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The study investigated the expression of GATA3, a transcription factor involved in immune regulation, in tubo-ovarian carcinomas and its association with clinicopathological factors and prognosis. Immunohistochemical analysis was performed on 91 tubo-ovarian carcinoma samples to determine the presence of GATA3-positive inflammatory cells in the tumor microenvironment. A threshold of 10% or higher was considered a positive expression. The results showed that 46.7% of tubo-ovarian carcinomas exhibited positive expression of GATA3 in inflammatory cells. There was no significant difference in GATA3 expression between patients who received pre-surgical chemotherapy and those who underwent primary surgery. However, high-grade serous carcinomas had a significantly higher proportion of GATA3-positive inflammatory cells compared to other subtypes. Advanced-stage tumors (stage III) had a higher percentage of GATA3-positive inflammatory cells compared to stage II and I tumors. Patients with positive GATA3 expression had a significantly lower disease-free survival rate. However, there was no significant association between GATA3 expression and chemotherapy response score. These findings suggest that increased expression of GATA3 in mononuclear inflammatory cells is associated with higher grade, advanced stage, and increased risk of recurrence in tubo-ovarian carcinoma. This implies that heightened GATA3 expression negatively impacts anti-tumor immunity, tumor growth progression, and invasiveness in tubo-ovarian carcinomas., (© 2024 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Objective: A Serous Tubal Intraepithelial Carcinoma (STIC) without concomitant invasive carcinoma is occasionally identified and associated with a high risk of subsequent peritoneal carcinomatosis. Management needs optimisation. This study explores professionals' opinions and clinical practices regarding the diagnosis, counselling, treatment and follow-up of isolated STIC to facilitate clinical decision making and optimise the direction of future research. A secondary aim is to assess international clinical guidelines., Design: Focus group study., Setting: Four online sessions., Population: International panel (n = 12 countries) of gynaecologists, gynaecologic oncologists, pathologists and medical oncologists (n = 49)., Methods: A semi-structured interview guide was used. Two independent researchers analysed transcripts by open and axial coding. Results were organised in domains. Relevant (inter)national guidelines were screened for recommendations regarding isolated STIC., Main Outcome Measures: Professionals' opinions and clinical practices regarding isolated STIC management., Results: Regarding pathology, most professionals identified the SEE-FIM protocol as standard of care for high-risk patients, whereas variation exists in the histopathological examination of fallopian tubes in the general population. Confirmation of STIC diagnosis by a specialised pathologist was recommended. Regarding work-up and follow-up after STIC diagnosis, there was variety and discordance. Data on outcomes is limited. As for treatment, chemotherapy and PARP inhibitors were not recommended by most. Eleven guidelines provided limited recommendations., Conclusions: We identified recommendations and highlighted knowledge gaps in the diagnosis and management of isolated STIC. Moreover, recommendations in clinical guidelines are limited. There is an agreed need for international collaboration for the prospective registration of isolated STIC., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

An endometrioid carcinogenic pathway of the fallopian tube with possible potential precursors including type II SCOUTs (secretory cell outgrowths) and E-TIN (endometrioid tubal intraepithelial neoplasia) has been recently documented. We report an incidental focus of E-TIN identified in a hysterectomy specimen for Grade 1 endometrioid type endometrial carcinoma. The lesion was present at the fimbriated end of left fallopian tube involving 1 plica. It comprised crowded glandular proliferation with a pseudostratified columnar lining. The cells displayed elongated nuclei with no remarkable nuclear atypia.Immunohistochemistry showed patchy loss of PAX 2 expression with multifocal aberrant nuclear and cytoplasmic staining for B-catenin. p53 was wild-type and ER was positive.In view of the co-existing endometrioid type endometrial carcinoma, a possible metastatic spread to the fallopian tube was considered. However, morphologically no obvious nuclear atypia noted, and no associated inflammatory response or desmoplastic stromal reaction identified within the tubal lesion. And on immunostaining, the endometrial tumour was distinct from the tubal lesion. For instance, PTEN was negative/lost in the endometrial tumour but retained in the tubal lesion and B-catenin was membranous in the endometrial tumour but aberrant with multifocal nuclear and cytoplasmic overexpression in the tubal lesion. WT1 was negative in the endometrial tumour but positively expressed by the tubal lesion. All the above findings favoured the possibility of the tubal lesion as being independent of the endometrial primary. In conclusion, we describe an incidental B-catenin aberrant endometrioid type proliferation of the fallopian tube/E-TIN, to raise awareness of such lesions., Competing Interests: Declarations. Competing interests: The authors have no relevant financial or non-financial interests to disclose., (© 2024. Crown.)

Background: Antibody-drug conjugates (ADC) have emerged as a highly promising systemic option in the treatment of recurrent ovarian cancer. The present study aimed to evaluate the treatment efficacy of folate receptor α (FRα)-targeting ADCs, associated treatment-related adverse events (TRAEs), and their impact on treatment safety., Methods: We conducted an electronic search to identify prospective trials of single-agent ADCs targeting FRα and those combined with chemotherapy in recurrent ovarian cancer. Information regarding the objective response rate (ORR) and TRAEs was collectively analyzed, and differences in subgroups based on FRα receptor expression levels were investigated. The protocol was registered with PROSPERO (CRD42023491151)., Results: Ten studies with a total of 940 patients (859 treated with Mirvetuximab soravtansine-gynx (MIRV)), 45 with Farletuzumab Ecteribulin (MORAb-202), and 36 with Luveltamab Tazevibulin (STRO-002) were included in this meta-analysis. Based on the pooled data, the ORR of the entire cohort was 37% (95% CI: 0.30-0.43), while that of the high-FRα expression group was 34% (95% CI: 0.26-0.42). The incidence of grade ≥ 3 adverse events was 27% (95% CI: 0.19-0.36)., Conclusion: FRα-targeting ADCs, including MIRV, demonstrated definite efficacy and good safety as novel choices for second-line and beyond treatment of advanced or recurrent ovarian cancer. Patients with high FRα expression showed ORR and PFS benefits similar to those in the overall cohort., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

In recent years, it has become clear that artificial intelligence (AI) models can achieve high accuracy in specific pathology-related tasks. An example is our deep-learning model, designed to automatically detect serous tubal intraepithelial carcinoma (STIC), the precursor lesion to high-grade serous ovarian carcinoma, found in the fallopian tube. However, the standalone performance of a model is insufficient to determine its value in the diagnostic setting. To evaluate the impact of the use of this model on pathologists' performance, we set up a fully crossed multireader, multicase study, in which 26 participants, from 11 countries, reviewed 100 digitalized H&E-stained slides of fallopian tubes (30 cases/70 controls) with and without AI assistance, with a washout period between the sessions. We evaluated the effect of the deep-learning model on accuracy, slide review time and (subjectively perceived) diagnostic certainty, using mixed-models analysis. With AI assistance, we found a significant increase in accuracy (p < 0.01) whereby the average sensitivity increased from 82% to 93%. Further, there was a significant 44 s (32%) reduction in slide review time (p < 0.01). The level of certainty that the participants felt versus their own assessment also significantly increased, by 0.24 on a 10-point scale (p < 0.01). In conclusion, we found that, in a diverse group of pathologists and pathology residents, AI support resulted in a significant improvement in the accuracy of STIC diagnosis and was coupled with a substantial reduction in slide review time. This model has the potential to provide meaningful support to pathologists in the diagnosis of STIC, ultimately streamlining and optimizing the overall diagnostic process., (© 2024 The Author(s). The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

Background: The clinical validity of the multifactorial BOADICEA model for epithelial tubo-ovarian cancer (EOC) risk prediction has not been assessed in a large sample size or over a longer term., Methods: We evaluated the model discrimination and calibration in the UK Biobank cohort comprising 199,429 women (733 incident EOCs) of European ancestry without previous cancer history. We predicted 10-year EOC risk incorporating data on questionnaire-based risk factors (QRFs), family history, a 36-SNP polygenic risk score and pathogenic variants (PV) in six EOC susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, BRIP1 and PALB2)., Results: Discriminative ability was maximised under the multifactorial model that included all risk factors (AUC = 0.68, 95% CI: 0.66-0.70). This model was well calibrated in deciles of predicted risk with calibration slope=0.99 (95% CI: 0.98-1.01). Discriminative ability was similar in women younger or older than 60 years. The AUC was higher when analyses were restricted to PV carriers (0.76, 95% CI: 0.69-0.82). Using relative risk (RR) thresholds, the full model classified 97.7%, 1.7%, 0.4% and 0.2% women in the RR < 2.0, 2.0 ≤ RR < 2.9, 2.9 ≤ RR < 6.0 and RR ≥ 6.0 categories, respectively, identifying 9.1 of incident EOC among those with RR ≥ 2.0., Discussion: BOADICEA, implemented in CanRisk ( www.canrisk.org ), provides valid 10-year EOC risks and can facilitate clinical decision-making in EOC risk management., (© 2024. The Author(s).)

At present, the prevailing concept is that high-grade serous carcinoma (HGSC) arises from the fallopian tubes (FTs). We report an HGSC case occurring in a serous ovarian cyst against the background of a serous tubal intraepithelial carcinoma (STIC)-like lesion. We also provide a literature review that contains references to clinical cases of the occurrence of STIC-like lesions in the ovary and phylogenetic studies that do not always reveal obvious bonds between early dysplastic serous lesions and HGSC. The article discusses cases of association between HGSCs of serous borderline tumors (SBTs) and low-grade serous carcinomas (LGSCs) in the context of their possible histogenetic relationship. We propose a concept in which high-grade serous carcinogenesis, represented by the p53-signature-STIC-HGSC continuity, occurs in the serous epithelium of both the FT and other locations., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 by the International Society of Gynecological Pathologists.)

The somatic BRCA1 or BRCA2 Pathogenic Variant (PV)/Likely PV (LPV) from Next Generation Sequencing (NGS) is the most important biomarker for PARP inhibitor use and maintenance-targeted therapies. A discrepancy in the detection rates of BRCA1 and BRCA2 PV/LPV was identified among the NGS platforms. The objective of this study was to compare the somatic BRCA results from two distinct platforms using the same cohort and to identify the causes of these differences. Patients with epithelial ovarian cancer who concurrently underwent tumor NGS using two different platforms between January 2022 and June 2023 were included in this study. The two platforms used were in-house tumor NGS (Illumina NextSeq 550Dx, SureSelectXT library kit, and datasets from 1000 Genomes, ESP6500, ExAC, and ClinVar) and GreenPlan homologous recombination deficiency (HRD) test (Illumina NextSeq 550Dx, customized Twist Bioscience library kit, and datasets from COSMIC and OncoKB). The results of somatic mutations in BRCA1 and BRCA2 were compared between the two platforms. Of the 118 patients, 11.9% (n = 14) exhibited a discordant interpretation of BRCA1 or BRCA2 between the two platforms. Eleven patients (9.3%) exhibited negative results in the in-house platform but positive results (eight seven as PV of BRCA1, one as PV of BRCA2, one as LPV of BRCA1, and two as LPV of BRCA2) in the GreenPlan HRD test, while three patients (2.6%) had positive BRCA pathogenic variants (two as PV of BRCA1 [c.3340G > T, c.5152 + 3 A > C], one as LPV of BRCA2 [c.8174G > T], and one as LPV of BRCA1 [c.5017&#95;5019delCAC]) in the in-house platform but a negative result in the GreenPlan HRD test. The discordance rate of somatic BRCA1 or BRCA2 mutations from different platforms was approximately 12%. In the case of the strong implication of BRCA PV/LPV with a negative result with one genetic test, different platforms could be considered in limited cases. Careful interpretation and further studies for the cross-validation of gene analysis platforms are needed., (© 2024. The Author(s).)

The NCCN Guidelines for Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer provide multidisciplinary diagnostic workup, staging, and treatment recommendations for this disease. These NCCN Guidelines Insights detail how the evolution of the use of PARP inhibitors as maintenance and single-agent regimens for the treatment of ovarian cancer informed panel recommendations in the guidelines.

Serous tubal intraepithelial carcinoma (STIC) is regarded as the origin of most high-grade serous carcinomas (HGSC). After a diagnosis of isolated STIC, risk of developing HGSC is substantial. Since surveillance cannot detect HGSC in time to cure the disease, there is no consensus on the optimal treatment after a diagnosis of isolated STIC, but chemotherapy is considered one of the possible strategies. In this case report, we describe 2 women with advanced-stage HGSC treated with 3 cycles of neoadjuvant chemotherapy followed by interval debulking surgery. In both women, histopathological examination showed a complete histopathological tumor response, but a vital STIC was found in both cases. The 2 cases presented here indicate that STICs may not respond to chemotherapy. Further research focused on the underlying biology and chemosensitivity of STIC, as well as the effectiveness of treatment to prevent HGSC in case of isolated STIC, is needed., Competing Interests: L.C.L.T.v.K.: Grants from Amgen, AstraZeneca, Bayer, Janssen-Cilag, Merck, NanoString, Roche, Servier. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, Janssen, NanoString, Novartis, Pfizer, and Roche. Support provided for attending meetings and/or travel from Roche, NanoString, and ThermoFisher. Advisory Board from Cyclomics, Janssen-Cilag, LOGEX, Merck, Menarini, Protyon, Roche. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from EORTC Melanoma Group, Commission Personalized Medicine – Belgium. Stock from Cyclomics. Receipt of equipment, materials, drugs, medical writing, gifts, or other services from LOGEX, Lynxcare, and NanoString. All are not related to this manuscript. J.B.: Grants from Dutch Cancer Society, AstraZeneca. All are not related to this manuscript. M.J.: Advisory board of Pierre Fabre. All are not related to this manuscript. The remaining authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: This is a protocol for a Cochrane Review (prognosis). The objectives are as follows: To evaluate the predictive value of the prognostic factor HRD status, as determined by various clinically validated HRD assays at the time of staging laparotomy, compared to BRCA1/2 mutation status for progression-free survival and overall survival in patients with tubo-ovarian high-grade serous carcinoma treated in the first-line setting with a combination of surgery and platinum-based chemotherapy and/or maintenance with PARP inhibitors., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: We report the first documented case of concurrent ectopic complete hydatidiform mole (CHM) and high-grade serous carcinoma (HGSC) of the fallopian tube, associated with unique histologic features and mutations in the HGSC., Case Report: The patient presented with pelvic pain and vaginal bleeding. Laboratory examination revealed a positive urine pregnancy test and high serum beta-human chorionic gonadotropin (β-hCG). Transvaginal ultrasound demonstrated a left adnexal mass suspicious for ectopic pregnancy. Salpingectomy was performed, and the fallopian tube, noted to be ruptured with a visible ectopic pregnancy, demonstrated chorionic villi with diffuse hydropic enlargement and mild trophoblast hyperplasia. p57/Kip2 immunohistochemical staining (IHC) showed loss of expression in villous cytotrophoblasts and stromal cells, confirming CHM. An incidental 0.5 cm focus of HGSC was identified in the fallopian tube, associated with serous tubal intraepithelial carcinoma (STIC). The tumor exhibited solid, transitional cell carcinoma-like, and acinar patterns, with intraluminal mucin highlighted by Alcian blue and PAS-D stains. Patient underwent staging surgery which resulted in the finding of a 0.7 cm HGSC in the left ovary with morphology concordant to the tubal mass, except for a pseudo-endometrioid pattern in the ovary. Notably, the HGSC is positive (2+, 90%) for FOLR1 antigen and harbored a pathogenic mutation (p.R273H) in exon 8 of the TP53 gene., Conclusion: This report emphasizes the crucial role of meticulous sampling and histopathologic examination of the fallopian tube, including the fimbriae, in all salpingectomy specimens. Furthermore, the case highlights the broad spectrum of morphologies encountered in HGSC, including mucinous differentiation. HGSC should be in the differential diagnosis when encountering mucin-producing high-grade carcinoma., (© 2024 by the Association of Clinical Scientists, Inc.)

Introduction: Epithelial ovarian cancer (EOC) is the fourth most common malignancy among Malaysian women. This study aims to evaluate the outcomes of EOC, fallopian tube cancer and primary peritoneal serous carcinoma (PPSC) between a centre managed by both clinical oncologists and gynaecologic oncologists, Institut Kanser Negara (IKN) and a centre managed solely by gynaecologic oncologists, Hospital Ampang (HA)., Materials and Methods: This retrospective cohort study involved data review of all the newly diagnosed patients with EOC, fallopian tube cancer and PPSC who received treatment in IKN and HA from January 2015 to December 2019, with follow-up continuing until December 2022. The primary outcome is overall survival (OS) and the secondary outcome is progression free survival (PFS) rates; estimated using the Kaplan-Meier method and compared using the logrank test. Another secondary outcome is to determine the prognostic factors affecting the OS of patients from these two cohorts using Cox regression analysis., Results: A total of 256 patients from both centres were recruited (106 and 150 patients from IKN and HA respectively) and at the time of diagnosis, more than half of the patients were diagnosed with advanced stage disease (67.5% and 62% from IKN and HA respectively). The median OS for patients with EOC was significantly longer for HA compared to IKN (69 months vs 39 months, p < 0.042). There was no significant difference in the median PFS for both centres. Furthermore, when the comparison was made based on the disease staging, there was no difference in the median OS and median PFS. Multivariate analysis identified that patients aged between 41 and 60 years (Hazard ratio [HR]: 2.83; 95% CI: 1.11, 7.25, p = 0.030), patients with medical illness (HR 1.51; 95% CI: 1.04, 2.21, p = 0.033), patients with advanced-stage disease (HR: 3.63; 95% CI: 2.20, 6.00, p < 0.001) and patients with ECOG ≥ 1 (HR: 2.00; 95%CI: 1.38, 2.91, p < 0.001) as independent risk factors for adverse outcome. Meanwhile, optimal surgery is found to be a protective factor (HR 0.60; 95% CI: 0.41, 0.89, p = 0.011). Patients with optimal surgery had reduced the risk of adverse outcome., Conclusion: Our findings confirmed that the median OS was significantly longer for patients with EOC in HA compared to IKN. However, there was no significant difference in the median OS based on the disease staging; therefore, we could not establish the non-inferiority outcome between the two centres. Furthermore, there was no significant difference in median PFS for both centres. This could be due to small sample size to be able to detect any difference. In addition, it could also be contributed by the different treatment options available and unequal volume of patients treated in both centres. Thus, further study with larger sample size and longer time period is needed to provide better guidance and treatments for the patients.

Ovarian high-grade serous carcinoma (HGSC) originates in the fallopian tube, with secretory cells carrying a TP53 mutation, known as p53 signatures, identified as potential precursors. p53 signatures evolve into serous tubal intraepithelial carcinoma (STIC) lesions, which in turn progress into invasive HGSC, which readily spreads to the ovary and disseminates around the peritoneal cavity. We recently investigated the genomic landscape of early- and late-stage HGSC and found higher ploidy in late-stage (median 3.1) than early-stage (median 2.0) samples. Here, to explore whether the high ploidy and possible whole-genome duplication (WGD) observed in late-stage disease were determined early in the evolution of HGSC, we analysed archival formalin-fixed paraffin-embedded (FFPE) samples from five HGSC patients. p53 signatures and STIC lesions were laser-capture microdissected and sequenced using shallow whole-genome sequencing (sWGS), while invasive ovarian/fallopian tube and metastatic carcinoma samples underwent macrodissection and were profiled using both sWGS and targeted next-generation sequencing. Results showed highly similar patterns of global copy number change between STIC lesions and invasive carcinoma samples within each patient. Ploidy changes were evident in STIC lesions, but not p53 signatures, and there was a strong correlation between ploidy in STIC lesions and invasive ovarian/fallopian tube and metastatic samples in each patient. The reconstruction of sample phylogeny for each patient from relative copy number indicated that high ploidy, when present, occurred early in the evolution of HGSC, which was further validated by copy number signatures in ovarian and metastatic tumours. These findings suggest that aberrant ploidy, suggestive of WGD, arises early in HGSC and is detected in STIC lesions, implying that the trajectory of HGSC may be determined at the earliest stages of tumour development. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Objective: First-line bevacizumab plus carboplatin and paclitaxel (CP) is approved for stage III/IV ovarian cancer treatment following initial surgical resection, based on global phase III GOG-0218 and ICON7 trials. This study evaluated the efficacy and safety of bevacizumab + CP as first-line ovarian cancer therapy in Chinese patients., Methods: Patients with newly diagnosed, International Federation of Gynecology and Obstetrics (FIGO) stage III/IV epithelial ovarian, fallopian tube, or primary peritoneal cancer post-primary surgery were randomized 1:1 to receive 6 cycles of CP with bevacizumab/placebo, followed by bevacizumab/placebo maintenance until unacceptable toxicity or disease progression. Primary endpoint was investigator-assessed progression-free survival (PFS). Stratification factors were FIGO stage and debulking status (stage III optimally debulked vs stage III suboptimally debulked vs stage IV) and Eastern Cooperative Oncology Group performance status (0 vs 1 or 2)., Results: Of randomized patients, 51 received bevacizumab + CP and 49 received placebo + CP. Median PFS was 22.6 months with bevacizumab + CP (95% confidence interval [CI]=18.6, not estimable) and 12.3 months (95% CI=9.5, 15.0) with placebo + CP (stratified hazard ratio=0.30; 95% CI=0.17, 0.53). Treatment-related grade 3/4 adverse events occurred in 46 of 49 (94%) patients receiving bevacizumab + CP, and 34 of 50 (68%) receiving placebo + CP., Conclusion: Bevacizumab + CP showed clinically meaningful improvement in PFS vs placebo + CP, consistent with GOG-0218 results. Safety data were aligned with the known bevacizumab safety profile. These results support first-line bevacizumab + CP therapy in Chinese patients with ovarian cancer., Trial Registration: ClinicalTrials.gov Identifier: NCT03635489., Competing Interests: W.X., L.J., A.R., Y.R., Z.Y., Z.H., H.A., W.L., Z.J., L.Z., D.W., Z.J., L.G., C.G., C.Y., and X.F. received institute research funding from F. Hoffmann-La Roche Ltd. N.S., W.H., and L.D. are employees of F. Hoffmann-La Roche Ltd. N.S. and W.H. own shares in F. Hoffmann-La Roche Ltd., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Background: Endometrial serous carcinoma (ESC) and tubo-ovarian high-grade serous carcinoma (HGSC) are characterized by late-stage presentation and high mortality. Current guidelines for prevention recommend risk-reducing salpingo-oophorectomy (RRSO) in patients with hereditary mutations in cancer susceptibility genes. However, HGSC displays extensive genetic heterogeneity with alterations in 168 genes identified in TCGA study, but current germline testing panels are often limited to the handful of recurrently mutated genes, leaving families with rare hereditary gene mutations potentially at-risk., Objective: To determine if there are rare germline mutations that may aid in early identification of more patients at-risk for ESC and/or HGSC by evaluating patients with concurrent ESC, HGSC or precursor lesions, and endometrial atypical hyperplasia (CAH) or low-grade endometrial endometrioid adenocarcinoma (LGEEA)., Methods: We performed targeted next-generation sequencing using TSO 500, a 523 gene panel, on formalin-fixed paraffin-embedded tumor and matched benign non-tumor tissue blocks from 5 patients with concurrent ESC, HGSC or precursor lesions, and CAH or LGEEA., Results: We identified germline pathogenic, likely pathogenic or uncertain significance variants in cancer susceptibility genes in 4 of 5 patients - affected genes included GLI1, PIK3R1, FOXP1, FANCD2, INPP4B and H3F3C. Notably, none of these genes were included in the commercially available germline testing panels initially used to evaluate the patients at the time of their diagnoses., Conclusion: Comprehensive germline testing of patients with concurrent LGEEA or CAH and ESC, HGSC or precursor lesions may aid in early identification of relatives at-risk for cancer who may be candidates for RRSO with hysterectomy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. One of the authors (RE) is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for [Gynecologic oncology] and was not involved in the editorial review or the decision to publish this article. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: KMF has received honoraria as a speaker for Illumina – unrelated to the current manuscript; RE receives/has received research funding from Clovis oncology, GSK, Merck and AstraZeneca – unrelated to the current manuscript; RE has received consulting fees and/or honoraria from AstraZeneca, Clovis, Eisai, GSK, Daiichi Sankyo, PMV Pharmaceuticals, Immunogen, Mersana, Myriad, Novocure, Onconova, Elevar therapeutics and Renegenron – unrelated to the current manuscript. WS has received honoraria from Guardant Health – unrelated to the current manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The use of bevacizumab has been hampered by safety concerns despite demonstrable progression-free survival (PFS) benefit in subjects with platinum-resistant ovarian cancer, highlighting the need for novel effective and safe antiangiogenic agents. This study aimed to characterize the tolerability, safety, and antitumor activities of escalating doses of anti-VEGF antibody suvemcitug plus chemotherapy in platinum-resistant ovarian cancer patients., Methods: This open-label, dose-escalation trial enrolled adult patients (≥18 years) with platinum-resistant histologically or cytologically-confirmed epithelial ovarian, fallopian tube and primary peritoneal cancer. Eligible patients received paclitaxel or topotecan plus escalating doses of suvemcitug 0.5, 1, 1.5, or 2 mg/kg once every two weeks. The primary endpoints were safety and tolerability, and antitumor activities of suvemcitug., Results: Twenty-nine subjects received paclitaxel (n = 11) or topotecan (n = 18). No dose-limiting toxicities occurred. The most common adverse events of special interest were proteinuria (41.4%), hypertension (20.7%) and epistaxis (10.3%). No gastrointestinal perforations occurred. Nine subjects (31.0%, 95% CI 15.3-50.8) demonstrated investigators-confirmed objective response, including complete response in 1 and partial response in 8. The median PFS was 5.4 months (95% CI 2.2-7.4)., Conclusions: Suvemcitug demonstrated an acceptable safety profile and promising antitumor activities in platinum-resistant ovarian cancer patients, supporting its further clinical development., Competing Interests: Declaration of competing interest Jiangsu Simcere Pharmaceuticals Co., Ltd., the sponsor of this trial, provided all trial costs, including investigational drugs, laboratory tests, and associated operational cost. Yan Wu, Haolin Sun, Jiajing Zhang, Xiyang Sun are full-time employees of Shandong Simcere Bio-Pharmaceutical Co., Ltd., a subsidiary of the parent company of the sponsor (Simcere Pharmaceuticals Co., Ltd.). All other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The majority of high-grade serous carcinomas (HGSC) of the ovary, fallopian tube, and peritoneum arise from the precursor lesion called serous tubal intraepithelial carcinoma (STIC). It has been postulated that cells from STICs exfoliate into the peritoneal cavity and give rise to peritoneal HGSC several years later. While co-existent STICs and HGSCs have been reported to share similarities in their mutational profiles, clonal relationship between temporally distant STICs and HGSCs have been infrequently studied and the natural history of STICs remains poorly understood., Methods: We performed focused searches in two national databases from the Netherlands and identified a series of BRCA1/2 germline pathogenic variant (GPV) carriers (n = 7) who had STIC, and no detectable invasive carcinoma, at the time of their risk-reducing salpingo-oophorectomy (RRSO), and later developed peritoneal HGSC. The clonal relationship between these STICs and HGSCs was investigated by comparing their genetic mutational profile by performing next-generation targeted sequencing., Results: Identical pathogenic mutations and loss of heterozygosity of TP53 were identified in the STICs and HGSCs of five of the seven patients (71%), confirming the clonal relationship of the lesions. Median interval for developing HGSC after RRSO was 59 months (range: 24-118 months)., Conclusion: Our results indicate that cells from STIC can shed into the peritoneal cavity and give rise to HGSC after long lag periods in BRCA1/2 GPV carriers, and argues in favor of the hypothesis that STIC lesions may metastasize., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Most extrauterine high-grade serous carcinomas (HGSCs) are thought to develop first in the distal fallopian tube. Most models of HGSC assume origin from relatively stable, noninvasive serous tubal intraepithelial carcinomas. However, widespread tumor involvement in the absence of a serous tubal intraepithelial carcinoma could occur after catastrophic genomic events (CGEs; such as chromothripsis or polyploidy). Twenty-six HGSCs assigned to fallopian tube (n = 9, group 1) and/or ovary (n = 9, group 2), and primary peritoneal (n = 8, group 3) were assessed by microarray (Oncoscan). CGEs were identified in 15/26 (57.7%); chromothripsis-like pattern in 13/26 (50.0%) and polyploidy in 6/26 (23.1%). CGE was seen in 4/9 (44.4%), 9/9 (100%), and 2/8 (25%) cases in groups 1. 2, and 3, respectively. Overall, CGEs were seen in 9/9 (100%) cases with grossly evident ovarian parenchymal involvement versus 6/17 (35.3%) without ( P = 0.0024). Ovarian size (measured on the long axis) correlated with CGE positivity ( P = 0.016). CGEs are significantly more common in HGSCs with ovarian parenchymal involvement compared with those limited to the fallopian tube and/or extraovarian tissues. These associations suggest geographically different tumor growth patterns and support the subdivision of HGSCs according to not only the stage but also tumor distribution. They have implications for clinical and pathologic presentation, trajectory of tumor evolution, and in the case of primary peritoneal HGSCs, potentially unique precursors to tumor transitions that could inform or influence cancer prevention efforts., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Mohsen Beheshti reports a relationship with Novartis Pharma GmbH that includes: board membership and consulting or advisory. Christian Pirich reports a relationship with Novartis Pharma GmbH that includes: board membership and consulting or advisory. Other authors declare that they have no conflict of intrest.

Physiologically, claudin 18 splice variant 2 (CLDN18.2) expression is restricted to the gastric epithelium, but its expression has been detected in solid cancers. Zolbetuximab, a chimeric IgG1 antibody targeting CLDN18.2, has demonstrated promising effects in patients suffering from CLDN18.2-positive, HER2-negative locally advanced gastric cancer and is currently being studied further. To date, little is known about CLDN18.2 expression in other histological subtypes of tubo-ovarian carcinoma (TOC) and their matching metastases.Using a cohort of all histological TOC subtypes, we investigated the immunohistochemical (IHC) CLDN18.2 expression in both TOCs (n = 536), their matching metastatic tissue (n = 385) and in 93 metastases without primary. Tissue microarrays comprised both the tumor center and periphery. IHC positivity was defined as biomarker expression of ≥ 75% in tumor cells with moderate-to-strong membranous staining.Overall CLDN18.2 positivity was 4.1% (21/515) in the TOC centers and 3.6% (18/498) in their peripheries. In primaries of mucinous tubo-ovarian carcinoma (MTOC), CLDN18.2 positivity rates were 45% (18/40) and 36.6% (15/41), respectively. Positivity rates for the corresponding metastases were 33% (4/12, center) and 27% (3/11, periphery). The expression was relatively homogenous throughout all tumor sites. With no expression in 99.5% of nonmucinous tumors, CLDN18.2 positivity was almost exclusively seen in the mucinous subtype.In tubo-ovarian carcinoma, CLDN18.2 expression was, with rare exceptions, restricted to the mucinous subtype. Among them, 33% of metastasized MTOCs presented with CLDN18.2 positivity. Hence, CLDN18.2 might display a promising target for personalized therapy in patients with advanced MTOC., (© 2024. The Author(s).)

Objective: Recent evidence suggests that the fimbriated end of the fallopian tube harbors the precursor cells for many high-grade ovarian cancers, opening the door for development of better screening methods that directly assess the fallopian tube in women at risk for malignancy. Previously we have shown that the karyometric signature is abnormal in the fallopian tube epithelium in women at hereditary risk of ovarian cancer. In this study, we sought to determine whether the karyometric signature in serous tubal intraepithelial carcinoma (STIC) is significantly different from normal, and whether an abnormal karyometric signature can be detected in histologically normal tubal epithelial cells adjacent to STIC lesions., Methods: The karyometric signature was measured in epithelial cells from the proximal and fimbriated portion of the fallopian tube in fallopian tube specimens removed from women at: 1) average risk for ovarian cancer undergoing surgery for benign gynecologic indications (n = 37), 2) hereditary risk of ovarian cancer (germline BRCA alterations) undergoing risk-reducing surgery (n = 44), and 3) diagnosed with fimbrial STICs (n = 17)., Results: The karyometric signature in tubes with fimbrial STICs differed from that of tubes with benign histology. The degree of karyometric alteration increased with increasing proximity to fimbrial STICs, ranging from moderate in the proximal portion of the tube, to greatest in both normal appearing fimbrial cells near STICs as well as in fimbrial STIC lesions., Conclusion: These data demonstrate an abnormal karyometric signature in STICs that may extend beyond the STIC, potentially providing an opportunity for early detection of fallopian tube neoplasia., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The aim of the study was to investigate if time to start chemotherapy (TTC) after primary debulking surgery (PDS) impacted relative survival (RS) in advanced epithelial ovarian/fallopian tube/primary peritoneal cancer (EOC)., Methods: Nationwide population-based study of women with EOC FIGO stages IIIC-IV, registered 2008-2018 in the Swedish Quality Register for Gynecologic Cancer, treated with PDS and chemotherapy. TTC was categorized into; ≤21 days, 22-28 days, 29-35 days, 36-42 days and > 42 days. Relative survival (RS) was estimated using the Pohar-Perme estimate of net survival. Multivariable analyses of excess mortality rate ratios (EMRRs) were estimated by Poisson regression models., Results: In total, 1694 women were included. The median age was 65.0 years. Older age and no residual disease were more common in TTC >42 days than 0-21 days. The RS at 5-years was 37.9% and did not differ between TTC groups. In the R0 (no residual disease) cohort (n = 806), 2-year RS was higher in TTC ≤21 days (91.6%) and 22-28 days (91.4%) than TTC >42 days (79.1%). TTC >42 days (EMRR 2.33, p = 0.026), FIGO stage IV (EMRR 1.83, p = 0.007) and non-serous histology (EMRR 4.20, p < 0.001) were associated with 2-year worse excess mortality compared to TTC 0-21 days, in the R0 cohort. TTC was associated with 2-year survival in the R0 cohort in FIGO stage IV but not in stage IIIC. TTC was not associated with RS in patients with residual disease., Conclusions: For the entire cohort, stage IV, non-serous morphology and residual disease, but not TTC, influenced 5-year relative survival. However, longer TTC was associated with a poorer 2-year survival for those without residual disease after PDS., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the clinical and pathological characteristics of primary mucinous gland lesions of the fallopian tubes. Methods: The clinical data, pathomorphological characteristics and immunophenotype of 14 cases of primary mucinous gland lesions of the fallopian tube diagnosed at Obstetrics and Gynecology Hospital of Fudan University from 2015 to 2023 were analyzed retrospectively. In addition, a comprehensive review of relevant literature was conducted. Results: The age of 14 patients ranged from 53 to 83 years, with an average of 65 years. Among them, 13 cases exhibited unilateral involvement while one case showed bilateral presentation. Nine cases were mucinous metaplasia of the fallopian tube, four cases were invasive mucinous adenocarcinoma and one case was mucinous carcinoma in situ. Morphologically, mucinous metaplasia of the fallopian tube was focal, with or without inflammation. The cells of mucinous adenocarcinoma or mucinous carcinoma in situ exhibited characteristics indicative of gastrointestinal differentiation. Immunohistochemical analysis revealed diffuse positive expression of CK7, and negative expression of SATB2. CDX2 demonstrated positive staining in two cases. One case exhibited diffuse and strongly positive mutant expression of p53, whereas the remaining cases displayed wild-type expression. MUC6 showed diffuse or focally positive staining in mucinous gland lesions characterized by gastric differentiation. Some cases of mucinous adenocarcinoma of fallopian tube were subject to AB-PAS staining, resulting in red to purple cytoplasmic staining. Conclusions: Primary mucinous lesions of the fallopian tube are exceedingly uncommon. All cases of mucinous adenocarcinoma of fallopian tubes in this study exhibit the morphology and immunohistochemical characteristics of gastrointestinal differentiation. Mucinous metaplasia of the fallopian tube is a benign lesion of incidental finding, which is closely related to inflammation or gastric differentiation. Mucinous lesions of cervix, ovary and digestive tract are excluded in all patients, confirming the independent existence of mucinous lesions within fallopian tubes.

Objective: To investigate the clinicopathological features, diagnosis and differential diagnosis of pseudocarcinomatous hyperplasia of the fallopian tubes. Methods: Sixteen cases of pseudocarcinomatous hyperplasia of the fallopian tubes diagnosed at Obstetrics and Gynecology Hospital of Fudan University from January 2011 to January 2024 were collected.The pathological sections were reviewed, the clinical and pathological data were consulted, and immunohistochemical examination was conducted along with follow-up. Results: The patients were aged from 19 to 57 years, with an average age of 41 and a median age of 38. Among the 16 cases, 4 were located in the right fallopian tubes, 6 in the left fallopian tubes, while the remaining cases presented bilaterally. The general manifestations were tubal edema, crispness and purulent secretion in the lumen. Morphologically, the fallopian tube mucosa exhibited a significant infiltration of neutrophils, lymphocytes and plasma cells. The epithelial cells of the fallopian tube displayed evident proliferation, stratification and disorganized arrangement leading to formation of small glandular cavity with back-to-back, fissure-like and sieve-like structures. Immunohistochemical analysis revealed positivity for CK7 and WT1, along with wild-type p53 expression, Ki-67 index ranged from 5% to 20%. During the follow-up period ranging from 1 to 156 months, all the patients remained free of disease. Conclusions: Pseudocarcinomatous hyperplasia of the fallopian tube is a rare non-neoplastic lesion, which can lead to epithelial hyperplasia and atypical hyperplasia. The most important significance of recognizing this lesion lies in avoiding misdiagnosis of fallopian tube cancer during intraoperative and postoperative pathological examination. This ensures that clinicians can administer correct clinical interventions.

Background: Currently, a lively debate exists within the scientific community regarding the most suitable procedure for treating stages IIIB-IVB carcinoma of the ovary, fallopian tubes, and peritoneum. The options under most consideration are primary cytoreductive surgery or neoadjuvant chemotherapy followed by interval cytoreductive surgery., Primary Objective: To compare overall survival at 5 years in patients who underwent primary cytoreductive surgery versus neoadjuvant chemotherapy and interval cytoreductive surgery for stage IIIB-IVB ovarian cancer STUDY HYPOTHESIS: The treatment with primary cytoreductive surgery results in superior patient survival compared with neoadjuvant chemotherapy followed by interval cytoreductive surgery., Trial Design: This is a multicenter, retrospective cohort observational study. Data will be collected from patients undergoing surgery in hospitals worldwide. Two arms will be compared: primary cytoreductive surgery and neoadjuvant chemotherapy followed by interval cytoreductive surgery., Major Inclusion/exclusion Criteria: Patients must have suspected or histologically confirmed International Federation of Gynecology and Obstetrics (FIGO) stages IIIB-IVB ovarian, peritoneal, or fallopian tube cancers. They must have undergone primary surgery or first course of neoadjuvant chemotherapy between January 1, 2018 and December 31, 2019. Based on all available information before the surgery (primary or interval), the patient must have been considered completely resectable., Primary Endpoint: Overall survival at 5 years from the first treatment (chemotherapy in the case of neoadjuvant chemotherapy and cytoreduction in the case of primary cytoreductive surgery)., Sample Size: An estimated total of 5000 patients will be enrolled in the study., Estimated Dates for Completing Accrual and Presenting Results: March 2025 TRIAL REGISTRATION: NCT06223763., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: We reviewed 63 reports from the literature on rare non-serous tumors of the fallopian tubes and carried out a comparative analysis of clinical manifestations and diagnostic methods. We also report our observations from patients with these tumors., Materials and Methods: Of 157 patients with primary fallopian tube cancer (FTC) treated in our regional oncological hospital between 1970 and 2020, there were nine (6%) cases of rare non-serous cancers, including one case each of choriocarcinoma, carcinosarcoma, and neuroendocrine tumor, and two cases each of non-keratinizing squamous cell carcinoma, mucinous adenocarcinoma, and clear cell adenocarcinoma., Results: For carcinosarcoma and squamous cell, clear cell, and transitional cell carcinomas, clinical history, patient age, and clinical manifestations were similar to the main group of FTCs. Choriocarcinoma differed significantly from other cancers of the fallopian tubes in terms of patient age and clinical course. Mucinous adenocarcinoma, mesothelioma, and borderline tumors, with rare exceptions, were almost always asymptomatic and were found only incidentally during surgery. Choriocarcinoma and carcinosarcoma had an aggressive course, while squamous cell, transitional cell, clear cell, and mucinous carcinomas were less aggressive. Since most rare non-serous tumors have a similar disease course to typical FTCs and there is a lack of appropriate treatment protocols for rare tumors, treatment options developed for ovarian tumors and FTC are justified for these tumors., Conclusion: Rare non-serous malignant fallopian tube tumors are very similar to serous and endometrioid FTC in terms of clinical manifestations and diagnosis., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, ein Teil von Springer Nature.)

Objective: To explore the sequential chemotherapy efficacy of different chemotherapeutic regimens in ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma. Methods: A retrospective analysis was conducted on clinical and pathological data of 100 patients with platinum-sensitive ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma treated at Peking University Peopel's Hospital from January 1992 to January 2019. All patients underwent staging surgery or cytoreductive surgery followed by adjuvant chemotherapy. Based on different postoperative adjuvant chemotherapy regimens, patients were divided into the sequential chemotherapy group (70 cases) and the conventional chemotherapy group (30 cases). Clinical and pathological characteristics, chemotherapy efficacy, adverse reactions, and prognosis were compared between the two groups. Results: (1) Clinical and pathological characteristics: the age, tumor types (including ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma), pathological types, International Federation of Gynecology and Obstetrics (FIGO) stage, postoperative residual disease size, presence of neoadjuvant chemotherapy, and total number of chemotherapy cycles were compared between the sequential chemotherapy group and the conventional chemotherapy group. There were no statistically significant differences observed in these characteristics between the two groups (all P >0.05). (2) Chemotherapy efficacy: the median sum of complete response (CR)+partial response (PR) duration in the sequential chemotherapy group was 80.0 months (range: 39 to 369 months), whereas in the conventional chemotherapy group, it was 28.0 months (range: 13 to 52 months). A statistically significant difference was observed between the two groups ( Z =-7.82, P <0.001). (3) Chemotherapy adverse reactions: in the sequential chemotherapy group, 55 cases (79%, 55/70) experienced bone marrow suppression and 20 cases (29%, 20/70) had neurological symptoms. In the conventional chemotherapy group, these adverse reactions occurred in 11 cases (37%, 11/30) and 2 cases (7%, 2/30), respectively. Statistically significant differences were observed between the two groups for both bone marrow suppression and neurological symptoms (all P <0.05). For the other chemotherapy adverse reactions compared between the two groups, no statistically significant differences were observed (all P >0.05). (4) Prognosis: during the follow-up period, the recurrence rate in the sequential chemotherapy group was 73% (51/70) and in the conventional chemotherapy group was 100% (30/30). The median sum of recurrence-free interval was 70.5 months (range: 19 to 330 months) in the sequential chemotherapy group and 15.0 months (range: 6 to 40 months) in the conventional chemotherapy group. Statistically significant differences were observed between the two groups for both recurrence rate and median recurrence-free interval (all P <0.01).In the sequential chemotherapy group, the median progression-free survival (PFS) time was 84.0 months (range: 34 to 373 months), and the median overall survival (OS) time was 87.0 months (range: 45 to 377 months). In contrast, in the conventional chemotherapy group, the median PFS time was 30.5 months (range: 14 to 60 months), and the median OS time was 37.5 months (range: 18 to 67 months). Statistically significant differences were observed between the two groups for both PFS and OS (all P <0.001). In the sequential chemotherapy group, the 3-year, 5-year, and 10-year OS rates were 100% (70/70), 93% (65/70), and 21% (15/70), respectively. In contrast, in the conventional chemotherapy group, the OS rates were 50% (15/30) at 3 years, 3% (1/30) at 5 years, and 0 at 10 years, respectively. The two groups were compared respectively, and the differences were statistically significant (all P <0.05). Conclusions: Sequential chemotherapy significantly prolongs PFS and OS in patients with ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma. The efficacy is superior to that of the conventional chemotherapy, with manageable adverse reactions. The use of sequential chemotherapy as first-line treatment for patients with ovarian epithelial carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma is recommended.

Objective: To characterize trends in ovarian, fallopian tube, and primary peritoneal cancer incidence and incidence-based mortality based on histology and site of origin., Methods: We obtained age-adjusted incidence and incidence-based mortality for patients with ovarian, fallopian tube, and primary peritoneal cancer from 2000 to 2019 from the US SEER 17 database. Joinpoint 4.9.1.0 was used to characterize log-linear time trends., Results: The incidence and incidence-based mortality of all cancers trended down during the study period. The incidence of epithelial cancers decreased from 2004 to 2019 (AAPC -1.2%, p < 0.001), including that of high-grade (2006-2019: APC -1.2%, p < 0.05) and low-grade (2003-2019: APC -2.4%, p < 0.05) epithelial cancers. There was no change in incidence or incidence-based mortality for ovarian stromal and germ cell cancers., Conclusion: There has been a decrease in the incidence and incidence-based mortality of ovarian, fallopian tube, and primary peritoneal cancer, primarily due to reductions in advanced stage epithelial cancers originating in the ovary, fallopian tube, or peritoneum., Competing Interests: Conflict of interest statement The authors declare that they have no relevant conflicts of interest or financial disclosures related to this research., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Literature data present new studies about precancerous lesions of pelvic serous carcinoma that originate from the tubal secretory cells. It has long been thought that ovarian cancer cannot be prevented by prophylactic screening or surgery. In recent years, gynecologists have adapted to new principles and so, during routine hysterectomies in perimenopausal women for benign uterine pathologies, salpingo-oophorectomy is performed as a prophylactic approach., Aim: The purpose of our article was to draw attention to the association between abnormal fallopian tube pathology and the presence of serous ovarian neoplasia in perimenopausal women at risk., Case Presentation: We report the case of a 45-year-old woman who had unspecific symptoms of abdominal pain and loss of appetite and weight. A pelvic magnetic resonance imaging was performed, and an ovarian mass was detected. Our case shows that the fallopian tube can be the primary point of origin for a pelvic disease, therefore prevention is possible with early computed tomography scan and annual ultrasound. The patient presented with a T1c staging post-surgery and her chances of survival could have decreased if she had postponed medical examination longer. We found a significant increase in the absolute number of tubal secretory cells in patients with ovarian neoplasia, which supports the assumption that serous tubal intraepithelial carcinoma lesions are found especially in the serous ovarian type., Conclusions: Our article is a strong suggestion that serous ovarian cancer originates from the fallopian tube and can potentially serve as a sensitive biomarker for early serous carcinogenesis within the fallopian tube.

Serous tubal intraepithelial carcinoma (STIC) is the fallopian tube precursor lesion for most cases of pelvic high-grade serous carcinoma (HGSC). To date, the morphologic, molecular, and clinical heterogeneity of STIC and a less atypical putative precursor lesion, termed serous tubal intraepithelial lesion, has not been well characterized. Better understanding of precursor heterogeneity could impact the clinical management of women with incidental STICs (without concurrent carcinoma) identified in cases of prophylactic or opportunistic salpingectomy. This study analyzed morphologic and molecular features of 171 STICs and 21 serous tubal intraepithelial lesions. We assessed their histologic features, Ki-67 and p53 staining patterns, and genome-wide DNA copy number alterations. We classified all precursor lesions into 2 morphologic subtypes, one with a flat surface (Flat) and the other characterized by budding, loosely adherent, or detached (BLAD) morphology. On the basis of pathology review by a panel of 8 gynecologic pathologists, we found 87 BLAD, 96 Flat, and 9 indeterminate lesions. As compared with Flat lesions, BLAD lesions were more frequently diagnostic of STIC ( P <0.0001) and were found concurrently with HGSC ( P <0.0001). BLAD morphology was also characterized by higher Ki-67 proliferation index ( P <0.0001), presence of epithelial stratification ( P <0.0001), and increased lymphocyte density ( P <0.0001). BLAD lesions also exhibited more frequent DNA copy number gain/amplification at the CCNE1 or CMYC loci canonical to HGSCs ( P <0.0001). Both BLAD morphology and STIC diagnoses are independent risk factors for an elevated Ki-67 proliferation index. No correlation was observed between BLAD and Flat lesions with respect to patient age, presence of germline BRCA1/2 mutation, or p53 staining pattern. These findings suggest that tubal precursor lesions are morphologically and molecularly heterogeneous, laying the foundation for further studies on the pathogenesis of HGSC initiation and identifying histologic features predictive of poor patient outcomes., Competing Interests: Supported by the Break Through Cancer (BTC-IOC), the Richard W. TeLinde Endowment from the Johns Hopkins University, NIH/NCI (U2CCA271891, P50CA228991, R01CA260628, and R01CA215483). C.D. is a consultant to Exact Sciences and has been paid in equity and income. C.D. is a founder of Belay Diagnostics. C.D. is an inventor of some technologies. The companies named above as well as other companies have licensed previously described technologies related to the work described in this paper from Johns Hopkins University. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as Johns Hopkins University. The terms of all of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Epithelial ovarian cancers (EOC) associated with germline or somatic BRCA pathogenetic variants have a significantly higher rate of TP53aberrations. The majority of TP53 mutations are detectable by immunohistochemistry and several studies demonstrated that an abnormal p53 pattern characterized high-grade EOCs. An abnormal p53 immunohistochemical staining in fallopian tube (serous tubal intraepithelial carcinoma (STIC) and "p53 signature" is considered as a precancerous lesion of high-grade EOCs and it is often found in fallopian tube tissues of BRCA germline mutated patients suggesting that STIC is an early lesion and the TP53 mutation is an early driver event of BRCA mutated high-grade EOCs. No relevant data are present in literature about the involvement of p53 abnormal pattern in EOC carcinogenesis of patients negative for germline BRCA variants. We describe TP53 mutation results in relationship to the immunohistochemical pattern of p53 expression in a series of EOCs negative for BRCA1 and BRCA2 germline mutations. In addition, we also investigated STIC presence and "p53 signature" in fallopian tube sampling of these EOCs. Our results demonstrate that TP53 alterations are frequent and early events in sporadic EOCs including also low-grade carcinomas. Also in this series, STIC is associated with an abnormal p53 pattern in fallopian tubes of high-grade EOCs. In summary, TP53 aberrations are the most frequent and early molecular events in EOC carcinogenesis independently from BRCA mutation status., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Epithelial ovarian and fallopian cancers are aggressive lesions that rarely metastasize to the central nervous system. Brain metastases usually occur in the setting of known primary disease or widespread metastatic disease. However, in extremely rare cases, an isolated intracranial neoplasm may be the first presentation of fallopian cancer. To the best of our knowledge, only one such case has been reported previously. We present an illustrative case with multimodality imaging and histopathologic correlation of a fallopian tube carcinoma first presenting with altered mental status secondary to an isolated brain metastasis. A 64-year-old female with no pertinent medical history presented with altered mentation. Initial workup identified a 1.6 cm avidly enhancing, solitary brain lesion at the gray-white junction with associated vasogenic edema concerning for either central nervous system lymphoma or metastatic disease. Additional imaging identified a 7.5 × 3 cm left adnexal lesion, initially thought to be a hydrosalpinx with hemorrhage, but magnetic resonance imaging suggested gynecologic malignancy. No lesions elsewhere in the body were identified. Given the lack of locoregional or systemic disease, the intracranial and pelvic lesions were assumed to represent synchronous but distinct processes. The intracranial lesion was biopsied. Preliminary results were suggestive of lymphoma, but further analysis was consistent with high-grade serous carcinoma of müllerian origin. Positron emission tomography/computed tomography was performed to evaluate for other neoplastic lesions, only highlighting the intracranial and pelvic lesions. At this point, a diagnosis of metastatic fallopian cancer was made. The patient was taken for robot-assisted laparoscopy with surgical debulking of the pelvic neoplasm, pathology demonstrating high-grade serous carcinoma of the fallopian tube, matching that of the intracranial lesion. Even though rare, metastatic fallopian cancer should be considered in patients with isolated brain lesions and adnexal lesions, even in the absence of locoregional or systemic disease., (Copyright © 2023 AAGL. Published by Elsevier Inc. All rights reserved.)

Backgrounds: There is still no consensus on the significance of Lymphadenectomy (LD) and the number of lymph nodes that need to be excised (ELNs) for adequate LD in patients with early-stage primary fallopian tube cancer (PFTC). Our endeavor is geared towards deepening comprehension of LD in early-stage PFTC and identify the optimal cut-off of ELNs., Methods: This SEER-based study analyzed the clinical data of patients with early-stage PFTC between 2000 and 2018. X-tile was employed to confirm the optimal cut-off of ELNs. The survival data between groups were analyzed by the Kaplan-Meier estimates, Log-rank test and Cox proportional hazards model., Results: There was significant improvement in both mean cancer-specific survival (CSS, p < 0.001) and overall survival (OS, p < 0.001) in LD group. Regardless of matched or not, LD was identified as an independent protective factor of CSS and OS. The optimal 3-year CSS-based cutoff of ELNs was 11 (p = 0.026) as determined by X-tile. Both the mean CSS (p = 0.001) and mean OS (p = 0.002) in adequate LD group (ELNs > 11, n = 574) were significantly longer than these in inadequate LD group (ELNs ≤ 11, n = 738). Adequate LD, FIGO stage, tumor grade and histology were significant prognostic factors for CSS and OS., Conclusion: LD is an independent protective prognostic factor of patients with early-stage PFTC. The association between ELNs > 11 and an improved prognosis is evident. Future studies are needed to further clarify the results above., (© 2023. The Author(s).)

Background and Objectives: To investigate histopathological changes and serous carcinoma precursors such as secretory cell outgrowths (SCOUTs) and p53 signature in the bilateral tubal ligation (BTL) materials used during cesarean section (S/C). Materials and Methods : In total, 138 patients underwent S/C and tubal sterilization (TS) between October 2020 and May 2021 at Konya City Hospital. Patients' data were obtained from the hospital's system. All data and findings were investigated and statistically evaluated. Results: The mean age was 34.62 years (22-44), the mean gravity was 4.89 (2-15) and the mean parity was 3.46 (1-10). In total, 5.79% SCOUT, 7.24% atypia and 9.42% p53 signatures were observed. Significant correlations were shown between the epithelial cell lineage and age between Ki-67, SCOUT, and gravity; between the Ki-67 results and gravity and parity; and between the p53 score and age. Conclusions : TS is a common, safe, and effective method worldwide. Today, BTL is increasing along with increasing S/C ratios. In addition to the reduced risk of ovarian cancers with ligation alone, precursor lesions such as hyperplasia, SCOUT, p53 signature, and STIL/Serous tubal intraepithelial carcinoma (STIC) are encountered in the ampulla materials obtained. Considering the low rates of re-anastomosis, tubal excision may be recommended instead of ligation in women of relatively higher gravity and age.

A 59-year-old woman underwent simple abdominal total hysterectomy with bilateral salpingo-oophorectomy, partial omentectomy, and extirpation of intrapelvic disseminated nodules for right fallopian tube cancer with rectal metastasis and peritoneal dissemination as primary debulking surgery(PDS). The histopathological diagnosis was high grade serous carcinoma( HGSC)of the right fallopian tube. After adjuvant chemotherapy with 4 courses of paclitaxel-carboplatin(TC), low anterior resection of the rectum for rectal metastasis and pelvic and para-aortic lymph node dissection were performed as interval debulking surgery(IDS). Histopathologically, lymph node metastasis was detected only in the right obturator lymph node. After adjuvant chemotherapy with 4 courses of TC, bevacizumab maintenance monotherapy was administered. Three years after PDS, laparoscopic splenectomy for splenic metastasis and extirpation of the solitary peritoneal metastases were performed as secondary debulking surgery(SDS). After adjuvant chemotherapy with 4 courses of TC, olaparib maintenance monotherapy was administered. The patient has remained alive without recurrence for 4 years after SDS and for 7 years after PDS. No case of metachronous splenic metastasis from fallopian tube cancer with synchronous rectal metastasis has been reported; however, long-term prognosis may be expected with PDS, IDS and SDS for platinum-sensitive HGSC.

Objectives: Although the Pipelle endometrial biopsy is widely performed as a practical and minimally invasive test for endometrial disease(s), its effectiveness in ovarian cancer has not been explored. The aim of the present study was to evaluate the results of Pipelle endometrial biopsy for ovarian, fallopian tube, and peritoneal cancers., Methods: A pre-treatment Pipelle-endometrial biopsy was performed in 90 patients with ovarian, fallopian tube, or peritoneal cancers between January 2014 and November 2021. We retrospectively analysed the association between the results of Pipelle endometrial biopsy and clinicopathological data. Moreover, we evaluated their impact on the following treatment in advanced cases initially treated with chemotherapy., Results: The sensitivity and false-negative rates for Pipelle endometrial biopsy were 25/90 (27.8%) and 65/90 (72.2%) in all patients, respectively, and 23/56 (41.0%) and 33/56 (58.9%) in cases with advanced disease (stages III and IV), respectively. Pipelle-positive endometrial biopsy-positive (Pipelle-positive) was not observed in 29 patients with clinical stage I disease, and Pipelle-positive patients exhibited significantly more high-grade serous carcinomas, and positive peritoneal, endometrial, and cervical cytologies than Pipelle-endometrial biopsy-negative cases. Surgical pathology was confirmed in 23 Pipelle-positive patients, and 17/23 (74.0%) had the same diagnosis as that for Pipelle endometrial biopsy. Conversely, 6/23 (26.0%) patients exhibited a minor diagnostic discrepancy between Pipelle endometrial biopsy and surgical pathology. Nineteen of the 38 (50.0%) patients initially treated with chemotherapy were identified as Pipelle-positive, contributing to a prompt histological diagnosis and pre-treatment tumour sampling. Companion diagnostic tests were performed using Pipelle endometrial biopsy samples from 4 inoperable patients., Conclusion: Although the positive rate of Pipelle endometrial biopsy in ovarian, fallopian tube, and peritoneal cancers is low, Pipelle endometrial biopsy may enable prompt histological diagnosis and initiation of chemotherapy while collecting tumour tissue for genetic testing in some cases with advanced disease.

Epithelial ovarian cancer (EOC) is a heterogeneous group of malignancies, including high-grade serous ovarian cancer (HGSC). HGSC is often diagnosed at advanced stages and is linked to TP53 variants. While BRCA variants elevate risk, most HGSC cases occur in individuals without known genetic variants, necessitating prevention strategies for people without known high-risk genetic variants. Effective prevention programs are also needed due to the lack of traditional screening options. An emerging primary prevention strategy is opportunistic salpingectomy, which involves removing fallopian tubes during another planned pelvic surgery. Opportunistic salpingectomy offers a safe and cost-effective preventative option that is gaining global adoption. With the publication of the first cohort study of patients who underwent salpingectomy, specifically for cancer prevention, attention has turned to broadening opportunities for salpingectomy in addition to more targeted approaches. Prevention opportunities are promising with increasing adoption of salpingectomy and the increased understanding of the etiology of the distinct histotypes of ovarian cancer. Yet, further research on targeted risk-reducing salpingectomy with thoughtful consideration of equity is necessary to reduce death and suffering from ovarian cancer.

Primary fallopian tube carcinoma (PFTC) is a rare disease. Its location, close association with epithelial ovarian carcinoma, and lack of specific signs and symptoms make diagnosis challenging especially in its early stages. We report a postmenopausal patient who presented with a 2-month history of abdominopelvic pain with watery vaginal discharge. Imaging findings showed a 7 cm complex left adnexal mass. The patient underwent a robotic-assisted total laparoscopic hysterectomy and bilateral salpingo-oophorectomy and surgical staging. Findings were significant for stage IA serous fallopian tube carcinoma. PFTC is sometimes missed preoperatively and intraoperatively. Available literature review has focused on the clinical and imaging characteristics of PFTC to aid in timely disease diagnosis. Minimally invasive surgery is a viable option in the diagnosis and management of early-stage ovarian cancer due to improved visualisation of pelvic structures, decreased length of hospital stay, decreased estimated blood loss and lower postoperative complication rates compared with laparotomy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Our study aimed to evaluate the incidence of pathological findings in asymptomatic Korean patients with BRCA1/2 pathogenic variants who underwent risk-reducing salpingo-oophorectomy and to assess their long-term prognosis., Methods: We retrospectively analyzed the medical records of patients with a germinal BRCA1/2 pathologic variant who had undergone risk-reducing salpingo-oophorectomy at Asan Medical Center (Seoul, Korea) between January 2013 and December 2020. All pathologic reports were made based on the sectioning and extensively examining the fimbriated end of the fallopian tube (SEE/FIM) protocol., Results: Out of 243 patients who underwent risk-reducing salpingo-oophorectomy, 121 (49.8%) had a BRCA1 mutation, 119 (48.9%) had a BRCA2 mutation, and three (1.2%) had both mutations. During the procedure, four (3.3%) patients with a BRCA1 mutation were diagnosed with serous tubal intraepithelial carcinoma (STIC) or serous tubal intraepithelial lesion (STIL), and another four patients (3.3%) were diagnosed with occult cancer despite no evidence of malignancy on preoperative ultrasound. In the BRCA2 mutation group, we found one (0.8%) case of STIC, but no cases of STIL or occult cancer. During the median follow-up period of 98 months (range, 44-104) for STIC and 54 months (range, 52-56) for STIL, none of the patients diagnosed with these precursor lesions developed primary peritoneal carcinomatosis., Conclusions: Risk-reducing salpingo-oophorectomy, in asymptomatic Korean patients with BRCA1/2 pathogenic variants, detected ovarian cancer and precursor lesions, including STIC or STIL. Furthermore, our follow-up period did not reveal any instances of primary peritoneal carcinomatosis, suggesting a limited body of evidence supporting the imperative need for adjuvant treatment in patients diagnosed with these precursor lesions during risk-reducing salpingo-oophorectomy., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Neuroendocrine neoplasms commonly arise from the gastrointestinal tract and lungs. Less commonly, they may occur in the gynecologic tract, typically within the ovary of a mature cystic teratoma. Primary neuroendocrine neoplasms of the fallopian tube are exceptionally rare and only a total of 11 cases have been reported in the literature. We describe the first case to our knowledge of a primary grade 2 neuroendocrine tumor of the fallopian tube in a 47-yr-old female. In this report, we describe the case's unique presentation, review the published literature on primary neuroendocrine neoplasms of the fallopian tube, discuss the treatment options, and speculate on their origin and histogenesis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 by the International Society of Gynecological Pathologists.)

Low-density lipoprotein (LDL) receptor-related protein 1B (LRP1B) is a member of the LDL receptor family and has often been discussed as a tumor suppressor gene, as its down-regulation is correlated with a poor prognosis in multiple carcinoma entities. Due to the high metastasis rate into the fatty peritoneal cavity and current research findings showing a dysregulation of lipid metabolism in tubo-ovarian high-grade serous carcinoma (HGSC), we questioned the prognostic impact of the LRP1B protein expression. We examined a well-characterized large cohort of 571 patients with primary HGSC and analyzed the LRP1B protein expression via immunohistochemical staining (both in tumor and stroma cells separately), performed precise bioimage analysis with QuPath, and calculated the prognostic impact using SPSS. Our results demonstrate that LRP1B functions as a significant prognostic marker for overall survival (OS) and progression-free survival (PFS) in HGSC on the protein level. High cytoplasmic expression of LRP1B in tumor, stroma, and combined tumor and stroma cells has a significantly positive association with a mean prolongation of the OS by 42 months (P = .005), 29 months (P = .005), and 25 months (P = .001), respectively. Additionally, the mean PFS was 18 months longer in tumor (P = .002), 19 months in stroma (P = .004), and 19 months in both cell types combined (P = .01). Our results remained significant in multivariate analysis. We envision LRP1B as a potential prognostic tool that could help us understand the functional role of lipid metabolism in advanced HGSC, especially regarding liposomal medications., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Serous tubal intraepithelial carcinoma (STIC) is a precursor lesion which is located in the distal fallopian tube and causes high grade serous ovarian carcinoma (HGSOC). The incidence of STIC for women underwent risk reducing salpingo-oophorectomy for BRCA mutation varies from 0.6 to 7% and its clinical outcomes are still unclear. The aim of this study was to demonstrate the incidence of STIC and HGSOC in BRCA1/2 mutation carriers after risk reducing salpingo-oophorectomy (RRSO) and the clinical outcomes of these patients., Material and Methods: We retrospectively reviewed the records of 48 BRCA1 and/or 2 mutation carriers who underwent prophylactic salpingo-oophorectomy with or without hysterectomy at the Department of Obstetrics and Gynecology, Bursa Uludag University between January 2000 and January 2022., Inclusion Criteria: BRCA 1 and/or 2 mutation carriers diagnosed by genetic testing, asymptomatic patients with no abnormal findings on pelvic examination., Exclusion Criteria: patients with no abnormal findings on pelvic examination and a presence of a personal history of ovarian, fallopian tube or peritoneal cancer., Results: A total of 48 BRCA 1 and/or 2 mutation carriers underwent RRSO. STIC was diagnosed in 1 (2,0%) patient and restaging surgery was not performed. Primary peritoneal carcinoma (PPC) did not develop during the 20 months follow-up period. One (2.0%) patient was diagnosed with occult ovarian cancer. Restaging surgery was performed and chemotherapy treatments were given after surgery. A pelvic recurrence developed 25 months after the occult cancer diagnosis in the follow up period. One (2.0%) patient with normal histopathological findings after RRSO was diagnosed with peritoneal cancer 57 months after the operation., Conclusion: The risk of PPC continues after RRSO. Therefore, close follow-up procedure is very important for early diagnosis and effective treatment of patients with PPC after RRSO., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest. The authors are solely responsible for the content and writing of the paper., (Copyright © 2023. Published by Elsevier Masson SAS.)

Ovarian cancer is the leading cause of death from gynecologic cancer worldwide. High-grade serous carcinoma (HGSC) is the most common and deadliest subtype of ovarian cancer. While the origin of ovarian tumors is still debated, it has been suggested that HGSC originates from cells in the fallopian tube epithelium (FTE), specifically the epithelial cells in the region of the tubal-peritoneal junction. Three main lesions, p53 signatures, STILs, and STICs, have been defined based on the immunohistochemistry (IHC) pattern of p53 and Ki67 markers and the architectural alterations of the cells, using the Sectioning and Extensively Examining the Fimbriated End Protocol. In this study, we performed an in-depth proteomic analysis of these pre-neoplastic epithelial lesions guided by mass spectrometry imaging and IHC. We evaluated specific markers related to each preneoplastic lesion. The study identified specific lesion markers, such as CAVIN1, Emilin2, and FBLN5. We also used SpiderMass technology to perform a lipidomic analysis and identified the specific presence of specific lipids signature including dietary Fatty acids precursors in lesions. Our study provides new insights into the molecular mechanisms underlying the progression of ovarian cancer and confirms the fimbria origin of HGSC., (© 2023. The Author(s).)

Incessant ovulation is believed to be a potential cause of epithelial ovarian cancer (EOC). Our previous investigations have shown that insulin-like growth factor (IGF2) and hepatocyte growth factor (HGF) in the ovulatory follicular fluid (FF) contributed to the malignant transformation initiated by p53 mutations. Here we examined the individual and synergistic impacts of IGF2 and HGF on enhancing the malignant properties of high-grade serous carcinoma (HGSC), the most aggressive type of EOC, and its precursor lesion, serous tubal intraepithelial carcinoma (STIC). In a mouse xenograft co-injection model, we observed that FF co-injection induced tumorigenesis of STIC-mimicking cells, FE25. Co-injection with IGF2 or HGF partially recapitulated the tumorigenic effects of FF, but co-injection with both resulted in a higher tumorigenic rate than FF. We analyzed the different transformation phenotypes influenced by these FF growth signals through receptor inhibition. The IGF signal was necessary for clonogenicity, while the HGF signal played a crucial role in the migration and invasion of STIC and HGSC cells. Both signals were necessary for the malignant phenotype of anchoring-independent growth but had little impact on cell proliferation. The downstream signals responsible for these HGF activities were identified as the tyrosine-protein kinase Met (cMET)/mitogen-activated protein kinase and cMET/AKT pathways. Together with the previous finding that the FF-IGF2 could mediate clonogenicity and stemness activities via the IGF-1R/AKT/mammalian target of rapamycin and IGF-1R/AKT/NANOG pathways, respectively, this study demonstrated the cooperation of the FF-sourced IGF and HGF growth signals in the malignant transformation and progression of HGSC through both common and distinct signaling pathways. These findings help develop targeted prevention of HGSC., (© 2023 Wiley Periodicals LLC.)

Aldehyde dehydrogenase (ALDH) enzymatic activity is a marker of cancer-initiating cells (CIC) in many tumor types. Our group and others have found that ALDH1A family inhibitors (ALDHi) can preferentially induce death of ovarian CIC in established ovarian cancer. We sought to determine if ALDHi, by targeting CIC at the time of tumor initiation, could function as a chemopreventive for ovarian cancer. As BRCA1/2 mutation carriers represent a population who could benefit from an ovarian cancer chemopreventive, we focused on BRCA mutation-associated tumor cell lines and murine tumor models. We found that, compared to BRCA wild-type cells, BRCA mutant ovarian cancer cells are more sensitive to the ALDHi673A. Similarly, while 673A treatment of wild-type fallopian tube epithelial (FTE) cells is non-toxic, 673A induces death in FTE cells with BRCA1 knockdown. Using a murine fallopian tube organoid model of ovarian carcinogenesis, we show that 673A reduced organoid complexity and significantly reduce colony formation of BRCA-mutant cells. Organoids that persisted after 673A treatment were predominantly BRCA1wt, but NF1 mutant, suggesting a resistance mechanism. Finally, using the BPRN (Brca1, Trp53, Rb1, Nf1 inactivated) mouse model of tubo-ovarian cancer, we evaluated the impact of intermittent 673A therapy on carcinogenesis. 673A treatment resulted in a significant reduction in serous tubal intraepithelial carcinoma (STIC) lesions and carcinomas. Collectively, the findings suggest that ALDHi, such as 673A, could serve as chemopreventive agents for BRCA1/2 mutation carriers., Competing Interests: Declaration of Competing Interest Dr. Buckanovich has patents related to the use of ALDH inhibitors in cancer therapies., (Copyright © 2023 Elsevier Inc. All rights reserved.)