Mara H. Rendi

Germline and Somatic Mutations in Homologous Recombination Genes Predict Platinum Response and Survival in Ovarian, Fallopian Tube, and Peritoneal Carcinomas

Purpose: Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain. Experimental Design: Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the homologous recombination pathway. Results: Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (P = 0.0002) and improved overall survival (P = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation. Conclusions: Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials. Clin Cancer Res; 20(3); 764–75. ©2013 AACR.

Colonization of the upper genital tract by vaginal bacterial species in nonpregnant women

OBJECTIVE The objective of the study was to evaluate the upper genital tract (UGT) presence of vaginal bacterial species using sensitive molecular methods capable of detecting fastidious bacterial vaginosis (BV)-associated bacteria. STUDY DESIGN Vaginal swabs were collected prior to hysterectomy. The excised uterus was sterilely opened and swabs collected from the endometrium and upper endocervix. DNA was tested in 11 quantitative polymerase chain reaction (PCR) assays for 12 bacterial species: Lactobacillus iners, L crispatus, L jensenii, Gardnerella vaginalis, Atopobium vaginae, Megasphaera spp, Prevotella spp, Leptotrichia/Sneathia, BVAB1, BVAB2, BVAB3, and a broad-range16S ribosomal ribonucleic acid gene assay. Endometrial fluid was tested with Luminex and an enzyme-linked immunosorbent assay for cytokines and defensins and tissue for gene expression of defensins and cathelicidin. RESULTS We enrolled 58 women: mean aged 43±7 years, mostly white (n=46; 79%) and BV negative (n=43; 74%). By species-specific quantitative PCR, 55 (95%) had UGT colonization with at least 1 species (n=52) or were positive by 16S PCR (n=3). The most common species were L iners (45% UGT, 61% vagina), Prevotella spp (33% UGT, 76% vagina) and L crispatus (33% UGT, 56% vagina). Median quantities of bacteria in the UGT were lower than vaginal levels by 2-4 log10 ribosomal ribonucleic acid gene copies per swab. There were no differences in the endometrial inflammatory markers between women with no bacteria, Lactobacillus only, or any BV-associated species in the UGT. CONCLUSION Our data suggest that the endometrial cavity is not sterile in most women undergoing hysterectomy and that the presence of low levels of bacteria in the uterus is not associated with significant inflammation.

Screening MRI in Women With a Personal History of Breast Cancer

BACKGROUND Screening MRI is recommended for individuals at high risk for breast cancer, based on genetic risk or family history (GFH); however, there is insufficient evidence to support screening MRI for women with a personal history (PH) of breast cancer. We compared screening MRI performance in women with PH vs GFH of breast cancer. METHODS We analyzed case-series registry data, collected at time of MRI and at 12-month follow-up, from our regional Clinical Oncology Data Integration project. MRI performance was compared in women with PH with those with GFH. Chi-square testing was used to identify associations between age, prior history of MRI, and clinical indication with MRI performance; logistic regression was used to determine the combined contribution of these variables in predicting risk of a false-positive exam. All statistical tests were two-sided. RESULTS Of 1521 women who underwent screening MRI from July 2004 to November 2011, 915 had PH and 606 had GFH of breast cancer. Overall, MRI sensitivity was 79.4% for all cancers and 88.5% for invasive cancers. False-positive exams were lower in the PH vs GFH groups (12.3% vs 21.6%, P < .001), specificity was higher (94.0% vs 86.0%, P < .001), and sensitivity and cancer detection rate were not statistically different (P > .99). Age (P < .001), prior MRI (P < .001), and clinical indication (P < .001) were individually associated with initial false-positive rate; age and prior MRI remained statistically significant in multivariable modeling (P = .001 and P < .001, respectively). CONCLUSION MRI performance is superior in women with PH compared with women with GFH. Screening MRI warrants consideration as an adjunct to mammography in women with a PH of breast cancer.

Female Reproductive System

Publisher Summary This chapter focuses on normal histology of the ovaries, fallopian tubes, uterus, cervix, vagina, and vulva in the actively cycling adult mouse and human female. The female genital system is dynamic in both the mouse and the human, with varying morphologic appearance based on hormonal influences during estrus/menstrual cycle, pregnancy, and ovarian senescence. Although both humans and mice are mammals with similar ovaries, fallopian tubes, uteri, and placentation, there are several structural and functional differences. In particular, the gross anatomy between the two species varies considerably, whereas the histologic appearance and basic functions tend to be more similar.

A framework for evaluating diagnostic discordance in pathology discovered during research studies

CONTEXT Little is known about the frequency of discordant diagnoses identified during research. OBJECTIVE To describe diagnostic discordance identified during research and apply a newly designed research framework for investigating discordance. DESIGN Breast biopsy cases (N = 407) from registries in Vermont and New Hampshire were independently reviewed by a breast pathology expert. The following research framework was developed to assess those cases: (1) compare the expert review and study database diagnoses, (2) determine the clinical significance of diagnostic discordance, (3) identify and correct data errors and verify the existence of true diagnostic discrepancies, (4) consider the impact of borderline cases, and (5) determine the notification approach for verified disagreements. RESULTS Initial overall discordance between the original diagnosis recorded in our research database and a breast pathology expert was 32.2% (131 of 407). This was reduced to less than 10% after following the 5-step research framework. Detailed review identified 12 cases (2.9%) with data errors (2 in the underlying pathology registry, 3 with incomplete slides sent for expert review, and 7 with data abstraction errors). After excluding the cases with data errors, 38 cases (9.6%) among the remaining 395 had clinically meaningful discordant diagnoses (κ = 0.82; SE, 0.04; 95% confidence interval, 0.76-0.87). Among these 38 cases, 20 (53%) were considered borderline between 2 diagnoses by either the original pathologist or the expert. We elected to notify the pathology registries and facilities regarding discordant diagnoses. CONCLUSIONS Understanding the types and sources of diagnostic discordance uncovered in research studies may lead to improved scientific data and better patient care.

Extracting a low-dimensional description of multiple gene expression datasets reveals a potential driver for tumor-associated stroma in ovarian cancer

Patterns in expression data conserved across multiple independent disease studies are likely to represent important molecular events underlying the disease. We present the INSPIRE method to infer modules of co-expressed genes and the dependencies among the modules from multiple expression datasets that may contain different sets of genes. We show that INSPIRE infers more accurate models than existing methods to extract low-dimensional representation of expression data. We demonstrate that applying INSPIRE to nine ovarian cancer datasets leads to a new marker and potential driver of tumor-associated stroma, HOPX, followed by experimental validation. The implementation of INSPIRE is available at http://inspire.cs.washington.edu.

Painful clitoromegaly caused by rare epithelioid hemangioma.

► Painful clitoromegaly may be caused by an infiltrating epithelioid hemangioma tumor. ► Epithelioid hemangiomas are usually benign. ► Rare forms are the aggressive epithelioid hemangioendotheliomas or epithelioid angiosarcomas. ► Endocrine and infectious causes of clitoromegaly must be ruled out.

Apparent diffusion coefficient values may help predict which MRI-detected high-risk breast lesions will upgrade at surgical excision: ADC Predicts High-Risk Lesion Upgrade

To investigate whether diffusion‐weighted imaging (DWI) features could assist in determining which high‐risk lesions identified on dynamic contrast‐enhanced (DCE) magnetic resonance imaging (MRI) and diagnosed on core needle biopsy (CNB) will upgrade to malignancy on surgical excision.

Histological features associated with diagnostic agreement in atypical ductal hyperplasia of the breast: illustrative cases from the B-Path study.

This study examined the case‐specific characteristics associated with interobserver diagnostic agreement in atypical ductal hyperplasia (ADH) of the breast.

Can MRI biomarkers at 3 T identify low-risk ductal carcinoma in situ? ☆,☆☆

OBJECTIVE The objective was to explore whether 3-T magnetic resonance imaging (MRI) can identify low-risk ductal carcinoma in situ (DCIS). METHODS Dynamic contrast-enhanced and diffusion-weighted (DWI) MRI features of 36 DCIS lesions [8 low risk, Van Nuys Pathologic Classification (VNPC) 1; 28 high risk, VNPC 2/3] were reviewed. An MRI model that best identified low-risk DCIS was determined using multivariate logistic regression. RESULTS Low-risk DCIS exhibited different DWI properties [i.e., higher contrast-to-noise ratio (P=.02) and lower normalized apparent diffusion coefficients (P=.04)] than high-risk DCIS. A model combining these DWI features provided best performance (area under receiver operating characteristic curve =0.86). CONCLUSIONS DWI may help identify DCIS lesions requiring less therapy.