Yasunori Harada

Bacillus Calmette–Guérin Perfusion Therapy for the Treatment of Transitional Cell Carcinoma in situ of the Upper Urinary Tract

Objectives: The aim of this study is to evaluate the efficacy and safety of intrarenal bacillus Calmette–Guérin (BCG) instillation as a treatment for transitional cell carcinoma in situ (CIS) of the upper urinary tract.Methods: Diagnostic criteria of upper urinary tract CIS were (1) positive urinary cytology, (2) negative multiple random biopsy of the bladder and prostatic urethra, (3) negative radiographic findings in the upper urinary tract and (4) two serial positive cytologies in selective ipsilateral urine sampling from the pyeloureteral system. Eleven patients diagnosed as having upper urinary tract CIS were enrolled in this study. Thus, 11 renal units were treated with BCG instillation. After placing a 6–french Double–J stent, BCG (80 mg) in 40 ml saline was instilled into the bladder weekly, 6 times in total as one course.Results: At the end of one course, 9 cases showed negative urinary cytology. Among these 9 cases, 2 showed recurrence in the upper urinary tract after 4 months and 8 months of disease–free interval, respectively. These 2 cases have received an additional course of BCG instillation, but the urinary cytology did not normalize. Mean recurrence–free time was 19.6 months. Of the other 7 cases who responded to the first course of instillation, 6 cases were alive with no evidence of the disease. The remaining patient died of rectal cancer with no evidence of transitional cell carcinoma (TCC). Of the 2 cases who showed positive urinary cytology even after the first course, 1 underwent nephroureterectomy. The other case was diagnosed as having malignant lymphoma 3 months after the end of this instillation therapy, and he died of malignant lymphoma. As side effects, 8 cases (72.7%) showed bladder irritability, and 4 presented fever higher than 38°C. However, no patient needed antitubercular treatment.Conclusion: As for the short–term response, BCG instillation for the treatment of upper urinary tract CIS is considered to be effective and safe. Longer follow–up and further experience with this treatment are required.

Clinical Study of Brain Metastasis of Renal Cell Carcinoma

Objectives: To evaluate the natural history and the efficacy of treatments for renal cell carcinoma (RCC) with brain metastasis, we reviewed 18 patients with this disease. Methods: Out of 325 cases with RCC treated at Osaka University Hospital from 1957 to 1993, 18 (5.5%, male:female ratio 16:2) cases developed brain metastases. Median follow-up was 44 months after the initial treatment of the primary lesion. Twelve patients had surgical resection of brain metastases (surgical group), and 7 of them received adjuvant radiotherapy. Six patients with poor performance status were treated with supportive therapy alone (nonsurgical group). Results: Of 18 RCC patients with brain metastasis, 16 were male and 2 female. All brain metastases except for 1 case were symptomatic. Median interval between the initial treatment of the primary lesion and the diagnosis of brain metastasis was 19 months. The most frequent metastatic site prior to brain was the lung, which was detected in 7 cases (38.9%). Median survival of the entire group, measured from the onset of brain metastasis, was 9.5 months. One-year survival rate after the diagnosis of brain metastasis was 43.2% (64.8% in surgical group, 0% in nonsurgical group), 3-year 18.5% and 5-year 0%. Among 109 metastatic RCC, 14 patients were treated by lymphokine-activated killer (LAK) therapy. Out of 14 metastatic RCC patients treated by LAK therapy, 3 (21.4%) developed brain metastases. On the other hand, out of 95 metastatic RCC patients without LAK therapy, 15 (15.8%) had brain metastases. There was no significant difference in the rate of brain metastases between these two groups. Conclusion: There was a trend for prognosis of the surgical group to be better compared to that of the nonsurgical group, although it is not statistically significant. The optimum treatment for brain metastasis of RCC remains undefined, but our data suggested surgical resection in selected patients might contribute to prolonged survival of patients with brain metastasis. LAK therapy was not necessarily the risk factor of the brain metastasis.

Oral Combination of Cyclophosphamide, Uracil plus Tegafur and Estramustine for Hormone-Refractory Prostate Cancer

Objective: To evaluate the clinical usefulness of an oral combination of cyclophosphamide, uracil plus tegafur (UFT) and estramustine in the treatment of patients with hormone-refractory prostate cancer (HRPC). Methods: Twenty-one patients were treated with oral administration of cyclophosphamide (100 mg/day), UFT (400 mg/day) and estramustine phosphate (560 mg/day). The median age of the patients was 70 years. Twelve patients had symptomatic bone metastasis, 6 had asymptomatic bone metastasis, 5 had lymph node metastasis, while 2 had only biochemical progression evaluated by prostate-specific antigen (PSA). Results: Twelve (57%) out of 21 patients showed a PSA decline of 50% or greater. The median response duration was 7 months (range 2–15 months). Among the 20 patients assessable for bone pain, 2 (10%) improved, 12 (60%) remained stable and 6 (30%) progressed. Among the 10 patients assessable for bone metastasis, 1 (10%) improved, 5 (50%) were stable and 4 (40%) progressed on bone scan. Among 3 patients assessable for measurable disease (lymph node metastasis), 2 (67%) showed partial response and 1 (33%) progression. Most toxicities were mild. Conclusions: The combination of cyclophosphamide, UFT and estramustine is an active and well-tolerated regimen for HRPC. To evaluate the survival benefit, further randomized studies are required.

ANGIOGENESIS INHIBITOR TNP-470 INHIBITS GROWTH AND METASTASIS OF A HORMONE-INDEPENDENT RAT PROSTATIC CARCINOMA CELL LINE

PURPOSE Inhibitory effects of TNP-470, a synthetic analogue of the antibiotic fumagillin secreted by Aspergillus fumigatus, were studied with respect to growth and lung metastasis of the hormone-independent rat prostatic carcinoma cell line AT6.3. MATERIALS AND METHODS Rat prostatic carcinoma AT6.3 cells were implanted in nude mice subcutaneously. Antimetastatic and growth-inhibitory effects of TNP-470 in vivo were examined 3 weeks after inoculation of AT6.3 cells. Direct growth-inhibitory effect was examined by MTT assay in vitro. RESULTS TNP-470 inhibited the growth of AT6.3 cells in vitro. Subcutaneously injected TNP-470 markedly reduced numbers and individual size of lung metastases from AT6.3 cells inoculated percutaneously or intravenously into male BALB/c-nu/nu mice. CONCLUSION This agent, which acts as an angiogenesis inhibitor, may prove to be clinically useful in preventing metastasis of hormone-independent prostatic cancer.

Loss of p73 Induction in a Cisplatin-Resistant Bladder Cancer Cell Line

BACKGROUND Cisplatin (CDDP) plays an important role in the treatment of transitional-cell carcinoma (TCC), but resistance develops. The mechanism is not entirely understood. METHODS To assess acquired resistance to CDDP, we established a CDDP-resistant subclone, CL8-2, of T24, which is a bladder cancer cell line. We examined the changes in the various pathways leading to apoptosis in the parent line and CL8-2. RESULTS The drug caused apoptosis of T24 cells but not CL8-2 cells. The CL8-2 cells were 6.4 times more resistant to CDDP than was T24. In both cell lines, the mismatch repair genes hMLH-1 and hMSH-2 were expressed at high levels. The p53 protein was not detected in either cell line but p73 protein was induced by CDDP treatment in T24 cells, which was followed by activation of caspases 3, 8, and 9. This phenomenon was not observed in CL8-2 cells. CONCLUSION These results suggest that loss of p73 induction may lead to CDDP resistance of TCC.

Clinical evaluation of human telomerase catalytic subunit in bladder washings from patients with bladder cancer.

PURPOSE We examined the expression of mRNA of human telomerase reverse transcriptase (hTERT), a catalytic subunit of the telomerase complex, in bladder washings as a tumor marker for the detection of bladder cancer. MATERIALS AND METHODS Bladder washings were obtained from 63 patients. We examined the expression of hTERT mRNA by the nested reverse transcription-polymerase chain reaction (RT-PCR) method and also measured the relative expressions of hTERT mRNA and beta(2)-microglobulin (beta(2)-MG) in these samples by RT-PCR analysis. Correlations between the relative expression of hTERT mRNA and clinical features were analyzed. We also compared the sensitivity of this assay with that of urinary cytology. RESULTS By nested RT-PCR, we detected three false-positive cases (11%) in the control group. Therefore, the relative expression values of hTERT mRNA and beta(2)-MG correlated strongly with tumor size, but not with multiplicity or histologic grade. When the cut-off value of the expression was fixed at 0.27%, the sensitivity and specificity of this assay were 74% and 93%, respectively. This assay was more sensitive than urinary cytology for the detection of bladder cancer. CONCLUSION These results suggest that the relative expression of hTERT mRNA in bladder washings is useful in screening for bladder cancer. Relative expression is of assistance in diagnosing bladder cancer.

Ureterosigmoidostomy, Conduit and Continent Urinary Diversion

diversion. However, operative techniques are standardized today and the pouchrelated complication rates well known (2.8–4% early complications, 18–36.3% late complications). When a continent diversion cannot be performed, conduit diversion is required. The colonic conduit should be preferred in children and when life expectancy is long. With increasing life ex-pectancy of our patients, careful long-term follow-up (metabolic alterations, vitamins and secondary malignancies) after any type of urinary diversion become increasingly important and should be the subject of investigation.