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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]

Over 75% percent of ovarian cancer patients are diagnosed with advanced‐stage disease characterized by unresectable intraperitoneal dissemination and the presence of ascites, or excessive fluid build‐up within the abdomen. Conventional treatments include cytoreductive surgery followed by multi‐line platinum and taxane chemotherapy regimens. Despite an initial response to treatment, over 75% of patients with advanced‐stage ovarian cancer will relapse and succumb to platinum‐resistant disease. Recent evidence suggests that fluid shear stress (FSS), which results from the movement of fluid such as ascites, induces epithelial‐to‐mesenchymal transition and confers resistance to carboplatin in ovarian cancer cells. This study demonstrates, for the first time, that FSS‐induced platinum resistance correlates with increased cellular protoporphyrin IX (PpIX), the penultimate downstream product of heme biosynthesis, the production of which can be enhanced using the clinically approved pro‐drug aminolevulinic acid (ALA). These data suggest that, with further investigation, PpIX could serve as a fluorescence‐based biomarker of FSS‐induced platinum resistance. Additionally, this study investigates the efficacy of PpIX‐enabled photodynamic therapy (PDT) and the secretion of extracellular vesicles under static and FSS conditions in Caov‐3 and NIH:OVCAR‐3 cells, two representative cell lines for high‐grade serous ovarian carcinoma (HGSOC), the most lethal form of the disease. FSS induces resistance to ALA‐PpIX‐mediated PDT, along with a significant increase in the number of EVs. Finally, the ability of PpIX‐mediated photodynamic priming (PDP) to enhance carboplatin efficacy under FSS conditions is quantified. These preliminary findings in monolayer cultures necessitate additional studies to determine the feasibility of PpIX as a fluorescence‐based indicator, and mediator of PDP, to target chemoresistance in the context of FSS. [ABSTRACT FROM AUTHOR]

Resistance to platinum‐based chemotherapies remains a significant challenge in advanced‐stage high‐grade serous ovarian carcinoma, and patients with malignant ascites face the poorest outcomes. It is, therefore, important to understand the effects of ascites, including the associated fluid shear stress (FSS), on phenotypic changes and therapy response, specifically FSS‐induced chemotherapy resistance and the underlying mechanisms in ovarian cancer. This study investigated the effects of FSS on response to cisplatin, a platinum‐based chemotherapy, and doxorubicin, an anthracycline, both of which are commonly used to manage advanced‐stage ovarian cancer. Consistent with prior research, OVCAR‐3 and Caov‐3 cells cultivated under FSS demonstrated significant resistance to cisplatin. Examination of the role of mitochondria revealed an increase in mitochondrial DNA copy number and intracellular ATP content in cultures grown under FSS, suggesting that changes in mitochondria number and metabolic activity may contribute to platinum resistance. Interestingly, no resistance to doxorubicin was observed under FSS, the first such observation of a lack of resistance under these conditions. Finally, this study demonstrated the potential of photodynamic priming using benzoporphyrin derivative, a clinically approved photosensitizer that localizes in part to mitochondria and endoplasmic reticula, to enhance the efficacy of cisplatin, but not doxorubicin, thereby overcoming FSS‐induced platinum resistance. [ABSTRACT FROM AUTHOR]

Mediation by multiple agents can affect the relation between neighborhood deprivation and segregation indices and ovarian cancer survival. In this paper, we examine a variety of potential clinical mediators in the association between deprivation indices (DIs) and segregation indices (SIs) with all-cause survival among women with ovarian cancer in the African American Cancer Epidemiology Study (AACES). We use novel Bayesian multiple mediation structural models to assess the joint role of mediators (stage at diagnosis, histology, diagnostic delay) combined with the DIs and SIs (Yost, ADI, Kolak's URB, ICE-income) and a set of confounders with survival. The confounder set is selected in a preliminary step, and each DI or SI is included in separate model fits. When multiple mediators are included, the total impact of DIs and SIs on survival is much reduced. Unlike the single mediator examples previously reported, the Yost, ADI and ICE-income indices do not display significant direct effects. This suggests that when important clinical mediators are included, the impact of neighborhood SES indices is significantly attenuated. It is also clear that certain behavioral and demographic measures such as physical activity, smoking, or adjusted family income do not have a significant role in survival when mediated by clinical factors. Multiple mediation via clinical and diagnostic-related measures reduces the contextual effects of neighborhood measures on ovarian cancer survival. The robust association of the Kolak URB index on survival may be due to its relevance to access to care, unlike SES-based indices whose impact was significantly reduced when important clinical mediators were included. [ABSTRACT FROM AUTHOR]

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

The article in the JNCI: Journal of the National Cancer Institute celebrates Glenn Algire's 1945 pioneering contribution to antiangiogenic therapy for cancer. Algire's observations on tumor angiogenesis laid the foundation for Judah Folkman's idea in 1971 that angiogenesis inhibitors could be used to treat cancer. The article discusses the development of VEGF inhibitors and other antiangiogenic drugs, as well as the challenges and potential future directions in antiangiogenic cancer therapy. It emphasizes the complexity of tumor angiogenesis regulation and the need to explore new strategies beyond VEGF-targeted therapies to improve efficacy in cancer treatment. [Extracted from the article]

Background Women with a family history of breast and/or ovarian cancer have an increased ovarian cancer risk. Yet it remains uncertain if common ovarian cancer risk factors—especially those that are modifiable—affect this high-risk population similarly to the general population. Methods Using the Danish and Swedish nationwide registers, we established 2 nested case-control study populations in women with a family history of breast and/or ovarian cancer (2138 ovarian cancers, 85 240 controls) and women without (10 730 ovarian cancers, 429 200 controls). The overall and histology-specific associations were assessed with conditional logistic regression. The country-specific estimates were combined based on a fixed-effect assumption. Results Multiparity, hysterectomy, tubal ligation, salpingectomy, and oral contraceptive (OC) use were associated with a reduced risk of ovarian cancer in women with and without a family history, while endometriosis and menopausal hormone therapy were associated with increased risk. Multiparity and OC use presented protective effects across all histologic subtypes except mucinous ovarian cancer, which was not associated with OC use. Menopausal hormone treatment increased the risk of serous ovarian cancer but decreased the risk of the mucinous and clear cell cancers. Endometriosis was especially related to an increased risk of endometrioid and clear cell ovarian cancer. Conclusion Factors associated with a decreased ovarian cancer risk were similar between women with and without a family history of breast and/or ovarian cancer. Given the higher baseline risk for women with a family history, special attention should be paid to risk factors like endometriosis and nulliparity in this high-risk population. [ABSTRACT FROM AUTHOR]

Background To estimate the incidence of primary peritoneal cancer after preventive bilateral oophorectomy in women with a BRCA1 or BRCA2 mutation. Methods A total of 6310 women with a BRCA1 or BRCA2 mutation who underwent a preventive bilateral oophorectomy were followed for a mean of 7.8 years from oophorectomy. The 20-year cumulative incidence of peritoneal cancer post-oophorectomy was estimated using the Kaplan-Meier method. A left-truncated Cox proportional hazards analysis was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) associated with the age at oophorectomy, year of oophorectomy, and family history of ovarian cancer as well as hormonal and reproductive risk factors. Results Fifty-five women developed primary peritoneal cancer (n = 45 in BRCA1 , 8 in BRCA2 , and 2 in women with a mutation in both genes). Their mean age at oophorectomy was 48.9 years. The annual risk of peritoneal cancer was 0.14% for women with a BRCA1 mutation and 0.06% for women with a BRCA2 mutation. The 20-year cumulative risk of peritoneal cancer from the date of oophorectomy was 2.7% for BRCA1 carriers and 0.9% for BRCA2 mutation carriers. There were no peritoneal cancers in BRCA1 carriers who had the operation before age 35 or in BRCA2 carriers who had the operation before age 45. Conclusions For BRCA1 mutation carriers, the annual risk of peritoneal cancer for 20 years post-oophorectomy is 0.14% per year. The risk is lower for BRCA2 carriers (0.06% per year). [ABSTRACT FROM AUTHOR]

Background Ovarian cancer is among the leading causes of gynecologic cancer-related death. Past ovarian cancer screening trials using combination of cancer antigen 125 testing and transvaginal ultrasound failed to yield statistically significant mortality reduction. Estimates of ovarian cancer sojourn time—that is, the period from when the cancer is first screen detectable until clinical detection—may inform future screening programs. Methods We modeled ovarian cancer progression as a continuous time Markov chain and estimated screening modality–specific sojourn time and sensitivity using a Bayesian approach. Model inputs were derived from the screening arms (multimodal and ultrasound) of the UK Collaborative Trial of Ovarian Cancer Screening and the Prostate, Lung, Colorectal and Ovarian cancer screening trials. We assessed the quality of our estimates by using the posterior predictive P value. We derived histology-specific sojourn times by adjusting the overall sojourn time based on the corresponding histology-specific survival from the Surveillance, Epidemiology, and End Results Program. Results The overall ovarian cancer sojourn time was 2.1 years (posterior predictive P value = .469) in the Prostate, Lung, Colorectal and Ovarian studies, with 65.7% screening sensitivity. The sojourn time was 2.0 years (posterior predictive P value = .532) in the United Kingdom Collaborative Trial of Ovarian Cancer Screening's multimodal screening arm and 2.4 years (posterior predictive P value = .640) in the ultrasound screening arm, with sensitivities of 93.2% and 64.5%, respectively. Stage-specific screening sensitivities in the Prostate, Lung, Colorectal and Ovarian studies were 39.1% and 82.9% for early-stage and advanced-stage disease, respectively. The histology-specific sojourn times ranged from 0.8 to 1.8 years for type II ovarian cancer and 2.9 to 6.6 years for type I ovarian cancer. Conclusions Annual screening is not effective for all ovarian cancer subtypes. Screening sensitivity for early-stage ovarian cancers is not sufficient for substantial mortality reduction. [ABSTRACT FROM AUTHOR]

The Nod-Like Receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome plays a role in regulating inflammatory signaling and is a well-established contributor to pyroptotic cell death. It has been investigated extensively in cancer but there remains limited evidence of its role within ovarian cancer (OC). Bioinformatic investigation of gene expression data has highlighted that higher expression of NLRP3 and genes associated with the NLRP3 complex appear to be positively correlated with OC and may also have prognostic significance. However, heterogeneity exists within the results and experimental data is limited and contradictory. If the NLRP3 inflammasome is to be exploited as a therapeutic target, further laboratory-based investigation is required to determine its role in cancer. Furthermore, its relationship with clinically important characteristics such as histopathological subtype may be of key significance in developing targeted therapies towards specific cohorts of patients. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptors (PPARs), including PPAR-α, PPAR-β/δ, and PPAR-γ, are involved in various cellular responses, including metabolism and cell proliferation. Increasing evidence suggests that PPARs are closely associated with tumorigenesis and metastasis. However, the exact role of PPARs in energy metabolism and cancer stem cell (CSC) proliferation remains unclear. This study investigated the role of PPARs in energy metabolism and tumorigenesis in ovarian CSCs. The expression of PPARs and fatty acid consumption as an energy source increased in spheroids derived from A2780 ovarian cancer cells (A2780-SP) compared with their parental cells. GW6471, a PPARα inhibitor, induced apoptosis in A2780-SP. PPARα silencing mediated by small hairpin RNA reduced A2780-SP cell proliferation. Treatment with GW6471 significantly inhibited the respiratory oxygen consumption of A2780-SP cells, with reduced dependency on fatty acids, glucose, and glutamine. In a xenograft tumor transplantation mouse model, intraperitoneal injection of GW6471 inhibited in vivo tumor growth of A2780-SP cells. These results suggest that PPARα plays a vital role in regulating the proliferation and energy metabolism of CSCs by altering mitochondrial activity and that it offers a promising therapeutic target to eradicate CSCs. [ABSTRACT FROM AUTHOR]

Gynecological cancer is a term referring to malignancies that typically involve ovarian, cervical, uterine, vaginal, and vulvar cancer. Combined, these cancers represent major causes of morbidity and mortality in women with a heavy socioeconomic impact. MiRNAs are small non-coding RNAs that are intensively studied in the field of cancer and changes in them have been linked to a variety of processes involved in cancer that range from tumorigenesis to prognosis and metastatic potential. This review aims to summarize the existing literature that has linked miRNAs with each of the female malignancies as potential biomarkers in diagnosis (circulating miRNAs), in tumor histology and prognosis (as tissue biomarkers), and for local (lymph node) and distant metastatic disease. [ABSTRACT FROM AUTHOR]

Neurotensin (NT) is a peptide involved in digestion, neuromodulation, and cancer progression. NT and its receptors (NTR1 and SORT1 mainly) have been widely studied in oncology. Data show that NT expression is under the control of sex steroid hormones, in particular estradiol. We focused on its involvement in three main female hormone-sensitive cancers, breast, ovarian, and endometrial cancer, in a narrative review. NT, NTR1, and SORT1 are mostly expressed in these three cancers, and their involvement in oncologic processes such as proliferation and invasion seems to match, as does their impact on prognosis for most. The development of NT receptor-targeted therapies, including theranostics and radioligand treatments, presents a promising avenue for personalized cancer treatment. [ABSTRACT FROM AUTHOR]

A 54-year-old patient presented in our clinic with pressure in the upper abdomen, dyspnea and abdominal distension. The clinical examination showed pleural effusion, ascites and an enlarged axillary lymph node on the right side. In gynecological sonography ascites, an ovarian cyst and peritoneal carcinosis in the pouch of Douglas were detected, which were potentially indicative of ovarian cancer. A staging laparoscopy was performed to confirm the diagnosis of ovarian cancer and to evaluate operability. Intraoperatively white milky ascites, white-yellow marbling of the liver and white stipple bedding on the diaphragm and liver were detected. The ovaries and the fallopian tubes were tumorously enlarged. Biopsies were taken from the right fimbrial funnel, the liver around the falciform ligament and the diaphragm. Histology of all abdominal biopsies and the axillary lymph node revealed high lymphatic infiltration matching a stage III B-cell-lymphoma. The patient was transferred to the hemato-oncological department for further therapy. Six cycles of cytostatic therapy with R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, prednisone) were initiated. The patient is doing well and in stable disease 6 months after completion of cytotoxic therapy. This case report presents a rare case of manifestation of an extra nodal B-cell-lymphoma with abdominal presentation that mimicked ovarian cancer. [ABSTRACT FROM AUTHOR]

Several soluble factors secreted by the stromal cells and cancer cells within the tumor microenvironment facilitate the progression and invasiveness of ovarian cancer. In ovarian cancer cells, lysophosphatidic acid (LPA) modulates the transcriptome profile and promotes cell invasiveness by the downregulation of autophagy. Here, we further elucidate this mechanism by focusing on the molecular and cellular events regulating autophagy. Transcriptomic and Western blotting analyses revealed NKX3-2, a transcriptional factor, to be among the genes hyperexpressed in LPA-stimulated ovarian cancer cells. Bioinformatic analyses revealed that in ovarian cancer patients, the expression of NKX3-2 positively correlates with genes involved in cell motility and migration, while it negatively correlates with macromolecular catabolic pathways. In various ovarian cancer cell lines, NKX3-2 silencing abrogated LPA-induced cell migration. Mechanistically, this effect is linked to the restoration of the HDAC6-mediated relocation of the lysosomes in the para-golgian area, and this results in an increase in autolysosome formation and the overall upregulation of autophagy. Silencing the expression of ATG7 or BECN1, two autophagy genes, rescued the migratory phenotype of the NKX3-2-silenced ovarian cancer cells. Taken together, these data reveal the mechanism by which the LPA-NKX3-2 axis promotes the invasiveness of ovarian cancer cells and supports the possibility of targeting NKX3-2 to reduce the migratory capacity of cancer cells in response to a permissive microenvironment. [ABSTRACT FROM AUTHOR]

Birds, especially the chick and hen, have been important biomedical research models for centuries due to the accessibility of the avian embryo and the early discovery of avian viruses. Comprehension of avian tumor virology was a milestone in basic cancer research, as was that of non-viral genesis, as it enabled the discovery of oncogenes. Furthermore, studies on avian viruses provided initial insights into Kaposi's sarcoma and EBV-induced diseases. However, the role of birds in human carcinogenesis extends beyond the realm of virology research. Utilization of CAM, the chorioallantoic membrane, an easily accessible extraembryonic tissue with rich vasculature, has enabled studies on tumor-induced angiogenesis and metastasis and the efficient screening of potential anti-cancer compounds. Also, the chick embryo alone is an effective preclinical in vivo patient-derived xenograft model, which is important for the development of personalized therapies. Furthermore, adult birds may also closely resemble human oncogenesis, as evidenced by the laying hen, which is the only animal model of a spontaneous form of ovarian cancer. Avian models may create an interesting alternative compared with mammalian models, enabling the creation of a relatively cost-effective and easy-to-maintain platform to address key questions in cancer biology. [ABSTRACT FROM AUTHOR]

Simple Summary: Tubo-ovarian cancers are associated with high mortality as they are often not detected until a late stage. Early diagnosis is associated with better patient outcomes, but there are currently no effective screening measures. We explore whether an optical imaging catheter can detect early or occult lesions in the fallopian tubes. This device collects three-dimensional structural images of tissue through optical coherence tomography (OCT) simultaneously with functional imaging through autofluorescence imaging (AFI). We image ex vivo fallopian tubes from n = 28 patients (n = 7 cancer patients) and explore eleven imaging biomarkers for their ability to distinguish early or occult disease. We find that high-grade serous ovarian carcinomas can be visually distinguished through this approach, and that there are several quantitative changes within the area of lesion and throughout the specimen that can be measured through these imaging biomarkers. We conclude that this approach shows promise and merits further investigation of its diagnostic potential. Background: There are currently no effective screening measures to detect early or occult tubo-ovarian cancers, resulting in late-stage detection and high mortality. This work explores whether an optical imaging catheter can detect early-stage tubo-ovarian cancers or precursor lesions where they originate in the fallopian tubes. Methods: This device collects co-registered optical coherence tomography (OCT) and autofluorescence imaging (AFI). OCT provides three-dimensional assessment of underlying tissue structures; autofluorescence imaging provides functional contrast of endogenous fluorophores. Ex vivo fallopian tubes (n = 28; n = 7 cancer patients) are imaged; we present methods for the calculation of and analyze eleven imaging biomarkers related to fluorescence, optical attenuation, and OCT texture for their potential to detect tubo-ovarian cancers and other lesions of interest. Results: We visualize folded plicae, vessel-like structures, tissue layering, hemosiderin deposits, and regions of fibrotic change. High-grade serous ovarian carcinoma appears as reduced autofluorescence paired with homogenous OCT and reduced mean optical attenuation. Specimens containing cancerous lesions demonstrate a significant increase in median autofluorescence intensity and decrease in Shannon entropy compared to specimens with no lesion. Non-cancerous specimens demonstrate an increase in optical attenuation in the fimbriae when compared to the isthmus or the ampulla. Conclusions: We conclude that this approach shows promise and merits further investigation of its diagnostic potential. [ABSTRACT FROM AUTHOR]

Simple Summary: Nutritional assessment indicators have been recognized as useful in predicting treatment-related adverse events. In maintenance therapy with PARP inhibitors in ovarian cancer, treatment discontinuation due to treatment-related adverse events has been reported, but factors predicting these events are not identified. Our study suggested that PNI and mGPS can predict the risk of treatment discontinuation due to PARP inhibitor-related adverse events before starting maintenance therapy. This insight opens avenues for more personalized treatment plans, potentially improving patient outcomes. Background: Nutritional status is an important factor influencing toxicity of treatment. Nutritional assessment indicators such as the Prognostic Nutritional Index (PNI), Controlling Nutritional Status (CONUT) score and modified Glasgow Prognostic Score (mGPS) have been reported to be associated with treatment-related adverse events (AEs) for various malignancies. However, there are no reports investigating the relationship between nutritional status and AEs from poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi), which are widely used in recent years as maintenance therapy for ovarian cancer. Objective: The primary objective was to investigate the usefulness of nutritional assessment indicators in predicting treatment discontinuation due to AEs from PARPi. Methods: This multicenter retrospective study included patients diagnosed with ovarian cancer who received maintenance therapy with PARPi from January 2018 to December 2023. PNI, CONUT score, and mGPS were calculated based on hematological parameters measured within 7 days before the start of PARPi therapy. Results: A total of 272 patients received maintenance therapy with PARPi during the period, but due to the absence of the blood collection of albumin levels within one week or other exclusion criteria, 71 patients were finally included in this analysis. AEs were seen in 59 patients (83.1%), including 25 (35.2%) severe events (grade ≥3 in Common Terminology Criteria for Adverse Events v5.0). Eighteen patients (25.4%) discontinued treatment due to PARPi-related AEs. Low PNI (<48.44) and high mGPS (≥1) were predictors of treatment discontinuation in both univariate and multivariate analyses. CONUT was not a significant predictor in this study. Conclusions: Our study suggested that PNI and mGPS can predict the risk of treatment discontinuation due to PARPi-related AEs before starting maintenance therapy. This insight opens avenues for more personalized treatment plans, potentially improving patient outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with ovarian cancer have elevated platelet counts and an increased risk of dying from blood clots. It is logical that this increased blood clot risk is caused by the increased numbers of platelets. However, to develop prevention for thrombosis in patients with ovarian cancer, it is important to know if the platelets in patients with ovarian cancer are different from the platelets in healthy individuals. In this study, we demonstrated through carefully controlled experiments that increased platelet aggregation, which is necessary for clotting, is caused by both the elevated numbers and altered behavior of platelets in patients with ovarian cancer. Furthermore, we show that the platelets from patients with ovarian cancer have elevated levels of platelet activation markers compared to healthy patients. Future experiments will evaluate why platelets in patients with ovarian cancer are more prone to clotting and will study medications that could reduce the increased blood clot risk. Background: Patients with ovarian cancer have high platelet counts, which correlate with disease burden, incidence, and lethality of blood clots (thrombosis). We hypothesized that elevated aggregation is associated with both increased platelet number and altered behavior of platelets in patients with ovarian cancer. Methods: Healthy controls and patients with suspected or diagnosed ovarian cancer were evaluated for complete blood counts. To evaluate the effects of platelet count versus platelet behavior, equal platelet-rich plasma (PRP) volumes versus equal platelet numbers were used in platelet aggregation assays. Arachidonic acid, adenosine diphosphate, and collagen platelet agonists were used to induce aggregation. Volunteers were grouped into healthy controls (23), benign/borderline cases (7), and cancer cases (25 ovarian, 1 colorectal, and 2 endometrial). Results: The rate and amount of platelet aggregation were higher in patients compared to healthy controls regardless of whether the same platelet number or PRP volume was used. Compared to healthy controls, patients with untreated ovarian cancer exhibited high levels of platelet activation markers, P-selectin (27.06 vs. 31.06 ng/mL, p = 0.03), and beta-thromboglobulin (3.073 vs. 4.091 µg/mL, p = 0.02) in their plasma. The significance of the elevation and its correlations with platelet number or PRP volume varied depending on the agonist. Platelet (305.88 vs. 134.12, p < 0.0001) and white blood cell (8.459 vs. 5.395, p < 0.01) counts (×109/L) were elevated pre-chemotherapy and decreased post-chemotherapy, respectively. Conclusions: Elevated platelet aggregation is caused by both altered platelet number and behavior in patients with ovarian cancer. These results support the study of antiplatelet agents for thrombosis prevention in these patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian, fallopian tube, and primary peritoneal cancers are often diagnosed at advanced stages due to nonspecific symptoms. This makes early detection challenging and impacts patient outcomes. This study sought to clarify the role of HE4 and CA125 in the follow-up of ovarian cancer patients and, potentially, improve early detection and management of recurrences. By monitoring changes in these markers over time, the researchers hoped to find a more reliable way to identify cancer recurrence before it is visible on CT scans. The findings suggest that tracking increases in these markers can predict a relapse earlier than CT scans, potentially allowing for earlier treatment. Further research is required to refine follow-up strategies and enhance outcomes for ovarian cancer patients. Background: Ovarian, fallopian tube, and primary peritoneal cancers often share clinical characteristics and are typically diagnosed at advanced stages due to nonspecific symptoms. The utility of tumor markers, particularly CA125 and HE4, in the diagnosis and follow-up of these cancers remains an area of active investigation. Objectives: The CEEGOG (Central and Eastern European Gynecologic Oncology Group) OX-01 study aimed to evaluate HE4's role alongside CA125 in follow-up for advanced-stage ovarian, fallopian tube, and primary peritoneal cancers. It assessed the potential for detecting recurrence using marker elevation and imaging methods, examining the necessity of dynamic monitoring and current cut-off values' accuracy for early relapse detection. Methods: In this multicenter prospective cohort study, 117 eligible patients with Stage III–IV cancers were included. Patients had elevated CA125 or HE4 at diagnosis and achieved complete remission after first-line treatment. HE4 and CA125 levels were monitored every 3–4 months in the first two years and every six months thereafter. CT scans were performed if markers exceeded set thresholds or increased by over 20%. Results: During a median follow-up of 13.7 months, 73% of patients relapsed. Median HE4 levels were significantly higher in relapsed patients. A 10 IU/mL increase from baseline in CA125 had a sensitivity of 83% and specificity of 93%, while a 15 pmol/L increase in HE4 had a sensitivity of 74% and specificity of 92% for predicting relapse up to three months before CT scan detection. Conclusions: The study found that dynamic changes in HE4 and CA125 levels, rather than predefined cut-off values, are crucial for early relapse detection. These markers may offer a significant lead time over imaging, potentially enabling earlier intervention. Further research is needed to validate these findings. [ABSTRACT FROM AUTHOR]