Nobuhisa Yoshikawa

Mesothelial cells promote peritoneal invasion and metastasis of ascites-derived ovarian cancer cells through spheroid formation

Patients with epithelial ovarian cancer (EOC) are often diagnosed with peritoneal metastasis and ascites, the accumulation of intraperitoneal fluid containing nonmalignant cells. However, the interactions between EOC and nonmalignant cells before peritoneal metastasis remain unclear. To investigate this, whole EOC spheroids were observed using a multiphoton microscope, and their invasion ability was assessed. Mesothelial cells were identified as notable components of ascites through morphological assessment, immunohistochemical/immunofluorescence staining, and single-cell RNA sequencing analyses. Almost all EOC cells were spheroids, with 60% containing mesothelial cells. EOC cells quickly generate aggregated spheroids with mesothelial cells, and these aggregated cancer-mesothelial spheroids (ACMSs) invade collagen or mesothelial layers. Mesothelial cells forming ACMSs initiated the invasion. RNA sequencing analysis revealed marked RNA expression changes in mesothelial cells, whereas the changes in EOC cells were minor. Transforming growth factor–β1–stimulated mesothelial cells showed increased invadopodium formation along with fascin-1 up-regulation. These findings suggest that EOC cells alter mesothelial cells through ACMSs, thereby elucidating the rapid spread of EOC in the abdominal cavity.

Genomic insights and therapeutic efficacy of PARP inhibitors in a high-LOH patient-derived xenograft from malignant transformation of ovarian teratoma

The malignant transformation of ovarian mature cystic teratoma (MTMCT) is a rare and aggressive condition often diagnosed at advanced stages with limited treatment options. Leveraging cancer genomic profiling (CGP), this study evaluated the efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors in a patient-derived xenograft (PDX) model of MTMCT with high loss of heterozygosity (LOH). Tumor samples from a patient with MTMCT were used to establish the PDX model. CGP revealed high LOH and actionable mutations, including STK11 (E256*) and EMSY amplification, suggesting potential sensitivity to PARP inhibitors. Mice treated with PARP inhibitors exhibited significantly reduced tumor volumes compared to controls. Whole-exome sequencing (WES) performed on control and post-treatment residual tumors demonstrated that while total LOH levels remained stable, copy-neutral LOH (CN-LOH) increased significantly, indicating treatment-induced genomic instability. Notably, STK11 (E256*) underwent CN-LOH in residual tumors, suggesting a role in acquired resistance. Furthermore, EMSY amplification, initially observed in the tumor and associated with PARP inhibitor sensitivity, was absent after treatment, reflecting clonal selection or adaptive resistance. These findings underscore the therapeutic potential of PARP inhibitors in high-LOH MTMCT while highlighting the emergence of resistance mechanisms, including CN-LOH and loss of EMSY amplification. They emphasize the importance of considering tumor evolution and treatment timing when interpreting CGP results, providing a foundation for further research into predictive biomarkers and resistance mechanisms in rare gynecologic malignancies.

Development and Validation of Predictive Risk Scores for Ovarian Clear Cell Carcinoma: A Penalized Regression Model

ABSTRACT Background The precision management of ovarian clear cell carcinoma (OCCC) faces limitations due to the absence of personalized prognostic tools. This study aimed to establish predictive risk scores to enable effective stratification and tailored treatment of OCCC. Methods Retrospective data from 206 OCCC patients treated between 2004 and 2019 at two hospitals were analyzed. Penalized regression models were utilized to develop three risk scores based on preoperative laboratory results and intraoperative findings. These scores underwent internal and external validation. Results The median follow‐up periods were 65.7 and 44.0 months for the derivation and validation cohorts, respectively. In internal validation with the derivation cohort, all three risk scores effectively identified the high‐risk group for tumor recurrence. Upon validation with the external cohort, Risk Score 3, which incorporated variables selected in most cross‐validations by the penalized regression (Elastic Net), distinctly differentiated the high‐ and low‐risk groups ( p  = 0.03). Risk Score 2, consisting solely of preoperatively available variables, also demonstrated marginal significance ( p  = 0.08). Conclusion Our findings underscore the significance and utility of the developed risk scores in tailoring personalized treatments for patients with OCCC.

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.

Long-term prognostic significance of ascites cytology in ovarian cancer cases in which R0 resection was achieved in the initial surgery: a multi-institutional retrospective cohort study

Abstract Background In ovarian cancer (OvCa), achieving complete resection (RO) in initial surgery is crucial for improving prognosis. However, patients with undetected microscopic metastasis post-RO surgery often have poorer outcomes. This study explores prognostic factors for OvCa patients who underwent RO surgery, focusing on the role of ascites cytology as an indicator of microscopic peritoneal metastasis. Methods We analyzed data from 975 OvCa cases in the Tokai Ovarian Tumor Study Group database (1986–2019). Excluding patients without chemotherapy or with distant metastasis, we examined prognostic factors using Cox regression analysis. Propensity score (PS) methods balanced the cytology-positive and -negative groups, with subgroup analysis for clinical stage and ascites volume. Results Multivariate analysis identified FIGO stage III and positive ascites cytology as poor prognostic factors for overall and progression-free survival. After PS adjustment, positive ascites cytology also shortened progression-free intervals post-recurrence, especially in cases with peritoneal or lymph node metastasis. Subgroup analysis revealed a more substantial prognostic impact of positive ascites cytology in early-stage cases. Conclusion The present results suggest that in OvCa patients with the R0 status, the presence of tumor cells in ascites is an independent negative prognostic factor and may be an indicator of peritoneal micro-metastasis.

Histology-specific long-term oncologic outcomes in patients with epithelial ovarian cancer who underwent complete tumor resection: The implication of occult seeds after initial surgery

Objective Assessing the histology-specific prognosis of epithelial ovarian cancer (OvCa) is clinically challenging, especially in a patient population with a favorable prognosis. This study investigated the histology-specific long-term oncologic outcomes in OvCa patients who underwent complete tumor resection using a large-scale patient cohort form multiple institutions under a central pathological review system. Methods A regional multi-institutional study was conducted from 1986 to 2019. Of the 4,898 patients with ovarian tumors enrolled, 1,175 patients who underwent complete tumor resection were classified into three classes based on clinically important prognostic factors: stage, cytology, ascites volume. For each class category, the effect of histology types on recurrence-free survival, the site of recurrence, and post-recurrence survival was evaluated. Results Recurrence-free survival varied significantly across different histologies (P &lt; 0.001). The risk of recurrence was higher in serous carcinoma compare to other histologies (P &lt; 0.001). The site of tumor recurrence varied by the histology type. Multinominal logistic regression analysis revealed that mucinous histology had a significantly higher likelihood of developing recurrent tumors at distant sites from the peritoneum compared to other histologies (P = 0.002). Conversely, serous histology was associated with better post-recurrence survival (Log-rank P &lt; 0.001). Conclusions Long-term oncologic outcomes significantly differ by histology type in OvCa patients who have undergone complete tumor resection at the initial surgery. A careful evaluation of the clinical background is necessary for these patients, and further clinical research into individualized treatment approaches is essential.

Update on the oncologic and obstetric outcomes of medroxyprogesterone acetate treatment for atypical endometrial hyperplasia and endometrial cancer

Abstract Aims To evaluate the safety and effectiveness of high‐dose oral medroxyprogesterone acetate (MPA) therapy as a fertility‐sparing treatment for patients diagnosed with atypical endometrial hyperplasia (AEH) and endometrioid carcinoma G1 without myometrial invasion (G1EC). Particular attention was given to the extended administration and readministration of MPA for patients with persistent disease following initial treatment and those with recurrence. Methods We conducted a retrospective analysis of data from 79 patients who underwent daily oral MPA treatment between 2005 and 2024 at Nagoya University Hospital. Patient characteristics, treatment outcomes, factors contributing to recurrence, and post‐MPA therapy pregnancies were examined. Results MPA therapy achieved a remarkable complete response (CR) rate of 91.1%. The median time to achieve CR was 26.0 and 40.0 weeks for AEH and G1EC patients, respectively. Importantly, 27 patients (39.7%) attained CR after more than 6 months of treatment, including 8 patients (11.8%) who achieved CR after more than a year of treatment. The recurrence rates were 52.9% for AEH and 64.7% for G1EC. Twenty eight patients resumed MPA treatment, and 23 achieved second CR. Notably, recurrence was not associated with clinical factors such as age, body mass index, or post‐CR pregnancy. Among patients who attempted pregnancy after achieving CR, 22 live births were successfully achieved. Conclusions High‐dose oral MPA therapy demonstrated both safety and efficacy for preserving fertility in patients with AEH and G1EC, resulting in a high CR rate. MPA extension and readministration proved to be beneficial strategies for managing patients with recurrence and persistent disease following initial treatment.

Spatial distribution of tumor‐resident macrophages as predictive biomarkers in endometrial cancer

Abstract Background To investigate the role of CD47 expression and its relationship with tumor‐resident macrophages, specifically at the tumor margin, in patients with type II endometrial cancer. This study aims to elucidate whether CD47 could serve as a prognostic marker and to understand the dynamics between CD47 and macrophages, which could inform new therapeutic strategies. Methods A retrospective cohort study was conducted involving 75 patients of type II endometrial. Immunohistochemical analysis was performed to assess CD47 expression and macrophage markers (CD68 and CD163). Results The study found no direct correlation between CD47 expression levels and overall survival ( p  = 0.32), challenging its role as an independent prognostic marker in type II endometrial cancer. The higher expression of CD47 had significantly less incidence of endometrioid carcinoma G3 ( p  = 0.047). The negative correlation between CD47 H‐score and the density of CD68‐positive macrophages at tumor margin was statistically significant ( p  = 0.049). A high density of CD68‐positive macrophages at the tumor margin but a low density of CD163‐positive macrophages at the tumor margin were associated with poorer prognosis ( p  = 0.036). Conclusions The complex interaction between CD47 and macrophages, particularly at the tumor margin, suggests new avenues for targeted therapy in type II endometrial cancer.

Real‐world data of poly (ADP‐ribose) polymerase inhibitor response in Japanese patients with ovarian cancer

AbstractBackgroundPoly (ADP‐ribose) polymerase (PARP) inhibitors have been increasingly used in the treatment of ovarian cancer, with BRCA positivity and homologous recombination deficiency (HRD) being common biomarkers used for predicting their efficacy. However, given the limitations of these biomarkers, new ones need to be explored.MethodsThis retrospective study included 181 ovarian cancer patients who received olaparib or niraparib at two independent hospitals in Japan between May 2018 and December 2022. Clinical information and blood sampling data were collected. Patient characteristics, treatment history, and predictability of treatment duration based on blood data before treatment initiation were examined.ResultsHigh‐grade serous carcinoma, BRCA positivity, HRD, and maintenance therapy after recurrence treatment were observed more frequently in the olaparib group than in the niraparib group. The most common reasons for treatment interruption were anemia, fatigue, and nausea in the olaparib group and thrombocytopenia in the niraparib group. Regarding response to olaparib treatment, complete response to the most recent treatment, maintenance therapy after the first chemotherapy, high‐grade serous carcinoma, and germline BRCA positivity were observed significantly more frequently among responders than among non‐responders. Furthermore, neutrophil counts were significantly higher among responders than among non‐responders.ConclusionsInflammation‐related blood data, such as neutrophil count, obtained at the initial pre‐treatment visit might serve as potential predictors for prolonged olaparib treatment. While this study offers valuable insights into potential indicators for prolonged olaparib treatment, it underscores the need for more expansive research to strengthen our understanding of PARP inhibitors and optimize treatment strategies in ovarian cancer.

The sarcopenia index measured using the lumbar paraspinal muscle is associated with prognosis in endometrial cancer

Abstract Objective The number of type-II endometrial cancer patients has been increasing and the prognosis is not favorable. We aim to investigate whether sarcopenia index in any of several different muscles could serve as a novel biomarker of prognosis in patients with type-II endometrial cancer. Methods We retrospectively investigated a total of 194 patients at four hospitals. Ninety patients were treated as derivation set and the other 104 patients as validation set. Using preoperative computed tomography images, we measured the horizontal cross-sectional area at the third lumbar spine level: the (i) psoas major, (ii) iliac and (iii) paraspinal muscle. The clinical information including recurrence-free survival and overall survival were retrospectively collected. These results were validated with external data sets of three hospitals. Results The median values of the sarcopenia index (cm2/m2) ± standard deviation with the first data of 90 patients using the psoas, iliac and paraspinal muscle were 3.4 ± 1.0, 1.7 ± 0.6 and 12.6 ± 3.2, respectively. In univariate analyses, the sarcopenia indexes measured using the psoas or paraspinal muscle were associated with recurrence-free survival and overall survival. On the other hand, in multivariate analyses, only the sarcopenia index using paraspinal muscle was significantly related to recurrence-free survival (hazard ratio = 3.78, 95% confidence intervals = 1.29–5.97, P = 0.009) and overall survival (hazard ratio = 3.13, 95% confidence interval = 1.18–8.26, P = 0.022). Paraspinal sarcopenia index was also related to overall survival (hazard ratio = 3.74, 95% confidence interval = 1.31–10.72, P = 0.014) even in patients with advanced stage. Serum albumin was significantly correlated with the sarcopenia index (P = 0.012). Within the analysis of the validation set, sarcopenia index using paraspinal muscle was related to recurrence-free survival (hazard ratio = 2.06, P = 0.045) in multivariate analysis and recurrence-free survival (P = 0.009) in patients with advanced stage. Conclusions The sarcopenia index using the paraspinal muscle, not psoas, could be a suitable index to predict recurrence-free survival and overall survival in patients with type-II endometrial cancer even in advanced stage.

Plasma-activated medium promotes autophagic cell death along with alteration of the mTOR pathway

AbstractThe biological function of non-thermal atmospheric pressure plasma has been widely accepted in several types of cancer. We previously developed plasma-activated medium (PAM) for clinical use, and demonstrated that PAM exhibits a metastasis-inhibitory effect on ovarian cancer through reduced MMP-9 secretion. However, the anti-tumor effects of PAM on endometrial cancer remain unknown. In this study, we investigated the inhibitory effect of PAM on endometrial cancer cell viability in vitro. Our results demonstrated that AMEC and HEC50 cell viabilities were reduced by PAM at a certain PAM ratio, and PAM treatment effectively increased autophagic cell death in a concentration dependent manner. In addition, we evaluated the molecular mechanism of PAM activity and found that the mTOR pathway was inactivated by PAM. Moreover, our results demonstrated that the autophagy inhibitor MHY1485 partially inhibited the autophagic cell death induced by PAM treatment. These findings indicate that PAM decreases the viability of endometrial cancer cells along with alteration of the mTOR pathway, which is critical for cancer cell viability. Collectively, our data suggest that PAM inhibits cell viability while inducing autophagic cell death in endometrial cancer cells, representing a potential novel treatment for endometrial cancer.

Downregulation of Chromosome 19 miRNA Cluster and the Tumor‐Suppressive Role of miR ‐517a‐3p in Choriocarcinoma

ABSTRACT Choriocarcinoma is a rare gynecologic malignancy. MicroRNAs, which are noncoding RNAs approximately 22 nucleotides in length, are known to regulate gene expression and play important roles in various cancers; however, their functions in choriocarcinoma remain largely unknown. This study aimed to identify disease‐specific microRNAs involved in choriocarcinoma development. Eleven cases of choriocarcinoma and five cases of complete hydatidiform mole treated at our institution were analyzed. Total RNA was extracted from trophoblast cells in formalin‐fixed, paraffin‐embedded specimens using laser capture microdissection, and microRNA sequencing was performed. The analysis revealed that 87 microRNAs were significantly upregulated, whereas 28 were downregulated in choriocarcinoma compared to complete hydatidiform mole. Notably, 13 of the 28 downregulated microRNAs belonged to the chromosome 19 microRNA cluster. In vitro experiments demonstrated that overexpression of miR‐517a‐3p, a representative member of this cluster, significantly suppressed cell proliferation, migration, and invasion in JEG‐3 and BeWo cell lines. Further transcriptome sequencing and computational analysis identified SRSF1 as a target gene of miR‐517a‐3p, which was validated by dual‐luciferase reporter assays. Knockdown of SRSF1 also led to significant reductions in proliferation, migration, and invasion, supporting its functional relevance. Immunohistochemical analysis confirmed that SRSF1 protein was highly expressed in choriocarcinoma tissues compared to complete hydatidiform mole. These findings indicate that downregulation of the chromosome 19 microRNA cluster is a characteristic feature of choriocarcinoma and that miR‐517a‐3p functions as a tumor suppressor by directly regulating SRSF1 expression.

Tumor growth direction predicts surgical difficulty in large uterine fibroids: A retrospective imaging‐based study

Abstract Objective To identify preoperative imaging features associated with retroperitoneal growth of large uterine fibroids and evaluate their impact on surgical outcomes. Methods This retrospective study included 20 patients who underwent hysterectomy for uterine fibroids measuring ≥10 cm between 2014 and 2024. Preoperative CT or MRI was evaluated for four features: bladder displacement, sigmoid colon deviation, cecal displacement, and hydronephrosis. Tumor growth direction (intraperitoneal vs. retroperitoneal) was determined intraoperatively. Operative time, blood loss, and complications were compared between groups. Results Eight tumors exhibited retroperitoneal growth. Bladder displacement, cecal shift, sigmoid colon deviation, and hydronephrosis were significantly more common in retroperitoneal cases (all p  &lt; 0.05). Retroperitoneal tumors were associated with significantly greater median blood loss (1591 mL vs. 651 mL, p  = 0.043), although operative time did not differ significantly (301 vs. 232 min, p  = 0.237). Organ injury or resection occurred only in the retroperitoneal group. A bubble plot illustrated the trend of increased surgical burden in retroperitoneal cases. Conclusion Retroperitoneal growth of large uterine fibroids is associated with increased intraoperative blood loss and surgical complexity. Four simple imaging features may serve as reliable indicators of growth direction and help guide preoperative planning.

Utility of manual vacuum aspiration followed by curettage in the treating hydatidiform mole: A retrospective analysis

AbstractAimWhile manual vacuum aspiration (MVA) is commonly employed for early first‐trimester abortions, its effectiveness in treating hydatidiform mole is still unclear. This study sought to evaluate the efficacy and safety of MVA in comparison to dilation and curettage (D&amp;C) for managing hydatidiform mole.MethodsWe conducted a retrospective review of medical records for 198 patients with hydatidiform mole treated at Nagoya University Hospital between 2004 and 2023. After excluding cases with incomplete data, we compared 106 patients who underwent D&amp;C with 60 patients treated with MVA followed by curettage. We evaluated the surgical duration, intraoperative blood loss, and the occurrence of post‐molar gestational trophoblastic neoplasia (GTN) in both groups.ResultsThe surgical duration and blood loss were similar between the MVA and D&amp;C groups. The average surgical time was 13.2 min for D&amp;C and 11.8 min for MVA (p = 0.145). Most cases in both groups experienced blood loss of less than 10 mL, with no significant difference (p = 0.066). Over a median follow‐up period of 33.4 months, 25 cases developed post‐molar GTN. All GTN cases originated from complete hydatidiform mole (25 of 132 cases, 18.9%), and none were from partial hydatidiform mole. Kaplan–Meier analysis, focusing only on patients with complete hydatidiform mole, indicated no significant difference in the time to onset of GTN between the D&amp;C and MVA groups (p = 0.632).ConclusionsMVA followed by curettage is a viable approach for treating molar pregnancy.

Expression of the chrXq27.3 miRNA cluster in recurrent ovarian clear cell carcinoma and its impact on cisplatin resistance

AbstractOvarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian cancer and exhibits dismal prognosis due to chemoresistance. Moreover, only few effective therapeutic options exist for patients with recurrent OCCC, and an understanding of its molecular characteristics is essential for the development of novel therapeutic approaches. In the present study, we investigated unique MicroRNAs (miRNA) profiles in recurrent/metastatic OCCC and the role of miRNAs in cisplatin resistance. Comprehensive miRNA sequencing revealed that expression of several miRNAs, including miR-508-3p, miR-509-3p, miR-509-3-5p, and miR-514a-3p was remarkably less in recurrent cancer tissues when compared with that in paired primary cancer tissues. These miRNAs are located in the chrXq27.3 region on the genome. Moreover, its expression was negative in omental metastases in two patients with advanced OCCC. In vitro analyses revealed that overexpression of miR-509-3p and miR-509-3-5p reversed cisplatin resistance and yes-associated protein 1 (YAP1) was partially responsible for the resistance. Immunohistochemistry revealed that YAP1 expression was inversely correlated with the chrXq27.3 miRNA cluster expression. In conclusion, these findings suggest that alteration of the chrXq27.3 miRNA cluster could play a critical role in chemoresistance and miRNAs in the cluster and their target genes can be potential therapeutic targets.

Niraparib as a therapeutic agent for the treatment of ovarian cancer meningeal dissemination with BRCA1 mutation

AbstractThis study analyzed a 63‐year‐old woman with hereditary BRCA1 mutation. She underwent interval debulking surgery after neoadjuvant chemotherapy for high‐grade serous ovarian carcinoma (HGSOC). After 2 years of postoperative chemotherapy, she developed headache and dizziness, and a suspected metastatic cerebellar mass in left ovary was detected. Pathological analysis of the mass revealed HGSOC, which was removed surgically. Eight months and another 6 months after the surgery, local recurrence was noted; hence, she underwent CyberKnife treatment. After 3 months, cervical spinal cord metastasis was found, evidenced by left shoulder pain. Moreover, meningeal dissemination was present around the cauda equina. Chemotherapy treatment, including bevacizumab, was ineffective and increased lesions were observed. After CyberKnife treatment for the cervical spinal cord metastasis, niraparib was initiated for the meningeal dissemination. The cerebellar lesions and meningeal dissemination improved within 8 months of niraparib treatment. Although meningeal dissemination is challenging to treat, niraparib may be useful in BRCA‐mutated HGSOC.

Does uterine preservation affect survival outcomes of patients with stage I ovarian sex cord-stromal cell tumours? A multi-institutional study

Sex cord-stromal tumours of the ovary are relatively uncommon neoplasms that account for 3 % of all ovarian cancers. Uterine preservation with careful staging is achievable; however, conservative surgery remains controversial. This study examined the prognostic effects of uterine preservation in patients with stage I sex cord-stromal tumours. This retrospective cohort study was undertaken between January 1986 and February 2019, and the clinicopathological data of 4897 women with malignant ovarian tumours were collected. Seventy-seven patients with stage I sex cord-stromal tumours were eligible for inclusion. The characteristics and survival outcomes of these patients were examined. To investigate the prognostic effects of uterine-preserving surgery, baseline imbalances between patients with and without uterine-preserving surgery were adjusted using an inverse probability of treatment weighting with propensity scores composed of independent clinical variables. The mean ages of patients in the uterine-preserving surgery and non-uterine-preserving surgery groups were 39.8 and 57.8 years, respectively. After inverse probability of treatment weighting adjustments, no significant differences in overall survival (p = 0.205) or recurrence-free survival (p=0.071) were observed between the uterine-preserving surgery and non-uterine-preserving surgery groups. Estimated 10-year overall survival rates were 98.7 % in the uterine-preserving surgery group and 95.9 % in the non-uterine-preserving surgery group, and 10-year recurrence-free survival rates were 87.2 % in the uterine-preserving surgery group and 78.2 % in the non-uterine-preserving surgery group. Uterine-preserving surgery did not significantly affect the site of tumour recurrence. Uterine-preserving surgery may be a feasible surgical option for patients with stage I sex cord-stromal tumours. Further research is needed to guarantee prognostic accuracy and develop effective therapeutic approaches for sex cord-stromal tumours.

The Preoperative Prognostic Nutritional Index for the Prediction of Outcomes in Patients with Early-Stage Ovarian Clear Cell Carcinoma

AbstractThe prognostic nutritional index (PNI), which reflects preoperative malnutrition, is useful for predicting the incidence of postoperative complications and has been reported in recent years to predict the long-term prognosis of various malignancies. The purpose of this study was to clarify the significance of PNI as a prognostic factor for early-stage clear cell ovarian carcinoma. A total of 82 patients with stage I–II (FIGO 2014) ovarian clear cell carcinoma undergoing primary surgery at our hospital from January 2005 to December 2017 were enrolled. PNI was calculated using the formula: 10 × serum albumin (g/ dL) + 0.005 × peripheral blood lymphocyte count (/mm3). Preoperative PNI exhibited relatively high area under the curve value (0.709) for 5 year survival, and the optimal cutoff value was 46.5. The overall survival was significantly shorter in the PNI-low group than in the PNI-high group. Multivariate analysis showed that high PNI was a significant independent prognostic factor for favorable prognosis (hazard ratio = 0.102, p = 0.010). There was no significant difference in recurrence-free survival between the two groups (p = 0.220), but the postrecurrence survival was significantly longer in the PNI-high group than in the PNI-low group (p = 0.0383). The preoperative PNI was a useful predictor of prognosis, even in early-stage ovarian clear cell carcinoma.

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.

Impact of age on clinicopathological features and survival of epithelial ovarian neoplasms in reproductive age

Little is known about the effect of age on the prognosis of epithelial ovarian neoplasms. In the reproductive age, fertility-sparing surgery had been widely implemented. This study aimed to elucidate impact of age on the clinicopathologic characteristics and survival of epithelial ovarian neoplasms in the reproductive age. The clinical records of patients diagnosed as epithelial ovarian cancer or epithelial borderline ovarian tumor at the age of 40 years or younger at multiple institutions in the Tokai Ovarian Tumor Study Group were reviewed retrospectively. All patients were stratified into two age groups: group A (≤ 30 years) and group B (31-40 years). Univariate and multivariate analyses were performed to evaluate overall survival and disease-free survival. A total of 583 patients (325 patients: cancer, 258 patients: borderline) were included. The median follow-up time was 62.0 months (range 1-270 months). Compared with group B, group A had a significantly higher rate of borderline tumor (66.7% vs. 32.7%, p < 0.001); stage I disease (85.9% vs. 70.4%, p < 0.001); mucinous type (69.2% vs. 35.6%, p < 0.001); conservative surgery (83.8% vs. 41.6%, p < 0.001); no adjuvant chemotherapy (67.2% vs. 44.7%, p < 0.001); and CA125 ≤ 35 U/mL (39.4% vs. 28.8%, p < 0.05). There was a significant difference in the overall survival (p = 0.0051) and the disease-free survival (p = 0.0039) between the two groups. Multivariate analysis revealed that the independent prognostic factors for the overall survival were age, stage, histology, and ascitic fluid cytology. In epithelial ovarian neoplasms, younger patients had a survival advantage over older patients.

Long-term post-recurrence survival outcomes in young women receiving fertility-sparing surgery for epithelial ovarian cancer

The aim of this study was to investigate long-term post-recurrence survival outcomes in young women receiving fertility-sparing surgery (FSS) to verify the feasibility of the limited surgery for epithelial ovarian cancer (OvCa). We performed a regional multicenter retrospective study from January 1986 and March 2020, using clinical data corrected under the central pathological review system. Patients with recurrent tumor after surgery for stage I epithelial OvCa, aged equal or younger than 45 years were included for this study. We evaluated effect of FSS regarding long-term post-recurrence survival with statistical adjustment of propensity score-based method. With the Kaplan-Meier method, original and adjusted survival curves were estimated for recurrence-after survival of patients with (n = 14) and without FSS (n = 26). Median time to disease-specific death was 18.6 months. In both original and adjusted cohorts, there were no significant difference between the two groups (log rank test; P > 0.05). Hazard ratio of disease-specific death was 1.264 (95% confidence interval, 0.563-2.836; P = 0.570) in original and 1.354 (95% confidence interval, 0.702-2.611; P = 0.366) in adjusted population. This result indicated that patients with FSS was not associated with poorer prognosis for recurrence-after survival than those without. When comparing patients not receiving FSS, patients receiving FSS with recurrence at spared ovary followed not significantly different survival outcome as well as those with extra-ovarian recurrence. There was no significant difference of long-term post-recurrence survival outcomes between patients of epithelial OvCa with and without FSS in young women of reproductive age.

Adjuvant taxane plus platinum chemotherapy for stage I ovarian clear cell carcinoma with complete surgical staging: are more than three cycles necessary?

Previous studies on adjuvant chemotherapy for patients with ovarian clear cell carcinoma (OCCC) have included a limited number of Asian patients with surgical stage I OCCC, despite differences in OCCC survival by race and stage. The aim of this study was to estimate the survival effect of the number of cycles of adjuvant taxane plus carboplatin chemotherapy in Asian patients with surgical stage I OCCC. We retrospectively identified 227 patients with surgical stage I OCCC at 14 institutions from 1995 to 2017. Kaplan-Meier analysis and Cox proportional hazard regression with inverse probability of treatment weighting (IPTW) adjustment were performed to evaluate overall survival (OS) and recurrence-free survival (RFS) in patients receiving ≤ 3 and 4-6 cycles of taxane plus platinum adjuvant chemotherapy. Eighty-nine and 138 patients received ≤ 3 and 4-6 cycles of adjuvant chemotherapy, respectively. There was no between-group difference in OS or RFS with or without IPTW adjustment. In Cox proportional hazards analysis, 4-6 cycles of adjuvant chemotherapy were not associated with improved OS (HR 1.090; 95% CI 0.518-2.291; p = 0.821) or RFS (HR 1.144; 95% CI 0.619-2.114; p = 0.669) compared to ≤ 3 cycles, even with IPTW adjustment. Subgroup analysis in different substages of stage I OCCC showed that the number of cycles of adjuvant chemotherapy had no impact on OS or RFS. Three or fewer cycles of taxane plus carboplatin chemotherapy may be a reasonable treatment regime for patients with surgical staging I OCCC.

Obesity contributes to the stealth peritoneal dissemination of ovarian cancer: a multi‐institutional retrospective cohort study

AbstractObjectiveThe clinical significance of a higher BMI on the prognosis of ovarian cancer remains controversial; therefore, a more detailed analysis is demanded. This study investigated the impact of BMI on peritoneum‐specific recurrence to clarify the involvement of adipose tissue in the proliferation of cancer cells at sites of peritoneal dissemination.MethodsAmong 4,730 patients with malignant ovarian tumors, 280 diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage IIB to IIIC epithelial ovarian cancer and who underwent complete resection in the primary surgery were included in the present study.ResultsThere were 42, 201, and 37 women in the low, normal, and high BMI groups, respectively. Peritoneum‐specific recurrence‐free survival and overall survival were both significantly shorter in patients with a high BMI than in those with a normal BMI (p = 0.028 and 0.018, respectively). No significant differences were observed in the distribution of sites of recurrence between these two groups. A multivariate analysis identified obesity as an independent prognostic factor in addition to pT3 tumor staging and positive ascites cytology.ConclusionsPatients with a high BMI had a significantly worse prognosis than those with a normal BMI, and peritoneal adipose tissue may have contributed to this difference.

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.

Sarcopenia as a Predictor of Survival Among Patients With Organ Metastatic Cervical Cancer

AbstractBackgroundThis study was conducted to investigate the prognostic significance of sarcopenia in patients with organ metastatic cervical cancer.MethodsAccordingly, the data of 40 patients with organ metastatic cervical cancer treated at our institute from December 2004 to December 2017 were retrospectively analyzed. The correlation between clinicopathological characteristics and survival was then evaluated using univariate and multivariate analyses. Psoas muscle index (PMI), calculated from the psoas muscle area at the L3 vertebral‐body level using computed tomography images obtained for pretreatment evaluation, was adopted as an index of sarcopenia.ResultsThe median follow‐up period was 14 months (range, 1–91 months). Kaplan‐Meier analysis showed a 3‐ and 5‐year overall survival (OS) rate of 46.1% and 35.8% for all patients, respectively. Receiver operating characteristic curve maximizing the area under the curve showed that the optimal PMI for predicting 1‐year survival was 3.72 cm2/m2. Patients with a PMI &gt; 3.72 cm2/m2 had significantly better OS than those with a PMI ≤ 3.72 cm2/m2 (P = .046). Multivariate analysis revealed that only PMI was significantly associated with OS in patients with organ metastatic cervical cancer. Furthermore, patients with a PMI &gt; 3.72 cm2/m2 who underwent concurrent chemoradiotherapy (CCRT) had a longer OS than those receiving other therapies (P &lt; .001).ConclusionsHigh PMI was determined to be a favorable prognostic factor for patients with organ metastatic cervical cancer. Moreover, patients with organ metastatic cervical cancer who have a PMI &gt; 3.72 cm2/m2 may benefit from CCRT as an initial treatment.

Significance of Concurrent Chemoradiotherapy as Primary Treatment in Patients with Metastatic Cervical Cancer

(1) This study investigated the prognostic impact of tumor size in patients with metastatic cervical cancer. (2) Methods: Seventy-three cervical cancer patients in our institute were stratified into two groups based on distant metastasis: para-aortic lymph node metastasis alone (IIIC2) or spread to distant visceral organs with or without para-aortic lymph node metastasis (IVB) to identify primary tumor size and concurrent chemoradiotherapy. (3) Results: The overall survival (OS) for patients with a tumor &gt;6.9 cm in size was significantly poorer than that for patients with a tumor ≤6.9 cm in the IVB group (p = 0.0028); the corresponding five-year OS rates in patients with a tumor ≤6.9 and &gt;6.9 cm were 53.3% and 13.4%, respectively. In the multivariate analysis, tumor size and primary treatment were significantly associated with survival in metastatic cervical cancer. (4) Conclusions: Tumor size ≤6.9 cm and concurrent chemoradiotherapy as the primary treatment were favorable prognostic factors for patients with metastatic cervical cancer.

Hypoalbuminemia for the prediction of survival in patients with stage IVB cervical cancer

We evaluated the prognostic significance of malnutrition in patients with metastatic cervical cancer. In this study, we retrospectively analyzed the cases of 43 patients with stage IVB (FIGO2018) cervical cancer treated at our institute from December 2004 to December 2017. We determined the correlation between clinicopathological characteristics and survival by performing univariate and multivariate analyses. The serum albumin value at diagnosis was used as an index of malnutrition. The median follow-up period was 16.4 months (range, 0.9–91.4 months). On Kaplan-Meier analysis, the 1- and 2-year overall survival (OS) rates for all patients were 61.6% and 48.6%, respectively. The optimal serum albumin for predicting 1-year survival was 3.3 g/dL, as determined by the receiver operating characteristic curve to maximize the area under the curve. The OS of the patients with albumin &gt;3.3 g/dL (n = 28) was significantly better than that of the patients with albumin ≤3.3 g/dL (n = 15) (p = 0.004). The univariate and multivariate analyses revealed that pretreatment serum albumin and mode of primary treatment were significantly associated with survival in patients with stage IVB cervical cancer. Hypoalbuminemia was an unfavorable prognostic factor for patients with metastatic cervical cancer.

An update of oncologic and obstetric outcomes of radical trachelectomy for early‐stage cervical cancer: The need for further minimally invasive treatment

AbstractAimsTo investigate the oncologic and obstetric outcomes of radical trachelectomy (RT) in patients with early‐stage cervical cancer and to evaluate the potential role of fertility‐preserving treatments in improving pregnancy outcomes while oncologic status is stable.MethodsIn this single‐institution study, we analyzed the oncologic and obstetric outcomes of 67 patients with early‐stage cervical cancer who underwent RT at Nagoya University Hospital.ResultsThe cancer recurrence rate (6.0%) and the mortality rate (1.5%) were comparable with those of previous studies. Of the 46 patients who attempted to conceive after RT, 19 (41.3%) became pregnant, and 16 gave birth. Of these 37.5% delivered at term, and delivery at less than 28 weeks of gestation occurred in 31.3% of pregnancies.ConclusionsRT is a viable treatment option for selected patients with early‐stage cervical cancer. However, the use of less invasive techniques, such as conization/simple trachelectomy and pelvic lymph node dissection, may improve pregnancy outcomes while oncologic status is stable.

Overcoming platinum-resistant ovarian cancer targeting the activated JAK-STAT pathways via extracellular vesicles

Abstract Platinum-resistant ovarian cancer (PROC) is a clinically severe unresolved issue, and it remains unclearly defined by molecular biology. Extracellular vesicles (EVs) play an essential role in cell-to-cell communication in the tumor microenvironment. This study aimed to investigate the molecular mechanisms of PROC, focusing on the unique ascites environment of ovarian cancer. Multi-transcriptome analyses using clinical samples revealed that PROC exhibited an activated Janus kinase (JAK)/signal transducer and activator of transcription pathway with high JAK1 expression in cancer cells. Immunohistochemistry for patient tissues confirmed the negative association between JAK1 expression and platinum response. JAK inhibitors were effective in PROC cell lines and cell- and patient-derived xenograft models, as well as synergistic with platinum. Furthermore, small RNA sequencing indicated that activated peritoneal mesothelial cell-derived EVs enriched in miR135a-5p increased JAK expression and platinum resistance in cancer cells. Collectively, EVs in ascites regulated platinum sensitivity in ovarian cancer cells, and JAK targeting therapeutic strategy overcomes PROC.

Small Extracellular Vesicles from adipose-derived stem cells suppress cell proliferation by delivering the let-7 family of microRNAs in ovarian cancer

Ovarian cancer is the leading cause of death among women with gynecological cancer, and novel treatment options are urgently needed. Extracellular vesicles (EVs), including exosomes, may be one of the most promising therapeutic tools for various diseases. In this study, we aimed to investigate the therapeutic effects of adipose-derived stem cell-derived EVs (ADSC-EVs) on ovarian cancer cell lines. ADSCs and the ovarian cancer cell lines SKOV3 and OV90 were used for analysis. ADSC-EVs were isolated through ultracentrifugation and validated using a cryotransmission electron microscope, nanoparticle tracking analysis, and western blotting. Then, the effect of ADSC-EVs on ovarian cancer cells was investigated using IncuCyte and microRNA sequencing. Moreover, the potential functions of miRNAs were evaluated by gain-of function analysis and in silico analysis. ADSC-EVs suppressed SKOV3 and OV90 cell proliferation. In particular, small EVs (sEVs) from ADSCs exhibited a stronger antitumor effect than ADSC-medium/large EVs (m/lEVs). Comparison of the miRNA profiles between ADSC-sEVs and ADSC-m/lEVs, along with downstream pathway analysis, suggested the involvement of the let-7 family. Overexpression of hsa-let-7b-5p and hsa-let-7e-5p significantly suppressed the proliferation of SKOV3 cells. In silico analysis revealed that four potential target genes of hsa-let-7b-5p and hsa-let-7e-5p were significantly associated with the prognoses of the patients. ADSC-sEVs had a stronger antitumor effect than ADSC-m/lEVs. Hsa-let-7b-5p and hsa-let-7e-5p, which are highly abundant in ADSC-sEVs, suppressed cell proliferation. These findings may open up new possibilities for therapeutic approaches using ADSC-sEVs.

In‐Tumor CRISPR ‐Cas9 Knockout Screening and Novel Therapy Development for Malignant Transformation of Ovarian Teratoma

ABSTRACT Malignant transformation of mature cystic teratoma (MTMCT) of the ovary is a rare but aggressive malignancy for which no standardized chemotherapy or effective targeted therapies currently exist. To identify therapeutic vulnerabilities in MTMCT, we performed a genome‐wide CRISPR‐Cas9 knockout screen using the MTMCT‐derived NOSCC1 cell line. Two parallel selective pressures were applied: in vivo tumorigenicity in immunodeficient mice and cisplatin exposure in vitro. From this screen, 67 negatively selected genes were identified, among which SOD1 and NDUFB4 emerged as top candidates based on high basal expression levels and clinical relevance. Integration with spatial transcriptomic data from three independent MTMCT patient tumors further supported the prioritization of these targets. SOD1 was selected for further investigation due to the availability of known pharmacological inhibitors. Both siRNA‐mediated knockdown and small‐molecule inhibition of SOD1 using LCS‐1 significantly suppressed MTMCT cell proliferation in vitro by inducing oxidative stress and impairing cell cycle progression. This antiproliferative effect was reversed by co‐treatment with N ‐acetylcysteine, a reactive oxygen species scavenger. In vivo validation using patient‐derived xenograft models demonstrated that oral administration of LCS‐1 led to significant tumor growth suppression and increased expression of apoptotic and DNA damage markers, including cleaved caspase‐3 and γH2AX. These findings establish SOD1 as a critical vulnerability in MTMCT and provide preclinical evidence supporting redox modulation as a therapeutic strategy for this highly chemoresistant and understudied ovarian cancer subtype. Our integrative approach combining functional genomics, spatial transcriptomics, and pharmacologic validation offers a framework for the discovery of novel targets in rare gynecologic malignancies.