Characterization of latently infected EBV+ antibody-secreting B cells isolated from ovarian tumors and malignant ascites.

Introduction: Intra-tumoral B cells mediate a plethora of immune effector mechanisms with key roles in anti-tumor immunity and serve as positive prognostic indicators in a variety of solid tumor types, including epithelial ovarian cancer (EOC). Several aspects of intra-tumoral B cells remain unclear, such as their state of activation, antigenic repertoires, and capacity to mature into plasma cells. Methods: B lymphocytes were isolated from primary EOC tissue and malignant ascites and were maintained in cell culture medium. The stably maintained cell lines were profiled with flow cytometry and B cell receptor sequencing. Secreted antibodies were tested with a human proteome array comprising more than 21,000 proteins, followed by ELISA for validation. Originating tumor samples were used for spatial profiling with chip cytometry. Results: Antibody-secreting B lymphocytes were isolated from the ovarian tumor microenvironment (TME) of four different EOC patients. The highly clonal cell populations underwent spontaneous immortalization in vitro, were stably maintained in an antibody-secreting state, and showed presence of Epstein-Barr viral (EBV) proteins. All originating tumors had high frequency of tumor-infiltrating B cells, present as lymphoid aggregates, or tertiary lymphoid structures. The antigens recognized by three of the four cell lines are coil-coil domain containing protein 155 (CCDC155), growth factor receptor-bound protein 2 (GRB2), and pyruvate dehydrogenase phosphatase2 (PDP2), respectively. Anti-CCDC155 circulating IgG antibodies were detected in 9 of 20 (45%) of EOC patients' sera. Tissue analyses with multiparameter chip cytometry shows that the antibodies secreted by these novel human B cell lines engage their cognate antigens on tumor cells. Discussion: These studies demonstrate that within the tumor-infiltrating lymphocyte population in EOC resides a low frequency population of antibody-secreting B cells that have been naturally exposed to EBV. Once stably maintained, these novel cell lines offer unique opportunities for future studies on intratumor B cell biology and new target antigen recognition, and for studies on EBV latency and/or viral reactivation in the TME of non-EBV related solid tumors such as the EOC.

The risk of ovarian cancer in hormone replacement therapy users: a systematic review and meta-analysis.

Background: With the increasing use of hormone replacement therapy (HRT), there is a need to understand its impact on the occurrence of female malignant tumors. This systematic review and meta-analysis aimed to assess the risk of ovarian cancer associated with HRT and its related risk factors. Methods: PUBMED, OVID, Embase, Cochrane, and Web of Science were searched from 1980 to April 2022 to identify studies on the risk of ovarian cancer and hormone replacement therapy. The random-effects model was used to estimate the pooled risk of HRT in ovarian cancer, both in cohort studies and case-control studies. Additionally, the analysis examined the outcomes associated with different types of estrogen plus progesterone regimens. Meta-regression and sensitive analysis were performed to evaluate the heterogeneity. Results: 21 cohort studies (involving 15,313 cases and 4,564,785 participants) and 30 case-control studies (including 18,738 cases and 57,747 controls) were analyzed. The pooled risks of ovarian cancer for HRT users were 1.20 (95% confidence interval [CI] 1.01-1.44) from cohort studies and 1.13 (95%CI 1.04-1.22) from case-control studies. However, after restricting the study period to recent decades, the significant results indicating a higher risk disappeared in cohort studies conducted after 2010 and in case-control studies conducted after 2006. Furthermore, the continuous use of estrogen-progesterone replacement therapy (EPRT) was associated with a risk comparable to that of sequential use. Subgroup analysis showed that both estrogen replacement treatment (ERT) and EPRT had minor risks; The risk further increased with prolonged exposure time, particularly for durations exceeding 10 years. Additionally, serous ovarian cancer appeared to be more susceptible than other pathological types. Conclusion: The risk of ovarian cancer associated with HRT has been decreasing over time. However, ERT may increase this risk, particularly when used for an extended period. It is recommended that long-time users consider continuous EPRT as a safer alternative. Systematic review registration: www.crd.york.ac.uk/prospero/, identifier CRD42022321279.

Investigation of Polymorphisms in Global Genome Repair Genes in Patients With Ovarian Cancer in the Turkish Population.

INTRODUCTION: Ovarian cancer (OC) poses significant challenges due to its high mortality rate, particularly in advanced stages where symptoms may not be evident. DNA repair mechanisms, including nucleotide excision repair (NER), are crucial in maintaining genomic stability and preventing cancer. This study focuses on exploring the role of two NER-related genes, Xeroderma Pigmentosum Complementation Group C (XPC) and DNA Damage Binding Protein 2 (DDB2), in OC susceptibility. OBJECTIVES: This study aims to investigate the association between variations in two NER-related genes, XPC rs2228001 and DDB2 rs830083, among a cohort of Turkish individuals with OC and control subjects. METHODS: Genotyping of XPC rs2228001 and DDB2 rs830083 was performed on 103 OC patients and 104 control subjects from the Turkish population using the Fast Real-Time 7500 PCR platform from Applied Biosystems. RESULTS: Individuals with the homozygous AA genotype of XPC rs2228001 exhibited a reduced likelihood of developing OC (OR 0.511; 95% CI 0.261 - 1.003; P-value 0.049), whereas those with the CC variant faced an elevated risk (OR = 2.32, 95% CI = 1.75-3.08; P-value 0.035). The presence of the A allele was associated with decreased OC occurrence (P-value = 0.035). Similarly, for DDB2 rs830083, individuals with the homozygous CG genotype had a diminished risk of OC (P-value 0.036), compared to those with the GG polymorphism (OR 1.895; 95% CI 1.033 - 3.476; P-value 0.038). Furthermore, the presence of the C allele was associated with a 1.89-fold decrease in the likelihood of OC. CONCLUSION: These findings shed light on the genetic factors influencing OC susceptibility, emphasizing the importance of DNA repair systems in disease. Further research in larger and more diverse populations is warranted to validate these findings, facilitating precise risk assessment, and potentially guiding tailored treatment strategies for OC patients.

Ovarian cancer is a serious disease with a high mortality rate, especially in its advanced stages when symptoms are often not obvious. Our cells have mechanisms to repair DNA damage and maintain stability in our genetic material. Two genes involved in one of these repair mechanisms, called nucleotide excision repair (NER), are Xeroderma Pigmentosum Complementation Group C (XPC) and DNA Damage Binding Protein 2 (DDB2). This study investigates how variations in these genes may influence the risk of developing ovarian cancer. Understanding these genetic factors could lead to improved methods for diagnosing and treating this challenging disease.

The anthraquinone derivative KA-4s reduces energy metabolism and enhances the sensitivity of ovarian cancer cells to cisplatin.

Ovarian cancer is the leading cause of death from female gynecological cancers. Cisplatin (DDP) is a first-line drug for ovarian cancer treatment. Due to DDP resistance, there is an urgent need for novel therapeutic drugs with improved antitumor activity. AMPK-mediated metabolic regulatory pathways are related to tumor drug resistance. Our study aimed to determine the relationship between reversing DDP resistance with the anthraquinone derivative KA-4s and regulating AMPK energy metabolism in ovarian cancer. The results showed that KA-4s inhibited the proliferation of ovarian cancer cells. The combination of KA-4s with DDP effectively promoted drug-resistant ovarian cancer cell apoptosis and inhibited cell migration and invasion. Moreover, KA-4s decreased the intracellular ATP level and increased the calcium ion level, leading to AMPK phosphorylation. Further studies suggested that the AMPK signaling pathway may be involved in the mechanism through which KA-4s reduce drug resistance. KA-4s inhibited mitochondrial respiration and glycolysis; downregulated the glucose metabolism-related proteins GLUT1 and GLUT4; the lipid metabolism-related proteins SREBP1 and SCD1; and the drug resistance-related proteins P-gp, MRP1, and LRP. The inhibitory effect of KA-4s on GLUT1 was confirmed by the application of the GLUT1 inhibitor BAY-876. KA-4s combined with DDP significantly increased the expression of p-AMPK and reduced the expression of P-gp. In a xenograft model of ovarian cancer, treatment with KA-4s combined with DDP reduced energy metabolism and drug resistance, inducing tumor apoptosis. Consequently, KA-4s might be evaluated as a new agent for enhancing the chemotherapeutic efficacy of treatment for ovarian cancer.

Real-life clinical benefit of oral metronomic cyclophosphamide administration in elderly and heavily pretreated epithelial ovarian cancer patients.

PURPOSE: Oral metronomic cyclophosphamide (OMC) implicates the daily administration of low doses of chemotherapy. Its antitumor activity combined with an oral administration route and a good toxicity profile makes OMC an attractive option for heavily pretreated patients. We retrospectively evaluated OMC's clinical benefit and objective response in recurrent ovarian cancer patients. METHODS: This is a retrospective observational study involving patients treated with OMC (50 mg daily) from 2017 to 2022 at the Academic Division Gynaecology, Mauriziano Hospital, Torino, Italy. Clinical benefit assessment included CA125 response, radiological response, and reported symptomatic improvement. Toxicities were reported using Common Terminology Criteria for Adverse Events version 5.0. RESULTS: Thirty-eight patients (average age 72, range 49-88) were included. 90% had FIGO stage III/IV at diagnosis and 64% underwent ≥ 3 previous lines of chemotherapy. Before OMC, 79% had ECOG 1 or 2. 8.6% of patients had a partial response (PR), and 40% a stable disease (SD). Median duration of response was 7.4 months. After 3 months on OMC, 51% experienced symptom improvement, and 53.3% experienced Ca125 reduction or stabilization. 66.7% of patients older than 75 responded to treatment; in 40% of cases, responses lasted ≥ 6 months (p = 0.08). No G3-4 hematological toxicities occurred. Nausea and fatigue G1-G2 were reported in 5 (13%) and 13 (34%) cases, respectively. CONCLUSION: OMC is a feasible therapeutic option for recurrent ovarian cancer, providing satisfying clinical responses with a good toxicity profile, even in elderly and heavily pretreated patients with a suboptimal performance status.

Pregnancy after advanced ovarian cancer with spontaneous uterine rupture in second trimester: A case report and review of the literature.

Fertility-preserving surgery (FPS) in advanced ovarian cancer (AOC) is extremely rare and consequently, information about the pregnancies of these patients is anecdotal. Therefore, management of the pregnancy after AOC is challenging, especially if an unexpected situation arises. A 31-year-old nulliparous woman was admitted to our tertiary hospital in the 18th week of twin pregnancy with sudden severe abdominal pain. Her medical history included a low-grade AOC stage IIIc diagnosed 2 years before pregnancy and treated by debulking FPS and systemic therapy with carboplatin/paclitaxel and bevacizumab. Clinical examination described normal vital signs and peritoneal irritation without any vaginal discharge. Sonography revealed free fluid in the pouch of Douglas and intact twin pregnancy. Laboratory work showed elevated leukocytes with neutrophilia. To evaluate appendicitis magnetic resonance imaging of the abdomen was indicated. This revealed a uterine rupture with the now extra-cavitary position of the twins. Simultaneously, the patient's symptoms deteriorated, and emergency surgery was necessary where hemoperitoneum with avital fetuses were present. Despite excessive blood loss the uterus could be repaired and preserved. Previous resection of the uterine serosa during her debulking FPS, administration of bevacizumab affecting smooth muscles, and overstretching the uterus in the twin pregnancy were considered as possible risk factors for the presenting uterine rupture. Pregnancy after AOC is possible but should be monitored closely, especially due to the hidden long-term consequences of its therapy. In the differential diagnosis of sudden abdominal pain during pregnancy uterine rupture should be considered even in patients with an unscared uterus.

Cancer-associated adipocytes in the ovarian cancer microenvironment.

The tumor microenvironment (TME) plays a critical role in high energy metabolism during tumorigenesis, progression and metastasis. Among them, adipocytes, as an important component of the TME, can transform into cancer-associated adipocytes (CAAs) through dedifferentiation via interactions with tumor cells. These CAAs provide nutrients, growth factors, cytokines and metabolites to the tumor and later transdifferentiate into other stromal cells at a later stage to alter tumor growth, metastasis and the drug response and ultimately influence the treatment and prognosis of ovarian cancer. This review outlines the physiological functions of CAAs and discusses the progress in the use of CAAs as therapeutic targets in ovarian cancer.

Identification and Validation of Prognostic Markers for Endometriosis-Associated Ovarian Cancer.

Background: Growing evidence suggests that endometriosis (EMs) is a risk factor for endometriosis-associated ovarian cancer (EAOC). The aim was to identify and validate gene signatures associated with EMs that may serve as potential biomarkers for evaluating the prognosis of patients with EAOC. Methods: The data of EMs and control samples was obtained from GEO database. The weighted gene co-expression network analysis (WGCNA) identified modular genes significantly associated with EMs. The KEGG pathway and GO functional enrichment analyses were also performed. Univariate Cox regression analysis was conducted to screen marker genes associated with the prognosis of EAOC patients. Finally, RT-qPCR and immunohistochemical verified the expression of ADAMTS19 and TUBB in normal ovarian and EAOC tissues, and the biological functions of ADAMTS19 and TUBB were preliminarily explored by CCK8 and Transwell assays. Results: The WGCNA identified 2 co-expression modules, which in total included 615 genes, and 7642 differentially expressed genes (DEGs) were detected thorough analysis of the EAOC dataset. After taking the intersection of 615 modular genes and 7642 DEGs, 214 shared genes were obtained, and univariate COX regression analysis pointed 10 genes associated with the prognosis of EAOC. Moreover, it was demonstrated by RT-qPCR and immunohistochemical staining experiments that ADAMTS19 expression was elevated, while TUBB expression was reduced in EAOC compared with normal ovarian cells and tissues. Finally, cell experiments revealed that ADAMTS19 promoted the proliferation and invasion in EAOC cells, while overexpression of TUBB inhibited these processes. Conclusions: The present study identified and validated new EMs-associated gene markers, which could serve as potential biomarkers for assessing the prognostic risk of EAOC patients. In addition, some of these genes may have significance as novel therapeutic targets and could be used to guide clinical applications.

SEfficacy and safety of apatinib in the treatment of patients with platinum­resistant ovarian cancer: A systematic review and network meta­analysis.

At present, the optimal therapeutic approach for the treatment of platinum-resistant recurrent ovarian cancer remains to be fully elucidated. The present systematic review and network meta-analysis aimed to elucidate the relative efficacy and safety of apatinib, administered either as monotherapy or in conjunction with chemotherapy, compared with chemotherapy alone, for the treatment of platinum-resistant recurrent ovarian cancer. The PubMed, Embase and Wanfang Data electronic databases were searched, where the search spanned from the conception of the databases until April 2023. A quality evaluation was conducted and R software was used for network meta-analysis. Following inclusion and exclusion criteria screening, the present analysis included 17 clinical trials, combining data from 1,228 patients with platinum-resistant recurrent ovarian cancer categorized into the following three treatment cohorts: i) 555 patients who received apatinib plus chemotherapy; ii) 229 patients who received apatinib alone; and iii) 444 patients who underwent conventional chemotherapy. Results of the present study demonstrated that the co-administration of apatinib with either tegiol [odds ratio (OR), 2.54; 95% CI, 1.06-6.11] or etoposide (OR, 2.12; 95% CI, 1.20-3.74) significantly improved the objective response rate (ORR) compared with that following apatinib monotherapy. By contrast, gemcitabine monotherapy resulted in inferior ORR efficacy compared with that following apatinib (OR, 0.47; 95% CI, 0.23-0.95). In addition, combinations of apatinib with etoposide (OR, 1.32; 95% CI, 1.06-1.64) or paclitaxel (OR, 1.52; 95% CI, 1.04-2.23) demonstrated a significantly improved disease control rates (DCR) compared with those following apatinib alone. According to the area under the cumulative ranking analysis, apatinib and paclitaxel in combination was the most efficacious treatment modality in terms of DCR. In terms of safety, the incidence of adverse events, such as hand-foot syndrome [relative risk (RR), 4.23; 95% CI, 1.80-9.95] and hypertension (RR, 4.80; 95% CI, 1.53-15.05), was found to be significantly higher in patients treated with apatinib-containing therapies, compared with those treated with chemotherapy alone. Consequently, the present meta-analysis highlighted the potential of apatinib, particularly in combination with chemotherapy, as a therapeutic strategy for patients with platinum-resistant recurrent ovarian cancer.

Correlation between cancer-related cognitive impairment and resting cerebral glucose metabolism in patients with ovarian cancer.

Background: An increasing number of research have applied neuroimaging techniques to explore the potential neurobiological mechanism of Cancer-related cognitive impairment (CRCI). Purpose: To explore the correlation between resting brain glucose metabolism and CRCI using 18F-FDG PET/CT in ovarian cancer (OC) patients. Methods: From December 2021 to March 2022, 38 patients with OC were selected as the study group, and 38 healthy women of the same age (±1 year) who underwent routine physical examination using PET/CT were selected as the control group. Patients received further assessment with the Montreal Cognitive Assessment Scale (MoCA) and Perceived Deficit Questionnaire (PDQ). Independent sample t-test and Spearman correlation were conducted for data analysis. Results: The resting brain glucose metabolism in the OC group was significantly lower than in the healthy controls. 60.52 % patients had neuropsychological impairment and retrospective memory were the most serious perceived cognitive impairments. The resting brain glucose metabolism in OC patients did not significantly correlate with neuropsychological performance but had significant positive correlation with subjective cognitive evaluation. Discussion: Resting glucose metabolism was low in OC patients and associated with subjective cognitive impairment but not objective neuropsychological test results. 18F-FDG PET/CT can be used to evaluate brain function in OC patients and provide reliable imaging indicators for early recognition of and intervention for changes in cognitive function.

AI-based automated segmentation for ovarian/adnexal masses and their internal components on ultrasound imaging.

Purpose: Segmentation of ovarian/adnexal masses from surrounding tissue on ultrasound images is a challenging task. The separation of masses into different components may also be important for radiomic feature extraction. Our study aimed to develop an artificial intelligence-based automatic segmentation method for transvaginal ultrasound images that (1) outlines the exterior boundary of adnexal masses and (2) separates internal components. Approach: A retrospective ultrasound imaging database of adnexal masses was reviewed for exclusion criteria at the patient, mass, and image levels, with one image per mass. The resulting 54 adnexal masses (36 benign/18 malignant) from 53 patients were separated by patient into training (26 benign/12 malignant) and independent test (10 benign/6 malignant) sets. U-net segmentation performance on test images compared to expert detailed outlines was measured using the Dice similarity coefficient (DSC) and the ratio of the Hausdorff distance to the effective diameter of the outline ( R HD - D ) for each mass. Subsequently, in discovery mode, a two-level fuzzy c-means (FCM) unsupervised clustering approach was used to separate the pixels within masses belonging to hypoechoic or hyperechoic components. Results: The DSC (median [95% confidence interval]) was 0.91 [0.78, 0.96], and R HD - D was 0.04 [0.01, 0.12], indicating strong agreement with expert outlines. Clinical review of the internal separation of masses into echogenic components demonstrated a strong association with mass characteristics. Conclusion: A combined U-net and FCM algorithm for automatic segmentation of adnexal masses and their internal components achieved excellent results compared with expert outlines and review, supporting future radiomic feature-based classification of the masses by components.

Single-cell RNA sequencing in ovarian cancer: revealing new perspectives in the tumor microenvironment.

Single-cell sequencing technology has emerged as a pivotal tool for unraveling the complexities of the ovarian tumor microenvironment (TME), which is characterized by its cellular heterogeneity and intricate cell-to-cell interactions. Ovarian cancer (OC), known for its high lethality among gynecologic malignancies, presents significant challenges in treatment and diagnosis, partly due to the complexity of its TME. The application of single-cell sequencing in ovarian cancer research has enabled the detailed characterization of gene expression profiles at the single-cell level, shedding light on the diverse cell populations within the TME, including cancer cells, stromal cells, and immune cells. This high-resolution mapping has been instrumental in understanding the roles of these cells in tumor progression, invasion, metastasis, and drug resistance. By providing insight into the signaling pathways and cell-to-cell communication mechanisms, single-cell sequencing facilitates the identification of novel therapeutic targets and the development of personalized medicine approaches. This review summarizes the advancement and application of single-cell sequencing in studying the stromal components and the broader TME in OC, highlighting its implications for improving diagnosis, treatment strategies, and understanding of the disease's underlying biology.

Outcomes of minimal residual disease at upfront debulking surgery compared with complete cytoreduction after neoadjuvant chemotherapy.

OBJECTIVE: The aim of this study was to compare surgical complexity, post-operative complications, and survival outcomes between patients with minimal residual disease (completeness of cytoreduction (CC) score) CC-1 at the time of primary debulking surgery and those with complete cytoreduction (CC-0) at the time of interval debulking surgery. METHODS: A retrospective multicenter study was conducted of patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage IIIC-IV) who underwent cytoreductive surgery achieving either minimal or no residual disease between January 2008 and December 2015. Patients underwent either primary or interval debulking surgery after receiving ≥3 cycles of neoadjuvant chemotherapy. The sub-group of patients with primary debulking surgery/CC-1 was compared with those with interval debulking surgery/CC-0. Overall survival and disease-free survival were estimated using the Kaplan-Meier method. RESULTS: A total of 549 patients were included, with upfront surgery performed in 175 patients (31.9%) and 374 patients (68.1%) undergoing interval debulking surgery. After primary debulking surgery, 157/175 (89.7%) had complete cytoreduction and 18/175 (10.3%) had minimal residual disease (primary debulking surgery/CC-1 group), while after interval debulking surgery, 324/374 (86.6%) had complete cytoreduction (interval debulking surgery/CC-0 group) and 50/374 (13.4%) had minimal residual disease. The rate of patients with peritoneal cancer index >10 was 14/17 (82.4%) for the primary debulking surgery/CC-1 group and 129/322 (40.1%) for the interval debulking surgery/CC-0 (p<0.001). The rate of patients with an Aletti score of ≥8 was 11/18 (61.1%) and 132/324 (40.7%), respectively (p=0.09) and the rate of major post-operative complications was 5/18 (27.8%) and 64/324 (19.8%), respectively (p=0.38). Overall median disease-free and overall survival were 19.4 months (95% CI 18.0 to 20.6) and 56.7 months (95%CI 50.2 to 65.8), respectively. Median disease-free survival for the primary debulking surgery/CC-1 group was 16.7 months (95% CI 13.6 to 20.0) versus 18.2 months (95% CI 16.4 to 20.0) for the interval debulking surgery/CC-0 group (p=0.56). Median overall survival for the primary debulking surgery/CC-1 group was 44.7 months (95% CI 34.3 to not reached) and 49.4 months (95% CI 46.2 to 57.3) for the interval debulking surgery/CC-0 group (p=0.97). CONCLUSIONS: Patients with primary debulking surgery with minimal residual disease and those with interval debulking surgery with no residual disease had similar survival outcomes. Interval surgery should be considered when achieving absence of residual disease is challenging at upfront surgery, given the lower tumor burden found during surgery.

Limitations of homologous recombination status testing and poly (ADP-ribose) polymerase inhibitor treatment in the current management of ovarian cancer.

Homologous recombination (HR) is a highly conserved DNA repair system, in which aberrations can lead to the accumulation of DNA damage and genomic scars known as homologous recombination deficiency (HRD). The identification of mutations in key genes (i.e., BRCA1, and BRCA2 (BRCA)) and the quantification of large-scale structural variants (e.g., loss of heterozygosity) are indicators of the HRD phenotype. HRD is a stable biomarker and remains unchanged during recurrence, but fails to reveal the molecular profile of tumor progression. Moreover, interpretation of the current HRD score lacks comprehensiveness, especially for the HR-proficient group. Poly (ADP-ribose) polymerase (PARP) enzymes play an important role in the repair of DNA single-strand breaks, the blockage of which using PARP inhibitors (PARPi) can generate synthetic lethality in cancer cells with HRD. Although numerous studies have demonstrated that the benefit of PARPi is substantial in ovarian cancer (OC) patients, the efficacy is limited by the development of resistance, and seems to be irrespective of HR and/or BRCA mutation status. Moreover, in addition to improving progression-free survival, long-term benefit as overall survival brought by PARPi for advanced, recurrent and refractory OC patients remains unclear. Therefore, further investigations are needed to uncover the role of HR genes beyond BRCA and their interactions with other oncogenic pathways, to determine the value of HRD in the recurrent setting, and to identify alternative strategies for the precise management of advanced, refractory OC patients.

Sarcopenia shortens overall survival of patients with platinum-resistant recurrent ovarian cancer: inverse probability of treatment-weighting analysis.

OBJECTIVE: The association between sarcopenia and prognosis in patients with platinum-resistant recurrent ovarian cancer remains unclear. This study investigated whether sarcopenia is a prognostic factor in patients with platinum-resistant recurrent ovarian cancer. METHODS: A total of 52 patients diagnosed with platinum-resistant recurrent ovarian cancer who had undergone non-platinum chemotherapy at our institution formed our study population. Body composition and clinicopathological data of these patients were collected retrospectively. Abdominal computed tomography (CT) scans obtained at the time of platinum-resistant recurrent ovarian cancer diagnosis were used to measure the cross-sectional area of skeletal muscles at L3 level. These values were corrected for height to calculate the skeletal muscle index, and accordingly sarcopenia was defined. Overall survival was defined as the primary outcome of the study. The impact of sarcopenia on overall survival was assessed using Cox proportional hazards regression models with inverse probability weighting of treatment based on propensity scores and log-rank tests. RESULTS: The median patient age was 63 years (IQR: 53-71). The most common International Federation of Gynecology and Obstetrics (FIGO) 2018 stage was stage III (50%) and the most common histology was serous or adenocarcinoma (67.3%). The optimal cut-off value of skeletal muscle index was 35.6 cm2/m2, which was calculated using the data of 21 patients with sarcopenia and 31 without sarcopenia. Sarcopenia was significantly associated with shorter overall survival (HR 1.93; 95% CI 1.06-3.49; p=0.03). Subgroup analysis based on patient attributes and prognostic factors suggested a consistent prognostic impact of sarcopenia. Sarcopenia was identified as a significant risk factor, particularly in patients who had higher CA125 levels (HR, 2.47; 95% CI, 1.07 to 5.69; p=0.034) and a higher neutrophil-to-lymphocyte ratio (HR, 2.92; 95% CI, 1.02 to 8.31; p=0.045). CONCLUSION: Sarcopenia significantly shortened the overall survival of patients with platinum-resistant recurrent ovarian cancer.

BRCA1/2 Mutations and Breast/Ovarian Cancer Risk: A New Insights Review.

Breast and ovarian cancers are significant global health concerns, and understanding their genetic underpinnings is essential for effective prevention and cure. This narrative review provides a comprehensive analysis of studies conducted between 1994 and June 2024, focusing on the link between specific mutations in the breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) and the associated risks of both breast and ovarian cancers. It encompasses the findings of various works, including observational studies and molecular profiling analyses. Conducted on large international cohorts, these studies present compelling evidence of the relationship between different BRCA1 and BRCA2 mutations and the varying risks of breast and ovarian cancer. Furthermore, this review highlights the significance of nonsense-mediated decay mutations and their impact on cancer risk, particularly concerning the age of breast cancer onset. The implications of these findings are far-reaching, offering valuable information for risk assessment and decision-making in managing individuals who carry BRCA1 or BRCA2 mutations. The molecular subtyping profile BluePrint is discussed as a potential tool for enhancing clinical care by aiding the selection of appropriate treatment options, such as endocrine therapy or chemotherapy, based on the tumor's molecular characteristics. In conclusion, we establish a robust link between specific BRCA1 and BRCA2 gene mutations and increased susceptibility to breast and ovarian cancers. These mutations impact cancer onset age and severity, underscoring the need for targeted testing and screening. The current study enhances cancer detection, prevention, and cure strategies.

Identification and validation of genes associated with prognosis of cisplatin-resistant ovarian cancer.

PURPOSE: To investigate the role of prognostic genes related to cisplatin resistance in ovarian cancer during disease progression. METHOD: The gene expression profile of the NCI-60 cell line was acquired through comprehensive analysis of the GEO database accession GSE116439. We performed a thorough analysis of gene expression differences in samples from seven individuals exposed to cisplatin concentrations of 0 nM compared to seven samples exposed to 15000 nM over a 24-h period. Key genes were initially identified through LASSO regression, followed by their enrichment through differential gene function analysis (GO) and pathway enrichment analysis (KEGG). Subsequently, a prognostic risk model was established for these key genes. The prognostic model's performance was assessed through K-M survival curves and ROC curves. To examine the variance in immune cell infiltration between the high and low-risk groups, CIBERSORTx analysis was employed. Finally, validation of prognostic gene expression in cisplatin-resistant ovarian cancer was carried out using clinical samples, employing RT-qPCR and Western Blot techniques. RESULTS: A total of 132 differential genes were found between cisplatin resistance and control group, and 8 key prognostic genes were selected by analysis, namely VPS13B, PLGRKT, CDKAL1, TBC1D22A, TAP1, PPP3CA, CUX1 and PPP1R15A. The efficacy of the risk assessment model derived from prognostic biomarkers, as indicated by favorable performance on both Kaplan-Meier survival curves and ROC curves. Significant variations in the abundance of Macrophages M1, T cells CD4 memory resting, T cells follicular helper, and T cells gamma delta were observed between the high and low-risk groups. To further validate our findings, RT-qPCR and Western Blot analyses were employed, confirming differential expression of the identified eight key genes between the two groups. CONCLUSION: VPS13B, TBC1D22A, PPP3CA, CUX1 and PPP1R15A were identified as poor prognostic genes of cisplatin resistance in ovarian cancer, while PLGRKT, CDKAL1 and TAP1 were identified as good prognostic genes. This offers a novel perspective for future advancements in ovarian cancer treatment, suggesting potential avenues for the development of new therapeutic targets.

A Predictive Model for Initial Platinum-Based Chemotherapy Efficacy in Patients with Postoperative Epithelial Ovarian Cancer Using Tissue-Derived Small Extracellular Vesicles.

Epithelial ovarian cancer (EOC) is an often-fatal malignancy marked by the development of resistance to platinum-based chemotherapy. Thus, accurate prediction of platinum drug efficacy is crucial for strategically selecting postoperative interventions to mitigate the risks associated with suboptimal therapeutic outcomes and adverse effects. Tissue-derived extracellular vesicles (tsEVs), in contrast to their plasma counterparts, have emerged as a powerful tool for examining distinctive attributes of EOC tissues. In this study, 4D data-independent acquisition (DIA) proteomic sequencing was performed on tsEVs obtained from 58 platinum-sensitive and 30 platinum-resistant patients with EOC. The analysis revealed a notable enrichment of differentially expressed proteins that were predominantly associated with immune-related pathways. Moreover, pivotal immune-related proteins (IRPs) were identified by LASSO regression. These factors, combined with clinical parameters selected through univariate logistic regression, were used for the construction of a model employing multivariate logistic regression. This model integrated three tsEV IRPs, CCR1, IGHV_35 and CD72, with one clinical parameter, the presence of postoperative residual lesions. Thus, this model could predict the efficacy of initial platinum-based chemotherapy in patients with EOC post-surgery, providing prognostic insights even before the initiation of chemotherapy.