Outcome In Ovarian Cancer Patients Research Articles

The Prognostic and Clinical Value of Neutrophil-to-Lymphocyte Ratio (NLR) in Ovarian Cancer: A Systematic Review and Meta-analysis

Background: Ovarian cancer (OC) is a major gynecological malignancy with varying prognosis. The Neutrophil-to-Lymphocyte Ratio (NLR) has been proposed as a potential prognostic biomarker. This study aimed to evaluate the prognostic and clinical value of NLR in OC.
 Methods: A systematic review and meta-analysis were performed following PRISMA guidelines, including studies that evaluated the association between NLR and survival outcomes in OC patients. Search was performed in PubMed, Embase, Web of Science, and Cochrane Library databases. Quality assessment was done using Newcastle-Ottawa Scale (NOS). Heterogeneity was assessed, and pooled hazard ratios (HRs) were calculated using fixed or random-effects models as appropriate.
 Results: Twenty studies involving various ethnicities, ages, and sample sizes were included. A high NLR was found to be inversely correlated with overall survival (OS) (HR= 1.21, 95% CI 1.09-1.34, P<0.001) and progression-free survival (PFS) (HR=1.20, 95% CI 1.03-1.38, P<0.001). Stratified analyses showed a stronger association in Asian patients, studies with smaller sample sizes, younger patients, and higher NLR cutoff values.
 Conclusions: The meta-analysis suggests a significant inverse association between NLR and survival outcomes in OC patients, emphasizing NLR's potential as a simple, cost-effective prognostic biomarker. However, substantial heterogeneity and influence of confounding factors underscore the need for further investigation.

Machine learning developed a PI3K/Akt pathway-related signature for predicting prognosis and drug sensitivity in ovarian cancer.

Ovarian cancer is one of the deadliest malignancies among females, generally having a poor prognosis. The PI3K/Akt pathway plays a vital role in the oncogenesis and progression of many types of cancer. Limited studies have fully clarified the role of PI3K/Akt pathway in the prognosis of ovarian cancer and its correlation with drug sensitivity. A prognostic PI3K/Akt pathway related signature (PRS) was constructed with 10 machine learning algorithms using TCGA, GSE14764, GSE26193, GSE26712, GSE63885 and GSE140082 datasets. Gaussian mixture and logistic regression were performed to identify the optimal models for classifying lymphatic and venous invasion. The optimal prognostic PRS developed by Lasso + survivalSVM algorithm acted as an independent risk factor for overall survival (OS) of ovarian cancer patients and had a good performance in evaluating OS rate of ovarian cancer patients. Significant correlation was obtained between PRS-based risk score and Immune score, ESTIMATE score, immune cells and cancer-related hallmarks. Low risk score indicated a lower immune escape score, TIDE score, and higher PD1&CTLA4 immunophenoscore in ovarian cancer. Moreover, PRS-based risk score acted as an indicator for drug sensitivity in the immunotherapy and chemotherapy of ovarian cancer patients. All in all, our study developed a prognostic PRS showing powerful and good performance in predicting clinical outcome of ovarian cancer patients. PRS could serve as an indicator for drug sensitivity in the chemotherapy and immunotherapy.

Gene expression of non-homologous end-joining pathways in the prognosis of ovarian cancer

Ovarian cancer is the deadliest gynecologic malignancy in women, with a 46% five-year overall survival rate. The objective of the study was to investigate the effects of non-homologous end-joining (NHEJ) genes on clinical outcomes of ovarian cancer patients. To determine if these genes act as prognostic biomarkers of mortality and disease progression, the expression profiles of 48 NHEJ-associated genes were analyzed using an array of statistical and machine learning techniques: logistic regression models, decision trees, naive-Bayes, two sample t-tests, support vector machines, hierarchical clustering, principal component analysis, and neural networks. In this process, the correlation of genes with patient survival and disease progression and recurrence was noted. Also, multiple features from the gene set were found to have significant predictive capabilities. APTX, BRCA1, PAXX, LIG1, and TP53 were identified as most important out of all the candidate genes for predicting clinical outcomes of ovarian cancer patients.

KLF5 Promotes Tumor Progression and Parp Inhibitor Resistance in Ovarian Cancer.

One major characteristic of tumor cells is the aberrant activation of epigenetic regulatory elements, which remodelthe tumor transcriptome and ultimately promotecancer progression and drug resistance. However, the oncogenic functions and mechanisms of ovarian cancer (OC) remain elusive. Here, super-enhancer (SE) regulatory elements that are aberrantly activated in OC are identified and it is found that SEs drive the relative specific expression of the transcription factor KLF5 in OC patients and poly(ADP-ribose) polymerase inhibitor (PARPi)-resistant patients. KLF5 expression is associated with poor outcomes in OC patients and can drive tumor progression in vitro and in vivo. Mechanistically, KLF5 forms a transcriptional complex with EHF and ELF3 and binds to the promoter region of RAD51 to enhance its transcription, strengthening the homologous recombination repair (HRR) pathway. Notably, the combination of suberoylanilide hydroxamic acid (SAHA) and olaparib significantly inhibits tumor growth and metastasis of PARPi-resistant OC cells with high KLF5. In conclusion, it is discovered that SEs-driven KLF5 is a key regulatory factor in OC progression and PARPi resistance;and potential therapeutic strategies for OC patients with PARPi resistance and high KLF5 are identified.

Does the diagnostic timing of cancer-associated thromboembolism influence the survival outcome in ovarian cancer patients?

Efforts were made to explore the influence of diagnostic timing for cancer-associated thromboembolic events on survival of ovarian cancer patients. We reviewed the medical records of 75 ovarian cancer patients with thromboembolism and evaluated the prognostic factors affecting disease-free survival and overall survival. These 75 patients were classified into two categories by the diagnostic timing of the thromboembolism, during (33 cases) and after (42 cases) initial diagnosis of ovarian cancer groups. The diagnostic timing of thromboembolism was not related to disease-free survival or overall survival of the studied population. Advanced disease stage, clear cell histology, interval debulking surgery, no recurrence/persistence of ovarian cancer, and patients treated with anticoagulant(s) treatment >3 months were associated with the disease-free survival. Advanced disease stage, clear cell histology, body mass index (BMI) ≥24kg/m2 at the diagnosis of ovarian cancer, and no recurrence/persistence of ovarian cancer influenced the overall survival. In the subgroup analysis, compared to the after initial ovarian cancer diagnosis group, patients with stage I/II disease, BMI <24kg/m2 at the diagnosis of ovarian cancer, or primary debulking surgery in the during cancer diagnosis group had longer disease-free survival, and overall survival benefit was observed in cases with stage I/II disease, or primary debulking surgery. The diagnostic timing of thromboembolism was not related to disease-free or overall survival of ovarian cancer patients, but associated with that of specific patient subgroups.

Timing of interval debulking surgery and postoperative chemotherapy after neoadjuvant chemotherapy in advanced epithelial ovarian cancer: a multicenter real-world study

BackgroundTo investigate the prognostic relevance of the time to interval debulking surgery (TTS) and the time to postoperative adjuvant chemotherapy (TTC) after the completion of neoadjuvant chemotherapy (NACT).MethodsA retrospective real-word study included 658 patients with histologically confirmed advanced epithelial ovarian cancer who received NACT at seven tertiary hospitals in China from June 2008 to June 2020. TTS was defined as the time interval from the completion of NACT to the time of interval debulking surgery (IDS). TTC was defined as the time interval from the completion of NACT to the initiation of postoperative adjuvant chemotherapy (PACT).ResultsThe median TTS and TTC were 25 (IQR, 20–29) and 40 (IQR, 33–49) days, respectively. Patients with TTS > 25 days were older (55 vs. 53 years, P = 0.012) and received more NACT cycles (median, 3 vs. 2, P = 0.002). Similar results were observed in patients with TTC > 40 days. In the multivariate analyses, TTS and TTC were not associated with PFS when stratified by median, quartile, or integrated as continuous variables (all P > 0.05). However, TTS and TTC were significantly associated with worse OS when stratified by median (P = 0.018 and 0.018, respectively), quartile (P = 0.169, 0.014, 0.027 and 0.012, 0.001, 0.033, respectively), or integrated as continuous variables (P = 0.018 and 0.011, respectively). Similarly, increasing TTS and TTC intervals were associated with a higher risk of death (Ptrend = 0.016 and 0.031, respectively) but not with recurrence (Ptrend = 0.103 and 0.381, respectively).ConclusionThe delays of IDS and PACT after the completion of NACT have adverse impacts on OS but no impacts on PFS, which indicates that reducing delays of IDS and PACT might ameliorate the outcomes of ovarian cancer patients treated with NACT.

PSMD8 can serve as potential biomarker and therapeutic target of the PSMD family in ovarian cancer: based on bioinformatics analysis and in vitro validation

BackgroundThe ubiquity-proteasome system is an indispensable mechanism for regulating intracellular protein degradation, thereby affecting human antigen processing, signal transduction, and cell cycle regulation. We used bioinformatics database to predict the expression and related roles of all members of the PSMD family in ovarian cancer. Our findings may provide a theoretical basis for early diagnosis, prognostic assessment, and targeted therapy of ovarian cancer.MethodsGEPIA, cBioPortal, and Kaplan–Meier Plotter databases were used to analyze the mRNA expression levels, gene variation, and prognostic value of PSMD family members in ovarian cancer. PSMD8 was identified as the member with the best prognostic value. The TISIDB database was used to analyze the correlation between PSMD8 and immunity, and the role of PSMD8 in ovarian cancer tissue was verified by immunohistochemical experiments. The relationship of PSMD8 expression with clinicopathological parameters and survival outcomes of ovarian cancer patients was analyzed. The effects of PSMD8 on malignant biological behaviors of invasion, migration, and proliferation of ovarian cancer cells were studied by in vitro experiments.ResultsThe expression levels of PSMD8/14 mRNA in ovarian cancer tissues were significantly higher than those in normal ovarian tissues, and the expression levels of PSMD2/3/4/5/8/11/12/14 mRNA were associated with prognosis. Up-regulation of PSMD4/8/14 mRNA expression was associated with poor OS, and the up-regulation of PSMD2/3/5/8 mRNA expression was associated with poor PFS in patients with ovarian serous carcinomas. Gene function and enrichment analysis showed that PSMD8 is mainly involved in biological processes such as energy metabolism, DNA replication, and protein synthesis. Immunohistochemical experiments showed that PSMD8 was mainly expressed in the cytoplasm and the expression level was correlated with FIGO stage. Patients with high PSMD8 expression had poor prognosis. Overexpression of PSMD8 significantly enhanced the proliferation, migration, and invasion abilities in ovarian cancer cells.ConclusionWe observed different degrees of abnormal expression of members of PSMD family in ovarian cancer. Among these, PSMD8 was significantly overexpressed in ovarian malignant tissue, and was associated with poor prognosis. PSMDs, especially PSMD8, can serve as potential diagnostic and prognostic biomarkers and therapeutic targets in ovarian cancer.

Targeting regeneration capacity of stem cells to improve surgical wound healing outcomes in ovarian cancer patients.

e17578 Background: Despite advancements in care and treatment, ovarian cancer continues to be a challenging and deadly disease. Currently, standard treatment comprises a combination of cytoreductive surgery, often followed by platinum-based chemotherapy, known to negatively affect wound healing recovery. Therefore, achieving optimal post-surgical wound healing is critical in preventing delays in treatment, which can greatly impact patient outcomes and overall survival. Adipose-derived stem cells (ASC) have been shown to be crucial in regeneration of tissue and wound closure, as well as in regulating inflammatory differentiation and proliferation processes. Thus, improving the regeneration capacity of ASCs in wounds may speed post-surgical recovery and subsequent treatments. While a number of compounds have been shown to potentiate the regeneration ability of ASCs, we hypothesize that naturally derived epigenetic compounds with anti-cancer properties (I3C and EGCG), as well as anti-inflammatory compounds (non-psychoactive cannabidiol, CBD), may have a role in increasing regeneration capacity of stem cells. Therefore, ASCs were primed with these compounds and expression of major inflammatory, anti-inflammatory, proliferation and regeneration markers was evaluated. Methods: ASCs were primed with either I3C 50uM, EGCG 10 uM, or CBD 100nM. Conditioned medium from these treatments was collected and underwent a protein array assay for detection of levels of 40 human inflammatory markers and cytokines according to the manufacturer instructions. A one-way ANOVA test and Tukey post-hoc testing analyzed intensities for each marker between the control group and each of the primed groups. Results: Our results indicate that ASCs primed with our epigenetic treatments significantly decrease expression of a multitude of inflammatory markers and cytokines. I3C primed ASCs showed significantly decreased expression of the following factors: I-309, IL-11, IL-12 p40, IL-12p70, IL-1α, IL-6sR, M-CSF, MIG, MIP-1α, MIP-1β, MIP-1δ, IL-6, MCP-1, TIMP-2. EGCG primed ASCs significantly decreased expression of IL-12p70, IL-13, IL-6sR, MIP-1α, MIP-1δ, RANTES, IL-6, IL-8, MCP-1, TIMP-2. CBD primed ASCs significantly decreased expression of IL-6. A p&lt; .05 was used. Conclusions: Priming ASCs with EGCG, I3C and CBD significantly down-regulate expression of a number of pro-inflammatory markers known to delay and interfere with the kinetics of wound healing processes, including wound inflammation, closure and scar formation. Therefore, these results suggest that naturally derived epigenetic compounds and CBD successfully potentiated ASCs’ ability to attenuate inflammation and wound healing processes. Consequently, our findings can lead to new diet and surgical ASC protocols which could optimize cancer post-operative wound healing closure time while decreasing inflammation.

Triple checkpoint blockade, but not anti-PD1 alone, enhances the efficacy of engineered adoptive T cell therapy in advanced ovarian cancer

Abstract Less than 50% of ovarian cancer patients survive five years after diagnosis. This rate has changed little in the last 30 years, highlighting the need for novel therapies. A promising strategy employs T cells engineered to target tumor-expressed proteins. Mesothelin (Msln) is overexpressed in ovarian cancers, contributes to the malignant and invasive phenotype and has limited expression in healthy cells, making it a candidate immunotherapy target. We used the immune-competent ID8 VEGFmouse model of advanced ovarian cancer to show that T cells engineered to express a Msln-specific T cell receptor (TCR Msln) can preferentially accumulate within established tumors, delay tumor growth and significantly prolong mouse survival. However, elements in the tumor microenvironment limited engineered T cell function. Tumor-bearing mice were therefore treated with TCR MslnT cells plus PD1, Tim-3 and/or Lag-3 checkpoint-blocking antibodies, alone or in combination. Triple checkpoint blockade, but not single- or double-agent treatments, dramatically increased effector cytokine production by intratumoral TCR MslnT cells. Single cell RNA-sequencing revealed gene expression changes in intratumoral TCR MslnT cells and myeloid cells consistent with immune activation and inflammation. Moreover, combining adoptive immunotherapy with triple checkpoint blockade prolonged survival in treated mice, relative to TCR Mslnwith or without single- or double-agent checkpoint blockade. These results suggest that disrupting multiple immune-inhibitory pathways simultaneously, which can be more safely pursued in a cell intrinsic form through genetic engineering, may be necessary to improve outcomes for ovarian cancer patients.

Identification and Validation of NK Marker Genes in Ovarian Cancer by scRNA-seq Combined with WGCNA Algorithm.

As an innate immune system effector, natural killer cells (NK cells) play a significant role in tumor immunotherapy response and clinical outcomes. In our investigation, we collected ovarian cancer samples from TCGA and GEO cohorts, and a total of 1793 samples were included. In addition, four high-grade serous ovarian cancer scRNA-seq data were included for screening NK cell marker genes. Weighted gene coexpression network analysis (WGCNA) identified core modules and central genes associated with NK cells. The "TIMER," "CIBERSORT," "MCPcounter," "xCell," and "EPIC" algorithms were performed to predict the infiltration characteristics of different immune cell types in each sample. The LASSO-COX algorithm was employed to build risk models to predict prognosis. Finally, drug sensitivity screening was performed. We first scored the NK cell infiltration of each sample and found that the level of NK cell infiltration affected the clinical outcome of ovarian cancer patients. Therefore, we analyzed four high-grade serous ovarian cancer scRNA-seq data, screening NK cell marker genes at the single-cell level. The WGCNA algorithm screens NK cell marker genes based on bulk RNA transcriptome patterns. Finally, a total of 42 NK cell marker genes were included in our investigation. Among which, 14 NK cell marker genes were then used to develop a 14-gene prognostic model for the meta-GPL570 cohort, dividing patients into high-risk and low-risk subgroups. The predictive performance of this model has been well-verified in different external cohorts. Tumor immune microenvironment analysis showed that the high-risk score of the prognostic model was positively correlated with M2 macrophages, cancer-associated fibroblast, hematopoietic stem cell, stromal score, and negatively correlated with NK cell, cytotoxicity score, B cell, and T cell CD4+Th1. In addition, we found that bleomycin, cisplatin, docetaxel, doxorubicin, gemcitabine, and etoposide were more effective in the high-risk group, while paclitaxel had a better therapeutic effect on patients in the low-risk group. By utilizing NK cell marker genes in our investigation, we developed a new feature that is capable of predicting patients' clinical outcomes and treatment strategies.

Metabolic reprogramming of the ovarian cancer microenvironment in the development of antiangiogenic resistance.

Antiangiogenic therapies, such as treatment with bevacizumab, display modest survival benefits in ovarian cancer (OC) patients. After a transient response, the upregulation of compensatory proangiogenic pathways and the adoption of alternative vascularization processes lead to the development of resistance. Considering the high mortality rate of OC, there is an urgent need to uncover the underlying mechanisms of antiangiogenic resistance for the development of novel and effective treatment strategies. Recent investigations have confirmed that metabolic reprogramming in the tumor microenvironment (TME) exerts an essential effect on tumor aggressiveness and angiogenesis. In this review, we provide an overview of the metabolic crosstalk between OC and the TME, highlighting the regulatory mechanisms underlying the development of antiangiogenic resistance. Metabolic interventions may interrupt this complex and dynamic interactive network, providing a promising therapeutic option to improve clinical outcome in OC patients.

Upregulation of programmed death ligand-1 in tumor-associated macrophages affects chemotherapeutic response in ovarian cancer cells.

To better understand the mechanism of chemoresistance in ovarian cancer cells, we aimed to investigate the influence of macrophages on the tumor cell response to carboplatin and identify the genes associated with chemoresistance. We mimicked the tumor microenvironment (TME) using a co-culture technique and compared the proliferation of ovarian cells with and without macrophages. We also examined M1 and M2 marker expression and the expression of key TME genes. Post the co-culture, we treated ovarian cancer cells with carboplatin and elucidated the function of programmed death-ligand 1 (PD-L1) in carboplatin chemoresistance. We investigated CD68 and PD-L1 expression in normal and cancerous ovarian tissues using immunohistochemistry (IHC). Finally, we analyzed the association between CD68 or PD-L1 expression and survival outcomes. Inducible nitric oxide synthase (iNOS) was downregulated, while the gene expression of M2 macrophage markers was increased in ovarian cancer cells. PD-L1, vascular endothelial growth factor (VEGF), Interleukin (IL)-6, IL-10, IL-12, signal transducer and activator of transcription 3 (STAT3), B-cell lymphoma 2 (BCL2), multidrug resistance 1 (MDR1), and colony stimulating factor 1 (CSF-1) were upregulated. Notably, PD-L1 was upregulated in both the ovarian cancer cells and macrophages. Ovarian cancer cells co-cultured with macrophages exhibited statistically significant carboplatin resistance compared to single-cultured ovarian cancer cells. PD-L1 silencing induced chemosensitivity in both types of co-cultured ovarian cancer cells. However, IHC results revealed no correlation between PD-L1 expression and patient survival or cancer stage. CD68 expression was significantly increased in cancer cells compared to normal or benign ovarian tumor cells, but it was not associated with the survival outcomes of ovarian cancer patients. Our study demonstrated that ovarian cancer cells interact with macrophages to induce the M2 phenotype. We also established that PD-L1 upregulation in both ovarian cancer cells and macrophages is a key factor for carboplatin chemoresistance.

Identification of an Autophagy-Related Signature for Prognosis and Immunotherapy Response Prediction in Ovarian Cancer.

Ovarian cancer (OC) is one of the most malignant tumors in the female reproductive system, with a poor prognosis. Various responses to treatments including chemotherapy and immunotherapy are observed among patients due to their individual characteristics. Applicable prognostic markers could make it easier to refine risk stratification for OC patients. Autophagy is closely implicated in the occurrence and development of tumors, including OC. Whether autophagy -related genes can be used as prognostic markers for OC patients remains unclear. The gene transcriptome data of 374 OC patients were downloaded from The Cancer Genome Atlas (TCGA) database. The correlation between the autophagy levels and outcomes of OC patients was identified through the single sample gene set enrichment analysis (ssGSEA). Recognized molecular markers of autophagy in different clinical specimens were detected by immunohistochemistry (IHC) assay. The gene set enrichment analysis (GSEA), ESTIMATE, and CIBERSORT analysis were applied to explore the correlation of autophagy with the tumor immune microenvironment (TIME). Single-cell RNA-sequencing (scRNA-seq) data from seven OC patients were included for characterizing cell-cell interaction patterns of autophagy-high or low tumor cells. Machine learning, Stepwise Cox regression and LASSO-Cox analysis were used to screen autophagy hub genes, which were used to establish an autophagy-related signature for prognosis evaluation. Four tumor immunotherapy cohorts were obtained from the GEO (Gene Expression Omnibus) database and the literature for autophagy risk score validation. The autophagy levels were closely related to the prognosis of the OC patients. Additionally, the autophagy levels were correlated with TIME status including immune score, and immune-cell infiltration. The scRNA-seq analysis found that tumor cells with high or low autophagy levels had different interactions with immune cells, especially macrophages. Eight autophagy-hub genes (ZFYVE1, AMBRA1, LAMP2, TRAF6, PDPK1, ATG2B, DAPK1 and TP53INP2) were screened for an autophagy-related signature. According to this signature, higher risk score was correlated with poor prognosis and better immunotherapy response in the OC patients. The autophagy-related signature is applicable to predict the prognosis and immune checkpoint inhibitors (ICIs) therapy efficiency in OC patients. It is possible to identify OC patients who will respond to ICIs therapy and have a favorable prognosis, although more verification is needed.

Peripheral and tumor-infiltrating immune cells are correlated with patient outcomes in ovarian cancer.

At present, there is still a lack of reliable biomarkers for ovarian cancer (OC) to guide prognosis prediction and accurately evaluate the dominant population of immunotherapy. In recent years, the relationship between peripheral blood markers and tumor-infiltrating immune cells (TICs) with cancer has attracted much attention. However, the relationship between the survival of OC patients and intratumoral- or extratumoral-associated immune cells remains controversial. In this study, four machine-learning algorithms were used to predict overall survival in OC patients based on peripheral blood indicators. To further screen out immune-related gene and molecular targets, we systematically explored the correlation between TICs and OC patient survival based on The Cancer Genome Atlas database. Using the TICs score method, patients were divided into a low immune infiltrating cell group and a high immune infiltrating cell group. The results showed that there was a significant statistical significance between the peripheral blood indicators and the survival prognosis of OC patients. Survival analysis showed that TICs play a crucial role in the survival of OC patients. Four core genes, CXCL9, CD79A, MS4A1, and MZB1, were identified by cross-PPI and COX regression analysis. Further analysis found that these genes were significantly associated with both TICs and survival in OC patients. These results suggest that both peripheral blood markers and TICs can be used as prognostic predictors in patients with OC, and CXCL9, CD79A, MS4A1, and MZB1 may be potential therapeutic targets for OC immunotherapy.

E2F8 knockdown suppresses cell proliferation and induces cell cycle arrest via Wnt/β-Catenin pathway in ovarian cancer.

Ovarian cancer is one of the leading causes of death in female reproductive system cancers. However, the pathogenesis of ovarian cancer remains elusive. Our aim is to investigate the potential targets for ovarian cancer. Two microarray datasets were obtained from the Gene Expression Omnibus public database. Using R package limma, the differentially expressed genes (DEGs) were identified from the datasets. There were 95 overlapping DEGs in two microarray datasets. GO, KEGG pathway analysis, and protein-protein interaction (PPI) network analysis were carried out based on the DEGs. Wnt signaling pathway and cell cycle were enriched in the KEGG pathway analysis. Moreover, the top 10 hub genes with the most nodes were determined by PPI network analysis. E2F8, one of hub genes was positively linked to a bad outcome in ovarian cancer patients. Furthermore, E2F8 knockdown suppressed cell proliferation and induced cell cycle arrest in ovarian cancer. In addition, we found that silencing E2F8 inhibited the Wnt/β-catenin signaling pathway. In ovarian cancer cells with E2F8 knockdown, overexpressing β-catenin restored both the suppressed capacity of cell proliferation and cell cycle progression. Therefore, our results revealed that E2F8 had an involvement in the development of ovarian cancer which might act as a therapeutic target.

Platelet to Lymphocyte Ratio as a Predictive Tool for the Perioperative and Postoperative Outcomes in Advanced Stage Ovarian Cancer.

Background: platelet to lymphocyte ratio remains a significant prognostic factor in different malignancies. The aim of the current paper is to study the correlation between the preoperative values of platelet to lymphocyte ratio (PLR) and the postoperative outcomes in ovarian cancer patients. Method: we conducted a retrospective study on 57 patients submitted to cytoreductive surgery between 2014-2020. We determined the optimal cut off value of PLR for predicting survival outcomes by using the Receiver Operating Characteristic curve a value of 350 being obtained. The patients were further classified in two groups according to the PLR value. Results: there were 37 patients with PLR 350 and respectively 20 patients with PLR 350. Patients in the second group were significantly older and presented significantly higher rates of perioperative complications, a significantly higher level of circulating platelets, of CA125 and respectively a significantly lower level of circulating lymphocytes and of preoperative hemoglobin level. Meanwhile, patients in the second group reported a significantly poorer disease free and overall survival. Conclusions: ovarian cancer patients with higher preoperative levels of PLR trend to have a poorer early and long-term postoperative outcome. Therefore, in such cases more aggressive systemic therapies might be needed.

SPP1 is a prognostic related biomarker and correlated with tumor-infiltrating immune cells in ovarian cancer

BackgroundSecreted phosphoprotein 1 (SPP1) plays a vital role in tumor progression of multiple cancer types However, it still awaits further exploration whether SPP1 is a bystander or an actual player in the modulation of immune infiltration in ovarian cancer.MethodsIn this study, the expression level of SPP1 was identified by Oncomine, GEPIA and TIMER databases, and the result of SPP1 immumohistochemical staining was acquired by The HPA database. The impact of SPP1 expression level on the clinical outcome of ovarian cancer patients were evaluated via Kaplan–Meier Plotter and PrognoScan dataset. Immune infiltration analyses were conducted using TIMER and TISIDB dataset. In addition, Functional enrichment analyses were performed with Metascape and GeneMANIA database. To verify these findings from the public database, the results were validated in a cohort of ovarian cancer patients.ResultsSPP1 was found to be overexpressed in ovarian tumor tissues and high SPP1 expression was correlated with shorter survivals. Notably, SPP1 expression was positively correlated with infiltrating levels of CD4 + T cells, CD8 + T cells, macrophages, neutrophils, and dendritic cells. Furthermore, SPP1 expression level showed strong correlation with diverse immune cells in ovarian cancer. Of note, functional enrichment analysis suggested that SPP1 was strongly correlated with immune response.ConclusionsThese findings imply that SPP1 is correlated with prognosis and immune cell infiltrating, offering a new potential immunotherapeutic target in ovarian cancer.Trial registrationNot applicable.

Molecular linking of HIPEC (Hyperthermic Intraperitoneal Chemotherapy) and T-regulatory cells (FOXp3) and Th-17 (RORɣ) in advanced epithelial ovarian cancer

Despite of multimodality treatment of Ovarian Cancer (OC), about two-thirds of patients have peritoneal recurrence with 5-year survival of 15–35%. HIPEC (Hyperthermic Intraperitoneal Chemotherapy) delivers cell-cycle non-specific chemotherapeutic agents along with the temperature of 41°C to 43 °C into the peritoneal cavity after achieving complete cytoreduction, improving overall survival around 50% and recurrence-free survival significantly. Cytoreductive surgery (CRS) and HIPEC may be Upfront OR Primary - when performed primarily , Interval - when performed after 3 to 6 six cycles of Neo-adjuvant chemotherapy(NACT) and S econdary- when performed for patients who have a recurrence after CRS. OC is associated frequently with tumor-infiltrating lymphocytes in OC microenvironment. Here, we sought to study the interaction of HIPEC on FOXp3 and RORɣ T cells in primary, interval and recurrent settings of HIPEC. We have seen the expression of FOXp3, RORɣ in tumor tissue and surrounding normal tissue of ovarian cancer patients. We also performed IHC of tumor tissue and qRT-PCR of cDNA, isolated from tumor tissue and adjacent normal tissue for the same expression and compared intra-group and among the groups.We studied the expression of FOXp3,RORɣ, Interleukin-10 (IL-10) and Interleukin-17 (IL-17) in peripheral blood mononuclear cells(PBMC) before and after HIPEC in one week and four weeks and compared the changes of expressions. We included 30 patients with FIGO stage III to IVA advanced Epithelial ovarian cancer patients, with minimum 10 patients in each subgroup i.e.,upfront, interval and secondary. The pilot study was conducted between June 2017 to February 2021 at the premier Institute, India after Ethical approval. Though there was highest expression of FOXp3 mRNA in recurrent group followed by upfront and interval. However, there was no difference in RORɣ T cell mRNA (by qRT-PCR) expression among three subgroups. We found the change in the expression of FOXp3 and RORɣ T cell in Peripheral blood mononuclear cells by flowcytometry, before and after HIPEC (around 1 week and 4 week after HIPEC) to be significant. In the interval group, there was decreased expression of pre-op Foxp3 compared to the upfront ( p = 0.0121) and control ( p = 0.0187). These findings suggest that neoadjuvant chemotherapy may reverse the immunosuppressive environment in ovarian cancers. In the upfront group, there was a transient increase of FOXp3 in one week post HIPEC ( p = 0.005) and then it decreased to below pre-op values in 4 weeks ( p = 0.022). There was no difference in pre-op RORγ and IL 17 among the three subgroups.However, RORγ was increased at four weeks post-HIPEC in the upfront group ( p = 0.009), interval group ( p = 0.032), and the recurrent group. ( p = 0.001). Overall these findings suggest that HIPEC can reverse the immunosuppressive mechanism in ovarian tumor microenvironment (TME),thereby improving survival In this study, we could come to a conclusion that there is a complex nature of interaction at a molecular and immunological level in epithelial ovarian cancer patients underwent HIPEC in different settings. There is an urgent need to explore bio-molecular markers to improve treatment outcomes of ovarian cancer patients. This basic research study exploring the role of FOXp3 Tregs and RORγ T-helper cells indicated their potential role as biomarkers in understanding ovarian cancer prognosis and the impact of therapeutic interventions like HIPEC in this study, on outcomes.

Incidence and predictors for chemotherapy modifications and their impact on the outcome of ovarian cancer patients

PurposeChemotherapy (CTX) is an important part of the treatment strategy of stage II–IV ovarian cancer. CTX modifications, such as delays, dose reductions or premature terminations might have a negative impact on overall survival (OS) and progression free survival (PFS). The goal of this study was to determine the incidence and predictors of CTX modifications and their influence on survival.MethodsAn observational retrospective cohort analysis of 192 ovarian cancer patients who were treated at the Department of Obstetrics and Gynaecology, Technical University Munich, Germany, according to international guidelines was performed including from 2009 to 2013. A potential association between patient and disease characteristics and CTX modifications was tested with multivariate logistic regression. OS and PFS were estimated by Kaplan–Meier analysis.Results44.8% (86/192) received a modification of CTX. 34 (17.7%) women discontinued CTX prematurely, 17 (8.9%) underwent a dose reduction, 16 (8.3%) experienced a CTX delay and 10 (5.2%) had both a delay and a dose modification. In nine (4.7%) patients, the dose needed to be divided. Leukopenia (p < 0.001) and anaemia (p = 0.003) were significantly more common in patients with CTX modifications. Significant predictors for CTX modifications were a history of thrombosis or embolism (p < 0.001) and residual tumour postoperatively (p = 0.003).Patients with CTX modifications showed a significantly lower OS as well as PFS (p < 0.001), even after adjustment for prognostic factors such as age, body-mass-index, residual tumour, histology, FIGO stage and grading (p = 0.005 for OS and p = 0.001 for PFS).ConclusionCTX modifications have a negative impact on survival. Significant predictors for such modifications are a history of thrombosis or embolism and the presence of residual postoperative tumour. Further studies are needed to avoid CTX modifications and to improve survival of ovarian cancer patients.

Germline BRCA mutation carriers are more likely to undergo cytoreductive surgery for relapsed, platinum sensitive, ovarian cancer

ObjectiveBRCA mutations have been associated with improved outcomes in ovarian cancer patients. This study's objective was to compare the secondary cytoreduction surgery (SCS) rates among ovarian cancer patients by BRCA mutation status. MethodsThe study was retrospective and included platinum sensitive recurrent high grade serous ovarian cancer patients from one Canadian center and two Israeli centers from January 1999 to December 2018. Demographic and genetic data, tumor characteristics, patterns of recurrence and surgical and medical treatments were obtained from electronic charts. Patients were grouped according to BRCA mutation status. Logistic regression analyses were used to explore potential prognostic factors of secondary cytoreduction. Results147 patients were enrolled, including 97 from Canada and 50 from Israel. Forty-seven patients (32%) had a BRCA mutation, including 39 (26.5%) germline mutations and 8 (5.5%) somatic mutations. Thirty-one patients (21.1%) underwent SCS. The rate of SCS was 33.3% among the germline BRCA mutation carriers and 15.7% among patients without germline BRCA mutation (p = 0.026). Predictors of secondary cytoreduction included germline BRCA mutation (OR = 2.5, p = 0.03), time to recurrence (OR = 1.004 per month, p < 0.001), absence of lymphatic recurrence (OR = 3.08, p = 0.013), three or fewer lesions at recurrence (OR = 36.74, p < 0.001) and absence of ascites (OR = 9.1, p = 0.034). After adjusting for the number of lesions at recurrence, no other variable remained a significant predictor. ConclusionGermline BRCA mutation carriers are more likely to undergo secondary cytoreduction. This may be mediated in part by lower volume disease at recurrence. This observation should be considered when planning surveillance for these patients after first-line treatment.