Prevalence of active cytomegalovirus infection at diagnosis of ovarian cancer and during chemotherapy and subsequent changes in cognitive functioning.

PURPOSE: One of the most frequently reported effects of cancer and its treatments is cancer-related cognitive impairment (CRCI). Viral infections may affect inflammation and immune function and therefore may influence patient symptoms, including CRCI. The goal of this study was to describe the prevalence of cytomegalovirus (CMV) infections at diagnosis, during, and after chemotherapy in individuals with ovarian cancer and explore CMV infection at diagnosis with cancer-related cognitive impairment (CRCI) following chemotherapy. METHODS: We recruited adults newly diagnosed with ovarian, primary peritoneal or fallopian tube cancer at a single academic cancer center into two prospective studies. In Study 1 (N = 71), participants provided blood samples at diagnosis. In Study 2 (N = 18), participants provided blood samples and completed symptom surveys before, during and after front-line adjuvant chemotherapy. Serum CMV DNA levels were assessed using digital PCR; >100 copies/mL of serum was considered positive for active CMV infection (CMV+). CRCI was measured using the Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog) questionnaire. Changes in FACT-Cog scores were compared by CMV status at diagnosis using t-tests at each time point. RESULTS: At diagnosis, 29.2% were CMV+ (28.2% in Study 1, 33.3% in Study 2). Following three cycles of chemotherapy (Study 2), CMV positivity rose to 60.0% and then back down to 31.3% after chemotherapy. We observed significant differences in CRCI following chemotherapy by CMV status at diagnosis. CONCLUSION: Our data suggest that active CMV infection is common among patients undergoing treatment for ovarian cancer and may contribute to symptoms of CRCI.

Cytomegalovirus and systemic inflammation at time of surgery is associated with worse outcomes in serous ovarian cancer.

OBJECTIVES: Cytomegalovirus (CMV) is a common infection that establishes latency in healthy people. CMV has been associated with alterations of the immune compartment leading to improved responses, while inflammation has been shown to adversely impact outcomes. We investigated whether CMV serostatus predicts outcomes in ovarian cancer in the presence or absence of inflammation. METHODS: A total of 106 patients with serous ovarian cancer from 2006 to 2009 were analyzed. CMV and systemic inflammation was measured using CMV immunoglobulin G (IgG) and C-reactive protein (CRP), respectively, in serum collected prior to cytoreduction. Patients were stratified by CMV IgG (non-reactive, reactive/borderline) and CRP (≤10, >10 mg/L) status. Overall survival (OS) and recurrence-free survival (RFS) were compared by group using log-rank tests and Cox proportional hazards regression models adjusting for age at surgery. RESULTS: Of 106 eligible patients, 40 (37.7%) were CMV+/CRP+, 24 (22.6%) CMV+/CRP-, 19 (17.9%) CMV-/CRP+, and 23 (21.7%) CMV-/CRP-. CRP+ had higher CA-125 levels (P = 0.05) and higher rates of suboptimal debulking (P = 0.03). There were no other significant differences in demographic, surgical, or pathologic factors between groups. CMV+/CRP+ patients median RFS and OS were 16.9 months (95% CI: 9.0-21.1) and 31.7 months (95% CI: 25.0-48.7), respectively, with a significantly worse RFS (aHR: 1.85, 95% CI: 1.05-3.24, P = 0.03) and OS (aHR: 2.12, 95% CI: 1.17-3.82, P = 0.01) compared to CMV-/CRP- (RFS = 31.2 months (95% CI: 16.0-56.4) and OS = 63.8 months (95% CI: 50.7-87.0)). CMV+/CRP- group displayed the longest OS (89.3 months). CONCLUSIONS: Previous exposure to CMV and high CRP at surgery portended worse RFS and OS compared to women who tested negative. The CMV+/CRP- group had the longest OS, indicating that CMV status alone, in the absence of inflammation, may be protective.

Dilution of Molecular-Pathologic Gene Signatures by Medically Associated Factors Might Prevent Prediction of Resection Status After Debulking Surgery in Patients With Advanced Ovarian Cancer.

PURPOSE: Predicting surgical outcome could improve individualizing treatment strategies for patients with advanced ovarian cancer. It has been suggested earlier that gene expression signatures (GES) might harbor the potential to predict surgical outcome. EXPERIMENTAL DESIGN: Data derived from high-grade serous tumor tissue of FIGO stage IIIC/IV patients of AGO-OVAR11 trial were used to generate a transcriptome profiling. Previously identified molecular signatures were tested. A theoretical model was implemented to evaluate the impact of medically associated factors for residual disease (RD) on the performance of GES that predicts RD status. RESULTS: A total of 266 patients met inclusion criteria, of those, 39.1% underwent complete resection. Previously reported GES did not predict RD in this cohort. Similarly, The Cancer Genome Atlas molecular subtypes, an independent de novo signature and the total gene expression dataset using all 21,000 genes were not able to predict RD status. Medical reasons for RD were identified as potential limiting factors that impact the ability to use GES to predict RD. In a center with high complete resection rates, a GES which would perfectly predict tumor biological RD would have a performance of only AUC 0.83, due to reasons other than tumor biology. CONCLUSIONS: Previously identified GES cannot be generalized. Medically associated factors for RD may be the main obstacle to predict surgical outcome in an all-comer population of patients with advanced ovarian cancer. If biomarkers derived from tumor tissue are used to predict outcome of patients with cancer, selection bias should be focused on to prevent overestimation of the power of such a biomarker.See related commentary by Handley and Sood, p. 9.

Cytokine-induced memory-like natural killer cells have enhanced function, proliferation, and in vivo expansion against ovarian cancer cells.

OBJECTIVE: Natural killer (NK) cells are lymphocytes well suited for adoptive immunotherapy. Attempts with adoptive NK cell immunotherapy against ovarian cancer have proven unsuccessful, with the main limitations including failure to expand and diminished effector function. We investigated if incubation of NK cells with interleukin (IL)-12, IL-15, and IL-18 for 16h could produce cytokine-induced memory-like (CIML) NK cells capable of enhanced function against ovarian cancer. METHODS: NK cells were preactivated briefly with IL-12, IL-15, and IL-18, rested, then placed against ovarian cancer targets to assess phenotype and function via flow cytometry. Real-time NK-cell-mediated tumor-killing was evaluated. Using ascites cells and cell-free ascites fluid, NK cell proliferation and function within the immunosuppressive microenvironment was evaluated in vitro. Finally, CIML NK cells were injected intraperitoneal (IP) into an in vivo xenogeneic mouse model of ovarian cancer. RESULTS: CIML NK cells demonstrate enhanced cytokine (IFN-γ) production and NK-cell-mediated killing of ovarian cancer. NK cells treated overnight with cytokines led to robust activation characterized by temporal shedding of CD16, induction of CD25, and enhanced proliferation. CIML NK cells proliferate more with enhanced effector function compared to controls in an immunosuppressive microenvironment. Finally, human CIML NK cells exhibited potent antitumor effects within a xenogeneic mouse model of ovarian cancer. CONCLUSIONS: CIML NK cells have enhanced functionality and persistence against ovarian cancer in vitro and in vivo, even when exposed to ascites fluid. These findings provide a strategy for NK cell-based immunotherapy to circumvent the immunosuppressive nature of ovarian cancer.

Appropriate Use of Prophylactic Antibiotic Agents in Gynecologic Surgeries at a Midwestern Teaching Hospital.

BACKGROUND: The purpose of this study was to establish compliance with guidelines published by the American College of Obstetricians and Gynecologists (ACOG) regarding prophylactic antibiotic use in gynecologic surgery at our institution, and define areas of improvement to promote antibiotic stewardship. PATIENTS AND METHODS: This was a retrospective cohort study at a single, large tertiary care and teaching hospital in Kansas. Patients who underwent inpatient or outpatient gynecologic surgery during 2013 were included. Based on published guidelines for prophylactic antibiotic agents for gynecologic surgery by ACOG, procedures were classified as antibiotic-indicated or antibiotic-not-indicated. Chi-square and Fisher exact test analysis were used to identify factors associated with antibiotic use. RESULTS: Of the 1,735 cases eligible for inclusion, 1,045 (60.2%) had antibiotic agents recommended per guidelines, and appropriate antibiotic agents were given in 1,031 (98.7%) of those cases. In 690 (39.8%) cases, prophylactic antibiotics were either not recommended or the guidelines are not well defined. Of the 690 cases without indication for antibiotic agents, 394 (57.1%) received prophylactic antibiotic agents. Agreement with guidelines varied substantially based on patient age, race, insurance status, area of residence, and if the procedure was a resident case (p < 0.05). Myomectomy, laparoscopy, and ectopic pregnancy procedures received antibiotic agents against recommendations 96.3%, 75.6%, and 45.5% of the time, respectively. CONCLUSIONS: Peri-operative antibiotics are often administered inappropriately to women undergoing gynecologic surgeries for which published guidelines are not well defined. Future studies need to identify strategies to reduce antibiotic use in surgical procedures unlikely to benefit from prophylaxis.

Natural Killer Cell-Based Immunotherapy in Gynecologic Malignancy: A Review.

Harnessing the immune system has proven an effective therapy in treating malignancies. Since the discovery of natural killer (NK) cells, strategies aimed to manipulate and augment their effector function against cancer have been the subject of intense research. Recent progress in the immunobiology of NK cells has led to the development of promising therapeutic approaches. In this review, we will focus on the recent advances in NK cell immunobiology and the clinical application of NK cell immunotherapy in ovarian, cervical, and uterine cancer.

Molecular characterization of endometrial cancer and therapeutic implications.

PURPOSE OF REVIEW: This article reviews the emerging comprehensive genomic classification of endometrial carcinoma and discusses the therapeutic implications of these subgroups. RECENT FINDINGS: Comprehensive, multiplatform evaluation of endometrial cancers by the Cancer Genome Atlas stratified the molecular aberrations into four distinct subtypes: POLE mutations, microsatellite instability, copy-number low/microsatellite stable, and copy-number high/'serous-like.' POLE-mutant tumors have a favorable prognosis and may often be overtreated. Microsatellite instability hypermutated tumors commonly have alterations in the phosphatidylinositide 3-kinases/AKT/mechanistic target of rapamycin pathway and limiting targeted therapy to this group may lead to greater response rates. Copy-number low/microsatellite stable tumors represent the majority of grade 1 and grade 2 endometrioid cancers and have an intermediate prognosis, few TP53 mutations, but frequent mutations in genes involved with Wingless-related integration site signaling. Approximately 25% of high-grade endometrioid tumors have mutational profiles that classify as copy-number high/'serous-like' and might benefit from treatment approaches similar to those for serous tumors. SUMMARY: Molecular characterization of endometrial cancer classifies tumors into prognostically significant subtypes with a broad range of therapeutic implications.

Histone variant HTZ1 shows extensive epistasis with, but does not increase robustness to, new mutations.

Biological systems produce phenotypes that appear to be robust to perturbation by mutations and environmental variation. Prior studies identified genes that, when impaired, reveal previously cryptic genetic variation. This result is typically interpreted as evidence that the disrupted gene normally increases robustness to mutations, as such robustness would allow cryptic variants to accumulate. However, revelation of cryptic genetic variation is not necessarily evidence that a mutationally robust state has been made less robust. Demonstrating a difference in robustness requires comparing the ability of each state (with the gene perturbed or intact) to suppress the effects of new mutations. Previous studies used strains in which the existing genetic variation had been filtered by selection. Here, we use mutation accumulation (MA) lines that have experienced minimal selection, to test the ability of histone H2A.Z (HTZ1) to increase robustness to mutations in the yeast Saccharomyces cerevisiae. HTZ1, a regulator of chromatin structure and gene expression, represents a class of genes implicated in mutational robustness. It had previously been shown to increase robustness of yeast cell morphology to fluctuations in the external or internal microenvironment. We measured morphological variation within and among 79 MA lines with and without HTZ1. Analysis of within-line variation confirms that HTZ1 increases microenvironmental robustness. Analysis of between-line variation shows the morphological effects of eliminating HTZ1 to be highly dependent on the line, which implies that HTZ1 interacts with mutations that have accumulated in the lines. However, lines without HTZ1 are, as a group, not more phenotypically diverse than lines with HTZ1 present. The presence of HTZ1, therefore, does not confer greater robustness to mutations than its absence. Our results provide experimental evidence that revelation of cryptic genetic variation cannot be assumed to be caused by loss of robustness, and therefore force reevaluation of prior claims based on that assumption.

The female-specific doublesex isoform regulates pleiotropic transcription factors to pattern genital development in Drosophila.

Regulatory networks driving morphogenesis of animal genitalia must integrate sexual identity and positional information. Although the genetic hierarchy that controls somatic sexual identity in the fly Drosophila melanogaster is well understood, there are very few cases in which the mechanism by which it controls tissue-specific gene activity is known. In flies, the sex-determination hierarchy terminates in the doublesex (dsx) gene, which produces sex-specific transcription factors via alternative splicing of its transcripts. To identify sex-specifically expressed genes downstream of dsx that drive the sexually dimorphic development of the genitalia, we performed genome-wide transcriptional profiling of dissected genital imaginal discs of each sex at three time points during early morphogenesis. Using a stringent statistical threshold, we identified 23 genes that have sex-differential transcript levels at all three time points, of which 13 encode transcription factors, a significant enrichment. We focus here on three sex-specifically expressed transcription factors encoded by lozenge (lz), Drop (Dr) and AP-2. We show that, in female genital discs, Dsx activates lz and represses Dr and AP-2. We further show that the regulation of Dr by Dsx mediates the previously identified expression of the fibroblast growth factor Branchless in male genital discs. The phenotypes we observe upon loss of lz or Dr function in genital discs explain the presence or absence of particular structures in dsx mutant flies and thereby clarify previously puzzling observations. Our time course of expression data also lays the foundation for elucidating the regulatory networks downstream of the sex-specifically deployed transcription factors.