Objective The presence of T cells within the epithelial component of tumors, as histologic evidence of anti-tumor immunity, has been associated with a survival advantage in multiple studies across diverse patient cohorts. We performed a meta-analysis of studies evaluating the prognostic value of tumor-infiltrating lymphocytes (TIL) on survival among women with ovarian cancer and to investigate factors associated with variations in this effect, including patient characteristics, surgical outcomes, tumor histology, and study protocols. Method Published studies that evaluated the association between TIL and patient survival were identified. Descriptive statistics, outcome data, and study quality were extracted from studies that met inclusion criteria. Hazard ratios and 95% confidence intervals were pooled across studies using the random-effects model. Publication bias was investigated using a funnel plot and heterogeneity was assessed with subgroup analysis and I2 statistics. Results Ten suitable studies comprising 1,815 patients with ovarian cancer were analyzed. Our results demonstrate that a lack of intraepithelial TILs is significantly associated with a worse survival among patients (pooled HR: 2.24, 95% CI; 1.71–2.91). Variations in the prognostic value of TIL status based on debulking status, scoring method, and geographic regions were identified. Conclusions Intraepithelial TILs are a robust predictor of outcome in ovarian cancer and define a specific class of patients, whose distinct tumor biology should be taken into account in devising appropriate therapeutic strategies.

MicroRNAs (miRNAs) are an abundant class of small noncodingRNAs that function as negative gene regulators. miRNA deregulation is involved in the initiation and progression of human cancer; however, the underlying mechanism and its contributions to genome-wide transcriptional changes in cancer are still largely unknown. We studied miRNA deregulation in human epithelial ovarian cancer by integrative genomic approach, including miRNA microarray (n ‫؍‬ 106), array-based comparative genomic hybridization (n ‫؍‬ 109), cDNA microarray (n ‫؍‬ 76), and tissue array (n ‫؍‬ 504). miRNA expression is markedly down-regulated in malignant transformation and tumor progression. Genomic copy number loss and epigenetic silencing, respectively, may account for the downregulation of Ϸ15% and at least Ϸ36% of miRNAs in advanced ovarian tumors and miRNA down-regulation contributes to a genome-wide transcriptional deregulation. Last, eight miRNAs located in the chromosome 14 miRNA cluster (Dlk1-Gtl2 domain) were identified as potential tumor suppressor genes. Therefore, our results suggest that miRNAs may offer new biomarkers and therapeutic targets in epithelial ovarian cancer.Dlk1-Gtl2 domain ͉ noncoding RNA

Immune checkpoint blockade has shown significant therapeutic efficacy in melanoma and other solid tumors, but results in ovarian cancer have been limited. With evidence that tumor immunogenicity modulates the response to checkpoint blockade, and data indicating that BRCA-deficient ovarian cancers express higher levels of immune response genes, we hypothesized that BRCA ovarian tumors would be vulnerable to checkpoint blockade. To test this hypothesis, we used an immunocompetent BRCA1-deficient murine ovarian cancer model to compare treatment with CTLA-4 or PD-1/PD-L1 antibodies alone or combined with targeted cytotoxic therapy using a PARP inhibitor. Correlative studies were performed in vitro using human BRCA1 cells. We found that CTLA-4 antibody, but not PD-1/PD-L1 blockade, synergized therapeutically with the PARP inhibitor, resulting in immune-mediated tumor clearance and long-term survival in a majority of animals (P < 0.0001). The survival benefit of this combination was T-cell mediated and dependent on increases in local IFNγ production in the peritoneal tumor environment. Evidence of protective immune memory was observed more than 60 days after completion of therapy. Similar increases in the cytotoxic effect of PARP inhibition in the presence of elevated levels of IFNγ in human BRCA1 cancer cells support the translational potential of this treatment protocol. These results demonstrate that CTLA-4 blockade combined with PARP inhibition induces protective antitumor immunity and significant survival benefit in the BRCA1 tumor model, and support clinical testing of this regimen to improve outcomes for women with hereditary ovarian cancer.

Rationale: Post-intensive care syndrome (PICS), defined as new or worsening impairment in cognition, mental health, or physical function after critical illness, is an important development in survivors. Although studies to date have focused on the frequency of these impairments, fundamental questions remain unanswered regarding the survivor experience and the impact of the critical illness event on survivor resilience and recovery.Objectives: To examine the association between resilience and neuropsychological and physical function and to contextualize these findings within the survivors' recovery experience. Methods:We conducted a mixed-methods pilot investigation of resilience among 43 survivors from two medical intensive care units (ICUs) within an academic health-care system. We interviewed survivors to identify barriers to and facilitators of recovery in the ICU, on the medical ward, and at home, using qualitative methods. We used a telephone battery of standardized tests to examine resilience, neuropsychological and physical function, and quality of life. We examined PICS in two ways. First, we identified how frequently survivors were impaired in one or more domains 6-12 months postdischarge. Second, we identified how frequently survivors reported that neuropsychological or physical function was worse. Measurements and Main Results:Resilience was low in 28% of survivors, normal in 63% of survivors, and high in 9% of survivors. Resilience was inversely correlated with self-reported executive dysfunction, symptoms of anxiety, depression, and post-traumatic stress disorder, difficulty with self-care, and pain (P , 0.05). PICS was present in 36 survivors (83.7%; 95% confidence interval, 69.3-93.2%), whereas 23 survivors (53.5%; 95% confidence interval, 37.6-68.8%) reported worsening of neuropsychological or physical function after critical illness. We identified challenges along the recovery path of ICU survivors, finding that physical limitations and functional dependence were the most frequent challenges experienced in the ICU, medical ward, and on return to home. Spiritual and family support facilitated recovery. Conclusions:Resilience was inversely correlated with neuropsychological impairment, pain, and difficulty with self-care. PICS was present in most survivors of critical illness, and 54% reported neuropsychological or physical function to be worse, yet resilience was normal or high in most survivors. Survivors experienced many challenges during recovery, while spiritual and family support facilitated recovery.