Role of the vaginal microbiological ecosystem and cytokine profile in the promotion of cervical dysplasia: a case-control study.

OBJECTIVE: To identify alterations in the cytokine profile and microbial ecosystem of the vagina in association with cervical dysplasia. METHODS: Demographics, lifestyle variables and Papanicolau (Pap) smear results of subjects presenting to the same site for gynecologic complaints, obstetric visits or colposcopy were prospectively recorded. Vaginal smear for Gram stain, aerobic and anaerobic culture, pH, and wet mount and KOH examination for Trichomonas vaginalis, Gardnerella vaginalis and yeast organisms were performed. Vaginal lavage specimens were centrifuged, and the pellets and supernatants were assayed for human papillomavirus (HPV) by polymerase chain reaction and for cytokines interleukin (IL)-1beta IL-6, IL-10 and IL-12 by enzyme-linked immunosorbent assay (ELISA) respectively. Subjects with abnormal Pap smears underwent colposcopy and biopsy as indicated. RESULTS: Of 51 patients, 32 were referred for colposcopy, 12 presented with gynecologic needs, and seven presented for obstetric visits. Median age was 24 years. Demographics did not differ significantly between the dysplasia and control groups except for a trend towards more sexual partners in the dysplasia group. Biopsies were performed in 81% (26/32) of patients presenting for colposcopy and 17 revealed cervical intraepithelial neoplasia. IL-1beta, IL-6, IL-10, and IL-12 levels were elevated in 63% (20/32), 38% (15/39), 4% (2/49), and 0% of samples respectively. Elevated vaginal lavage IL-1beta was associated with a 6.1 odds ratio (95% confidence interval 1.06-35) of cervical dysplasia. Alterations in other variables studied were not associated with cervical dysplasia. CONCLUSIONS: Elevated IL-1beta, possibly representing a complex host inflammatory response to multiple pathogens, was demonstrated in patients with cervical dysplasia

Aurora A Functional Single Nucleotide Polymorphism (SNP) Correlates With Clinical Outcome in Patients With Advanced Solid Tumors Treated With Alisertib, an Investigational Aurora A Kinase Inhibitor

BACKGROUND: Alisertib (MLN8237) is an investigational, oral, selective Aurora A kinase inhibitor. Aurora A contains two functional single nucleotide polymorphisms (SNPs; codon 31 [F/I] and codon 57 [V/I]) that lead to functional changes. This study investigated the prognostic and predictive significance of these SNPs. METHODS: This study evaluated associations between Aurora A SNPs and overall survival (OS) in The Cancer Genome Atlas (TCGA) database. The Aurora A SNPs were also evaluated as predictive biomarkers for clinical outcomes to alisertib in two phase 2 studies (NCT01045421 and NCT01091428). Aurora A SNP genotyping was obtained from 85 patients with advanced solid tumors receiving single-agent alisertib and 122 patients with advanced recurrent ovarian cancer treated with alisertib plus weekly paclitaxel (n=62) or paclitaxel alone (n=60). Whole blood was collected prior to treatment and genotypes were analyzed by PCR. FINDINGS: TCGA data suggested prognostic significance for codon 57 SNP; solid tumor patients with VV and VI alleles had significantly reduced OS versus those with II alleles (HR 1.9 [VI] and 1.8 [VV]; p<0.0001). In NCT01045421, patients carrying the VV alleles at codon 57 (n=53, 62%) had significantly longer progression-free survival (PFS) than patients carrying IV or II alleles (n=32, 38%; HR 0.5; p=0.0195). In NCT01091428, patients with the VV alleles at codon 57 who received alisertib plus paclitaxel (n=47, 39%) had a trend towards improved PFS (7.5months) vs paclitaxel alone (n=32, 26%; 3.8months; HR 0.618; p=0.0593). In the paclitaxel alone arm, patients with the VV alleles had reduced PFS vs modified intent-to-treat (mITT) patients (3.8 vs 5.1months), consistent with the TCGA study identifying the VV alleles as a poor prognostic biomarker. No significant associations were identified for codon 31 SNP from the same data set. INTERPRETATION: These findings suggest that Aurora A SNP at codon 57 may predict disease outcome and response to alisertib in patients with solid tumors. Further investigation is warranted

TRAIL Receptor Signaling Regulation of Chemosensitivity In Vivo but Not In Vitro

Background: Signaling by Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) and Fas ligand (FasL) has been proposed to contribute to the chemosensitivity of tumor cells treated with various other anti-cancer agents. However, the importance of these effects and whether there are differences in vitro and in vivo is unclear. Methodology/Principal Findings: To assess the relative contribution of death receptor pathways to this sensitivity and to determine whether these effects are intrinsic to the tumor cells, we compared the chemosensitivity of isogenic BJAB human lymphoma cells where Fas and TRAIL receptors or just TRAIL receptors were inhibited using mutants of the adaptor protein FADD or by altering the expression of the homeobox transcription factor Six1. Inhibition of TRAIL receptors did not affect in vitro tumor cell killing by various anti-cancer agents indicating that chemosensitivity is not significantly affected by the tumor cell-intrinsic activation of death receptor signaling. However, selective inhibition of TRAIL receptor signaling caused reduced tumor regression and clearance in vivo when tested in a NOD/SCID mouse model. Conclusions: These data show that TRAIL receptor signaling in tumor cells can determine chemosensitivity in vivo but not in vitro and thus imply that TRAIL resistance makes tumors less susceptible to conventional cytotoxic anti-cancer drugs a

Bevacizumab induced hypertension in gynecologic cancer: Does it resolve after completion of therapy?

Hypertension (HTN) induced by bevacizumab is a side effect that is often thought to resolve after treatment. However, there are currently no reports on rates of resolution. We assess the incidence and timing of the resolution of bevacizumab induced HTN. We evaluated all patients treated with bevacizumab for gynecologic malignancies at a single institution from 2012 through 2014. HTN was retrospectively diagnosed and staged by CTCAE v4.0 criteria. Resolution of HTN was defined as ≥2 values return to baseline blood pressure and/or discontinuation/decrease of blood pressure medications. We identified 104 patients; 35 were excluded due to receiving bevacizumab at time of analysis. Grade 2 or higher induced HTN was identified in 34/69 (49.3%) patients, of which 26/69 (37.7%) had grade 2 HTN and 8/69 (11.6%) had grade 3/4 HTN. Onset of HTN occurred at a median of 67 (14–791) days. Resolution of HTN occurred in 28/34 (82.4%) patients with a median time to resolution of 87 (3–236) days. BMI, history of HTN, blood pressure medications, prior bevacizumab treatment, number of bevacizumab cycles, CA-125 and albumin at initiation of treatment were not independent risk factors associated with developing HTN in multivariate analysis. Median PFS for those with HTN was 12.5 (1.9–45.8) months vs 11.0 (2.1–44.7) for those without (p = 0.17). Hypertension induced by bevacizumab resolved in 82% of patients in a median of 87 days. There were no identifiable risk factors associated with induced HTN and HTN was not a biomarker for improved prognosis in our cohort

Awareness of symptoms and risk factors of ovarian cancer in a population of women and healthcare providers

Background: Awareness of ovarian cancer among women and healthcare providers is understudied. An early awareness of ovarian cancer may lead to early detection and treatment of ovarian cancer. Objectives: The purpose of this study was to determine the level of that awareness among a sample of women and providers. Methods: Written surveys were developed by the authors based on available literature and were administered to women (n = 857) and healthcare providers (n = 188) attending or volunteering at a community health fair. Chi-square tests for independence and z tests were used for analysis. Findings: Healthcare providers were significantly more likely to identify the symptoms and risk factors for ovarian cancer. Forty percent of women reported being at least slightly familiar with the symptoms of ovarian cancer. Women who were familiar with symptoms were significantly more likely to identify symptoms and risk factors correctly and to report symptoms immediately to a provider. Identification of symptoms among healthcare providers ranged from 59%–93%. Identification of ovarian cancer symptoms and risk factors is poor among women, and knowledge deficits are present in providers. Increasing familiarity and awareness could lead to improvements in early diagnosis

Randomized phase III trial of gemcitabine plus docetaxel plus bevacizumab or placebo as first-line treatment for metastatic uterine leiomyosarcoma: an NRG Oncology/Gynecologic Oncology Group study

PURPOSE: Fixed-dose rate gemcitabine plus docetaxel achieves objective response in 35% of patients with uterine leiomyosarcoma (uLMS). This study aimed to determine whether the addition of bevacizumab to gemcitabine-docetaxel increases progression-free survival (PFS) in uLMS. PATIENTS AND METHODS: In this phase III, double-blind, placebo-controlled trial, patients with chemotherapy-naive, metastatic, unresectable uLMS were randomly assigned to gemcitabine-docetaxel plus bevacizumab or gemcitabine-docetaxel plus placebo. PFS, overall survival (OS), and objective response rates (ORRs) were compared to determine superiority. Target accrual was 130 patients to detect an increase in median PFS from 4 months (gemcitabine-docetaxel plus placebo) to 6.7 months (gemcitabine-docetaxel plus bevacizumab). Treatment effects on PFS and OS were described by hazard ratios (HRs), median times to event, and 95% CIs. RESULTS: In all, 107 patients were accrued: gemcitabine-docetaxel plus placebo (n = 54) and gemcitabine-docetaxel plus bevacizumab (n = 53). Accrual was stopped early for futility. No statistically significant differences in grade 3 to 4 toxicities were observed. Median PFS was 6.2 months for gemcitabine-docetaxel plus placebo versus 4.2 months for gemcitabine-docetaxel plus bevacizumab (HR, 1.12; P = .58). Median OS was 26.9 months for gemcitabine-docetaxel plus placebo and 23.3 months for gemcitabine-docetaxel plus bevacizumab (HR, 1.07; P = .81). Objective responses were observed in 17 (31.5%) of 54 patients randomly assigned to gemcitabine-docetaxel plus placebo and 19 (35.8%) of 53 patients randomly assigned to gemcitabine-docetaxel plus bevacizumab. Mean duration of response was 8.6 months for gemcitabine-docetaxel plus placebo versus 8.8 months for gemcitabine-docetaxel plus bevacizumab. CONCLUSION: The addition of bevacizumab to gemcitabine-docetaxel for first-line treatment of metastatic uLMS failed to improve PFS, OS, or ORR. Gemcitabine-docetaxel remains a standard first-line treatment for uLMS