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Purpose: It is unknown whether compliance with recommended monitoring tests during observation of localized prostate cancer has changed over time., Materials and Methods: We performed a retrospective cohort study of Medicare beneficiaries diagnosed with low- or intermediate-risk prostate cancer in 2004-2016 who were initially managed with observation for a minimum of 12 months. The primary objective was to examine rates of PSA testing, prostate biopsy, and prostate MRI. We used multivariable mixed effects Poisson regression to determine whether rates of PSA testing and prostate biopsy increased over time. In addition, we identified clinical, sociodemographic, and provider factors associated with the frequency of monitoring tests during observation., Results: We identified 10,639 patients diagnosed at a median age of 73 (IQR 69-77) years. The median follow-up time was 4.3 (IQR 2.7-6.6) years after diagnosis. Among patients managed without treatment for 5 years, 98% received at ≥1 PSA test, 48.0% ≥1 additional prostate biopsy, and 31.0% ≥1 prostate MRI. Among patients managed with observation for ≥12 months, mixed effects Poisson regression revealed that rates of PSA testing and biopsy increased over time (per calendar year: RR 1.02, 95% CI: 1.02-1.03 and RR 1.10, 95% CI: 1.08-1.11, respectively). Clinical and sociodemographic factors including age, clinical risk, race/ethnicity, census tract poverty, and region were associated with rates of biopsy and PSA testing., Conclusions: Use of recommended monitoring tests including repeat prostate biopsy remains low among Medicare beneficiaries undergoing observation for low- and intermediate-risk prostate cancer.

Purpose: Human bladder cancer cells resistant to anti-epidermal growth factor receptor therapy often co-express platelet-derived growth factor receptor-β. We determined whether there is functional crosstalk between epidermal growth factor receptor and platelet-derived growth factor receptor-β, and how this regulates biological functions in bladder cancer cases., Materials and Methods: We determined heterodimerization and co-localization of epidermal growth factor receptor and platelet-derived growth factor receptor-β by immunoprecipitation and confocal microscopy, respectively. We tested the antiproliferative effects of specific inhibitory monoclonal antibodies to each receptor by (3)H-thymidine uptake assay. We transfected the nonplatelet-derived growth factor receptor-β expressing bladder cancer cell line UMUC5 with the platelet-derived growth factor receptor-β gene. These cells were analyzed in vitro by (3)H-thymidine uptake and by Matrigel™ invasion assay, and in vivo for tumorigenicity, metastatic potential and orthotopic growth. In a treatment study nude mice were inoculated with orthotopic tumors and treated with the inhibitory antibodies alone and in combination., Results: Immunoprecipitation revealed epidermal growth factor receptor/platelet-derived growth factor receptor-β heterodimers in all platelet-derived growth factor receptor-β expressing cell lines. Forced expression of platelet-derived growth factor receptor-β in epidermal growth factor receptor sensitive UMUC5 cells (50% inhibitory concentration less than 10 nM) significantly decreased responsiveness to epidermal growth factor receptor inhibition (50% inhibitory concentration greater than 100 nM) and increased invasive potential 3-fold as well as tumorigenicity. Increased invasiveness was associated with epidermal growth factor triggered platelet-derived growth factor receptor-β transactivation, increased mitogen activated protein kinase and glycogen synthase kinase-3β phosphorylation, and decreased E-cadherin. Inhibition of epidermal growth factor receptor and platelet-derived growth factor receptor-β receptors blocked cell invasion, decreased cell proliferation, reduced xenograft tumor growth and increased E-cadherin expression., Conclusions: In epidermal growth factor receptor expressing bladder cancer co-expression of platelet-derived growth factor receptor-β has implications for tumor biology. Thus, it should be further evaluated as a strategy involving dual receptor targeting., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: The epidermal growth factor receptor inhibitor gefitinib (Iressa) is currently being studied in patients with bladder cancer and it has significant anti-angiogenic activity. We investigated the relationship between the modulation of vascular endothelial growth factor (Santa Cruz Biotechnology, Santa Cruz, California) expression and the biological efficacy of gefitinib for bladder cancer., Materials and Methods: In vitro the 4 bladder cancer cell lines 253JB-V, UMUC-3, KU-7 and UMUC-13 were treated with gefitinib and vascular endothelial growth factor secretion was measured. The effects of gefitinib on vascular endothelial growth factor promoter, proliferation, cell cycle and downstream signals were evaluated. In vivo 253JB-V and UMUC-13 were injected into nude mice and tumors were treated with 2 mg gefitinib per day. Tumor kinetics were determined and the levels of phospho-epidermal growth factor receptor (Biosource), vascular endothelial growth factor, phospho-vascular endothelial growth factor (Cell Signaling Technology), angiogenesis and apoptosis were measured., Results: Epidermal growth factor receptor (Neomarkers, Fremont, California) phosphorylation was blocked efficiently in all cell lines at concentrations of 0.5 microM or greater. Gefitinib (1 microM) induced an accumulation of cells in G0/G1 without apoptosis in 253J B-V cells, whereas it had no effect in other cell lines. Gefitinib inhibited vascular endothelial growth factor secretion in 253JB-V and UMUC-13 (concentration inhibiting a 50% response 0.5 and 0.1 microM, respectively) but not in UMUC-3 or KU-7. Gefitinib decreased vascular endothelial growth factor promoter activity in 253JB-V and UMUC-13 by 40% to 60%. In vivo the growth of 253JB-V tumors was significantly inhibited by gefitinib, whereas no effect was demonstrated in UMUC-13 tumors. Vascular endothelial growth factor expression and vascular endothelial growth factor receptor activation were significantly decreased in 253JB-V tumors and to a greater extent in resistant UMUC-13 tumors. Gefitinib inhibited angiogenesis and induced apoptosis in sensitive 253JB-V tumors only., Conclusions: Epidermal growth factor receptor blockade exerts an anti-angiogenic effect on bladder cancer cells, in part by modulating vascular endothelial growth factor expression. However, down-regulation of vascular endothelial growth factor expression is not sufficient to inhibit bladder cancer growth and it should not be used as a predictor of the therapeutic efficacy of gefitinib.

Purpose: We determined the value of preoperative transurethral prostatic urethral biopsy in predicting final distal urethral margin status at radical cystectomy., Materials and Methods: Of 1,006 patients undergoing radical cystectomy at our institution between 1990 and 2004, 252 were men who underwent ileal neobladder and form the basis of this report. Variables collected include pathology of prostatic urethral biopsies, final pathology of the prostate, frozen section of the distal urethra, final urethral margins and survival data., Results: Median patient age was 61 years. Data regarding preoperative transurethral resection prostatic urethral biopsy and/or frozen section of the urethra at the time of surgery were available for 245 of 252 patients (transurethral resection of the prostatic urethra alone in 127, urethral frozen section alone in 68 and both in 50). The incidence of positive distal urethral margin on final pathological examination was 1.1% (3 of 252) and urethral recurrence was 0.7% (2 of 252). The correlation between transurethral resection findings and frozen section margins was only 68%, and 16 patients with positive transurethral resection findings had negative frozen section margins. The negative predictive value of transurethral resection biopsy with respect to final margins was 99.4% and that of frozen section was 100%., Conclusions: While patients with no tumor on transurethral resection biopsy of the prostatic urethra have a high likelihood of negative urethral margins on final pathological evaluation, optimal negative predictive value is obtained with frozen sections. Furthermore, a positive transurethral resection prostatic urethral biopsy does not correlate with final margin and should not exclude patients from consideration for orthotopic diversion.

Purpose: Expression of various members of the ErbB family (epidermal growth factor receptor/ErbB-1, ErbB-2, ErbB-3 and ErbB-4) is associated with disease stage and survival in patients with urothelial carcinoma. We examined the correlation of ErbB family receptor expression with the progression of urothelial carcinoma and survival., Materials and Methods: A urothelial carcinoma tissue array was constructed from 248 archival paraffin blocks and quality control studies were ascertained. The tissue microarray was stained for epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4, and analyzed using an automated reader. Patient data included grade, stage, growth pattern, recurrence and survival., Results: Kaplan-Meier estimates of 5-year overall and recurrence-free survival were 58% and 27%, respectively. Patients with high grade, invasive or nonpapillary disease had a worse prognosis than patients with low grade, superficial or papillary disease (p <0.0001). High epidermal growth factor receptor or low ErbB-4 expression was associated with nonpapillary, high grade and invasive tumors as well as with significantly shorter recurrence-free and overall survival (p <0.002, 0.028 and 0.047, respectively). Levels of ErbB-2 and ErbB-3 expression were not associated with overall or recurrence-free survival., Conclusions: The expression profiles of ErbB-4 and epidermal growth factor receptor are prognostic in urothelial carcinoma. They may help in selecting patients at high risk with bladder cancer for more aggressive therapy.

Purpose: Sarcomatoid carcinoma and carcinosarcoma of the bladder are rare tumors that contain epithelial and mesenchymal elements, and may portend a worse prognosis than conventional urothelial carcinoma. We investigated the survival of patients with the 2 tumor subtypes compared to survival in those with urothelial carcinoma., Materials and Methods: Cases of sarcomatoid carcinoma, carcinosarcoma and high grade urothelial carcinoma of the bladder were identified from the Surveillance, Epidemiology and End Results Program. Demographic and pathological characteristics were compared. Differences in survival based on histological subtype were estimated using Kaplan-Meier analysis and multivariate Cox proportional hazards regression., Results: Overall unadjusted survival rates for 46,515 patients with urothelial carcinoma, 135 with sarcomatoid carcinoma and 166 with carcinosarcoma were 77%, 54% and 48% at 1 year, and 47%, 37% and 17% at 5 years, respectively. Sarcomatoid carcinoma and carcinosarcoma presented at a similar age but at a higher T stage and with more frequent regional and distant metastases compared to urothelial carcinoma. On multivariate analysis patients with sarcomatoid carcinoma (HR 1.18, 95% CI 0.91-1.52) and carcinosarcoma (HR 2.00, 95% CI 1.65-2.41) were at higher risk for death compared to those with urothelial carcinoma. Overall mortality was worse with carcinosarcoma than with sarcomatoid carcinoma (HR 1.70, 95% CI 1.23-2.34)., Conclusions: Compared to patients with urothelial carcinoma those with sarcomatoid carcinoma and carcinosarcoma present at a more advanced stage and are at greater risk for death even after adjusting for stage at presentation. The survival rate of sarcomatoid carcinoma is better than that of carcinosarcoma, offering some justification for the continued differentiation of these tumor types for clinical prognostication.

Purpose: We defined the growth rate and reviewed our experience in the surgical management of growing teratoma syndrome in patients with nonseminomatous germ cell tumors., Materials and Methods: Nine patients were clinically diagnosed with growing teratoma syndrome at our center from 1980 to 2003. The defining criteria of growing teratoma syndrome were growing metastatic mass in the retroperitoneum or other site consisting entirely of mature teratoma detected on serial abdominal/pelvic imaging during chemotherapy, and a significant decrease in or normalization of tumor markers., Results: Precise serial abdominal/pelvic radiological measurements of the retroperitoneal masses were available for 7 of 9 patients. The median growth rate of growing teratoma syndrome measured as the increase in diameter during chemotherapy was 0.7 cm per month. The median growth rate measured as the increase in tumor volume was 12.9 cc per month. Median time from the start of chemotherapy to retroperitoneal lymph node dissection was 5.4 months (range 2.7 to 21.6). Pathological evaluation of the retroperitoneal lymph node dissection specimen revealed teratoma with no viable tumor in all 9 cases. There were 2 intraoperative complications (1 aortic and 1 ureteral injury) and 4 postoperative complications (2 ileus, 1 acute pancreatitis and 1 chylous ascites). At a median followup of 2 years 7 patients were alive without disease, 1 died of postoperative sepsis and 1 died of an unknown cause., Conclusions: The growth rate of growing teratoma syndrome can vary significantly, which must be taken into account when evaluating cases. Retroperitoneal lymph node dissection is an effective treatment for growing teratoma syndrome, providing excellent local control and a low risk of progression.

Purpose: We evaluated the recurrence pattern in patients with nonseminomatous germ cell tumors treated with post-chemotherapy retroperitoneal lymph node dissection and determined the optimal surveillance strategy in these patients., Materials and Methods: Between 1980 and 2003, 236 patients with clinical stage IIA-III nonseminomatous germ cell tumors underwent post-chemotherapy retroperitoneal lymph node dissection. Patients with increased preoperative tumor markers (alpha-fetoprotein greater than 15 ng/ml and/or beta-human chorionic gonadotropin greater than 2.2 U/ml) were excluded from study resulting in 198 patients for analysis. We retrospectively reviewed medical records for pertinent clinical and treatment related outcomes. In our patient population recurrence developed in 45 (23%) patients and 22 (11%) died of disease at a median followup of 41 months (range 6 to 250) after retroperitoneal lymph node dissection., Results: The clinical stage of testis cancer was IIA in 17, IIB in 49, IIC in 83 and III in 49 patients. Of the 45 patients with postoperative recurrence, 16 had concomitant multiple sites of recurrence with a total of 64 sites reported. Of the cases of recurrence 21 (46.7%) were in those of clinical stage III, 18 (40%) stage IIC and 6 (11.8%) stage IIB disease. The most frequent site of recurrence was the chest (32, 49%), followed by the abdomen (14, 22%), supraclavicular lymph nodes (8, 13%), brain (5, 8%) and other sites (5, 8%)., Conclusions: Based on the recurrence pattern we propose stage specific surveillance guidelines for the followup of patients after post-chemotherapy retroperitoneal lymph node dissection. These guidelines help identify patients at high risk for disease progression and, thus, requiring more stringent postoperative followup.