We screened human prostate cancer tissues for the presence of somatic mutations in the hormone binding domain of the androgen receptor (AR) gene. Exons E-H were amplified from genomic DNA using the polymerase chain reaction and analyzed by denaturing gradient gel electrophoresis (DGGE), which separates DNA fragments that differ by only a single base. We detected a mutation in exon E of the hormone binding domain in 1 of 26 specimens of untreated organ-confined stage B prostate cancer. The mutation was not detectable in peripheral blood lymphocyte DNA. Lymphocyte DNA (wild-type AR) migrated in DGGE as a single band. The tumor DNA migrated in DGGE as four bands, consistent with the presence of cells with mutant AR plus cells with wild-type AR and indicating that the tumor contained a somatic mutation. To our knowledge, a somatic AR gene mutation has not been reported previously. Sequencing revealed a G --A substitution in codon 730, changing valine to methionine. Codon 730 is in a region highly conserved among all steroid receptors. The abundance of the mutated fragment (about 50% of the DNA in the specimen) indicates its presence in cells with a growth advantage. A somatic mutation could be detected by DGGE if it represented at least 10% of the sample. Failure to detect mutations in other specimens analyzed may be due to this limit of sensitivity, the presence of mutations in other parts of the AR, or a low frequency of mutations in early stage disease.Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer deaths in men in the U.S.(1). Recognition that androgen is required for the development of prostate cancer (2) and its growth (3) has been the basis for continuing interest in the role of the androgen receptor (AR) in prostate cancer (1,(4)(5)(6). The AR is a member of the superfamily of genes that code for the steroid and thyroid hormone receptor family of ligand-dependent nuclear transcription factors, all of which have an N-terminal domain that affects transcription efficiency, a central DNA
Summary Introduction The 4Kscore Test is a prebiopsy blood test that incorporates four prostate protein biomarkers along with patient clinical information to determine a man's risk for high‐grade, aggressive (Gleason ≥7) prostate cancer. However, some men likely to benefit from the test may be seen in primary care settings where the digital rectal examination (DRE) information is not always obtained. In this study, we assessed the clinical validity of the 4Kscore Test when the DRE information was not included in the algorithm. Methods The Prospective 4Kscore Validation Study enrolled 1012 men scheduled for prostate biopsy across 26 urology practices in the United States. The 4Kscore was calculated for each patient with and without DRE information. The primary outcome was Gleason ≥7 prostate cancer on prostate biopsy. The contribution of DRE to the predictive accuracy of the test was evaluated by area under the receiver operating curve (AUC‐ROC), risk calibration and clinical consequences. Results High‐grade, aggressive prostate cancer was found in 231 (23%) of the 1012 patients. Both versions of the 4Kscore Test, with and without DRE, showed excellent discrimination (AUC=0.821 with DRE and AUC=0.818 without DRE input) and excellent calibration. No clinically significant difference was found between the two versions of the 4Kscore. Conclusions The 4Kscore Test algorithm, whether DRE findings are available or not, performs well in predicting a man's risk of high‐grade, aggressive prostate cancer. Patients who are suspected of having aggressive prostate cancer can safely have their risk better defined by 4Kscore even if a DRE has not been performed recently.
Between August 1991 and June 1994, endoureterotomy was performed in nine patients for total ureteral occlusion. Four of these patients had an associated ureterovaginal fistula. The total ureteral occlusions were iatrogenic in eight patients and the result of trauma in one. The prone split leg position was used to facilitate simultaneous antegrade and retrograde ureteroscopy in all nine patients. The "cut-to-the-light" technique was utilized in six patients and a new technique employing a fascial incising needle was used in five patients. Five patients developed ureteral strictures within 5 months of the primary procedure that were corrected endoscopically. With a mean follow-up of 22 months, all nine patients have a successful outcome. Endoscopic management of difficult urteral disease such as total urteral occlusion and ureterovaginal fistula is a useful alternative to open surgery.
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