High-resolution array-based comparative genomic hybridization of bladder cancers identifies mouse double minute 4 (MDM4) as an amplification target exclusive of MDM2 and TP53.

PURPOSE: Loss of p53 function in urothelial cell carcinoma (UCC) by mutation or inactivation disrupts normal cell cycle checkpoints, generating a favorable milieu for genomic instability, a hallmark of UCC. The aim of this study was to characterize novel DNA copy number changes to identify putative therapeutic targets. EXPERIMENTAL DESIGN: We report our findings using array comparative genomic hybridization on a whole-genome BAC/PAC/cosmid array with a median clone interval of 0.97 Mb to study a series of UCC cases. TP53 status was determined by direct sequencing, and an in-house tissue microarray was constructed to identify protein expression of target genes. RESULTS: Array comparative genomic hybridization allowed identification of novel regions of copy number changes in addition to those already known from previous studies. A novel amplification previously unreported in UCC was identified at 1q32. A chromosome 1 tile path array was used to analyze tumors that showed gains and amplification; the mouse double minute 4 (MDM4) homologue was identified as the amplified gene. MDM4 mRNA expression correlated with copy number and tumor grade. Copy number changes of MDM4 and MDM2 occurred exclusively in tumors with wild-type p53. Overexpression of MDM4 corresponded to disruption of p53 transcriptional activity. Immunohistochemistry on an independent series by tissue microarray identified an inverse relationship between Mdm4 and Mdm2, with Mdm4 expression highest in invasive UCC. CONCLUSION: The data indicate that gain/amplification and overexpression of MDM4 is a novel molecular mechanism by which a subset of UCC escapes p53-dependent growth control, thus providing new avenues for therapeutic intervention.

Pyrexia after cardiac surgery: natural history and association with infection.

BACKGROUND: Pyrexia is common after major surgery, and infection is often an important consideration. To investigate the natural history and association with infection, we performed a prospective observational study. METHODS: From November 2000 to January 2001, we studied 219 patients undergoing cardiac surgery screening daily for wound, respiratory, urinary tract, and other infections. Pyrexia was defined as temperature above 37.5 degrees C. RESULTS: Of 219 patients, 7 intraoperative deaths occurred and 1 patient was excluded because of preoperative endocarditis, leaving 211. The mean age (SD) was 64 (10) years, consisting of 172 male patients (81.5%). The proportion pyrexial on days 1, 2, and 5 was 30.0%, 25.8%, and 10.3%, respectively. More patients undergoing urgent or emergency procedures (17.7% versus 7.8%; P =.03) subsequently developed pyrexia. However, there were no differences in wound infection (3.4% versus 8.3%; P =.13), positive cultures for respiratory (14.7% versus 11.4%; P =.16), urinary tract (5.2% versus 2.0%; P =.09), or other infection (8.6% versus 7.3%; P =.71) in patients experiencing postoperative pyrexia compared with those who did not. CONCLUSIONS: Pyrexia is common after cardiac surgery and resolves in the majority of patients by day 5. Because there is no association between early pyrexia and infection, diagnosis of early postoperative infection by pyrexia alone is insufficient and is better established by clinical assessment with microbiological evidence.