The Female Reproductive Tract Microbiome-Implications for Gynecologic Cancers and Personalized Medicine.

The microbial colonization of the lower female reproductive tract has been extensively studied over the past few decades. In contrast, the upper female reproductive tract including the uterine cavity and peritoneum where the ovaries and fallopian tubes reside were traditionally assumed to be sterile under non-pathologic conditions. However, recent studies applying next-generation sequencing of the bacterial 16S ribosomal RNA gene have provided convincing evidence for the existence of an upper female reproductive tract microbiome. While the vaginal microbiome and its importance for reproductive health outcomes has been extensively studied, the microbiome of the upper female reproductive tract and its relevance for gynecologic cancers has been less studied and will be the focus of this article. This targeted review summarizes the pertinent literature on the female reproductive tract microbiome in gynecologic malignancies and its anticipated role in future research and clinical applications in personalized medicine.

Update on primary HPV screening for cervical cancer prevention.

In the coming decade, primary testing for human papillomavirus (HPV) will likely become the standard of care for cervical cancer screening in both low- and high-resource settings. This change comes as evidence has accumulated to support HPV testing as more sensitive to detect high-grade precancerous disease. Furthermore, negative HPV testing has demonstrated a lower cumulative incidence of cervical intraepithelial neoplasia (CIN) grade 3 or worse pathology (CIN3+) when compared to negative "Pap smears" over several rounds of screening. While many countries have begun pilot programs to transition to primary HPV screening and some have completely transitioned for certain uses, there remains much to be refined about this tool for cervical cancer prevention, as evidenced by the myriad of ways it is being utilized. In the United States, the use of primary HPV testing to screen for cervical cancer has been supported by a consensus statement from the Society of Gynecologic Oncologists and American Society for Colposcopy and Cervical Pathology along with experts from American College of Obstetricians and Gynecologists/American Cancer Society/American Society of Cytopathology/College of American Pathologists/and American Society for Clinical Pathology. Additionally, recently proposed United States Preventive Services Task Force guideline changes, and recent Food and Drug Administration approval of the second test for primary HPV screening highlight the broadening availability and support for primary HPV screening. The aim of this review is to summarize the evidence supporting the safety and effectiveness of primary HPV screening and its use in different high-resource settings.

All-Cause Mortality After Fertility-Sparing Surgery for Stage I Epithelial Ovarian Cancer.

OBJECTIVE: To compare all-cause mortality between women who underwent fertility-sparing surgery with those who underwent conventional surgery for stage I ovarian cancer. METHODS: In a cohort study using the National Cancer Database, we identified women younger than 40 years diagnosed with stage IA and unilateral IC epithelial ovarian cancer between 2004 and 2012. Fertility-sparing surgery was defined as conservation of one ovary and the uterus. The primary outcome was time from diagnosis to death. We used propensity score methods to assemble a cohort of women who underwent fertility-sparing or conventional surgery but were otherwise similar on observed covariates and conducted survival analyses using the Kaplan-Meier method and Cox proportional hazard models. RESULTS: We identified 1,726 women with stage IA and unilateral IC epithelial ovarian cancer of whom 825 (47.8%) underwent fertility-sparing surgery. Fertility-sparing surgery was associated with younger age, residence in the northeastern and western United States, and serous or mucinous histology (P<.05 for all). Propensity score matching yielded a cohort of 904 women who were balanced on observed covariates. We observed 30 deaths among women who underwent fertility-sparing surgery and 37 deaths among propensity-matched women who underwent conventional surgery after a median follow-up of 63 months. Fertility-sparing surgery was not associated with hazard of death (hazard ratio 0.80, 95% confidence interval [CI] 0.49-1.29, P=.36). The probability of survival 10 years after diagnosis was 88.5% (95% CI 82.4-92.6) in the fertility-sparing group and 88.9% (95% CI 84.9-92.0) in the conventional surgery group. In patients with high-risk features such as clear cell histology, grade 3, or stage IC, 10-year survival was 80.5% (95% CI 68.5-88.3) among women who underwent fertility-sparing surgery and 83.4% (95% 76.0-88.7) among those who had conventional surgery (hazard ratio 0.86, 95% CI 0.49-1.53, P=.61). CONCLUSION: Compared with conventional surgery, fertility-sparing surgery was not associated with increased risk of death in young women with stage I epithelial ovarian cancer.

Indications and risk factors for midurethral sling revision.

INTRODUCTION AND HYPOTHESIS: To determine the indications and risk factors for needing midurethral sling revision in a cohort of women undergoing midurethral sling placement. METHODS: This was a case-control study of all women undergoing midurethral sling placement for stress urinary incontinence (SUI) between January 2003 and December 2013. Cases were patients who underwent midurethral sling placement followed by sling revision (incision, partial or complete excision). Controls were patients who underwent sling placement only. Once all subjects had been identified, the electronic medical record was queried for demographic and perioperative and postoperative data. RESULTS: Of 3,307 women who underwent sling placement, 89 (2.7%, 95% CI 1.9 - 3.4) underwent sling revision for one or more of the following indications: urinary retention (43.8%), voiding dysfunction (42.7%), recurrent urinary tract infection (20.2%), mesh erosion (21.3%), vaginal pain/dyspareunia (7.9%), and groin pain (3.4%). The median time from the index to the revision surgery was 7.8 months (2.3 - 17.9 months), but was significantly shorter in patients with urinary retention. The type of sling placed (retropubic or transobturator) was not associated with indication for revision. Patients who underwent revision surgery were more likely to have had previous SUI surgery (adjusted odds ratio 4.4, 95% CI 1.7 - 6.5) and to have undergone concomitant vaginal apical suspension (adjusted odds ratio 2.4, 95% CI 1.4 - 4.5). CONCLUSIONS: The rate of sling revision after midurethral sling placement was 2.7%. Urinary retention and voiding dysfunction were the most common indications. Patients with a history of previous SUI surgery and concomitant apical suspension at the time of sling placement may be at higher risk of requiring revision surgery.

Deguelins, Natural Product Modulators of NF1-Defective Astrocytoma Cell Growth Identified by High-Throughput Screening of Partially Purified Natural Product Extracts.

A high-throughput screening assay for modulators of Trp53/NF1 mutant astrocytoma cell growth was adapted for use with natural product extracts and applied to a novel collection of prefractionated/partially purified extracts. Screening 68 427 samples identified active fractions from 95 unique extracts, including the terrestrial plant Millettia ichthyotona. Only three of these extracts showed activity in the crude extract form, thus demonstrating the utility of a partial purification approach for natural product screening. The NF1 screening assay was used to guide purification of active compounds from the M. ichthyotona extract, which yielded the two rotenones deguelin (1) and dehydrodeguelin (2). The deguelins have been reported to affect growth of a number of cancer cell lines. They potently inhibited growth of only one of a panel of NF1/Trp53 mutant murine astrocytoma cell lines, possibly related to epigenetic factors, but had no effect on the growth of normal astrocytes. These results suggest the potential utility of deguelins as tools for further investigating NF1 astrocytoma cell growth. These bioprobes were identified only as a result of screening partially purified natural product extracts.

Radiation therapy for glioma stem cells.

Radiation therapy is the most effective adjuvant treatment modality for virtually all patients with high-grade glioma. Its ability to improve patient survival has been recognized for decades. Cancer stem cells provide new insights into how tumor biology is affected by radiation and the role that this cell population can play in disease recurrence. Glioma stem cells possess a variety of intracellular mechanisms to resist and even flourish in spite of radiation, and their proliferation and maintenance appear tied to supportive stimuli from the tumor microenvironment. This chapter reviews the basis for our current use of radiation to treat high-grade gliomas, and addresses this model in the context of therapeutically resistant stem cells. We discuss the available evidence highlighting current clinical efforts to improve radiosensitivity, and newer targets worthy of further development.

Hyperthermia Sensitizes Glioma Stem-like Cells to Radiation by Inhibiting AKT Signaling.

Glioma stem-like cells (GSC) are a subpopulation of cells in tumors that are believed to mediate self-renewal and relapse in glioblastoma (GBM), the most deadly form of primary brain cancer. In radiation oncology, hyperthermia is known to radiosensitize cells, and it is reemerging as a treatment option for patients with GBM. In this study, we investigated the mechanisms of hyperthermic radiosensitization in GSCs by a phospho-kinase array that revealed the survival kinase AKT as a critical sensitization determinant. GSCs treated with radiation alone exhibited increased AKT activation, but the addition of hyperthermia before radiotherapy reduced AKT activation and impaired GSC proliferation. Introduction of constitutively active AKT in GSCs compromised hyperthermic radiosensitization. Pharmacologic inhibition of PI3K further enhanced the radiosensitizing effects of hyperthermia. In a preclinical orthotopic transplant model of human GBM, thermoradiotherapy reduced pS6 levels, delayed tumor growth, and extended animal survival. Together, our results offer a preclinical proof-of-concept for further evaluation of combined hyperthermia and radiation for GBM treatment.