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Objective: To explore vascularity and associated molecules in renal cell carcinoma (RCC) and to study their correlations to disease outcome., Methods: Tissue samples from 51 Japanese patients with renal cell carcinoma (RCC) were obtained between November 1997 and August 2000. Pyrimidine nucleoside phosphorylase and vascular endothelial growth factor (VEGF) levels of RCC and normal kidney tissue were determined by enzyme-linked immunosorbent assay. Microvessel density (MVD) was measured by immunohistochemistry using anti-factor-VIII-related antigen and CD34. The number of infiltrating tumor-associated macrophages (TAM) was measured by immunohistochemistry using anti-CD68 antibody., Results: Pyrimidine nucleoside phosphorylase and VEGF levels were significantly higher in RCC than in normal kidney tissue. The VEGF level was higher in more progressive (high grade, larger or symptomatic) RCC. Although MVD as determined by the factor VIII level was higher in larger tumors, MVD determined by CD34 was higher in low-grade and low-stage tumors. Patients with symptoms, large tumor or high stage showed higher numbers of TAM. VEGF level and TAM were significantly higher in patients with recurrence than in those without recurrence. In univariate analysis, VEGF, TAM and CD34 tumor grade and stage were identified as prognostic factors. Moreover, TAM was the only independent prognostic factor by multivariate analysis. Among these parameters, only TAM and MVD as determined by factor VIII showed significant correlations., Conclusion: TAM and VEGF are substantially involved in tumor progression of RCC. As the TAM count is well correlated to the MVD, the main mechanism of tumor progression by TAM might be angiogenesis.

Aim: In order to clarify the initial step of the mechanism by which bacillus Calmette-Guérin (BCG) exhibits antitumor activity via the immune response induced in the bladder submucosa after intravesical BCG therapy for human bladder cancer, various cytokines secreted in the urine after BCG instillation were measured., Methods: After transurethral resection of bladder cancer, a 6-week course of BCG instillation was performed. At the first and sixth weeks' dosings, spontaneously excreted urine was collected before and 4, 8, and 24 h after BCG instillation. The urinary cytokines were determined by Sandwich enzyme-linked immunosorbent assay using monoclonal antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF)-alpha, granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1beta, IL-8, interferon (IFN)-gamma, and IL-12., Results: After the BCG therapy, various cytokines, such as GM-CSF, TNF-alpha, G-CSF, IL-1beta, IL-8, IFN-gamma, and IL-12 were secreted, comprising the immune response cascade. The mean urinary excretions of GM-CSF and TNF-alpha 4 h after the sixth week's instillation were significantly higher than the pre-instillation levels. There were no significant increases in the urinary IFN-gamma or IL-12 levels between 4 and 24 h after the sixth week's instillation. The TNF-alpha level 4 h after the sixth week's instillation had a strong tendency towards the absence of recurrence, with a mean follow-up of 54.1 months. The Kaplan-Meier curve showed the 2, 5, and 10-year recurrence-free survival rates were 72.4%, 65.8%, and 56.4%, respectively., Conclusions: We suggested that the urinary levels of TNF-alpha might be essential in antitumor activity after BCG therapy and might play an important role in the prevention of bladder tumor recurrence.

Background: This study aimed to immunohistochemically examine the expression of proliferating cell nuclear antigens (PCNA) and p53 protein in transitional cell carcinomas (TCC) of the urinary bladder, and to investigate possible correlations of this expression with the tumor grade or stage, tumor recurrence, and prognosis of the disease., Materials and Methods: The immunohistochemical status of the PCNA and p53 proteins were determined on paraffin-embedded sections from 128 patients with TCC of the urinary bladder, using PC-10 and DO7 as the primary antibodies. Positive stainings were represented by scores (Labeling Index; LI, %) calculated as the percent of positive cells among all neoplastic cells counted. The findings were compared to the patients' histopathological features. Patients who underwent transurethral resection were divided into groups with "low" and "high" scores for PCNA and p53, respectively, and the tumor recurrence rate was compared among the groups. Patients who underwent total cystectomy were similarly divided into "low" and "high" score groups, and survival rates of the groups were compared., Results: PCNA expression was observed in 66 of 128 patients (51.6%), with a mean labeling index of 26.6%. Overexpression of p53 was observed in 65 of 128 patients (50.8%), with a mean labeling index of 35.3%. There were significant correlations of the PCNA and p53 indices with both histological grade and stage of the tumor. In the TUR group, there were no statistically significant differences in recurrence rate between the groups with high or low scores for either PCNA or p53. In the total cystectomy group, there was a significant correlation between survival rate and positive staining for PCNA, but not for p53. The relationship between 2 parameters, PCNA and p53 scores, was not significant (linear correlation coefficient, r = 0.67)., Conclusions: PCNA and p53 status in transitional cell carcinomas of the urinary bladder is related to the histopathological findings. We also suggest that immunohistochemical staining for PCNA provides significant clinical information which may be useful in the initial selection of therapy. However, overexpression of p53 does not appear to represent an independent prognostic marker in bladder tumors.

Background: Long-term results after transurethral resection (TUR) and prophylactic intravesical Tokyo 172 bacillus Calmette-Guérin (BCG) therapy for primary superficial bladder cancer were analyzed by multivariate analysis, and factors affecting the recurrence of bladder tumors after this therapy were examined., Methods: One-hundred and forty-one consecutive patients with primary superficial bladder cancer who consulted the Department of Urology at Wakayama Medical College and affiliated hospitals between May 1985 and May 1990 were studied. Tokyo strain BCG was given intravesically (80 mg in 40 ml saline) weekly for 6 weeks., Results: The 5-year cumulative recurrence-free rate by the Kaplan-Meier method was 0.702 in 141 patients with primary superficial bladder cancer. The 5-year recurrence-free function using the proportional hazard model was 0.743. Using the Cox proportional hazard model, variables that significantly contributed to recurrence after intravesical BCG included female sex, tumor size less than 1 cm in diameter, and T1 tumor stage. Patient age, tumor type, multiplicity, tumor grade, and concomitant carcinoma in situ did not contribute to recurrence., Conclusion: Long-term results showed that prophylactic intravesical Tokyo strain BCG after TUR for primary superficial bladder cancer is also effective in preventing the recurrence of bladder cancer, and the biologic behavior of superficial bladder cancer other than stage T1 tumor may be altered after intravesical BCG.

Background: Past studies have analyzed individual jobs in dyestuff factories, materials manufactured and handled, age at exposure, and the duration of exposure in factories as factors related to the occurrence of urothelial tumors. None of these studies was based on long-term observation, and the factors involved in the occurrence of urothelial tumors remain controversial. In this study, various factors that may affect the occurrence of urothelial tumors in dye workers were assessed by multivariate analysis., Methods: Three hundred and sixty-three workers in nine member factories of the Dyestuff Industrial Cooperative Association were included the study. Factory A is a large dyestuff chemical factory in Wakayama City with 218 dye workers. The other eight smaller factories employ a total of 145 dye workers. Correlations of tumor occurrence with a variety of factors, such as dyestuff intermediates manufactured and handled, types of job in the factory, age at the beginning of occupational exposure, and the duration of exposure were examined by multivariate analysis using multiple logistic models., Results: Urothelial tumors were found in 58 (16.0%) of the 363 dye workers in the nine member factories of the Cooperative Association examined in the present study. The incidence in workers in Factory A, 5.5% (12 patients), was significantly (P < 0.01) lower than the overall incidence, while that in the eight small factories, 31.7% (46 patients), was significantly (P < 0.01) higher than the overall incidence. The risk factors significantly related to tumor occurrence in the 363 dye workers were benzidine (odds ratio, 8.302) as a dyestuff intermediate, manufacturing work (odds ratio, 4.631), and a long period of exposure (odds ratio, 1.018). Correlations of the tumor occurrence with the various factors were examined by multivariate analysis using multiple logistic models. In the total of 363 workers, benzidine as an intermediate (P < 0.05), manufacturing work (P < 0.01) and the duration of exposure (P < 0.01) were found to have contributed to the urothelial tumor occurrence. In Factory A, benzidine as an intermediate (P < 0.01) and duration of exposure (P < 0.05) contributed significantly to tumor occurrence., Conclusions: 1) The manufacturing and handling of benzidine and duration of exposure contribute significantly to the occurrence of occupational urothelial tumor, the former more strongly than the latter; 2) the contribution of different job types to tumor occurrence may be dependent upon the industrial health and safety practices in each factory.