Gynecologic neuroendocrine carcinoma (NEC) is a rare and aggressive malignancy with limited treatment options and poor prognosis. Homologous recombination deficiency (HRD) is an established predictive biomarker for poly(ADP-ribose) polymerase (PARP) inhibitor response in ovarian cancer, but its clinical relevance in NEC remains unclear. Case presentation A 71-year-old woman presented with a large pelvic mass and multiple pulmonary metastases. Primary debulking surgery was performed, and histopathology revealed large-cell NEC (LCNEC) of presumed gynecologic origin. Postoperatively, the patient received paclitaxel-carboplatin plus bevacizumab. HRD testing demonstrated a high genomic instability score without BRCA1/2 mutations. After six cycles of chemotherapy, the pulmonary lesions showed a partial response. Maintenance therapy with bevacizumab plus olaparib was initiated, and the patient achieved complete radiologic remission, remaining disease-free for 1 year. Conclusion HRD-positive gynecologic NEC may respond to PARP inhibitor-based therapy even in the absence of BRCA mutations. HRD assessment may help identify patients with NEC who could benefit from targeted treatment strategies.

e17613 Background: Recently, omentum has been suggested to be immunologically active. Therefore, we investigated the effect of prior omentectomy on the efficacy of lenvatinib + pembrolizumab (LP) therapy in patients with endometrial cancer (EC). Methods: This retrospective study included 95 patients with recurrent EC treated with LP between December 2021 and March 2025 at our institutions. The primary outcomes were progression-free survival (PFS) and overall survival (OS). Multivariable Cox regression analyses included factors such as omentectomy status, MMR status, FIGO stage (I/II or III/IV), histology (endometrioid or others), platinum-free interval (PFI) (<6 or ≥6 months) and the number of prior regimens (1 or ≥2). Results: Overall, 95 patients were enrolled in the study (omentectomy group, 50; no-omentectomy group, 45). Moreover, six patients in the no-omentectomy group, did not undergo primary surgery and predominantly presented with stage IV disease. Molecular profiling was used to identify 9 dMMR and 86 pMMR tumors. Advanced stage (III/IV), endometrioid histology, PFI <6 month, and ≥2 prior regimens were observed in 64%, 42%, 64%, and 30% of the patients in the omentectomy group and 58%, 60%, 60%, and 31% of the patients in the no-omentectomy group. Patients in the no-omentectomy had a significantly longer median PFS (15.4 vs. 8.2 months; p = 0.001) and OS (34.9 vs. 21.7 months; p = 0.090). Multivariable analysis revealed that omentectomy was independently associated with shorter PFS (HR 2.18; 95% CI, 1.23–3.88; p = 0.008), but was not an independent predictor of OS (HR 1.11; 95% CI 0.58–2.12; p = 0.750) [Table]. Histology-specific analyses of the major subtypes, including endometrioid carcinoma ( n = 48), serous carcinoma ( n = 20), and carcinosarcoma ( n = 18), revealed that omentectomy was associated with more favorable outcomes only in patients with serous carcinoma. Therefore, further analysis, excluding patients with serous carcinoma, was performed. In this non-serous cohort, multivariable Cox regression analyses demonstrated that omentectomy remained independently associated with shorter PFS (HR 3.29; 95% CI, 1.69–6.41; p < 0.001) and had a trend toward shorter OS (HR 1.99; 95% CI, 0.93–4.26; p = 0.076). Conclusions: Patients without prior omentectomy had better outcomes following LP therapy. Thus, omentum may contribute to antitumor immune regulation. Progression-free survival Overall survival Variables HR 95% CI p -value HR 95% CI p -value Omentectomy status OMTx vs No-OMTx 2.18 1.23–3.88 0.008 1.11 0.58–2.12 0.750 MMR status dMMR vs pMMR 0.36 0.13–1.00 0.051 0.19 0.04–0.87 0.032 FIGO stage III/IV vs I/II 1.00 0.58–1.75 0.992 1.48 0.74–2.98 0.272 Histology non-endometrioid vs endometrioid 1.09 0.63–1.88 0.768 2.47 1.22–5.00 0.012 PFI ≥6 vs <6 months 0.47 0.26–0.85 0.012 0.34 0.15–0.77 0.009 Number of prior regimens ≥2 vs 1 0.91 0.51–1.61 0.744 1.03 0.52–2.05 0.937

Introduction:Whether obesity (body mass index [BMI] ≥30 kg/m²) independently affects perioperative outcomes in robot-assisted surgery for endometrial cancer remains uncertain. Materials and methods:We conducted a retrospective single-center cohort including 119 consecutive patients who underwent a uniform robotic procedure-total hysterectomy with bilateral salpingo-oophorectomy and pelvic lymphadenectomy using the da Vinci Xi system-between November 2018 and June 2025. Patients were grouped by BMI ≥ 30 (n = 32) versus < 30 (n = 87). Outcomes were estimated blood loss (EBL), operative time, lymph-node yield, and length of stay (LOS). Multivariable linear regression adjusted for age, prior abdominal/pelvic surgery, comorbidity history (diabetes, hypertension, dyslipidemia), operating surgeon, and surgical year (2018-2020 vs 2021-2025). Results:BMI ≥ 30 was independently associated with higher EBL and longer operative time, and prior surgery also prolonged operative time. Surgeon effects were pronounced for efficiency and nodal retrieval; BMI was not associated with lymph-node yield. LOS was not associated with BMI; however, LOS was higher in later surgical years and varied by surgeon. Conclusion:In standardized robot-assisted endometrial cancer surgery, obesity increased intraoperative workload (blood loss and operative time) without reducing lymph-node yield. LOS reflected surgeon- and time-related factors rather than BMI. These findings support the feasibility of robotic surgery in patients with obesity and underscore the importance of surgeon experience, pathway fidelity, and ongoing quality improvement.

Uterine carcinosarcoma (UCS) is a rare and aggressive malignancy that typically affects postmenopausal women. Its occurrence in young adults, particularly due to hereditary breast and ovarian cancer syndrome (HBOC), is exceptionally uncommon. The present report describes a case of a 21-year-old woman with persistent uterine bleeding who was found to have a uterine mass with para-aortic and pelvic lymphadenopathy and multiple pulmonary metastases. To control bleeding and obtain a definitive diagnosis, the patient underwent a total hysterectomy with bilateral salpingo-oophorectomy. Histopathological examination revealed International Federation of Gynecology and Obstetrics stage IVB UCS. This manifested as poorly differentiated carcinoma and heterologous sarcomatous components with chondrosarcomatous and rhabdomyosarcomatous differentiation. Comprehensive genomic profiling identified a BRCA1 frameshift mutation, a TP53 splice-site mutation, a PIK3CA mutation and a positive homologous recombination deficiency (HRD) signature. After genetic counseling, germline genetic testing for BRCA1 and TP53 was performed. This confirmed a pathogenic germline BRCA1 mutation. The patient was treated with four cycles of paclitaxel and carboplatin, followed by an additional four cycles of combination chemotherapy with durvalumab. The patient achieved a complete radiologic response. Maintenance therapy with durvalumab and olaparib was initiated, and the patient has remained progression-free for 10 months. To the best of our knowledge, this represents one of the youngest reported cases of UCS associated with HBOC. The case highlights the value of genomic profiling and germline testing for personalized treatment strategies. The successful use of platinum-based chemotherapy, immune checkpoint blockade and poly (ADP-ribose) polymerase inhibition to treat this HRD-positive, mismatch repair-proficient tumor demonstrates the potential of biomarker-driven therapy for UCS.

Relationship between subtyping methodologies. A, Comparison of transcriptomic subgrouping approaches: composition of Tothill subtypes across each of the TCGA subtypes; labeled P value represents comparison of Tothill subtype frequency across all TCGA subtypes by the Chi-squared test. B, Distribution of homologous recombination repair (HRR)-centric subtypes across each of the TCGA transcriptomic subtypes; labeled P value represents comparison of BRCA1/2m frequency across all groups by Chi-squared test; Bonferroni-adjusted P = 0.009. C, Distribution of HRR-centric subtypes across each of the Tothill transcriptomic subtypes; labeled P value represents comparison of BRCA1/2m frequency across all groups by the Chi-squared test; Bonferroni-adjusted P = 0.003. BRCA2m, BRCA2 mutant; BRCA1m, BRCA1 mutant; EMSY-overxp; overexpression of EMSY; nBRCA-HRRm, non-BRCA1/2 HRR gene mutation; CCNE1g, gain of CCNE1; HRRwt, non-CCNE1g HRR wild-type.

Molecular landscape of HGSOC. 1Mutation in non-BRCA1/2 HRR genes: 3 BRIP1, 2 CHEK2, 1 RAD51C, 1 PALB2, 1 concurrent BAP1 and NBN. CCNE1 CN gain, ≥4 copies by TaqMan CN assay. EMSY CN amplification, ≥6 copies by TaqMan CN assay.

Clinicopathologic features of patients with HGSOC.

OBJECTIVE:Clear cell ovarian carcinoma (CCOC) is generally associated with a favourable prognosis, however up to 30 % of low-stage cases relapse within five years. The benefit of adjuvant chemotherapy in early-stage disease (FIGO IA-IC1) remains uncertain. This study aimed to identify molecular and immune markers associated with relapse in a well-characterized CCOC cohort. METHODS:We analyzed 85 CCOC cases identified through the Edinburgh Ovarian Cancer Database. Targeted DNA sequencing assessed genomic alterations, while CD3 and CD8 immunohistochemistry evaluated tumour immune infiltration. Tumours were stratified by stage (IA-IC1, IC2-II, III-IV), and progression-free survival (PFS) analysis included stage, age, genomic features, and immune markers. RESULTS:Common genomic alterations included ARID1A (49 %) and PIK3CA (42 %) mutations, PIK3-AKT pathway perturbations (60 %), and mismatch repair-related mutational signatures (25.9 %). Genomic features were not significantly associated with tumour stage; however, low-stage tumours (IA-IC1) were enriched in CD3+ (40 % cases) and CD8+ (29 % cases) tumour-infiltrating lymphocytes (TILs) compared to higher-stage tumours (IC2-II: 13 %/7 %; III-IV: 9 %/0 %). In univariate analysis, low CD3+ TIL levels were significantly associated with reduced PFS (HR = 4.4, P = 0.042), and ARID1A wild-type status was linked to poorer PFS in low-stage tumours (HR = 7.2, P = 0.088). Notably, the combination of ARID1A wild-type status and CD3+ TIL depletion identified a high-risk subgroup with increased relapse risk (HR = 11.7, P = 0.051). CONCLUSIONS:The combination of ARID1A wild-type status and low CD3+ TIL levels suggests higher relapse risk in low-stage CCOC. These findings warrant further investigation into targeted and immune-based therapies for high-risk early-stage patients.

Primary carcinosarcomas are a rare type of cervical tumors. A 75-year-old female patient diagnosed with stage IB2 cervical carcinosarcoma (CCS) was treated with radical surgery followed by adjuvant chemoradiotherapy. She survived without recurrence for 3 years after the surgery. Double somatic mutations of the ATM (c.802C > T [p.Glu268*], variant allele frequency [VAF] of 48.5

Tumor-infiltrating immune cells across high-grade serous carcinoma subtypes. A, CD3+ infiltration across HRR-centric subtypes; labeled P value represents comparison of BRCA2m and CCNE1g groups using the Mann–Whitney U test. B, CD3+ infiltration across TCGA transcriptomic subtypes; labeled P value represents comparison of IMR and PRO groups using the Mann–Whitney U test. C, CD3+ infiltration across Tothill transcriptomic subtypes; labeled P value represents comparison of C2 and C5 groups using the Mann–Whitney U test. BRCA2m, BRCA2 mutant; BRCA1m, BRCA1 mutant; EMSY-overxp; overexpression of EMSY; CCNE1g, gain of CCNE1; HRRwt, non-CCNE1g HRR wild-type.

PTEN and RB loss in HGSOC. A, Frequency of loss of PTEN protein expression across HRR-centric subtypes. B, Frequency of loss of RB protein expression across HRR-centric subtypes. C, Impact of RB loss on survival in patients based on HRR status. Multivariable hazard ratio (mHR) for HRR-ab: RB loss vs. HRR-ab RB-intact = 0.50; 95% CI, 0.30–0.84; mHR for HRRwt/CCNE1g: RB loss vs. HRRwt/CCNE1g: RB-intact = 0.71; 95% CI, 0.48–1.06. BRCA2m, BRCA2 mutant; BRCA1m, BRCA1 mutant; EMSY-overxp; overexpression of EMSY; nBRCA-HRRm, non-BRCA1/2 HRR gene mutation; CCNE1g, gain of CCNE1; HRRwt, non-CCNE1g HRR wild-type. HRR-ab, HRR-aberrant: BRCA1m, BRCA2m, EMSY-overxp, or nBRCA-HRRm.

HRR pathway (HRR)–centric subtyping of high-grade serous carcinoma. A, HRR-centric classification taxonomy. B, OS profile of HRR-centric subtypes. C, Chemosensitivity of HRR-centric subtypes at first-line treatment (left) and treatment for disease relapse (right) as determined by CA125 tumor marker (top) and radiology (bottom). BRCA2m, BRCA2 mutant; BRCA1m, BRCA1 mutant; EMSY-overxp; overexpression of EMSY; CCNE1g, gain of CCNE1; HRRwt, non-CCNE1g HRR wild-type.

PARP inhibitors have changed the management of advanced high-grade epithelial ovarian cancer (EOC), especially homologous recombinant (HR)-deficient advanced high-grade EOC. However, the effect of PARP inhibitors on HR-proficient (HRP) EOC is limited. Thus, new therapeutic strategy for HRP EOC is desired. In recent clinical study, the combination of PARP inhibitors with anti-angiogenic agents improved therapeutic efficacy, even in HRP cases. These data suggested that anti-angiogenic agents might potentiate the response to PARP inhibitors in EOC cells. Here, we demonstrated that anti-angiogenic agents, bevacizumab and cediranib, increased the sensitivity of olaparib in HRP EOC cells by suppressing HR activity. Most of the γ-H2AX foci were co-localized with RAD51 foci in control cells. However, most of the RAD51 were decreased in the bevacizumab-treated cells. RNA sequencing showed that bevacizumab decreased the expression of CRY1 under DNA damage stress. CRY1 is one of the transcriptional coregulators associated with circadian rhythm and has recently been reported to regulate the expression of genes required for HR in cancer cells. We found that the anti-angiogenic agents suppressed the increase of CRY1 expression by inhibiting VEGF/VEGFR/PI3K pathway. The suppression of CRY1 expression resulted in decrease of HR activity. In addition, CRY1 inhibition also sensitized EOC cells to olaparib. These data suggested that anti-angiogenic agents and CRY1 inhibitors will be the promising candidate in the combination therapy with PARP inhibitors in HR-proficient EOC.

Logistic regression classifiers' normalized coefficient and confidence interval

ObjectiveAn effective treatment strategy for epithelial ovarian cancer (EOC) with homologous recombination (HR)-proficient (HRP) phenotype has not been established, although poly (ADP-ribose) polymerase inhibitors (PARPi) impact the disease course with HR-deficient (HRD) phenotype. Here, we aimed to clarify the cellular effects of paclitaxel (PTX) on the DNA damage response and the therapeutic application of PTX with PARPi in HRP ovarian cancer.MethodsTwo models with different PTX dosing schedules were established in HRP ovarian cancer OVISE cells. Growth inhibition and HR activity were analyzed in these models with or without PARPi. BRCA1 phosphorylation status was examined in OVISE cells by inhibiting CDK1, which was reduced by PTX treatment. CDK1 expression was evaluated in EOC patients treated with PTX-based neoadjuvant chemotherapy.ResultsPTX suppressed CDK1 expression resulting in impaired BRCA1 phosphorylation in OVISE cells. The reduced CDK1 activity by PTX could decrease HR activity in response to DNA damage and therefore increase the sensitivity to PARPi. Immunohistochemistry showed that CDK1 expression was attenuated in samples collected after PTX-based chemotherapy compared to those collected before chemotherapy. The decrease in CDK1 expression was greater with dose-dense PTX schedule than with the conventional PTX schedule.ConculsionsPTX could act synergistically with PARPi in HRP ovarian cancer cells, suggesting that the combination of PTX with PARPi may be a novel treatment strategy extending the utility of PARPi to EOC. Our findings provide cules for future translational clinical trials evaluating the efficacy of PTX in combination with PARPi in HRP ovarian cancer.

Diagnostic accuracy of clinicopathological factors using Machine Learning Algorithms

Pretreatment peripheral blood tests of 334 patients with epithelial ovarian cancer and 101 patients with benign ovarian tumor

Explanation and evaluation of the random forest (RF) classifier. (A) Schematic illustration of the classification of samples by the RF. (B, C) Representative classification trees from the discrimination between malignant and benign tumors. These trees are only representations out of 4,000 trees constructed in the RF classifier. The final class is determined as a result of voting by all 4,000 trees. (D, E) The highest accuracy of prediction (D) and the AUC (E) using different numbers of samples in RF classification between malignant and benign tumors. The mean accuracy and AUC with these 95% confidence intervals were presented for 10 independent sets of randomly selected data of 20%, 40%, 60%, and 80% of patients from the training and test cohorts.

BACKGROUND/AIM:We investigated the predictive value of scoring systems of peritoneal disseminations for complete surgery (CS) at primary debulking surgery (PDS) in advanced ovarian cancer.PATIENTS AND METHODS:We retrospectively enrolled eligible patients with clinical stages III or IVA selected for PDS from January 2015 to December 2019. Concern variables were predictive index value (PIV) and peritoneal cancer index (PCI) from operative and pathological reports. Primary endpoints were cutoffs to predict operative completeness using the receiver operating characteristic curve.RESULTS:Among 111 patients, PIV ≥8 and PCI ≥13 were the best predictors of incomplete PDS, including optimal and suboptimal surgeries (AUC=0.821 and 0.855, respectively). CS rates in PIV ≤6 and PCI ≤12 were significantly higher than in PIV ≥8 (89.3% vs. 47.2%; p<0.05) and PCI ≥13 (90.9% vs. 41.2%: p<0.05).CONCLUSION:PIV and PCI are potential predictors for CS at PDS.

Ovarian clear cell carcinoma (OCCC), one of the histopathological types of ovarian cancer, has a poor prognosis when it recurs; however, it is difficult to precisely predict the risk of recurrence. Here, we analyzed pathological images of OCCC to elucidate the relationship between pathological findings and recurrence, and using machine learning, we established a classifier to predict the recurrence and several other prognosis indicators of this disease. In total, 110 patients with OCCC treated with primary surgery at a single institution were enrolled in this study. We used the deep-learning neural networks to process the whole slide images of OCCC obtained by digitally scanning the original hematoxylin and eosin-stained glass slides. The images were preprocessed and used as input to the machine learning pipeline. We fine-tuned its parameters to predict the recurrence, progression-free survival, and the overall survival days of all patients. We predicted the recurrence of OCCC with an overall accuracy of 93%, area under the receiver operating characteristic curve of 0.98, and sensitivity/specificity above 0.92 using Resnet 34. Furthermore, we predicted progression-free survival/overall survival of the patients with ~90% accuracy. In conclusion, our study demonstrates the feasibility of using a machine learning system to predict different features of OCCC samples using histopathological images as input. This novel application provides accurate prognosis information and aids in the development of personalized treatment strategies.