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Background: The effect of primary cytoreductive surgery vs interval cytoreductive surgery on International Federation of Gynecology and Obstetrics stage IV ovarian cancer outcomes remains uncertain and may vary depending on the stage and the location of extraperitoneal metastasis. Emulating target trials through causal assessment, combined with propensity score adjustment, has become a leading method for evaluating interventions using observational data., Objective: This study aimed to assess the effect of primary vs interval cytoreductive surgery on progression-free and overall survival in patients with International Federation of Gynecology and Obstetrics stage IV ovarian cancer using target trial emulation., Study Design: Using the comprehensive French national health insurance database, we emulated a target trial to explore the causal impacts of primary vs interval cytoreductive surgery on stage IV ovarian cancer prognosis (Surgery for Ovarian cancer FIGO 4: SOFI-4). The clone method with inverse probability of censoring weighting was used to adjust for informative censoring and to balance baseline characteristics between the groups. Subgroup analyses were conducted based on the stages and extraperitoneal metastasis locations. The study included patients younger than 75 years of age, in good health condition, who were diagnosed with stage IV ovarian cancer between January 1, 2014, and December 31, 2022. The primary and secondary outcomes were respectively 5-year progression-free survival and 7-year overall survival., Results: Among the 2772 patients included in the study, 948 (34.2%) were classified as having stage IVA ovarian cancer and 1824 (65.8%) were classified as having stage IVB ovarian cancer at inclusion. Primary cytoreductive surgery was performed for 1182 patients (42.6%), whereas interval cytoreductive surgery was conducted for 1590 patients (57.4%). The median progression-free survival for primary cytoreductive surgery was 19.7 months (interquartile range, 19.3-20.1) as opposed to 15.7 months (interquartile range, 15.7-16.1) for those who underwent interval cytoreductive surgery. The median overall survival was 63.1 months (interquartile range, 61.7-65.4) for primary cytoreductive surgery in comparison with 55.6 months (interquartile range, 53.8-56.3) for interval cytoreductive surgery. The findings of our study indicate that primary cytoreductive surgery is associated with a 5.0-month increase in the 5-year progression-free survival (95% confidence interval, 3.8-6.2) and a 3.9-month increase in 7-year overall survival (95% confidence interval, 1.9-6.2). These survival benefits of primary over interval cytoreductive surgery were observed in both the International Federation of Gynecology and Obstetrics stage IVA and IVB subgroups. Primary cytoreductive surgery demonstrated improved progression-free survival and overall survival in patients with pleural, supradiaphragmatic, or extra-abdominal lymph node metastasis., Conclusion: This study advocates for the benefits of primary cytoreductive surgery over interval cytoreductive surgery for patients with stage IV ovarian cancer and suggests that extraperitoneal metastases like supradiaphragmatic or extra-abdominal lymph nodes should not automatically preclude primary cytoreductive surgery consideration in suitable patients., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate disease characteristics and survival according to BRCA status, administration of poly-(ADP-ribose) polymerase inhibitors (PARPi), and surgery in patients with ovarian cancer and brain metastases., Methods: This is a monocentric retrospective cohort of patients with ovarian cancer and brain metastases treated between 2000 and 2021. Data were collected by a retrospective review of medical records and analyzed according to: (1) BRCA mutation; (2) PARPi before and after brain metastases; (3) surgery for brain metastases., Results: Eighty-five patients with ovarian cancer and brain metastasis and known BRCA status (31 BRCA mutated ( BRCA m), 54 BRCA wild-type ( BRCA wt)) were analyzed. Twenty-two patients had received PARPi before brain metastases diagnosis (11 BRCA m, 11 BRCA wt) and 12 after (8 BRCA m, 4 BRCA wt). Brain metastases occurred >1 year later in patients who had received previous PARPi. Survival was longer in the BRCA m group (median post-brain metastasis survival: BRCA m 23 months vs BRCA wt 8 months, p=0.0015). No differences were found based on BRCA status analyzing the population who did not receive PARPi after brain metastasis (median post-brain metastasis survival: BRCA m 8 months vs BRCA wt 8 months, p=0.31). In the BRCA m group, survival was worse in patients who had received previous PARPi (median post-brain metastasis survival: PARPi before, 7 months vs no-PARPi before, 24 months, p=0.003). If PARPi was administered after brain metastases, survival of the overall population improved (median post-brain metastasis survival: PARPi after, 46 months vs no-PARPi after, 8 months, p=0.00038).In cases of surgery for brain metastases, the prognosis seemed better (median post-brain metastasis survival: surgery 13 months vs no-surgery 8 months, p=0.036). Three variables were significantly associated with prolonged survival at multivariate analysis: BRCA mutation, multimodal treatment, and ≤1 previous chemotherapy line., Conclusions: BRCA mutations might impact brain metastasis occurrence and lead to better outcomes. In a multimodal treatment, surgery seems to affect survival even in cases of extracranial disease. PARPi use should be considered as it seems to prolong survival if administered after brain metastasis., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Ovarian cancer (OC) is the most lethal gynecological cancer. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy appears to increase survival, and normothermic intraperitoneal chemotherapy (IPC) could improve overall survival (OS). Furthermore, intraperitoneal epinephrine could decrease the toxicity of chemotherapy by decreasing the systemic absorption of chemotherapy. The goal of this study was to assess the effects of CRS and IPC with intraperitoneal epinephrine, as first-line therapy, on the survival of patients with serous epithelial OC (EOC) with peritoneal metastases., Methods: A prospective monocentric database was retrospectively searched for all patients with advanced serous EOC treated by interval or consolidative CRS plus IPC with intraperitoneal epinephrine after neoadjuvant chemotherapy. OS and disease-free survival (DFS), postoperative complications, and prognostic factors were analyzed., Results: From January 2003 to December 2017, 124 patients with serous EOC were treated with interval (n = 58) or consolidative (n = 66) complete CRS plus IPC with intraperitoneal epinephrine. The median follow-up was 77.8 months, the median OS was 60.8 months, and the median DFS was 21.2 months. In our multivariate analysis, a higher Peritoneal Cancer Index (PCI) and positive lymph node status resulted in worse OS, while higher World Health Organization score, higher PCI score, and positive lymph node status were risk factors for worse DFS. Grade 3 or higher surgical morbidity occurred in 27.42% of cases; only 3.2% had grade 3 renal toxicity and mortality was 0.8%., Conclusion: CRS and IPC with intraperitoneal epinephrine in stage III EOC offer good OS and DFS with acceptable morbidity and mortality rates., (© 2021. Society of Surgical Oncology.)

Background: Numerous studies have examined the prognostic value of ubiquitin-specific protease 7 (USP7) in cancer, but the results remain controversial. Differences in assessment assays (mRNA/protein) used could be a potential confounding factor. Thus, we extracted studies that measured the protein expression and performed a meta-analysis to assess the prognostic role of USP7 expression in cancer and to identify clinicopathological features associated with USP7 expression., Methods: PubMed, Scopus, Web of Science Core Collection, Wiley Online Library, and Google Scholar were searched from inception to July 2020. Pooled hazard ratios were calculated to evaluate the association between USP7 expression and overall survival (OS). In addition, pooled odds ratios were calculated to identify clinicopathological features associated with USP7 expression., Results: Eight studies in China were included in our meta-analysis, which had a total of 1192 patients and assessed five types of cancer. The pooled results revealed that a high expression of USP7 was associated with poor OS, especially in epithelial ovarian cancer (EOC). Moreover, USP7 expression was increased in patients with tumour-node-metastasis (TNM) stages III-IV, poor pathological grade, and positive lymph node metastasis. For patients with EOC, a high USP7 expression positively correlated with lymph node metastasis., Conclusion: A high USP7 expression may promote cancer progression and predict unfavourable prognosis of cancer patients, especially those with EOC. Our findings suggest that USP7 inhibitors might be promising therapeutics for cancer patients with such characteristics., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Background: The reported incidence of platinum resistant recurrence (PRR) (recurrence within 6 months of the last dose of platinum therapy) after interval debulking/cytoreductive surgery (CRS) is high compared to that after primary CRS. The goal was to study PRR following a total parietal peritonectomy (TPP), that addresses occult disease more completely., Methods: This is a prospective multi-center study (CTRI/2018/08/015350). A TPP was performed during interval CRS following a fixed surgical protocol. Patients with a follow-up of 6 months(M) or more were included in this analysis. The incidence and patterns of PRR and factors affecting recurrence were analyzed., Results: From July 2018 to October 2019, 70 patients with serous carcinoma were included. The median surgical PCI was 15 [range 5-37]. A CC-0 resection was obtained in 55 (78.5%); CC-1 in 10 (14.2%). Occult residual disease was seen in 40%. At a median follow-up of 13 months, 17 (24.2%) had developed recurrence/progression. PRR was seen in 5 (7.1%) patients. The sites of progression (>1 in 2 patients) were pleura (n = 1), visceral peritoneum (n = 2), retroperitoneal nodes (n = 2), mediastinal nodes (n = 1) and small bowel mesentery (n = 2). Overall, though the most common site of recurrence was the visceral peritoneum (N = 9), seven (>40%) patients did not develop recurrence in the visceral peritoneum. Patients with high PCI and grade 3-4 complications had a higher probability of developing recurrence., Conclusions: TPP performed during interval CRS resulted in a very low incidence of PRR. These findings need confirmation in a larger series. The benefit of TPP over conventional surgery should be evaluated in a randomized trial., Competing Interests: Declaration of competing interest, (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

The extent of peritoneal metastases (PM) largely determines the possibility of complete or optimal cytoreductive surgery in advanced ovarian cancer. An objective scoring system to quantify the extent of PM can help clinicians to decide whether or not to embark on CRS. Therefore several scoring systems have been developed by different research teams and this review summarizes their performance in predicting a complete or optimal cytoreduction in patients with advanced ovarian cancer. A systematic search in the MEDLINE database revealed 19 articles that described a total of five main scoring systems to predict the completeness of CRS in patients with FIGO stage III-IV ovarian cancer based on the surgical exploration of the abdominal cavity; PCI, PIV, Eisenkop, Espada, and Kasper. The Peritoneal Cancer Index (PCI) and the Predictive Index Value (PIV) were mentioned most frequently and showed AUCs of 0.69-0.92 and 0.66-0.98, respectively. Due to the use of different cut-offs sensitivities and specificities greatly varied. Therefore with the current data, no scoring system could be identified as best. An objective measure of the extent of disease can be of great clinical use for identifying ovarian cancer patients for which a complete (or optimal) CRS is achievable, however due to local differences in treatment strategies and surgical policy a widely adopted objective scoring system with a standard cut-off value is not feasible. Nevertheless, objective scoring systems can play an important role to guide treatment decisions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Sonke reports institutional research support outside the submitted work, from AstraZeneca, Merck, Novartis, and Roche, during the conduct of the study. All other authors have no conflicts of interest to enclose., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Preoperative assessment of peritoneal metastases is an important factor for treatment planning and selection of candidates for cytoreductive surgery (CRS) in primary advanced stage (FIGO stages III-IV) epithelial ovarian cancer (EOC). The primary aim was to evaluate the efficacy of DW-MRI, CT, and FDG PET/CT used for preoperative assessment of peritoneal cancer index (PCI)., Material and Methods: In this prospective observational cohort study, 50 advanced stage EOC patients were examined with DW-MRI and FDG PET/CT with contrast enhanced CT as part of the diagnostic program. All patients were deemed amenable for upfront CRS. Imaging PCI was determined for DW-MRI, CT, and FDG PET/CT by separate readers blinded to the surgical findings. The primary outcome was agreement between the imaging PCI and PCI determined at surgical exploration (the reference standard) evaluated with Bland-Altman statistics., Results: The median surgical PCI was 18 (range: 3-32). For all three imaging modalities, the imaging PCI most often underestimated the surgical PCI. The mean differences between the surgical PCI and the imaging PCI were 4.2 (95% CI: 2.6-5.8) for CT, 4.4 (95% CI: 2.9-5.8) for DW-MRI, and 5.3 (95% CI: 3.6-7.0) for FDG PET/CT, and no overall statistically significant differences were found between the imaging modalities (DW-MRI - CT, p = 0.83; DW-MRI - FDG PET/CT, p = 0.24; CT - FDG PET/CT, p = 0.06)., Conclusion: Neither DW-MRI nor CT nor FDG PET/CT was superior in preoperative assessment of the surgical PCI in patients scheduled for upfront CRS for advanced stage EOC., Competing Interests: Declaration of competing interest Corresponding author Mette Schou Mikkelsen received a grant from “The Danish Cancer Research Foundation (Dansk Kraeftforskningsfond)”. With this exception, all authors have no declarations of interest regarding this article., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objective: Despite radical surgery and chemotherapy, most patients with ovarian cancer die due to disease progression. M-Trap is an implantable medical device designed to capture peritoneal disseminated tumor cells with the aim to focalize the disease. This trial analyzed the safety and performance of the device., Methods: This first-in-human prospective, multi-center, non-blinded, single-arm study enrolled 23 women with high-grade serous advanced ovarian cancer. After primary or interval debulking surgery, 3 M-Trap devices were placed in the peritoneum of the abdominal cavity. 18-months post-implantation or at disease progression, devices were initially removed by laparoscopy. The primary safety endpoint was freedom from device and procedure-related major adverse events (MAEs) through 6-months post-implantation compared to an historical control. The primary performance endpoint was histopathologic evidence of tumor cells capture., Results: Only one major adverse event was attributable to the device. 18 women were free of device and procedure related MAEs (78.3%). However, the primary safety endpoint was not achieved (p = 0.131), primarily attributable to the greater surgical complexity of the M-Trap patient population. 62% of recurrent patients demonstrated tumor cell capture in at least one device with a minimal tumor cell infiltration. No other long-term device-related adverse events were reported. The secondary performance endpoint demonstrated a lack of disease focalization., Conclusions: The M-Trap technology failed to meet its primary safety objective, although when adjusted for surgical complexity, the study approved it. Likewise, the devices did not demonstrate the anticipated benefits in terms of tumor cell capture and disease focalization in recurrent ovarian cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to evaluate the patterns of recurrence and factors affecting the same after interval cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in primary stage IIIC and IV A epithelial ovarian cancer., Methods: In this retrospective multicentric study, all patients with FIGO stages III-C and IV-A epithelial ovarian carcinoma were treated with CRS and HIPEC after receiving neoadjuvant chemotherapy. Relevant clinical and demographic data were captured. Multivariable logistic regression was performed to evaluate the factors affecting recurrence after CRS and HIPEC., Results: From January 2017 to Jan 2020, 97, consecutive patients of Stage IIIC/IVA epithelial ovarian cancer underwent interval cytoreductive surgery and HIPEC after receiving neoadjuvant chemotherapy. The median duration of follow up duration was 20 months [1-36months]. 21/97 (21.6%) patients presented with disease recurrence. Visceral recurrences involving the lungs, liver and brain were seen in 8/21 (38%) of cases and comprised the commonest sites. On multivariable analysis, nodal involvement (p = 0.05), selective peritonectomy (p = 0.001) and leaving behind residual disease <0.25 mm (CC1) (p = 0.01) was associated with increased risk of disease recurrence. Extent of peritonectomy (OS,p = 0.56, PFS p = 0.047, Log Rank test) and nodal positivity (OS, p = 0.13,PFS,p = 0.057, Log Rank test) were found to impact progression free survival but had no impact on overall survival., Conclusion: There is a higher incidence of systemic recurrences in patients with Stage IIIC/IVA epithelial ovarian carcinoma after CRS and HIPEC. Extent of peritonectomy and nodal clearance impacts patterns of recurrence and progression free survival., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Increasing evidence indicates that site-distant metastases are associated with survival outcomes in patients with epithelial ovarian cancer. This study aimed to investigate the prognostic values of site-distant metastases and clinical factors and develop a prognostic nomogram score individually predicting overall survival (OS, equivalent to all-cause mortality) and cancer specific survival (CSS, equivalent to cancer-specific mortality) in patients with epithelial ovarian cancer., Methods: We retrospectively collected data on patients with epithelial ovarian cancer from the Surveillance, Epidemiology, and End Results (SEER) database between 1975 and 2016. Multivariate Cox regression was performed to identify survival trajectories. A nomogram score was used to predict long-term survival probability. A comparison between the nomogram and the International Federation of Gynecology and Obstetrics (FIGO 2018) staging system was conducted using time-dependent receiver operating characteristic (tROC) curve., Results: A total of 131,050 patients were included, 18.2, 7.8 and 66.1% had localized, regional and distant metastases, respectively. Multivariate analysis identified several prognostic factors for OS including race, grade, histology, FIGO staging, surgery, bone metastasis, liver metastasis, lung metastasis, and lymphatic metastasis. Prognostic factors for CSS included grade, site, FIGO staging, surgery, bone metastasis, brain metastasis, lung metastasis, lymphatic metastasis, and insurance. Following bootstrap correction, the C-index of OS and CSS was 0.791 and 0.752, respectively. These nomograms showed superior performance compared with the FIGO 2018 staging criteria (P < 0.05)., Conclusions: A novel prognostic nomogram score provides better prognostic performance than the FIGO 2018 staging system. These nomograms contribute to directing clinical treatment and prognosis assessment in patients harboring site-distant metastases.

A large cell neuroendocrine carcinoma of the ovary is presented because of tubal metastases with peculiar growth patterns: pagetoid and serous tubal intraepithelial carcinoma-like. The possibility that a tubal intraepithelial carcinoma could represent a metastasis should be considered by pathologists.

This study analyzed the surgical outcomes after initial implementation of a cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) program in government settings in India. Methods: Ovarian cancer patients undergoing cytoreductive surgery and HIPEC from May 2015 to April 2019 were identified from a prospectively maintained database. Treatment characteristics and surgical outcomes were analyzed. Results: The study identified 101 patients. The mean peritoneal cancer index (PCI) was 7 ± 6, with higher PCI scores in primary and recurrent cases. Major morbidities were recorded in 24.7% of patients. High PCI score, completeness of cytoreduction and major morbidities were independent predictors of overall survival in multivariate analysis. Conclusion: The application of HIPEC in limited-resource settings is feasible with acceptable major morbidities. This program should receive similar priority in government systems.

Objective(s): To identify recurrence patterns and outcomes in women with advanced or recurrent epithelial ovarian cancer (EOC) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC)., Methods: This is an IRB-approved single-institution cohort study of women who underwent CRS+HIPEC for advanced or recurrent EOC followed in a prospective registry from 1/12/2014-3/1/2020. Recurrence locations were defined as pelvic, upper abdominal (UA) and/or extra-peritoneal (EP). Univariate analysis assessed associations between recurrence location, progression-free survival (PFS), and overall survival (OS)., Results: In total, 92 women with EOC underwent interval (56.5%; n=52) or recurrent CRS+HIPEC (43.5%; n=40). For interval CRS+HIPEC, recurrence locations were pelvic in 50.0% (n=15), UA in 23.3% (n=7) and EP in 56.7% (n=17); 40.0% (n=12) were EP alone. Similarly, for recurrent CRS+HIPEC, recurrence locations were pelvic (22.5%, n=9), UA (5.0%, n=2) and EP (60.0%, n=24); 66.7% (n=20) were EP alone. For both interval and recurrent CRS+HIPEC, median PFS was 10.5 vs. 13.0 months for pelvic and UA vs. EP only recurrences (p=0.02). Similarly, median OS was 29.2 months for pelvic and UA and not reached for EP only (p=0.05). For interval CRS+HIPEC, there was no difference in median PFS (10.6 vs. 11.7 months, p=0.68) and OS (27.1 vs. 24.8 months, p=0.96) for pelvic and UA vs EP alone. However, for recurrent CRS+HIPEC, pelvic and UA sites of recurrence were associated with reduced PFS (10.0 vs. 18.1 months, p=0.03) and OS (33.6 months vs. not reached, p=0.02) vs. EP only., Conclusions: In women with advanced or recurrent EOC undergoing CRS+HIPEC, one-half of patients experience their first recurrence outside of the peritoneal cavity. Providers must be aware of the risk of EP failure in patients treated with CRS+HIPEC., Competing Interests: Declaration of Competing Interest All authors have no relevant conflicts of interest to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Intraperitoneal with intravenous chemotherapy (IP/IV) is the recommended option for patients with stage III cancer with optimally debulked (<1 cm residual) disease based on randomized controlled trials and showing important improvements in overall survival and progression free survival. However, its application has not been largely adopted due to its difficult administration that requires a trained nurse staff. The aim of this work was to study the completion and the toxicity of an IP outpatient chemotherapy regimen in optimally debulked stage III ovarian cancer patients., Methods: A single-center, retrospective observational study in women with stage III ovarian cancer following optimal cytoreductive surgery (<1 cm) followed by IP/IV chemotherapy from 2009 to 2017. The IP/IV regimen was as it follows: IV paclitaxel 175 mg/m 2 in 3 h, day 1; IP cisplatin (100 mg/m 2 -until December 2013-or 75 mg/m 2 ), day 2; IP paclitaxel 60 mg/m 2 , day 8, each 21 days for six cycles., Results: A total of 60 patients received IP/IV regimen. Of these, 41 patients (68.3%) completed the six IP chemotherapy cycles and 51 (84.9%) completed four or more cycles. Most of the adverse events reported were non-hematological and G1-2. There was no difference neither in adherence nor in the frequency of adverse events between both cisplatin groups. Despite a high rate of adverse events, IP chemotherapy can be delivered with a high completion rate and manageable toxicity to patients with optimally debulked ovarian cancer.

Objective: To investigate the detailed roles and mechanisms of tumor-derived exosomes in progression and metastasis of ovarian cancer in vitro., Methods: Exosomes were isolated by differential centrifugation method; the morphology, size and biological markers of exosomes were separately defined by transmission electron microscopy, nanoS90 and Western blotting; Trans-well chambers assay was used to assess the ability of migration and invasion of recipient cells uptaking the exosomes from HO8910PM cells. The downstream molecule was screened by mass spectrometry.CD44 was identified by western blotting and the function of CD44 was identified by trans-well chambers assay and CCK8 assay., Results: Exosomes derived from HO8910PM cells could be transferred to HO8910 cells and promote cell migration and invasion in the recipient cells of ovarian cancer. And CD44 could be transferred to the HO8910 cells through exosomes from HO8910PM cells and influence the migration and invasion ability of HO8910 cells., Conclusion: The more aggressive subpopulation can transfer a metastatic phenotype to the less one via secreting exosomes within a heterogeneous tumor. CD44 may be a potential therapeutic approach for ovarian cancer.

Currently, there is increasing evidence that long noncoding RNAs (lncRNAs) initiate and promote the progression of epithelial ovarian cancer (EOC). In this study, we revealed the roles and the potential mechanisms of long intergenic non-protein coding RNA 1133 (LINC01133) in EOC, which remains not well understood. We found that LINC01133 was upregulated in EOC tissues and cell lines. Besides, it was associated with the clinicopathological feature of metastasis. Functional experiments demonstrated that LINC01133 could facilitate cancer cell migration and invasion in vitro and tumor metastasis in vivo. Further molecular mechanisms studies indicated that LINC01133 and miR-495-3p reciprocally repressed expression of each other. We also realized that LINC01133 shared the same binding sites for miR-495-3p with tumor protein D52 (TPD52). We confirmed that TPD52 functioned as a direct target of miR-495-3p and mediated the enhancing effect of LINC01133 on cancer metastasis. Generally, our study showed that LINC01133 interacted with miR-495-3p to promote metastasis in EOC by regulating TPD52. LINC01133 also provided a potential therapeutic perspective for future clinical treatment., Competing Interests: Declaration of competing interest All authors declare that no competing interest exists., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) after neoadjuvant chemotherapy (NACT) showed promise as initial treatment for stage IIIC (SIII) epithelial ovarian cancer (EOC); however, stage IV (SIV) outcomes are rarely reported. We assessed our experience and outcomes treating newly diagnosed SIV EOC with NACT plus CRS/HIPEC compared to SIII patients., Methods: Advanced EOC from 2015-2018 managed with NACT (carboplatin/paclitaxel) due to unresectable disease or poor performance status followed by interval CRS/HIPEC were reviewed. Perioperative factors were assessed. Overall survival (OS) and progression-free survival (PFS) were analyzed by stage., Results: Twenty-seven FIGO stage IIIC ( n  = 12) and IV ( n  = 15) patients were reviewed. Median NACT cycles were 3 and 4, respectively. Post-NACT omental caking, ascites, and pleural effusions decreased/resolved in 91%, 91%, and 100% of SIII and 85%, 92%, and 71% of SIV. SIII/SIV median PCI was 21 and 20 obtaining 92% and 100% complete cytoreduction (≤0.25 cm), respectively. Median organ resections were 6 and 7, respectively. Grade III/IV surgical complications were 0% SIII and 23% SIV, without hospital mortality. Median time to adjuvant chemotherapy was 53 and 74 days, respectively ( p =0.007). SIII OS at 1 and 2 years was 100% and 83% and 87% and 76% in SIV ( p =0.269). SIII 1-year PFS was 54%; median PFS: 12 months. SIV 1- and 2- year PFS was 47% and 23%; median PFS: 12 months ( p =0.944)., Conclusion: Outcomes in select initially diagnosed and unresectable SIV EOC are similar to SIII after NACT plus CRS/HIPEC. SIV EOC may benefit from CRS/HIPEC, and further studies should explore this treatment approach., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Carlos A. Munoz-Zuluaga et al.)

Immunosuppressive tumor microenvironment (TME) and ascites-derived spheroids in ovarian cancer (OC) facilitate tumor growth and progression, and also pose major obstacles for cancer therapy. The molecular pathways involved in the OC-TME interactions, how the crosstalk impinges on OC aggression and chemoresistance are not well-characterized. Here, we demonstrate that tumor-derived UBR5, an E3 ligase overexpressed in human OC associated with poor prognosis, is essential for OC progression principally by promoting tumor-associated macrophage recruitment and activation via key chemokines and cytokines. UBR5 is also required to sustain cell-intrinsic β-catenin-mediated signaling to promote cellular adhesion/colonization and organoid formation by controlling the p53 protein level. OC-specific targeting of UBR5 strongly augments the survival benefit of conventional chemotherapy and immunotherapies. This work provides mechanistic insights into the novel oncogene-like functions of UBR5 in regulating the OC-TME crosstalk and suggests that UBR5 is a potential therapeutic target in OC treatment for modulating the TME and cancer stemness.

Background: Selected patients with platinum sensitive recurrent ovarian cancer may benefit from cytoreductive surgery (CRS). The aim was to study the pattern of peritoneal involvement in these patients that has not been done before., Methods: A comparison was made between the surgical and pathological findings in 60 patients undergoing salvage CRS from July 2018 to December 2019. The sites of residual disease, correlation with surgical and pathological peritoneal cancer index (PCI), small bowel involvement and regional lymph node involvement were studied., Results: Fifty-eight (96.6%) had serous carcinoma and 2 (3.4%) clear cell carcinoma. The median surgical PCI (sPCI) was 7 [range 0-27] and median pathological PCI (pPCI) 4 [range 0-21]. CC-0 resection was performed in 81.6%. The upper regions (region 1,2,3) were the commonest sites of residual disease (63.3%) followed by lower regions (region 5,6,7) in 55.0%, middle regions (regions 0,4,8) in 53.3% and small bowel regions (regions 9-12) in 26.6%. Small bowel involvement was associated with a higher sPCI and pPCI (p < 0.001 for both). Regional nodes were involved in 46.6%. A pathological complete response was seen in 8 (13.3%) patients of which 2 had residual disease in regional nodes. Microscopic disease in 'normal appearing' peritoneum was seen in 21%., Conclusions: The parietal peritoneum was the commonest site of recurrence. Small bowel involvement occurred late and was associated with more extensive disease. Regional lymph node involvement was seen nearly 50% and was a common site for occult disease. The role of more extensive parietal peritoneal resection for recurrent disease should be evaluated prospectively., Competing Interests: Declaration of competing interest The authors have no conflicts of interest. The authors received no funding for this study., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objective: High-grade serous ovarian cancer (HGSOC) is lethal mainly due to extensive metastasis. Cancer cell stem-like properties are responsible for HGSOC metastasis. LGR4, a G-protein-coupled receptor, is involved in the maintenance of stem cell self-renewal and activity in some human organs., Methods: TCGA and CCLE databases were interrogated for gene mRNA in ovarian cancer tissues and cell lines. Gain and loss of functions of LGR4, ELF3, FZD5 and WNT7B were performed to identify their roles in ovarian cancer cell epithelial phenotype and stem-like properties. In vivo experiments were performed to observe the effect of LGR4 on ovarian cancer cell growth and peritoneal seeding. The binding of ELF3 to LGR4 gene promoter was investigated by dual-luciferase reporter assays and ChIP., Results: LGR4 was shown to be overexpressed in HGSOCs and maintain the epithelial phenotype of HGSOC cells. LGR4 knockdown suppressed POU5F1, SOX2, PROM1 (CD133) and ALDH1A2 expression. Furthermore, LGR4 knockdown reduced CD133 + and ALDH + subpopulations and impaired tumorisphere formation. To the contrary, LGR4 overexpression enhanced POU5F1 and SOX2 expression and tumorisphere formation capacity. LGR4 knockdown inhibited HGSOC cell growth and peritoneal seeding in xenograft models. Mechanistically, LGR4 and ELF3, an epithelium-specific transcription factor, formed a reciprocal regulatory loop, which was positively modulated by WNT7B/FZD5 ligand-receptor pair. Consistently, knockdown of ELF3, WNT7B, and FZD5, respectively, disrupted HGSOC cell epithelial phenotype and stem-like properties., Conclusion: Together, these data demonstrate that WNT7B/FZD5-LGR4/ELF3 axis maintains HGSOC cell epithelial phenotype and stem-like traits; targeting this axis may prevent HGSOC metastasis., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Ultra-radical surgery to achieve complete resection in advanced epithelial ovarian cancer (EOC) has been widely accepted without strong supporting data. Our objective was to assess overall survival after a structured shift to an ultra-radical upfront surgical treatment algorithm and to investigate changes in the distribution of primary treatments after this shift., Patients and Methods: In this population-based cohort study, all women with suspected EOC in the Stockholm-Gotland region of Sweden reported to the Swedish Quality Registry for Gynecologic Cancer (SQRGC) and National Cancer Registry (NCR) were selected in two 3-year cohorts, based on year of diagnosis (before (cohort1) or after (cohort 2) change in surgical treatment algorithm) and followed for at least three years. 5-year overall survival (OS) in non-surgically and surgically treated women was analyzed. Moreover, proportional distribution of primary treatment was evaluated., Results: 752 women were included in the final analysis (n = 364 and 388 in cohort 1 and 2 respectively) with a median follow-up of 29 and 27 months. The complete resection rate increased from 37 to 67% (p ≤ 0.001) as well as proportion non-surgically treated women, 24 to 33%. No improvement in OS was observed in non-surgically (HR 0.76 (95% CI, 0.58-1.01); p = 0.06) or surgically treated (HR 0.94 (95% CI, 0.75-1.18); p = 0.59) women, even when complete resection was achieved (HR 1.31 (95% CI, 0.89-1.92); p = 0.17)., Conclusion: A shift to ultra-radical upfront surgery in EOC did not improve survival despite a significant increase in complete resection rate. Identifying the limitations of surgical treatment remains a challenge., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: We assessed the utility of video-assisted thoracic surgery (VATS) in defining extent of intrathoracic disease in advanced ovarian carcinoma with moderate-to-large pleural effusions., Methods: Beginning in 2001, VATS was performed on all patients with suspected advanced ovarian carcinoma and moderate-to-large pleural effusions, evaluating for macroscopic intrathoracic disease. The algorithm recommended primary debulking surgery (PDS) for ≤1 cm, neoadjuvant chemotherapy (NACT)/interval debulking surgery (IDS) for >1 cm intrathoracic disease. We reviewed records of patients undergoing VATS from 10/01-01/19. Differences between treatment groups were tested using standard statistical techniques., Results: One-hundred patients met eligibility criteria (median age, 60; median CA-125 level, 1158 U/mL; medium serum albumin, 3.8 g/dL). Macroscopic pleural disease was found in 70 (70%). After VATS, 50 (50%) underwent attempted PDS (PDS group), 50 (50%) received NACT (NACT/IDS group). Forty-seven (94%) underwent IDS. Median overall survival (OS) for the entire cohort (n = 100) was 44.5 months (95% CI: 37.8-51.7). The PDS group had significantly longer survival than the NACT/IDS group [45.8 (95% CI: 40.5-87.8) vs. 37.4 months (95% CI: 33.3-45.2); p = .016]. On multivariable analysis, macroscopic intrathoracic disease (HR 2.18, 95% CI: 1.14-4.18; p = .019) and age ≥ 65 (HR 1.98, 95% CI: 1.16-3.40; p = .013) were independently associated with elevated death risk. Patients with the best outcome had no macroscopic disease at VATS and underwent PDS (median OS, 87.8 months)., Conclusions: VATS is useful in therapeutic decision-making for PDS vs. NACT/IDS in advanced ovarian cancer with moderate-to-large pleural effusions., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Brain metastasis from epithelial ovarian carcinoma (EOC) is rarely seen having rate of 1-3% with very poor prognosis. Studies on brain metastatic EOC is limited with low number of participants. An increasing trend in EOC related to brain metastasis has been reported recently confronting managing clinicians with new challenges. Therefore, more information on this issue is needed. We aimed to analyze a single radiotherapy center experience on EOC related brain metastases., Materials and Methods: Data of all patients treated between January 1998 and December 2016 at a radiation center of a university hospital were reviewed retrospectively. Clinicopathological characteristics, treatment details and outcome were analyzed., Results: We identified only ten cases with EOC related brain metastasis in our department during 18-year period. Two patients were excluded because of data unavailability and therefore our study was performed among 8 patients. The median time between EOC diagnosis and detection of brain metastasis was 19.8 months. Brain metastasis was multiple in majority (75%). Extracranial metastasis at the time of brain metastasis was 62.5%. All patients died in the follow-up. The median survival time after the diagnosis of brain metastasis was 4.5 months. The median overall survival (OS) after the diagnosis of EOC was 28.9 months. The interval between the initial diagnosis and brain metastasis was negatively correlated with survival after brain metastasis (B-OS) occurred as time interval (p = 0.047). Presence of extracranial metastasis at time of occurrence of brain metastasis and application of multimodal treatment after brain metastasis were positively correlated with B-OS time (p = 0.007, p = 0.046, respectively)., Conclusion: Prognosis of brain metastasis from EOC remains poor. The factors associated with better B-OS were the longer time between initial diagnosis and brain metastasis, absence of extracranial disease at time of brain metastasis, and application of the multimodal treatment., Competing Interests: Declaration of Competing Interest None of the authors declare conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Objectives: In the United States, trends in the initial treatment approach for ovarian cancer reflect a shift in paradigm toward the increased use of neoadjuvant chemotherapy and interval cytoreductive surgery. The aim of this study was to evaluate the trends in surgical cytoreductive procedures in ovarian cancer patients who underwent either primary or interval cytoreductive surgery., Methods: This retrospective, population-based study examined patients with stage III/IV ovarian cancer diagnosed between January 2000 and December 2013 identified using SEER-Medicare. Small or large bowel resection, ostomy creation, and upper abdominal procedures were identified using relevant billing codes and compared over time. A 1:1 primary and interval cytoreductive propensity matched cohort was created using demographic and clinical variables. 30-day complications and the use of acute care services were compared., Results: A total of 5417 women were identified. 34% underwent bowel resections, 16% ostomy creation, and 8% upper abdominal procedures. There was an increase in bowel resections and upper abdominal procedures from 2000 to 2013 in patients who underwent primary cytoreductive surgery. Compared with patients who received primary cytoreduction, patients who underwent interval cytoreductive surgery were less likely to undergo bowel resection (OR=0.50; 95% CI [0.41, 0.61]) or ostomy creation (OR=0.48; 95% CI [0.42, 0.56]). Upper abdominal procedures did not differ between groups. For patients who underwent primary cytoreductive surgery, these procedures were associated with intensive care unit stay (4.6% vs <2%, P<0.01). In both primary and interval cytoreductive surgery patients, the receipt of bowel and upper abdominal procedures was associated with multiple 30-day postoperative complications and higher rates of readmission and emergency room visits., Conclusions: The performance of upper abdominal procedures in ovarian cancer patients increased from 2000 to 2013. Interval cytoreductive surgery was associated with decreased likelihood of bowel surgery. In matched primary and interval cytoreductive surgery cohorts, the receipt of these procedures were associated with the increased likelihood of postoperative complications and use of acute care services., Competing Interests: Competing interests: LAM: received research funding from AstraZeneca for unrelated research, and has participated in an advisory board for Clovis Oncology in 2016. CCS: received research funding from AstraZeneca for unrelated research., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To investigate the association between CT imaging traits and texture metrics with proteomic data in patients with high-grade serous ovarian cancer (HGSOC)., Methods: This retrospective, hypothesis-generating study included 20 patients with HGSOC prior to primary cytoreductive surgery. Two readers independently assessed the contrast-enhanced computed tomography (CT) images and extracted 33 imaging traits, with a third reader adjudicating in the event of a disagreement. In addition, all sites of suspected HGSOC were manually segmented texture features which were computed from each tumor site. Three texture features that represented intra- and inter-site tumor heterogeneity were used for analysis. An integrated analysis of transcriptomic and proteomic data identified proteins with conserved expression between primary tumor sites and metastasis. Correlations between protein abundance and various CT imaging traits and texture features were assessed using the Kendall tau rank correlation coefficient and the Mann-Whitney U test, whereas the area under the receiver operating characteristic curve (AUC) was reported as a metric of the strength and the direction of the association. P values < 0.05 were considered significant., Results: Four proteins were associated with CT-based imaging traits, with the strongest correlation observed between the CRIP2 protein and disease in the mesentery (p < 0.001, AUC = 0.05). The abundance of three proteins was associated with texture features that represented intra-and inter-site tumor heterogeneity, with the strongest negative correlation between the CKB protein and cluster dissimilarity (p = 0.047, τ = 0.326)., Conclusion: This study provides the first insights into the potential associations between standard-of-care CT imaging traits and texture measures of intra- and inter-site heterogeneity, and the abundance of several proteins., Key Points: • CT-based texture features of intra- and inter-site tumor heterogeneity correlate with the abundance of several proteins in patients with HGSOC. • CT imaging traits correlate with protein abundance in patients with HGSOC.

Advanced ovarian cancer usually spreads to the omentum. However, the omental cell-derived molecular determinants modulating its progression have not been thoroughly characterized. Here, we show that circulating ITLN1 has prognostic significance in patients with advanced ovarian cancer. Further studies demonstrate that ITLN1 suppresses lactotransferrin's effect on ovarian cancer cell invasion potential and proliferation by decreasing MMP1 expression and inducing a metabolic shift in metastatic ovarian cancer cells. Additionally, ovarian cancer-bearing mice treated with ITLN1 demonstrate marked decrease in tumor growth rates. These data suggest that downregulation of mesothelial cell-derived ITLN1 in the omental tumor microenvironment facilitates ovarian cancer progression.

Epithelial ovarian cancer (EOC) metastasis occurs by exfoliation of cells and multicellular aggregates (MCAs) from the tumor into the peritoneal cavity, adhesion to and retraction of peritoneal mesothelial cells and subsequent anchoring. Elevated levels of lysophosphatidic acid (LPA) have been linked to aberrant cell proliferation, oncogenesis, and metastasis. LPA disrupts junctional integrity and epithelial cohesion in vitro however, the fate of free-floating cells/MCAs and the response of host peritoneal tissues to LPA remain unclear. EOC MCAs displayed significant LPA-induced changes in surface ultrastructure with the loss of cell surface protrusions and poor aggregation, resulting in increased dissemination of small clusters compared to untreated control MCAs. LPA also diminished the adhesive capacity of EOC single cells and MCAs to murine peritoneal explants and impaired MCA survival and mesothelial clearance competence. Peritoneal tissues from healthy mice injected with LPA exhibited enhanced mesothelial surface microvilli. Ultrastructural alterations were associated with restricted peritoneal susceptibility to metastatic colonization by single cells as well as epithelial-type MCAs. The functional consequence is an LPA-induced dissemination of small mesenchymal-type clusters, promoting a miliary mode of peritoneal seeding that complicates surgical removal and is associated with worse prognosis.

Objective: This study is aimed to analyze the clinical outcome of recurrent ovarian cancer patients bearing isolated lymph-node recurrence (ILNR) who underwent salvage lymphadenectomy (SL). The prognostic role of clinicopathological variables and the mutational status of BRCA1/2 have also been investigated., Methods: This retrospective, single-institutional study included women with platinum-sensitive lymph node recurrence underwent to SL between June 2008 and June 2018. Univariate and multivariate analysis was performed to evaluate the impact of clinical parameters, and BRCA1/2 mutational status on post salvage lymphadenectomy progression-free survival (PSL-PFS)., Results: As of June 2019, the median follow-up after SL was 30 months, and the relapse has been documented in 48 (56.5%) patients. In the whole series, the median PSL-PFS was 21 months, and the 3-year PSL-PFS was 36.7%. The median PSL-PFS, according to patients with ILNR (N = 71) versus patients with lymph-nodes and other sites of disease (N = 14), was 27 months versus 12 months, respectively. Univariate analysis of variables conditioning PSL-PFS showed that platinum-free interval (PFI) ≥12 months, normal Ca125 serum levels, and number of metastatic lymph-nodes ≤3 played a statistically significant favorable role. In multivariate analysis, PFI duration ≥12 months and the number of metastatic lymph nodes ≤3 were shown to keep their favorable, independent prognostic value on PSL-PFS., Conclusions: In the context of SL, the patients with long PFI and low metastatic lymph node numbers at ILNR diagnosis have the best outcome. The BRCA mutational status seems not associated with clinical variables and PSL-PFS, differently from other sites of disease in ROC patients., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: The surgical treatment of advanced ovarian cancer aims to resect all visible tumor to no gross residual, these procedures are often extensive with need of prolonged attention to detail. Our objective was to investigate the association between week-day of surgery, time of year (season) when surgery was performed and non-radical surgery (surgical failure) in advanced ovarian cancer. Material and methods: Women diagnosed with primary invasive epithelial ovarian cancer in the Stockholm/Gotland Region, Sweden were identified in the regional Swedish Quality Registry of Gynecologic Cancer (SQRGC). Data of all women with International Federation of Gynecology and Obstetrics (FIGO) stages III and IV were validated against the National Cancer Registry. Women subjected to surgery with curative intent were selected and included in the analysis. Uni- and multivariable regression analyses were performed. Results: Out of 538 women identified in the SQRGC-string ovary between 2014 and 2016, 240 were eligible for analysis. In 29% of women, complete radical resection was not achieved. There was a significant trend of increased non-radical resection when surgery was performed from Monday through Thursday ( p  = .03). The adjusted odds of non-radical surgery increased if surgery was performed on Thursday rather than Monday (Odds Ratio (OR) 3.04, 95% Confidence Interval (CI) 1.05-8.79, p  = .04). Surgery performed during summer compared to the rest of the year, did not significantly increase the adjusted odds of non-radical surgery (OR 1.92, 95% CI 0.91-4.07, p  = .09). Conclusion: Complete surgical resection of tumor is one of the strongest prognostic factors for survival in advanced epithelial ovarian cancer. For this reason, advanced ovarian cancer surgery should be scheduled early in the week.

High grade serous ovarian cancer (HGSC) is the most common and deadly type of ovarian cancer, largely due to difficulties in early diagnosis and rapid metastasis throughout the peritoneal cavity. Previous studies have shown that expression of Notch3 correlates with worse prognosis and increased tumorigenic cell behaviors in HGSC. We investigated the mechanistic role of Notch3 in a model of metastatic ovarian cancer using the murine ovarian surface epithelial cell line, ID8 IP2. Notch3 was activated in ID8 IP2 cells via expression of the Notch3 intracellular domain (Notch3IC). Notch3IC ID8 IP2 cells injected intraperitoneally caused accelerated ascites and reduced survival compared to control ID8 IP2, particularly in early stages of disease. We interrogated downstream targets of Notch3IC in ID8 IP2 cells by RNA sequencing and found significant induction of genes that encode adhesion and extracellular matrix proteins. Notch3IC ID8 IP2 showed increased expression of ITGA1 mRNA and cell-surface protein. Notch3IC-mediated increase of ITGA1 was also seen in two human ovarian cancer cells. Notch3IC ID8 IP2 cells showed increased adhesion to collagens I and IV in vitro. We propose that Notch3 activation in ovarian cancer cells causes increased adherence to collagen-rich peritoneal surfaces. Thus, the correlation between increased Notch3 signaling and poor prognosis may be influenced by increased metastasis of HGSC via increased adherence of disseminating cells to new metastatic sites in the peritoneum., Competing Interests: The authors have declared that no competing interests exist.

In March 2019, Harter et al. published the results of the LION study (Lymphadenectomy in patients with advanced ovarian neoplasms) which raises the question of pelvic and para-aortic lymphadenectomy for patients with advanced-stage epithelial ovarian cancer (EOC). These results influenced the new French recommendations published in December 2018 by the French National Cancer Institute (INCa). Thus, it no longer seems consistent to perform a systematic lymphadenectomy for patients for whom there is no argument for nodal involvement, when a macroscopic complete peritoneal cytoreductive surgery has been performed. The question of preoperative lymph node assessment is therefore essential, whereas more than half of the patients in the LION study had metastatic lymph node involvement that was histologically proven. For the assessment of lymph node status by imaging, superior sensitivity for Positron Emission Tomography is demonstrated in comparison with CT-scan or Magnetic Resonance Imaging. Nevertheless, thoraco-abdomino-pelvic CT-scan with contrast injection remains the gold standard for this indication. In the absence of suspected involvement, supra-renal, mesenteric, coelio-hepatic, and cardio-phrenic lymphadenectomy are not recommended. Lymphadenectomies should always be performed in the other situations of EOC management apart from the rare case of stage 1 expansile subtype mucinous carcinoma. The aim of this review is to discuss lymphadenectomy indications for the surgical management of EOC by taking into account new data from the scientific literature., (Copyright © 2019 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

An integral step in the development of solid tumors is the recruitment of blood vessels to fuel tumor growth. Antiangiogenic therapies can inhibit this process and control solid tumor growth. Thrombospondin-1 is an antiangiogenic protein possessing three type I repeats (3TSR) near the center of the protein and a CD47-binding peptide (CD47) in its C-terminus. Previously, we showed that treatment with recombinant 3TSR induces tumor regression, normalizes tumor vasculature, and improves uptake of chemotherapy drugs in an orthotopic, syngeneic mouse model of advanced stage epithelial ovarian cancer (EOC). While effective, this intervention required daily intraperitoneal injections. To circumvent this, here we employ adeno-associated virus (AAV) gene therapy vectors to express 3TSR alone or in combination with the CD47-binding peptide of TSP-1 and evaluate the impact on tumor development and survival in a mouse model of EOC. A single intraperitoneal injection of 1 × 10 11  vg of AAV expressing 3TSR, CD47-binding peptide, or 3TSR + CD47 effectively suppressed primary tumor growth; however, only AAV-3TSR was able to inhibit development of secondary lesions at 90-days post-tumor implantation and significantly improve survival. Taken together, AAV-mediated expression of 3TSR appears safe and effective at inhibiting tumor development and represents a novel, less invasive approach for treating ovarian carcinoma.

Completeness of cytoreduction is one of the most important prognostic factors impacting outcomes of cytoreductive surgery (CRS). To what extent the surrounding normal peritoneum needs to be removed is not known. We hypothesized that the extent of peritoneal resection should be different for different tumors and performed this study to find evidence to support this rationale. To determine the extent of resection of surrounding tissue for any tumor, the mechanisms of tumor development and spread, tumor morphology, the possibility of finding disease in the surrounding normal tissue, and the pattern of lymph node metastases should be known. Surgical resections also depend on patterns of recurrence and the impact of varying extent of resection on survival. We performed a review of literature pertaining to pathways and patterns of peritoneal cancer spread to determine the scientific basis for the extent of peritonectomy. We also reviewed studies comparing less and more extensive peritoneal resection. There is no consensus on the extent of lymphadenectomy required for most PM. Based on this review, we provide recommendations for the extent of peritoneal resection and the extent of lymph node dissection that should be performed for some common peritoneal tumors and identify areas that require further research. We propose that a systematic method of synoptic reporting of pathological specimens of CRS should be developed to capture information regarding the disease distribution within the peritoneal cavity and morphology of PM from different tumors. This can in future be used to establish standard guidelines for such resections.

Ovarian cancer metastasizes to organs in the abdominal cavity, such as the omentum that is a rich source of adipose-derived mesenchymal stem cells (ADSCs). In present, ADSCs have received more and more attention for their roles in the development of cancer. In this study, we examined α-smooth muscle actin (α-SMA) expression and carcinoma-associated fibroblast (CAF)-like differentiation capabilities in ADSCs from omentum of different patients. The effects of ADSCs on the proliferation and invasion of epithelial ovarian cancer cells (EOCCs) were also assessed in vitro and in vivo. Our results showed that ADSCs from omentum of ovarian cancer patients, no matter whether metastasis or not, expressed higher levels of α-SMA than ADSCs from patients with benign gynecologic disease. Using direct and indirect co-culture system, we found that EOCCs induced ADSCs to express CAF markers, including α-SMA and fibroblast activation protein, via the transforming growth factor beta 1 (TGF-β1) signaling pathway. Moreover, co-cultured ADSCs exhibited functional properties similar to those of CAFs, including the ability to promote EOCCs proliferation, progression and metastasis both in vitro and in vivo. Furthermore, blocking the TGF-β1 pathway can counteract the CAF-like differentiation and tumor promotion effect of ADSCs. Our results suggest that ADSCs are a source of CAFs and that they participate in the interaction between EOCCs and the omental microenvironment. EOCCs could induce ADSCs in the omentum to differentiate before ovarian cancer metastasis, which participate in the formation of omental metastatic niches and promote the proliferation and invasion of ovarian cancer., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Most women with epithelial ovarian cancer (EOC) suffer from peritoneal carcinomatosis upon first clinical presentation. Extensive peritoneal carcinomatosis has a poor prognosis and its pathophysiology is not well understood. Although treatment with systemic intravenous chemotherapy is often initially successful, peritoneal recurrences occur regularly. We hypothesized that insufficient or poorly-perfused microvasculature may impair the therapeutic efficacy of systemic intravenous chemotherapy but may also limit expansive and invasive growth characteristic of peritoneal EOC metastases. In 23 patients with advanced EOC or suspicion thereof, we determined the angioarchitecture and perfusion of the microvasculature in peritoneum and in peritoneal metastases using incident dark field (IDF) imaging. Additionally, we performed immunohistochemical analysis and 3-dimensional (3D) whole tumor imaging using light sheet fluorescence microscopy of IDF-imaged tissue sites. In all metastases, microvasculature was present but the angioarchitecture was chaotic and the vessel density and perfusion of vessels was significantly lower than in unaffected peritoneum. Immunohistochemical analysis showed expression of vascular endothelial growth factor and hypoxia inducible factor 1α, and 3D imaging demonstrated vascular continuity between metastases and the vascular network of the peritoneum beneath the elastic lamina of the peritoneum. We conclude that perfusion of the microvasculature within metastases is limited, which may cause hypoxia, affect the behavior of EOC metastases on the peritoneum and limit the response of EOC metastases to systemic treatment.

Background: The aim was to study the patterns of target region (greater omentum, lesser omentum, falciform and umbilical round ligament) involvement in patients undergoing cytoreductive surgery (CRS) from various primary tumors, factors affecting involvement and implications on surgical practice., Methods: All patients undergoing CRS from July 2018 to December 2018 were included in this prospective study. The incidence of target region involvement in presence and absence of visible disease and the impact of primary tumor site, PCI and other variables on target region involvement was evaluated., Results: In 191 patients, greater omentum was involved in over 15% of patients irrespective of the primary tumor type and in 15.7% in absence of visible disease. 75% of these had PCI <20. The involvement of the other three target regions was higher than 20% in ovarian cancer, appendiceal tumors and peritoneal mesothelioma. Involvement of these 3 regions was associated with a higher PCI (p < 0.001 for all) and omental involvement (p < 0.001for all). 2.1% of colorectal cancer patients had umbilical round ligament involvement, 4.2% had falciform ligament involvement and none had lesser omentum involvement., Conclusions: Target region involvement varies according to primary tumour site and disease extent. Resection of the greater omentum should be performed during CRS for PM arising from all primary sites. Resection of other target organs may be performed for selected patients with ovarian cancer, peritoneal mesothelioma and mucinous appendiceal tumors in absence of visible disease. For other patients, it should be done only in presence of visible disease., Competing Interests: Declaration of competing interest The authors have no disclosures or conflict of interests., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Detachment of cancer cells from the primary tumor and formation of spheroids in ascites is required for implantation metastasis in epithelial ovarian cancer (EOC), but the underlying mechanism of this process has not been thoroughly elucidated. To mimic this process, ovarian cancer cells were grown in 3D and 2D culture. Hey and OVCA433 spheroids exhibited decreased cell proliferation and enhanced adhesion and invasion. SMYD3 expression was elevated in ovarian carcinoma spheroids in association with increased H3K4 methylation. Depletion of SMYD3 by transient siRNA, stable shRNA knockdown and the SMYD3 inhibitor BCI-121 all decreased spheroid invasion and adhesion. Gene expression arrays revealed downregulation of integrin family members. Inhibition assays confirmed that invasion and adhesion of spheroids are mediated by ITGB6 and ITGAM. SMYD3-deficient cells regained the ability to invade and adhere after forced overexpression of SMYD3, ITGB6 and ITGAM. However, this biological ability was not restored by forced overexpression of SMYD3 in ITGB6- and/or ITGAM-deficient cancer cells. SMYD3 and H3K4me3 binding at the ITGB6 and ITGAM promoters was increased in spheroids compared to that in monolayer cells, and the binding was decreased when SMYD3 expression was inhibited, consistent with the expression changes in integrins. SMYD3 expression and integrin-mediated adhesion were also activated in an intraperitoneal xenograft model and in EOC patient spheroids. In vivo, SMYD3 knockdown inhibited tumor metastasis and reduced ascites volume in both the intraperitoneal xenograft model and a PDX model. Overall, our results suggest that the SMYD3-H3K4me3-integrin pathway plays a crucial role in ovarian cancer metastasis to the peritoneal surface., (© 2019 UICC.)

Epithelial ovarian cancer (EOC) is considered to secrete various factors in order to promote peritoneal dissemination through cell-to-cell interaction between cancer and mesothelial cells. We previously revealed that TGF-β secreted from EOC induces normal human peritoneal mesothelial cells (HPMCs) to differentiate into cancer-associated mesothelial cells (CAMCs). However, the relationship between tumor cells and CAMCs in EOC is still unclear. We hypothesized that CAMCs also secrete chemokines that attract cancer cells and induce peritoneal dissemination of EOC. We examined chemokines secreted from HPMCs and CAMCs by human chemokine array, and revealed that conditioned medium of CAMCs (CAMCs-CM) included many types of chemokines. The signals of CCL2 were the highest compared with other chemokines. The secretion and relative expression of CCL2 were significantly higher in CAMCs. Recombinant CCL2 promoted trans-mesothelial migration of HPMCs and the migration and invasion by EOC cells. In addition, CCL2 secreted from CAMCs promoted invasion of EOC cells. Furthermore, the neutralizing antibody of CCL2 reduced invasion by EOC. Clinical outcomes of patients whose tissue expressed higher CCR2 were significantly poorer than in patients whose tissue expression was lower. CCL2 activated the phosphorylation of p38 mitogen-activated protein kinase (MAPK). In addition, CAMCs-CM activated the p38 MAPK pathway. Phosphorylation of p38 MAPK reduced with the presence of neutralizing antibody of CCL2. In conclusion, these data indicate CCL2 in CAMCs-CM promoted the malignant potential of EOC. CCL2 plays a crucial role in the tumor microenvironment of EOC.

Background: Ovarian cancer represents a major global health burden that is rarely associated with distant metastasis. Axillary lymph node metastasis from ovarian cancer is rare and is reported only in few case reports in literature., Case Presentation: We report three cases of ovarian carcinoma associated with axillary lymph node metastasis as well as a brief literature review. The pathologic subtype in one case was malignant mixed Mullerian tumor, while the other two cases were high-grade serous ovarian carcinoma. Axillary nodal metastasis was reported as a synchronous event in one case, while it was reported as recurrence events in the other two cases., Conclusion: Physicians should be aware of this uncommon mode of metastasis in ovarian cancer cases. Multi-disciplinary discussion is crucial in the management of these cases to offer them the best suitable treatment.

Objective: To describe accurately the oncological outcomes after hepatic resection (HR) in recurrent ovarian carcinoma (ROC) evaluating clinic-pathological variables and mutational status of BRCA1/2. Although HR is considered a challenging situation in ROC patients, assessment of BRCA1/2 mutational status seems to have a relevant clinical value to guide surgical therapy., Methods: Patients who underwent HR for ROC at the Catholic University of Rome, between June 2012 and October 2017 were included. Exclusion criteria were represented by extra-abdominal disease and presence of diffuse peritoneal carcinomatosis requiring more than 2 bowel resections. Details relative to HR were collected and BRCA analysis was performed. Predictive factors of post-HR progression free survival (PHR-PFS) were assessed by univariate analyses using Cox-proportional hazard regression models., Results: Thirty-four patients undewent HR within secondary cytoreductive surgery (SCS). Six patients (17.6%) presented with hepatic relapse only, while the remaining 28 patients (82.4%) had concomitant extra-hepatic disease. In the whole series, the 3-yr PHR-PFS was 49.1% and the 3-yr post-HR overall survival was 72.9%. Univariate analysis of variables conditioning PHR-PFS showed that only BRCA mutational status played a statistically significant favourable role: the 3-yr PHR-PFS rate was 81.0% in BRCA mutated patient compared to 15.2% in wild type ones (p value: 0.001)., Conclusions: Our clinical analyses suggest that in ROC patients with liver disease the assessment of germline and somatic BRCA mutational status can help to select patients elegible for SCS., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Study Objective: To estimate pulmonary complications and diaphragm recurrence after resection of diaphragm metastases by minimally invasive surgery (MIS) for epithelial ovarian cancer (EOC)., Design: Retrospective analysis (Canadian Task Force classification III)., Setting: Mayo Clinic in Scottsdale, Arizona, from January 1, 2004, through January 31, 2014., Patients: Selected cohort of 29 patients., Interventions: Diaphragm resection by MIS (robotics, 21; laparoscopy, 8) for EOC., Measurements and Main Results: To assess for pulmonary complications most likely due to diaphragm resection, patients were excluded if they had preoperative pleural effusions or pulmonary disease or had undergone additional upper abdominal procedures. Mean patient age was 58.7 years (standard deviation, 14.9) and mean BMI was 24.2 kg/m 2 (standard deviation, 3.4). The mean size of diaphragm metastases was 56.7 mm (range, 2-145). Full-thickness resection was performed in 6 patients; 23 had peritoneal resection. Complete resection was achieved in all patients with no conversions to laparotomy. Two patients (6.9%) had pulmonary complications (pleural effusion). Six patients (20.7%) had diaphragm recurrence; 10 patients (34.5%) had recurrence at other abdominal sites., Conclusion: Resection of diaphragm metastases by MIS appears to be feasible and safe for selected patients, with similar recurrence as other abdominal sites., (Copyright © 2019. Published by Elsevier Inc.)

Background: In many malignancies including ovarian cancer, different angiogenic factors have been related to poor prognosis. However, data on their relations to each other or importance as a prognostic factor in ovarian cancer is missing. Therefore, we investigated the expressions of VEGF-A, VEGF-C, and VEGF-D, and the receptors VEGFR1, VEGFR2, and VEGFR3 in patients with malignant epithelial ovarian neoplasms. We further compared expression levels between primary tumors and related distant omental metastases., Methods: This study included 86 patients with malignant ovarian epithelial tumors and 16 related distant metastases. Angiogenic factor expression was evaluated using immunohistochemistry (n = 102) and qRT-PCR (n = 29)., Results: Compared to primary high grade serous ovarian tumors, the related omental metastases showed higher expressions of VEGF-A (p = 0.022), VEGF-D (p = 0.010), and VEGFR1 (p = 0.046). In univariate survival analysis, low epithelial expression of VEGF-A in primary tumors was associated with poor prognosis (p = 0.024), and short progression-free survival was associated with high VEGF-C (p = 0.034) and low VEGFR3 (p = 0.002). The relative expressions of VEGF-D, VEGFR1, VEGFR2, and VEGFR3 mRNA determined by qRT-PCR analyses were significantly correlated with the immunohistochemically detected levels of these proteins in primary high grade serous ovarian cancer and metastases (p = 0.004, p = 0.009, p = 0.015, and p = 0.018, respectively)., Conclusions: The expressions of VEGF receptors and their ligands significantly differed between malignant ovarian tumors and paired distant metastases. VEGF-A, VEGF-D, and VEGFR1 protein expressions seem to be higher in distant metastases than in the primary high grade serous ovarian cancer lesions.

Background: The epithelial-mesenchymal transition (EMT), which is a change in the cell phenotype from epithelial to mesenchymal morphology, is an important step in the invasion process and metastasis of ovarian carcinomas. It is known that the suppression of cell adhesion molecules such as E-cadherin and the expression of mesenchymal markers such as Vimentin are key processes in EMT. There is controversy in the literature about the EMT status of ovarian carcinomas., Aim: To investigate EMT status using immunohistochemical expression of E-cadherin in benign, primary malignant serous ovarian tumors and metastases from them in order to assess their significance in tumor progression., Materials and Methods: The study included a retrospective investigation of 217 ovarian epithelial tumors. Ninety-two cases of serous ovarian tumors and metastases were examined for expression of E-cadherin., Results: In our study, the predominant histological subtype in benign ovarian tumors and carcinomas was serous (73% and 61%, respectively). 65% of benign tumors demonstrated EMT negative status. The majority of carcinomas demonstrated EMT positive status (82%), whereas negative EMT status was only observed in 18% of cases. 89% of the metastases showed EMT positive status, whereas only 11% of them showed negative EMT status. In 6 selected cases with positive EMT status we found Vimentin expression in tumor cells., Conclusion: Positive EMT status (reduced E-cadherin expression) is a characteristic of ovarian carcinomas and metastases, but not of benign serous ovarian tumors.

Objectives: We evaluated four different treatment regimens for advanced-stage mucinous epithelial ovarian cancer., Methods: We conducted a multicenter randomized factorial trial (UK and US). Patients were diagnosed with primary mEOC: FIGO stage II-IV or recurrence after stage I disease. Treatment arms were paclitaxel-carboplatin, oxaliplatin-capecitabine, paclitaxel-carboplatin-bevacizumab, or oxaliplatin-capecitabine-bevacizumab. Chemotherapy was given 3-weekly for 6 cycles, and bevacizumab (3-weekly) was continued as maintenance (for 12 cycles). Endpoints included overall-survival (OS), progression-free survival (PFS), toxicity and quality of life (QoL)., Results: The trial stopped after 50 patients were recruited due to slow accrual. Median follow-up was 59 months. OS hazard ratios (HR) for the two main comparisons were: 0.78 (p = 0.48) for Oxal-Cape vs. Pac-Carbo (each with/without bevacizumab), and 1.04 (p = 0.92) for bevacizumab vs. no bevacizumab. Corresponding PFS HRs were: 0.84 and 0.80. Retrospective central pathology review revealed only 45% (18/40) cases with available material had confirmed primary mEOC. Among these, OS HR for Oxal-Cape vs. Pac-Carbo was 0.36 (p = 0.14); PFS HR = 0.62 (p = 0.40). Grade 3-4 toxicity was seen in 61% Pac-Carbo, 61% Oxal-Cape, 54% Pac-Carbo-Bev, and 85% Oxal-Cape-Bev. QoL was similar between the four arms., Conclusion: mEOC/GOG0241 represents an example of a randomized rare tumor trial. Logistical challenges led to early termination, including difficulties in local histopathological diagnosis and accessing drugs outside their labelled indication. There was misalignment between central funders who support clinical trials in rare cancers and the deprioritisation of such work by those managing and funding research at a local level. Rare cancer trials should include centralised pathology review before treatment. Clinical trial registry number: ISRCTN83438782., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Late-line treatment options for patients with ovarian cancer are few, with the proportion of patients achieving an overall response typically less than 10%, and median overall survival after third-line therapy of 5-9 months. In this study (QUADRA), we investigated the activity of niraparib monotherapy as the fourth or later line of therapy., Methods: QUADRA was a multicentre, open-label, single-arm, phase 2 study that evaluated the safety and activity of niraparib in adult patients (≥18 years) with relapsed, high-grade serous (grade 2 or 3) epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with three or more previous chemotherapy regimens. The study was done in the USA and Canada, and 56 sites screened patients (50 sites treated at least one patient). Patients received oral niraparib 300 mg once daily continuously, beginning on day 1 and every cycle (28 days) thereafter until disease progression. The primary objective was the proportion of patients achieving an investigator-assessed confirmed overall response in patients with homologous recombination deficiency (HRD)-positive tumours (including patients with BRCA and without BRCA mutations) sensitive to their last platinum-based therapy who had received three or four previous anticancer therapy regimens (primary efficacy population). Efficacy analyses were additionally done in all dosed patients with measurable disease at baseline., Findings: Between April 1, 2015 and Nov 1, 2017, we screened 729 patients for eligibility and enrolled 463 patients, who were initiated on niraparib therapy. At the time of database lock (April 11, 2018), enrolment had closed and the study was ongoing, with 21 patients still on treatment. Patients had received a median of four (IQR 3-5) previous lines of therapy, and the median follow-up for overall survival was 12·2 months (IQR 3·7-22·1). 151 (33%) of 463 patients were resistant and 161 (35%) of 463 patients were refractory to the last administered platinum therapy. 13 (28%) of 47 patients in the primary efficacy population achieved an overall response according to RECIST (95% CI 15·6-42·6; one-sided p=0·00053). The most common drug-related grade 3 or worse treatment-emergent adverse events were anaemia (113 [24%] of 463 patients) and thrombocytopenia (95 [21%] of 463 patients). The most common treatment-emergent serious adverse events were small intestinal obstruction (34 [7%] of 463 patients), thrombocytopenia (34 [7%] of 463 patients), and vomiting (27 [6%] of 463 patients). One death due to gastric haemorrhage was considered treatment related., Interpretation: We observed clinically relevant activity of niraparib among women with heavily pretreated ovarian cancer, especially in patients with HRD-positive platinum-sensitive disease, which includes not only patients with a BRCA mutation but also a population with BRCA wild-type disease. We identified no new safety signals. Our data support expansion of the treatment indication for poly(ADP-ribose) polymerase inhibitors to include patients with HRD-positive ovarian cancer beyond those with BRCA mutations., Funding: Tesaro., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aims: We evaluated the prognostic significance of postoperative re-elevation of cancer antigen-125 (CA-125) levels in patients with ovarian cancer and preoperative normalization of CA-125 levels after neoadjuvant chemotherapy (NAC)., Methods: The data of 103 patients with preoperative CA-125 normalization after NAC at the Yonsei Cancer Hospital (2006-2017) were analyzed. We compared the clinical characteristics and survival outcomes among patients with normal postoperative CA-125 levels and those with re-elevated CA-125 levels after interval debulking surgery (IDS). CA-125 elevation was defined as levels >35 U/mL., Results: Among 103 patients, 52 (50.5%) and 51 (49.5%) had normal and re-elevated CA-125 levels after IDS, respectively. Patients with CA-125 re-elevation underwent more radical surgeries during IDS than those with normal CA-125 levels (p = 0.018). We found no significant differences in progression-free survival (PFS; p = 0.726) or overall survival (OS; p = 0.293) between the two groups. Moreover, patients with persistent CA-125 elevation (3 weeks after IDS) did not have inferior PFS (p = 0.171 and p = 0.208, respectively) or OS (p = 0.128 and p = 0.095, respectively) compared to patients with early normalization (within 3 weeks of IDS) or normal CA-125 levels. Multivariate regression showed that CA-125 re-elevation had no effect on recurrence (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.43-1.30) or death (HR, 0.99; 95% CI, 0.33-2.98)., Conclusion: Among patients with preoperative CA-125 normalization after NAC, postoperative CA-125 re-elevation had no prognostic value. Novel and reliable biomarkers reflecting the tumor response after IDS should be identified., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objectives: The goals were to study • The pattern of pathological response to neoadjuvant chemotherapy (NACT) and its clinical implications • The impact of chemotherapy response grade (CRG) on survival METHODS: A retrospective analysis of patients undergoing interval cytoreductive surgery (CRS) between January 2013 to December 2017 was performed. The surgical and pathological reports were analyzed and surgical and pathological PCI compared. The pathological response to chemotherapy was assessed using the score developed by Bohm. et al., Results: In 79 patients, it was observed that sites involved by disease first like ovaries and pelvic peritoneum (lower region) were the last to respond preceded by the omentum, right upper quadrant (RUQ) peritoneum (upper region) and parietal peritoneum (middle region). Microscopic residual disease was seen in 20.2% in normal looking areas of peritoneum and in 20% with no gross residual disease in the RUQ. Visual inspection during surgery overestimated the disease extent in 40.5% and underestimated it in 15.1%. There was no difference in the progression free (p = 0.587) and overall survival (p = 0.157) between patients with CRG 1, 2 and 3 (poor, moderate, and complete/near complete response, respectively). Retroperitoneal nodes were positive in 0% with CRG 3, 27.5% with CRG 2 and 72.7% with CRG 1 (p < 0.0001)., Conclusions: The pathological response to NACT follows a specific pattern. Visual inspection is of limited value in assessing disease extent following NACT. Surgery following NACT should target sites involved before NACT and not just residual disease. The response in regional nodes should be included in chemotherapy response scores., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Aim: The aim of this study was to determine the clinicopathological characteristics, treatment details and outcome of patients with brain metastasis from epithelial ovarian carcinoma (EOC)., Methods: This study included 21 patients diagnosed with brain metastasis from EOC between 1999 and 2009., Results: Median age was 61 years (range 38-77). The median time elapsed from EOC diagnosis to brain metastasis detection was 32 months. Single brain metastases were found in 10 (48%) cases, and there was extra-cranial disease in 11 (52%) cases. During the mean 86 months of follow-up, 18 of the patients (86%) died of the disease and 3 (14%) were alive with disease. The median survival time after the initial diagnosis of brain metastasis was 9 months. The median overall survival (OS) from initial diagnosis of EOC was 50 months. In univariate analysis, prolonged time from initial diagnosis to central nervous system metastasis (more than 32 months) (p = 0.001), treatment with radiotherapy (p < 0.001), optimal cytoreductive operation (p = 0.02) were all positively correlated with OS., Conclusion: The prognosis of patients with brain metastasis from EOC is still poor. The significant predictors of survival in our series were whole brain radiotherapy, prolonged elapsed time from initial diagnosis to brain metastasis and optimal cytoreductive surgery., (© 2019 S. Karger AG, Basel.)

KDM6B, also known as JMJD3, is a member of the family of histone lysine demethylase (KDMs), which is closely related to many types of cancers. However, its role and the underlying mechanisms in ovarian cancer remain unknown. Here we show that KDM6B is elevated in epithelial ovarian cancer and its expression level is closely related with metastasis and invasion. In addition, survival analysis showed that high expression of KDM6B was associated with low overall survival in ovarian cancer patients. Overexpression of KDM6B in epithelial ovarian cancer cells promoted proliferation, epithelial-mesenchymal transition (EMT), migration and invasion in vitro, and enhanced metastatic capacities in vivo. On the contrary, silencing KDM6B in invasive and metastatic ovarian cancer cells inhibited these processes. Mechanistically, we found that KDM6B exerts its function by modulating the transforming growth factor-β1 (TGF-β1) expression, and TGF-β1 signal pathway inhibitor LY2157299 significantly inhibited KDM6B-induced proliferation, migration, metastasis, and EMT in ovarian cancer cells. Our findings, for the first time, reveal the pivotal role of KDM6B in the invasion and metastatic behavior of epithelial ovarian cancer. Thus, targeting KDM6B may be a useful strategy to interfere with these behaviors of epithelial ovarian cancer., (© 2018 Wiley Periodicals, Inc.)

Objectives: To investigate ultrasound features and the best cut-off value of the cancer antigen 125/carcinoembryonic antigen (CA125/CEA) ratio to discriminate ovarian metastases from benign and primary malignant ovarian neoplasms in two selected groups of morphological ovarian masses, namely multilocular masses with five or more locules and multilocular-solid masses., Methods: Patients with multilocular (five or more locules) or multilocular-solid ovarian masses, operated on within 3 months of ultrasound examination, and with tumor markers (CEA and CA125) available at diagnosis, were identified retrospectively from three ultrasound centers. The masses were described using the International Ovarian Tumor Analysis (IOTA) terminology. Ultrasound and clinical characteristics were compared between those with an ovarian neoplasm (including benign and primary malignant neoplasms) and those with an ovarian metastasis. Receiver-operating characteristics curve (ROC) analysis was used to evaluate the ability of CA125, CEA and CA125/CEA to differentiate between ovarian neoplasms and ovarian metastases, and their predictive performance was assessed., Results: In total, 350 (88.4%) patients with an ovarian neoplasm (including 99 benign, 43 borderline and 197 primary epithelial ovarian carcinomas, seven malignant rare tumors and four other types of invasive ovarian tumor) and 46 (11.6%) patients with an ovarian metastasis were analyzed. On ultrasound examination, ovarian neoplasms were smaller than ovarian metastases (median largest diameter, 97 (range, 20-387) mm vs 146 (range, 43-259) mm, respectively; P < 0.0001) and presented with a lower number of cysts with > 10 locules (18.9% vs 54.3%; P < 0.0001). ROC curve analysis showed that the best cut-off value of CEA for distinguishing between ovarian neoplasms and ovarian metastases was 2.33 ng/mL. The predictive performance of this CEA cut-off value was: area under the curve (AUC), 0.791 (95% CI, 0.711-0.870); accuracy, 73.7%; sensitivity, 73.1%; specificity, 78.3%; positive predictive value (PPV), 96.2%; and negative predictive value (NPV), 27.7%. The best cut-off value of CA125/CEA for distinguishing between ovarian neoplasms and ovarian metastases was 11.92. The predictive performance of this CA125/CEA cut-off value was: AUC, 0.758 (95% CI, 0.683-0.833); accuracy, 79.8%; sensitivity, 82.3%; specificity, 60.9%; PPV, 94.1%; and NPV, 31.1%., Conclusions: CA125/CEA ratio and CEA alone did not show any significant difference in their ability to distinguish between ovarian neoplasms (including benign and malignant) and ovarian metastases in masses with multilocular and those with multilocular-solid morphology. Therefore, in this morphological subgroup of ovarian masses, CEA alone is sufficient to differentiate between ovarian neoplasms and ovarian metastases. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.)