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Mucinous ovarian cancer (MOC) is a rare pathological type different from epithelial ovarian cancer, and the clinical treatment should refer to serous ovarian cancer (SOC) guidelines. However, since the clinicopathological features of MOC are significantly different from SOC, careful differentiation is needed in diagnosis and treatment. Surgery combined with adjuvant chemotherapy is the standard treatment for MOC. However, due to the low prevalence rate, it is difficult to carry out clinical trials, hence lacking evidence-based medicine and consensus on the indications of intraoperative appendectomy and the choice of postoperative adjuvant chemotherapy. In addition, further translational preclinical studies of targeted therapy and immunotherapy are needed to facilitate the diagnosis and individualized treatment of MOC.

Ovarian clear cell carcinoma (OCCC) has distinct clinical and molecular features and heterogeneous prognosis. Insights into the somatic genomic abnormalities of OCCC provide the basis for deeper understanding and potential therapeutic avenues. Herein, we performed extensive genomic profiling in Chinese patients to illustrate the mutation landscape and genetic prognostic biomarkers of OCCC. We used targeted DNA sequencing on 61 OCCC cases with a panel of 520 cancer-related genes. Correlations between clinicopathological features and survival were evaluated. Nomogram-based models were constructed to predict progress-free survival (PFS). We detected 763 somatic mutations spanning 286 genes. The most frequent genetic alterations, ARID1A (49%) and PIK3CA (48%), were concurrently mutated. Comprehensive copy number alterations (CNAs) were identified in chromosomes 20q13.2 and 8q. Most (73.7%) patients harboured potentially targetable driver mutations. The mean and median tumour mutational burden were 7.0 and 3.0 mutations/Mb, respectively. Microsatellite instability (high) was identified in 8.2% of patients. Mutation of the base-excision repair pathway was significantly higher in patients of stage II/III/IV. ATM mutation was associated with platinum sensitivity (p <.05). Survival analysis identified chr8q CNAs in all patients, PIK3CA mutations in stage I patients and SWI/SNF complex (ARID1A and SMARCA4) mutations in stage II/III/IV patients as potential prognosticators (p <.05). Integration of genetic alterations (SWI/SNF complex mutations, ATM mutations and chr8q CNAs) improved the performance of a nomogram based on tumour stage and residual disease (concordance index 0.75 vs. 0.70, p <.05). We described somatic genomic alterations in Chinese OCCC patients and observed different genomic alterations between stage I and stage II/III/IV tumours. Genetic factors may supplement clinical factors in nomogram modelling for PFS prediction. We performed extensive genomic profiling in a well-annotated cohort of 61 Chinese ovarian clear cell carcinoma (OCCC) patients. PIK3CA mutations were associated with worse overall survival (OS) in stage I OCCC, and SWI/SNF gene mutations were associated with improved OS in stage II/III/IV disease. We propose an easy-to-use nomogram using clinical factors (tumour stage and residual disease) and genetic alterations (SWI/SNF complex mutations, ATM mutations and chr8q CNAs) to predict the progress-free survival (PFS) of OCCC. [ABSTRACT FROM AUTHOR]

Peritoneal implantation and lymph node metastasis have different driving mechanisms in ovarian cancer. Elucidating the underlying mechanism of lymph node metastasis is important for treatment outcomes. A new cell line, FDOVL, was established from a metastatic lymph node of a patient with primary platinum-resistant ovarian cancer and was then characterized. The effect of NOTCH1-p.C702fs mutation and NOTCH1 inhibitor on migration was evaluated in vitro and in vivo. Ten paired primary sites and metastatic lymph nodes were analyzed by RNA sequencing. The FDOVL cell line with serious karyotype abnormalities could be stably passaged and could be used to generated xenografts. NOTCH1-p.C702fs mutation was found exclusively in the FDOVL cell line and the metastatic lymph node. The mutation promoted migration and invasion in cell and animal models, and these effects were markedly repressed by the NOTCH inhibitor LY3039478. RNA sequencing confirmed CSF3 as the downstream effector of NOTCH1 mutation. Furthermore, the mutation was significantly more common in metastatic lymph nodes than in other peritoneal metastases in 10 paired samples (60% vs. 20%). The study revealed that NOTCH1 mutation is probably a driver of lymph node metastasis in ovarian cancer, which offers new ideas for the treatment of ovarian cancer lymph node metastasis with NOTCH inhibitors. [ABSTRACT FROM AUTHOR]

Struma ovarii is a rare variety of specialized monodermal mature ovarian teratoma, it is composed predominantly of thyroid tissue. Ascites is present in one third of patients. The combination of struma ovarii, marked ascites and elevated CA125 is a rare condition, which may mimic ovarian cancer. We described two cases presenting with pelvic mass, ascites and elevated serum CA125 levels, frozen section and final pathology turned out to be struma ovarii. Ascites disappeared and the level of CA125 returned to normal level after operation. One of the cases was associated with pleural effusion, leading to a condition called pseudo-Meigs' syndrome. Then we reviewed the related literatures to explore the possible mechanism of ascites and pleural effusion, the reason of CA125 elevation and imaging manifestations of struma ovarii. In conclusion, struma ovarii should be considered in the differential diagnosis preoperatively, when presented with pelvic mass, ascites and an elevated CA125 level. [ABSTRACT FROM AUTHOR]

Background: To investigate the alterations of peripheral lymphocyte subpopulations in ovarian cancer patients compared to benign or borderline counterparts. The possible clinicopathological implications were also evaluated. Methods: We enrolled 112 treatment-naive ovarian cancer patients, 14 borderline tumor patients and 44 benign tumor patients between 09/2016 and 01/2019. Flow cytometry was used to measure the peripheral lymphocyte subsets consisting of T cells (CD3+, CD3+CD4+, CD3+CD8+ and CD8+CD28+), regulatory T cells (Tregs, CD4+CD25+CD127−), natural killer cells (NK cells, CD3−CD56+) and B cells (CD19+). Results: Most ovarian cancer patients were high-grade serous carcinoma (84.8%), followed by clear cell carcinoma (8.03%). Late-stage tumor (FIGO III + IV) accounted for 82.1%. The study showed that the proportions of peripheral lymphocyte subsets underwent apparent changes in ovarian cancer patients. We observed elevated levels of Treg cells in patients with both ovarian borderline and malignant tumor compared to those with benign tumors, which achieved statistic significance. In contrast, CD3+CD8+ T and CD8+CD28+ T cells were significantly lower in ovarian cancer patients. Interestingly, low level of B cells was correlated to clear cell carcinoma (P = 0.024), advanced tumor (P = 0.028) and platinum-resistant recurrence (P = 0.014). Regarding the changes of lymphocyte subsets after surgery, CD8+CD28+ T cells had a significant decreasing tendency (P = 0.007) while B cells were the opposite (P < 0.001). Conclusions: Ovarian cancer patients have altered circulating lymphocyte profile (elevated Treg cell, depressed CD3+CD8+ T and CD8+CD28+ T cells). Low level of B cells might be related to disease aggressiveness, and it recovered after the removal of tumor, which merits further study. Highlights: 1 Ovarian cancer patients have altered circulating lymphocyte profile 2 Low level of B cells might be related to disease aggressiveness, and it recovered after the removal of tumor. [ABSTRACT FROM AUTHOR]

Background: To investigate changes in peripheral lymphocyte subsets after splenectomy during cytoreductive surgery for advanced or recurrent ovarian cancers. Methods: We enrolled 83 patients with advanced or recurrent ovarian cancer who underwent cytoreductive surgery. Twenty patients who also underwent splenectomy were assigned to the splenectomy cohort and the rest were assigned to the non-splenectomy cohort. Flow cytometry was used to measure peripheral lymphocyte subsets consisting of T cells, regulatory T cells, natural killer cells, B cells, and activation antigens before and after surgery. Results: There was no difference in the number and distribution of peripheral lymphocyte subsets between the two cohorts before surgery. After surgery, we observed elevated levels of T cells (CD3+, CD3+CD8+) in the splenectomy cohort compared to those in the non-splenectomy cohort, and the difference was statistically significant. CD8+CD28+ T cells had a significant decreasing tendency (P = 0.011) while CD3+/HLA-DR+ T cells showed the opposite trend (P = 0.001) in the splenectomy cohort. The proportion of Tregs (P = 0.005) and B cells (P < 0.001) including CD3−/HLA-DR+ B cells (P = 0.007) increased after surgery, and the absolute number of T cells and NK cells decreased to different extents (P < 0.001) in the non-splenectomy cohort. The post-operative percentage of CD8+CD28+ T cells was less than the pre-operative percentage (P = 0.022), which was similar to the splenectomy cohort. There was no significant difference in progression-free survival or overall survival between the groups after a median follow-up time of 41 months. Conclusions: The changes in peripheral lymphocyte populations were different between patients with and those without splenectomy during cytoreductive surgery for ovarian cancers. T cells were increased and activated in the splenectomy cohort, whereas, B cells were increased and activated in the non-splenectomy cohort. [ABSTRACT FROM AUTHOR]

Background: Glucose metabolism has been suggested as a therapeutic target in ovarian clear cell carcinoma (CCC). We attempted to clarify 18F-FDG PET/CT-based metabolic metrics in the recurrent ovarian CCC patients and their prognostic values.Methods: Quantitative metabolic parameters included maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Two different methods were employed for defining the threshold SUV to delineate MTV: 1) SUV of 2.5 (designated as MTV); 2) a fixed ratio including 40% (MTV40), 50% (MTV50) and 60% (MTV60) of SUVmax. The Kaplan-Meier model and Cox regression were used in survival analysis.Results: Among the 35 patients, platinum-resistant recurrence accounted for 34.3% and the median progression-free survival was 13 months (range, 2-135). Fifteen (42.9%) patients presented with single tumor recurrence, while 51 recurrent lesions were identified, with the most common sites in pelvis (29.4%), followed by lymph node metastases (19.6%) and peritoneal carcinomatosis (15.7%). Except four patients with FDG-inavid tumor, the median SUVmax of the 31 patients with high glucose metabolic activity was 7.10 (range, 3.00-20.60). After a median follow-up of 36.5 months (range, 7-155), 22 patients (64.7%) were dead from disease. The median post-relapse survival (PRS) was 17 months (range, 4-126). Platinum-resistant recurrence, peritoneal carcinomatosis and high TLG60 proved to be negative predicators of overall survival after multivariate analysis.Conclusions: TLG60, platinum-resistant recurrence and peritoneal carcinomatosis were independent negative predicators of overall survival. Whether patients with higher TLG60 required more aggressive treatment warranted further study. [ABSTRACT FROM AUTHOR]

Ovarian cancer is an intra-abdominal tumor in which the presence of ascites facilitates metastatic dissemination, and associated with poor prognosis. However, the significance of metabolic alterations in ovarian cancer cells in the ascites microenvironment remains unclear. Here we show ovarian cancer cells exhibited increased aggressiveness in ascites microenvironment via reprogramming of lipid metabolism. High lipid metabolic activities are found in ovarian cancer cells when cultured in the ascites microenvironment, indicating a metabolic shift from aerobic glycolysis to β-oxidation and lipogenesis. The reduced AMP-activated protein kinase (AMPK) activity due to the feedback effect of high energy production led to the activation of its downstream signaling, which in turn, enhanced the cancer growth. The combined treatment of low toxic AMPK activators, the transforming growth factor beta-activated kinase 1 (TAK1) and fatty acid synthase (FASN) inhibitors synergistically impair oncogenic augmentation of ovarian cancer. Collectively, targeting lipid metabolism signaling axis impede ovarian cancer peritoneal metastases. Rain Chen et al. show that lipid metabolism is highly active in ovarian cancer cells in an ascites microenvironment, causing increased aggressiveness. They show that combined treatment of AMPK activators and TAK1/FASN inhibitors could impair ovarian cancer peritoneal metastasis. [ABSTRACT FROM AUTHOR]

Ovarian cancer is characteristic of superficial implantation and peritoneal carcinomatosis. Hudson introduced a novel technique 50 years ago, which removed the entire Douglas pouch as a false capsule of the tumor (Hudson, 1968 [ 1 ]). Angeles et al. standardized the procedure in 10 steps in a previous publication (Angeles et al., 2019 [ 2 ]). We made small modifications of the Hudson procedure in this video. Ovarian cancer is characteristic of superficial implantation and peritoneal carcinomatosis. Hudson introduced a novel technique 50 years ago, which removed the entire Douglas pouch as a false capsule of the tumor (Hudson, 1968 [ 1 ]). Angeles et al. standardized the procedure in 10 steps in a previous publication (Angeles et al., 2019 [ 2 ]). We made small modifications of the Hudson procedure in this video. The key points of the procedure were summarized as follows. Firstly, dissecting off the pelvic parietal peritoneum very superficially. Secondly, the round ligament, infundibulo-pelvic ligament, medial umbilical ligament, and umbilical artery are divided and ligated in the extraperitoneal space. Thirdly, the bladder is mobilized caudally and the vesico-vaginal space is exposed after completely dissecting off the vesical peritoneum. Fourthly, the ureter is isolated and mobilized laterally. Then, uterine vessels and parametria are divided and ligated, which is followed by colpotomy to access the recto-vaginal septum. By retracting the total specimen cranially, the Douglas pouch is dissected retrogradely according to Hudson procedure. Lastly, the peritoneum of the mesorectum and mesosigmoid is shaved at the pelvic brim. Therefore, using this method, almost all the pelvic visceral peritoneum was dissected (). In addition, we didn't intentionally expose the anatomical spaces (pre-vesical, para-vesical, para-rectal, and pre-sacral) completely, which was effective and time-saving. Complete removal of the disseminated tumors in both parietal and visceral peritoneum was achieved by the method introduced in our video. Our method, modified from Hudson procedure, is effective for complete cytoreduction in selected ovarian cancer patients with extensive peritoneal carcinomatosis sparing rectosigmoid resection. • Ovarian cancer is characteristic of superficial implantation and peritoneal carcinomatosis. • Complete removal of the disseminated tumors was achieved by total pelvic peritonectomy. • We made small modifications of the Hudson procedure in this video. [ABSTRACT FROM AUTHOR]

Background: The benefits of secondary cytoreduction for platinum-sensitive relapsed ovarian cancer are still widely debated. We aimed to assess the efficacy of secondary cytoreduction plus chemotherapy versus chemotherapy alone in this patient population.Methods: This multicentre, open-label, randomised, controlled, phase 3 trial (SOC-1), was done in four primarily academic centres in China (two in Shanghai, one in Hangzhou, and one in Guangzhou). Eligible patients were women aged 18 years and older with platinum-sensitive relapsed epithelial ovarian cancer with a platinum-free interval of at least 6 months after the end of first-line platinum-based chemotherapy and were predicted to have potentially resectable disease according to the international model (iMODEL) score and PET-CT imaging. iMODEL score was calculated using six variables: International Federation of Gynecology and Obstetrics stage, residual disease after primary surgery, platinum-free interval, Eastern Cooperative Oncology Group performance status, serum level of cancer antigen 125 at recurrence, and presence of ascites at recurrence. An iMODEL score of 4·7 or lower predicted a potentially complete resection. As per a protocol amendment, patients with an iMODEL score of more than 4·7 could only be included if the serum level of cancer antigen 125 was more than 105 U/mL, but the principal investigators assessed the disease to be resectable by PET-CT. Eligible participants were randomly assigned (1:1) via a permuted block design (block size of six) and stratified by study centre, iMODEL score, residual disease at primary surgery, and enrolment in the Shanghai Gynecologic Oncology Group SUNNY trial, to undergo secondary cytoreductive surgery followed by intravenous chemotherapy (six 3-weekly cycles of intravenous paclitaxel [175 mg/m2] or docetaxel [75 mg/m2] combined with intravenous carboplatin [area under the curve of 5 mg/mL per min]; surgery group) or intravenous chemotherapy alone (no surgery group). Primary endpoints were progression-free survival and overall survival, analysed in all participants randomly assigned to treatment, regardless of treatment received (intention-to-treat [ITT] population). Here, we report the final analysis of progression-free survival and the prespecified interim analysis of overall survival. Safety was assessed in all participants who received their assigned treatment and had available adverse event data. This study is registered with ClinicalTrials.gov, NCT01611766, and is ongoing but closed to accrual.Findings: Between July 19, 2012, and June 3, 2019, 357 patients were recruited and randomly assigned to the surgery group (182) or the no surgery group (175; ITT population). Median follow-up was 36·0 months (IQR 18·1-58·3). In the no surgery group, 11 (6%) of 175 participants had secondary cytoreduction during second-line therapy while 48 (37%) of 130 participants who had disease progression crossed-over and had surgery at a subsequent recurrence. Median progression-free survival was 17·4 months (95% CI 15·0-19·8) in the surgery group and 11·9 months (10·0-13·8) in the no surgery group (hazard ratio [HR] 0·58; 95% CI 0·45-0·74; p<0·0001). At the interim overall survival analysis, median overall survival was 58·1 months (95% CI not estimable to not estimable) in the surgery group and 53·9 months (42·2-65·5) in the no surgery group (HR 0·82, 95% CI 0·57-1·19). In the safety population, nine (5%) of 172 patients in the surgery group had grade 3-4 surgical morbidity at 30 days, and no patients in either group had died at 60 days after receiving assigned treatment. The most common grade 3-4 adverse events during chemotherapy were neutropenia (29 [17%] of 166 patients in the surgery group vs 19 [12%] of 156 patients in the no surgery group), leucopenia (14 [8%] vs eight [5%]), and anaemia (ten [6%] vs nine [6%]). Four serious adverse events occurred, all in the surgery group. No treatment-related deaths occurred in either group.Interpretation: Secondary cytoreduction followed by chemotherapy was associated with significantly longer progression-free survival than was chemotherapy alone in patients with platinum-sensitive relapsed ovarian cancer, and patients should be counselled about the option of secondary cytoreduction in specialised centres. Long-term survival outcomes will be assessed using mature data on overall survival.Funding: Zhongshan Development Program.Translation: For the Chinese translation of the abstract see Supplementary Materials section. [ABSTRACT FROM AUTHOR]

To determine the incidence and predisposing factors of preoperative venous thromboembolism (VTE), especially pulmonary embolism (PE) in patients with ovarian cancer. This retrospective study included 387 patients with primary ovarian cancer, whose preoperative work up included both ultrasonography of lower extremity vein and spiral computed tomography pulmonary angiogram, from September 2013 to November 2016. SPSS 22 was used for statistical analyses. The incidence of preoperative VTE and PE was 13.4% (52 patients), 9.3%(36 patients), respectively. Both the univariate and multivariate analyses revealed that D-dimer (DDI) level, age, and massive ascites were associated with preoperative VTE. Moreover, DDI level (odds ratio [OR] 3.133, 95% confidence interval [CI] 1.193–8.225, p =.02), massive ascites (OR 9.972, 95% CI 3.687–26.968, p <.001), and preoperative deep vein thrombosis (OR 5.977, 95% CI 2.073–17.228, p =.001) were independent predictors for preoperative PE. Additionally, the incidence of preoperative VTE and PE increased with increasing DDI levels (p <.001). DDI level < 1.5 μg/ml has 100% negative predictive value and 100% sensitivity for diagnosis of preoperative VTE and PE; however, DDI >5 μg/ml, the incidence of preoperative VTE and PE were 18.4% and 14.2% respectively. Moreover, DDI value was significantly correlated with preoperative PE volume (r = 0.746, p <.001). Preoperative VTE and PE are common events in patients with ovarian cancer. DDI level is a useful parameter for diagnosing and evaluating preoperative VTE and PE. • For ovarian cancer patients, the incidence of preoperative VTE and PE was 13.4% (52 patients), 9.3% (36 patients), respectively. • DDI level, massive ascites, and preoperative deep vein thrombosis were independent predictors for preoperative PE of ovarian cancer patients. • The incidence of preoperative VTE and PE increased with increasing DDI levels (p <.001), and DDI level < 1.5 μg/ml has 100% negative predictive value for diagnosis of preoperative PE/VTE in ovarian cancer patients. • DDI value was significantly correlated with preoperative PE volume (r = 0.746, p <.001). [ABSTRACT FROM AUTHOR]

Increasing evidence shows that Traditional Chinese Medicine (TCM) has an obvious appeal for cancer treatment, but there is still a lack of scientific investigation of its underlying molecular mechanisms. Bitter melon or bitter gourd (Momordica charantia) is an edible fruit that is commonly consumed, and it is used to cure different diseases in various ancient folk medical practices. We report that a bioactive protein, MAP30, isolated from bitter melon seeds exhibited potent anticancer and anti-chemoresistant effects on ovarian cancer cells. Functional studies revealed that MAP30 inhibited cancer cell migration, cell invasion, and cell proliferation in various ovarian cancer cells but not normal immortalized ovarian epithelial cells. When administered with cisplatin, MAP30 produced a synergistic effect on cisplatin-induced cell cytotoxicity in ovarian cancer cells. When low doses of cisplatin and MAP30 were co-injected intraperitoneally, a remarkable reduction of tumor dissemination and tumor growth was observed in an ovarian cancer ascites mouse model. Notably, blood tests confirmed that MAP30 did not cause any adverse effects on liver and kidney functions in the treated mice. MAP30 activated AMP-activated protein kinase (AMPK) signaling via CaMKKβ and induced cell cycle arrest in the S-phase. MAP30 modulated cell metabolism of ovarian cancer cells via suppression of GLUT-1/-3-mediated glucose uptake, adipogenesis, and lipid droplet formation in tumor development and progression. MAP30 also induced an increase in intracellular Ca2+ ion concentration, which triggered ROS-mediated cancer cell death via apoptosis and ferroptosis. Collectively, these findings suggest that natural MAP30 is a non-toxic supplement that may enhance chemotherapeutic outcomes and benefit ovarian cancer patients with peritoneal metastases. [ABSTRACT FROM AUTHOR]