Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied, and few laboratory models exist that reflect the biology of the human disease. Here, we describe a biobank of patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer. Organoid lines can be established efficiently from patient biopsies acquired before and after disease recurrence and are interconvertible with orthotopic xenografts. Notably, organoid lines often retain parental tumor heterogeneity and exhibit a spectrum of genomic changes that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles, as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Our studies indicate that patient-derived bladder tumor organoids represent a faithful model system for studying tumor evolution and treatment response in the context of precision cancer medicine.
Purpose The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer. Patients and Methods The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK_FOCSS) after quality-control analysis. Results In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK_FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001). Conclusion These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.
Background-The role of malnutrition has not been well studied in patients undergoing surgery for renal cell carcinoma (RCC). Objective-Our aim was to evaluate whether nutritional deficiency (ND) is an important determinant of survival following surgery for RCC.Design, setting, and participants-A total of 369 consecutive patients underwent surgery for locoregional RCC from 2003 to 2008. ND was defined as meeting one of the following criteria:© 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author: Vanderbilt University Medical Center, Department of Urologic Surgery, A1302 Medical Center North, Nashville, TN 37215, todd.morgan@vanderbilt.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Author contributions: Todd M. Morgan had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Michael S. Cookson is a financially affiliated consultant for Watson and Endo, a financially affiliated lecturer for Firmagon and Sanofi-Aventis, is compensated financially for a scientific study/trial by GlaxoSmith Kline, and is noncompensated for scientific research at Astra Zeneca. S. Duke Herrell is a financially affiliated consultant for Aesculap Inc, Covidien Surgical Devices, and Wilex. He is a financially affiliated investigator for Wilex and a financially compensated stockholder at Veran Medical Tech. Sam S. Chang is a compensated consultant for Sanofi-Aventis, Endo, Allergan, and Centocor Orth Biotech. Peter E. Clark is a compensated consultant for Galil Medical. All other authors have nothing to disclose. NIH Public AccessAuthor Manuscript Eur Urol. Author manuscript; available in PMC 2012 June 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript body mass index <18.5 kg/m 2 , albumin <3.5 g/dl, or preoperative weight loss ≥5% of body weight.Intervention-All patients underwent radical or partial nephrectomy.Measurements-Primary outcomes were overall and disease-specific mortality. Covariates included age, Charlson comorbidity index (CCI), preoperative anemia, tumor stage, Fuhrman grade, and lymph node status. Multivariate an...
Injection with botulinum toxin A is an effective adjunct to physical therapy in the treatment of piriformis syndrome. H-reflex prolongation by flexion, adduction, and internal rotation (FAIR test) beyond 1.86 msec (3 SD) of the mean is a clinical indication of piriformis syndrome.
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