On Molecular Classification of Bladder Cancer: Out of One, Many.

Comparative analysis showed that bladder cancer classification systems identify overlapping subtypes but at different levels. Muscle-invasive bladder cancer shows remarkable heterogeneity, and six subtypes were identified that differ in transcriptional networks, marker profiles, and expression of actionable targets

Continent urinary tract reconstruction - the Lund experience.

The Department of Urology in Lund, Sweden, has a long association with innovations in reconstructive urology. The authors from that department describe their experience over a long period with orthotopic bladder substitution and continent cutaneous urinary diversion. They conclude that continent urinary tract reconstruction is associated with a high incidence of early and late complications. They also found that for storage and emptying, their Lundiana pouch was superior to the Goldwasser neobladder. OBJECTIVE: To assess the early and late complications and functional results in patients undergoing continent reconstruction of the urinary tract, i.e. orthotopic bladder substitution (OBS) or continent cutaneous diversion (CCD). PATIENTS AND METHODS: The medical records of all patients undergoing OBS (Goldwasser technique) or CCD ('Lundiana' technique) for malignant or benign disease during 1987-1999 and followed to December 2001 were reviewed. There were 67 patients with neobladders, 77 with a Lundiana pouch who had undergone radical cystectomy and 22 with a Lundiana pouch operated for benign disorders. RESULTS: Early complications requiring reoperation occurred in 12% of the cystectomy group, with no difference with type of reconstruction, and in 10% with benign diseases. Four patients (3%) undergoing radical cystectomy died from early cardiovascular complications, two after surgery for intra-abdominal complications. Intestinally related complications and wound dehiscence requiring re-operation occurred in nine and six patients, respectively. The incidence of late complications requiring open surgery was 22% and 23% after cystectomy with OBS and CCD, respectively. The value in patients with benign diseases undergoing CCD was also 23%. Stone formation in the pouch was common, occurring in 12% in patients with OBS and in 10% after CCD. The pouch perforated or ruptured in four patients. The incidence of uretero-intestinal stricture using the Le Duc technique was 2.4% and renal function was well preserved. The incidence of revisional surgery of the Lundiana pouch outlet for incontinence was low and all patients but four were continent. The functional outcome in patients with OBS was less good; some needed pouch augmentation or an artificial urinary sphincter. Most patients used incontinence products and many needed clean intermittent self-catheterization. CONCLUSION: Continent urinary tract reconstruction is associated with a high incidence of early and late complications. For storage and emptying, the CCD Lundiana pouch is superior to the OBS of Goldwasser

Systematic review of the association between socioeconomic status and bladder cancer survival with hospital type, comorbidities, and treatment delay as mediators

Objectives:  To review the current evidence on the relationship between three proposed mediators (comorbidities, hospital type, and treatment delays) for the relationship between socioeconomic status (SES) and bladder cancer survival. Materials and methods:  Six different searches using OVID (Medline and Embase) were carried out to collate information available between the proposed mediators with both SES and survival in bladder cancer. This systematic review was conducted according to a pre-defined protocol and in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results:  A total of 49 studies were included in the review across the six searches (one appeared in two searches). There was a wealth of studies investigating the relationship between each of the proposed mediators with survival in bladder cancer patients. In general, a higher SES, lower comorbidities, and a larger hospital volume were all found to be associated with a decreased risk of death in bladder cancer patients. There was, however, a paucity of studies investigating the associations between these mediators and SES in bladder cancer patients. Conclusions:  To gain a deeper understanding of the relationship between SES and survival identified in several observational studies, further investigations into the relationship between the proposed mediators and SES are warranted. Moreover, modifiable mediators, eg, treatment delay, highlight the importance of the standardization of clinical care across SES groups for all bladder cancer patients

Tiling resolution array CGH and high density expression profiling of urothelial carcinomas delineate genomic amplicons and candidate target genes specific for advanced tumors.

ABSTRACT: BACKGROUND: Urothelial carcinoma (UC) is characterized by nonrandom chromosomal aberrations, varying from one or a few changes in early-stage and low-grade tumors, to highly rearranged karyotypes in muscle-invasive lesions. Recent array-CGH analyses have shed further light on the genomic changes underlying the neoplastic development of UC, and have facilitated the molecular delineation amplified and deleted regions to the level of specific candidate genes. In the present investigation we combine detailed genomic information with expression information to identify putative target genes for genomic amplifications. METHODS: We analyzed 38 urothelial carcinomas by whole-genome tiling resolution array-CGH and high density expression profiling to identify putative target genes in common genomic amplifications. When necessary expression profiling was complemented with Q-PCR of individual genes. RESULTS: Three genomic segments were frequently and exclusively amplified in high grade tumors; 1q23, 6p22 and 8q22, respectively. Detailed mapping of the 1q23 segment showed a heterogeneous amplification pattern and no obvious commonly amplified region. The 6p22 amplicon was defined by a 1.8 Mb core region present in all amplifications, flanked both distally and proximally by segments amplified to a lesser extent. By combining genomic profiles with expression profiles we could show that amplification of E2F3, CDKAL1, SOX4, and MBOAT1 as well as NUP153, AOF1, FAM8A1 and DEK in 6p22 was associated with increased gene expression. Amplification of the 8q22 segment was primarily associated with YWHAZ (14-3-3-zeta) and POLR2K over expression. The possible importance of the YWHA genes in the development of urothelial carcinomas was supported by another recurrent amplicon paralogous to 8q22, in 2p25, where increased copy numbers lead to enhanced expression of YWHAQ (14-3-3-theta). Homozygous deletions were identified at 10 different genomic locations, most frequently affecting CDKN2A/CDKN2B in 9p21 (32%). Notably, the latter occurred mutually exclusive with 6p22 amplifications. CONCLUSION: The presented data indicates 6p22 as a composite amplicon with more than one possible target gene. The data also suggests that amplification of 6p22 and homozygous deletions of 9p21 may have complementary roles. Furthermore, the analysis of paralogous regions that showed genomic amplification indicated altered expression of YWHA (14-3-3) genes as important events in the development of UC

A Molecular Taxonomy for Urothelial Carcinoma.

PURPOSE: Even though urothelial cancer is the fourth most common tumor type among males, progress in treatment has been scarce. A problem in day-to-day clinical practice is that precise assessment of individual tumors is still fairly uncertain; consequently efforts have been undertaken to complement tumor evaluation with molecular biomarkers. An extension of this approach would be to base tumor classification primarily on molecular features. Here, we present a molecular taxonomy for urothelial carcinoma based on integrated genomics. EXPERIMENTAL DESIGN: We use gene expression profiles from 308 tumor cases to define five major urothelial carcinoma subtypes: urobasal A, genomically unstable, urobasal B, squamous cell carcinoma like, and an infiltrated class of tumors. Tumor subtypes were validated in three independent publically available data sets. The expression of 11 key genes was validated at the protein level by immunohistochemistry. RESULTS: The subtypes show distinct clinical outcomes and differ with respect to expression of cell-cycle genes, receptor tyrosine kinases particularly FGFR3, ERBB2, and EGFR, cytokeratins, and cell adhesion genes, as well as with respect to FGFR3, PIK3CA, and TP53 mutation frequency. The molecular subtypes cut across pathologic classification, and class-defining gene signatures show coordinated expression irrespective of pathologic stage and grade, suggesting the molecular phenotypes as intrinsic properties of the tumors. Available data indicate that susceptibility to specific drugs is more likely to be associated with the molecular stratification than with pathologic classification. CONCLUSIONS: We anticipate that the molecular taxonomy will be useful in future clinical investigations. Clin Cancer Res; 1-10. ©2012 AACR

Molecular changes during progression from nonmuscle invasive to advanced urothelial carcinoma

Molecular changes occurring during invasion and clinical progression of cancer are difficult to study longitudinally in patient-derived material. A unique feature of urothelial bladder cancer (UBC) is that patients frequently develop multiple nonmuscle invasive tumors, some of which may eventually progress to invade the muscle of the bladder wall. Here, we use a cohort of 73 patients that experienced a total of 357 UBC diagnoses to study the stability or change in detected molecular alterations during cancer progression. The tumors were subtyped by gene expression profiling and analyzed for hotspot mutations in FGFR3, PIK3CA and TERT, the most frequent early driver mutations in this tumor type. TP53 alterations, frequent in advanced UBC, were inferred from p53 staining pattern, and potential genomic alterations were inferred by gene expression pattern

Recurrent and multiple bladder tumors show conserved expression profiles

<p>Abstract</p> <p>Background</p> <p>Urothelial carcinomas originate from the epithelial cells of the inner lining of the bladder and may appear as single or as multiple synchronous tumors. Patients with urothelial carcinomas frequently show recurrences after treatment making follow-up necessary. The leading hypothesis explaining the origin of meta- and synchronous tumors assumes a monoclonal origin. However, the genetic relationship among consecutive tumors has been shown to be complex in as much as the genetic evolution does not adhere to the chronological appearance of the metachronous tumors. Consequently, genetically less evolved tumors may appear chronologically later than genetically related but more evolved tumors.</p> <p>Methods</p> <p>Forty-nine meta- or synchronous urothelial tumors from 22 patients were analyzed using expression profiling, conventional CGH, LOH, and mutation analyses.</p> <p>Results</p> <p>We show by CGH that partial chromosomal losses in the initial tumors may not be present in the recurring tumors, by LOH that different haplotypes may be lost and that detected regions of LOH may be smaller in recurring tumors, and that mutations present in the initial tumor may not be present in the recurring ones. In contrast we show that despite apparent genomic differences, the recurrent and multiple bladder tumors from the same patients display remarkably similar expression profiles.</p> <p>Conclusion</p> <p>Our findings show that even though the vast majority of the analyzed meta- and synchronous tumors from the same patients are not likely to have originated directly from the preceding tumor they still show remarkably similar expressions profiles. The presented data suggests that an expression profile is established early in tumor development and that this profile is stable and maintained in recurring tumors.</p