Shinya Matsuzaki

Intrauterine manipulator use during laparoscopic hysterectomy for endometrial cancer: association for pathological factors and oncologic outcomes

To examine the association between intrauterine manipulator use and pathological factors and oncologic outcomes in patients with endometrial cancer who had laparoscopic hysterectomy in Japan. This was a nationwide retrospective cohort study of the tumor registry of the Japan Society of Obstetrics and Gynecology. Study population was 3846 patients who had laparoscopic hysterectomy for endometrial cancer from January 2015 to December 2017. An automated 1-to-1 propensity score matching with preoperative and intraoperative demographics was performed to assess postoperative pathological factors associated with the intrauterine manipulator. Survival outcomes were assessed by accounting for possible pathological mediators related to intrauterine manipulator use. Most patients had preoperative stage I disease (96.5%) and grade 1-2 endometrioid tumors (81.9%). During the study period, 1607 (41.8%) patients had intrauterine manipulator use and 2239 (58.2%) patients did not. In the matched cohort, the incidences of lymphovascular space invasion in the hysterectomy specimen were 17.8% in the intrauterine manipulator group and 13.3% in the non-manipulator group. Intrauterine manipulator use was associated with a 35% increased odds of lymphovascular space invasion (adjusted odds ratio 1.35, 95% confidence interval (CI) 1.08 to 1.69). The incidences of malignant cells identified in the pelvic peritoneal cytologic sample at hysterectomy were 10.8% for the intrauterine manipulator group and 6.4% for the non-manipulator group. Intrauterine manipulator use was associated with a 77% increased odds of malignant peritoneal cytology (adjusted odds ratio 1.77, 95% Cl 1.29 to 2.31). The 5 year overall survival rates were 94.2% for the intrauterine manipulator group and 96.6% for the non-manipulator group (hazard ratio (HR) 1.64, 95% Cl 1.12 to 2.39). Possible pathological mediators accounted HR was 1.36 (95%Cl 0.93 to 2.00). This nationwide analysis of predominantly early stage, low-grade endometrial cancer in Japan suggested that intrauterine manipulator use during laparoscopic hysterectomy for endometrial cancer may be associated with an increased risk of lymphovascular space invasion and malignant peritoneal cytology. Possible mediator effects of intrauterine manipulator use on survival warrant further investigation, especially with a prospective setting.

The value of vaginal cytology for postoperative surveillance of endometrial cancer

The value of conducting vaginal cytology surveillance after endometrial cancer (EC) surgery has not been fully established, yet in Japan it is still performed routinely in many institutions. We have retrospectively examined its diagnostic and prognostic values. We studied 759 EC cases that underwent hysterectomy at our hospital in Osaka, Japan from January 2010 to December 2019. Information on the clinicopathological factors at the time of initial and postoperative treatments, and the sites and diagnostic timing of recurrences were extracted from medical records and analyzed. Recurrences from primary EC were observed in 11.2% of the patients (85/759). In 23.5% of the cases (20/85), the recurrence included a vaginal component. The two most common single-sites of recurrence were vagina (14.1%, 12/85) and lung (12.9%, 11/85). The diagnosis of vaginal recurrence was made from symptoms and gynecological examination in 14 of the 20 cases. Only one was diagnosed solely by vaginal cytology; in that case, macroscopic lesions appeared two months after obtaining the abnormal cytology. We found that, in postoperative follow-up surveillance for EC, most cases of vaginal recurrence were first diagnosed by a careful pelvic examination. For current routine postoperative practice, monitoring critical symptoms and conducting careful gynecological examinations has been shown to be more important than cytological examinations.

Effects of aspirin and statin use on venous thromboembolism prophylaxis and survival in patients with endometrial cancer

Acetylsalicylic acid (aspirin) and statins are commonly used to manage and prevent cardiovascular diseases. Recent studies have suggested the benefits of aspirin or statin use in venous thromboembolism (VTE) prophylaxis and survival outcome improvement in women with endometrial cancer. In this study, we reviewed the effects of aspirin or statin use on VTE prophylaxis and survival outcome in women with endometrial cancer. Among women with endometrial cancer, aspirin use exerted a modest effect on VTE prophylaxis, whereas statin use was associated with a decreased prevalence of VTE, especially in women with obesity and type II cancer, compared with those in non-users. Aspirin use improved cause-specific survival in women with endometrial cancer, aged less than 60 years, who were obese and presented with type I cancer. Statin use was associated with better cause-specific survival in women with type II cancer. The combination of aspirin and statins may be the most effective strategy in improving on VTE prophylaxis and survival outcomes in obese women with type II cancer. Targeting of the appropriate population with endometrial cancer may enhance the efficacy of aspirin or statins on VTE prophylaxis and survival outcomes in women with endometrial cancer.

Clinico‐pathological significance of suspicious peritoneal cytology in endometrial cancer

AbstractBackground and ObjectivesSuspicious peritoneal cytology refers to the result of peritoneal cytology testing that is insufficient in either quality or quantity for a definitive diagnosis of malignancy. This study examined characteristics and survival outcomes related to suspicious peritoneal cytology in endometrial cancer.MethodsA population‐based retrospective study by querying the National Cancer Institute's Surveillance, Epidemiology, and End Results Program was conducted. A total of 41,229 women with Stage I–III endometrial cancer who had peritoneal cytologic sampling at hysterectomy from 2010 to 2016 were examined. A Cox proportional hazard regression model and a competing risk analysis with Fine‐Gray model were fitted to assess survival outcome related to suspicious peritoneal cytology.ResultsSuspicious peritoneal cytology was seen in 702 (1.7%) cases. In multivariable models, suspicious peritoneal cytology was associated with increased risk of endometrial cancer mortality (subdistribution‐hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.29–2.20, p < 0.001) and all‐cause mortality (adjusted‐HR: 1.55, 95% CI: 1.27–1.90, p < 0.001) compared with negative peritoneal cytology. Sensitivity analysis demonstrated that suspicious peritoneal cytology had discrete overall survival improvement compared with malignant peritoneal cytology in a propensity score weighting model (HR: 0.85, 95% CI: 0.72–0.99, p = 0.049).ConclusionOur study suggests that suspicious peritoneal cytology may be a prognostic factor for decreased survival in endometrial cancer.

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.

CD70 antibody‐drug conjugate: A potential novel therapeutic agent for ovarian cancer

AbstractThis study aimed to investigate the cytotoxicity of a cluster of differentiation 70 antibody‐drug conjugate (CD70‐ADC) against ovarian cancer in in vitro and in vivo xenograft models. CD70 expression was assessed in clinical samples by immunohistochemical analysis. Western blotting and fluorescence‐activated cell sorting analyses were used to determine CD70 expression in the ovarian cancer cell lines A2780 and SKOV3, and in the cisplatin‐resistant ovarian cancer cell lines A2780cisR and SKOV3cisR. CD70 expression after cisplatin exposure was determined in A2780 cells transfected with mock‐ or nuclear factor (NF)‐κB‐p65‐small interfering RNA. We developed an ADC with an anti‐CD70 monoclonal antibody linked to monomethyl auristatin F and investigated its cytotoxic effect. We examined 63 ovarian cancer clinical samples; 43 (68.3%) of them expressed CD70. Among patients with advanced stage disease (n = 50), those who received neoadjuvant chemotherapy were more likely to exhibit high CD70 expression compared to those who did not (55.6% [15/27] vs 17.4% [4/23], P < .01). CD70 expression was confirmed in A2780cisR, SKOV3, and SKOV3cisR cells. Notably, CD70 expression was induced after cisplatin treatment in A2780 mock cells but not in A2780‐NF‐κB‐p65‐silenced cells. CD70‐ADC was cytotoxic to A2780cisR, SKOV3, and SKOV3cisR cells, with IC50 values ranging from 0.104 to 0.341 nmol/L. In A2780cisR and SKOV3cisR xenograft models, tumor growth in CD70‐ADC treated mice was significantly inhibited compared to that in the control‐ADC treated mice (A2780cisR: 32.0 vs 1639.0 mm3, P < .01; SKOV3cisR: 232.2 vs 584.9 mm3, P < .01). Platinum treatment induced CD70 expression in ovarian cancer cells. CD70‐ADC may have potential therapeutic implications in the treatment of CD70 expressing ovarian cancer.

Surgical Management for Transposed Ovarian Recurrence of Cervical Cancer: A Systematic Review with Our Experience

In early-stage cervical cancer, ovarian metastasis is relatively rare, and ovarian transposition is often performed during surgery. Although rare, the diagnosis and surgical approach for recurrence at transposed ovaries are challenging. This study focused on the diagnosis and surgical management of transposed ovarian recurrence in cervical cancer patients. A 45-year-old premenopausal woman underwent radical hysterectomy, bilateral salpingectomy, and pelvic lymphadenectomy following postoperative concurrent chemoradiotherapy for stage IB1 cervical cancer. During the initial surgery, the ovary was transposed to the paracolic gutter, and no postoperative complications were observed. Ovarian recurrence was diagnosed using positron emission tomography–computed tomography, and a laparoscopic bilateral oophorectomy was performed. A systematic review identified nine women with transposed ovarian recurrence with no other metastases of cervical cancer, and no studies have discussed the optimal surveillance of transposed ovaries. Of those (n = 9), four women had died of the disease within 2 years of the second surgery, and the prognosis of transposed ovarian cervical cancer seemed poor. Nevertheless, three women underwent laparoscopic oophorectomies, none of whom experienced recurrence after the second surgery. Few studies have examined the surgical management of transposed ovarian recurrence. The optimal surgical approach for transposed ovarian recurrence of cervical cancer requires further investigation.

Nonlinear Optics with Near-Infrared Excitation Enable Real-Time Quantitative Diagnosis of Human Cervical Cancers

Abstract Histopathologic analysis through biopsy has been one of the most useful methods for the assessment of malignant neoplasms. However, some aspects of the analysis such as invasiveness, evaluation range, and turnaround time from biopsy to report could be improved. Here, we report a novel method for visualizing human cervical tissue three-dimensionally, without biopsy, fixation, or staining, and with sufficient quality for histologic diagnosis. Near-infrared excitation and nonlinear optics were employed to visualize unstained human epithelial tissues of the cervix uteri by constructing images with third-harmonic generation (THG) and second-harmonic generation (SHG). THG images enabled evaluation of nuclear morphology in a quantitative manner with six parameters after image analysis using deep learning. It was also possible to quantitatively assess intraepithelial fibrotic changes based on SHG images and another deep learning analysis. Using each analytical procedure alone, normal and cancerous tissue were classified quantitatively with an AUC ≥0.92. Moreover, a combinatory analysis of THG and SHG images with a machine learning algorithm allowed accurate classification of three-dimensional image files of normal tissue, intraepithelial neoplasia, and invasive carcinoma with a weighted kappa coefficient of 0.86. Our method enables real-time noninvasive diagnosis of cervical lesions, thus constituting a potential tool to dramatically change early detection. Significance: This study proposes a novel method for diagnosing cancer using nonlinear optics, which enables visualization of histologic features of living tissues without the need for any biopsy or staining dye.

Characteristics and outcomes of women with adenocarcinoma versus squamous cell carcinoma of the vulva: A Japanese Gynecologic Oncology Group study

Studies on vulvar adenocarcinoma are lacking. Thus, we aimed to compare the characteristics and survival outcomes between vulvar adenocarcinoma and squamous cell carcinoma (SCC). This was a preplanned sub-analysis of a previously organized nationwide retrospective observational study in Japan conducted between 2001 and 2010 (JGOG-1075S). Surgically treated women with stage I-IV vulvar invasive adenocarcinoma were compared to those with SCC. Multivariable analysis was performed to identify patient and tumor characteristics related to adenocarcinoma. Inverse probability of treatment weighting was used to balance the background differences, and a Cox proportional hazards regression model was fitted to estimate the effect of the histological type on survival. Forty-eight women with adenocarcinoma were compared with 537 women with SCC. On multivariable analysis, women with adenocarcinoma were younger (median age, 64.5 vs. 70 years, adjusted odds ratio [OR] per age 0.975, 95% confidence interval [CI] 0.955-0.995, P = 0.016) and had higher positive surgical margin rates (31.2% vs. 18.4%, adjusted OR 2.376, 95% CI 1.188-4.754, P = 0.014) than those with SCC. However, according to the weighted model, the survival outcomes were comparable (hazard ratio for progression-free survival, 1.088, 95% CI 0.740-1.601, P = 0.667 and hazard ratio for overall survival, 1.008, 95% CI 0.646-1.573, P = 0.973). Similar associations were observed when the cohort was stratified by age (≤70 or >70 years), stage (I-II or III-IV), and surgical margin (negative or positive) (all, P > 0.05). Vulvar adenocarcinoma is characterized by a younger age at diagnosis and higher positive surgical margin rates than SCC, but the survival outcomes are comparable.

The Effect of Surgeon Volume on the Outcome of Laser Vaporization: A Single-Center Retrospective Study

Although laser vaporization is a popular minimally invasive treatment for cervical intraepithelial neoplasia (CIN), factors influencing CIN recurrence are understudied. Moreover, the effect of surgeon volume on patients’ prognosis after laser vaporization for CIN is unknown. This single-center retrospective study evaluated the predictive value of surgeon volume and patient characteristics for laser vaporization outcomes in women with pathologically confirmed CIN2. Histologically confirmed CIN2 or higher grade after laser vaporization was defined as persistent or recurrent. Various patient characteristics were compared between women with and those without recurrence to examine the predictive factors for laser vaporization. There were 270 patients with a median age of 36 (18–60) years. The median follow-up period was 25 (6–75.5) months and the median period between treatment and persistence or recurrence was 17 (1.5–69) months. The median annual number of procedures for all seven surgeons was 7.8. There were 38 patients (14.1%) with persistent or recurrent lesions—24 had CIN2, 13 had CIN3, and one had adenocarcinoma in situ. Patient age, body mass index, surgeon volume, and history of prior CIN treatment or invasive cervical cancer were not significantly correlated with lesion persistence or recurrence. In conclusion, laser vaporization has comparable success rates and is a feasible treatment for both low- and high-volume surgeons.

Population-Based Survival Analysis of Stage IVB Small-Cell Neuroendocrine Carcinoma in Comparison to Major Histological Subtypes of Cervical Cancer

The aim of the current study is to investigate the survival outcome of stage IVB SCNEC of the uterine cervix in comparison to major histological subtypes of cervical cancer. A population-based retrospective cohort study was conducted using the Osaka Cancer Registry data from 1994 to 2018. All FIGO 2009 stage IVB cervical cancer patients who displayed squamous cell carcinoma (SCC), adenocarcinoma (A), adenosquamous cell carcinoma (AS), or small-cell neuroendocrine carcinoma (SCNEC) were first identified. The patients were classified into groups according to the types of primary treatment. Then, their survival rates were examined using the Kaplan–Meier method. Overall, in a total of 1158 patients, clearly differential survival rates were observed according to the histological subtypes, and SCNEC was associated with shortest survival. When examined according to the types of primary treatments, SCNEC was associated with significantly decreased survival when compared to SCC or A/AS, except for those treated with surgery. In patients with FIGO 2009 stage IVB cervical cancer, SCNEC was associated with decreased survival when compared to SCC or A/AS. Although current treatments with either surgery, chemotherapy or radiotherapy have some therapeutic efficacies, to improve the prognosis, novel effective treatments specifically targeting cervical SCNEC need to be developed.

Relative survival of large cell to small cell neuroendocrine carcinoma of the uterine cervix.

This retrospective study compared clinico-pathological characteristics and survival of large cell to small cell neuroendocrine carcinomas of the uterine cervix identified in the Commission-on-Cancer's National Cancer Database from 2004 to 2022 (n = 2051). Large cell neuroendocrine carcinoma, reported in 16.3%, was more likely to be T1 classification (37.1% vs 29.5%) and have smaller cervical tumor (median size, 47 and 59 mm) but less likely to be T3 classification (15.6% vs 22.4%) and N1 classification (36.8% vs 45.1%) than small cell neuroendocrine carcinoma (all, p < .05). In propensity score inverse probability of treatment weighting, large cell neuroendocrine carcinoma had overall survival comparable to small cell neuroendocrine carcinoma (5-year rates, 33.8% vs 30.9%, hazard ratio 1.02, 95% confidence interval 0.86 to 1.20). This survival association was consistent across stage I, II, III, and IV diseases. In the secondary cohort of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program, cause-specific survival from cervical cancer was similar between large cell and small cell neuroendocrine carcinomas (5-year rates, 36.1% vs 39.1%, hazard ratio 1.25, 95% confidence interval 0.88 to 1.76). In conclusion, these data suggest that large cell neuroendocrine carcinoma represents less than 20% of neuroendocrine carcinomas of the uterine cervix, and although tumor characteristics appear to be less aggressive, oncologic outcomes are dismal and similar to small cell neuroendocrine carcinoma.

Clinico-pathological characteristics and survival outcome associated with uterine leiomyosarcoma variants: epithelioid and myxoid types

Epithelioid and myxoid types represent uterine leiomyosarcoma variants, and their clinico-pathologic characteristics and survival outcomes have been under-studied because of their rarity. The objective of this study was to assess clinico-pathologic characteristics and survival associated with uterine leiomyosarcoma variants. This retrospective cohort study queried the Commission-on-Cancer's National Cancer Database. The study population included 7410 patients with uterine leiomyosarcoma, including conventional, epithelioid, and myxoid types, who had primary hysterectomy from 2010 to 2022. Demographic characteristics were assessed using descriptive analysis; overall survival was assessed using a multivariable Cox proportional hazards regression model. Epithelioid and myxoid types were reported in 478 (6.5%) and 327 (4.4%) patients, respectively. The proportion of the epithelioid variant increased from 5.5% in 2010-2014 to 7.8% in 2019-2022 (p = .005). The epithelioid type was associated with higher rates of lympho-vascular space invasion (33.1% vs 22.0%-23.7%) and nodal metastasis (6.9% vs 3.4%-3.6%), whereas the myxoid type was associated with a higher rate of stage I disease (64.5% vs 56.1%-58.7%) (all, p < .05). Compared with the conventional type, the epithelioid type was associated with improved overall survival (adjusted hazard ratio [aHR] 0.87, 95% confidence interval [CI] 0.75 to 0.99) including stage I (aHR 0.75, 95%CI 0.60 to 0.93) and stage III (aHR 0.59, 95% CI 0.39 to 0.91) disease; the myxoid type was also associated with improved overall survival (aHR 0.68, 95%CI 0.57 to 0.82) including stage I (aHR 0.62, 95% CI 0.47 to 0.82) and stage IV (aHR 0.60, 95% CI 0.41 to 0.88) disease. Across all three types, larger tumor size, lympho-vascular invasion, and higher stage were associated with decreased overall survival, with the survival impact of larger tumor size being more prominent in variants. For stage II to IV epithelioid type, adjuvant chemotherapy was associated with improved overall survival (aHR 0.43, 95% CI 0.29 to 0.64). The results of this cohort study suggest that uterine leiomyosarcoma variants (epithelioid and myxoid) exhibit distinct histopathologic characteristics and survival compared with the conventional type. These data also endorse the importance of accurate diagnosis, research inclusion criteria, and development of collaborative networks.

Association of sentinel lymph node biopsy and isolated tumor cells in cervical cancer.

This retrospective cohort study examined 4991 patients with the American Joint Commission on Cancer T1-2 classification who underwent primary anti-cancer surgery, including lymph node evaluation (sentinel lymph node biopsy n = 976, and lymphadenectomy n = 4015), identified in the National Cancer Database from 2018 to 2022. In propensity score inverse probability of treatment weighting, the sentinel lymph node biopsy group had a 2-fold higher rate of low-volume metastasis (isolated tumor cells or micro-metastasis) than the lymphadenectomy group (2.7% vs 1.3%, OR 2.03, 95% CI 1.26 to 3.27). When the low-volume metastasis was further stratified, sentinel lymph node biopsy was associated with increased odds of isolated tumor cells (OR 2.33, 95% CI 1.30 to 4.17) compared with micro-metastasis (OR 1.58, 95% CI 0.70 to 3.57). This association was consistent in the Surveillance, Epidemiology, and End Results Program data from 2018 to 2022 (n = 2973), and sentinel lymph node biopsy was associated with increased odds of isolated tumor cells (OR 3.31, 95% CI 1.65 to 6.64) compared with micro-metastasis (OR 1.12, 95% CI 0.58 to 2.16) compared with lymphadenectomy. In conclusion, these data suggest that sentinel lymph node mapping and biopsy with ultra-staging can identify more isolated tumor cells in cervical cancer.