Expression of the platelet-derived growth factor receptor in prostate cancer and treatment implications with tyrosine kinase inhibitors.

The platelet-derived growth factor receptor (PDGFR) is a receptor tyrosine kinase overexpressed in a subset of solid tumors and therefore is the target of drugs inhibiting this function such as imatinib mesylate (Gleevec). Thus far, drug therapy has played a limited role in the treatment of localized prostate cancer (PCa). This study characterizes PDGFR-beta expression in a wide spectrum of PCa samples to provide empirical data as part of a rational treatment strategy. A survey of five published prostate expression array studies, including 100 clinically localized PCa, did not identify tumors with increased PDGFR-beta expression level. Protein expression of PDGFR-beta, as determined by immunohistochemistry, revealed 5% of clinically localized PCa and 16% of metastatic PCa cases to show moderate or strong expression. To develop a strategy to detect patients most likely to profit from Gleevec treatment, we analyzed cDNA expression array data from 10,000 transcripts for PDGFR-beta expression and divided tumors in groups based on PDGFR-beta expression level. Performing a supervised analysis to identify potential comarkers of PDGFR-beta in PCa, we identified a set of genes whose expression was associated with PDGFR-beta status including early growth response 1 (Egr1), an upstream effector of PDGF (4.2-fold upregulation), alpha-methylacyl-CoA racemase, as well as v-Maf and neuroblastoma suppressor of tumorigenicity (both with a 2.2-fold downregulation). Taken together, this study suggests that only a small subset of PCas may be amenable to tyrosine kinase inhibitors specific for PDGFR.

Intravitreal bevacizumab and ranibizumab for choroidal neovascularization secondary to endogenous endophthalmitis.

PURPOSE: To report two patients with endogenous endophthalmitis complicated by choroidal neovascularization managed with intravitreal bevacizumab (Avastin, Genentech, Inc., South San Francisco, CA) or ranibizumab (Lucentis, Genentech, Inc., South San Francisco, CA) and their respective outcomes. METHODS: Retrospective chart review of 2 patients, one a 54-year-old diabetic woman on chemotherapy for pemphigus vulgaris and the other a 77-year-old diabetic male with cellulitis, who were treated for endogenous endophthalmitis complicated by choroidal neovascularization. RESULTS: The patients were managed with off-label intravitreal anti-vascular endothelial growth factor injections. The first patient received one dose of intravitreal bevacizumab (Avastin) with improvement in vision and anatomy. The second patient received four doses of intravitreal ranibizumab (Lucentis) with improvement in vision and structural appearance. CONCLUSION: Choroidal neovascularization secondary to endogenous endophthalmitis responds to anti-vascular endothelial growth factor therapy with bevacizumab or ranibizumab.

A characteristic phenotypic retinal appearance in Norrie disease.

PURPOSE: To describe a striking retinal finding that the authors have only seen in Norrie disease eyes and to determine if a particular genotype corresponds to this dramatic presentation. METHODS: This is a retrospective, interventional case report of four patients seen in the clinic over a 1-year period. All patients had analysis of the Norrie gene by direct sequencing. RESULTS: All patients presented with a similar retinal appearance of dense stalk tissue, globular dystrophic retina, and peripheral avascular retina with pigmentary changes. Each patient was found to have a mutation in the Norrie gene affecting a cystine residue in the cystine knot domain. The mutations are predicted to disrupt the structure of the protein product, norrin, which is required for activation of the Wnt receptor:beta-catenin pathway. CONCLUSIONS: No other vitreoretinopathy that the authors have seen demonstrates this characteristic retinal presentation of severe retinal dysplasia. All four patients were found to have mutations in the Norrie gene which alter the cystine knot motif. Mutations affecting this domain appear to have devastating effects on retinal development and indicate phenotype correlates with mutations affecting the cystine knot domain.

Prostate cancer involving the bladder neck: recurrence-free survival and implications for AJCC staging modification. American Joint Committee on Cancer.

OBJECTIVES: In the American Joint Committee on Cancer (AJCC) TNM staging system, prostate cancer involving the bladder neck after radical prostatectomy is considered pT4 disease, suggesting a high risk of recurrence. The recurrence risk with pathologic invasion of the bladder neck, however, has not been definitively compared with that associated with extra-organ disease. We therefore compared the recurrence risk in cases with bladder neck involvement with that of cases with extraprostatic extension and/or seminal vesicle invasion. METHODS: The study cohort was composed of 1123 men with clinically localized prostate cancer treated with prostatectomy as monotherapy. The preoperative prostate-specific antigen (PSA) level, bladder neck involvement, margin positivity, Gleason score, and other pathologic categories were assessed as covariates contributing to the PSA-recurrence risk in univariate and multivariable models. RESULTS: Bladder neck involvement was found in 60 (5%) of 1123 cases. In univariate analysis, the bladder neck was the site-specific margin with the greatest PSA-recurrence risk of focal involvement (relative risk 1.52, 95% confidence interval [CI] 1.15 to 2.00, P = 0.0030). The PSA-recurrence relative risk with extraprostatic extension was 3.05 (95% CI 2.13 to 4.38, P <0.0001) and with seminal vesicle invasion was 8.59 (95% CI 5.76 to 12.82, P <0.0001). In the multivariable model, the PSA-recurrence risk with bladder neck involvement (relative risk 1.19, 95% CI 0.72 to 1.96, P = 0.5) was not a significant independent prognostic factor. Extraprostatic extension (relative risk 2.25, 95% CI 1.54 to 3.27, P <0.0001) and seminal vesicle invasion (relative risk 4.12, 95% CI 2.57 to 6.62, P <0.0001) were significant independent predictors of PSA recurrence. CONCLUSIONS: Any staging system should be evidence based. The current AJCC system for staging bladder neck involvement, however, is contrary to the available evidence. Reclassification of bladder neck involvement as part of the pT3 category should be considered.