Anticancer effects of Erzhimaoling decoction in high-grade serous ovarian cancer in vitro and in vivo.

BACKGROUND: High-grade serous ovarian cancer (HGSOC) is a common gynecologic malignancy with a poor prognosis. The traditional Chinese medicine formula Erzhimaoling decoction (EZMLD) has anticancer potential. This study aims to elucidate the anticancer effects of EZMLD on HGSOC in vitro and in vivo. MATERIALS AND METHODS: EZMLD-containing serum was prepared from Sprague-Dawley rats for treating SKOV3 ovarian cancer cells at varying concentrations for 24 h and 48 h to determine the IC50. Concentrations of 0%, 5%, and 10% for 24 h were chosen for subsequent in vitro experiments. The roles of METTL3 and METTL14 in SKOV3 cells were explored by overexpressing these genes and combining EZMLD with METTL3/14 knockdown. Investigations focused on cell viability and apoptosis, apoptosis-related protein expression, and KRT8 mRNA m6A modification. For in vivo studies, 36 BALB/c nude mice were divided into six groups involving EZMLD (6.75, 13.5, and 27 g/kg) and METTL3 or METTL14 knockdowns, with daily EZMLD gavage for two weeks. RESULTS: In vitro, EZMLD-containing serum had IC50 values of 8.29% at 24 h and 5.95% at 48 h in SKOV3 cells. EZMLD-containing serum decreased SKOV3 cell viability and increased apoptosis. EZMLD upregulated METTL3/14 and FAS-mediated apoptosis proteins, while downregulating Keratin 8 (KRT8). EZMLD increased KRT8 mRNA m6A methylation. METTL3/14 overexpression reduced SKOV3 cell viability and increased apoptosis, while METTL3/14 knockdown mitigated EZMLD's effects. In vivo, EZMLD suppressed SKOV3 xenografts growth, causing significant apoptosis and modulating protein expression. CONCLUSIONS: EZMLD has therapeutic potential for ovarian cancer and may be considered for other cancer types. Future research may explore its broader effects beyond cell apoptosis.

The molecular prognostic score, a classifier for risk stratification of high-grade serous ovarian cancer.

BACKGROUND: The clinicopathological parameters such as residual tumor, grade, the International Federation of Gynecology and Obstetrics (FIGO) score are often used to predict the survival of ovarian cancer patients, but the 5-year survival of high grade serous ovarian cancer (HGSOC) still remains around 30%. Hence, the relentless pursuit of enhanced prognostic tools for HGSOC, this study introduces an unprecedented gene expression-based molecular prognostic score (mPS). Derived from a novel 20-gene signature through Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression, the mPS stands out for its predictive prowess. RESULTS: Validation across diverse datasets, including training and test sets (n = 491 each) and a large HGSOC patient cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium (n = 7542), consistently shows an area-under-curve (AUC) around 0.7 for predicting 5-year overall survival. The mPS's impact on prognosis resonates profoundly, yielding an adjusted hazard-ratio (HR) of 6.1 (95% CI: 3.65-10.3; p < 0.001), overshadowing conventional parameters-FIGO score, residual disease, and age. Molecular insights gleaned from mPS stratification uncover intriguing pathways, with focal-adhesion, Wnt, and Notch signaling upregulated, and antigen processing and presentation downregulated (p < 0.001) in high-risk HGSOC cohorts. CONCLUSION: Positioned as a robust prognostic marker, the 20-gene signature-derived mPS emerges as a potential game-changer in clinical settings. Beyond its role in predicting overall survival, its implications extend to guiding alternative therapies, especially targeting Wnt/Notch signaling pathways and immune evasion-a promising avenue for improving outcomes in high-risk HGSOC patients.

Uterine serous carcinoma and uterine carcinosarcoma: molecular features, clinical advances, and emerging therapies.

Endometrial cancer, including high-grade subtypes, has a rising incidence and mortality. Uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS) make up a small but increasing proportion of endometrial cancer cases and account for a significant portion of endometrial cancer mortality. Despite being molecularly and clinically distinct, both USC and UCS have a poor prognosis. Thus far, there have been few therapeutic strategies directed at these endometrial cancer subtypes. This review summarizes the genomic and molecular features of USC and UCS, clinical advances in the treatment of primary advanced and recurrent endometrial cancer, and novel molecularly-driven treatment strategies.

Single-nuclei sequencing of uterine serous carcinoma reveals racial differences in immune signaling.

Significant racial disparities exist between Black and White patients with uterine serous carcinoma (USC). While the reasons for these disparities are unclear, several studies have demonstrated significantly different rates of driver mutations between racial groups, including TP53. However, limited research has investigated the transcriptional differences of tumors or the composition of the tumor microenvironment (TME) between these groups. Here, we report the single-nuclei RNA-sequencing profiles of primary USC tumors from diverse racial backgrounds. We find that there are significant differences between the tumors of Black and White patients. Tumors from Black patients exhibited higher expression of specific genes associated with aggressiveness, such as PAX8, and axon guidance and synaptic signaling pathways. We also demonstrated that T cell populations are reduced in the tumor tissue compared to matched benign, while anti-inflammatory macrophage populations are retained within the TME. Furthermore, we investigated the connection between PAX8 overexpression and immunosuppression in USC through regulation of several cytokines and chemokines. Notably, we show that PAX8 activity can influence macrophage gene expression and protein secretion. These studies provide a detailed understanding of the USC transcriptome and TME, and identify differences in tumor biology from patients of different racial backgrounds.

Integrating single-cell and spatial transcriptomic analysis to unveil heterogeneity in high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSOC) presents significant challenges due to its heterogeneity and late-stage diagnoses. Using single-cell and spatial transcriptomics to elucidate the complex landscape of HGSOC to understand its underlying mechanism. Our analysis reveals significant inter- and intra-tumoral diversity, manifested through distinct cellular subpopulations and varied microenvironmental niches. Notably, our findings highlight a widespread immunosuppressive environment, marked by complex networks of cell-cell interactions, particularly evident in areas of elevated tumor cell density within metastatic samples. We identify the exclusive presence of COL14A1+ neoplastic cells in metastatic specimens, alongside a strong correlation between CD8A+ NKT cells and poor prognosis, and elevated CHODL expression in HGSOC metastasis tissues. Furthermore, knockdown experiments targeting CHODL demonstrate its role in reducing migration and invasion abilities in HGSOC cells. A pivotal discovery of our study is the delineation of specific cellular signatures correlated with adverse outcomes, notably a subset of CHODL+ neoplastic cells characterized by a distinct metabolic phenotype with a predilection for lipid metabolism. The therapeutic targeting of this metabolic pathway with existing inhibitors appears promising in curbing tumor proliferation. These findings enhance our understanding of HGSOC heterogeneity and reveal potential therapeutic targets, promising more effective management strategies for this aggressive cancer subtype.

The intratumoral microbiota biomarkers for predicting survival and efficacy of immunotherapy in patients with ovarian serous cystadenocarcinoma.

BACKGROUND: Ovarian serous cystadenocarcinoma, accounting for about 90% of ovarian cancers, is frequently diagnosed at advanced stages, leading to suboptimal treatment outcomes. Given the malignant nature of the disease, effective biomarkers for accurate prediction and personalized treatment remain an urgent clinical need. METHODS: In this study, we analyzed the microbial contents of 453 ovarian serous cystadenocarcinoma and 68 adjacent non-cancerous samples. A univariate Cox regression model was used to identify microorganisms significantly associated with survival and a prognostic risk score model constructed using LASSO Cox regression analysis. Patients were subsequently categorized into high-risk and low-risk groups based on their risk scores. RESULTS: Survival analysis revealed that patients in the low-risk group had a higher overall survival rate. A nomogram was constructed for easy visualization of the prognostic model. Analysis of immune cell infiltration and immune checkpoint gene expression in both groups showed that both parameters were positively correlated with the risk level, indicating an increased immune response in higher risk groups. CONCLUSION: Our findings suggest that microbial profiles in ovarian serous cystadenocarcinoma may serve as viable clinical prognostic indicators. This study provides novel insights into the potential impact of intratumoral microbial communities on disease prognosis and opens avenues for future therapeutic interventions targeting these microorganisms.

Endometrial serous carcinoma with a corded and hyalinized pattern: a clinicopathological and molecular analysis.

A corded and hyalinized pattern has been described in endometrial endometrioid carcinoma. Herein, we describe a clinicopathological and molecular analysis of the first reported case of endometrial serous carcinoma with a corded and hyalinized pattern.A 64-year-old woman underwent hysterectomy and bilateral salpingo-oophorectomy due to a 5.5 cm endometrial lesion. Histologically, the tumor was composed of a minor (20%) serous carcinoma component and a predominant corded component embedded in a hyaline-to-myxoid matrix. This component showed diffuse and strong p53 and p16 expression, heterogeneous positivity for epithelial markers and WT1, focal positivity for estrogen and progesterone receptors, retained MMR, SMARCA4/BRG1, and SMARCB1/INI1 expression, and negativity for smooth muscle, germ cell, sex cord, neuroendocrine, endothelial, and melanocytic markers and GATA3. Next-generation sequencing showed a mutation of uncertain significance in APC and no mutations in MLH1, MSH2, MSH6, PMS2, MUTYH, POLE, POLD1, EPCAM, or CTNNB1. The patient had a recurrence on the vaginal stump after 15 months.In conclusion, endometrial serous carcinoma can show a corded and hyalinized pattern, which may represent a diagnostic challenge.

Targeted proteomics of plasma extracellular vesicles uncovers MUC1 as combinatorial biomarker for the early detection of high-grade serous ovarian cancer.

BACKGROUND: The five-year prognosis for patients with late-stage high-grade serous carcinoma (HGSC) remains dismal, underscoring the critical need for identifying early-stage biomarkers. This study explores the potential of extracellular vesicles (EVs) circulating in blood, which are believed to harbor proteomic cargo reflective of the HGSC microenvironment, as a source for biomarker discovery. RESULTS: We conducted a comprehensive proteomic profiling of EVs isolated from blood plasma, ascites, and cell lines of patients, employing both data-dependent (DDA) and data-independent acquisition (DIA) methods to construct a spectral library tailored for targeted proteomics. Our investigation aimed at uncovering novel biomarkers for the early detection of HGSC by comparing the proteomic signatures of EVs from women with HGSC to those with benign gynecological conditions. The initial cohort, comprising 19 donors, utilized DDA proteomics for spectral library development. The subsequent cohort, involving 30 HGSC patients and 30 control subjects, employed DIA proteomics for a similar purpose. Support vector machine (SVM) classification was applied in both cohorts to identify combinatorial biomarkers with high specificity and sensitivity (ROC-AUC > 0.90). Notably, MUC1 emerged as a significant biomarker in both cohorts when used in combination with additional biomarkers. Validation through an ELISA assay on a subset of benign (n = 18), Stage I (n = 9), and stage II (n = 9) plasma samples corroborated the diagnostic utility of MUC1 in the early-stage detection of HGSC. CONCLUSIONS: This study highlights the value of EV-based proteomic analysis in the discovery of combinatorial biomarkers for early ovarian cancer detection.

The impact of Paclitaxel-based hyperthermic intraperitoneal chemotherapy in advanced high-grade serous ovarian cancer patients - interim analysis of safety and immediate efficacy of a randomized control trial (C-HOC trial).

OBJECTIVE: This study evaluates the potential superiority of combining paclitaxel-based hyperthermic intraperitoneal chemotherapy (HIPEC) with sequential intravenous neoadjuvant chemotherapy over intravenous neoadjuvant chemotherapy alone in Chinese patients with Federation of Gynecology and Obstetrics (FIGO) stage IIIC, IVA and IVB high-grade serous ovarian/fallopian tube carcinoma (HGSOC). This interim analysis focuses on the safety and immediate efficacy of both regimens to determine the feasibility of the planned trial (C-HOC Trial). METHODS: In a single-center, open-label, randomized control trial, FIGO stage IIIC, IVA, and IVB HGSOC patients (FAGOTTI score ≥ 8 during laparoscopic exploration) unsuitable for optimal cytoreduction in primary debulking surgery (PDS) were randomized 2:1 during laparoscopic exploration. The Experiment Group (HIPEC Group) received one cycle of intraperitoneal neoadjuvant laparoscopic hyperthermic intraperitoneal chemotherapy (paclitaxel) followed by three cycles of intravenous chemotherapy (paclitaxel plus carboplatin), while the Control Group received only three cycles of intravenous chemotherapy. Both groups subsequently underwent interval debulking surgery (IDS). The adverse effects of chemotherapy, postoperative complications, and pathological chemotherapy response scores (CRS) after IDS were compared. RESULTS: Among 65 enrolled patients, 39 HIPEC Group and 21 Control Group patients underwent IDS. Grade 3-4 chemotherapy-related adverse effects were primarily hematological with no significant differences between the two groups. The HIPEC Group exhibited a higher proportion of CRS 3 (20.5% vs. 4.8%; P = 0.000). R0 resection rates in IDS were 69.2% (HIPEC Group) and 66.7% (Control Group). R2 resection occurred in 2.6% (HIPEC Group) and 14.3% (Control Group) cases. No reoperations or postoperative deaths were reported, and complications were managed conservatively. CONCLUSIONS: Combining HIPEC with IV NACT in treating ovarian cancer demonstrated safety and feasibility, with no increased chemotherapy-related adverse effects or postoperative complications. HIPEC improved tumor response to neoadjuvant chemotherapy, potentially enhancing progression-free survival (PFS). However, the final overall survival results are pending, determining if HIPEC combined with IV NACT is superior to IV NACT alone.

Type I or Type II Endometrial Carcinoma? Role of BRCA1 Immunohistochemistry.

OBJECTIVES: Investigation of diagnostic and prognostic relevance of BRCA1 immunohistochemistry (IHC) in endometrial carcinoma. METHODS: Ninty four specimens of endometrial carcinomas were evaluated. Full sections stained with hematoxylin & eosin were revaluated for assessment of tumor type, grade, myometrial, & lympho-vascular invasion (LVI). Tissue microarray blocks were constructed using the pencil tip method and immunostained with Anti-BRCA1 antibody. BRCA1 was correlated with clinicopathological parameters as well as disease free survival and overall survival. RESULTS: There was a statistically significant difference (P=0.001) between serous and endometroid carcinomas regarding BRCA1 expression where most cases of serous carcinoma showed negative expression. No statistically significant difference was found between BRCA1 positive and negative cases regarding disease free survival (DFS) or overall survival. Serous histotype, high grade, advanced stage, and omental deposits were the parameters significantly associated with decreased DFS. CONCLUSION: Results of this study can support inclusion of BRCA1 IHC in a panel to differentiate both endometroid and serous carcinomas. The current study found no prognostic relevance for BRCA1 in terms of overall survival and disease-free survival.

Targeting estrogen metabolism in high-grade serous ovarian cancer shows promise to overcome platinum resistance.

The high mortality rate due to chemoresistance in patients with high-grade ovarian cancer (HGSOC) emphasizes the urgent need to determine optimal treatment strategies for advanced and recurrent cases. Our study investigates the interplay between estrogens and chemoresistance in HGSOC and shows clear differences between platinum-sensitive and -resistant tumors. Through comprehensive transcriptome analyzes, we uncover differences in the expression of genes of estrogen biosynthesis, metabolism, transport and action underlying platinum resistance in different tissues of HGSOC subtypes and in six HGSOC cell lines. Furthermore, we identify genes involved in estrogen biosynthesis and metabolism as prognostic biomarkers for HGSOC. Additionally, our study elucidates different patterns of estrogen formation/metabolism and their effects on cell proliferation between six HGSOC cell lines with different platinum sensitivity. These results emphasize the dynamic interplay between estrogens and HGSOC chemoresistance. In particular, targeting the activity of steroid sulfatase (STS) proves to be a promising therapeutic approach with potential efficacy in limiting estrogen-driven cell proliferation. Our study reveals potential prognostic markers as well as identifies novel therapeutic targets that show promise for overcoming resistance and improving treatment outcomes in HGSOC.

Adjuvant Treatment of Stage I-II Serous Endometrial Cancer: A Single Institution 20-Year Experience.

Background: Serous endometrial carcinoma (SEC) is a high-risk subtype of endometrial cancer. The effectiveness of multiple adjuvant therapies, namely chemotherapy (CT), radiotherapy (RT), and sequential/concurrent chemotherapy with radiotherapy (CRT), have previously been investigated. However, optimal management of early-stage SEC remains unclarified. Methods: All cases of early-stage SEC (FIGO 2009 stages I-II) treated in our institution from 2002 to 2019 were identified. Patient data were documented until September 2023. Overall survival (OS) and disease-free survival (DFS) were computed using Kaplan-Meier estimates and Cox's proportional hazard model; descriptive statistical analysis was performed. Results: A total of 50 patients underwent total hysterectomy-bilateral salpingo-oophorectomy and omentectomy, displaying stage IA (60%), IB (24%), and II (16%) disease. The median follow-up was 90.9 months. Patients underwent adjuvant CRT (n = 36, 72%), CT (n = 6, 12%), or RT (n = 6, 12%). Two patients were observed and excluded from analyses. The 42 patients who received radiotherapy had pelvic external beam radiotherapy (n = 10), vaginal brachytherapy (n = 21), or both (n = 11). CRT had better OS (HR 0.14, 95%CI 0.04-0.52, p < 0.005) and DFS (HR 0.25, 95%CI 0.07-0.97, p = 0.05) than CT alone. RT displayed no OS or DFS benefits compared to CT/CRT. Recurrences were mostly distant. Acute and late G3-4 toxicities were primarily hematologic. Conclusions: Our data underline the challenge of treating SEC. CRT appears to be superior to CT alone but not to RT. Most recurrences were distant, highlighting the need for optimized systemic treatment options.

FANCD2 expression affects platinum response and further characteristics of high grade serous ovarian cancer in cells with different genetic backgrounds.

High-grade serous ovarian cancer (HGSOC) is the most prevalent subtype of ovarian cancer and demonstrates 5-year survival of just 40%. One of the major causes of mortality is the development of tumour resistance to platinum-based chemotherapy, which can be modulated by dysregulation of DNA damage repair pathways. We therefore investigated the contribution of the DNA interstrand crosslink repair protein FANCD2 to chemosensitivity in HGSOC. Increased FANCD2 protein expression was observed in some cell line models of platinum resistant HGSOC compared with paired platinum sensitive models. Knockdown of FANCD2 in some cell lines, including the platinum resistant PEO4, led to increased carboplatin sensitivity. Investigation into mechanisms of FANCD2 regulation showed that increased FANCD2 expression in platinum resistant cells coincides with increased expression of mTOR. Treatment with mTOR inhibitors resulted in FANCD2 depletion, suggesting that mTOR can mediate platinum sensitivity via regulation of FANCD2. Tumours from a cohort of HGSOC patients showed varied nuclear and cytoplasmic FANCD2 expression, however this was not significantly associated with clinical characteristics. Knockout of FANCD2 was associated with increased cell migration, which may represent a non-canonical function of cytoplasmic FANCD2. We conclude that upregulation of FANCD2, possibly mediated by mTOR, is a potential mechanism of chemoresistance in HGSOC and modulation of FANCD2 expression can influence platinum sensitivity and other tumour cell characteristics.

Neoadjuvant and adjuvant pembrolizumab in advanced high-grade serous carcinoma: the randomized phase II NeoPembrOV clinical trial.

This open-label, non-comparative, 2:1 randomized, phase II trial (NCT03275506) in women with stage IIIC/IV high-grade serous carcinoma (HGSC) for whom upfront complete resection was unachievable assessed whether adding pembrolizumab (200 mg every 3 weeks) to standard-of-care carboplatin plus paclitaxel yielded a complete resection rate (CRR) of at least 50%. Postoperatively patients continued assigned treatment for a maximum of 2 years. Postoperative bevacizumab was optional. The primary endpoint was independently assessed CRR at interval debulking surgery. Secondary endpoints were Completeness of Cytoreduction Index (CCI) and peritoneal cancer index (PCI) scores, objective and best response rates, progression-free survival, overall survival, safety, postoperative morbidity, and pathological complete response. The CRR in 61 pembrolizumab-treated patients was 74% (one-sided 95% CI = 63%), exceeding the prespecified ≥50% threshold and meeting the primary objective. The CRR without pembrolizumab was 70% (one-sided 95% CI = 54%). In the remaining patients CCI scores were ≥3 in 27% of the standard-of-care group and 18% of the investigational group and CC1 in 3% of the investigational group. PCI score decreased by a mean of 9.6 in the standard-of-care group and 10.2 in the investigational group. Objective response rates were 60% and 72%, respectively, and best overall response rates were 83% and 90%, respectively. Progression-free survival was similar with the two regimens (median 20.8 versus 19.4 months in the standard-of-care versus investigational arms, respectively) but overall survival favored pembrolizumab-containing therapy (median 35.3 versus 49.8 months, respectively). The most common grade ≥3 adverse events with pembrolizumab-containing therapy were anemia during neoadjuvant therapy and infection/fever postoperatively. Pembrolizumab was discontinued prematurely because of adverse events in 23% of pembrolizumab-treated patients. Combining pembrolizumab with neoadjuvant chemotherapy is feasible for HGSC considered not completely resectable; observed activity in some subgroups justifies further evaluation to improve understanding of the role of immunotherapy in HGSC.

High-grade serous ovarian cancer (HGSOC) with fallopian tube involvement.

INTRODUCTION: Literature data present new studies about precancerous lesions of pelvic serous carcinoma that originate from the tubal secretory cells. It has long been thought that ovarian cancer cannot be prevented by prophylactic screening or surgery. In recent years, gynecologists have adapted to new principles and so, during routine hysterectomies in perimenopausal women for benign uterine pathologies, salpingo-oophorectomy is performed as a prophylactic approach. AIM: The purpose of our article was to draw attention to the association between abnormal fallopian tube pathology and the presence of serous ovarian neoplasia in perimenopausal women at risk. CASE PRESENTATION: We report the case of a 45-year-old woman who had unspecific symptoms of abdominal pain and loss of appetite and weight. A pelvic magnetic resonance imaging was performed, and an ovarian mass was detected. Our case shows that the fallopian tube can be the primary point of origin for a pelvic disease, therefore prevention is possible with early computed tomography scan and annual ultrasound. The patient presented with a T1c staging post-surgery and her chances of survival could have decreased if she had postponed medical examination longer. We found a significant increase in the absolute number of tubal secretory cells in patients with ovarian neoplasia, which supports the assumption that serous tubal intraepithelial carcinoma lesions are found especially in the serous ovarian type. CONCLUSIONS: Our article is a strong suggestion that serous ovarian cancer originates from the fallopian tube and can potentially serve as a sensitive biomarker for early serous carcinogenesis within the fallopian tube.

An increase of serum CA-125 to two times of nadir level strongly predicts the image-identified relapse of serous ovarian cancer.

Using 70 U/ml or 35 U/ml as CA125 routine abnormal threshold may result in omissions in the relapse detection of Ovarian cancer (OvCa). This study aimed to clarify the association between a biochemical relapse (only the elevation of CA125) and an image-identified relapse to predict the relapsed lesions better. 162 patients who achieved complete clinical response were enrolled from women diagnosed with stage I-IV serous ovarian, tubal, and peritoneal cancers from January 2013 to June 2019 at our center. The CA125 level of 2 × nadir was defined as the indicator of image-identified relapse (P < 0.001). Compared to CA125 level exceeding 35 U/ml, the 2 × nadir of CA125 improve the sensitivity of image-identified relapse (84.9% vs 67.4%, P < 0.001); the 2 × nadir value can act as an earlier warning relapse signal with a longer median time to image-identified relapse (2.7 vs. 0 months, P < 0.001). Of the relapsed population, there was no difference of CA125 changing trend between the neoadjuvant chemotherapy (NACT) and primary debulking surgery (PDS) group after initial treatment. Compared with 35 U/ml, CA125 reaching 2 × nadir during the follow-up process might be a more sensitive and early relapse signal in patients with serous OvCa. This criterion may help guide patients to be recommended for imaging examination to detect potential relapse in time.

New immune phenotypes for treatment response in high-grade serous ovarian carcinoma patients.

Despite advances in surgical and therapeutic approaches, high-grade serous ovarian carcinoma (HGSOC) prognosis remains poor. Surgery is an indispensable component of therapeutic protocols, as removal of all visible tumor lesions (cytoreduction) profoundly improves the overall survival. Enhanced predictive tools for assessing cytoreduction are essential to optimize therapeutic precision. Patients' immune status broadly reflects the tumor cell biological behavior and the patient responses to disease and treatment. Serum cytokine profiling is a sensitive measure of immune adaption and deviation, yet its integration into treatment paradigms is underexplored. This study is part of the IMPACT trial (NCT03378297) and aimed to characterize immune responses before and during primary treatment for HGSOC to identify biomarkers for treatment selection and prognosis. Longitudinal serum samples from 22 patients were collected from diagnosis until response evaluation. Patients underwent primary cytoreductive surgery or neoadjuvant chemotherapy (NACT) based on laparoscopy scoring. Twenty-seven serum cytokines analyzed by Bio-Plex 200, revealed two immune phenotypes at diagnosis: Immune High with marked higher serum cytokine levels than Immune Low. The immune phenotypes reflected the laparoscopy scoring and allocation to surgical treatment. The five Immune High patients undergoing primary cytoreductive surgery exhibited immune mobilization and extended progression-free survival, compared to the Immune Low patients undergoing the same treatment. Both laparoscopy and cytoreductive surgery induced substantial and transient changes in serum cytokines, with upregulation of the inflammatory cytokine IL-6 and downregulation of the multifunctional cytokines IP-10, Eotaxin, IL-4, and IL-7. Over the study period, cytokine levels uniformly decreased in all patients, leading to the elimination of the initial immune phenotypes regardless of treatment choice. This study reveals distinct pre-treatment immune phenotypes in HGSOC patients that might be informative for treatment stratification and prognosis. This potential novel biomarker holds promise as a foundation for improved assessment of treatment responses in patients with HGSOC. ClinicalTrials.gov Identifier: NCT03378297.

Timing of whole genome duplication is associated with tumor-specific MHC-II depletion in serous ovarian cancer.

Whole genome duplication is frequently observed in cancer, and its prevalence in our prior analysis of end-stage, homologous recombination deficient high grade serous ovarian cancer (almost 80% of samples) supports the notion that whole genome duplication provides a fitness advantage under the selection pressure of therapy. Here, we therefore aim to identify potential therapeutic vulnerabilities in primary high grade serous ovarian cancer with whole genome duplication by assessing differentially expressed genes and pathways in 79 samples. We observe that MHC-II expression is lowest in tumors which have acquired whole genome duplication early in tumor evolution, and further demonstrate that reduced MHC-II expression occurs in subsets of tumor cells rather than in canonical antigen-presenting cells. Early whole genome duplication is also associated with worse patient survival outcomes. Our results suggest an association between the timing of whole genome duplication, MHC-II expression and clinical outcome in high grade serous ovarian cancer that warrants further investigation for therapeutic targeting.

Deep fine-KNN classification of ovarian cancer subtypes using efficientNet-B0 extracted features: a comprehensive analysis.

This study presents a robust approach for the classification of ovarian cancer subtypes through the integration of deep learning and k-nearest neighbor (KNN) methods. The proposed model leverages the powerful feature extraction capabilities of EfficientNet-B0, utilizing its deep features for subsequent fine-grained classification using the fine-KNN approach. The UBC-OCEAN dataset, encompassing histopathological images of five distinct ovarian cancer subtypes, namely, high-grade serous carcinoma (HGSC), clear-cell ovarian carcinoma (CC), endometrioid carcinoma (EC), low-grade serous carcinoma (LGSC), and mucinous carcinoma (MC), served as the foundation for our investigation. With a dataset comprising 725 images, divided into 80% for training and 20% for testing, our model exhibits exceptional performance. Both the validation and testing phases achieved 100% accuracy, underscoring the efficacy of the proposed methodology. In addition, the area under the curve (AUC), a key metric for evaluating the model's discriminative ability, demonstrated high performance across various subtypes, with AUC values of 0.94, 0.78, 0.69, 0.92, and 0.94 for MC. Furthermore, the positive likelihood ratios (LR+) were indicative of the model's diagnostic utility, with notable values for each subtype: CC (27.294), EC (9.441), HGSC (12.588), LGSC (17.942), and MC (17.942). These findings demonstrate the effectiveness of the model in distinguishing between ovarian cancer subtypes, positioning it as a promising tool for diagnostic applications. The demonstrated accuracy, AUC values, and LR+ values underscore the potential of the model as a valuable diagnostic tool, contributing to the advancement of precision medicine in the field of ovarian cancer research.

Comparison of Outcomes in Bowel Resections by Gynecologic Oncologists Versus General Surgeons During Maximal Cytoreductive Surgery for Advanced Ovarian Cancer: Gynecologic Oncology Research Investigators Collaboration Study (GORILLA-3006).

BACKGROUND: This report describes the oncologic outcomes for patients with advanced ovarian cancer who had bowel surgery performed by gynecologic oncologists (GOs) and compares the outcomes with those for bowel surgery performed by general surgeons (GSs) during maximal cytoreductive surgery. METHODS: Patients from six academic institutions who had FIGO stage III or IV ovarian cancer and underwent any bowel surgeries during maximal cytoreductive surgery were eligible for the study. The patients were divided into two groups according to whether bowel surgery was performed by a GO or a GS. In both groups, the GOs were mainly involved in extra bowel debulking procedures. Perioperative and survival outcomes were compared between the two groups. RESULTS: The 761 patients in this study included 113 patients who underwent bowel surgery by a GO and 648 who had bowel surgery by a GS. No discernible differences were observed in age, American Society of Anesthesiology (ASA) score, FIGO stage, histologic type, timing of cytoreductive surgery (primary or interval debulking surgery), or complications between the two groups. The GO group exhibited a shorter operation time than the GS group. Kaplan-Meier analysis showed no survival differences between the two groups. In the Cox analysis, non-serous cell types and gross residual diseases were associated with adverse effects on overall survival. However, performance of bowel surgery by a GO did not have an impact on survival. CONCLUSION: Performance of bowel surgery by a GO during maximal cytoreductive surgery is both feasible and safe. These results should be reflected in the training system for GOs regarding bowel surgery, and further research is needed to confirm that GOs can play a more leading role in performing extra-uterine procedures.