 5% in group II; however, there was no significant difference (p=0.083). Disease-free survival and overall survival, were almost same between the groups (hazard ratio [HR]=2.11; 95% confidence interval [CI]=0.681-6.588; p=0.187) and (HR=1.531; 95% CI=0.392-5.975; p=0.537), respectively. SLN mapping, ultrastaging, and immunohistochemical staining can identify low-volume metastases that may not be identified with classic lymphadenectomy and hematoxylin & eosin staining. It has been observed that adding PLA beyond SLN mapping did not provide an additional positive contribution to survival. For endometriod type grade I-II patients, detection of bilateral SLNs in both hemipelvis only, if detectable, is an adequate approach.

Characteristics of endometrial cancer progressed to extrauterine lesions following fertility preserving medroxyprogesterone acetate therapy for young endometrial cancer patients

Medroxyprogesterone acetate (MPA) is an effective fertility-preserving treatment for early endometrial cancer and atypical endometrial hyperplasia (AEH), and rarely leads to the development of extrauterine lesions (ELs). We aimed to clarify the characteristics of patients who developed ELs post-MPA therapy. We analyzed the clinicopathological factors and prognoses of 319 patients with endometrioid carcinoma grade 1 (EMG1) and AEH treated with MPA at our institution. All patients underwent imaging before MPA treatment to rule out ELs. Seven patients (2.2%) with EMG1 showed EL after MPA treatment. Two patients developed EL during the initial treatment, 2 during repeated treatment, and 3 during follow-up. Two patients had peritoneal dissemination, 3 had regional lymph node metastasis, 1 had distant metastasis at the Virchow lymph node, and 1 had ovarian metastasis. ELs were diagnosed using imaging tests in 6 patients and elevated tumor markers in 3 (overlapping) patients. One patient was diagnosed with ELs pathologically after hysterectomy. Upon EL diagnosis, patients underwent standard treatment, including hysterectomy and chemotherapy, that was followed by a diagnosis of EMG1 for 5, EMG2 for 1, and EMG3 for 1 patient. One patient died 15 months after start of therapy and another died 119 months post-treatment initiation, while the others have been survived. Only 2.2% of all patients developed ELs post-MPA treatment, but some cases were fatal. It is essential to conduct imaging tests and screen for tumor markers during and after MPA treatment regularly and also when cancer progression is suspected.

Development and validation of a prediction model for lymph node metastasis based on molecular typing in clinically early-stage endometrial carcinoma

To develop and externally validate a machine learning-based preoperative model integrating molecular typing and clinical features to predict lymph node metastasis (LNM) in patients with early-stage endometrial carcinoma (EC). This retrospective study included 465 patients with clinically early-stage EC treated at Qilu Hospital of Shandong University. Tumors were classified into molecular subtypes using The Cancer Genome Atlas-based methods. Least Absolute Shrinkage and Selection Operator regression identified five preoperative predictors: molecular typing (CN-H vs. non-CN-H), histological subtype, depth of myometrial invasion, neutrophil-to-lymphocyte ratio, and CA125 levels. Multiple machine learning algorithms were evaluated, and logistic regression (LR) was selected based on optimal discrimination and clinical applicability. Model performance was assessed using area under the curve (AUC), calibration plots, and decision curve analysis (DCA). A web-based nomogram was developed for clinical use. The LR model demonstrated excellent discrimination, with AUCs of 0.843 in the training cohort and 0.809 in the testing cohort. The CN-H subtype was significantly associated with increased LNM risk. The model enabled effective risk stratification and calibration curves and DCA confirmed the model's accuracy and clinical utility. By integrating molecular and preoperative clinical features, this model offers accurate LNM risk stratification for early-stage EC. It supports clinical decision-making and has been implemented as a user-friendly online tool. Further prospective multicenter validation is warranted.

Differentiation of uterine fibroids and sarcomas by MRI and serum LDH levels: a multicenter study of the KAMOGAWA study

In the differential diagnosis between uterine fibroids and uterine sarcomas, real-world magnetic resonance imaging (MRI) diagnostic information is scarce; furthermore, high diagnostic sensitivity is important in clinical practice. We previously developed a diagnostic algorithm to detect uterine sarcoma with high sensitivity using simple MRI images and serum lactate dehydrogenase (LDH) levels. In this multicenter study, we investigated the preoperative diagnosis of sarcoma in the real world and further validated the usefulness of our diagnostic algorithm. Of 154 uterine sarcomas and 154 uterine fibroids treated at 15 centers between January 2006 and December 2020, 139 sarcomas (16 smooth muscle tumors of uncertain malignant potential) and 141 fibroids with diffusion-weighted imaging information were included in the analysis. The diagnostic algorithm was validated by 3 radiologists who were blinded to the clinical information and pathologic diagnoses and who read the MRIs. The sensitivity/specificity of preoperative diagnosis was 77.7%/92.9% for the preoperative report; 92.1%/72.3% for algorithm A; and 82.0%/85.8% for algorithm B (McNemar's test p<0.05). Comparison of overall survival rates among 3 groups (Group 1: negative A, Group 2: positive A and negative B; Group 3: positive B) using algorithms A and B showed p=0.012. On multivariate analysis, stage, and serum LDH level were independent prognostic factors. MRI is useful for preoperative diagnosis of uterine sarcoma, and the sarcoma diagnostic algorithm presented in this study is an option for diagnosing sarcoma with greater sensitivity. This information should be shared with patients.

Radical hysterectomy or chemoradiotherapy for clinically early-stage cervical cancer with suspicious lymph nodes on imaging: a retrospective cohort study

The optimal treatment of clinically early-stage cervical cancer with suspicious lymph nodes on pretreatment imaging is unclear. Therefore, we aimed to compare surgery (i.e., radical hysterectomy and pelvic lymphadenectomy±adjuvant therapy) with primary chemoradiotherapy as treatment strategies in this patient group regarding recurrence-free, overall survival and toxicity. Women diagnosed between 2009-2017 with the International Federation of Gynecology and Obstetrics (2009) stage IA-IIA and suspicious nodes based on radiologic assessment of pretreatment imaging were retrospectively selected from the Netherlands Cancer Registry. Cox proportional hazard was used to estimate survival and logistic regression for toxicity. Inverse probability weighting was used to correct for confounding. Grade ≥2 surgery-related (≤30 days) and grade ≥3 chemotherapy or radiotherapy-related (≤6 months) toxicity were collected. Missing data were imputed. Of 330 patients included, 131 (40%) received surgery (followed by adjuvant therapy in 54%) and 199 (60%) chemoradiotherapy. Pathological nodal status was known in 100% of the surgery group and 32% (n=63) of the chemoradiotherapy group, of whom 43% (56/131) and 89% (56/63), respectively, had metastases. After adjustment for confounders, the recurrence-free survival (hazard ratio [HR]=0.67; 95% confidence interval [CI]=0.34-1.31) and overall survival (HR=0.75; 95% CI=0.38-1.47) were not significantly different between both groups, while surgery was associated with more toxicity (odds ratio=2.82; 95% CI=1.42-5.60), mainly surgery-related. In patients with clinically early-stage cervical cancer and suspicious nodes on imaging, surgery and primary chemoradiotherapy yielded comparable results in terms of survival, whereas surgery might be associated with more (surgery-related) short-term toxicity.

Subsequent primary cancer incidence in cervical cancer survivors: insights from a comprehensive cohort study utilizing combined Japanese population-based cancer registries

This study aimed to evaluate the incidence of subsequent primary cancer (SPC) among cervical cancer survivors in Japan. Data from the cancer registries of Osaka, Kanagawa, and Miyagi prefectures were combined. The cohort included individuals diagnosed with invasive and in situ cervical cancer between 1980 and 2010, with the SPC incidence evaluated until 2015. The incidence and standardized incidence ratio (SIR) for different SPC sites were calculated. In addition, the association between SPC and radiotherapy was examined via competitive regression analysis. A total of 49,824 cervical cancer survivors were followed for up to 35 years, during which 4,507 (9.0%) of these survivors experienced SPC. Aside from the initial cancer, SPC was the most common cause of death among cervical cancer survivors. The most frequent SPC sites were the colorectal, breast, lung, and stomach, consistent with the frequency in the general population. A significant increase in the SIRs for bladder, lung, and colorectal cancers was observed (2.52, 1.63, and 1.44, respectively). Individuals who underwent radiotherapy had a higher risk of developing bladder cancer than those who did not, with a subdistribution hazard ratio of 2.28. The SIR for lung cancer significantly increased, particularly for the smoking-associated types, indicating the influence of smoking habits among survivors. Increased risk of specific SPCs was seen in both invasive and in situ cancer survivors. Cervical cancer survivors should be informed about the risks of SPCs and educated on the prevention methods. Our study provides valuable insights into specific actions SPC prevention.

Efficacy and toxicity of PARP inhibitor in elderly patients with homologous recombination-deficient newly diagnosed advanced ovarian cancer: the role of dose modification

To investigate the impact of age on the progression-free survival (PFS) and dose modification, discontinuation and adverse events of poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) maintenance therapy in homologous recombination-deficient (HRD) ovarian cancer patients. We analyzed 324 patients with advanced stage III-IV epithelial ovarian cancer who had either BRCA mutation or HRD between July 2019 and November 2022. The primary objective was to evaluate the efficacy of PARPis by comparing PFS between patients who received PARPis and those who did not, specifically within 2 age groups: patients aged <60 years and those aged ≥60 years. The secondary objective included evaluating the rates of dose modification, discontinuation, and occurrence of treatment-emergent adverse events in patients who used PARPis. Of the 324 patients, 139 patients (42.9%) were diagnosed at ≥60 years. The use of PARPis resulted in a significant improvement in PFS in both age groups (hazard ratio [HR]=0.37; p<0.01) for patients aged <60 years (HR=0.41; p<0.01) for those aged ≥60 years. The multivariable Cox proportional hazards analysis revealed no significant difference in the PFS benefit between the 2 age groups (HR=0.95; 95% confidence interval [CI]=0.65-1.37; p=0.76). Dose modifications were more frequent in the elderly cohort (63.9% vs. 46.5%; p=0.04). PARPis significantly improved PFS in elderly ovarian cancer patients with BRCA mutations and HRD, with a toxicity profile similar to that of younger patients. Elderly patients benefited from frequent dose modifications without any negative impact on PFS outcomes.

A decade data of HPV genotypes in metropolitan regions of Indonesia: paving the way for a national cervical cancer elimination strategy

Human papillomavirus (HPV) infection is a global public health concern and associated with cervical cancer. HPV genotype mapping has an essential role in prevention and control strategy in developing more suitable HPV vaccine for Indonesia. This was a descriptive retrospective cross-sectional study from 2012 until 2022 at Kalgen Laboratory, Jakarta from all over the metropolitan regions. The total 76,413 samples were collected with consecutive sampling, which 694 excluded, thus final samples used were 75,719. HPV DNA test was performed using the polymerase chain reaction (PCR): SPF10-DEIA-LiPA25 methods. HPV genotyping procedures included DNA extraction, PCR using the HPV XpressMatrix kit, and hybridization. From 75,719 samples, 93.4% was negative for intraepithelial lesion or malignancy (NILM). Among 6.6% of total 75,719 samples of abnormal cytology groups, 53.8% were atypical squamous cells of undetermined significance (ASCUS), 32.9% were low grade intraepithelial lesion (LSIL), and 13.3% were high grade intraepithelial lesion (HSIL). The most common high risk HPV genotypes among HSIL were 16, 18, 52, 58, 33, 51, and 53. Single HPV infection was more common compared to multiple infections. This study showed that HR-HPV types among HSIL were 16, 18, 52, 58, 33, 51, and 53. HPV 52 was the most frequent type among NILM, ASCUS, and LSIL. Thus, it could serve as a potential future reference to create a more suitable HPV nonavalent vaccine for Indonesian population based on its different epidemiology.

Japan Society of Gynecologic Oncology 2023 guidelines for treatment of uterine body neoplasm

The Japan Society of Gynecologic Oncology (JSGO) guideline for the treatment of uterine body neoplasm are revised from the 2018 guideline. This guideline aimed to provide standardized care for uterine body neoplasm, indicate appropriate current treatment methods for uterine body neoplasm, minimize variances in treatment methods among institutions, improve disease prognosis and treatment safety, reduce the economic and psychosomatic burden on patients by promoting the performance of appropriate treatment, and enhance mutual understanding between patients and healthcare professionals. The guidelines were prepared through the consensus of the JSGO guideline committee, based on a careful review of evidence from the literature searches and the medical health insurance system and actual clinical practice situations in Japan. The main features of the 2023 revision are as follows: 1) The Guidelines Formulation Committee members were asked to understand Minds' medical guideline development method in advance. 2) The clinical question (CQ) was changed to Patient, Intervention, Comparison, Outcome format as much as possible. 3) Introduced the "body of evidence," which summarizes the results of research reports collected for the CQs by outcome and study design, and the strength of evidence for each body of evidence was rated from levels A to D. 4) Introduction of systematic reviews in some CQs. 5) The strength of evidence, the balance of benefits and harms, value and hope for patients, and clinical applicability were considered while drafting recommendations. Herein, we present the English version of the JSGO guidelines 2023 for the treatment of uterine body neoplasm.

Analysis of fertility-preserving treatment outcomes in patients with POLE-mutated endometrioid carcinoma

To explore the clinical outcomes of fertility-sparing treatment (FST) in patients with POLE-mutated endometrioid carcinoma (EEC). A total of 9 EEC patients who received FST and were classified to the POLE-mutated subtype in Peking University People's Hospital from April 2020 to October 2023, were retrospectively collected. Clinical and pathological data were analyzed to describe the outcomes of FST in patients with POLE-mutated EEC. A total of 9 patients with EEC including 6 cases with well-differentiated (G1) and 3 cases with moderately-differentiated (G2). The average age was 34.8±2.1 years. POLE mutation sites were P286R (5 cases), V411L (2 cases), L424I (1 cases), and S459F (1 cases), respectively. The median follow-up time was 16 months (9-41 months). The complete response (CR) rate was 88.9% (8/9), with a median time to CR of 5.5 months (3-18 months). The partial response (PR) rate was 11.1% (1/9). The relapse rate was 50.0% (4/8), with a median recurrence time of 9.5 months (5-25 months). Of these, 75% (3/4) underwent secondary FST, with all achieving CR again (3/3). Three of 5 who were out-of-indication patients achieved CR by individual therapy. FST in patients with POLE-mutated EEC achieve a CR rate of 88.9% in this study, the largest number of retrievable reports. In certain patients who are out-of-indication, individualized treatment may also result in remission. However, unlike surgical patients, some patients experience disease recurrence and whether POLE-mutated EEC is sensitive to conventional therapy in FST is controversial given its pathogenesis.

The impact of cytoreductive surgery on outcomes in high tumor burden ovarian cancer after induction of PARP inhibitors

In advanced ovarian cancer, achieving R0 resection is a critical strategy for improving prognosis. However, even with R0 resection, the prognosis of patients with a high tumor burden remains poor. This study aimed to assess whether the introduction of poly(ADP-ribose) polymerase inhibitors (PARPi) has enhanced outcomes in such cases. We retrospectively analyzed patients with International Federation of Gynecology and Obstetrics (FIGO) stage III-IV ovarian cancer treated between January 2015 and December 2021. Patients were classified into Group A (pre-PARPi introduction) and Group B (post-PARPi introduction). Complete macroscopic resection was defined as R0. Progression-free survival (PFS), stratified by the Aletti Surgical Complexity Score (Aletti_SCS), was the primary endpoint and was evaluated using Cox regression models. A total of 434 patients were included. In Group A, among those who achieved R0, the median PFS was 23.5 months for patients with high Aletti_SCS (95% confidence interval [CI]=14-30) and not reached for those with low Aletti_SCS (95% CI=30-not reached; adjusted hazard ratio [HR]=0.36, 95% CI=0.20-0.62). In Group B, the median PFS was not reached in both patients with high Aletti_SCS (95% CI=not reached-not reached) and low Aletti_SCS (95% CI=22-not reached; adjusted HR=4.98, 95% CI=1.14-21.78). Following the introduction of PARPi, there was a trend toward improved PFS in patients with a higher Aletti_SCS who underwent R0 resection. These findings suggest that R0 resection may improve prognosis even in cases with a high tumor burden in the PARPi era.

Knowledge and awareness of cervical cancer and prevention measures among female students in Poland: a cross-sectional, decade apart study

Cervical cancer (CC) is a global health issue, despite the availability of effective preventive measures. The objective of this investigation was to evaluate the comprehension of CC and its preventive measures among 17-25-year-old female students living in southern Poland, to compare the results with the data obtained in 2012 and to propose actionable recommendations for improving the current state of affairs. The study collected data from 464 female students during a ten-month period in 2022 using a pre-validated tool developed by our group, CCKP-64 categorized into sections: personal information, basic CC knowledge, risk factor assessment, awareness of primary and secondary prevention, and sources of information. The 98.92% of participants were aware of CC, 42.24% linked it to an infection. Genetic factors and human papillomavirus (HPV) infection were commonly identified as risk factors. Most of the participants (81.90%) knew about the Pap smear and planned to undergo the test (74.74%). The most common sources of information were the Internet (81.68%), family and friends (46.77%), and medical staff (42.89%). Comparison with the 2012 cohort indicated a decrease in awareness of HPV vaccine existence (69.85% vs. 53.23%, p<0.001) and cytological examination (91.21% vs. 81.90%, p<0.001), but increase in percentage of vaccinated population (9.35% vs. 19.43%, p=0.001). The insufficient knowledge and deteriorating trends in CC prevention among young women over the last decade are concerning. The proportion of vaccinated women remains unsatisfactory. Measures to enhance awareness of national reimbursed HPV vaccination program are necessary.

Intra- and postoperative complications associated with diaphragmatic surgery for advanced ovarian cancer

Diaphragmatic resection is frequently required to achieve optimal cytoreduction with no residual disease in patients with advanced ovarian cancer. Pleural effusion and pneumothorax are known short-term postoperative complications of diaphragmatic resection; however, few studies have reported intraoperative and long-term postoperative complications of this procedure. We investigated the intraoperative, as well as short- and long-term postoperative complications of diaphragmatic resection. Of the patients with stage III/IV ovarian cancer, who were initially treated at our hospital between 2008 and 2020, 267 patients who underwent diaphragmatic resection were included in this study. We recorded details regarding the type of diaphragmatic resection, type of closure, and intraoperative, as well as short- and long-term postoperative complications. Of the 264 patients who underwent right-sided diaphragmatic resection, 235 underwent full-thickness resection and 29 underwent peritoneal stripping. Of the 118 patients who underwent left-sided diaphragmatic resection, 23 underwent full-thickness resection and 95 underwent peritoneal stripping. Intraoperative complications occurred in 5 patients (massive bleeding from the right hepatic vein [n=1], massive bleeding during excision of the liver adherent to the diaphragm [n=1], and lung injury [n=3]). Short-term complications included pleural effusion that necessitated drainage in 2 and pneumothorax after drain removal in 1 patient. Long-term complications included right diaphragmatic hernia in 1, left diaphragmatic hernia in 2, and pancreaticopleural fistula in 1 patient. Diaphragmatic resection was associated with a low incidence of intra- and postoperative complications, which highlights the safety of this approach for management of advanced ovarian cancer.

Effects of tumor spillage prevention in laparoscopic radical hysterectomy for early-stage cervical cancer: a propensity score-matched analysis

Minimally invasive radical hysterectomy has a worse prognosis than open surgery, but the reasons for the poor prognosis remain unclear. Tumor spillage occurs when the tumor is exposed to the surgical field and has been suggested to be related to a poor prognosis. This study aimed to compare the prognostic value of tumor spillage in laparoscopic radical hysterectomy and evaluate whether tumor spillage prevention improves oncological safety. We compared the prognosis of patients who underwent laparoscopic radical hysterectomy between December 2014 and November 2021 with or without tumor spillage prevention, including surgeries without prevention and those with failed prevention. Prevention consisted of vaginal cuff formation or closure of the vaginal canal with clips to prevent tumor exposure at the time of colpotomy. The primary endpoint was disease-free survival, which was adjusted using propensity scores to compare patients. In total, 165 patients received tumor spillage prevention, and 61 did not or failed to receive such prevention. The median follow-up was 4.4 years. Patients who did not undergo prevention or failed prevention had significantly shorter disease-free survival than those who did (hazard ratio [HR]=3.54; 95% confidence interval [CI]=1.23-10.23). The same trend was observed after adjusting for propensity score matching. Patients who did not or failed to receive prevention were more likely to experience local recurrence (HR=4.01; 95% CI=1.13-14.24). Tumor spillage prevention was associated with longer disease-free survival in laparoscopic radical hysterectomy.

Trends and characteristics of fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer in Japan: a survey by the Gynecologic Oncology Committee of the Japan Society of Obstetrics and Gynecology

The objective of this study was to examine the current trends in fertility-sparing (FS) treatment for young atypical endometrial hyperplasia (AEH) and endometrial cancer (EC) patients in Japan. This study was conducted by the Committee on Gynecologic Oncology of the Japan Society of Obstetrics and Gynecology (JSOG) in the 2017-2018 fiscal year. A nationwide, retrospective questionnaire-style survey-as performed. We collected the data of 413 patients from 102 JSOG gynecological cancer registered institutions. FS treatment was performed with medroxyprogesterone (MPA) (87.2%) or MPA + metformin (11.6%). Pathological complete remission (CR) after initial treatment was achieved in 78.2% of patients. The significant clinicopathological factors correlated to CR after initial treatment were histology (AEH vs. endometrioid carcinoma grade 1 [ECG1]), body mass index (BMI) (<25 vs. ≥25 kg/m²), and treatment period (<6 vs. ≥6 months). ECG1, time to complete remission (TTCR) ≥6 months, maintenance therapy (-), and pregnancy (-) were associated with a significantly higher risk of recurrence on multivariate analysis. The total pregnancy rate was 47%, and the live birth rate was 40.1%. Patients who received infertility treatments showed a higher live birth rate (50.6%) than those who did not (7.7%). In this survey, we confirmed that FS treatment in Japan is centered on MPA alone and in combination with metformin, and that the treatment efficacy is similar to that reported in previous reports. A multicenter survey study in Japan showed FS treatment for young AEH and EC patients in compliance with the indications is feasible.

ATF1 regulates MAL2 expression through inhibition of miR-630 to mediate the EMT process that promotes cervical cancer cell development and metastasis

The existence of activating transcription factor 1 (ATF1) could be employed as a clinical marker in the context of cervical cancer development, although its specific mechanism has not been fully clarified. To evaluate the presence of ATF1, miR-630, and myelin and lymphocyte protein 2 (MAL2) in cervical malignancies, we conducted quantitative reverse transcription polymerase chain reaction, immunohistochemistry, and Western blot assays; further studied the expansion, migration, invasion and epithelial-mesenchymal transition (EMT) of cervical carcinoma cells using colony formation assay, transwell, loss cytometry, Western blot. Chromatin immunoprecipitation (ChIP) and RNA immunoprecipitation (RIP) were used to verify that ATF1 could directly transcriptionally repress miR-630; dual luciferase reporter assay and RIP assay were employed to confirm that miR-630 targeted to repress MAL2. In cervical cancer cases, elevated ATF1 expression and reduced miR-630 expression were detected, displaying a negative relationship between them. Inhibition of ATF1 hindered the growth, migration, infiltration, and EMT in cervical carcinoma cells, while upregulation of miR-630 mitigated the aggressive characteristics of these cells. ATF1 was found to transcriptionally repress miR-630 by TransmiR and ALGGEN prediction and ChIP validation. MicroRNA modulates gene expression and affects cancer progression, and we discovered that miR-630 regulates cancer progression by targeting and inhibiting MAL2. ATF1, which modulates the miR-630/MAL2 pathway, affects the EMT process and cervical carcinoma cell growth and spread. Therefore, ATF1 may serve as a promising marker and treatment target for cervical malignancies intervention.

Cost-effectiveness analysis of single-dose or 2-dose of bivalent, quadrivalent, or nonavalent HPV vaccine in a low/middle-income country setting

To compare the health impact and economic benefits among individuals who did not receive the human papillomavirus (HPV) vaccine to those who received a single dose, or 2 doses. The comparison was stratified by 4 types of vaccine in conjunction with primary HPV screening in a low/middle-income country setting. A Markov model was employed to simulate HPV infection and cervical cancer in a cohort of 100,000 12-year-old girls free of HPV. The study scrutinized 9 strategies: 1 dose and 2 doses of 2vHPV (Cervarix All vaccination programs yielded 41,298-71,057 QALYs gained accompanied by cost savings of 14,914,186-19,821,655 USD compared to no vaccination. Administering 2 doses of 9vHPV vaccine emerged as the most cost-effective strategy, boasting 406 USD/QALY, within a lower willingness to pay threshold. Sensitivity analysis demonstrated an 80% probability of the cost-effectiveness of the 2 doses of 9vHPV vaccine regimen. Furthermore, uncertainty around the costs of vaccination and vaccine efficacy exerted the most substantial influence on the cost-effectiveness findings. Oping for 2 doses of 9vHPV vaccine in conjunction with a primary HPV screening represents the most cost-effective option for implementing a school-based HPV vaccination program targeting 12-year-old girls in Thailand. Such findings provide valuable insights for policymakers in the realm of cervical cancer prevention.

An overview of the current debate between using minimally invasive surgery versus laparotomy for interval cytoreductive surgery in epithelial ovarian cancer

The standard of care for treatment of advanced-stage epithelial ovarian cancer is primarily surgery followed by platinum-based chemotherapy, with the operative goal to achieve complete gross resection. Cytoreductive surgeries for epithelial ovarian cancer historically were performed via open laparotomy; however, as minimally invasive techniques became more widely accepted within gynecologic oncology, interest in employing this approach in the setting of cytoreductive surgery for epithelial ovarian cancer has grown. The purpose of this review was to examine the current debate between the use of minimally invasive surgery versus laparotomy as an approach to interval cytoreductive surgery in advanced epithelial ovarian cancer. While numerous retrospective and feasibility studies have found comparable outcomes with respect to complete gross residual disease, progression-free survival, and overall survival between minimally invasive and laparotomy approaches to interval cytoreductive surgery for epithelial ovarian cancer, methodological challenges limit the utility of these data. Given potential risks of underestimating disease burden and failing to achieve complete resection using a minimally invasive approach, further rigorous studies are needed to evaluate the safety and efficacy of minimally invasive surgery in this setting and to better define the subset of patients who would receive the greatest benefit from a minimally invasive approach.

A phase I dose-finding trial of hyperthermic intraperitoneal docetaxel combined with cisplatin in patients with advanced-stage ovarian cancer

To identify the maximum tolerated dose (MTD) of docetaxel combined with a fixed dose of cisplatin (75 mg/m²) delivered as hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with ovarian cancer. In this phase I trial, a time-to-event Bayesian optimal interval design was used. Docetaxel was given at a starting dose of 60 mg/m² and was increased in 5 mg/m² increments until the MTD was determined or the maximum dose level of 75 mg/m² was reached. The dose-limiting toxicity (DLT) rate was set at 25%, with a total sample size of 30 patients. HIPEC was delivered immediately following debulking surgery at a target temperature of 43°C for 90 minutes. From August 2022 to November 2022, 30 patients were enrolled. Among the patients who received a dose of docetaxel ≤65 mg/m², no DLT was reported. DLTs were observed in one patient who received 70 mg/m² docetaxel (grade 3 anaemia) and in three patients who received 75 mg/m² docetaxel (one case of grade 3 anaemia, one case of grade 3 hepatic impairment and one case of grade 4 thrombocytopenia). Patients treated with docetaxel 75 mg/m² in combination with cisplatin 75 mg/m² had an estimated DLT rate of 25%, which was the closest to the target DLT rate and was therefore chosen as the MTD. Docetaxel, in combination with a fixed dose of cisplatin (75 mg/m²), can be used safely at intraperitoneal doses of 75 mg/m² in ovarian cancer patients who received HIPEC (43°C, 90 minutes) following debulking surgery. ClinicalTrials.gov Identifier: NCT05410483.

Intraoperative frozen section pathology of vaginal margin in radical hysterectomy on the prognosis and quality of life for patients with IB2–IIA2 cervical cancer: study protocol for a multicenter randomized controlled trial

Several risk factors have been identified that compromise the treatment outcome in patients with early-to-mid-stage cervical cancer (CC) who are primarily treated with radical surgery. However, there is no report on the impact of intraoperative frozen pathology examination of vaginal margins on the prognosis of patients with CC. This study aimed to conduct a randomized controlled trial (RCT) to determine whether selective vaginal resection can reduce the incidence of operative complications and the risk of postoperative radiotherapy. The impact of the length of the vagina removed in radical hysterectomy (RH) on prognosis and quality of life (QoL) for IB2-IIA2 CC patients will be investigated. A multicenter, non-inferiority, RCT at 7 institutions in China is designed to investigate the effect of intraoperative frozen pathology exam of vaginal margin in RH on the survival outcomes for patients with IB2-IIA2 CC. Eligible patients aged 18-70 years will be randomly assigned online by one-to-one random allocation to receive intraoperative frozen pathology exam of vaginal margin or not. If frozen pathology indicates positive margin, continue resection of 1 centimeter of vaginal tissue until negative margin is achieved. The primary end point is 2-year disease-free survival (DFS). Adverse events (AEs) caused by further vagina resection, 5-year DFS, 2-year overall survival (OS), 5-year OS and AEs caused by radiotherapy and QoL are secondary end points. A total of 310 patients will be enrolled from 7 tertiary hospitals in China within 3-year period and followed up for 5 years. Chinese Clinical Trial Registry Identifier: ChiCTR2000035668.

Evaluation of clinical usefulness of HPV-16 and HPV-18 genotyping for cervical cancer screening

High-risk human papillomavirus (HR-HPV) infection is a leading cause of cervical cancer, of which human papillomavirus (HPV)-16 and HPV-18 account for about 70% of cases. Since HPV infection is common, it is important to focus on the HPV genotypes that pose the highest risk for effective cervical cancer screening. In this study, we evaluated the clinical usefulness of HPV-16/HPV-18 genotyping for cervical cancer screening. A total of 86,022 women aged 25 years or older was analyzed in this study. Sensitivity, specificity, positive predictive value, and negative predictive value of HPV genotyping and cytology were analyzed. In addition, we subdivided participants into two groups according to cytology results, negative for intraepithelial lesion of malignancy (NILM) and atypical squamous cells of undetermined significance (ASC-US), and analyzed absolute risk (AR) and relative risk (RR) of cervical intraepithelial neoplasia (CIN) 3 or worse according to HPV genotype. The AR of CIN 3 or worse was 77.0 times higher in HR-HPV-positive compared to HR-HPV-negative. Compared to 12 other HR-HPV-positive, the AR of CIN 3 or worse was 4.2 times higher in HPV-16 and/or HPV-18 positive. This finding was more evident in women with NILM than in women with ASC-US. The RR of CIN 3 or worse was 7.0 in women with NILM and 4.5 in women with ASC-US. Regardless of the cytology results, the risk of CIN 3 or worse was higher in HPV-16/HPV-18 than in other HR-HPV. HPV-16/HPV-18 genotyping is recommended to screen women with a high risk of cervical cancer.

Challenges and perspectives on less invasive surgery for early-stage cervical cancer: a critical analysis of the SHAPE trial and its implications

Application of precision medicine based on next-generation sequencing and immunohistochemistry in ovarian cancer: a real-world experience

To evaluate the landscape of gene alterations and immunohistochemistry (IHC) profiles of patients with ovarian cancer for targeted therapy and investigate the real-world experience of applying precision medicine. Patients diagnosed with ovarian cancer between January 2015 and May 2021 at Severance Hospital and who underwent tumor next-generation sequencing (NGS) were reviewed. Data on germline mutation, IHC markers for mismatch repair deficiency (MMRd), programmed death ligand 1 (PD-L1) expression, and human epidermal growth factor receptor 2 (HER2) expression were acquired. The use of matched therapy and its clinical outcomes were evaluated. Of the 512 patients who underwent tumor NGS, 403 underwent panel-based germline testing. In patients who underwent both tests, tumor NGS identified 39 patients (9.7%) with A comprehensive review of germline mutation, IHC, and tumor NGS helped identify candidates for precision therapy in patients with ovarian cancer, a proportion of whom received matched therapy.

Ten-year treatment outcomes of consolidation hyperthermic intraperitoneal chemotherapy for ovarian cancer (HIPEC-KOV-03R)

We aimed to evaluate the long-term efficacy of consolidation hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with primary epithelial ovarian cancer. This retrospective cohort study included patients who underwent second-look surgery either with or without HIPEC after having complete or partial response to primary cytoreductive surgery and adjuvant platinum-based chemotherapy between January 1991 and December 2003 at Seoul St. Mary's Hospital. The 10-year progression-free survival (PFS), overall survival (OS), and toxicity within postoperative 28 days were investigated. A total of 87 patients were identified, 44 (50.6%) received second-look surgery with HIPEC whereas 43 (49.4%) received only second-look surgery. The 10-year PFS and OS were significantly longer in the HIPEC group compared with the control group (PFS, 53.6% vs. 34.9%, log-rank p=0.009; OS, 57.0% vs. 34.5%, log-rank p=0.025). Multivariable analysis identified HIPEC as an independent favorable prognostic factor for PFS (adjusted hazard ratio [HR]=0.42; 95% confidence interval [CI]=0.23-0.77; p=0.005) but not for OS (adjusted HR=0.58; 95% CI=0.32-1.07; p=0.079). The more common adverse events in the HIPEC group were thrombocytopenia (90.9% vs. 68.3%, p=0.005), elevated liver enzymes (65.9% vs. 29.3%, p=0.002), and wound complications (18.2% vs. 2.4%, p=0.032). However, these adverse events were reversible and did not delay subsequent consolidation chemotherapy. The consolidation HIPEC demonstrated a significant improvement in 10-year PFS but not OS, with acceptable toxicity in patients with primary epithelial ovarian cancer. Further randomized controlled trials are warranted to confirm these results.

Is it time to change surgery for early-stage low-risk cervical cancer to simple hysterectomy?

Gut microbiome associated with PARP inhibitor efficacy in patients with ovarian cancer

To investigate an association between the gut microbiome and efficacy of poly(ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer. This study conducted fecal microbiome analysis (16S rRNA gene sequencing) and circulating tumor DNA (ctDNA) profiling for ovarian cancer patients who underwent PARPi maintenance therapy. Fecal and blood samples were collected at the baseline and the progressive disease (PD) or last follow-up. The relative abundance of gut microbes and progression-free survival (PFS) were analyzed using linear discriminant analysis of effect size and the Cox proportional hazard model according to Baseline samples were available from 23 High fecal composition of

Humanized patient-derived xenograft mouse model bearing ovarian clear cell carcinoma

The study aimed to establish humanized patient-derived xenograft (PDX) mouse models of ovarian clear cell carcinoma (OCCC) and evaluate their therapeutic responses. PDX models and their humanized counterparts (CD34+ humanized PDX models) derived from the same tumor source were developed, and the therapeutic responses were compared between the models. Treatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor significantly reduced tumor size in traditional OCCC PDX models (p=0.021). Although differences in tumor growth between traditional PDX models and humanized PDX models were observed, they were not statistically significant (p=0.438). However, treatment effects of PI3K inhibitor differed significantly between conventional and humanized mice (p=0.006). In the Humanized PDX cohort, both programmed cell death protein-1 antibody monotherapy and PI3K inhibitor treatment slowed tumor growth relative to controls, with a synergistic effect noted during the latter part of the study, though these effects were not statistically significant. This pioneering study successfully develop a humanized PDX model for OCCC, highlighting differential responses to treatments compared to conventional PDX models.

The automatic diagnosis artificial intelligence system for preoperative magnetic resonance imaging of uterine sarcoma

Magnetic resonance imaging (MRI) is efficient for the diagnosis of preoperative uterine sarcoma; however, misdiagnoses may occur. In this study, we developed a new artificial intelligence (AI) system to overcome the limitations of requiring specialists to manually process datasets and a large amount of computer resources. The AI system comprises a tumor image filter, which extracts MRI slices containing tumors, and sarcoma evaluator, which diagnoses uterine sarcomas. We used 15 types of MRI patient sequences to train deep neural network (DNN) models used by tumor filter and sarcoma evaluator with 8 cross-validation sets. We implemented tumor filter and sarcoma evaluator using ensemble prediction technique with 9 DNN models. Ten tumor filters and sarcoma evaluator sets were developed to evaluate fluctuation accuracy. Finally, AutoDiag-AI was used to evaluate the new validation dataset, including 8 cases of sarcomas and 24 leiomyomas. Tumor image filter and sarcoma evaluator accuracies were 92.68% and 90.50%, respectively. AutoDiag-AI with the original dataset accuracy was 89.32%, with 90.47% sensitivity and 88.95% specificity, whereas AutoDiag-AI with the new validation dataset accuracy was 92.44%, with 92.25% sensitivity and 92.50% specificity. Our newly established AI system automatically extracts tumor sites from MRI images and diagnoses them as uterine sarcomas without human intervention. Its accuracy is comparable to that of a radiologist. With further validation, the system could be applied for diagnosis of other diseases. Further improvement of the system's accuracy may enable its clinical application in the future.

Fertility and prognosis assessment between bleomycin/etoposide/cisplatin and paclitaxel/carboplatin chemotherapy regimens in the conservative treatment of malignant ovarian germ cell tumors: a multicenter and retrospective study

To evaluate the impact of bleomycin/etoposide/cisplatin (BEP) and paclitaxel/carboplatin (PC) chemotherapy regimens on the fertility and prognostic outcomes in malignant ovarian germ cell tumor (MOGCT) patients who underwent fertility-sparing surgery (FSS). A propensity score matching algorithm was performed between the BEP and PC groups. The χ² test and the Kaplan-Meier method were used to compare the fertility outcome, disease-free survival (DFS) and overall survival (OS). The Cox proportional hazards regression analysis was used to identify risk factor of DFS. We included 213 patients, 185 (86.9%) underwent BEP chemotherapy, and 28 (13.1%) underwent PC chemotherapy. The median age was 22 years (range, 8-44 years), and the median follow-up period was 63 months (range, 2-191 months). Fifty-one (29.3%) patients had a pregnancy plan, and 35 (85.4%) delivered successfully. In the before and after propensity score matching cohorts, there were no significant differences in spontaneous abortion, selective termination of pregnancy, during-pregnancy status, and live birth between the BEP and PC groups (p>0.05). Fourteen (6.6%) patients experienced recurrence, including 11 (5.9%) in the BEP group and 3 (10.7%) in the PC group. Four (1.9%) patients in the BEP group died. Kaplan-Meier analysis revealed no significant differences in DFS (p=0.328) and OS (p=0.446) between the BEP and PC groups, and the same survival results were observed in the after matching cohort. The PC regimen is as safe as the BEP regimen for MOGCT patients with fertility preservation treatment, and no differences were observed in fertility and clinical prognosis.

Niraparib in Japanese patients with platinum-sensitive recurrent ovarian cancer: final results of a multicenter phase 2 study

This study evaluated the long-term safety and efficacy of niraparib in Japanese patients with platinum-sensitive recurrent ovarian cancer. This was a follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with platinum-sensitive, relapsed ovarian cancer. Participants received niraparib (starting dose 300 mg) once daily in continuous 28-day cycles. The primary endpoint was the incidence of Grade 3 or 4 thrombocytopenia-related events (defined as the overall incidence of the MedDRA Preferred Terms "thrombocytopenia" and "platelet count decreased") occurring in the 30 days after initial administration of niraparib, and secondary endpoints included evaluation of treatment-emergent adverse events and progression-free survival. Nineteen patients (median age, 62 years; median body weight, 53.9 kg) were enrolled. As previously reported, the incidence of Grade 3 or 4 thrombocytopenia-related events during the first 30 days of treatment was 31.6%. At data cutoff, median (range) treatment exposure was 504.0 (56-1,054) days and mean ± standard deviation dose intensity was 154.4±77.5 mg/day. The most common treatment-emergent adverse events were nausea (n=14, 73.7%), decreased platelet count (n=12, 63.2%), decreased neutrophil count (n=11, 57.9%), anemia, vomiting, and decreased appetite (all n=9, 47.4%). One patient was diagnosed with treatment-related leukemia, which resulted in death. Median (95% confidence interval) progression-free survival was 18.0 (5.6-26.7) months. Overall, the safety profile of niraparib was considered manageable in this study population of Japanese patients with platinum-sensitive, relapsed ovarian cancer and was consistent with that observed in studies of non-Japanese patients. ClinicalTrials.gov Identifier: NCT03759587.

Niraparib as maintenance therapy in Japan: a retrospective observational study using a Japanese claims database

Epithelial ovarian cancer (EOC) is the leading cause of female mortality in gynecologic malignancies, with a rising incidence in Japan. This study aimed to validate the treatment patterns and safety of niraparib as maintenance therapy for EOC following initial chemotherapy in clinical practice in Japan. Leveraging claims data between April 2008 and December 2022, this descriptive study comprised EOC-diagnosed patients receiving initial platinum-based chemotherapy, debulking surgery, and niraparib as maintenance therapy. Patient characteristics, prescription status, transfusion details, and laboratory data were assessed and reported as summary statistics and frequencies. Among 291 patients, the median age was 64.0 years and 94.5% received a 200-mg daily dose of niraparib. At week 12, 78.7% (229/291) continued niraparib treatment, 21.3% (62/291) discontinued, and 52.2% (152/291) required treatment interruptions. Of the 62 patients who discontinued treatment, 27 patients initiated subsequent EOC treatment within 12 weeks following niraparib discontinuation. Blood transfusions were needed in 10.3% (30/291), and of 55 patients with available laboratory data, 61.8% (34/55) had decreased platelet count <100,000/µL, 25.5% (14/55) had decreased hemoglobin level <8 g/dL, and 22.7% (5/22) had decreased neutrophil count <1,000/µL, meeting the criteria for treatment interruption. Among those with thrombocytopenia, 88.2% (30/34) were able to either resume or continue treatment. Niraparib demonstrated favorable tolerability in Japanese patients with advanced EOC, with effective management of thrombocytopenia through dose adjustments and supportive care, supporting its viability as post-chemotherapy maintenance therapy.

Effect of quality control program on surgical management in advanced ovarian cancer

We investigated the effect of our quality control (QC) program on the management strategy, completeness of the surgery, and clinical outcomes in advanced ovarian cancer. A retrospective review of medical records from January 2005 to December 2019 identified 129 patients with advanced ovarian cancer. Cases were categorized into group 1 (2005-2013) and group 2 (2014-2019) before and after implementation of the QC program. Comparisons included clinicopathological variables, operative details, recurrence and survival outcomes. In Group 2 (n=44), after QC program implementation, primary debulking surgery (PDS) decreased (87.1% vs. 63.6%) and interval debulking surgery (IDS) increased (12.9% vs. 36.4%), indicating a shift in surgical strategy. Optimal resection rates improved significantly for PDS in group 2 (50.0% to 75.0%, p=0.007) and remained high for IDS in both groups (81.8% vs. 81.3%, p>0.999). Post-QC, advanced debulking procedures and co-operation with other departments increased in the IDS (p0.05), whereas postoperative hospital stay was significantly shorter in group 2 (17 days vs. 22 days, p=0.001). Median recurrence-free survival increased after QC, although not statistically significant (19.18 months vs. 25.38 months, p=0.855). With QC program, treatment strategies and clinical outcomes were significantly improved in advanced ovarian cancer. Systematic QC monitoring program should be considered as routine surveillance for better surgical outcomes.

Lymphadenectomy in clinically early epithelial ovarian cancer and survival analysis: comment

Prevalence and prognostic value of PD-L1 expression and tumor mutational burden in persistent, recurrent, or metastatic cervical cancer

To evaluate the prevalence and prognostic role of programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) in patients with non-immunotherapy-treated advanced cervical cancer. Clinical data were retrospectively collected from medical records between January 1, 2008, and December 31, 2016, at Asan Medical Center (Korea); archived tumor samples were assessed for PD-L1 expression (combined positive score [CPS] ≥1) and TMB (≥175 mutations/exome). Overall survival (OS) was defined as time from advanced diagnosis or initiation of first-line or second-line systemic therapy until death/last follow-up. The association of OS with PD-L1 expression and TMB were analyzed using the log-rank test and Cox proportional hazards model adjusted for covariates. Of 267 patients, 76.0% had squamous cell carcinoma (SCC), 24.0% had adenocarcinoma (AC)/adenosquamous carcinoma (ASC), 64.4% had PD-L1 CPS ≥1, and 32.6% had TMB ≥175 mutations/exome. PD-L1 CPS ≥1 and TMB ≥175 mutations/exome were more prevalent in SCC than in AC/ASC (73.9% and 37.2% vs. 34.4% and 17.7%). There was no association between OS and PD-L1 expression (CPS ≥1 vs. <1: adjusted hazard ratio [HR]=1.14; 95% confidence interval [CI]=0.84-1.53 from advanced diagnosis); OS trended shorter for the subgroup with TMB ≥175 versus <175 mutations/exome (adjusted HR=1.29; 95% CI=0.95-1.75). Retrospective analysis of non-immunotherapy-treated patients with advanced cervical cancer demonstrated a higher prevalence of PD-L1 CPS ≥1 and TMB ≥175 mutations/exome in SCC versus AC/ASC. PD-L1 CPS ≥1 was not associated with OS; TMB ≥175 mutations/exome showed a trend toward shorter OS. Additional studies are needed to confirm these findings.

First-line bevacizumab plus chemotherapy in Chinese patients with stage III/IV epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer: a phase III randomized controlled trial

First-line bevacizumab plus carboplatin and paclitaxel (CP) is approved for stage III/IV ovarian cancer treatment following initial surgical resection, based on global phase III GOG-0218 and ICON7 trials. This study evaluated the efficacy and safety of bevacizumab + CP as first-line ovarian cancer therapy in Chinese patients. Patients with newly diagnosed, International Federation of Gynecology and Obstetrics (FIGO) stage III/IV epithelial ovarian, fallopian tube, or primary peritoneal cancer post-primary surgery were randomized 1:1 to receive 6 cycles of CP with bevacizumab/placebo, followed by bevacizumab/placebo maintenance until unacceptable toxicity or disease progression. Primary endpoint was investigator-assessed progression-free survival (PFS). Stratification factors were FIGO stage and debulking status (stage III optimally debulked vs stage III suboptimally debulked vs stage IV) and Eastern Cooperative Oncology Group performance status (0 vs 1 or 2). Of randomized patients, 51 received bevacizumab + CP and 49 received placebo + CP. Median PFS was 22.6 months with bevacizumab + CP (95% confidence interval [CI]=18.6, not estimable) and 12.3 months (95% CI=9.5, 15.0) with placebo + CP (stratified hazard ratio=0.30; 95% CI=0.17, 0.53). Treatment-related grade 3/4 adverse events occurred in 46 of 49 (94%) patients receiving bevacizumab + CP, and 34 of 50 (68%) receiving placebo + CP. Bevacizumab + CP showed clinically meaningful improvement in PFS vs placebo + CP, consistent with GOG-0218 results. Safety data were aligned with the known bevacizumab safety profile. These results support first-line bevacizumab + CP therapy in Chinese patients with ovarian cancer. ClinicalTrials.gov Identifier: NCT03635489.

LncRNA STARD7-AS1 suppresses cervical cancer cell proliferation while promoting autophagy by regulating miR-31-5p/TXNIP axis to inactivate the mTOR signaling

Cervical cancer (CC) is a serious gynecologic health issue for women worldwide. Long non-coding RNA (lncRNA) has been well-documented in controlling malignant behavior of various cancer cells. The role of lncRNA STARD7-AS1 in regulating CC cell proliferation and autophagy and its possible mechanism were investigated in this work. RNA expression and protein levels were quantified by reverse transcription quantitative polymerase chain reaction and western blotting. The location of STARD7-AS1 in CC cells was examined using subcellular fraction assays. Cell Counting Kit-8 assays and colony forming assays were performed to measure CC cell viability and proliferation. Autophagy in CC cells was evaluated using macrophage-derived chemokine (MDC) staining and transmission electron microscopy. The binding between microRNA (miR)-31-5p and STARD7-AS1 (or thioredoxin-interacting protein [TXNIP]) was determined by performing luciferase reporter, RNA pull-down or RNA immunoprecipitation assays. STARD7-AS1 overexpression significantly suppressed CC cell viability and proliferation while notably inducing autophagy. STARD7-AS1 upregulated TXNIP expression via interaction with miR-31-5p. In addition, the effects of STARD7-AS1 on CC cell proliferation and autophagy were reversed by TXNIP silencing. The suppressive effect of STARD7-AS1 overexpression on phosphorylated levels of mTOR and S6K1 was countervailed by TXNIP deficiency. In conclusion, lncRNA STARD7-AS1 inhibits CC cell proliferation and promotes cell autophagy by targeting the miR-31-5p/TXNIP axis to inactivate the mTOR signaling.

Unveiling pembrolizumab effectiveness in diverse subtypes of MSI-high endometrial cancers

The efficacy of pembrolizumab in patients with microsatellite instability (MSI)-high cancers has been reported; however, the differences in efficacy according to the subtypes of MSI-high endometrial cancers (ECs) remain unclear. MSI-high ECs are classified into at least 3 groups based on their molecular characteristics: This study included 12 patients with MSI-high EC who received pembrolizumab treatment. Patients were categorized into 3 groups based on The overall response rate was 75% (3/4) in the SP group, while it was 100% including one complete response patient in the LLS-associated and the LS-associated group, respectively. The sensitivity and positive predictive value of EPM2AIP1 IHC for Pembrolizumab may be more effective in LLS and LS-associated groups. EPM2AIP1 IHC was less predictive than

Comparison of postoperative adjuvant platinum-based chemotherapy and no further therapy after radical surgery in intermediate-risk early-stage cervical cancer

To identify a relatively high-risk population in postoperative intermediate-risk cervical cancer and evaluate the effect of platinum-based adjuvant chemotherapy (CT). We retrospectively reviewed the medical records of patients with stage IA2-IIA cervical cancer who had been treated with radical hysterectomy and pelvic lymphadenectomy and classified as the intermediate-risk group for recurrence by postoperative pathological examination from January 2007 to December 2018 at 3 medical centers in Japan. First, patients with intermediate-risk were stratified by histological type and the number of intermediate-risk factors (IRF; large tumor diameter, lymph vascular space invasion, and deep cervical stromal invasion) and then divided into 2 groups: high and low-risk population (estimated 5-year recurrence-free survival [RFS] rate with no further therapy [NFT] <90% and ≥90%, respectively). Second, the efficacy of CT for the high-risk population was evaluated by comparing RFS and overall survival (OS) between the patients receiving CT and those with NFT. In total, 133 patients were included in the analysis. Among patients with squamous cell carcinoma (SCC) with all IRF or those with non-SCC with 2 to 3 IRF, the 5-year estimated RFS was <90% when treated with NFT. In this population, adjuvant CT was significantly superior to NFT regarding RFS (log-rank, p=0.014), although there was no statistical difference in OS. Patients with SCC with all 3 IRFs and those with non-SCC with 2 to 3 IRFs were at high risk for recurrence. Adjuvant CT is a valid treatment option for these populations.

Efficacy and safety of combined anlotinib-oral etoposide treatment for patients with platinum-resistant ovarian cancer

Despite the availability of numerous treatment options, managing patients with platinum-resistant ovarian cancer (PROC) remains challenging, and the prognosis of PROC is notably unfavorable. This retrospective study aimed to assess the efficacy and safety of combined anlotinib-oral etoposide treatment for patients with PROC. Data of 23 patients who were diagnosed with PROC from January 2020 to November 2022 and treated with anlotinib combined with oral etoposide for at least 2 cycles were retrospectively analyzed. Among per-protocol patients, 9 (45.0%; 95% confidence interval [CI]=21.1-68.9) of 20 patients achieved partial response and 17 (85.0%, 95% CI=67.9-100.0) of 20 patients achieved disease control. The median progression-free survival was 8.7 months (95% CI=5.3-11.6). The incidence of adverse events (any grade) was 100%, and the incidence of grade 3-4 adverse events was 54.5%. Anlotinib combined with etoposide emerged effective for the treatment of PROC.

Comprehensive characterization of genomic features and clinical outcomes following targeted therapy and secondary cytoreductive surgery in OCCC: a single center experience

Ovarian clear cell carcinoma (OCCC) is associated with chemoresistance. Limited data exists regarding the efficacy of targeted therapies such as immune checkpoint inhibitors (ICI) and bevacizumab, and the role of secondary cytoreductive surgery (SCS). We retrospectively analyzed genomic features and treatment outcomes of 172 OCCC patients treated at our institution from January 2000 to May 2022. Next-generation sequencing (NGS) was performed where sufficient archival tissue was available. 64.0% of patients were diagnosed at an early stage, and 36.0% at an advanced stage. Patients with advanced/relapsed OCCC who received platinum-based chemotherapy plus bevacizumab followed by maintenance bevacizumab had a median first-line progression-free survival (PFS) of 12.2 months, compared with 9.3 months for chemotherapy alone (hazard ratio=0.69; 95% confidence interval [CI]=0.33, 1.45). In 27 patients who received an ICI, the overall response rate was 18.5% and median duration of response was 7.4 months (95% CI=6.5, 8.3). In 17 carefully selected patients with fewer than 3 sites of relapse, median PFS was 35 months (95% CI=0, 73.5) and median overall survival was 96.8 months (95% CI=44.6, 149.0) after SCS. NGS on 58 tumors revealed common mutations in Our study demonstrates encouraging outcomes with bevacizumab and ICI, and SCS in select relapsed OCCC patients. Prospective trials are warranted.

Abnormal p53 expression is associated with poor outcomes in grade I or II, stage I, endometrioid carcinoma: a retrospective single-institute study

The Cancer Genome Atlas study revealed an association between copy-number high (p53 abnormal) genetic mutation and poor prognosis in endometrial cancer in 2013. This retrospective study investigated outcomes in patients with abnormal p53 expression and stage I, low-grade endometrial endometrioid carcinoma (EEC). We enrolled women with stage I, grade 1 or 2 EEC who received comprehensive staging and adjuvant therapy between January 2019 and December 2022 at MacKay Memorial Hospital, Taipei, Taiwan. Pathologists interpreted immunohistochemistry stains of cancerous tissues to detect p53 mutation. We compared recurrence, survival, progression-free survival, and overall survival between p53 abnormal and p53 normal groups. Of the 115 patients included, 26 had pathologically confirmed abnormal p53 expression. Of these 26 patients, five (19.2%) experienced recurrence, and two died due to disease progression. By contrast, no patients in the normal p53 group experienced disease recurrence or died due to disease progression. Significant intergroup differences were discovered in recurrent disease status (19.4% vs. 0%, p<0.001), mortality (7.7% vs. 0%, p<0.001), and progression-free survival (p<0.001). The overall survival (p=0.055) also showed powerful worse trend. For patients with stage I, low-grade EEC, abnormal p53 expression may be used as an indicator of poor prognosis. Therefore, we suggest considering aggressive adjuvant therapies for these patients.

Optimal number of neoadjuvant chemotherapy cycles prior to interval debulking surgery in advanced epithelial ovarian cancer: a systematic review and meta-analysis of progression-free survival and overall survival

Neoadjuvant chemotherapy (NACT) represents a treatment option in patients with advanced epithelial ovarian cancer (AEOC) who are not good candidates for primary debulking surgery. Usually, 3 cycles of chemotherapy before surgery have been considered the best option for patient survival, although quite often some patients receive more than 3 cycles. The aim of this systematic review and meta-analysis was to identify the optimal number of NACT cycles reporting better survival in AEOC patients. PubMed, Cochrane Library, and Scopus were searched for original articles that analyzed the relationship between the number of chemotherapy cycles and clinical outcomes in AEOC patients before interval debulking surgery (IDS). The main outcomes were progression-free survival (PFS) and overall survival (OS). A total of 22 studies comprising 7,005 patients diagnosed with AEOC were included in our analysis. In terms of survival, the reviewed studies dividing the patients in ≤3 NACT cycles vs. >3, showed a trend for a decrease in PFS and a significant reduction in OS with an increasing number of cycles, while a difference in both PFS and OS was revealed if early IDS included patients with 4 NACT cycles. These results should be interpreted with caution due to the complex characteristics of AEOC patients. In conclusion, our review and meta-analysis revealed that there is not enough evidence to determine the optimal number of NACT treatments before surgery. Further research in the form of well-designed randomized controlled trials is necessary to address this issue. PROSPERO Identifier: CRD42022334959.

Patient and clinician priorities for information on treatment outcomes for advanced ovarian cancer: a Delphi exercise

Patients with advanced ovarian cancer face a range of treatment options, and there is unwarranted variation in treatment decision-making between UK providers. Decision support tools that produce data on treatment outcomes as a function of individual patient characteristics, would help both patients and clinicians to make informed, preference- and values-based choices. However, data on treatment outcomes to include in such tools are lacking. Following a literature review, a questionnaire was designed for use in a Delphi process to establish which treatment outcomes are important to both patients and clinicians in decision-making for treatment for advanced ovarian cancer. Patient and clinician panels were established. Following 2 Delphi rounds, consensus was achieved for 7/11 items in the patient panel and 8/11 items in the clinician panel. Consensus across both panels was achieved for inclusion of both overall survival and progression free survival as important items in the decision-making process, although there remained differences of opinion as to whether these should be presented as relative or absolute values. Information needs for treatment decision-making in ovarian cancer differ between and within patient and clinician groups. Whilst overall survival and progression free survival are universally accepted as important data items, decision support tools will need to be nuanced to allow presentation of a range of outcomes and associated probabilities, and in a range of formats, that can be tailored to the preferences of clinician and patients.

QL1604 plus paclitaxel-cisplatin/carboplatin in patients with recurrent or metastatic cervical cancer: an open-label, single-arm, phase II trial

QL1604 is a highly selective, humanized monoclonal antibody against programmed death protein 1. We assessed the efficacy and safety of QL1604 plus chemotherapy as first-line treatment in patients with advanced cervical cancer. This was a multicenter, open-label, single-arm, phase II study. Patients with advanced cervical cancer and not previously treated with systemic chemotherapy were enrolled to receive QL1604 plus paclitaxel and cisplatin/carboplatin on day 1 of each 21-day cycle for up to 6 cycles, followed by QL1604 maintenance treatment. Forty-six patients were enrolled and the median follow-up duration was 16.5 months. An 84.8% of patients had recurrent disease and 13.0% had stage IVB disease. The objective response rate (ORR) per Response Evaluation Criteria in Advanced Solid Tumors (RECIST) v1.1 was 58.7% (27/46). The immune ORR per immune RECIST was 60.9% (28/46). The median duration of response was 9.6 months (95% confidence interval [CI]=5.5-not estimable). The median progression-free survival was 8.1 months (95% CI=5.7-14.0). Forty-five (97.8%) patients experienced treatment-related adverse events (TRAEs). The most common grade≥3 TRAEs (>30%) were neutrophil count decrease (50.0%), anemia (32.6%), and white blood cell count decrease (30.4%). QL1604 plus paclitaxel-cisplatin/carboplatin showed promising antitumor activity and manageable safety profile as first-line treatment in patients with advanced cervical cancer. Programmed cell death protein 1 inhibitor plus chemotherapy may be a potential treatment option for the patient population who have contraindications or can't tolerate bevacizumab, which needs to be further verified in phase III confirmatory study.

TET3-mediated DNA demethylation modification activates SHP2 expression to promote endometrial cancer progression through the EGFR/ERK pathway

Src homology phosphotyrosin phosphatase 2 (SHP2) has been implicated in the progression of several cancer types. However, its function in endometrial cancer (EC) remains unclear. Here, we report that the ten-eleven translocation 3 (TET3)-mediated DNA demethylation modification is responsible for the oncogenic role of SHP2 in EC and explore the detailed mechanism. The transcriptomic differences between EC tissues and control tissues were analyzed using bioinformatics tools, followed by protein-protein interaction network establishment. EC cells were treated with shRNA targeting SHP2 alone or in combination with isoprocurcumenol, an epidermal growth factor receptor (EGFR) signaling activator. The cell biological behavior was examined using cell counting kit-8, colony formation, flow cytometry, scratch assay, and transwell assays, and the median inhibition concentration values to medroxyprogesterone acetate/gefitinib were calculated. The binding of TET3 to the SHP2 promoter was verified. EC cells with TET3 knockdown and combined with SHP2 overexpression were selected to construct tumor xenografts in mice. TET3 and SHP2 were overexpressed in EC cells. TET3 bound to the SHP2 promoter, thereby increasing the DNA hydroxymethylation modification and activating SHP2 to induce the EGFR/extracellular signal-regulated kinase (ERK) pathway. Knockdown of TET3 or SHP2 inhibited EC cell malignant aggressiveness and impaired the EGFR/ERK pathway. Silencing of TET3 inhibited the tumorigenic capacity of EC cells, and ectopic expression of SHP2 or isoprocurcumenol reversed the inhibitory effect of TET3 knockdown on the biological activity of EC cells. TET3 promoted the DNA demethylation modification in the SHP2 promoter and activated SHP2, thus activating the EGFR/ERK pathway and leading to EC progression.

Therapeutic effects of surgical debulking of metastatic lymph nodes in cervical cancer IIICr: a trial protocol for a phase III, multicenter, randomized controlled study (KGOG1047/DEBULK trial)

Bulky or multiple lymph node (LN) metastases are associated with poor prognosis in cervical cancer, and the size or number of LN metastases is not yet reflected in the staging system and therapeutic strategy. Although the therapeutic effects of surgical resection of bulky LNs before standard treatment have been reported in several retrospective studies, well-planned randomized clinical studies are lacking. Therefore, the aim of the Korean Gynecologic Oncology Group (KGOG) 1047/DEBULK trial is to investigate whether the debulking surgery of bulky or multiple LNs prior to concurrent chemoradiation therapy (CCRT) improves the survival rate of patients with cervical cancer IIICr diagnosed by imaging tests. The KGOG 1047/DEBULK trial is a phase III, multicenter, randomized clinical trial involving patients with bulky or multiple LN metastases in cervical cancer IIICr. This study will include patients with a short-axis diameter of a pelvic or para-aortic LN ≥2 cm or ≥3 LNs with a short-axis diameter ≥1 cm and for whom CCRT is planned. The treatment arms will be randomly allocated in a 1:1 ratio to either receive CCRT (control arm) or undergo surgical debulking of bulky or multiple LNs before CCRT (experimental arm). CCRT consists of extended-field external beam radiotherapy/pelvic radiotherapy, brachytherapy and LN boost, and weekly chemotherapy with cisplatin (40 mg/m²), 4-6 times administered intravenously. The primary endpoint will be 3-year progression-free survival rate. The secondary endpoints will be 3-year overall survival rate, treatment-related complications, and accuracy of radiological diagnosis of bulky or multiple LNs. ClinicalTrials.gov Identifier: NCT05421650; Clinical Research Information Service Identifier: KCT0007137.

Analysis of East Asia subgroup in Study 309/KEYNOTE-775: lenvatinib plus pembrolizumab versus treatment of physician’s choice chemotherapy in patients with previously treated advanced or recurrent endometrial cancer

In the global phase 3 Study 309/KEYNOTE-775 (NCT03517449) at the first interim analysis, lenvatinib+pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus treatment of physician's choice chemotherapy (TPC) in patients with previously treated advanced/recurrent endometrial cancer (EC). This exploratory analysis evaluated outcomes in patients enrolled in East Asia at the time of prespecified final analysis. Women ≥18 years with histologically confirmed advanced, recurrent, or metastatic EC with progressive disease after 1 platinum-based chemotherapy (2 if 1 given in neoadjuvant/adjuvant setting) were enrolled. Patients were randomized 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks (≤35 cycles) or TPC (doxorubicin or paclitaxel). Primary endpoints were PFS per RECIST v1.1 by blinded independent central review and OS. No alpha was assigned for this subgroup analysis. Among 155 East Asian patients (lenvatinib+pembrolizumab, n=77; TPC, n=78), median follow-up time (data cutoff: March 1, 2022) was 34.3 (range, 25.1-43.0) months. Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS (lenvatinib+pembrolizumab vs. TPC) were 0.74 (0.49-1.10) and 0.64 (0.44-0.94) in the mismatch repair proficient (pMMR) and all-comer populations, respectively. HRs (95% CI) for OS were 0.68 (0.45-1.02) and 0.61 (0.41-0.90), respectively. ORRs were 36% with lenvatinib+pembrolizumab and 22% with TPC (pMMR) and 39% and 21%, respectively (all-comers). Treatment-related adverse events occurred in 97% and 96% (grade 3-5, 74% and 72%), respectively. Lenvatinib+pembrolizumab provided clinically meaningful benefit with manageable safety compared with TPC, supporting its use in East Asian patients with previously treated advanced/recurrent EC. ClinicalTrials.gov Identifier: NCT03517449.

A predictive model for lymph node metastasis using tumor location in presumed early-stage endometrioid endometrial cancer patients

The aim of this study was to identify high- and low-risk subgroups of patients with lymph node (LN) metastasis in presumed early-stage endometrioid endometrial cancer (EC) patients. Clinicopathologic data of presumed early-stage endometrioid EC patients (n=361) treated with lymphadenectomy between March 2000 and July 2022 were analyzed. None of the patient had definite evidence of LN metastasis in a preoperative magnetic resonance imaging (MRI). A received operating characteristic curve analysis was conducted to define the sensitivity and specificity for the combined preoperative risk factors for LN metastasis, which was determined by multivariate analysis. Nineteen patients (5.3%) had LN metastasis. Multivariate analysis identified cervical stromal invasion on MRI (odds ratio [OR]=4.386; 95% confidence interval [CI]=1.020-18.852; p=0.047), cornual location of tumor on MRI (OR=36.208; 95% CI=7.902-165.913; p<0.001), and lower uterine segment/isthmic location of tumor on MRI (OR=8.454; 95% CI=1.567-45.610; p=0.013) as independent prognostic factors associated with LN metastasis. Patients were categorized into low- and high-risk groups according to risk criteria. Significant differences in the rates of LN metastasis were observed between the two groups (0.4% vs. 22.2%, p<0.001). Approximately 95% of presumed early-stage endometrioid EC patients did not have LN metastasis. A model using tumor location was significantly correlated with the risk of LN metastasis. Even in presumed early-stage endometrioid EC patients, therefore, tumor location should be investigated to determine whether to perform LN assessment.

Prognostic factors of adult granulosa cell tumors of the ovary: a Turkish retrospective multicenter study

To define the clinical, histopathological features and the prognostic factors affecting survival in patients with adult granulosa cell tumors of the ovary (AGCT). A 322 patients whose final pathologic outcome was AGCT treated at nine tertiary oncology centers between 1988 and 2021 participated in the study. The mean age of the patients was 51.3±11.8 years and ranged from 21 to 82 years. According to the International Federation of Gynecology and Obstetrics 2014, 250 (77.6%) patients were stage I, 24 (7.5%) patients were stage II, 20 (6.2%) patients were stage III, and 3 (7.8%) were stage IV. Lymphadenectomy was added to the surgical procedure in 210 (65.2%) patients. Lymph node involvement was noted in seven (3.3%) patients. Peritoneal cytology was positive in 19 (5.9%) patients, and 13 (4%) had metastases in the omentum. Of 285 patients who underwent hysterectomy, 19 (6.7%) had complex hyperplasia with atypia/endometrial intraepithelial neoplasia, and 8 (2.8%) had grade 1 endometrioid endometrial carcinoma. It was found that 93 (28.9%) patients in the study group received adjuvant treatment. Bleomycin, etoposide, cisplatin was the most commonly used chemotherapy protocol. The median follow-up time of the study group was 41 months (range, 1-276 months). It was noted that 34 (10.6%) patients relapsed during this period, and 9 (2.8%) patients died because of the disease. The entire cohort had a 5-year disease-free survival (DFS) of 86% and a 5-year disease-specific survival of 98%. Recurrences were observed only in the pelvis in 13 patients and the extra-abdominal region in 7 patients. The recurrence rate increased 6.168-fold in patients with positive peritoneal cytology (95% confidence interval [CI]=1.914-19.878; p=0.002), 3.755-fold in stage II-IV (95% CI=1.275-11.063; p=0.016), and 2.517-fold in postmenopausal women (95% CI=1.017-6.233; p=0.046) increased. In this study, lymph node involvement was detected in 3.3% of patients with AGCT. Therefore, it was concluded that lymphadenectomy can be avoided in primary surgical treatment. Positive peritoneal cytology, stage, and menopausal status were independent prognostic predictors of DFS.

LncRNA linc01194 promotes the progress of endometrial carcinoma by up-regulating SOX2 through binding to IGF2BP1

Endometrial carcinoma (EC) is one of the most common gynecological malignant tumors. Our study showed that long non-coding RNA (lncRNA) linc01194 plays an important role in EC. We explored the mechanism of lncRNA linc01194 in EC. The expression of lncRNA linc01194 was detected in The Cancer Genome Atlas database and starBase database. The potential targeted protein of linc01194 was predicted through the starBase database. To determine the role of linc01194 in EC, we downregulated or upregulated the level of linc01194 in EC cell lines and analyzed the cell behaviors and the changes of its potential target proteins. The expression of linc01194 in EC tissues is higher than that in normal endometrial tissues. The knockdown of linc01194 inhibited the cell proliferation, invasion and migration and promoted the apoptosis of EC cells, while overexpression of linc01194 promoted cell proliferation, invasion and migration and inhibited the apoptosis of EC cells. The starBase database revealed that linc01194 could bind to insulin-like growth factor 2 binding protein 1 (IGF2BP1). Previous results showed that in EC, IGF2BP1 could promote the expression of sex-determining region Y-box 2 (SOX2) by promoting the stability of SOX2 mRNA. Our results showed that linc01194 regulate the expression of IGF2BP1 and SOX2. Linc01194 can promote the expression of downstream protein SOX2 through binding to IGF2BP1, thus promoting the occurrence and development of EC.

Feasibility of laparoscopic Visceral-Peritoneal Debulking (L-VPD) in patients with stage III–IV ovarian cancer: the ULTRA-LAP trial pilot study

A non-randomized prospective clinical trial (ULTRA-LAP) was registered to test safety, side effects and efficacy of laparoscopic Visceral-Peritoneal Debulking (L-VPD) in patients with stage III-IV ovarian cancer (OC). A pilot study was designed to identify which OC patients are suitable to undergo L-VPD. Between March 2016 and October 2021, all consecutive patients with OC underwent exploratory laparoscopy (EXL). All patients whose disease was deemed amenable for a complete resection (CR) at imaging review and EXL, underwent VPD. In all patients a consistent attempt was made at completing L-VPD. Two hundred and eight OC had EXL in the study period: 121 underwent interval VPD and 87 up-front VPD. Overall, 158 patients had VPD by laparotomy (75.9%) and 50 (24.1%) had L-VPD, of which 34 patients as interval (iL-VPD) and 16 as up-front (uL-VPD). Intra- and post-operative morbidity was very low in the L-VPD group. CR rate was 98% in L-VPD group and 94% in VPD. Most common reason for conversion was diaphragmatic disease extending dorsally. In the pilot study of ULTRA-LAP, L-VPD was completed in 24,1% of OC. Initial analysis supports the feasibility of L-VPD in 2 groups of OC: those with no gross disease at interval surgery and those with gross visible disease at upfront or interval surgery, but limited to: pelvis (including recto-sigmoid), gastro colic omentum, peritoneum and diaphragm, the latter not requiring dorsal liver mobilization. Both groups had 100% feasibility and have been thus forth recruited to ULTRA-LAP. ClinicalTrials.gov Identifier: NCT05862740.

Effect of tumor burden and radical surgery on survival difference between upfront, early interval or delayed cytoreductive surgery in ovarian cancer

We sought to evaluate the impact on survival of tumor burden and surgical complexity in relation to the number of cycles of neoadjuvant chemotherapy (NACT) in patients with advanced ovarian cancer (OC) with minimal (CC-1) or no residual disease (CC-0). This retrospective study included patients with International Federation of Gynaecology and Obstetrics IIIC-IV stage OC who underwent debulking surgery at 4 high-volume institutions between January 2008 and December 2015. We assessed the overall survival (OS) of primary debulking surgery (PDS group), early interval debulking surgery after 3-4 cycles of NACT (early IDS group) and delayed debulking surgery after 6 cycles (DDS group) with CC-0 or CC-1 according to peritoneal cancer index (PCI) and Aletti score. Five hundred forty-nine women were included: 175 (31.9%) had PDS, 224 (40.8%) early IDS and 150 (27.3%) DDS. Regardless of Aletti score, median OS after PDS was significantly higher than after early IDS or DDS, but the survival difference was higher in women with an Aletti score 10, there were no differences between PDS and early IDS, but DDS was associated with decreased OS. The benefit of complete PDS compared with NACT was maximal in patients with a low complexity score. In patients with low tumor burden, there was a survival benefit of PDS over early IDS or DDS. In women with high tumor load, DDS impaired the oncological outcome.

Impact of incomplete surgery and adjuvant chemotherapy for the intraoperative rupture of capsulated stage I epithelial ovarian cancer: a multi-institutional study with an in-depth subgroup analysis

The aim of the present study was to examine the effects of incomplete surgery and adjuvant chemotherapy on the prognosis of patients with intraoperative rupture of capsulated stage I epithelial ovarian cancer (OvCa). A regional retrospective study was conducted between 1986 and 2019. Among 4,730 patients with malignant ovarian tumors, 534 women with International Federation of Gynecology and Obstetrics stage IA and IC1 epithelial OvCa were eligible. Differences in survival outcomes were examined between patients with stage IA and IC1 tumors and the effects of uterine preservation, complete-staging lymphadenectomy, and adjuvant chemotherapy were investigated by an in-depth subgroup analysis. To analyze therapeutic effects, baseline imbalances were adjusted using propensity score (PS). The prognosis of patients with stage IC1 tumors was worse than those with stage IA. Surgical spill did not affect the site of recurrence. In the PS-adjusted subgroup analysis, uterine preservation (hazard ratio [HR]=1.669; 95% confidence interval [CI]=1.052-2.744), incomplete-staging lymphadenectomy (HR=1.689; 95% CI=1.211-2.355), and the omission of adjuvant chemotherapy (HR=3.729; 95% CI=2.090-6.653) significantly increased the HR of recurrence for patients with stage IC1 tumors compared to those with stage IA tumors. Adjuvant chemotherapy decreased the impact of rupture with uterine preservation (HR=0.159; 95% CI=0.230-1.168) or incomplete-staging lymphadenectomy (HR=0.987; 95% CI=0.638-1.527). The present results suggest intraoperative rupture of capsulated stage I epithelial OvCa is associated with a poor prognosis. When chemotherapy is given for patients receiving incomplete surgery, there is no longer an increased risk of recurrence observed with the rupture.

A single-arm, phase II study of niraparib and bevacizumab maintenance therapy in platinum-sensitive, recurrent ovarian cancer patients previously treated with a PARP inhibitor: Korean Gynecologic Oncology Group (KGOG 3056)/NIRVANA-R trial

Given the expanding clinical use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPis), there is a significant need for optimal strategies with which to treat patients whose cancer progresses while using a PARPi. However, the treatment consensus after PARPi has not been established. The aim of the Korean Gynecologic Oncology Group (KGOG) 3056/NIRVANA-R trial is to investigate the efficacy of niraparib in combination with bevacizumab as a maintenance therapy in platinum-sensitive ovarian cancer patients who were previously treated with a PARPi. The KGOG 3056/NIRVANA-R is a multi-centre, investigator-initiated, single-arm, phase II trial of patients with platinum-sensitive recurrent ovarian cancer recruited from seven KGOG sites. This study included patients with platinum-sensitive recurrent epithelial ovarian cancer who received at least 2 previous courses of platinum-containing therapy and had been treated with a PARPi. Mucinous histology type was excluded. Patients who had responded to the last platinum regimen (either complete or partial response) were eligible to participate in this study. Forty-four patients will be recruited. All enrolled patients are treated with niraparib and bevacizumab for maintenance therapy until disease progression, unacceptable toxicity, or withdrawal of patient consent. The primary endpoint of the study is 6-month progression-free survival rate. Accrual is expected to be completed in 2022, followed by presentation of results in 2023. ClinicalTrials.gov Identifier: NCT04734665.

Prognosis in primary mucinous ovarian carcinoma: focusing on the five pathological findings indicating metastatic mucinous carcinoma to the ovary

Pathological features indicating metastatic mucinous carcinoma to the ovary (MMCO) have been rarely reported in primary mucinous ovarian carcinoma (PMOC). However, little is known about how often they are observed in PMOC and how they relate to patient prognosis. In this study, we investigated the pathological features indicating MMCO in a large cohort of PMOCs and analyzed their association with patient prognosis. We reviewed surgically treated PMOC patients diagnosed at the Seoul National University Hospital from 1995 to 2019, according to the updated WHO classification, and investigated the presence of pathological features indicating MMCO. A total of 144 patients with PMOCs were included. The 5 pathological findings indicating MMCO, including an infiltrative invasive pattern, the absence of benign or borderline components, a smaller tumor size, the presence of signet ring cells and the presence of extracellular mucin were observed in PMOC (21.6%, 43.1%, 20.8%, 4.3% and 12.9%, respectively), and were significantly correlated with poor overall and progression-free survival rates in PMOC. The patient's prognosis worsened as the extent of the infiltrative invasive pattern increased (p<0.001). In addition, the prognostic power was stronger when the 5 pathological factors were analyzed together (new grouping system) than when analyzed individually (p<0.001) and the new grouping system was identified as an independent prognostic factor regardless of FIGO stage. Five pathological findings indicating MMCO in PMOC were significantly associated with poor prognosis in PMOC patients. Also, the new grouping system combining these findings was identified as an independent prognostic factor.

Clinical Trial Protocol for HyNOVA: Hyperthermic and Normothermic intraperitoneal chemotherapy following interval cytoreductive surgery for stage III epithelial OVArian, fallopian tube and primary peritoneal cancer (ANZGOG1901/2020)

Ovarian cancer is the most lethal gynecological cancer, causing over 200,000 deaths worldwide in 2020. Initial standard treatment for primary ovarian cancer is optimal cytoreductive surgery (CRS) preceded and/or followed by intravenous platinum-based chemotherapy. However, most women develop recurrence within the peritoneal cavity and die of disease. Results of the OVIHIPEC 1 trial (2018) showed improved survival of 34% when hyperthermic intraperitoneal chemotherapy (HIPEC) was given immediately following interval-CRS in women with stage III disease. However, it is unknown if the effect of HIPEC is due to hyperthermia, one extra cycle of intraperitoneal (IP) chemotherapy, or other factors. There is also concern that hyperthermia might be associated with an increase in adverse events (AEs) due to a heightened systemic inflammatory response. HyNOVA is a seamless, multi-stage randomized study that attempts to answer these questions by comparing HIPEC to normothermic intraperitoneal chemotherapy (NIPEC), focusing on safety (stage 1), then assessing activity (stage 2) and effectiveness (stage 3). In this initial study, we hypothesize that NIPEC will result in a lower rate of severe AEs compared to HIPEC. This initial stage of HyNOVA is a phase II study of 80 women with International Federation of Gynaecology and Obstetrics stage III epithelial ovarian cancer, with at least stable disease following 3-4 cycles of neoadjuvant chemotherapy, achieving interval-CRS to <2.5 mm residual disease. Participants are randomized 1:1 to receive IP cisplatin 100 mg/m² for 90 minutes either as HIPEC, heated to 42°C (41.5°C-42.5°C), or NIPEC, at 37°C (36.5°C-37.5°C). The primary outcome is the proportion of AEs ≥ grade 3 occurring within 90 days. Secondary outcomes are AE of interest, surgical morbidity, patient reported outcomes, resource allocation, feasibility, progression-free survival and overall survival. AEs are measured using both CTCAE v5.0 and Clavien-Dindo classification, particularly infection, pain, bowel dysfunction, and anemia. Tertiary outcomes are potential predictive biomarkers measured before and after HIPEC/NIPEC including circulating cell-free tumor DNA, tissue factors, and systemic inflammatory markers. There are 4 participating Australian sites with experience in CRS and HIPEC for peritoneal malignancy. HyNOVA is funded by an MRFF grant (APP1199155). ANZCTR Identifier: ACTRN12621000269831.

Transabdominal cardiophrenic lymph node dissection for cytoreductive surgery in advanced ovarian cancer

Minimizing residual tumors is one of the most important prognostic factors in the management of advanced ovarian cancer [1]. In ovarian cancer patients with cardiophrenic lymph node (LN) metastases, transabdominal cardiophrenic lymph node dissection (CPLND) has been performed along with the surgery on the primary site [2]. However, CPLND for the complicated locations in the thoracic cavity is still technically challenging. This video aims to share our surgical technique for the transabdominal CPLND. A 60-year-old woman who presented with suspicious bilateral ovarian cancer was hospitalized for cytoreductive surgery. Preoperative CT demonstrated peritoneal seeding and multiple LN metastases including right anterior, lateral, posterior, and left anterior cardiophrenic LNs. The gynecology and general surgery team underwent hysterectomy, bilateral salpingo-oophorectomy, supracolic omentectomy, lower anterior resection, right diaphragmatic and bladder peritonectomy, pelvic and paraaortic LN dissection, and appendectomy. The thoracic surgeon took over the operation because the pelvic cavity was regarded as R0. CPLND was performed by transabdominal, subxiphoid approach. The procedure is narrated in the video. Complete clearance of CPLN leaving no gross residual disease was possible without complication. A long, transverse incision of the anterior diaphragm was closed with a 1-0 polypropylene in the way of double layered continuous running suture and 8 times ties for the final knot. Transabdominal CPLND can be used safely and effectively without change of patient's position and with minimal diaphragmatic injury. However, this approach may be unfeasible for metastatic internal mammary LN dissection and still needs meticulous surgical skills to avoid complications.

Insights into ovarian cancer care: report from the ANZGOG Ovarian Cancer Webinar Series 2020

Epithelial ovarian cancer (EOC) is among the top ten causes of cancer deaths worldwide, and is one of the most lethal gynecological malignancies in high income countries, with incidence and death rates expected to rise particularly in Asian countries where ovarian cancer is among the 5 most common cancers. Despite the plethora of randomised clinical trials investigating various systemic treatment options in EOC over the last few decades, both progression-free and overall survival have remained at approximately 16 and 40 months respectively. To date the greatest impact on treatment has been made by the use of poly (ADP-ribose) polymerase (PARP) inhibitors in women with advanced EOC and a

Overview of fuzuloparib in the treatment of ovarian cancer: background and future perspective

Over the last decade, clinical trials using various poly ADP ribose polymerase (PARP) inhibitors on patients with ovarian cancer have shown promising results. The introduction of PARP inhibitors has changed the treatment landscape and improved outcomes for patients with ovarian cancer. Fuzuloparib, developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd., is a novel orally available small molecule PARP inhibitor. By introducing the trifluoromethyl group into chemical structure, fuzuloparib exhibits higher stability and lower inter-individual variability than other PARP inhibitors. Several clinical trials (FZOCUS series and others) have been carried out to assess the efficacy and safety of fuzuloparib through different lines of treatments for advanced or recurrent ovarian cancer in both treatment and maintenance. Here, we present the most recent data from these studies, discuss current progress and potential future directions.

Impact of metformin on survival outcome in ovarian cancer: a nationwide population-based cohort study

Investigation of new drugs (INDs) is a tremendously inefficient process in terms of time and cost. Drug repositioning is another method used to investigate potential new agents in well-known drugs. This study assessed the survival impact of metformin medication on ovarian cancer. A national sample cohort of the Korean National Health Insurance Service Data was analyzed. Cox proportional hazards regression was used to analyzing hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for underlying diseases and medications as confounding factors for overall survival (OS) and cancer-specific survival (CSS). A total of 866 eligible patients were included from among 1,025,340 cohort participants. Among them, 101 (11.7%) were metformin users. No difference in OS was observed between non-users and users. No difference in OS was observed according to age and Charlson Comorbidity Index. Long-term metformin use (≥720 days) was associated with better OS (adjusted HR=0.244; 95% CI=0.090-0.664; p=0.006). A multivariate Cox proportional hazards model showed that long-term metformin use was an independent favorable prognostic factor for OS (HR=0.193; 95% CI=0.070-0.528; p=0.001) but not for CSS (HR=0.599; 95% CI=0.178-2.017; p=0.408). Long-term metformin use reduced all-cause mortality, but not CSS in ovarian cancer. Whether metformin itself reduces deaths because of ovarian cancer requires further investigation.

Trend analysis of process quality indicators for the Korean National Cervical Cancer Screening Program from 2005 to 2013

This study sought to examine changes in trends for quality indicators of the population-based Korean National Cancer Screening Program (KNCSP) for cervical cancer from years 2005 to 2013. Our study data were derived from the KNCSP database. Cervical cancer diagnosis information was ascertained through linkage with the Korean National Cancer Registry and the KNCSP database. Performance measures for cervical cancer screening were estimated, including participation rate, positive rate, crude detection rate (CDR), interval cancer rate (ICR), positive predictive value (PPV), sensitivity, and specificity. Joinpoint analysis was applied to calculate annual percentage changes (APCs) in all indicators according to socio-demographic factors. A significant increasing trend was noted in participation rates (APC=13.4%; 95% confidence interval [CI]=10.5, 16.4). PPV and specificity increased from years 2005 to 2009 and remained stable till 2013. An increasing trend was discovered in CDRs for cervical cancer in situ (APC=3.9%; 95% CI=1.0, 6.9), whereas a decreasing trend was observed in ICRs for invasive cervical cancer (APC=-2.5%; 95% CI=-4.5, -0.5). Medical Aid recipients and women older than 70 years showed the lowest participation rates, but higher CDRs and ICRs, compared to other groups. In general, most of the quality indicators for cervical cancer screening improved from 2005 to 2009 and remained stable to 2013. The KNCSP for cervical cancer in Korea has improved in terms of participation rate and accuracy of the screening test. These results may be attributed to the National Quality Improvement Program for KNCSP.

Early-stage epithelial ovarian cancer: is systematic lymph node staging mandatory?

Time for enhancing government-led primary prevention of cervical cancer

The impact of lymph node dissection on survival in patients with clinical early-stage ovarian cancer

To estimate the impact of lymph node dissection on survival in patients with apparent early-stage epithelial ovarian cancer (EOC). We conducted a retrospective review of patients with clinical stage I-II EOC. All patients underwent primary surgery at Sun Yat-sen University Cancer Center between January 2003 and December 2015. Demographic features and clinicopathological information as well as perioperative adverse events were investigated, and survival analyses were performed. A total of 400 ovarian cancer patients were enrolled, and patients were divided into 2 groups: 81 patients did not undergo lymph node resection (group A), and 319 patients underwent lymph node dissection (group B). In group B, the median number of removed nodes per patient was 25 (21 pelvic and 4 para-aortic nodes). In groups A and B, respectively, the 5-year progression-free survival (PFS) rates were 83.3% and 82.1% (p=0.305), and the 5-year overall survival (OS) rates were 93.1% and 90.9% (p=0.645). The recurrence rate in the retroperitoneal lymph nodes was not associated with lymph node dissection (p=0.121). The median operating time was markedly longer in group B than in group A (220 minutes vs. 155 minutes, p<0.001), and group B had a significantly higher incidence of lymph cysts at discharge (32.9% vs. 0.0%, p<0.001). In patients with early-stage ovarian cancer, lymph node dissection was not associated with a gain in OS or PFS and was associated with an increased incidence of perioperative adverse events.

A single-arm phase II study of olaparib maintenance with pembrolizumab and bevacizumab in BRCA non-mutated patients with platinum-sensitive recurrent ovarian cancer (OPEB-01)

The optimal treatment of ClinicalTrials.gov Identifier: NCT04361370, Clinical Research Information Service Identifier: KCT0005144.

Current status and future directions of ovarian cancer prognostic models

How to start niraparib in real-world Asian ovarian cancer patients?

Peripheral bloodBRCA1methylation profiling to predict familial ovarian cancer

Familial cancer appears at a young age and its incidence is increasing. About 12% of familial ovarian cancer cases are associated with Using peripheral blood DNA from 55 subjects without a history of cancer [cancer(-)] and 52 ovarian cancer patients, we examined Our data suggest a predictive role of

Role of diagnostic laparoscopy in deciding primary treatment in advanced-stage ovarian cancer

We evaluated the usefulness of preoperative diagnostic laparoscopy for treatment planning in patients with advanced-stage ovarian cancer. We retrospectively analyzed 614 patients diagnosed with advanced-stage ovarian cancer between January 2010 and May 2018. Primary debulking surgery (PDS) or neoadjuvant chemotherapy (NAC) followed by interval debulking surgery were selected based on preoperative laparoscopic (Group 1, n=192) and computed tomography findings (Group 2, n=422). The primary outcomes in the PDS and NAC groups were suboptimal cytoreduction (residual disease >1 cm) rate and non-high-grade serous carcinoma (non-HGSC) rate, respectively. The patients who underwent PDS in group 1 and group 2 were 49 (25.5%) and 279 (66.1%), respectively. The suboptimal cytoreduction rate after PDS was lower in Group 1 than in Group 2 (2.0% vs 11.1%, p=0.023). Moreover, Group 1 showed a tendency toward a lower proportion of non-HGSC patients who underwent NAC than that in Group 2 (9.1% vs. 15.4%, p=0.069). Further, Group 1 showed lower rates of postoperative morbidity than Group 2 (5.2% vs. 10.4%, p=0.033). However, Kaplan-Meier analysis showed no significant differences in survival outcomes between the 2 groups. Diagnostic laparoscopy reduced the suboptimal cytoreduction rate in the PDS group and the implementation rate of NAC in non-HGSC patients. Moreover, it reduced postoperative morbidity without affecting survival in both groups. Thus, diagnostic laparoscopy is a valuable diagnostic tool for determining the primary treatment.

FIGO staging in ovarian carcinoma and histological subtypes

Significance of serum CA125 level in surgically resected cervical adenocarcinoma with adverse features

Unlike cervical squamous cell carcinoma, there are no consensus criteria for serum tumor markers in cervical adenocarcinoma. This study aimed to identify the prognostic value of preoperative carbohydrate antigen 125 (CA125) levels in cervical adenocarcinoma patients with adverse pathologic features. A total of 105 patients who underwent radical hysterectomy followed by adjuvant radiotherapy (RT) or concurrent chemoradiation therapy were included. Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were evaluated using the Cox proportional hazard regression model. Using a cutoff value of 50 U/mL, 83 and 22 patients had low- and high-CA125, respectively. Patients with high-CA125 had a larger tumor size, more frequent parametrial extension, and more frequent lymph node metastasis than those with low-CA125. During a median follow-up of 59.3 (interquartile range, 32.7-97.8) months, patients with high-CA125 showed inferior 5-year LRFS, DMFS, and OS rates compared to those with low-CA125 (38.5% vs. 70.0%; 37.0% vs. 69.4%; 43.6% vs. 78.1%, respectively, all p<0.05). In multivariable analysis, the high-CA125 remained significant prognostic factor for LRFS, DMFS, and OS (all p<0.05). Furthermore, 12 patients with high-CA125 at recurrence exhibited lower 5-year OS rates than 21 patients with low-CA125 at recurrence (0.0% vs. 51.3%, p=0.003). In this retrospective analysis, the serum CA125 level at diagnosis and recurrence was related to the extent of disease and prognosis of cervical adenocarcinoma with adverse pathologic features. A CA125 level of ≥50 U/mL may be a prognostic surrogate marker for cervical adenocarcinoma in patients with the presence of adverse factors.

SP1-induced lncRNA MCF2L-AS1 promotes cisplatin resistance in ovarian cancer by regulating IGF2BP1/IGF2/MEK/ERK axis

Cisplatin resistance is a huge problem encountered in ovarian cancer treatment. Our study probed the roles and the underlying mechanisms of lncRNA MCF2L-AS1 in ovarian cancer cisplatin-resistance. SKOV3 and IGROV-1 cells were subjected to gradually increasing concentrations of cisplatin to construct ovarian cancer cisplatin-resistance cells. Cell proliferation was evaluated by cell counting kit-8 and colony formation assays. Cell apoptosis was assessed using Annexin V and PI staining. The relationships between SP1, MCF2L-AS1 and insulin-like growth factor-2 mRNA binding protein 1 (IGF2BP1) were verified by RNA pull-down, RIP, ChIP and dual-luciferase reporter gene assay, respectively. Tumor xenograft experiment was employed to evaluate the effects of MCF2L-AS1 silencing on ovarian cancer cisplatin-resistance in vivo. TUNEL staining and immunohistochemistry were performed in tumor tissue. MCF2L-AS1 and IGF2BP1 were upregulated in cisplatin-resistant cells. MCF2L-AS1 silencing suppressed cell proliferation of cisplatin-resistant cells, while promoted the apoptosis, suggesting that MCF2L-AS1 knockdown suppressed ovarian cancer cells cisplatin-resistance. Meanwhile, MCF2L-AS1 silencing enhanced cisplatin sensitivity in ovarian cancer parental cells and IGF2BP1 overexpression impaired cisplatin sensitivity of parental cells. MCF2L-AS1 activated IGF2/MEK/ERK pathway through interacting with IGF2BP1. Transcription factor SP1 activated MCF2L-AS1 expression. MCF2L-AS1 knockdown inhibited ovarian cancer cisplatin-resistance in vivo. SP1-induced MCF2L-AS1 promoted ovarian cancer cisplatin-resistance through activation of IGF2/MEK/ERK pathway via interacting with IGF2BP1.

Prognostic influence of an early time to chemotherapy following primary cytoreductive surgery for advanced epithelial ovarian cancer

The current investigation analyzes the prognostic role of the time to chemotherapy (TTC) interval following primary cytoreductive surgery for patients with advanced epithelial ovarian cancer. Characteristics and outcome data for 509 consecutive patients with stage IIIB-IVB ovarian, fallopian tube, and peritoneal cancer who had primary cytoreductive surgery between January 2000 and December 2019 are utilized. A univariate Cox regression determined the association of categorical variables with progression-free survival (PFS) and overall survival (OS). Significant variables (p≤0.05) on univariate analysis were applied to Cox proportional hazard regression. The median TTC was 19 days and overall follow-up was 62.2 months. The PFS and OS were 25.5 months and 78.4 months for the study cohort plus 28.4 months and OS 84.5 months for patients rendered grossly disease-free. An early TTC (7-14 vs. 15-21 vs. 22-28 vs. >28 days) was associated with an improved PFS (41.7 vs. 30.6 vs. 18.9 vs. 17.9 months; p<0.001) and OS (132.7 vs. 104.6 vs. 56.5 vs. 48.0 months; p<0.001). The performance status, histology, disease distribution, dimension of residual disease, and categorical plus continuous TTC were predictors of PFS and OS. The use of maintenance therapy was also a predictor of PFS, and the route of chemotherapy administration was a predictor of OS. For advanced epithelial ovarian cancer, a TTC of less than 21-days was observed to independently improve the PFS and OS. A 7-14 days TTC trended towards a further extension of the OS.

Incidence of gastrointestinal perforation associated with bevacizumab in combination with neoadjuvant chemotherapy as first-line treatment of advanced ovarian, fallopian tube, or peritoneal cancer: analysis of a Japanese healthcare claims database

To assess the incidence of bevacizumab-associated gastrointestinal (GI) perforation during first-line treatment of patients with ovarian, fallopian tube, or peritoneal cancer receiving neoadjuvant chemotherapy (NAC) in Japanese real-world clinical practice. A retrospective study was conducted using a healthcare claims database owned by Medical Data Vision Co., Ltd. (study period, 2008-2020). Patients who initiated first-line treatment of ovarian, fallopian tube, or peritoneal cancer were identified and divided into NAC and primary debulking surgery (PDS) groups. The incidence of bevacizumab-associated GI perforation was compared within the NAC group and between the groups. Paclitaxel + carboplatin (TC) was most commonly used as first-line treatment (39.5% and 59.6% in the NAC and PDS groups, respectively). TC + bevacizumab was used in 9.3% and 11.6% of patients in the NAC and PDS groups, respectively. In the NAC group receiving TC, the proportion of patients with risk factors for GI perforation was lower among patients with versus without concomitant bevacizumab. The incidence of GI perforation in the NAC group was 0.38% (1/266 patients) in patients receiving TC + bevacizumab and 0.18% (2/1,131 patients) in patients receiving TC without bevacizumab (risk ratio=2.13; 95% confidence interval [CI]=0.19 to 23.36; risk difference=0.20; 95% CI=-0.58 to 0.97). None of the 319 patients in the PDS group receiving TC + bevacizumab had GI perforation. No notable increase was observed in GI perforation associated with NAC containing bevacizumab. We conclude that bevacizumab is prescribed with sufficient care in Japan to avoid GI perforation.

Association of menopause, aging and treatment procedures with positive margins after therapeutic cervical conization for CIN 3: a retrospective study of 8,856 patients by the Japan Society of Obstetrics and Gynecology

The Japan Society of Obstetrics and Gynecology conducted a retrospective multi-institutional survey of patients who underwent cervical conization in Japan. This study aimed to determine the predictive factors for positive surgical margins in cervical intraepithelial neoplasia grade 3 (CIN 3) patients after therapeutic cervical conization and those for positive margins in patients who did not experience recurrence and did not undergo additional treatment. In 2009 and 2013, 14,832 patients underwent cervical conization at 205 institutions in Japan. Of these, 8856 patients who underwent therapeutic conization fulfilled the inclusion criteria. Their histologic findings and clinical outcomes were evaluated based on standard statistical procedures and clinical and demographic characteristics. Negative and positive margins were observed in 7,585 and 1,271 (14.4%) patients, respectively. The predictors of positive margins were menopausal status (p<0.001), loop electrosurgical excision procedure (p<0.001), and Shimodaira-Taniguchi (S-T) conization (p<0.001). Of 1,271 patients with positive margins, 1,060 underwent no additional treatment; among those 1,060 patients, 129 (12.2%) experienced recurrence. The predictors of positive margins in patients who did not undergo additional treatment and did not experience recurrence were age, parity, gravidity, S-T conization, and laser scalpel conization. Menopausal status and treatment procedures were associated with positive margins after therapeutic conization of CIN 3. It is important to understand the characteristics of treatment procedures and select an appropriate procedure for each case. For elderly or menopausal patients with positive margins, immediate additional treatment is recommended.

Frequency and clinical features of deficient mismatch repair in ovarian clear cell and endometrioid carcinoma

To clarify the frequency of deficient mismatch repair (dMMR) in Japanese ovarian cancer patients, we examined microsatellite instability (MSI) status and immunohistochemistry (IHC) subtypes, including endometrioid carcinoma (EMC), clear cell carcinoma (CCC), or a mixture of both (Mix). We registered 390 patients who were diagnosed with EMC/CCC/Mix between 2006 and 2015 and treated at seven participating facilities. For 339 patients confirmed eligible by the Central Pathological Review Board, MSI, IHC, and MutL homolog 1 methylation analyses were conducted. The tissues of patients with Lynch syndrome (LS)-related cancer histories, such as colorectal and endometrial cancer, were also investigated. MSI-high (MSI-H) status was observed in 2/217 CCC (0.9%), 10/115 EMC (8.7%), and 1/4 Mix (25%). Additionally, loss of MMR protein expression (LoE-MMR) was observed in 5/219 (2.3%), 16/115 (14.0%), and 1/4 (25%) patients with CCC, EMC, and Mix, respectively. Both MSI-H and LoE-MMR were found significantly more often in EMC (p<0.001). The median (range) ages of patients with MMR expression and LoE-MMR were 54 (30-90) and 46 (22-76) (p=0.002), respectively. In the multivariate analysis, advanced stage and histological type were identified as prognostic factors. The dMMR rate for EMC/CCC was similar to that reported in Western countries. In Japan, it is assumed that the dMMR frequency is higher because of the increased proportion of CCC.

Major clinical research advances in gynecologic cancer in 2021

In the 2021 series, we not only summarized the major clinical research advances in gynecologic oncology but also added discussions to every part, based on communications at the conference. A review of cervical cancer included adjuvant treatments such as radiation and chemoradiation (concurrent or sequential) after radical hysterectomy in early cervical cancer, and immune checkpoint inhibitors in advanced, recurrent, and metastatic disease. Ovarian cancer research included studies of secondary cytoreductive surgery in platinum-sensitive recurrent ovarian cancer, and various trials of immune checkpoint inhibitors with or without vascular endothelial growth factor inhibitors and conventional chemotherapy. The rechallenge of poly (ADP-ribose) polymerase inhibitor maintenance in heavily pretreated ovarian cancer were also addressed. For uterine corpus cancer, dostarlimab (anti-programmed cell death protein 1 antibody) alone, or a tyrosine kinase inhibitor in combination with pembrolizumab for advanced, metastatic, or recurrent endometrial cancer were reviewed. The survival differences between the intensive and minimalist follow-up protocols were also described. In this review, we compared salpingectomy with delayed oophorectomy and salpingo-oophorectomy in terms of quality of life in BRCA 1 and 2 pathogenic variant carriers.

The impact of systematic retroperitoneal lymphadenectomy on long-term oncologic outcome of women with advanced ovarian clear-cell carcinoma

The impact of systematic retroperitoneal lymphadenectomy (SRL) remains controversial in patients with advanced ovarian clear-cell carcinoma (CCC) who are optimally debulked. Between 1986 and 2017, a total of 3,227 women with epithelial ovarian carcinoma were analyzed in a multi-institutional study. Among them, 166 optimally debulked women with stage IIB-IV CCC were collected (residual tumor of <1 cm). All patients were divided into 2 groups: 1) Group I (n=112): underwent standard radical surgery with SRL, 2) Group II (n=54): underwent non-staging limited surgery. The pathological slides were assessed based on central pathological review. Oncologic outcomes were compared between the two groups using a propensity score (PS)-matching technique to adjust for various clinicopathologic factors. The median follow-up duration of all surviving women was 52.8 (1.6-184.2) months. Overall, 88 patients (53.0%) experienced recurrence and 68 patients (41.0%) died of the disease. In the original cohort, the 5-year overall survival (OS) rates of groups I and II were 57.9 and 64.9%, respectively (log-rank p=0.415). In the PS-adjusted cohort, the 5-year OS rates were 64.9 and 58.8% in women in groups I and II, respectively (p=0.453). Furthermore, in the PS-matched cohort after adjustment for multiple clinicopathologic factors, there was no significant difference in OS between the 2 groups (group I vs. group II; hazard ratio=1.170; 95% confidence interval=0.633-2.187; p=0.615). This study suggests that the performance of SRL including radical surgery may not lead to a significant improvement in the oncologic outcome of advanced CCC patients with optimal cytoreduction.

Immunonutrition in ovarian cancer: clinical and immunological impact?

Malnutrition is frequent in ovarian cancer (OC) patients and may compromise post-operative outcomes. The aim of this study is to evaluate the impact of pre-operative immunonutrition on the surgical outcome of OC patients, and on their nutritional, inflammatory and peripheral blood immune status. A prospective study was performed between September 2016 and April 2020. Immune-enhancing enteral nutrition was administered to 42 patients before surgery according to their nutritional status assessed by the Malnutritional Universal Screening Tool. Biochemical and hematological monitoring was performed before and after immunonutrition. Post-operative outcomes were assessed and compared with those of a similar group of patients treated without nutritional support. Of the 42 immune-nourished patients, 23 (54.8%) had a low, 11 (26.2%) an intermediate and 8 (19%) a high risk of malnutrition. After the immunonutritional intake, significant variations of prealbumin, creatinine and white blood cells were detected. All T cell populations had an increasing trend, in particular CD3 Pre-operative immunonutrition improves the surgical outcome of OC patients. After immunonutrition, an increase of CD3

The impact of interval between primary cytoreductive surgery with bowel resection and initiation of adjuvant chemotherapy on survival of women with advanced ovarian cancer: a multicenter cohort study

Our aim was to determine if the time interval between bowel resection and initiation of adjuvant chemotherapy impacts survival in advanced ovarian cancers. This was a retrospective cohort study using data from two cancer centers, Princess Margaret Cancer Centre in Toronto, Ontario, Canada and Samsung Comprehensive Cancer Center in Seoul, South Korea. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage III or IV ovarian cancer that underwent large bowel resection during primary cytoreductive surgery (PCS) were included. Ninety-one women were eligible of which the majority (90.1%) were diagnosed with high-grade serous cancer. The median interval from PCS to chemotherapy for all patients was 21 days (7-86 days). Patients were stratified into 3 groups: 1) Interval ≤14 days, 32 (35.2%) patients; 2) Interval between 15-28 days, 27 (29.6%) patients; and 3) Interval between 29-90 days, 32 (35.2%) patients. Surgical procedures and postoperative outcomes were similar between groups. Multivariate analysis indicated that PCS to chemotherapy interval of 2-4 weeks, younger age, and completion of 4 or more adjuvant chemotherapy cycles were independent prognostic factors of favorable overall survival. Initiation of adjuvant chemotherapy between 2 to 4 weeks after PCS with bowel resection may improve survival outcomes in women with advanced ovarian cancer by maximizing the benefit of PCS plus adjuvant chemotherapy.

Microscopic diseases remain in initial disseminated sites after neoadjuvant chemotherapy for stage III/IV ovarian, tubal, and primary peritoneal cancer

This study aimed to evaluate the presence of pathological residual tumor (pRT) in each initial disseminated site after neoadjuvant chemotherapy (NACT) to assess the appropriate surgical margins during interval debulking surgery (IDS) for a favorable prognosis. This prospective descriptive study included patients with stage IIIC-IV epithelial ovarian, fallopian tubal, and peritoneal cancer. One hundred eleven patients underwent diagnostic exploratory laparotomy, and their initial intra-abdominal dissemination statuses were recorded. Any tumor >1 cm in diameter found during the exploratory laparotomy was resected during IDS even if it was macroscopically invisible after NACT. The pRT rate after NACT and negative predictive value (NPV; probability that sites with macroscopically invisible tumors have no pRT) during IDS were assessed in each disseminated site. A median of 5 NACT cycles were performed. Sites with a high incidence of pRT and low NPV included the rectosigmoid colon (71.4%, 38.6%), transverse mesentery (70.3%, 50.0%), greater omentum (68.3%, 51.7%), right diaphragm (61.9%, 48.1%), paracolic gutters (61.1%, 50.0%), and vesicouterine pouch (56.6%, 50.0%). Organs/tissues with a high incidence of pRT featured a low NPV. The median progression-free survival and overall survival in this cohort were 27.7 and 71.9 months, respectively. Even if a disseminated site >1 cm in diameter before NACT is invisible during IDS, microscopic disease remains present within it. The appropriate surgical margins for IDS with a favorable prognosis could be secured by resecting a lesion of >1 cm before NACT even if it is invisible during IDS.

Systematic lymph node dissection during interval debulking surgery for advanced epithelial ovarian cancer: a systematic review and meta-analysis

To evaluate the efficacy and safety of systematic lymph node dissection (SyLND) at the time of interval debulking surgery (IDS) for advanced epithelial ovarian cancer (AEOC). Systematic literature review of studies including AEOC patients undergoing SyLND versus selective lymph node dissection (SeLND) or no lymph node dissection (NoLND) after neoadjuvant chemotherapy (NACT). Primary endpoints included progression-free survival (PFS) and overall survival (OS). Secondary endpoints included severe postoperative complications, lymphocele, lymphedema, blood loss, blood transfusions, operative time, and hospital stay. Nine retrospective studies met the eligibility criteria, involving a total of 1,660 patients: 827 (49.8%) SyLND, 490 (29.5%) SeLND, and 343 (20.7%) NoLND. The pooled estimated hazard ratios (HR) for PFS and OS were, respectively, 0.88 (95% confidence interval [CI]=0.65-1.20; p=0.43) and 0.80 (95% CI=0.50-1.30; p=0.37). The pooled estimated odds ratios (ORs) for severe postoperative complications, lymphocele, lymphedema, and blood transfusions were, respectively, 1.83 (95% CI=1.19-2.82; p=0.006), 3.38 (95% CI=1.71-6.70; p<0.001), 7.23 (95% CI=3.40-15.36; p<0.0001), and 1.22 (95% CI=0.50-2.96; p=0.67). Despite the heterogeneity in the study designs, SyLND after NACT failed to demonstrate a significant improvement in PFS and OS and resulted in a higher risk of severe postoperative complications. PROSPERO Identifier: CRD42022303577.

Current status of hereditary breast and ovarian cancer practice among gynecologic oncologists in Japan: a nationwide survey by the Japan Society of Gynecologic Oncology (JSGO)

The practices pertaining to hereditary breast and ovarian cancer (HBOC) in Japan have been rapidly changing owing to the clinical development of poly(ADP-ribose) polymerase inhibitors, the increasing availability of companion diagnostics, and the broadened insurance coverage of HBOC management from April 2020. A questionnaire of gynecologic oncologists was conducted to understand the current status and to promote the widespread standardization of future HBOC management. A Google Form questionnaire was administered to the members of the Japan Society of Gynecologic Oncology. The survey consisted of 25 questions in 4 categories: respondent demographics, HBOC management experience, insurance coverage of HBOC management, and educational opportunities related to HBOC. A total of 666 valid responses were received. Regarding the prevalence of HBOC practice, the majority of physicians responded in the negative and required human resources, information sharing and educational opportunities, and expanded insurance coverage to adopt and improve HBOC practice. Most physicians were not satisfied with the educational opportunities provided so far, and further expansion was desired. They remarked on the psychological burdens of many HBOC managements. Physicians reported these burdens could be alleviated by securing sufficient time to engage in HBOC management, creating easy-to-understand explanatory material for patients, collaboration with specialists in genetic medicine, and educational opportunities. Gynecologic oncologists in Japan are struggling to deal with psychological burdens in HBOC practice. To promote the clinical practice of HBOC management, there is an urgent need to strengthen human resources and improve educational opportunities, and expand insurance coverage for HBOC management.

Factors predicting postoperative morbidity after cytoreductive surgery for ovarian cancer: a systematic review and meta-analysis

Advances in ovarian cancer cytoreductive surgery have enabled more extensive procedures to achieve maximal cytoreduction but with a consequent increase in postoperative morbidity and mortality. The aim of this study was to evaluate factors for postoperative morbidity after extensive cytoreductive surgery for primary epithelial ovarian cancer (EOC), particularly those which may be modifiable. Electronic databases were searched. Meta-analysis was conducted using random-effects models. Fifteen relevant studies, involving 15,325 ovarian cancer patients, were included in this review. Severe 30-day postoperative complications occurred in 2,357 (15.4%) patients. The postoperative mortality rate was 1.92%. Meta-analysis demonstrated that patient with following risk factors; age (p0 (p=0.001), albumin level <3.5 g/dL (p<0.001), presence of ascites on CT scan (p=0.013), stage IV disease (p<0.001) and extensive surgical procedure (p<0.001) has a significantly increase risk of developing postoperative complications. Surgical procedures including peritonectomy (p=0.012), splenectomy (p<0.001) and colon surgery (p<0.001) were significant predictors for postoperative complications. Moreover, we found that patients who received neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS) had a lower risk of developing severe complications compared to those who underwent primary debulking surgery (PDS) (p<0.001). Our study demonstrated that patient performance status and hypoalbuminemia were the only significant adjustable preoperative risk factors associated with postoperative complications. Patients who underwent NACT-IDS had a lower risk of developing severe complications compared to PDS. International Prospective Register of Systematic Reviews (PROSPERO) Identifier: CRD42021282770.

A step towards the ambition of precision oncology in recurrent ovarian cancer

Diagnostic performance of microRNA-34a, let-7f and microRNA-31 in epithelial ovarian cancer prediction

To correlate the genome-wide methylation signature of microRNA genes with dysregulated expression of selected candidate microRNA in tissue and serum samples of epithelial ovarian cancer (EOC) and control using quantitative reverse transcription polymerase chain reaction (qRT-PCR), and evaluation of EOC predictive value of candidate microRNA at an early stage. We performed Methylated DNA Immunoprecipitation coupled with NGS (MeDIP-NGS) sequencing of 6 EOC and 2 normal tissue samples of the ovary. Expression of selected microRNA from tissue (EOC=85, normal=30) and serum (EOC=50, normal=15) samples was evaluated using qRT-PCR. We conducted bioinformatics analysis to identify the candidate miRNA's potential target and functional role. MeDIP-NGS sequencing revealed hypermethylation of several microRNAs gene promoters. Three candidate microRNAs were selected (microRNA-34a, let-7f, and microRNA-31) from MeDIP-NGS data analysis based on log2FC and P-value. The relative expression level of microRNA-34a, let-7f, and microRNA-31 was found to be significantly reduced in early-stage EOC tissues and serum samples (p<0.0001). The receiver operating characteristic analysis of microRNA-34a, let-7f and miR-31 showed improved diagnostic value with area under curve(AUC) of 92.0 (p<0.0001), 87.9 (p<0.0001), and 85.6 (p<0.0001) and AUC of 82.7 (p<0.0001), 82.0 (p<0.0001), and 81.0 (p<0.0001) in stage III-IV and stage I-II EOC serum samples respectively. The integrated diagnostic performance of microRNA panel (microRNA-34a+let-7f+microRNA-31) in late-stage and early-stage serum samples was 95.5 and 96.9 respectively. Our data correlated hypermethylation-associated downregulation of microRNA in EOC. In addition, a combined microRNA panel from serum could predict the risk of EOC with greater AUC, sensitivity, and specificity.

Differences in age at diagnosis of ovarian cancer for each BRCA mutation type in Japan: optimal timing to carry out risk-reducing salpingo-oophorectomy

We examined a correlation between age at diagnosis of OC and common mutation types in 3,517 probands that received The average age at diagnosis of OC in g There appears to be no difference in the age at diagnosis of OC depending on the type of

Phase II study of niraparib in recurrent or persistent rare fraction of gynecologic malignancies with homologous recombination deficiency (JGOG2052)

Poly (adenosine diphosphate)-ribose polymerase (PARP) inhibitors for tumors with homologous recombination deficiency (HRD), including pathogenic mutations in JGOG2052 is a single-arm, open-label, multi-center, phase 2 clinical trial to evaluate the efficacy and safety of niraparib monotherapy for a recurrent or persistent rare fraction of gynecologic malignancies with Japan Primary Registries Network (JPRN) Identifier: jRCT2031210264.

Bone health after RRBSO among BRCA1/2 mutation carriers: a population-based study

Examine the risks of fractures and osteoporosis after risk-reducing bilateral salpingo-oophorectomy (RRBSO) among women with In this retrospective population-based study in British Columbia, Canada, between 1996 to 2017, we compared risks of osteoporosis and fractures among women with The mean age at RRBSO was 42.4 years (range, 26-49) and the median follow-up for women with Women with

Reducing distal pancreatectomy by posterolateral approach for splenectomy in the surgical management of ovarian cancer

PARP inhibitors in ovarian cancer: overcoming resistance with combination strategies

The use of PARP inhibitors (PARPi) in patients with epithelial ovarian cancer is expanding, with the transition from use in recurrent disease to the first-line setting. This is accompanied with an increasing population of patients who develop acquired PARPi resistance. Coupled with those patients with primary PARPi resistance, there is an urgent need to better understand mechanisms of resistance and identify means to overcome this resistance. Combination therapy offers the potential to overcome innate and acquired resistance, by either working synergistically with PARPi or by restoring homologous recombination deficiency, targeting the homologous recombination repair pathway through an alternate strategy. We discuss mechanisms of PARPi resistance and data on novel combinations which may restore PARPi sensitivity.

Biomarker-guided targeted therapy in platinum-resistant ovarian cancer (AMBITION; KGOG 3045): a multicentre, open-label, five-arm, uncontrolled, umbrella trial

Management of heavily pre-treated platinum-resistant ovarian cancer remains a therapeutic challenge. Outcomes are poor with non-platinum, single-agent chemotherapy (CT); however, molecularly targeted anticancer therapies provide new options. This open-label, investigator-initiated, phase 2 umbrella trial (NCT03699449) enrolled patients with platinum-resistant ovarian cancer (at least 2 prior lines of CT and Eastern Cooperative Oncology Group 0/1) to receive combination therapy based on homologous recombination deficiency (HRD) and programmed death ligand 1 (PD-L1) status determined by archival tumour sample assessment. HRD-positive patients were randomised to either olaparib 200mg bid tablet + cediranib 30mg qd (arm 1) or olaparib 300mg bid tablet + durvalumab 1,500mg q4w (arm 2). HRD-negative patients were allocated to either durvalumab 1,500 mg q4w + pegylated liposomal doxorubicin (PLD) or topotecan or weekly paclitaxel (6 cycles; arm 3, those with PD-L1 expression) or durvalumab 1,500 mg q4w + tremelimumab 75mg q4w (4 doses) + PLD or topotecan or weekly paclitaxel (4 cycles; arm 4, those without PD-L1 expression). Arm 5 (durvalumab 1,500 mg q4w + tremelimumab 300mg [1 dose] + weekly paclitaxel [60 mg/m² D1,8,15 q4w for 4 cycles] was initiated after arm 4 completed. The primary endpoint was objective response rate (ORR; Response Evaluation Criteria in Solid Tumours 1.1). Between Dec 2018 and Oct 2020, 70 patients (median 57 years; median 3 prior treatment lines [range 2-10]) were treated (n=16, 14, 5, 18, and 17, respectively). Overall ORR was 37.1% (26/70, 95% confidence interval=25.9, 49.5); 2 achieved complete response. ORR was 50%, 42.9%, 20%, 33.3%, and 29.4%, respectively. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 37.5%, 35.7%, 20%, 66.7%, and 35.3% of patients, respectively. No TRAEs leading to treatment discontinuation and no grade 5 TRAEs were observed. This study, the first biomarker-driven umbrella trial in platinum-resistant recurrent ovarian cancer, suggests clinical utility with biomarker-driven targeted therapy. All treatment combinations were manageable, and without unexpected toxicities. ClinicalTrials.gov Identifier: NCT03699449.

Posterior pelvic exenteration for ovarian cancer: surgical and oncological outcomes

Posterior pelvic exenteration (PPE) can be required to achieve complete resection in ovarian cancer (OC) patients with large pelvic disease. This study aimed to analyze morbidity, complete resection rate, and survival of PPE. Ninety patients who underwent PPE in our Comprehensive Cancer Center between January 2010 and February 2021 were retrospectively identified. To analyze practice evolution, 2 periods were determined: P1 from 2010 to 2017 and P2 from 2018 to 2021. A 82.2% complete resection rate after PPE was obtained, with rectal anastomosis in 96.7% of patients. Complication rate was at 30% (grade 3 in 9 patients), without significant difference according to periods or quality of resection. In a binary logistic regression adjusted on age and stoma, only age of 51-74 years old was associated with a lower rate of complication (odds ratio=0.223; p=0.026). Median overall and disease-free survivals (OS and DFS) from initial diagnosis were 75.21 and 29.84 months, respectively. A negative impact on OS and DFS was observed in case of incomplete resection, and on DFS in case of final cytoreductive surgery (FCS: after ≥6 chemotherapy cycles). Age ≥75-years had a negative impact on DFS for new OC surgery. For patients with complete resection, OS and DFS were decreased in case of interval cytoreductive surgery and FCS in comparison with primary cytoreductive surgery. PPE is an effective surgical measure to achieve complete resection for a majority of patients. High rate of colorectal anastomosis was achieved without any mortality, with acceptable morbidity and high protective stoma rate.

Survival benefits of retroperitoneal lymphadenectomy for optimally-resected advanced ovarian high-grade serous carcinoma: a multi-institutional retrospective study

The survival benefits of retroperitoneal lymphadenectomy (RLNA) for epithelial ovarian cancer (EOC) remain controversial because clinical behaviors differ among subtypes. The purpose of the present study was to clarify whether RLNA increases the survival rate of advanced high-grade serous carcinoma (HGSC). This was a retrospective cohort analysis of 3,227 patients with EOC treated between 1986 and 2017 at 14 institutions. Among them, 335 patients with stage IIB-IV HGSC who underwent optimal cytoreduction (residual tumor of <1 cm) were included. Patients were divided into the RLNA group (n=170) and non-RLNA group (n=165). All pathological slides were assessed based on a central pathological review. Oncologic outcomes were compared between the two groups in the original and weighted cohorts adjusted with the inverse probability of treatment weighting. The median observation period was 49.8 (0.5-241.5) months. Overall, 219 (65%) out of 335 patients had recurrence or progression, while 146 (44%) died of the disease. In the original cohort, RLNA was a significant prognostic factor for longer progression-free survival (PFS) (hazard ratio [HR]=0.741; 95% confidence interval [CI]=0.558-0.985) and overall survival (OS) (HR=0.652; 95% CI=0.459-0.927). In the weighted cohort in which all variables were well balanced as standardized differences decreased, RLNA was also a significant prognostic factor for more favorable oncologic outcomes (PFS, adjusted HR=0.742; 95% CI=0.613-0.899) and OS, adjusted HR=0.620; 95% CI=0.488-0.787). The present study demonstrated that RLNA for stage III-IV HGSC with no residual tumor after primary debulking surgery contributed to better oncologic outcomes.

Posterior pelvic exenteration, a crucial component in the surgeon’s toolbox for optimizing surgical cytoreduction for advanced ovarian cancer

Prognostic value of complete metabolic response on 18F-FDG-PET/CT after three cycles of neoadjuvant chemotherapy in advanced high-grade serous ovarian cancer

We investigated the prognostic value of complete metabolic response (CMR) on ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT) after 3 cycles of neoadjuvant chemotherapy (NAC) in advanced high-grade serous ovarian cancer (HGSC). PET/CT at baseline and after 3 cycles of NAC were performed; peak standardized uptakes were measured. PET parameters were compared with NAC parameter: cancer antigen-125 (CA-125) normalization before interval debulking surgery (IDS) and chemotherapy response score (CRS) to predict platinum-sensitivity. Kaplan-Meier analysis was used to determine correlations between PET parameters and survival. Prognostic factors were obtained by multivariate Cox regression analysis. Between 2007 and 2020, 102 patients were recruited: 19 (18.6%) were designated as CMR group and 83 (81.4%) as non-CMR group. CMR after 3 cycles of NAC showed the highest accuracy in predicting platinum-sensitivity (area under the curve [AUC]=0.729; 95% confidence interval [CI]=0.552-0.823; p=0.017), compared with CA-125 normalization before IDS (AUC=0.626; 95% CI=0.542-0.758; p=0.010) and CRS (AUC=0.613; 95% CI=0.490-0.735; p=0.080). CMR demonstrated better prognosis than non-CMR in progression-free survival (PFS) (median PFS, 23.9 months vs. 16.4 months; p=0.021) and overall survival (OS) (median OS, not reached vs. 69.7 months; p=0.025). In multivariate analysis, CMR was associated with a lower risk of recurrence (adjusted hazard ratio [aHR]=0.50; 95% CI=0.27-0.92; p=0.027) and death (aHR=0.23; 95% CI=0.05-0.99; p=0.048). CMR after 3 cycles of NAC can be a prognostic factor for both recurrence and death in advanced HGSC.

Predictors of postoperative pancreatic fistula after splenectomy with or without distal pancreatectomy performed as a component of cytoreductive surgery for advanced ovarian cancer

Splenectomy with or without distal pancreatectomy is occasionally performed during cytoreductive surgery for advanced ovarian cancer. We investigated pre-, intra-, postoperative risk factors and predictors of clinically relevant postoperative pancreatic fistula (CR-POPF) in patients who underwent cytoreductive surgery for advanced ovarian cancer. We investigated 165 consecutive patients with ovarian, fallopian tube, and peritoneal carcinoma categorized as stage III/IV disease, who underwent splenectomy with or without distal pancreatectomy as a component of cytoreductive surgery performed as initial treatment at Chiba University Hospital. Patient characteristics, clinical factors, and surgical outcomes were compared between those with and without CR-POPF. CR-POPF occurred in 20 patients (12%). There were no significant intergroup differences in the characteristics between patients with CR-POPF and patients without CR-POPF except for operative time, intraoperative blood loss, amylase (AMY) levels in drain fluid on postoperative day (POD)1 and POD3, and pancreatic stump thickness. Multivariate analysis showed that the POD3 drain fluid AMY level was the only significant risk factor and predictor of CR-POPF in patients who underwent cytoreductive surgery for advanced ovarian cancer. The receiver operating characteristic curve of the POD3 drain fluid AMY level, which predicted development of CR-POPF showed an area under the curve of 0.77, and the optimal cut-off value of AMY was 808 U/L. A pancreatic fistula did not occur in patients with POD3 drain fluid AMY levels <130 U/L. The POD3 drain fluid AMY level can be early diagnostic predictor CR-POPF after splenectomy with or without distal pancreatectomy for advanced ovarian cancer.

Conditional relative survival of cervical cancer: a Korean National Cancer Registry Study

Conditional relative survival (CRS) considers changes in prognosis over time and may offer more useful estimates for survivors. We aimed to investigate CRS among patients with cervical cancer stratified by various factors that influence survival probability. This nationwide retrospective study used data from the Korean Central Cancer Registry. We included 78,606 patients diagnosed with cervical cancer as their first cancer between January 1, 1996 and December 31, 2015, and who were followed until December 31, 2016. CRS and the conditional probabilities of death for the following 1 year were stratified by age at diagnosis, histology, cancer stage, treatment, year of diagnosis, and social deprivation index. The 5-year relative survival rate at the time of diagnosis was 80.6% for all cases. The probability of surviving an additional 5 years conditioned on having already survived 1, 2, 3, 4, and 5 years after diagnosis was 85.7%, 90.6%, 93.5%, 95.3%, and 94.3%, respectively. Patients with poorer initial survival estimates (older, advanced stage, non-squamous cell histology) generally showed the largest increases in CRS over time. Patients aged ≥70 years had the highest probability of death in the first year after diagnosis (24.5%), but the conditional probability of death in the 2nd, 3rd, 4th, and 5th years declined abruptly to 13.1%, 7.5%, 5.4%, and 3.9%, respectively. The CRS rates for patients with cervical cancer improved over time, particularly among patients with poorer initial prognoses. Our estimates enable patients to make better informed decisions regarding follow-up care and their personal life.

The extent of aortic lymphadenectomy in locally advanced cervical cancer impacts on survival

The prognostic impact of surgical paraaortic staging remains unclear in patients with locally advanced cervical cancer (LACC). The objective of our study was to evaluate the results of the surgical technique of preoperative aortic lymphadenectomy in LACC related to tumor burden and disease spread to assess its influence on survival. Data of 1,072 patients with cervical cancer were taken from 11 Spanish hospitals (Spain-Gynecologic Oncology Group [GOG] working group). Complete aortic lymphadenectomy surgery (CALS) was considered when the lymph nodes (LNs) were excised up to the left renal vein. The extent of the disease was performed evaluating the LNs by calculating the geometric means and quantifying the log odds between positive LNs and negative LNs. The Kaplan-Meier method was used to estimate the survival distribution. A Cox proportional hazards model was used to account for the influence of multiple variables. A total of 394 patients were included. Pathological analysis revealed positive aortic LNs in 119 patients (30%). LODDS cut-off value of -2 was established as a prognostic indicator. CALS and LODDS <-2 were associated with better disease free survival and overall survival than suboptimal aortic lymphadenectomy surgery and LODDS ≥-2. In a multivariate model analysis, CALS is revealed as an independent prognostic factor in LACC. When performing preoperative surgical staging in LACC, it is not advisable to take simple samples from the regional nodes. Radical dissection of the aortic and pelvic regions offers a more reliable staging of the LNs and has a favorable influence on survival.

Constructing a prediction model for lymph node metastasis in patients with incidental finding of endometrial cancer based on Fully-Connected Network

Rare studies focused on patients with incidental diagnosis of endometrial cancer (EC) after hysterectomy. We intended to construct a prediction model of lymph node metastasis (LNM) based on Fully-Connected Network (FC Network) for these patients. A total of 3,920 cases of EC that met the criteria from Obstetrics & Gynecology Hospital of Fudan University between January 2016 and February 2023 and 1995 cases from Fudan University Shanghai Cancer Center between January 2013 and October 2020 were retrospectively included for the construction of a predicting model which was based on FC Network. At the same time, 572 cases were prospectively collected for external validation. The sensitivity of the model was 0.946. Lympho-vascular space invasion, myometrial invasion, tumor grade, microcystic elongated and fragmented invasion, progesterone receptor, and cancer antigen 125 were used to construct a simplified nomogram. The area under the curve of the nomogram was 0.890 and 0.885 in validation and prospective cohorts, respectively. The model we proposed has good sensitivity and can be used to predict the risk of LNM in patients with incidentally found EC. The simplified nomogram can be used as a substitute in certain situations. Based on another study, the threshold of 5% and 25% can be used for risk stratification.

Comparison between laparoscopic and abdominal radical hysterectomy for stage IB1 and tumor size &lt;2 cm cervical cancer with visible or invisible tumors: a multicentre retrospective study

To compare 5-year disease-free survival (DFS) and overall survival (OS) rates of laparoscopic radical hysterectomy (LRH) and abdominal radical hysterectomy (ARH) for stage IB1 and tumor size <2 cm with visible or invisible tumors. We retrospectively compared the oncological outcomes of 1,484 cervical cancer patients with IB1 and tumor size <2 cm on final pathology, who received ARH (n=899) or LRH (n=585) between January 2004 and December 2016. Patients were divided into visible tumor subgroup (ARH: n=668, LRH: n=444) and invisible tumor subgroup (ARH: n=231, LRH: n=141) according to tumor type. LRH and ARH showed similar 5-year DFS and OS rates (93.3% vs. 93.1%, p=0.997; 96.2% vs. 97.5%, p=0.351) in total study population. LRH was not associated with worse 5-year DFS rate (hazard ratio [HR]=0.96; 95% confidence interval [CI]=0.58-1.58; p=0.871) or OS rate (HR=1.37; 95% CI=0.65-2.89; p=0.409) by multivariable analysis. In the visible tumor subgroups, LRH and ARH showed similar 5-year DFS and OS rates (91.9% vs. 91.9%, p=0.933; 95.0% vs. 96.9%, p=0.276), and LRH was not associated with worse 5-year DFS or OS rate (p=0.804, p=0.324). In the invisible tumor subgroups, LRH and ARH also showed similar 5-year DFS and OS rates (97.3% vs. 97.1%, p=0.815; 100% vs. 99.5%, p=0.449), and LRH was not associated with worse 5-year DFS rate (p=0.723). Among patients with stage IB1 and tumor size <2 cm, whether the tumor is visible or not, the oncological outcomes of LRH and ARH among cervical cancer patients are comparable. This suggests that LRH may be suitable for stage IB1 and tumor size <2 cm with visible or invisible tumors. International Clinical Trials Registry Platform Identifier: CHiCTR180017778.

Towards the elimination of cervical cancer in Japan

Does adenocarcinoma have a worse prognosis than squamous cell carcinoma in patients with cervical cancer? A real-world study with a propensity score matching analysis

To compare survival outcomes between cervical adenocarcinoma (ADC) and squamous cell carcinoma (SCC) using a propensity score matching (PSM) analysis based on the Surveillance, Epidemiology, and End Results (SEER) Program. Patients diagnosed with cervical cancer between 1998 and 2016 were identified from the SEER database. The Kaplan-Meier method and Cox regression analysis were used to analyze survival. A subgroup analysis of overall survival (OS) between patients with ADC and SCC was performed after the 1:1 PSM analysis. Of the 33,148 patients, 24,591 (79.19%) had SCC and 8,557 (25.81%) had ADC. In the unmatched cohort, after adjustment in multivariate analysis, patients with ADC had a worse prognosis than patients with SCC (hazard ratio [HR]=1.12; 95% confidence interval [CI]=1.07-1.18; p<0.001). In the propensity matched cohort, Kaplan-Meier analysis and subgroup analysis showed that ADC was associated with a worse prognosis than SCC (p=0.001). An analysis stratified by SEER stage revealed a worse prognosis for patients with ADC patients presenting with a regional disease than patients with SCC (HR=1.24; 95% CI=1.14-1.36 p<0.001), but no statistically significant differences were observed between the localized disease (HR=0.97; 95% CI=0.86-1.10; p=0.664) and distant disease (HR=1.09; 95% CI=0.97-1.22; p=0.162) subgroups. The significant differences in survival outcomes between patients with cervical ADC and SCC were only observed in the regional disease subgroup, but not in the localized disease and distant disease subgroups.

Report from the 36th Annual Meeting of the Korean Society of Gynecologic Oncology (KSGO)

Kallikrein 5 overexpression is associated with poor prognosis in uterine cervical cancer

Kallikrein 5 (KLK5), which is frequently observed in normal cervico-vaginal fluid, is known to be related to prognosis in several solid tumors. We investigated the prognostic significance of KLK5 in uterine cervical cancer using tumor tissue microarray and immunohistochemistry staining. We analyzed samples of 165 patients with uterine cervical cancer who received definitive radiation therapy between 2004 and 2012. We divided patients into two groups stratified by their KLK5 activity by immunohistochemistry staining: negative/weak (0-1+) (n=120 patients) and moderate/strong (2-3+) group (n=45 patients). Patient and tumor characteristics, patterns of failure, and survival outcomes were compared. Univariable and multivariable analyses were performed to identify prognostic factors. Patients with KLK5 2-3+ were younger (median: 52 vs. 60 years) and had frequent paraaortic lymph node involvement (40.0% vs. 18.3%) than those with KLK5 0-1+. With a median follow-up of 60.8 (interquartile range, 47.5-77.9) months, patients with KLK5 2-3+ had inferior 5-year locoregional recurrence-free survival and distant metastasis-free survival of 61.7% (vs. 77.5% in KLK5 0-1+ group) and 59.4% (vs. 72.8% in the KLK5 0-1+ group), respectively (all p<0.05). KLK5 2-3+ expression retained its significance after adjusting for other well-known prognostic factors of tumor size and stage in multivariable analysis. KLK5 overexpression is associated with the aggressiveness of cervical cancer and may underlie the diminished response to conventional treatments. Therefore, KLK5 could be a reliable prognostic factor in cervical cancer.

Surgical or imaging lymph node assessment in locally advanced cervical cancer: a systematic review and meta-analysis

To evaluate the survival impact of imaging vs surgical nodal assessment in patients with cervical cancer stage IB2-IVA prior to definitive chemoradiotherapy (CRT). PubMed, MEDLINE, Cochrane Library, and ClinicalTrials.gov were used to search for publications in English and Chinese over a 50-year period. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols was used to conduct this review. Inclusion criteria were studies that compared survival outcomes in International Federation of Gynecology and Obstetrics 2009 stage IB2-IVA cervical cancer patients with pre-therapy pelvic and/or aortic lymphadenectomy (LND) or imaging. One or more of the following modalities were used for nodal assessment: computed tomography (CT), magnetic resonance imaging, or positron emission tomography-CT. The National Institutes of Health Quality Assessment Tool was utilized to assess study quality. The initial search identified 65 studies, and five met the inclusion criteria. There were a total of 1,112 patients. Seven hundred and fifty-four underwent pelvic and/or aortic LND and 358 had imaging. When compared to LND, imaging had a sensitivity and specificity of 88.9% and 22.2% for pelvic lymph node (LN), and 33%-62.5% and 92%-95.5% for para-aortic LN. There were no differences in progression-free survival (PFS) (hazard ratio [HR]=1.13; 95% confidence interval [CI]=0.73-1.74; I²=75%; p<0.01) and overall survival (OS) (HR=1.06; 95% CI=0.66-1.69; I²=75%; p<0.01) between surgical and imaging nodal assessment. Imaging and surgical nodal assessment has comparable PFS and OS in patients with cervical cancer stage IB2-IVA. PROSPERO Identifier: CRD42020155486.

High mobility group box 3 promotes cervical cancer proliferation by regulating Wnt/β-catenin pathway

High mobility group box 3 (HMGB3) plays an important role in the development of various cancer. This study aims to explore whether HMGB3 regulates cervical cancer (CC) progression and elucidate the underlying mechanism. HMGB3 expression in clinical patients' tumor samples were determined by real-time quantitative polymerase chain reaction (qRT-PCR) and western blot. HMGB3 overexpression/knockdown were used to investigate its function. Cell apoptosis and cycle were detected by Annexin V/PI staining and flow cytometry. In vivo tumor model was made by subcutaneous injection of HeLa cells transfected with shRNAs targeting HMGB3 (sh-HMGB31) into the flank area of nude mice. Western blot was used to detect the levels of β-catenin, c-Myc, and matrix metalloproteinase-7 (MMP-7) in Hela and CaSki cells transfected with sh-HMGB3 or shRNAs targeting β-catenin. Both messenger RNA and protein levels of HMGB3 were upregulated in CC tissues from patients. High expression level of HMGB3 had positive correlation with serosal invasion, lymph metastasis, and tumor sizes in CC patient. Functional experiments showed that HMGB3 could promote CC cell proliferation both in vitro and in vivo. The expression levels of c-Myc and MMP-7 were increased, resulting in regulating cell apoptosis, cell cycle, and activating Wnt/β-catenin pathway. Our data indicated that HMGB3 may serve as an oncoprotein. It could be used as a potential prognostic marker and represent a promising therapeutic strategy for CC treatment.

Age-specific predictors of cervical dysplasia recurrence after primary conization: analysis of 3,212 women

This study aimed to identify predictors of recurrence/persistence of cervical intraepithelial neoplasia grade 2+ (CIN2+) lesion (r-CIN2+) after primary conization. Retrospective analysis involving all consecutive women having conization for CIN2+ between 1998 and 2018. The risk of r-CIN2+ was assessed using Kaplan-Meier and Cox models. Data of 3,212 women were retrospectively identified. After a mean follow-up of 47 (±22.2) months, 112 (3.5%) patients developed r-CIN2+. Mean time interval between prior conization and diagnosis of r-CIN2+ was 26.2 (±13.2) months. Via multivariate analysis, presence of high-risk human papillomavirus (HPV) types at the time of CIN2+ diagnosis, hazard ratio (HR)=3.40 (95% confidence interval [CI]=1.66-6.95) for HPV16/18 and HR=2.59 (95% CI=1.21-5.55) for HPV types other than 16/18, positive margins at primary conization, HR=4.11 (95% CI=2.04-8.26) and HPV persistence after conization, HR=16.69 (95% CI=8.20-33.9), correlated with r-CIN2+, independently. Considering age-specific HPV types distribution, we observed that HPV16/18 infection correlated to an increased risk of r-CIN2+ only in young women (aged ≤25 years; p=0.031, log-rank test); while in the older population (>25 years) HPV type(s) involved had not impact on r-CIN2+ risk (p>0.200, log-rank test). HPV persistence is the main factor predicting r-CIN2+. Infection from HPV16/18 has a detrimental effect in young women, thus highlighting the need of implementing vaccination against HPV in this population. Further prospective studies are warranted for tailoring clinical decision-making for post-conization follow-up on the basis of risk factors.

Management of patients with intermediate-risk early stage cervical cancer

Different surgical methods for FIGO stage IVB cervical cancer patients receiving chemotherapy: a population-based study

To assess survival differences between non-extensive surgery (NES) and extensive surgery (ES) in International Federation of Gynecology and Obstetrics (FIGO) stage IVB cervical cancer patients receiving chemotherapy from a population-based database, the Surveillance, Epidemiology and End Results. Propensity matching was conducted to minimize heterogeneity. Survival analysis was performed by the Kaplan-Meier method, log-rank test, and Cox proportional hazards model. A total of 154 patients met screening criteria, among whom 84 patients (84/154) underwent NES while 70 patients (70/154) underwent ES. After matching, no survival advantage was observed in ES group compared with NES group (p=0.066; hazard ratio [HR]=1.54; 95% confidence interval [CI]=0.97-2.42). Stratified analyses suggested ES prolonged overall survival in patients with histology other than squamous cell carcinoma and adenocarcinoma (p=0.028; HR=0.36; 95% CI=0.15-0.89) and American Joint Committee on Cancer (AJCC) T stage T1 (p=0.009; HR=0.18; 95% CI=0.05-0.66). Despite no survival benefit after regional lymph node surgery (p=0.629; HR=0.88; 95% CI=0.53-1.47), subgroup analyses demonstrated that patients younger than 50 (p=0.006; HR=0.21; 95% CI=0.07-0.64), with AJCC T stage T1 (p=0.002; HR=0.09; 95% CI=0.02-0.42), T3 (p=0.001; HR=0.02; 95% CI=0.00-0.21), hematogenous metastasis (p=0.036; HR=0.27; 95% CI=0.08-0.92) and without surgery of other sites (p In conclusion, ES or regional lymph node surgery may provide survival advantage for certain subgroup of FIGO IVB cervical cancer patients receiving chemotherapy. However, it deserves large scale prospective clinical trials to confirm.

In reply: the evaluation of IgG titers' stability from blood samples is necessary

Comments on: a phase 1/2a, dose-escalation, safety and preliminary efficacy study of oral therapeutic vaccine in subjects with cervical intraepithelial neoplasia 3

Comparing efficacy of high-dose rate brachytherapy versus helical tomotherapy in the treatment of cervical cancer

Boost radiation using brachytherapy (BT) is a standard treatment for local disease control in concomitant chemoradiation therapy (CCRT) for advanced cervical cancer. However, it is associated with gastrointestinal and genitourinary complications. Hence, this study investigates the feasibility of helical tomotherapy (HT) as an alternative to BT. Medical records of patients who underwent CCRT between 2000 and 2017 at a single institution were retrospectively reviewed. Patients with stage IIB-IVA cancers were selected based on the 2009 criteria of The International Federation of Gynaecology and Obstetrics. External beam radiation combined with chemotherapy was followed by either BT or HT. The propensity score matching of both groups was calculated using logistic regression analysis. Disease outcomes and treatment-related adverse events were compared between the 2 groups. The matched population included 70 BT patients and 35 HT patients. The 5-year progression-free survival rates for BT and HT were 72.6% and 72.5%, respectively (p=0.721). There was no difference in the overall survival rate between the two groups (p=0.203). The presence of acute and chronic gastrointestinal complications was also similar between the groups (p=0.460 and p=0.563, respectively). The chronic genitourinary toxicities were also comparable (p=0.105). HT boost treatment showed comparable disease outcomes with those observed with conventional BT in patients with advanced cervical cancer. HT could be a complementary boost protocol as a single modality or hybrid with BT in selected patients. Further studies with longer follow-up periods are warranted to confirm long-term outcomes.

Chemoradiotherapy is not superior to radiotherapy alone after radical surgery for cervical cancer patients with intermediate-risk factor

There is no consensus on whether giving adjuvant concurrent chemoradiotherapy (CCRT) is more effective than adjuvant radiotherapy (RT) alone in patients with early stage cervical cancer and intermediate-risk factor(s). The purpose of this study was to evaluate survival difference according to adjuvant treatment in the intermediate-risk group. From 2000 to 2014, the medical records of patients with stage IB-IIA cervical cancer and a history of radical hysterectomy with pelvic lymph node dissection, followed by pelvic RT at a dose ≥40 Gy were retrospectively reviewed. Among these, 316 patients with one or more intermediate-risk factor(s) and no high-risk factors were included. The criteria defined the intermediate-risk group as those patients with any of the following intermediate-risk factors: lymphovascular space involvement, over one-half stromal invasion, or tumor size ≥4 cm. The median follow-up duration was 70 months (range: 3-203 months). According to adjuvant treatment (adjuvant RT alone vs. adjuvant CCRT), the 5-year recurrence-free survival rates (90.8% vs. 88.9%, p=0.631) and 5-year overall survival rates (95.9% vs. 91.0%, p=0.287) did not show a significant difference in patients with any of the intermediate-risk factors. In multivariate analysis, a distinct survival difference according to adjuvant treatment was not found regardless of the number of risk factors. The present study showed that giving RT together with chemotherapy is not more effective than RT alone for stage IB-IIA cervical cancer patients with intermediate-risk factor(s). ClinicalTrials.gov Identifier: NCT01101451.

Pathologic discrepancies between colposcopy-directed biopsy and loop electrosurgical excision procedure of the uterine cervix in women with cytologic high-grade squamous intraepithelial lesions

To investigate pathologic discrepancies between colposcopy-directed biopsy (CDB) of the cervix and loop electrosurgical excision procedure (LEEP) in women with cytologic high-grade squamous intraepithelial lesions (HSILs). We retrospectively identified 297 patients who underwent both CDB and LEEP for HSILs in cervical cytology between 2015 and 2018, and compared their pathologic results. Considering the LEEP to be the gold standard, we evaluated the diagnostic performance of CDB for identifying cervical intraepithelial neoplasia (CIN) grades 2 and 3, adenocarcinoma in situ, and cancer (HSIL+). We also performed age subgroup analyses. Among the study population, 90.9% (270/297) had pathologic HSIL+ using the LEEP. The diagnostic performance of CDB for identifying HSIL+ was as follows: sensitivity, 87.8%; specificity, 59.3%; balanced accuracy, 73.6%; positive predictive value, 95.6%; and negative predictive value, 32.7%. Thirty-three false negative cases of CDB included CIN2,3 (n=29) and cervical cancer (n=4). The pathologic HSIL+ rate in patients with HSIL- by CDB was 67.3% (33/49). CDB exhibited a significant difference in the diagnosis of HSIL+ compared to LEEP in all patients (p<0.001). In age subgroup analyses, age groups <35 years and 35-50 years showed good agreement with the entire data set (p=0.496 and p=0.406, respectively), while age group ≥50 years did not (p=0.036). A significant pathologic discrepancy was observed between CDB and LEEP results in women with cytologic HSILs. The diagnostic inaccuracy of CDB increased in those ≥50 years of age.

Completion hysterectomy after chemoradiotherapy for locally advanced adeno-type cervical carcinoma: updated survival outcomes and experience in post radiation surgery

To compare patient survival outcomes between completion hysterectomy and conventional surveillance in locally advanced adenocarcinoma of the cervix after concurrent chemoradiotherapy (CCRT). Patients with adenocarcinoma of the cervix after CCRT were identified in a tertiary academic center database from 2004 to 2018. Patients received completion hysterectomy or surveillance after CCRT. We compared the progression-free survival (PFS) and overall survival (OS) between the patients with or without adjuvant hysterectomy. Surgery features, operative complications, and pathologic characteristics were documented. Patient outcomes were also analyzed according to clinicopathologic factors. A total of 78 patients were assigned to completion surgery and 97 to surveillance after CCRT. The PFS was better in the surgery group compared to the CCRT only group, at 3 years the PFS rates were 68.1% and 45.2%, respectively (hazard ratio [HR]=0.46; 95% confidence interval [CI]=0.282-0.749; p=0.002). Adjuvant surgery was also associated with a higher rate of OS (HR=0.361; 95% CI=0.189-0.689; p=0.002), at 3 years, 87.9% and 67%, respectively. Tumor stage, size, lymph-vascular space invasion (LVSI), lymphadenopathy were associated with PFS but not with OS. Hysterectomy specimens revealed 64.1% (50/78) of the patients had pathologic residual tumor. Patients age less than 60, tumor size over 4 cm, stage IIB and persistent residual disease after CCRT were most likely to benefit from hysterectomy. Hysterectomy was associated with a lower rate of locoregional recurrence but did not reach statistical significance (5.13% vs. 13.5%, p=0.067). Completion hysterectomy after CCRT was associated with better survival outcome compared with the current standard of care.

Human papillomavirus (HPV) DNA detection in uterine cervix cancer after radiation indicating recurrence: a systematic review and meta-analysis

The causal association of human papillomavirus (HPV) in uterine cervical cancer was well established and this oncogenic virus was reported to be a biomarker for overall recurrence and central pelvic recurrence. The objective of the present systematic review and meta-analysis was to assess the role of HPV DNA testing in early detection of recurrence among cervical cancer survivors after radiotherapy. We performed a systematic review and meta-analysis by means of searching electronic databases for published articles between January 1984 and June 2018, on the basis of standard systematic review guidelines prescribed by major agencies namely Cochrane Collaboration (https://www.cochrane.org) and Campbell Collaboration (https://www.campbellcollaboration.org). The meta-analysis component was further modified appropriately for the synthesis of sensitivity and specificity results. A total of 1,055 cervical cancer cases who had received pelvic radiation with or without chemotherapy from ten cohort studies were evaluated. The overall pooled sensitivity and specificity of HPV DNA testing was 0.84 (95% confidence interval [CI]= 0.66-0.94) and 0.35 (95% CI=0.20-0.54) respectively. The positive likelihood ratio was 1.3 (95% CI=1.0-1.7) and the negative likelihood ratio was 0.45 (95% CI=0.18-1.10) with an estimated diagnostic odds ratio of 3 (95% CI=1-9). The screening for HPV DNA testing during follow-up facilitates early detection of recurrence after radiotherapy.

Safety evaluation of abdominal trachelectomy in patients with cervical tumors ≥2 cm: a single-institution, retrospective analysis

For oncologic safety, vaginal radical trachelectomy is generally performed only in patients with cervical cancers smaller than 2 cm. However, because inclusion criteria for abdominal trachelectomy are controversial, we evaluated the safety of abdominal trachelectomy for cervical cancers ≥2 cm. We began performing abdominal trachelectomies at our institution in 2005, primarily for squamous cell carcinoma ≤3 cm or adenocarcinoma/adenosquamous carcinoma ≤2 cm. If a positive sentinel lymph node or cervical margin was diagnosed intraoperatively by frozen section, the trachelectomy was converted to a hysterectomy. Medical records of these patients were reviewed retrospectively. Patients who had undergone simple abdominal trachelectomy were excluded from this study. We attempted trachelectomy in 212 patients. Among the 135 patients with tumors <2 cm, trachelectomy was successful in 120, one of whom developed recurrence and none of whom died of their disease. Among 77 patients with tumors ≥2 cm, trachelectomy was successful in 62, 2 of whom developed recurrence and 1 of whom died of her disease. The overall relapse rate after trachelectomy was 1.6% (0.8% in <2 cm group and 3.2% in ≥2 cm group), and the mortality rate was 0.5% (0% in <2 cm group and 1.6% in ≥2 cm group). Recurrence-free survival (p=0.303) and overall survival (p=0.193) did not differ significantly between the <2 cm and ≥2 cm groups. Abdominal trachelectomy with intraoperative frozen sections of sentinel lymph nodes and cervical margins is oncologically safe, even in patients with tumors ≥2 cm.

The basic principles of oncologic surgery during minimally invasive radical hysterectomy

Surgery of primary sites for stage IVB cervical cancer patients receiving chemoradiotherapy: a population-based study

The purpose of this study was to analyze the impact of surgery of primary sites on stage IVB cervical cancer patients from a population-based database, the Surveillance, Epidemiology and End Results (SEER). Propensity score matching was performed to minimize heterogeneity in patient between with-surgery group and without-surgery group. Clinicopathological characteristics were compared using the χ² or Fisher's exact test. Survival analysis included the Kaplan-Meier method, log-rank test, and Cox proportional hazards model. Between 2010-2015, a total of 1,139 International Federation of Gynecology and Obstetrics (FIGO) stage IVB cervical cancer patients receiving chemoradiotherapy (CRT) were included in this retrospective study. Within post-matching cohort, the median duration of overall survival (OS) in stage IVB cervical cancer patients receiving CRT was 22 months. The overall 5-year survival rate was 25.7%. The increasing American Joint Committee on Cancer T stage (T1 vs. T2, p=0.033, hazard ratio [HR]=1.79, 95% confidence interval [CI]=1.05-3.05; T1 vs. T3, p=0.003, HR=2.20, 95% CI=1.31-3.67; T1 vs. T4, p=0.037, HR=2.75, 95% CI=1.06-7.12) and visceral metastasis (with vs. without, p=0.038, HR=1.60, 95% CI=1.03-2.49) was reported as independent risk factors of OS. Surgery of primary sites combined with CRT tended to prolong the survival of stage IVB cervical cancer patients (p<0.001, HR=0.36, 95% CI=0.21-0.61) compared with CRT, especially for patients without visceral metastasis (p=0.005, HR=0.31, 95% CI=0.14-0.70). In conclusion, patients with stage IVB cervical cancer may achieve their best outcomes through CRT combined with surgery of primary sites. However, it deserves large scale prospective clinical trials to confirm.

Selection criteria and colpotomic approach for safe minimally invasive radical hysterectomy in early-stage cervical cancer

To evaluate oncologic outcomes of minimally invasive radical hysterectomy (RH) in early cervical cancer before and after the application of parametrial invasion (PMI) criterion on magnetic resonance imaging (MRI) and vaginal colpotomy (VC). A total of 216 International Federation of Gynecology and Obstetrics stage IB-IIA cervical cancer patients who underwent minimally invasive RH was identified between April 2006 and October 2018. Patients were classified into the pre-PMI intracorporeal or VC (IVC) (n=117) and post-PMI VC groups (n=99). In the pre-PMI IVC group, PMI criterion (intact stromal ring) on MRI was not applied and the patients received IVC. In the post-PMI VC group, surgical candidates were selected using the PMI criterion on MRI and all patients received VC only. Oncologic outcomes and prognostic factors associated with disease recurrence were analyzed. The rate of positive vaginal cuff margins in the pre-PMI IVC group was higher than that in the post-PMI VC group (11.1% vs. 1.0%, p=0.003). Two-year disease-free survival was different between the 2 groups (84.5% in pre-PMI IVC vs. 98.0% in post-PMI VC groups, p=0.005). Disrupted stromal ring on MRI (hazard ratio [HR]=20.321; 95% confidence interval [CI]=4.903-84.218; p<0.001) and intracorporeal colpotomy (HR=3.059; 95% CI=1.176-7.958; p=0.022) were associated with recurrence. The intact cervical stromal ring on MRI might identify the low-risk group of patients in terms of PMI and lymphovascular/stromal invasion in early cervical cancer. Minimally invasive RH should be performed in optimal candidates with an intact stromal ring on MRI, using VC.

Clinical response and safety of apatinib monotherapy in recurrent, metastatic cervical cancer after failure of chemotherapy: a retrospective study

To observe the safety and short-term efficacy of apatinib in the treatment of recurrent, metastatic cervical cancer in patients who have already received more than two kinds of comprehensive treatment. Forty-eight patients with recurrent or metastatic cervical cancer after radiotherapy or surgery who received apatinib between June 2016 and June 2017 were involved in this study. These patients experienced progression after first-line or second-line chemotherapy. There were 38 patients with cervical squamous cell carcinoma, 8 with adenocarcinoma, and 2 with adenosquamous carcinoma. Progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (AEs) were reviewed and evaluated. All patients had complete follow-up records, and the median follow-up time was 14.5 months (5.5-20.5 months). Among the 48 patients, 14.58% achieved a partial response and 52.08% achieved stable disease. The overall response rate and disease control rate were 14.58% and 66.67%, respectively. The median time that the 48 patients received oral apatinib was 8.2 months. The median PFS was 4.6 months (95% confidence interval [CI]=3.31-5.26) and OS was 13.9 months (95% CI=8.37-17.96). The main apatinib-related adverse reactions were leukopenia (37.5%), neutropenia (41.67%), hemorrhage (37.5%), hypertension (33.33%), proteinuria (12.5%), fatigue (37.5%), and hand-foot syndrome (27.08%). Most of them were grade 1-2, and no drug-related death occurred. Apatinib can improve the disease control rate of recurrent and metastatic cervical cancer when chemotherapy has failed, and the treatment is well tolerated. This represents that apatinib may be a new treatment option for metastatic cervical cancer patients.

High-risk human papillomavirus testing as a primary screening for cervical cancer: position statement by the Korean Society of Obstetrics and Gynecology and the Korean Society of Gynecologic Oncology

Based on emerging data and current knowledge regarding high-risk human papillomavirus (hrHPV) testing as a primary screening for cervical cancer, the Korean Society of Obstetrics and Gynecology and the Korean Society of Gynecologic Oncology support the following scientific facts: • Compared to cytology, hrHPV screening has higher sensitivity and detects more cases of high-grade cervical intraepithelial neoplasia. • Qualified hrHPV testing can be considered as an alternative primary screening for cervical cancer to the current cytology method. • The starting age of primary hrHPV screening should not be before 25 years because of possible overtreatment in this age, which has a high human papillomavirus (HPV) prevalence but rarely progresses to cancer. The screening interval should be no sooner than every 3 years and no longer than every 5 years. • Before the introduction of hrHPV screening in Korea, research into comparative effectiveness of primary hrHPV screening for cervical cancer should be conducted to determine the appropriate HPV assay, starting age, and screening interval.

Association between resection margin and local recurrence in the treatment of primary squamous cell vulvar carcinoma

Our aim was to assess the potential correlation between resection-free margin and local recurrence in the treatment of squamous cell vulvar carcinoma (SCC). Seventy-five patients with primary SCC of the vulva and adequately follow-up that were operated in our university hospital between January 2008 to December 2018, were retrospectively evaluated with focus on resection-free margin and its impact on local recurrence. Several prognostic factors were analysed for possible correlation. Median patient age and follow-up was 62.8 years and 57.4 months, respectively. Among all patients, 27 (36%) local recurrences were documented, for a median local recurrence-free survival (LRFS) of 68.1 months for patients resected R0 and 65.6 months for those initially R1 resected (p=0.750). There was also no statistically significant difference (p=0.750) when evaluating the LRFS relative to the absence or not of inguinal lymph node involvement, although there was a numerical difference of approximately 17 months (73.9 vs. 57.3 months). For initially R0 resected patients, no significant influence of the resection-free margin in millimeters on LRFS was noted for a median of 58.4 versus 57.3 months for patients with a free margin of 0.1-3 mm and those with a free margin of >3 mm, respectively (p=0.800). Eleven patients received adjuvant chemoradiotherapy, all for nodal inguinal involvement. Among them, 5 patients developed recurrence, while the other 6 remained free of disease. The extend of resection-free margin does not appear to adversely affect LRFS suggesting that smaller margins could be applied to minimize morbidity without compromising local control.

Association between hospital treatment volume and survival of women with gynecologic malignancy in Japan: a JSOG tumor registry-based data extraction study

Associations between hospital treatment volume and survival outcomes for women with 3 types of gynecologic malignancies, and the trends and contributing factors for high-volume centers were examined. The Japan Society of Obstetrics and Gynecology tumor registry databased retrospective study examined 206,845 women with 80,741, 73,647, and 52,457 of endometrial, cervical, and ovarian tumor, respectively, who underwent primary treatment in Japan between 2004 and 2015. Associations between the annual treatment volume and overall survival (OS) for each tumor type were examined using a multivariable Cox proportional hazards model with restricted cubic splines. Institutions were categorized into 3 groups (low-, moderate-, and high-volume centers) based on hazard risks. Hazard ratio (HR) for OS each the 3 tumors decreased with hospital treatment volume. The cut-off points of treatment volume were defined for high- (≥50, ≥51, and ≥27), moderate- (20-49, 20-50, and 17-26), and low-volume centers (≤19, ≤19, and ≤16) by cases/year for endometrial, cervical, and ovarian tumors, respectively. Multivariate analysis revealed younger age, rare tumor histology, and initial surgical management as contributing factors for women at high-volume centers (all, p<0.001). The proportion of high-volume center treatments decreased, whereas low-volume center treatments increased (all p<0.001). Treatment at high-volume centers improved OS than that at other centers (adjusted HR [aHR]=0.83, 95% confidence interval [CI]=0.78-0.88; aHR=0.78, 95% CI=0.75-0.83; and aHR=0.90, 95% CI=0.86-0.95 for endometrial, cervical, and ovarian tumors). Hospital treatment volume impacted survival outcomes. Treatments at high-volume centers conferred survival benefits for women with gynecologic malignancies. The proportion of treatments at high-volume centers have been decreasing recently.

Autologous cervical tumor lysate pulsed dendritic cell stimulation followed by cisplatin treatment abrogates FOXP3+ cells in vitro

Dendritic cells (DCs) are administered as immunotherapeutic adjuvants after the completion of standard treatment in most settings. However, our Phase I trial indicated that one patient out of four, who received autologous tumor lysate-pulsed dendritic cell (TLDC) also received cisplatin chemotherapy and experienced complete regression of her lung lesion, continuing to be disease free till date. Hence, the objective of our current study is to evaluate the sustenance or augmentation of immune responses when autologous human papillomavirus positive cervical tumor lysate pulsed DC- are combined with cisplatin, using co-culture assays in vitro. Before treatment, peripheral blood and punch biopsy samples were collected from 23 cervical cancer patients after obtaining an informed consent. DC functionality was confirmed through phenotypic and functional assays using autologous peripheral blood mononuclear cells as responders. For cisplatin experiments, the drug was added at 150, 200 (clinical dose equivalent), and 400 μM concentrations to DCs alone or DC-T cell co-cultures. Phenotypic assessment and functional characterization of DCs was done using flow cytometry. Cytokine enzyme-linked immunosorbent assay and interferon (IFN)-γ enzyme-linked immune absorbent spot assays were also performed. The functionality of TLDCs was not compromised upon cisplatin treatment in vitro even at the highest (400 μM) concentration. Even though cisplatin treatment reduced the secretion of IFN-γ and interleukin (IL)-12p40 in co-cultures stimulated with TLDCs, this effect was not significant (p>0.05). A doubling of IFN-γ secretion following cisplatin treatment was observed in at least one of three independent experiments. Additional experiments showed a reduction in both FOXP3+ regulatory T cells and IL-10 levels. Our results provide evidence that cisplatin treatment may be given after autologous TLDC administration to maintain or improve a productive anti-tumor response in vaccinated patients.

Should adjuvant chemotherapy be formally studied among patients found to have pelvic lymph node metastases following radical hysterectomy with lymphadenectomy for early-stage cervical cancer?

Predictive factors of surgical complications after pelvic exenteration for gynecological malignancies: a large single-institution experience

To evaluate pre-operative predictors of early (<30 days) severe complications (grade Dindo 3+) in patients with gynecological malignancy submitted to pelvic exenteration (PE). We retrospectively analyzed 129 patients submitted to surgery at Fondazione Policlinico Gemelli between 2010 and 2019. We included patients affected by primary or recurrent/persistent cervical, endometrial, or vulvar/vaginal cancers. Post-operative complications were graded according to the Dindo classification. Logistic regression was used to analyze potential predictors of complications. We performed 63 anterior PE, 10 posterior PE, and 56 total PE. The incidence of early severe post-operative complications was 27.9% (n=36), and the early mortality rate was 2.3% (n=3). More frequent complications were related to the urinary diversion and intestinal surgery. In univariable analysis, hemoglobin ≤10 g/dL (odds ratio [OR]=4.2; 95% confidence interval [CI]=1.65-10.7; p=0.003), low albumin levels (OR=3.9; 95% CI=1.27-12.11; p=0.025), diabetes (OR=4.15; 95% CI=1.22-14.1; p=0.022), 2+ comorbidities at presentation (OR=5.18; 95% CI=1.49-17.93; p=0.012) were predictors of early severe complications. In multivariable analysis, only low hemoglobin and comorbidities at presentation were independent predictors of complications. Pelvic exenteration is an aggressive surgery characterized by a high rate of post-operative complications. Pre-operative assessment of comorbidities and patient health status are crucial to better select the right candidate for this type of surgery.

Outcomes and prognostic factors of surgically treated extramammary Paget’s disease of the vulva

Extramammary Paget's disease (EMPD) of the vulva is a rare disease which predominantly presents in postmenopausal Caucasian women. As yet, no studies on Asian female patients with EMPD have been performed. This study aimed to identify the clinical features of patients with vulvar EMPD in Korea, and to evaluate the risk factors of recurrence and postoperative complications in surgically treated EMPD. We retrospectively reviewed 47 patients with vulvar EMPD who underwent wide local excision or radical vulvectomy. The clinical data and surgical and oncological outcomes following surgery were extracted from medical records and analyzed. Univariate and multivariate analyses for predicting recurrence and postoperative complications were performed. 21.3% of patients had complications after surgery, and wound dehiscence was the most common. 14.9% of patients experienced recurrence, and the median interval to recurrence from initial treatment was 69 (range 33-169) months. Vulvar lesions larger than 40 mm was the independent risk factor of postoperative complications (odds ratio [OR]=7.259; 95% confidence interval [CI]=1.545-34.100; p=0.012). Surgical margin status was not associated with recurrence in surgically treated vulvar EMPD patients (OR=0.83; 95% CI=0.16-4.19; p=1.000). Positive surgical margin is a frequent finding in the patients with vulvar EMPD, but disease recurrence is not related with surgical margin status. Since EMPD is a slow growing tumor, a surveillance period longer than 5 years is required.

Number of FoxP3+ regulatory T-cells are associated with recurrence in vulvar squamous cell carcinoma

Surgical management is essential in early-stage vulvar squamous cell carcinoma (SCC), but these surgical procedures often cause significant morbidity. Immunotherapy may be a new treatment option in these patients. FoxP3+ Tregs suppress anti-tumor immune responses. High intratumoral FoxP3+ Treg infiltration has been reported to be associated with poor prognosis in most solid tumors. However, there are also conflicting results. We evaluated FoxP3+ lymphocyte infiltration in vulvar SCC and aimed to determine its relationship with prognosis and clinicopathological parameters. Cases diagnosed with vulvar SCC in our department were retrospectively reviewed. The paraffin block that best reflects the morphology was selected, and immunohistochemical studies were performed in accordance with the manufacturer's instructions. FoxP3+ lymphocyte counts were made in tumoral stroma and within tumoral cell islands separately in hot-spot areas. We found a positive correlation between high FoxP3+ lymphocyte count and good prognostic parameters. There was less recurrence in the group with high FoxP3+ lymphocyte counts in tumoral cell islands. Overall survival was not statistically different between these groups. Less lymphovascular invasion was observed in the group with high lymphocyte count in the tumoral stroma. In vulvar SCC, FoxP3+ Treg infiltration into the tumor stroma and into tumoral cell islands is associated with good prognostic features. In these tumors, stage appeared as the only independent prognostic parameter. Studies to be conducted in larger series may reveal whether Tregs can be targeted in cancer treatment.

Combined laparoscopic and transperineal endoscopic total pelvic exenteration for the vaginal stump recurrence of cervical cancer

Total pelvic exenteration (TPE) is sometimes required for radical treatment of locally advanced or recurrent gynecologic cancer [1]. However, TPE with a transabdominal approach requires highly advanced techniques in the case of repeated surgery due to the effects of primary surgery and/or chemoradiotherapy, especially when a transabdominal approach is used. Recent technical advances in transanal/transperineal endoscopic surgery have proved beneficial for complicated surgery in the deep pelvis [2]. Here we introduce our surgical procedure for combined laparoscopic and transperineal endoscopic TPE (TpTPE) for pelvic recurrence of cervical cancer. A 42-year-old woman was diagnosed with vaginal stump recurrence of cervical cancer involving the rectum, bladder, and ureters following hysterectomy and pelvic lymph node dissection as primary surgery and chemotherapy/chemoradiotherapy for previous recurrences. We decided to perform TpTPE with a combined laparoscopic approach. The GelPOINT advanced access platform was fixed through a perineal skin incision around the tightly closed anus, external urethral orifice, and vagina. With sufficient pneumopelvic pressure (12 mmHg), TpTPE was performed under a good surgical view without any effect of the primary surgery. A ureterostomy and sigmoid colostomy were created and a right gracilis muscle flap was used to reconstruct the pelvic defect. The total operative time and estimated blood loss were 887 minutes and 497 mL, respectively. Histopathological examination revealed recurrent cervical cancer invading the rectum, bladder, and bilateral ureters with negative surgical margins. The postoperative course was uneventful except for paralytic ileus. The patient was discharged on postoperative day 18. TpTPE is a technically feasible and effective approach for locally advanced pelvic tumors.

Predicting prognosis according to the updated WHO classification in patients with endocervical adenocarcinoma treated with surgery and radiotherapy

The recently updated World Health Organization classification divides endocervical adenocarcinomas (ADCs) into human papillomavirus (HPV)-associated (HPVA) and HPV-independent (HPVI) ADCs. This study aimed to investigate the differences in the clinical features and treatment outcomes between patients with HPVA and HPVI. We retrospectively reviewed the electronic medical records and pathology slides of 123 patients with endocervical ADC who underwent radical hysterectomy and adjuvant radiation therapy. Tumor characteristics, patterns of failure, and survival outcomes were compared between HPVA and HPVI ADCs. Eighty-one (65.9%) and 42 (34.1%) patients were diagnosed with HPVA and HPVI ADCs, respectively. HPVI ADC showed more frequent positive vaginal resection margin (VRM) and peritoneal seeding than HPVA ADC. After a median follow-up of 58.1 months, local recurrence and distant metastasis were more frequently observed in HPVI ADC than in HPVA ADC. Both local recurrence-free survival (77.3% vs. 91.8%) and distant metastasis-free survival (50.1% vs. 73.7%) rates of HPVI ADC were lower than those of HPVA ADC. Disease-free survival was not significantly different between HPVI and HPVA ADCs. We demonstrated that HPVI ADC exhibited higher rates of VRM involvement and peritoneal seeding than those of HPVA ADC, resulting in higher rates of local recurrence and distant metastasis. Further studies with larger populations are warranted to explore optimal treatment strategies based on the histological subtypes of endocervical ADC.

An evaluation of prognostic factors, oncologic outcomes, and management for primary and recurrent squamous cell carcinoma of the vulva

To evaluate prognostic factors, outcomes, and management patterns of patients treated for squamous cell carcinoma of the vulva. One hundred sixty-four women were retrospectively identified with primary squamous cell carcinoma of the vulva treated at our institution between 1/1996-12/2018. Descriptive statistics were performed on patient, tumor, and treatment characteristics. The χ² tests and t-tests were used to compare categorical variables and continuous variables, respectively. Recurrence free survival (RFS), overall survival (OS), and disease-specific survival (DSS) were analyzed with Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards. Median follow-up was 52.5 months. Five-year RFS was 67.9%, 60.0%, 42.1%, and 20.0% for stage I-IV, respectively. Five-year DSS was 86.2%, 81.6%, 65.0%, and 42.9% for stage I-IV, respectively. On multivariate analysis, positive margins predicted overall RFS (hazard ratio [HR]=3.55; 95% confidence interval [CI]=1.18-10.73; p=0.025), while presence of lichen sclerosus on pathology (HR=2.78; 95% CI=1.30-5.91; p=0.008) predicted local RFS. OS was predicted by nodal involvement (HR=2.51; 95% CI=1.02-6.13; p=0.043) and positive margins (HR=5.19; 95% CI=2.03-13.26; p=0.001). Adjuvant radiotherapy significantly improved RFS (p=0.016) and DSS (p=0.012) in node-positive patients. Median survival after treatment of local, groin, and pelvic/distant recurrence was 52, 8, and 5 months, respectively. For primary treatment, more conservative surgical approaches can be considered with escalation of treatment in patients with concurrent precursor lesions, positive margins, and/or nodal involvement. Further studies are warranted to improve risk stratification in order to optimize treatment paradigms for vulvar cancer patients.

A novel gene signature associated with poor response to chemoradiotherapy in patients with locally advanced cervical cancer

We aimed to investigate the distinct transcriptional landscape in poor responders to concurrent chemoradiotherapy (CCRT) and to gain mechanistic insights into treatment resistance in cervical cancer. RNA sequencing was performed in patients with locally advanced cervical cancer treated with platinum-based CCRT. Transcriptome data of no durable benefit (NDB; progression-free period 5 years) patients were compared. The NDB score was estimated for each patient using differentially expressed genes between NDB and DCB patients. The potential response to programmed death-1 blockade was estimated using the tumor immune dysfunction and exclusion (TIDE) score and T-cell-inflamed gene expression profile (GEP). NDB patients exhibited a distinct transcriptional profile compared to DCB patients, such as higher signatures of extracellular matrix organization and epithelial-to-mesenchymal transition. The fraction of cancer-associated fibroblasts (CAFs) within the tumor was significantly higher in NDB patients than in DCB patients. High NDB scores were significantly associated with poor survival in the Cancer Genome Atlas cervical cancer cohort (n=274; p=0.015) but only in patients who received curative aim radiotherapy (p=0.002). Patients with high NDB scores displayed significantly higher TIDE prediction scores and lower T-cell-inflamed GEP scores than those with low NDB scores. Patients with cervical cancer having poor CCRT or RT outcomes exhibited a distinct gene signature that could predict treatment outcomes. For poor responders, immune checkpoint inhibitors may be less effective whereas CAF-targeting treatments may be a promising approach.

Comparison of treatment outcomes of surgery and radiotherapy, including concurrent chemoradiotherapy for stage Ib2-IIb cervical adenocarcinoma patients: a retrospective study

The study compared the treatment outcomes of surgery versus radiotherapy, including concurrent chemoradiotherapy, in stage Ib2-IIb cervical adenocarcinoma patients in Japan. Of 57,470 patients diagnosed with stage I-IV cervical cancer from January 2001-December 2011, 1,932 patients with stage Ib2-IIb cervical adenocarcinoma were initially treated by surgery or radiotherapy. The primary endpoint was 5-year overall survival (OS) in all and 614 propensity score-matched (PSM) patients (307 per group). We compared OS and prognosis factors based on age, primary stage, and treatment arm. In Japan, >80% (n=1,573) of stage Ib2-IIb cervical adenocarcinoma patients underwent surgery. The 5-year OS of surgery vs. radiotherapy groups were 82.1% (n=704) vs. 79.7% (n=59) (hazard ratio [HR]=1.494; 95% confidence interval [CI]=0.826-2.702; p=0.181) for stage Ib2, 76.6% (n=239) vs. 66.7% (n=54) (HR=1.679; 95% CI=0.986-2.858; p=0.053) for stage IIa, and 71.1% (n=630) vs. 58.9% (n=246) (HR=1.711; 95% CI=1.341-2.184; p65 years), treatment arm (radiotherapy), and stage IIb significantly affect OS in cervical adenocarcinoma patients. Surgery may be considered for <65-year-old patients with stage IIb adenocarcinoma.

Accuracy of human papillomavirus tests on self-collected urine versus clinician-collected samples for the detection of cervical precancer: a systematic review and meta-analysis

The human papillomavirus (HPV) test is an effective screening tool to prevent cervical cancer. Urinary sampling for HPV detection improves the accessibility and participation of screening services and reduces the cost and burden on physicians. The clinical accuracy of urinary HPV test has yet to be determined via meta-analysis. This study assessed the clinical accuracy of these tests to detect cervical intraepithelial neoplasia (CIN) 2 or worse. Relevant studies were identified using the PubMed, Embase, and Cochrane databases. Research eligibility was based on the clinical accuracy of HPV test on clinician-collected samples as a comparator test, and urine as an index test. The reference standard was the presence of CIN2 or worse. The pooled absolute, relative sensitivity, and specificity of the urinary HPV test versus clinician-collected samples were assessed using a bivariate model. The pooled sensitivity of urinary HPV test was significantly lower than that of clinician-collected samples (ratio=0.84, 95% confidence interval [CI]=0.78-0.91). However, some polymerase chain reaction (PCR)-based HPV test such as GP5+/6+ (relative sensitivity=0.98, 95% CI=0.91-1.05), SPF10 (relative sensitivity=0.98, 85% CI=0.88-1.08) and non GP5+/6+ PCR (relative sensitivity=1.00, 95% CI=0.88-1.14) showed similar sensitivity in both the urine and clinician-collected samples. Our findings indicate that HPV test with some PCR-based assay on urine versus clinician-collected samples demonstrate similar clinical accuracy to detect CIN2 or worse. It suggests that urinary HPV test may present itself as a decent alternative screening tool for the detection of cervical pre-cancer. PROSPERO identifier: CRD42021227901.

The systemic immune-inflammation index (SII) is an independent prognostic parameter of survival in patients with invasive vulvar cancer

To assess the prognostic value of the systemic immune-inflammation index (SII) in patients with vulvar cancer. Data of 130 consecutive patients who underwent primary surgical resection for vulvar cancer at the Medical University of Vienna between 1999 and 2018 was retrospectively analyzed. The SII was defined as platelets × neutrophils/lymphocytes as previously described. Its prognostic value on disease-specific survival (DSS) and overall survival (OS) was evaluated by univariate log-rank tests and multivariable cox regression models. Prediction accuracy was assessed by receiver operating characteristics curves and Youden's J statistics. A Hosmer-Lemeshow test was performed to confirm the model's goodness of fit. A pre-therapeutic high serum SII (>866.4) was associated with advanced International Federation of Gynecology and Obstetrics (FIGO)-stage. In univariate survival analysis, a high SII was associated with both DSS (p<0.001) and OS (p=0.001). A multivariate cox regression model confirmed the prognostic value of SII regarding DSS (p<0.001) and OS (p=0.014) independently from patients' age and FIGO stage. Pretherapeutic SII may serve as a promising predictor for survival in patients with vulvar cancer. After clinical validation, the SII may be used to improve both pre-treatment patient risk stratification and patient counseling.

Patterns of definitive radiotherapy practice for cervical cancer in South Korea: a survey endorsed by the Korean Radiation Oncology Group (KROG 20-06)

The Korean Radiation Oncology Group conducted a nationwide questionnaire survey to evaluate the patterns of clinical practice for patients with cervical cancer receiving definitive radiation therapy (RT) in South Korea. Practicing radiation oncologists from 93 centers in South Korea were administered a questionnaire survey via e-mail. The survey focused on demographic characteristics, diagnostic evaluation, indications for definitive RT, RT techniques, RT field and dose prescription, lymph node (LN) boost RT, brachytherapy, and chemotherapy. The response rate was 62.4% (58/93 institutions). Of the 2,134 patients treated at the radiation oncology department in 2019, 48.8% underwent definitive RT. The selection of patients for definitive concurrent chemoradiation therapy and RT field, and RT dose prescription varied greatly. The upper border of the pelvis was commonly used as the bony landmark for external beam RT (81%-88% of respondents). Most (96.6%) centers performed LN boost RT with median total doses of 59 Gy and 59.2 Gy for pelvic and retroperitoneal LN, respectively. With 50% of the centers offering brachytherapy, image-guided brachytherapy and volume-based prescription were applied in 48.3% and 37.9%, respectively. Upfront concurrent chemoradiation therapy with varying prescription doses was considered by 60.4% respondents in cases of supraclavicular LN metastasis. Most differences were noted in the indications for treatment, RT field, and prescription dose. This finding can serve as a reference for establishing practical RT guidelines for the management of locally advanced cervical cancer.

The trend and outcome of postsurgical therapy for high-risk early-stage cervical cancer with lymph node metastasis in Japan: a report from the Japan Society of Gynecologic Oncology (JSGO) guidelines evaluation committee

The Japan Society of Gynecologic Oncology published the first guidelines for the treatment of cervical cancer in 2007. The aim of this research was to evaluate the influence of the introduction of the first guideline on clinical trends and outcomes of patients with early-stage cervical cancer who underwent surgery. This analysis included 9,756 patients who were diagnosed based on the pathological Tumor-Node-Metastasis (pTNM) classification (i.e., pT1b1, pT1b2, pT2b and pN0, pN1, pNX) and received surgery as a primary treatment between 2004 and 2009. Data of these patients were retrospectively reviewed, and clinicopathological trends were assessed. The influence of the introduction of the guideline on survival was determined by using a competing risk model. For surgery cases, the estimated subdistribution hazard ratio (HR) by the competing risk model for the influence of the guideline adjusted for age, year of registration, pT classification, pN classification, histological type, and treatment methods was 1.024 (p=0.864). Following the introduction of the first guideline in 2007, for patients with lymph node metastasis, the use of chemotherapy (CT) as a postsurgical therapy increased, whereas that of concurrent chemoradiotherapy (CCRT)/radiotherapy (RT) decreased (p<0.010). For pN1 cases, the estimated subdistribution HR by the competing risk model for the influence of the guideline was 1.094 (p=0.634). There was no significance in the postsurgical therapy between CT and CCRT/RT (p=0.078). Survival of surgical cases was not improved by the introduction of the guidelines. It is necessary to consider more effective postsurgical therapy for high-risk early-stage cervical cancer.

Hospital volume-outcome relationship in vulvar cancer treatment: a Japanese Gynecologic Oncology Group study

Human papillomavirus testing as a primary screening tool for cervical cancer

Vulvar melanoma: an analysis of prognostic factors and treatment patterns

Melanoma comprises 5% to 10% of vulvar cancers and prognosis is poor. The purpose of this study was to identify prognostic factors and treatment patterns for vulvar melanoma using the National Cancer Database (NCDB). The NCDB was queried for patients with invasive vulvar melanoma from 2004-2015. Descriptive statistics were generated to describe clinical and treatment details. Multivariable Cox regression and the Kaplan-Meier method were used to examine overall survival (OS). 1,917 patients with vulvar melanoma met inclusion criteria. Median follow-up time was 32 months (range, 0-151 months). Older age, larger tumor size, advanced disease stage, increased Charlson-Deyo comorbidity score, and care at a non-academic center were independent predictors for decreased OS. Surgical management of the primary site, lymph node surgery, and insurance provided a significant survival benefit. Use of immunotherapy for vulvar melanoma has increased over time. Two-year OS with immunotherapy in patients with distant metastatic disease was higher, although this did not reach statistical significance (33% vs. 12%, p=0.054). Vulvar melanoma has a poor prognosis for those with regional and distant metastatic disease. Extent of disease, tumor size, and patient age are important prognostic factors. Other favorable factors included insurance and surgical management. The use of immunotherapy has increased over time and may improve survival in those with distant disease. These data support further investigation into the role of immunotherapy for vulvar melanoma to optimize outcomes.

The prognostic significance of tumor-infiltrating lymphocytes in cervical cancer

To predict the prognosis of cervical cancer, we constructed a novel model with 5 specific cell types and identified a potential biomarker. We employed CIBERSORT and xCell method to evaluate the abundances of 23 cells types in tumor microenvironment. Five specific cell types were filtrated to determine different immunotypes by applying least absolute shrinkage and selection operator (LASSO) Cox regression method. The expression of immune checkpoints (ICPs) and effectors were validated by immunohistochemistry. Correlation analysis was performed to examine the relevance between PIK3CA mutational status and ICPs. Unsupervised clustering of patients on the basis of tumor infiltrating lymphocytes and fibroblasts identified patients with shorter overall survival (OS) (hazard ratio [HR]=3.0729; 95% confidence interval [CI]=1.5103-6.2522; p=0.0118). An immunoscore (IS) signature consisting of 5 immune cell types infiltrating in tumor core (CD8T, activated NK cells, neutrophils, activated mast cells, macrophages) was constructed using LASSO Cox regression analysis. Receiver operating characteristic curves confirmed that the area under the curve of IS was significantly higher to that of International Federation of Gynecology and Obstetrics staging alone (0.637 vs. 0.55). Survival analysis revealed patients in high IS group exhibited a poorer OS (HR=3.0113; 95% CI=1.8746-4.8373; p<0.0001). The multivariate analysis indicated the IS was an independent prognostic factor. In addition, the lower IS related to higher expression of ICPs and neoantigen load. The identification of IS in cervical cancer tissues could facilitate patient risk stratification and selection of immunotherapeutic responses, but more prospective studies are needed to assess its reliability.

Long-term outcomes of cervical cancer patients with complete metabolic response after definitive chemoradiotherapy

We investigated the importance of metabolic parameters measured with The clinical data and PET parameters including standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of 122 patients having CMR in post-treatment With a median follow-up of 8.4 years, 55 patients (45%) presented with disease a median of 19.7 months after ChRT. For SUVp, MTVp, TLGp, SUVln, MTVln, and TLGp, the cut-off values for OS determined by receiver operating curve analysis were 15.8, 48.7 cm³, 552.3, 8.7, 7.0 cm³, respectively. All metabolic PET parameters were significant prognostic factors for OS and PFS in univariate analysis. International Federation of Gynecology and Obstetrics (FIGO) stage was predictive of both OS and PFS, while pelvic and/or para-aortic lymph node metastasis were predictive of OS only. In multivariate analysis, FIGO stage ≥IIB, MTVp ≥49.8 cm³, and TLGp ≥597.4 were predictive of worse OS. Advanced stage, presence of lymph node metastasis, higher TLGp, and larger MTVln were significant factors for poor PFS rates. We found that advanced stage and higher TLGp values were significant predictors for poor survival and higher progression rates. Volumetric PET parameters could be used to predict treatment outcomes in patients with CMR after definitive ChRT.

Fertility-sparing surgery for women with stage I cervical cancer of 4 cm or larger: a systematic review

To investigate current evidence on oncological, fertility and obstetric outcomes of patients with stage I cervical cancer of 4 cm or larger undergoing fertility-sparing surgery (FSS). Systematic review of studies including women affected by stage I cervical cancer ≥4 cm who underwent FSS. Main outcome measures: disease-free survival (DFS), overall survival (OS), pregnancy rate, live birth rate, premature delivery rate. Fifteen studies met all eligibility criteria for this systematic review, involving 48 patients affected by cervical cancer ≥4 cm who completed FSS. Three patients (6.3%) experienced a recurrence and one of them (2.1%) died of disease. The 5-year DFS rate was 92.4%. The 5-year OS rate was 97.6%. A significantly shorter 5-year DFS was reported for high-risk patients (G3, non-squamous histotype, diameter ≥5 cm) compared with low-risk (74.7% vs. 100%; log-rank test, p=0.024). Data about fertility outcomes were available for 12 patients. Five patients out of 12 (41.7%) attempted to conceive with an estimated pregnancy rate of 80%, a live birth rate of 83.3% and a premature delivery rate of 20%. Women with high tumor grade, aggressive histology and tumor size ≥5 cm have a higher risk of recurrence. Oncologic outcomes are encouraging among low-risk patients; however, the lack of high-quality studies makes it difficult to draw any firm conclusions. Prospective multicentric clinical trials with a proper selection of inclusion/exclusion criteria should be conducted in women with low-risk factors, strong desire to preserve their fertility and high likelihood to conceive.

Brachytherapy utilization rate and effect on survival in cervical cancer patients in Korea

External beam radiation therapy (EBRT) with concurrent chemotherapy followed by intracavitary brachytherapy is the standard treatment in locally advanced cervical cancer. This study examined the brachytherapy utilization rate and evaluated the effect of brachytherapy on survival in cervical cancer patients in Korea. In this study, data from the Korea Central Cancer Registry and Korean National Health Insurance Service and data on mortality from Statistics Korea were linked and used. Patients with other cancers, distant metastasis at diagnosis, or unknown stage or who underwent hysterectomy were excluded. A total of 12,721 cervical cancer patients were analyzed in this study. The brachytherapy utilization rate (%) was calculated as the proportion of patients who received brachytherapy among those who received curative EBRT. The brachytherapy utilization rate decreased from 84% in 2005 to 78% in 2013 (p<0.001). Brachytherapy utilization rates varied by region, ranging from 72% to 100% except for in Jeju Island, where the rate was 56%. The brachytherapy utilization rate was lower in patients older than 80 years; patients with localized disease, non-squamous cell carcinoma, or Charlson comorbidity index 3 or more; patients diagnosed after 2010; patients from certain regions; patients receiving medical aid; and patients who underwent gynecologic procedures. Multivariable Cox regression analysis showed that brachytherapy when added to curative EBRT was independently associated with better cancer-specific survival (CSS) and overall survival (OS) than curative EBRT only. The brachytherapy utilization rate decreased from 2005 to 2013 and varied by region in Korea. Brachytherapy use is independently associated with significantly higher CSS and OS in cervical cancer.

The incidence of urologic complications requiring urologic procedure in radical hysterectomy and difference between abdominal radical hysterectomy and laparoscopic radical hysterectomy

To evaluate the incidence of urologic complications requiring a urologic procedure during the perioperative period and compare the differences between abdominal radical hysterectomy (ARH) and laparoscopic radical hysterectomy (LRH). We identified all Korean women who underwent radical hysterectomy (RH) between January 2006 and December 2019 using the National Health Insurance Service database. Complications requiring surgical intervention-based urologic procedures between ARH and LRH were investigated. A total of 12,068 patients were classified into the ARH group and 8,837 patients were classified into the LRH group. Urologic complications requiring urologic procedures occurred in 1,546 of 20,905 patients (7.40%) who underwent RH. The most common urologic procedure was double-J insertion (R326, 5.18%), followed by bladder repair (R3550, 0.90%). There was no significant difference in urologic complications requiring urologic procedures between the ARH and LRH groups (odds ratio [OR]=1.027; 95% confidence interval [CI]=0.925-1.141; p=0.612). The incidence of bladder repair (R3550) was significantly higher in patients who underwent LRH (OR=1.620; 95% CI=1.220-2.171; p<0.001). Urologic complications requiring urologic procedures were statistically higher in the LRH group during the first half (OR=1.446; 95% CI=1.240-1.685; p<0.001), but more in the ARH group during the second half (OR=0.696; 95% CI=0.602-0.804; p<0.001) of the study period. There was no difference of urologic complications between ARH and LRH with regard to urologic procedures. The incidence of urologic procedures decreases with time in patients who underwent LRH.

Preclinical investigation of patient-derived cervical cancer organoids for precision medicine

Advanced cervical cancer is still difficult to treat and in the case of recurrent cancer, it is desirable to utilize personalized treatment rather than uniform treatment because the type of recurrence is different for each individual. Therefore, this study aimed to establish a patient-derived organoid (PDO) platform to determine the effects of chemotherapy, radiation therapy, and targeted therapy in cervical cancer. We established organoids from 4 patients with various types of cervical cancer. The histopathological and gene profiles of these organoid models were compared to determine their characteristics and the maintenance of the patient phenotype. Each type of organoid was also subjected to anticancer drug screening and radiation therapy to evaluate its sensitivity. We established PDOs to recapitulate the main elements of the original patient tumors, including the DNA copy number and mutational profile. We selected 7 drugs that showed growth inhibition in cervical cancer organoids out of 171 using an Food and Drug Administration -approved drug library. Moreover, adenocarcinoma and large-cell neuroendocrine carcinoma showed resistance to radiation therapy. whereas squamous cell carcinoma and villoglandular carcinoma showed a significant response to radiotherapy. Our results showed that patient-derived cervical cancer organoids can be used as a platform for drug and radiation sensitivity testing. These findings suggest that patient-derived cervical cancer organoids could be used as a personalized medicine platform and may provide the best treatment options for patients with various subtypes of cervical cancer.

Risk factors for and delayed recognition of genitourinary fistula following radical hysterectomy for cervical cancer: a population-based analysis

This study aimed to identify the risk factors for genitourinary fistulas and delayed fistula recognition after radical hysterectomy for cervical cancer. This study was a retrospective analysis of data collected in the Major Surgical complications of Cervical Cancer in China (MSCCCC) database from 2004-2016. Data on sociodemographic characteristics, clinical characteristics, and hospital characteristics were extracted. Differences in the odds of genitourinary fistula development were investigated with multivariate logistic regression analyses, and differences in the time to recognition of genitourinary fistula were assessed by Kruskal-Wallis test. In this study, 23,404 patients met the inclusion criteria. Surgery in a cancer center, a women's and children's hospital, a facility in a first-tier city, or southwest region, stage IIA, type C1 hysterectomy, laparoscopic surgery and ureteral injury were associated with a higher risk of ureterovaginal fistula (UVF) (p<0.050). Surgery in southwest region, bladder injury and laparoscopic surgery were associated with greater odds of vesicovaginal fistula (VVF) (p<0.050). Surgery at cancer centers and high-volume hospitals was associated with an increase in the median time to UVF recognition (p=0.016; p=0.005). International Federation of Gynecology and Obstetrics (FIGO) stage IIA1-IIB was associated with delayed recognition of VVF (p=0.040). Intraoperative urinary tract injury and surgical approach were associated with differences in the development of UVFs and VVFs. Patients who underwent surgery in cancer centers and high-volume hospitals were more likely to experience delayed recognition of UVF. Patients with FIGO stage IIA1-IIB disease were more likely to experience delayed recognition of VVF.

Immunosensitivity and specificity of insulinoma-associated protein 1 (INSM1) for neuroendocrine neoplasms of the uterine cervix

Previously, we reported that insulinoma-associated protein 1 (INSM1) immunohistochemistry (IHC) showed high sensitivity for neuroendocrine carcinoma of the uterine cervix and was an effective method for histopathological diagnosis, but that its specificity remained to be verified. Therefore, the aim was to verify the specificity of INSM1 IHC for a large number of non-neuroendocrine neoplasia (NEN) of the cervix. RNA sequences were performed for cell lines of small cell carcinoma (TCYIK), squamous cell carcinoma (SiHa), and adenocarcinoma (HeLa). A total of 104 cases of formalin-fixed and paraffin-embedded specimens, 16 cases of cervical NEN and 88 cases of cervical non-NEN, were evaluated immunohistochemically for conventional neuroendocrine markers and INSM1. All processes without antigen retrieval were performed by an automated IHC system. The transcripts per million levels of INSM1 in RNA sequences were 1505 in TCYIK, 0 in SiHa, and HeLa. INSM1 immunoreactivity was shown only in the TCYIK. Immunohistochemical results showed that 15 cases of cervical NEN showed positive for INSM1; the positivity score of the tumor cell population and the stain strength for INSM1 were high. Two of the 88 cases of cervical non-NENs were positive for INSM1 in one case each of typical adenocarcinoma and squamous cell carcinoma. The sensitivity of INSM1 for cervical NEN was 94%; specificity, 98%; the positive predictive value, 88%; and the negative predictive value, 99%. INSM1 is an adjunctive diagnostic method with excellent specificity and sensitivity for diagnosing cervical NEN. Higher specificity can be obtained if morphological evaluation is also performed.

Transvaginal cervical tumor-concealing no-look no-touch technique in minimally invasive radical hysterectomy for early-stage cervical cancer: a novel operation technique

The Laparoscopic Approach to Cervical Cancer (LACC) trial demonstrated that minimally invasive radical hysterectomy was inferior to the open approach [1]; this unexpected result could be attributed to the spillage of cancer cells [2]. Following the LACC trial, laparoscopic radical hysterectomy without an intrauterine manipulator upon completion of a vaginal cuff closure became the new standard treatment method [3]. However, the lack of intrauterine manipulator results in poor visualization and inadequate paracervical tissue resection. This study describes the no-look no-touch technique to address this difficulty. The core procedures in our no-look, no-touch laparoscopic radical hysterectomy are: (Step 1) Creation and closure of a vaginal cuff; (Step 2) Manipulation of the uterus without an intra-uterine manipulator; and (Step 3) Exposure of the paracervical tissues by the suspension technique. The patient eligibility for our procedure is as follows: 1) previously untreated cervical cancer (those who underwent diagnostic conization could be included); 2) clinical stage IA2, IB1, IB2, and IIA1 based on the 2018 International Federation of Gynecology and Obstetrics staging system; 3) histologically confirmed cervical cancer, including squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma. The important indication for this procedure is in cases where the tumor is less than 4 cm in diameter. We previously reported that our no-look no-touch technique enables smooth performance of laparoscopic radical hysterectomy without worsening oncologic outcomes [4]. According to a recent systematic review and meta-analysis [5], minimally invasive radical hysterectomy with vaginal cuff closure is a safe treatment option; however, it involves a steep learning curve, which has impeded its increased application. This video will hopefully make minimally invasive radical hysterectomy with protective maneuvers against cancer cell spillage more accessible. Based on our experiences, we propose that our transvaginal cervical tumor-concealing no-look no-touch technique will mitigate the risk of surgical spill of tumor cells during minimally invasive radical hysterectomy. The informed consent for use of this video was taken from the patient.

Minimally invasive radical hysterectomy and the importance of avoiding cancer cell spillage for early-stage cervical cancer: a narrative review

Radical hysterectomy is a standard surgery to treat early-stage uterine cervical cancer. The Laparoscopic Approach to Cervical Cancer (LACC) trial has shown that patients receiving minimally invasive radical hysterectomy have a poorer prognosis than those receiving open radical hysterectomy; however, the reason for this remains unclear. The LACC trial had 2 concerns: the learning curve and the procedural effects. Appropriate management of the learning curve effect, including surgeons' skills, is required to correctly interpret the result of surgical randomized controlled trials. Whether the LACC trial managed the learning curve effect remains controversial, based on the surgeons' inclusion criteria and the distribution of institutions with recurrent cases. An appropriate surgical procedure is also needed, and avoiding intraoperative cancer cell spillage plays an important role during cancer surgery. Cancer cell spillage during minimally invasive surgery to treat cervical cancer is caused by several factors, including 1) exposure of tumor, 2) the use of a uterine manipulator, and 3) direct handling of the uterine cervix. Unfortunately, these issues were not addressed by the LACC trial. We evaluated the results of minimally invasive radical hysterectomy while avoiding cancer cell spillage for early-stage cervical cancer. Our findings show that avoiding cancer cell spillage during minimally invasive radical hysterectomy may ensure an equivalent oncologic outcome, comparable to that of open radical hysterectomy. Therefore, evaluating the importance of avoiding cancer cell spillage during minimally invasive surgery with a better control of the learning curve and procedural effects is needed.

Comparison of the safety between cervical conization and hysterectomy for patients with cervical adenocarcinoma in situ

To compare the safety between cervical conization (CC) alone and hysterectomy for patients with adenocarcinoma in situ (AIS) of the cervix. Patients diagnosed with AIS after CC during 2007-2021 were identified by computerized databases at Women's Hospital of Zhejiang University School of Medicine. A total of 453 AIS patients were divided into 2 groups according to uterus preservation: hysterectomy group (n=300) and CC(s) alone group (n=153). The prevalence of residual disease and disease recurrence was compared between patients treated by CC(s) alone and hysterectomy. The prevalence of residual disease in specimens from women who had a hysterectomy and repeat CC were compared between positive and negative margins of CC. The factors influencing residual disease and disease recurrence were assessed. Among 310 specimens from women who had a hysterectomy or repeat CC, the prevalence of residual disease was 50.6% (45/89) for a positive margin and 2.3% (5/221) for a negative margin (p=0.000). Four patients had recurrence of vaginal intraepithelial neoplasia in those treated by hysterectomy and one had recurrence of cervical squamous intraepithelial neoplasia in those treated by CC(s) alone. The prevalence of recurrence was 0.7% (1/153) for CC(s) alone and 1.3% (4/300) for hysterectomy (p=0.431). Hysterectomy did not influence residual disease or disease recurrence. CC is an efficacious and safe option for patients with AIS of the cervix provided the margin is negative.

Intraoperative frozen pathology exam of Common iliac lymph nodes and Para-Aortic lymphadenectomy on the prognosis and quality of life for patients with IB2-IIA2 Cervical Cancer: trial protocol for a randomized controlled trial (C-PACC trial)

The impact of para-aortic lymphadenectomy (PALD) on prognosis and quality of life (QoL) for IB2-IIA2 cervical cancer patients remain controversial. And whether intraoperative frozen pathology exam on common iliac lymph nodes could help predict para-aortic lymph node (PALN) metastasis was unanswered with high-level evidence. A multi-center, randomized controlled study is intended to investigate the effect of PALD on the prognosis and QoL in cervical cancer patients and to assess the value of intraoperative frozen pathological evaluation of common iliac nodes metastasis for the prediction of PALN metastasis. After choosing whether to receive intraoperative frozen pathological examination of bilateral common iliac lymph nodes, eligible patients will be randomly assigned (1:1) to receive PALD or not. The primary end point is 2-year progression-free survival (PFS). The secondary end points include 5-year PFS, 2-year overall survival (OS), 5-year OS, adverse events (AEs) caused by PALD, AEs caused by radiotherapy and QoL. A total of 728 patients will be enrolled from 8 hospitals in China within 3-year period and followed up for 5 years. Chinese Clinical Trial Register Identifier: ChiCTR2000035668.

Validation of HPV triage in cytology-based cervical cancer screening for ASC-US cases using Japanese data

In Japan, cervical cancer screening consists of a cytology examination performed once every 2 years. We verified whether the risk of cervical intraepithelial neoplasia (CIN) 3 disease or higher (CIN3+) was equivalent to that of cytology negative cases (negative for intraepithelial lesion or malignancy [NILM]) for patients with a cytological diagnosis of "atypical squamous cells of undetermined significance (ASC-US)" who tested negative for human papillomavirus (HPV). Data from a total of 22,925 cases who had undergone cervical cancer screening at least twice or who had completed follow-up examinations after cervical screening at a single facility between April 2013 and April 2018 were analyzed. The cumulative incidence of CIN3+ was calculated for each category of initial cytology finding and HPV result (NILM, > ASC-US, ASC-US/HPV (unknown), ASC-US/HPV The hazard ratio for the cumulative incidence of CIN3+ in 2 years relative to that for NILM cases was 2.7 (95% confidence interval=1.0-7.8) for > ASC-US cases, 0.5 (0.1-1.7) for ASC-US/HPV (unknown), 0.8 (0.3-2.4) for ASC-US/HPV Because the cumulative incidence of CIN3+ at 2 years for the ASC-US/HPV

Impact of adjuvant chemotherapy on the overall survival of patients with resectable bulky small cell neuroendocrine cervical cancer: a JSGO-JSOG joint study

The aim of this study was to review the clinicopathological characteristics of small cell neuroendocrine cervical cancer (SCNEC) and to identify the optimal treatment. The Japanese Society of Gynecologic Oncology conducted a retrospective cohort study of SCNECs enrolled in the Gynecological Tumor Registry of the Japan Society of Obstetrics and Gynecology between 2004 and 2015. All cases were modified and unified by International Federation of Gynecology and Obstetrics 2008 (Union for International Cancer Control 7th edition). There were 822 registered patients diagnosed with SCNEC from 2004 to 2015 which comprised 1.1% (822/73,698) of all uterine cervical cancer cases. Rates of lymph-node and distant metastasis were significantly higher in T1b2 (38.9% and 13.7%, respectively) than T1b1 (14.2% and 4.4%, respectively) (p4 cm in size had greater rates of lymph-node and distant metastasis when compared with tumors ≤4 cm. Adjuvant chemotherapy, rather than radiotherapy, may improve prognosis after surgery in T1bN1M0 SCNEC.

Prognostic factors of dose-response relationship for nodal control in metastatic lymph nodes of cervical cancer patients undergoing definitive radiotherapy with concurrent chemotherapy

Regional control is occasionally unsatisfactory in cervical cancer, with the optimal radiation dose for nodal metastases in definitive radiotherapy (RT) with concurrent chemotherapy (CRT) remaining controversial. We investigated dose-response relationship for nodal local control in cervical cancer. We identified 115 patients with 417 metastatic nodes who received definitive CRT for cervical cancer with nodal metastases. External beam radiation therapy and brachytherapy plans were summated to determine total dose received by each node. Prognostic factors of nodal control and dose-response relationship were investigated using Cox-regression and restricted cubic spline function. The 2-year progression-free survival rate was 69.4%. Among 43 patients with failures, 17 patients (37.5%) had regional failure included in first failure sites of which all except one were in-field only regional failures. Total 30 nodes showed recurrence at initial metastatic site after treatment. Neutrophil-to-lymphocyte ratio (NLR) ≥3.1, total radiation dose (minimum dose received by 98% of the target volume in equivalent dose in 2 Gy per fractions), and initial nodal volume ≥5.29 mL were poor prognostic factors (all p<0.050) of nodal local control. Restricted cubic spline functions revealed strongest dose-response relationship in high NLR (NLR ≥3.1) and initial nodal volume ≥5.29 mL subgroup. Initial nodal volume, radiation dose

Development of a prognostic prediction support system for cervical intraepithelial neoplasia using artificial intelligence-based diagnosis

Human papillomavirus subtypes are predictive indicators of cervical intraepithelial neoplasia (CIN) progression. While colposcopy is also an essential part of cervical cancer prevention, its accuracy and reproducibility are limited because of subjective evaluation. This study aimed to develop an artificial intelligence (AI) algorithm that can accurately detect the optimal lesion associated with prognosis using colposcopic images of CIN2 patients by utilizing objective AI diagnosis. We identified colposcopic findings associated with the prognosis of patients with CIN2. We developed a convolutional neural network that can automatically detect the rate of high-grade lesions in the uterovaginal area in 12 segments. We finally evaluated the detection accuracy of our AI algorithm compared with the scores by multiple gynecologic oncologists. High-grade lesion occupancy in the uterovaginal area detected by senior colposcopists was significantly correlated with the prognosis of patients with CIN2. The detection rate for high-grade lesions in 12 segments of the uterovaginal area by the AI system was 62.1% for recall, and the overall correct response rate was 89.7%. Moreover, the percentage of high-grade lesions detected by the AI system was significantly correlated with the rate detected by multiple gynecologic senior oncologists (r=0.61). Our novel AI algorithm can accurately determine high-grade lesions associated with prognosis on colposcopic images, and these results provide an insight into the additional utility of colposcopy for the management of patients with CIN2.

Incidence and risk factors for the development of cerebral metastasis in cervical cancer patients

Cerebral metastasis (CM) in cervical cancer (CC) cases, although rare, results in high lethality rates. The present study aimed to assess CM incidence in a Brazilian reference CC center and evaluate the risk factors for CM development. Retrospective observational study of patients diagnosed with CC between 2010 and 2017. Cumulative CM incidence and incidence density were evaluated. Characteristics associated to CM development risks were identified using crude (cOR) or adjusted (aOR) odds ratios. A total of 3,397 patients were included in this study. Patient age ranged from 18 to 101 years, with a mean age of 48.8±14.0. After a mean follow-up time of 3.2±2.1 years, 51 CM cases were identified, resulting in a cumulative incidence of 1.5% (95% confidence intervals [CI]=1.12-1.97) and an incidence density at the end of the 6th year of 27.4 per 1,000 women/year. Advanced clinical stage (aOR=3.15; 95% CI=1.16-8.58; p=0.025), the presence of previous lung metastasis (aOR=4.04; 95% CI=1.82-8.94; p=0.001) and the adenocarcinoma (aOR=2.90; 95% CI=1.46-5.76; p=0.002), adenosquamous carcinoma (aOR=7.33; 95% CI=2.87-18.73; p<0.001), undifferentiated carcinoma (aOR=14.37; 95% CI=3.77-54.76; p<0.001) and neuroendocrine carcinoma (aOR=21.31; 95% CI=6.65-68.37, p<0.001) histological types were associated with a higher risk for CM development. CM risk was higher in the first years of follow-up, with no cases observed after the 6th year. CC patients in advanced clinical stages, displaying previous lung metastasis and non-squamous histological types are at high risk of developing CM.

Efficacy and safety of cisplatin combined with paclitaxel concurrent radiotherapy in patients with locally advanced cervical squamous cell carcinoma

This study aimed to compare outcomes and adverse events of patients with locally advanced cervical cancer (LACC) undergoing concurrent chemoradiotherapy (CCRT) with cisplatin single-agent chemotherapy vs. CCRT with cisplatin combined with paclitaxel dual-agent therapy. The primary outcomes are overall survival (OS), progression-free survival (PFS), local recurrence (LR), distant metastasis (DM) and the occurrence of adverse events. This retrospective cohort study included patients with FIGO 2009 stage IB1-IVA cervical squamous cell carcinoma undergoing radical CCRT. Patients were divided into groups A and B, treatment outcomes were compared between the two groups after 1:1 proportional propensity score matching. Medical records of 1,203 patients were reviewed and 572 patients were finally included for propensity score matching. After propensity score matching, 121 pairs of patients were selected for analysis. The OS, PFS, LR and DM rates were 78.5% and 83.5% (p=0.417), 73.3% and 78.5% (p=0.312), 6.6% and 2.5% (p=0.123), 19% and 15.7% (p=0.497) for groups A and B, respectively. Further subgroup analysis according to stage and lymph node metastatic status showed no difference in survival between the two groups. The incidence of grade 3-4 acute haematological toxicities was different between the two groups (p<0.05). Cisplatin combined with paclitaxel CCRT couldn't improve the survival rates of patients with LACC. However, the hematological toxicity of combination chemotherapy is more severe but controllable. Cisplatin single-agent therapy remains the first choice for CCRT. Further prospective studies are indicated to provide evidence for the efficacy of cisplatin plus paclitaxel in dual-agent concurrent therapy.

Significance of histology and nodal status on the survival of women with early-stage cervical cancer: validation of the 2018 FIGO cervical cancer staging system

To assess the efficacy of the FIGO 2018 classification system for nodal-specific classifications for early-stage cervical cancer; specifically, to examine the impact of nodal metastasis on survival and the effect of postoperative treatments, according to histological subtypes. This society-based retrospective observational study in Japan examined 16,539 women with the 2009 FIGO stage IB1 cervical cancer who underwent primary surgical treatment from 2004 to 2015. Associations of cause-specific survival (CSS) with nodal metastasis and postoperative adjuvant therapy were examined according to histology type (squamous cell carcinoma [SCC], n=10,315; and non-SCC, n=6,224). The nodal metastasis rate for SCC was higher than that for non-SCC (10.7% vs. 8.3%, p<0.001). In multivariable analysis, the impact of nodal metastasis on CSS was greater for non-SCC tumors (adjusted-hazard ratio [HR], 3.11; 95% confidence interval [CI], 2.40-4.02) than for SCC tumors (adjusted-HR, 2.20; 95% CI, 1.70-2.84; p<0.001). Propensity score matching analysis showed significantly lower CSS rates for women with pelvic nodal metastasis from non-SCC tumors than from SCC tumors (5-year CSS rate, 75.4% vs. 90.3%, p<0.001). The CSS rates for women with nodal metastasis in SCC histology were similar between the postoperative concurrent chemoradiotherapy/radiotherapy and chemotherapy groups (89.2% vs. 86.1%, p=0.42), whereas those in non-SCC histology who received postoperative chemotherapy improved the CSS (74.1% vs. 67.7%, p=0.043). The node-specific staging system in the 2018 FIGO cervical cancer classification is applicable to both non-SCC tumors and SCC tumors; however, the prognostic significance of nodal metastases and efficacy of postoperative therapies vary according to histology.

Trends in cervical cancer screening rates among Korean women: results of the Korean National Cancer Screening Survey, 2005–2020

This study aimed to analyze the trends in cervical cancer screening rates, including organized and opportunistic cancer screening rates, with the Papanicolaou test among Korean women. Data were collected from a nationwide, cross-sectional, Korean National Cancer Screening Survey. To evaluate the cervical cancer screening rates, we used the screening approach of " The cervical cancer screening rate was 56.0% in 2020. From 2005 to 2013, there was a rising trend in cervical cancer screening rates (APC=2.70%, 95% confidence interval [CI]:1.05 to 4.38), followed by a falling trend (APC=-2.67%, 95% CI:-4.3 to -1.01). The falling trend was significantly associated with age (≥40 years), education level (below the 15th grade), household income (below the middle-income level), and residence (all residential areas). The recent falling trend was more common in women with a low socioeconomic status, which suggests that there is a socioeconomic gap in cervical cancer screening. Moreover, young women in their thirties had a low screening rate. Therefore, an active participation strategy for women vulnerable to cervical cancer is required.

Oncologic outcomes according to the level of disease burden in patients with metachronous distant metastases from uterine cervical cancer: a Korean Radiation Oncology Group study (KROG 18-10)

This study aimed to evaluate the oncologic outcomes according to disease burden in uterine cervical cancer patients with metachronous distant metastases. Between 2005 and 2015, 163 patients with metachronous distant metastases from uterine cervical cancer after receiving a definitive therapy were evaluated at seven institutions in Korea. Low metastatic burden was defined as less than 5 metastatic sites, whereas high metastatic burden was others. Each metastasis site was divided based on the lymph node (LN) and organs affected. The overall survival (OS) and progression-free survival (PFS) were assessed. Cox proportional hazards models, including other clinical variables, were used to evaluate the survival outcomes. The median follow-up duration was 22.2 months (range: 0.3-174.8 months). Para-aortic LNs (56.4%), lungs (26.4%), supraclavicular LNs (18.4%), and peritoneum (13.5%) were found to be the common metastasis sites. Among 37 patients with a single metastasis, 17 (45.9%) had LN metastases and 20 (54.1%) had organ metastases. The 1- and 2-year OS rates were 73.9% and 55.0%, respectively, whereas the PFS rates were 67.2% and 42.9%, respectively. SCC Ag after recurrence and high metastatic burden were significant factors affecting the OS (p=0.004 and p<0.001, respectively). Distant organ recurrence, short disease-free interval (≤2 years), and high metastatic burden were unfavorable factors for PFS (p=0.003, p=0.011, and p=0.002, respectively). A favorable oncologic outcome can be expected by performing salvage treatments in selected patients with a long disease-free interval, low metastatic burden, and/or lymphatic-only metastasis.

The course forward: next generation sequencing as part of the next generation management of patients with locally advanced cervical cancer

Treatment patterns and survival outcomes according to histologic subtype in malignant ovarian germ cell tumors: a nationwide real-world cohort study

Homologous recombination deficiency in high-grade serous ovarian carcinoma: clinical pathological characteristics, impact of neoadjuvant chemotherapy, and prognostic implications

Long-term chemotherapy-induced peripheral neuropathy evaluated using patient-reported outcomes in gynecologic malignancies

Clinical and prognostic insights into Trousseau’s syndrome in gynecologic malignancies: a multicenter study

Gram-positive targeting antibiotics are associated with progression and death in women with platinum-sensitive recurrent high grade epithelial ovarian cancer

Radiotherapy patterns of care for recurrent ovarian cancer by gynecologic and radiation oncologists: a Korean Gynecologic Oncology Group study (KGOG-3064S1)