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The drivers of immune evasion are not entirely clear, limiting the success of cancer immunotherapies. Here we applied single-cell spatial and perturbational transcriptomics to delineate immune evasion in high-grade serous tubo-ovarian cancer. To this end, we first mapped the spatial organization of high-grade serous tubo-ovarian cancer by profiling more than 2.5 million cells in situ in 130 tumors from 94 patients. This revealed a malignant cell state that reflects tumor genetics and is predictive of T cell and natural killer cell infiltration levels and response to immune checkpoint blockade. We then performed Perturb-seq screens and identified genetic perturbations-including knockout of PTPN1 and ACTR8-that trigger this malignant cell state. Finally, we show that these perturbations, as well as a PTPN1/PTPN2 inhibitor, sensitize ovarian cancer cells to T cell and natural killer cell cytotoxicity, as predicted. This study thus identifies ways to study and target immune evasion by linking genetic variation, cell-state regulators and spatial biology.

Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander women. Participants in this study included 1734 Asian (n = 785 case and 949 control participants), 266 Native Hawaiian/Pacific Islander (n = 99 case and 167 control participants), 1149 Hispanic (n = 505 case and 644 control participants), and 24 189 White (n = 9981 case and 14 208 control participants) from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% CIs for risk associations by race and ethnicity. Heterogeneity in EOC risk associations by race and ethnicity (P ≤ .02) was observed for oral contraceptive (OC) use, parity, tubal ligation, and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in Native Hawaiian/Pacific Islander and Asian women. The inverse association for tubal ligation with risk was most pronounced for Native Hawaiian/Pacific Islander participants (odds ratio (OR) = 0.25; 95% CI, 0.13-0.48) compared with Asian and White participants (OR = 0.68 [95% CI, 0.51-0.90] and OR = 0.78 [95% CI, 0.73-0.85], respectively). Differences in EOC risk factor associations were observed across racial and ethnic groups, which could be due, in part, to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies. This article is part of a Special Collection on Gynecological Cancers.

INTRODUCTION: Niraparib first-line maintenance (1LM) therapy has demonstrated clinical benefit for patients with ovarian cancer (OC) in clinical trial and real-world settings, but data on factors associated with real-world patient outcomes remain limited. This analysis identified patient characteristics associated with time to next treatment (TTNT), a proxy for real-world progression-free survival, in patients with OC treated with 1LM niraparib monotherapy. METHODS: This retrospective observational study used a USA nationwide electronic health record-derived deidentified database and included adult patients diagnosed with OC who initiated 1LM niraparib monotherapy after first-line platinum-based chemotherapy. Patients were followed until the earliest occurrence of last clinical activity, death, or end of study period. TTNT was measured from 1LM niraparib initiation to the start of second-line treatment or death. Cox proportional hazards models assessed univariable and multivariable associations between baseline characteristics and TTNT. RESULTS: Of 7872 patients diagnosed with OC, 526 met the eligibility criteria and were included in this analysis. Median (IQR) duration of follow-up was 14.1 (7.4-23.6) months. In univariable analyses, age, BRCA/homologous recombination deficiency (HRD) status, socioeconomic status, stage at initial diagnosis, cytoreductive surgery type, and residual disease status were significantly associated with observed TTNT and were introduced into the multivariable model with other clinically relevant variables. In the multivariable analysis, BRCA/HRD status, cytoreductive surgery type, and residual disease status were significantly associated with observed TTNT after covariate adjustment. Conversely, age, Eastern Cooperative Oncology Group performance status, disease stage, niraparib starting dose status, and first-line bevacizumab use were not associated with observed TTNT. CONCLUSION: This real-world, retrospective, observational analysis offers valuable insights on prognostic factors associated with TTNT in patients with OC treated with 1LM niraparib monotherapy after first-line platinum-based chemotherapy. Future studies are needed to examine how additional patient characteristics associated with clinical outcomes may guide treatment decisions and improve outcomes.

PurposeThe purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC).Experimental designRB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss.ResultsRB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1.ConclusionsCo-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants and documentation revised for clarity and ease of use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 uncertain significance or conflicting, 14 pathogenic and/or likely pathogenic, and 13 benign and/or likely benign. Review resolved classification for 11/13 uncertain significance or conflicting variants and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants.

OBJECTIVE: Previous studies have shown that first-line (1L) maintenance therapy (MT) with poly(ADP-ribose) polymerase inhibitors and/or bevacizumab improves outcomes among patients with advanced ovarian cancer (OC); however, these treatments are underutilized. This study aimed to provide a real-world understanding of MTs among patients with advanced OC who received 1L platinum-based chemotherapy (PBC). METHODS: A retrospective chart review using iKnowMed electronic health records to identify patients aged ≥18 years with advanced OC who initiated 1L PBC between January 1, 2018-December 31, 2020. Following 1L PBC, patients could have received MT or active surveillance (AS). Kaplan-Meier methods were used to estimate time to treatment discontinuation (TTD), real-world progression-free survival (rwPFS), and overall survival (OS). RESULTS: Of the 600 chart-reviewed patients included, 239 (39.8 %) received MT and 315 (52.5 %) received AS. Patients who were

High-grade serous ovarian cancers (HGSOCs) likely consist of poorly differentiated stem-like cells (PDSLCs) and differentiated tumor cells. Conventional therapeutics are incapable of completely eradicating PDSLCs, contributing to disease progression and tumor relapse. Primary NK cells are known to effectively lyse PDSLCs, but they exhibit low or minimal cytotoxic potential against well-differentiated tumors. We have introduced and discussed the characteristics of super-charged NK (sNK) cells in this review. sNK cells, in comparison to primary NK cells, exhibit a significantly higher capability for the direct killing of both PDSLCs and well-differentiated tumors. In addition, sNK cells secrete significantly higher levels of cytokines, especially those known to induce the differentiation of tumors. In addition, we propose that a combination of sNK and chemotherapy could be one of the most effective strategies to eliminate the heterogeneous population of ovarian tumors; sNK cells can lyse both PDSLCs and well-differentiated tumors, induce the differentiation of PDSLCs, and could be used in combination with chemotherapy to target both well-differentiated and NK-induced differentiated tumors.

•Chronic chemical peritonitis caused by spontaneous rupture of a mature cystic teratoma may result in prolonged hospitalization and respiratory decline and can mimic a gynecologic malignancy.•Earlier surgical intervention for mature teratoma may prevent morbidity.•Inclusion of a gynecologic oncologist is advised for management discussions and/or surgical back-up.•Complex benign gynecologic surgeries may have some benefit for gynecologic oncologic trainees, which can be used for later oncologic cases.

BACKGROUND: Studies evaluating the effectiveness of immune checkpoint inhibitors (ICI) for endometrial cancer (EC) are limited. This study aimed to assess the efficacy of PD-1/PD-L1 inhibitors as monotherapy for EC by conducting a meta-analysis. The predictive significance of MMR status, a biomarker for ICI response, also required further investigation. METHODS: A systematic literature search was conducted in English databases until September 2023. The analysis included objective response rate (ORR), disease control rate (DCR), adverse events (AEs), and odds ratios (OR), along with their corresponding 95% confidence intervals (CI). RESULTS: There were twelve trials totaling 685 individuals. PD-1/PD-L1 inhibitor monotherapy resulted in an ORR for 34% (95% CI = 24-44%) of the pooled EC patients. Subgroup analysis revealed a significantly higher ORR in dMMR EC (45%) compared to pMMR EC (8%), with an OR of 6.36 (95% CI = 3.64-11.13). The overall DCR was 42%, with dMMR EC at 51% and pMMR EC at 30% (OR = 2.61, 95% CI = 1.69-4.05). Grade three or higher adverse events (AEs) occurred in 15% of cases (95% CI = 9-24%) of the pooled incidence of AEs, which was 68% (95% CI = 65-72%). CONCLUSIONS: This meta-analysis provides significant evidence for the effectiveness of PD-1/PD-L1 inhibitors as monotherapy for EC. Notably, dMMR EC patients demonstrated superior treatment efficacy with PD-1/PD-L1 inhibitor immunotherapy. Further research is required to explore subclassifications of EC based on dMMR molecular subtypes, enabling improved treatment strategies and outcomes for EC patients.

Cancer-related cognitive impairments (CRCI) are neurological complications associated with cancer treatment, and greatly affect cancer survivors' quality of life. Brain-derived neurotrophic factor (BDNF) plays an essential role in neurogenesis, learning and memory. The reduction of BDNF is associated with the decrease in cognitive function in various neurological disorders. Few pre-clinical studies have reported on the effects of chemotherapy and medical stress on BDNF levels and cognition. The present study aimed to compare the effects of medical stress and cisplatin on serum BDNF levels and cognitive function in 9-month-old female Sprague Dawley rats to age-matched controls. Serum BDNF levels were collected longitudinally during cisplatin treatment, and cognitive function was assessed by novel object recognition (NOR) 14 weeks post-cisplatin initiation. Terminal BDNF levels were collected 24 weeks after cisplatin initiation. In cultured hippocampal neurons, we screened three neuroprotective agents, riluzole (an approved treatment for amyotrophic lateral sclerosis), as well as the ampakines CX546 and CX1739. We assessed dendritic arborization by Sholl analysis and dendritic spine density by quantifying postsynaptic density-95 (PSD-95) puncta. Cisplatin and exposure to medical stress reduced serum BDNF levels and impaired object discrimination in NOR compared to age-matched controls. Pharmacological BDNF augmentation protected neurons against cisplatin-induced reductions in dendritic branching and PSD-95. Ampakines (CX546 and CX1739) and riluzole did not affect the antitumor efficacy of cisplatin in vitro. In conclusion, we established the first middle-aged rat model of cisplatin-induced CRCI, assessing the contribution of medical stress and longitudinal changes in BDNF levels on cognitive function, although future studies are warranted to assess the efficacy of BDNF enhancement in vivo on synaptic plasticity. Collectively, our results indicate that cancer treatment exerts long-lasting changes in BDNF levels, and support BDNF enhancement as a potential preventative approach to target CRCI with therapeutics that are FDA approved and/or in clinical study for other indications.

High-grade serous ovarian carcinoma (HGSOC), the deadliest form of ovarian cancer, is typically diagnosed after it has metastasized and often relapses after standard-of-care platinum-based chemotherapy, likely due to advanced tumor stage, heterogeneity, and immune evasion and tumor-promoting signaling from the tumor microenvironment. To understand how spatial heterogeneity contributes to HGSOC progression and early relapse, we profiled an HGSOC tissue microarray of patient-matched longitudinal samples from 42 patients. We found spatial patterns associated with early relapse, including changes in T cell localization, malformed tertiary lymphoid structure (TLS)-like aggregates, and increased podoplanin-positive cancer-associated fibroblasts (CAFs). Using spatial features to compartmentalize the tissue, we found that plasma cells distribute in two different compartments associated with TLS-like aggregates and CAFs, and these distinct microenvironments may account for the conflicting reports about the role of plasma cells in HGSOC prognosis.

ImportancePreventive bilateral salpingo-oophorectomy is offered to women at high risk of ovarian cancer who carry a pathogenic variant in BRCA1 or BRCA2; however, the association of oophorectomy with all-cause mortality has not been clearly defined.ObjectiveTo evaluate the association between bilateral oophorectomy and all-cause mortality among women with a BRCA1 or BRCA2 sequence variation.Design, setting, and participantsIn this international, longitudinal cohort study of women with BRCA sequence variations, information on bilateral oophorectomy was obtained via biennial questionnaire. Participants were women with a BRCA1 or BRCA2 sequence variation, no prior history of cancer, and at least 1 follow-up questionnaire completed. Women were followed up from age 35 to 75 years for incident cancers and deaths. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs for all-cause mortality associated with a bilateral oophorectomy (time dependent). Data analysis was performed from January 1 to June 1, 2023.ExposuresSelf-reported bilateral oophorectomy (with or without salpingectomy).Main outcomes and measuresAll-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality.ResultsThere were 4332 women (mean age, 42.6 years) enrolled in the cohort, of whom 2932 (67.8%) chose to undergo a preventive oophorectomy at a mean (range) age of 45.4 (23.0-77.0) years. After a mean follow-up of 9.0 years, 851 women had developed cancer and 228 had died; 57 died of ovarian or fallopian tube cancer, 58 died of breast cancer, 16 died of peritoneal cancer, and 97 died of other causes. The age-adjusted HR for all-cause mortality associated with oophorectomy was 0.32 (95% CI, 0.24-0.42; P

BACKGROUND: Residual disease following cytoreductive surgery in patients with ovarian cancer has been associated with poorer survival outcomes compared with no residual disease. We performed a meta-analysis to assess the impact of varying levels of residual disease status on survival outcomes in patients with ovarian cancer who have undergone primary cytoreductive surgery or interval cytoreductive surgery in the setting of new therapies for this disease. METHODS: Medline, Embase, and Cochrane databases (January 2011 - July 2020) and grey literature, bibliographic and key conference proceedings, were searched for eligible studies. Fixed and random-effects meta-analyses compared progression and survival by residual disease level across studies. Heterogeneity between comparisons was explored via type of surgery, disease stage, and type of adjuvant chemotherapy. RESULTS: Of 2832 database and 16 supplementary search articles screened, 50 studies were selected; most were observational studies. The meta-analysis showed that median progression-free survival and overall survival decreased progressively with increasing residual disease (residual disease categories of 0 cm, > 0-1 cm and > 1 cm). Compared with no residual disease, hazard ratios (HR) for disease progression increased with increasing residual disease category (1.75 [95% confidence interval: 1.42, 2.16] for residual disease > 0-1 cm and 2.14 [1.34, 3.39] for residual disease > 1 cm), and also for reduced survival (HR versus no residual disease, 1.75 [ 1.62, 1.90] for residual disease > 0-1 cm and 2.32 [1.97, 2.72] for residual disease > 1 cm). All comparisons were significant (p

Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10-8). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.

Gynecologic malignancies have high incidence rates both nationally and internationally, and cervical, endometrial, and ovarian cancers account for high mortality rates worldwide. Significant research is ongoing to develop targeted therapies to address unmet needs in the field and improve patient outcomes. As tumors mutate and progress through traditional lines of treatment, new therapies must be developed to overcome resistance and target cancer-specific receptors and mutations. Recent advances in the development of immunotherapy and antibody-drug conjugates have resulted in compelling and clinically meaningful results in cervical, endometrial, and ovarian cancers. In the last decade, several immunotherapy agents have received FDA approval or NCCN guideline recommendation for the treatment of gynecologic malignancies, including dostarlimab for advanced or recurrent endometrial cancer and pembrolizumab for advanced or recurrent cervical and endometrial cancers. Several other immunotherapeutic agents are under active investigation. Development of antibody-drug conjugates including tisotumab vedotin in cervical cancer, mirvetuximab soravtansine in ovarian cancer, and trastuzumab deruxtecan in multiple gynecologic cancers has translated into exciting efficacy signals, prompting full drug approvals and additional investigation. This article aims to review recent novel advances in targeted treatments for gynecologic malignancies, highlighting the trials and data underlying these novel interventions.

ObjectiveTo describe the participation of racial and ethnic minority groups (REMGs) in gynecologic oncology trials.MethodsGynecologic oncology studies registered on ClinicalTrials.gov between 2007 and 2020 were identified. Trials with published results were analyzed based on reporting of race/ethnicity in relation to disease site and trial characteristics. Expected enrollment by race/ethnicity was calculated and compared to actual enrollment, adjusted for 2010 US Census population data.Results2146 gynecologic oncology trials were identified. Of published trials (n = 252), 99 (39.3%) reported race/ethnicity data. Recent trials were more likely to report these data (36% from 2007 to 2009; 51% 2013-2015; and 53% from 2016 to 2018, p = 0.01). Of all trials, ovarian cancer trials were least likely to report race/ethnicity data (32.1% vs 39.3%, p = 0.011). Population-adjusted under-enrollment for Blacks was 7-fold in ovarian cancer, Latinx 10-fold for ovarian and 6-fold in uterine cancer trials, Asians 2.5-fold in uterine cancer trials, and American Indian and Alaska Native individuals 6-fold in ovarian trials. Trials for most disease sites have enrolled more REMGs in recent years - REMGs made up 19.6% of trial participants in 2007-2009 compared to 38.1% in 2016-2018 (p

Bacterial flagella and type IV pili (TFP) are surface appendages that enable motility and mechanosensing through distinct mechanisms. These structures were previously thought to have no components in common. Here, we report that TFP and some flagella share proteins PilO, PilN, and PilM, which we identified as part of the Helicobacter pylori flagellar motor. H. pylori mutants lacking PilO or PilN migrated better than wild type in semisolid agar because they continued swimming rather than aggregated into microcolonies, mimicking the TFP-regulated surface response. Like their TFP homologs, flagellar PilO/PilN heterodimers formed a peripheral cage that encircled the flagellar motor. These results indicate that PilO and PilN act similarly in flagella and TFP by differentially regulating motility and microcolony formation when bacteria encounter surfaces.

The diagnosis, treatment, and management of gynecologic malignancies benefit from both positron emission tomography/computed tomography (PET/CT) and MRI. PET/CT provides important information on the local extent of disease as well as diffuse metastatic involvement. MRI offers soft tissue delineation and loco-regional disease involvement. The combination of these two technologies is key in diagnosis, treatment planning, and evaluating treatment response in gynecological malignancies. This review aims to assess the performance of PET/MRI in gynecologic cancer patients and outlines the technical challenges and clinical advantages of PET/MR systems when specifically applied to gynecologic malignancies.

Background: There is evidence indicating that chemoresistance in tumor cells is mediated by the reconfiguration of the tricarboxylic acid cycle, leading to heightened mitochondrial activity and oxidative phosphorylation (OXPHOS). Previously, we have shown that ovarian cancer cells that are resistant to chemotherapy display increased OXPHOS, mitochondrial function, and metabolic flexibility. To exploit this weakness in chemoresistant ovarian cancer cells, we examined the effectiveness of the mitochondrial inhibitor CPI-613 in treating preclinical ovarian cancer. Methods: Chemosensitive OVCAR3, and chemoresistant CAOV3 and F2 ovarian cancer cells lines and their xenografts in nude mice were used. Functional metabolic studies were performed using Seahorse instrument. Metabolite quantification was performed using LC/MS/MS. Results: Mice treated with CPI-613 exhibited a notable increase in overall survival and a reduction in tumor development and burden in OVCAR3, F2, and CAOV3 xenografts. CPI-613 suppressed the activity of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complex, which are two of its targets. This led to a reduction in OXPHOS and tricarboxylic acid cycle activity in all 3 xenografts. The addition of CPI-613 enhanced the responsiveness of chemotherapy in the chemoresistant F2 and CAOV3 tumors, resulting in a notable improvement in survival rates and a reduction in tumor size as compared to using chemotherapy alone. CPI-613 reduced the chemotherapy-induced OXPHOS in chemoresistant tumors. The study revealed that the mechanism by which CPI-613 inhibits tumor growth is through mitochondrial collapse. This is evidenced by an increase in superoxide production within the mitochondria, a decrease in ATP generation, and the release of cytochrome C, which triggers mitochondria-induced apoptosis. Conclusion: Our study demonstrates the translational potential of CPI-613 against chemoresistant ovarian tumors. [ABSTRACT FROM AUTHOR]

Genetic testing for breast cancer predisposing genes has expanded beyond BRCA1 and BRCA2 and now includes panels of 20 or more genes. It is now recommended that all women diagnosed with breast cancer at age 65 or below be offered testing for an extended gene panel. The rationale for testing includes personalizing the management of breast cancer according to the mutation found. For BRCA1 and BRCA2 carriers, the finding of a mutation has clear implications for cancer management, but for other genes, such as ATM, the management implications are less clear. Women with an ATM mutation have a lifetime risk of breast cancer of approximately 25%, the majority of which are ER-positive. The risk of ovarian cancer is approximately 5%. It is not yet clear how the identification of an ATM mutation in a patient newly diagnosed with breast cancer should impact on her treatment and follow-up. At present, these women are treated in the same way as women without a mutation. It is important that large prospective studies be conducted looking at various treatment modalities in women with breast cancer and an ATM mutation in order to optimize outcomes. [ABSTRACT FROM AUTHOR]

Background: Despite remarkable achievements in applying chimeric antigen receptor (CAR)-T cells to treat hematological malignancies, they remain much less effective against solid tumors, facing several challenges affecting their clinical use. We previously showed that multichain DNAX-activating protein (DAP) CAR structures could enhance the safety and efficacy of CAR-T cells when used against solid tumors. In particular, mesothelin (MSLN)-targeted CAR-T cell therapy has therapeutic potential in MSLN-positive solid tumors, including ovarian cancer and mesothelioma. Methods: In vitro cell killing assays and xenograft model were utilized to determine the anti-tumor efficacy of MSLN targeting DAP-CAR-T cells and other CAR-T cells. ELISA and flow cytometry analysis were used to assess the cytokine secretion capacity and proliferation ability. Eight patients with MSLN expression were enrolled to evaluate the safety and efficacy of MSLN-DAP CAR-T cell therapy. Single-cell sequencing was performed to explore the dynamics of immune cells in patients during treatment and to identify the transcriptomic signatures associated with efficacy and toxicity. Results: We found that multichain DAP-CAR formed by combining a natural killer cell immunoglobulin-like receptor truncator and DAP12 exhibited better cytotoxicity and tumor-killing capacity than other natural killer cell-activated receptors associated with DAP12, DAP10, or CD3Z. The safety and efficacy of MSLN-DAP CAR-T cell therapy in patients with ovarian cancer and mesothelioma were evaluated in a single-arm, open-label clinical trial (ChiCTR2100046544); two patients achieved partial response, while four patients had a stable disease status. Furthermore, single-cell sequencing analysis indicated that KT032 CAR-T cell infusion could recruit more immune cells and temporarily remodel the TME. Conclusions: Our study highlights the safety and therapeutic efficacy of multiple-chain DAP-CAR-T cell therapy targeting MSLN to treat patients with ovarian cancer and mesothelioma. Trial registration: ChiCTR.org.cn, ChiCTR2100046544. May 21, 2021. [ABSTRACT FROM AUTHOR]

Adequate nutrition in a hospital setting is essential for achieving optimal health outcomes in oncology patients. This study specifically investigated the interrelationships between nutritional status, daily habits, and hospital length of stay (LOS) in ovarian cancer patients undergoing chemotherapy. A prospective longitudinal study was conducted from August 2019 to January 2022 in a tertiary hospital. Throughout the study, nutritional status, biochemical indicators, diet, and physical activity were meticulously recorded at different stages of chemotherapy: before chemotherapy (T0), the first course (T1), third course (T2), and fifth course (T3). To determine the factors influencing LOS, a generalized estimation equation (GEE) was employed. A total of 460 patients completed the follow-up period. The findings revealed a decline in nutritional risk among patients by 9.90% at T1, 17.62% at T2 and 18.26% at T3 (χ2 = 79.220, P < 0.001). The proportion of people receiving enteral nutrition showed an upward trend (χ2 = 15.202, P < 0.001). Notably, the proportion of patients adhering to a healthier diet increased by 40.44% by the study's conclusion, while the number of patients abstaining from physical activity or engaging in solely low-intensity activities decreased by 21.08%. Moreover, as the chemotherapy cycle progressed, daily activity steps exhibited an upward trajectory (F = 5.986, P < 0.001), while the LOS experienced a significant reduction (F = 21.298, P < 0.001). This study identified hypoproteinemia (protein level < 34 g/L), a high nutritional risk (NRS 2002 score ≥ 3), a short duration of sleep (≤ 7 h/day), and a lower daily activity level as risk factors for LOS. Receiving enteral nutrition support is a protective factor for LOS. Significant improvements in nutritional status, diet, and physical activity have been observed among ovarian cancer patients during their chemotherapy cycles. Reduced nutritional risks, implementation of nutritional support, good physical activity, and adequate sleep were associated with a shorter LOS. [ABSTRACT FROM AUTHOR]

The heterogeneity and immunosuppression microenvironment of ovarian cancer seriously restrict the efficiency of monomodal treatment. Emerging multimodal therapy strategies based on sonodynamic therapy with enhanced antitumor effects have attracted intensive attention in the quest to combat cancer. However, exploring highly efficient sonosensitizers integrating chemodynamic/sonodynamic/immunotherapies with reversing immunosuppressive tumor microenvironment (TME) capacity is urgently desired but remains challenging. Here, a facile strategy is designed to synthesize immunomodulating sonocatalytic nanoagents (IrT‐SCN) with dual‐functional Ir‐N centers and narrow bandgap for reversing immunosuppression and potentiating ovarian cancer immunotherapy. IrT‐SCN with dual‐functional centers Ir‐N2 and Ir‐N4 and conjugated networks show a reduced bandgap, moderate interaction with H2O2, and efficient production of reactive oxygen species (ROS). Such ROS capabilities include: 1) utilizing H2O2 in TME to catalytically generate potent O2, as well as abundant superoxide anion (•O2−) and singlet oxygen (1O2) radicals; 2) external ultrasound (US) irradiation can also boost the production of 1O2 simultaneously; 3) M1 polarization of tumor‐associated macrophages and enhanced immune effect can promote the outcome of cancer treatment. This finding provides proof‐of‐concept evidence for the future development of immunomodulating sonocatalytic nanoagents for oncological treatments and other ROS‐related biomedical fields. [ABSTRACT FROM AUTHOR]

STK11 (serine-threonine kinase 11), also known as LKB1 (liver kinase B1) is a highly conserved master kinase that regulates cellular metabolism and polarity through a complex signaling network involving AMPK and 12 other AMPK-related kinases. Germline mutations in LKB1 have been causatively linked to Peutz-Jeghers Syndrome (PJS), an autosomal dominant hereditary disease with high cancer susceptibility. The identification of inactivating somatic mutations in LKB1 in different types of cancer further supports its tumor suppressive role. Deleterious mutations in LKB1 are frequently observed in patients with epithelial ovarian cancer. However, its inconsistent effects on tumorigenesis and cancer progression suggest that its functional impact is genetic context-dependent, requiring cooperation with other oncogenic lesions. In this review, we summarize the pleiotropic functions of LKB1 and how its altered activity in cancer cells is linked to oncogenic proliferation and growth, metastasis, metabolic reprogramming, genomic instability, and immune modulation. We also review the current mechanistic understandings of this master kinase as well as therapeutic implications with particular focus on the effects of LKB1 deficiency in ovarian cancer pathogenesis. Lastly, we discuss whether LKB1 deficiency can be exploited as an Achilles heel in ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Circular RNAs (circRNAs) are important regulators for ovarian cancer (OC). Circ_0001741 has been found to be highly expressed in OC samples and is involved in regulating paclitaxel resistance in OC cells. Therefore, circ_0001741 may play a vital role in OC process, and its potential molecular mechanism is worth further revealing. Methods: Circ_0001741, miR-491-5p, and PRSS8 levels in OC tumor tissues and cells were quantified by quantitative real-time PCR or western blot. The proliferation, apoptosis and metastasis of OC cells were detected by cell counting kit 8 assay, Edu assay, flow cytometry, and transwell assay. RNA interaction was verified by dual-luciferase reporter assay and RIP assay. Xenograft assay was used to detect the effect of circ_0001741 knockdown on OC tumor growth in vivo. Results: Circ_0001741 was upregulated in OC tissues and cell lines. Knockdown of circ_0001741 repressed OC cell proliferation, metastasis, and enhanced apoptosis. Mechanistically, miR-491-5p was targeted by circ_0001741, and miR-491-5p inhibitor could attenuate the effect of circ_0001741 silencing on OC cell progression. Meanwhile, PRSS8 was a target of miR-491-5p, and miR-491-5p overexpression inhibited OC cell progression by targeting PRSS8. Circ_0001741 regulated PRSS8 expression by sponging miR-491-5p. Besides, circ_0001741 knockdown also inhibited OC tumor growth in vivo. Conclusion: Our data showed that circ_0001741 could promote the growth and metastasis of OC cells through the miR-491-5p/PRSS8 axis, which provided a potential molecular target for the treatment of OC. [ABSTRACT FROM AUTHOR]

Ovarian cancer is one of the most common gynecological malignancies. The current first-line treatment strategies for advanced ovarian cancer include surgery, chemotherapy, and maintenance therapy. Bevacizumab and poly (ADP-ribose) polymerase inhibitors (PARPi) are primary maintenance treatments for advanced ovarian cancer. Previously, many patients declined these therapies before medicare coverage because of high costs. Bevacizumab and apatinib are anti-tumor angiogenic agents. In this case study, we describe a patient with advanced ovarian cancer who underwent neoadjuvant chemotherapy, interval debulking surgery, and adjuvant chemotherapy. She declined bevacizumab and PARPi maintenance therapy owing to the prohibitive expenses. The patient was administered off-label apatinib and achieved a progression-free survival of 54 months. Thus, apatinib may offer substantial therapeutic value as a first-line maintenance therapy in advanced ovarian cancer. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is to develop a novel therapeutic approach for the treatment of ovarian cancer while investigating the role of tumor-infiltrating lymphocytes (TILs) in the context of ovarian cancer therapy. The primary aim is to establish a technical procedure for the isolation of tumor cells, lymphocytes, and dendritic cells (DCs) derived from ovarian cancer tissues or ascites. Subsequently, the focus lies on the generation of dendritic cell-tumor infiltrating lymphocytes (DC-TILs) exhibiting specific cytotoxic capabilities aimed at targeted therapeutic interventions. The cytotoxic impact of DC-TIL interactions on tumor cells was investigated through in vitro experimentation. This research aims to provide fundamental experimental insights for the future clinical advancement of TIL therapy in ovarian cancer. Methods: The experimental samples included fresh surgical specimens and ascites specimens procured from three patients (ranging in age from 32 to 75), sourced from the Department of Gynecology at the Third Bethune Hospital of Jilin University. TILs were extracted through in vitro isolation from solid tumor tissues, while primary tumor cells and DCs were obtained from ascites specimens. Tumor-specific antigens derived from patient tumor cells were utilized to stimulate the maturation of DCs. TILs were subsequently co-cultured with antigen-stimulated DC cells. Subsequently, TILs with specific killing effects were obtained, and the cytotoxic impact of DC-TILs on tumor cells was detected in vitro. Results: (1) TILs were successfully obtained through expansion from the tumor tissue of a patient diagnosed with ovarian cancer. (2) DCs were successfully induced from ascites cells harvested from patients diagnosed with ovarian cancer. (3) TILs significantly enhanced the cytotoxicity of tumor cells following DC stimulation. Conclusion: TILs have the capacity to augment the cytotoxicity directed towards tumor cells following DC stimulation. [ABSTRACT FROM AUTHOR]

Background: High levels of LLT1 expression have been found in several cancers, where it interacts with CD161 on NK cells to facilitate tumor immune escape. Targeting LLT1 could potentially relieve this inhibitory signal and enhance anti-tumor responses mediated through NK cells. Using the 'The Cancer Genome Atlas' (TCGA) database, we investigated the role of LLT1 in the tumor microenvironment (TME) across various cancers. Identifying such biomarkers could create new therapeutic options for patients in addition to complementing existing immunotherapies. Methods: LLT1 expression was evaluated in 33 cancers using TCGA transcriptome data. Univariate Cox regression analysis was employed to assess the correlation of LLT1 expression with patient survival. The relationship between LLT1 expression with immune infiltrates, immune gene signatures, and cancer genomic biomarkers (TMB, MSI, and MMR) was also investigated. Immunofluorescence studies were conducted to validate LLT1 expression in tumors. Furthermore, using the CRI iAtlas data, we evaluated LLT1 distribution and its correlation with other immune checkpoint genes in patients non-responsive to existing immune checkpoint therapies across multiple solid cancers. Results: High expression of LLT1 was observed in 12 cancers, including BRCA, CHOL, ESCA, GBM, HNSC, KIRC, KIRP, LIHC, LUAD, STAD, SARC, and PCPG. In certain cancers like COAD, KICH, and KIRC, high LLT1 expression was associated with poor prognosis. Further analysis revealed that upregulated LLT1 was associated with an abundance of NK and T cell infiltrates in the TME, as well as exhaustive immune biomarkers, and inversely associated with pro-inflammatory and tumor suppressor signatures. High LLT1 expression is also positively correlated with genomic biomarkers in certain cancers. Immunofluorescence studies confirmed moderate to high LLT1 expression in immune-resistant prostate cancer, glioma, ovarian cancer, and immune-sensitive liver cancer cell lines. An independent assessment of clinical cohorts from CRI iAtlas showed a correlation of upregulated LLT1 with multiple immunosuppressive genes in patients non-responsive to current ICIs. Conclusions: The biomarker analysis revealed a clear association between elevated LLT1 expression and an immunosuppressive TME in patient cohorts from TCGA and clinical databases. Therefore, this study provides a foundation for utilizing LLT1 as a potential target to improve clinical responses in ICI non-responsive patients with upregulated LLT1. [ABSTRACT FROM AUTHOR]

Objectives: The study aimed to compare the diagnostic efficacy of the machine learning models with expert subjective assessment (SA) in assessing the malignancy risk of ovarian tumors using transvaginal ultrasound (TVUS). Methods: The retrospective single-center diagnostic study included 1555 consecutive patients from January 2019 to May 2021. Using this dataset, Residual Network(ResNet), Densely Connected Convolutional Network(DenseNet), Vision Transformer(ViT), and Swin Transformer models were established and evaluated separately or combined with Cancer antigen 125 (CA 125). The diagnostic performance was then compared with SA. Results: Of the 1555 patients, 76.9% were benign, while 23.1% were malignant (including borderline). When differentiating the malignant from ovarian tumors, the SA had an AUC of 0.97 (95% CI, 0.93–0.99), sensitivity of 87.2%, and specificity of 98.4%. Except for Vision Transformer, other machine learning models had diagnostic performance comparable to that of the expert. The DenseNet model had an AUC of 0.91 (95% CI, 0.86–0.95), sensitivity of 84.6%, and specificity of 95.1%. The ResNet50 model had an AUC of 0.91 (0.85–0.95). The Swin Transformer model had an AUC of 0.92 (0.87–0.96), sensitivity of 87.2%, and specificity of 94.3%. There was a statistically significant difference between the Vision Transformer and SA, and between the Vision Transformer and Swin Transformer models (AUC: 0.87 vs. 0.97, P = 0.01; AUC: 0.87 vs. 0.92, P = 0.04). Adding CA125 did not improve the diagnostic performance of the models in distinguishing benign and malignant ovarian tumors. Conclusion: The deep learning model of TVUS can be used in ovarian cancer evaluation, and its diagnostic performance is comparable to that of expert assessment. [ABSTRACT FROM AUTHOR]

Background: Transcript variants and protein isoforms are central to unique tissue functions and maintenance of homeostasis, in addition to being associated with aberrant states such as cancer, where their crosstalk with the mutated tumor suppressor p53 may contribute to genomic instability and chromosomal rearrangements. We previously identified several novel splice variants in ovarian cancer RNA-sequencing datasets; herein, we aimed to elucidate the biological effects of the Integrin Subunit Beta 8 variant (termed pITGB8-205). Methods: Resolution of the full-length sequence of pITGB8-205 through rapid amplification of cDNA ends (RACE-PCR). Cell cycle analysis and karyotype studies were performed to further explore genomic instability. RNA-seq and proteomics analyses were used to identify the differential expression of the genes. Results: This full-length study revealed a unique 5' sequence in pITGB8-205 that differed from the reported ITGB8-205 sequence, suggesting differential regulation of this novel transcript. Under a p53 mutant background, overexpression of pITGB8-205 triggered genetic instability reminiscent of oncogene-induced replicative stress with extensive abnormal mitoses and chromosomal and nuclear aberrations indicative of chromosomal instability, leading to near whole-genome duplication that imposes energy stress on cellular resources. Micronuclei and aneuploidy are striking features of pITGB8-205-overexpressing p53-mutant cells but are not enhanced in p53 wild-type (WT) cells. RNA-seq and proteomics analyses further suggested that p53 inactivation in ovarian cancer provides a permissive intracellular molecular niche for pITGB8-205 to mediate its effects on genomic instability. This observation is pivotal considering that most high-grade serous ovarian carcinoma (HGSC) tumors express mutant p53. The resulting aneuploid clones with enhanced self-renewal and survival capabilities disrupt clonal dominance under stress yet maintain a balance between replicative stress and prosurvival advantages. Conclusion: pITGB8-205-overexpressing clones sustain ovarian tumor cell survival, achieve homeostasis and are formidable opponents of therapy. [ABSTRACT FROM AUTHOR]

Acquired or de novo resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) is a major challenge to ovarian cancer treatment. Therefore, strategies to overcome PARPi resistance are critical to improve prognosis. The purpose of this study is to evaluate whether inhibition of ADAM17 sensitizes ovarian cancer to treatment with olaparib, a PARPi, thereby bypassing resistance mechanisms and improving treatment response. Thus, we analyzed the effect of olaparib in combination with the ADAM17 inhibitor GW280264X in ovarian cancer using a 2D monolayer and a 3D spheroid model followed by a multicontent readout (viability, caspase activation and cytotoxicity). To emphasize the translational aspect of our work, we performed corresponding experiments on primary cells derived from ovarian cancer patients initially screened for their mutation status of the breast cancer gene (BRCA 1/2). In 2D, we observed a significant reduction in cell viability and a subsequent increase in apoptosis of the combined treatment (olaparib + GW280264X) compared with olaparib mono-treatment. The combined treatment allows a substantial dose reduction of olaparib rendering a strong synergistic effect. Using a 3D spheroid model from primary cells, we confirmed the 2D monoculture results and demonstrated not only increased caspase activity under the combined treatment but also a substantial gain in cytotoxicity compared to the mono-treatment. Our study proposes ADAM17 inhibition sensitizing ovarian cancer to olaparib treatment and improving treatment response. [ABSTRACT FROM AUTHOR]

The diagnosis and treatment of ovarian cancer (OC) are still a grand challenge, more than 70% of patients are diagnosed at an advanced stage with a dismal prognosis. Magnetic resonance imaging (MRI) has shown superior results to other examinations in preoperative assessment, while cisplatin‐based chemotherapy is the first‐line treatment for OC. However, few previous studies have brought together the two rapidly expanding fields. Here a technique is presented using cisplatin prodrug (Pt‐COOH), Fe3+, and natural polyphenols (Gossypol) to construct the nanoparticles (HA@PFG NPs) that have a stable structure, controllable drug release behavior, and high drug loading capacity. The acidic pH values in tumor sites facilitate the release of Fe3+, Pt‐COOH, and Gossypol from HA@PFG NPs. Pt‐COOH with GSH consumption and cisplatin‐based chemotherapy plus Gossypol with pro‐apoptotic effects displays a synergistic effect for killing tumor cells. Furthermore, the release of Fe3+ at the tumor sites promotes ferroptosis and enables MRI imaging of OC. In the patient‐derived tumor xenograft (PDX) model, HA@PFG NPs alleviate the tumor activity. RNA sequencing analysis reveals that HA@PFG NPs ameliorate OC symptoms mainly through IL‐6 signal pathways. This work combines MRI imaging with cisplatin‐based chemotherapy, which holds great promise for OC diagnosis and synergistic therapy. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusions Explored the correlation between CD1a expression in recurrence and prognosis of ovarian cancer (OV).The CD1a expression profile in OV, recurrent OV, and normal tissues, as well as corresponding clinical data, were obtained from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), Gene Expression Omnibus (GEO), and Genotype Tissue Expression (GTEx) databases. Meanwhile, immunohistochemical detection of CD1a expression in normal and OV tissues. Kaplan–Meier curves were plotted to estimate the hazard ratio (HR) of survival in OV. In addition, the correlation between CD1a and immune cells in OV, as well as the CD1a expression profile and corresponding survival time in pan‐cancer were obtained from TCGA database.CD1a was overexpressed in OV and was significantly under‐expressed in recurrent OV (TCGA‐OV, p < 0.0001 and ICGC‐OV, p < 0.0001). CD1a immunohistochemistry is significantly overexpressed in OV compared to normal tissue (p < 0.05). Recurrent OV (ICGC, p < 0.001; GSE17260, p < 0.001; GSE32062, p < 0.05). The prognosis in OV was significantly better when CD1a is overexpressed compared to under‐expressed (HR [low], 1.426: 95% confidence interval [CI], 0.912–2.128; p = 0.050). Meanwhile, the overexpression of CD1a has a better prognosis than low expression in OV and recurrent OV (p = 0.004, HR [low] = 2.462, 95%CI [1.346–4.504] and p = 0.011, HR [low] = 2.199, 95%CI [1.202–4.024]). In addition, CD1a expression was closely correlated with immune cells, the CD8+ T cells, macrophages, and NK cells, while uncharacterized cells were significantly different (p = 2.65e−6, p = 7.52e−13, p = 8.28e−12, and p = 5.89e−8, respectively). Moreover, CD1a expression affected the prognosis in various other cancers.CD1a expression affected the recurrence and prognosis of OV and is closely related to various immune cell levels. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer among women worldwide, and its incidence rate is still increasing, especially among younger women. Nationally, it constitutes one-fifth of all cancer cases and almost 40% of all female cancers. With a median age of 51 years, breast cancer is diagnosed at least a decade earlier, and at more advanced stages compared to Western societies. Hereditary cancers account for 10% or more of all cancer burden worldwide. With expanded indications, increased number of genes tested, and significant decline in cost of testing, such proportion will probably increase. Individuals with pathogenic variants of BRCA1 and BRCA2 are at higher risk of breast, ovarian, pancreatic and many other cancers. Over the past two decades, several highly penetrant cancer-susceptibility genes were identified across almost all tumor sites, thus increasing the need for comprehensive cancer genetic programs that address the testing process, counselling patients and at-risk family members, and then deal with all testing results and its consequences. In addition to its important role in preventing more cancers in index patients themselves and among their close relatives, identification of pathogenic or likely pathogenic variants, mostly in BRCA1 or BRCA2 , may inform therapeutic decisions in common cancers including breast, ovarian, prostate and pancreatic cancers. In this manuscript, we describe the experience of a comprehensive cancer center, in a resource-limited country in establishing a comprehensive clinical cancer genetics program that can serve as an example for others who share similar demographic and financial restrains. [ABSTRACT FROM AUTHOR]

We assessed real-world trends in the use of maintenance therapy [MT] (i.e., polyADP-ribose polymerase inhibitors (PARPi) and/or bevacizumab following platinum-based chemotherapy), among U.S. patients with ovarian cancer. Using Medicare and commercial administrative health claims data from Optum's de-identified Clinformatics® Data Mart Database, we identified patients who had been diagnosed with ovarian cancer between January 1, 2010, and March 31, 2021, and received platinum-based chemotherapy and MT. Multivariable logistic regression and Cox proportional hazards regression were used to evaluate associations between demographic and clinical characteristics and MT use. Our study included 6339 patients, with a median age of 70 years. The majority were White (70.1 %), Medicare-insured (71.9 %), and were treated in the South (42.5 %). Of the 31.5 % who received MT, 18.1 % received bevacizumab alone, 10.2 % PARPi alone, and 3.3 % both. After adjusting for insurance type, PARPi and bevacizumab use increased significantly from 2017 to 2020. Patients with a high Elixhauser comorbidity index were more likely to receive MT than were patients with a low index [OR (95 % CI): 1.46 (1.28–1.67), p < 0.0001]. PARPi use was significantly associated with treatment in the South [1.42 (1.10–1.83), p = 0.01]. Compared to patients who received neither agents, those who received bevacizumab, alone or in combination with PARPi, had a higher risk of death [HR = 2.02 (95 % CI: 1.70–2.28, p < 0.0001) and 1.66 (1.24–2.23), p = 0.001, respectively]. The majority of patients with ovarian cancer are not utilizing maintenance therapy after platinum-based chemotherapy. Age, comorbidity status, and geographic region of treatment were associated with MT use. Understanding the factors and real-world outcomes associated with MT use is important to support patients in making value concordant and informed decisions. • Age, comorbidity status, and geographic region of treatment were associated with ovarian cancer maintenance therapy use. • After adjusting for insurance type, both PARPi and bevacizumab use increased significantly from 2017 to 2020. • We found relatively low use of PARPi plus bevacizumab, despite being associated with a longer progression-free survival. [ABSTRACT FROM AUTHOR]

Ovarian cancer has poor 5-year survival, particularly among non-Hispanic (NH) Black patients. Efforts to identify patients at high-risk of functional limitations and frailty may improve outcomes. In this study, we examined how healthcare access (HCA) and race/ethnicity relate to frailty among patients with ovarian cancer. We identified Hispanic, NH Black, and NH White patients diagnosed at ages ≥6 5 years with ovarian cancer between 2009 and 2015 using SEER-Medicare. Log-binomial regression was used to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs) for the association between HCA and race/ethnicity with pre- or post-diagnosis frailty, adjusting for age and comorbidities. A total of 6041 patients with ovarian cancer were included, including 91.8% NH White, 6.6% NH Black, and 1.7% Hispanic. Pre-diagnosis, 14.7% of patients were defined as frail (NH White: 14.3%; NH Black: 17.9%; Hispanic: 20.8%). Post-diagnosis, frailty prevalence increased to 58.8% (NH White: 58.2%; NH Black: 65.2%; Hispanic: 70.2%). No statistically significant associations were observed between race/ethnicity and pre- or post-diagnosis frailty in fully adjusted models. After adjustment for patient characteristics and healthcare accessibility and availability, higher healthcare affordability was associated with a decreased prevalence of pre-diagnosis frailty (PR: 0.91, 95% CI: 0.8 5, 0.98). Patients with ovarian cancer have a high prevalence of frailty after diagnosis, particularly NH Black and Hispanic patients. Improving healthcare affordability may prevent or help manage frailty in Medicare patients, improve receipt of cancer treatment, and increase cancer survival. • This study examined how healthcare access and race/ethnicity are related to frailty in ovarian cancer patients. • Prior to diagnosis, about 15% of patients were defined as frail, which increased to nearly 60% in the year after diagnosis. • Higher healthcare affordability was associated with a reduced prevalence of frailty prior to diagnosis. [ABSTRACT FROM AUTHOR]

To assess the efficacy and toxicity of paclitaxel and carboplatin (PC) compared to bleomycin, etoposide, and cisplatin (BEP) for treatment of newly diagnosed Stage IIA-IV or recurrent chemotherapy-naive ovarian sex cord-stromal tumors (SCST). This phase II noninferiority trial randomly assigned patients to receive PC (6 cycles P 175 mg/m2 and C AUC = 6 IV every 3 weeks), or BEP (4 cycles B 20 units/m2 IV push day 1, E 75 mg/m2 IV days 1–5, and cisplatin 20 mg/m2 IV days 1–5 every 3 weeks). The primary endpoint was progression- free survival (PFS). This trial is registered with ClinicalTrials.gov , NCT01042522. At the interim analysis, 63 patients (31 PC and 32 B.P. had accrued between Feb 8, 2010 and Apr 30, 2020. Median age was 48 years. 87% had granulosa cell tumors. 37% had measurable disease. The DSMB closed accrual early for futility of PC arm. The futility analysis was supported by an estimated HR = 1.11 [95% CI: 0.57 to 2.13] which exceeded the pre-determined threshold for non-inferiority (1.10). Median PFS was 27.7 months [11.2 to 41.0] for PC and 19.7 months for BEP [95% CI: 10.4–52.7]. PC patients had fewer grade 3 or higher adverse events (PC 77% vs BEP 90%). The study met its pre-specified criterion for stopping early for futility and so failed to demonstrate non-inferiority of PC versus BEP in ovarian SCSTs, in a non-inferiority test with a hazard ratio margin of 1.1. Both PC and BEP may be considered in patients with advanced/recurrent SCST. • Paclitaxel and carboplatin (PC) are well tolerated in patients with sex cord-stromal ovarian tumors (SCSTs). • Both PC and bleomycin/etoposide/cisplatin are regimens to be considered for patients with advanced/recurrent SCSTs. • No significant differences in outcomes or adverse effects were detected between these two regimens. [ABSTRACT FROM AUTHOR]

This study compares baseline clinical characteristics, physical function testing, and patient-reported outcomes for patients undergoing primary cytoreductive surgery versus neoadjuvant chemotherapy, with the goal of better understanding unique patient needs at diagnosis. Patients with suspected advanced stage (IIIC/IV) epithelial ovarian cancer undergoing either primary cytoreductive surgery or neoadjuvant chemotherapy were enrolled in a single-institution, non-randomized prospective behavioral intervention trial of prehabilitation. Baseline clinical characteristics were abstracted. Physical function was evaluated using the Short Physical Performance Battery, Fried Frailty Index, gait speed, and grip strength. Patient-reported outcomes were evaluated using Patient-Reported Outcomes Measurement Information System metrics and the Perceived Stress Scale. There were no significant differences in demographics or clinical characteristics between cohorts at enrollment, with the exception of performance status, clinical stage, and albumin. While gait speed and grip strength were lower amongst neoadjuvant chemotherapy patients, there were no significant differences in physical function using the Short Physical Performance Battery and Fried Frailty Index. Patients in the neoadjuvant chemotherapy cohort reported decreased perception of physical function and increased fatigue on Patient-Reported Outcomes Measurement Information System metrics. A larger proportion of patients in the neoadjuvant cohort reported severe levels of emotional distress and anxiety, as well as greater perceived stress at diagnosis. Our findings suggest that patients undergoing neoadjuvant chemotherapy for advanced ovarian cancer present with increased psychosocial distress and decreased perception of physical function at diagnosis and may benefit most from early introduction of supportive care. • Ovarian cancer patients undergoing NACT report decreased perception of physical function compared to those undergoing PCS. • NACT patients report increased emotional distress/anxiety and perceived stress when compared to those undergoing PCS. • NACT patients may benefit most from early initiation of supportive care services. [ABSTRACT FROM AUTHOR]

In patients with platinum-sensitive relapsed ovarian cancer (PSROC) harboring pathogenic/likely pathogenic variants (PV) in BRCA1 and BRCA2 genes, olaparib maintenance monotherapy (OMT) is a viable option. Our study aimed to evaluate the impact of different BRCA1/2 PV in survival outcomes and safety of OMT in BRCA1/2 -mutated PSROC patients, focusing on the type and location of PV. We assessed the outcomes of 100 BRCA1/2 -mutated PSROC patients treated at our institute, analyzing progression-free survival (PFS) and overall survival (OS). Germline and tumor BRCA1/2 genotyping was conducted using Illumina's next-generation sequencing (NGS). PFS and OS were significantly shorter in PSROC patients with PV in BRCA1 compared to those with PV in BRCA2 (PFS:14.0 vs. 38.8 months, p = 0.007, OS: 21.8 vs. 62.0 months, p = 0.011). Notably, there was a significant difference in PFS based on the intragenic location of BRCA1 PV, with shorter PFS in patients with 1st/2nd relapse, harboring PV in BRCA1 RING domain compared to those with PV in the DNA binding domain (DBD) and BRCT domains (12.4 vs. 23.0 months, p = 0.046). No differences in PFS and OS were observed between patients with germline versus somatic BRCA1/2 PV (PFS:14.9 vs.19.3, p = 0.316, OS: not reached vs. 25.8 months; p = 0.224). However, there were significant differences in the reasons for OMT discontinuation between patients with germline and somatic BRCA1/2 PV, primarily due to adverse side effects. In summary, the type and location of BRCA1 and BRCA2 PV provide additional insight into the expected survival outcomes of olaparib MT in PSROC patients. Trial registration number: ISRCTN42408038, Name of registry: ISRCTN registry, Date of registration: 24/11/2015. • BRCA1/2 mutation location impacts the outcome of relapsed ovarian cancer patients on olaparib maintenance monotherapy (OMT). • Patients on OMT with BRCA1 pathogenic variant (PV) had shorter progression free survival (PFS) compared to BRCA2 PV. • Patients on OMT with PV in BRCA2 or in BRCA1 DNA binding domain had better PFS compared to PV in BRCA1 RING domain. • No significant difference in PFS between patients on OMT with germline or somatic BRCA1/2 PV was observed. • Adverse events in patients on OMT were not significantly different between germline and somatic PV in BRCA1/2. [ABSTRACT FROM AUTHOR]

High-grade (HGOC) and low-grade ovarian carcinoma (LGOC) are distinct malignancies with different biological features, treatment paradigms, and life expectancies. However, differences in quality of life (QOL), sleep, and depressive symptoms have not been examined by grade, and neither have inflammatory profiles associated with these symptoms. We aim to characterize QOL and biomarkers by OC grade. Participants included patients with HGOC (N = 578) or LGOC (N = 85). Participants completed baseline assessments of psychosocial factors prior to primary surgery or neoadjuvant chemotherapy and contributed saliva for cortisol and blood for interleukin-6 (IL-6) quantification. Samples were collected intraoperatively to quantify tumor cortisol. General linear models were used to examine differences in biological and psychological variables by grade. At baseline, patients with LGOC reported less depression (p = 0.018) and sleep disturbances (p = 0.014), but no significant difference in depressive mood (p = 0.11) or QOL (p = 0.51) compared to patients with HGOC, adjusting for age and disease stage. There were trends towards lower tumor cortisol levels (p = 0.078) in LGOC compared to HGOC. One-year post-diagnosis, we found a significant improvement in QOL and fatigue, and a decrease in vegetative depression and IL-6 levels irrespective of grade. We present the first characterization of psychosocial experiences of patients with LGOC. Despite having a better disease prognosis, patients with LGOC were just as likely to have mood disturbances as those with HGOC. There was a trend towards differences in tumor cortisol by grade. Our findings highlight the need to address well-being in patients with both low- and high-grade ovarian malignancies. • Low-grade ovarian cancer patients report less vegetative depression than high-grade. • Both low- and high-grade patients report sleep disturbances that do not improve over time. • No difference in overall quality of life by grade at baseline or over time. • Trend towards lower tumor cortisol in low- versus high-grade patients. • No systematic differences in IL-6 or cortisol by grade were observed. [ABSTRACT FROM AUTHOR]

To determine whether a multimodal assay combining serum microRNA with protein biomarkers and metadata improves triage assessment of an adnexal mass. Serum samples from 468 training subjects (191 cancer cases and 277 benign adnexal mass controls or healthy controls) were analyzed for seven protein biomarkers and 180 miRNA. Circulating analyte data were combined with age and menopausal status (metadata) into a neural network model to classify samples as cases or controls. Forward regression with ten-fold cross-validation minimized the dimensionality of the model while maximizing linear separation between cases and controls. Model validation proceeded using both internal (44 cases and 56 controls) and external validation sets (51 cases and 59 controls). The total study population comprised 678 subjects, including 286 cases and 392 controls. Overall, 290 (43%) of the subjects were premenopausal. A panel of 10 miRNA delivered optimal performance when combined with protein and metadata features. The combined model improved the Receiver Operator Characteristic Area Under the Curve (ROC AUC) on the internal (AUC = 0.9; 95% CI 0.81–0.95) and external validation sets (AUC = 0.95; 95% CI 0.90–0.98) compared to miRNA alone or proteins plus metadata (without miRNA). On external validation, the combined model offered 92% sensitivity at 80% specificity overall, with 80% and 100% sensitivity for early and late-stage cancers, respectively, including 78% sensitivity for early-stage, serous ovarian cancers and 82% sensitivity for early-stage, non-serous cancers. A multimodal assay combining miRNA with protein biomarkers, age, and menopausal status improves surgical triage of an adnexal mass. • Serum miRNA and protein biomarkers are complementary in estimating the risk of malignancy of an ovarian mass. • An integrated model with proteins, miRNA, and metadata offers the most accurate classification performance. • The addition of miRNA improves sensitivity and specificity for identification of early-stage ovarian cancer. [ABSTRACT FROM AUTHOR]

We conducted a multi-institutional observational study to investigate whether maintenance hormone therapy following primary treatment of low-grade advanced-stage ovarian cancer (LGSOC) is associated with an overall survival advantage. We included patients with histologically confirmed stage III or IV LGSOC diagnosed between Jan 1, 2004, and Dec 31, 2019, treated in Commission on Cancer-accredited cancer programs in the US. Patients who received hormone therapy within six months of diagnosis were matched to controls who did not initiate hormone therapy during this timeframe by risk-set propensity score matching. The primary outcome was the risk of death from any cause within five years of initiation of HT or observation. There were 296 patients who initiated maintenance hormone therapy within six months of diagnosis and 2805 potential controls. Patients who received hormone therapy were more often treated in academic medical centers (55% vs. 44%), diagnosed later in the study period (62% vs. 23% diagnosed in 2018–2019), and frequently received no chemotherapy during initial treatment (45% vs. 17%). After risk set propensity score matching, we identified 225 patients treated with HT and 225 untreated controls who were otherwise similar with respect to measured covariates. In the matched cohort, hormone therapy was associated with a reduction in the risk of death (hazard ratio 0.60; 95% CI 0.38–0.94), corresponding to a 60-month survival of 75% compared with 65%. Following primary management of LGSOC, maintenance hormone therapy was associated with improved overall survival compared with observation. • Hormone maintenance therapy for low-grade serous carcinoma has increased substantially since 2004. • Hormone maintenance therapy for low-grade serous carcinoma is associated with an overall survival benefit. • An ongoing trial will assess the therapeutic benefit of hormone therapy in patients with low-grade serous carcinoma. [ABSTRACT FROM AUTHOR]

Ovarian cancer is the malignant tumor with the highest mortality rate in gynecology. We aimed to identify novel genes that promote ovarian cancer progression and epithelial-mesenchymal transition under hypoxic conditions. We screened SVIL as a hypoxia-associated target in ovarian cancer and explored the related molecular mechanisms. We assessed the effects of SVIL on ovarian cancer progression and metastasis in clinical samples and cellular hypoxia models. Further, we investigated the relevant pathways of SVIL and confirmed the effects of SVIL on ovarian cancer progression by using nude mouse in situ tumor models. We found that SVIL was significantly highly expressed in the hypoxic environment of ovarian cancer, and SVIL expression correlated with patient prognosis.CCK8, Wound-healing assay, Transwell assay, Western Blot, and apoptosis assays revealed that knockdown of SVIL inhibited the activation of the TGFβ1/smad2/3 pathway, which attenuated the progression and epithelial-mesenchymal transition(EMT) of ovarian cancer and alleviated cisplatin resistance by increasing cisplatin-induced apoptosis. Furthermore, in a nude mouse ovarian cancer in situ model, we found that the knockdown of SVIL significantly inhibited tumor growth and metastasis. SVIL highly expressed in the hypoxic microenvironment can increase ovarian cancer progression and cisplatin resistance by activating TGFβ1/smad2/3 pathway. Our study demonstrated that SVIL may be a novel target for the treatment of ovarian cancer. [Display omitted] • SVIL was overexpressed in ovarian cancer and correlated with patient prognosis. • Knockdown of SVIL inhibited the activation of the TGFβ1/smad2/3 pathway. • SVIL attenuated the resistant progression and EMT of ovarian cancer. • Knockdown of SVIL significantly inhibited tumor growth and metastasis. • SVIL is a novel target for the treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

Individuals with germline BRCA1 and BRCA2 pathogenic variants (BRCA carriers) are at high risk of developing high grade serous ovarian carcinoma (HGSC). HGSC is predominantly driven by TP53 mutations, but mutations in this gene are also commonly found in non-cancerous tissue as a feature of normal human aging. We hypothesized that HGSC predisposition in BRCA carriers may be related to increased TP53 somatic evolution, which could be detectable by ultra-deep sequencing of TP53 mutations in gynecological liquid biopsies. Duplex sequencing was used to identify TP53 mutations with high sensitivity in peritoneal washes and cervical liquid-based cytology (LBC) collected at surgery from 60 individuals including BRCA1 and BRCA2 carriers, and non-carriers. TP53 mutation pathogenicity was compared across groups and with TP53 cancer mutations. TP53 mutations were more abundant in cervical LBC than in peritoneal washes but increased with age in both sample types. In peritoneal washes, but not in cervical LBC, pathogenic TP53 mutation burden was increased in BRCA1 carriers compared to non-carriers, independently of age. Five individuals shared identical pathogenic TP53 mutations in peritoneal washes and cervical LBC, but not in blood. Ultra-deep sequencing of TP53 mutations in peritoneal washes collected at surgery reveals increased burden of pathogenic TP53 mutations in BRCA1 carriers. This excess of pathogenic TP53 mutations might be linked to the elevated risk of HGSC in these individuals. In some patients, concordant TP53 mutations were found in peritoneal washes and cervical LBCs, but the cell of origin remains unknown and deserves further investigation. • TP53 mutations are prevalent in cervical LBCs and peritoneal washes and their frequency increases with age. • Pathogenic TP53 mutation burden in peritoneal wash is associated with BRCA1 germline mutation, chemotherapy, BMI, and age. • Most mutations in cervical LBCs and peritoneal washes were not identified in blood DNA. • Identical mutations were identified in cervical LBCs and peritoneal washes of some patients, but cell of origin is unknown. [ABSTRACT FROM AUTHOR]

To evaluate if exercise and sitting time during chemotherapy were associated with chemotherapy side-effects, completion of planned chemotherapy and survival. We used data from the Ovarian cancer Prognosis And Lifestyle (OPAL) Study, a national prospective cohort of adults with newly-diagnosed epithelial ovarian cancer. At 3-monthly questionnaires we asked about exercise and sitting time in the past week, and treatment-related side-effects. Details about treatment, toxicities, progression and death were abstracted from medical records. We used linear, logistic and Cox regression, respectively, to assess associations between both exercise and sitting time, and chemotherapy side-effects and completion (≥85% relative dose intensity) and survival. 503 eligible participants were included in one or more analyses. Patients participating in higher-intensity exercise (≥30 min of moderate-vigorous exercise/week; 24%) reported significantly better Functional Assessment of Chronic Illness/Cancer Therapy (FACIT)-Fatigue (32.2 vs. 26.7) and FACT-Trial Outcome Index (69.4 vs. 61.7) scores, and were less likely to have clinician-reported moderate-severe neurotoxicity (odds ratio [OR]:0.50; 95% confidence interval [95%CI]:0.29–0.88), than minimal exercisers (<30 min moderate-vigorous exercise/week & <120 min walking/week; 52%). Participating in higher-intensity exercise was also possibly associated with greater chemotherapy completion (OR:1.70; 95%CI:0.90–3.20), particularly for paclitaxel. Sitting time was not associated with chemotherapy completion. For patients with advanced disease who underwent cytoreduction and received first-line carboplatin and paclitaxel, there was a suggestion higher-intensity exercise during chemotherapy may improve survival (HR:0.68; 95%CI:0.47–1.01). Patients with ovarian cancer who carry out moderate-vigorous exercise during chemotherapy have fewer side-effects and potentially better completion of planned chemotherapy and overall survival. • Patients doing higher-intensity exercise during chemotherapy reported less fatigue and fewer treatment side-effects. • Higher-intensity exercise during chemotherapy was associated with less moderate-severe clinician-reported neurotoxicity. • Chemotherapy completion appeared better in higher-intensity exercisers, especially among those on 3-weekly regimens. • Sitting less during chemotherapy was associated with fewer side-effects, but not chemotherapy completion. • There was a suggestion higher-intensity exercise may improve survival in advanced disease patients having typical treatment. [ABSTRACT FROM AUTHOR]

Tumor heterogeneity is associated with poor prognosis and drug resistance, leading to therapeutic failure. Here, we used tumor evolution analysis to determine the intra- and intertumoral heterogeneity of high-grade serous ovarian cancer (HGSOC) and analyze the correlation between tumor heterogeneity and prognosis, as well as chemotherapy response, through single-cell and spatial transcriptomic analysis. We collected and curated 28 HGSOC patients' single-cell transcriptomic data from five datasets. Then, we developed a novel text-mining-based machine-learning approach to deconstruct the evolutionary patterns of tumor cell functions. We then identified key tumor-related genes within different evolutionary branches, characterized the microenvironmental cell compositions that various functional tumor cells depend on, and analyzed the intra- and intertumoral heterogeneity as well as the tumor microenvironments. These analyses were conducted in relation to the prognosis and chemotherapy response in HGSOC patients. We validated our findings in two spatial and seven bulk transcriptomic datasets (total: 1,030 patients). Using transcriptomic clusters as proxies for functional clonality, we identified a significant increase in tumor cell state heterogeneity that was strongly correlated with patient prognosis and treatment response. Furthermore, increased intra- and intertumoral functional clonality was associated with the characteristics of cancer-associated fibroblasts (CAFs). The spatial proximity between CXCL12-positive CAFs and tumor cells, mediated through the CXCL12/CXCR4 interaction, was highly positively correlated with poor prognosis and chemotherapy resistance in HGSOC. Finally, we constructed a panel of 24 genes through statistical modeling that correlate with CXCL12-positive fibroblasts and can predict both prognosis and the response to chemotherapy in HGSOC patients. Our study offers insights into the collective behavior of tumor cell communities in HGSOC, as well as potential drivers of tumor evolution in response to therapy. There was a strong association between CXCL12-positive fibroblasts and tumor progression, as well as treatment outcomes. [ABSTRACT FROM AUTHOR]

A growing body of research has established a correlation between tumors and persistent chronic inflammatory infiltration. As a primary instigator of inflammation, the majority of microbiomes naturally residing within our bodies engage in a mutually beneficial symbiotic relationship. Nevertheless, alterations in the microbiome's composition or breaches in the normal barrier function can disrupt the internal environment's homeostasis, potentially leading to the development and progression of various diseases, including tumors. The investigation of tumor-related microbiomes has contributed to a deeper understanding of their role in tumorigenesis. This review offers a comprehensive overview of the microbiome alterations and the associated inflammatory changes in ovarian cancer. It may aid in advancing research to elucidate the mechanisms underlying the ovarian cancer-associated microbiome, providing potential theoretical support for the future development of microbiome-targeted antitumor therapies and early screening through convenient methods. [ABSTRACT FROM AUTHOR]

Introduction: Phosphoinositide-3-kinase (PI3K) is overexpressed in many tumors and is, thus, an ideal target for cancer treatments. Accordingly, there is an urgent need for the development of PI3K inhibitors with high potency and low toxicity. Methods: In this study, we designed and synthesized a series of 2,4-dimorpholinopyrimidine-5-carbonitrile derivatives, which were evaluated for their PI3K inhibitory potency. Results and discussion: Compound 17p demonstrated comparable PI3Kα inhibitory activity (IC50: 31.8 ± 4.1 nM) to the positive control, BKM-120 (IC50: 44.6 ± 3.6 nM). In addition, 17p showed significant inhibitory activity against PI3Kδ (IC50: 15.4 ± 1.9 nM) and significant isoform selectivity against PI3Kβ, PI3Kγ, and mTOR. Furthermore, 17p exhibited good antiproliferative activities against cancer cell activity and good safety in the Ames and hERG tests while having outstanding liver microsomal stability in vitro , with half-lives of 38.5 min in rats and 127.9 min in humans. In addition, in an apoptosis assay, 17p could induce dose-dependent cytotoxicity in the ovarian cancer cell line A2780. In a pharmacokinetic study, 17p was stable (T ½: 2.03 h) and showed high bioavailability (46.2%). Collectively, these results indicate that 17p could be a promising PI3K agent for cancer treatment. [ABSTRACT FROM AUTHOR]

Early detection of ovarian cancer (OC) is crucial for effective management and treatment, as well as reducing mortality rates. However, the current diagnostic methods for OC are time-consuming and have low accuracy. Surface plasmon resonance (SPR) biosensors offer a promising alternative to conventional techniques, as they enable rapid and less invasive screening of various circulating indicators. These biosensors are widely used for biomolecular interaction analysis and detecting tumor markers, and they are currently being investigated as a rapid diagnostic tool for early-stage cancer detection. Our main focus is on the fundamental concepts and performance characteristics of SPR biosensors. We also discuss the latest advancements in SPR biosensors that enhance their sensitivity and enable high-throughput quantification of OC biomarkers, including CA125, HE4, CEA, and CA19-9. Finally, we address the future challenges that need to be overcome to advance SPR biosensors from research to clinical applications. The ultimate goal is to facilitate the translation of SPR biosensors into routine clinical practice for the early detection and management of OC. [ABSTRACT FROM AUTHOR]