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Background To date, research has not determined the optimal procedure for adjuvant androgen deprivation therapy (ADT) in patients with locally advanced prostate cancer (PCa) treated for 6 months with neoadjuvant ADT and external-beam radiation therapy (EBRT). Methods A multicenter, randomized, phase 3 trial enrolled 303 patients with locally advanced PCa between 2001 and 2006. Participants were treated with neoadjuvant ADT for 6 months. Then, 280 patients whose prostate-specific antigen levels were less than pretreatment levels and less than 10 ng/mL were randomized. All 280 participants were treated with 72 Gy of EBRT in combination with adjuvant ADT for 8 months. Thereafter, participants were assigned to long-term ADT (5 years in all; arm 1) or intermittent ADT (arm 2). The primary endpoint was modified biochemical relapse-free survival (bRFS) with respect to nonmetastatic castration-resistant prostate cancer (nmCRPC) progression, clinical relapse, or any cause of death. Results The median follow-up time after randomization was 8.2 years. Among the 136 and 144 men assigned to trial arms 1 and 2, respectively, 24 and 30 progressed to nmCRPC or clinical relapse, and 5 and 6 died of PCa. The 5-year modified bRFS rates were 84.8% and 82.8% in trial arms 1 and 2, respectively (hazard ratio, 1.132; 95% confidence interval, 0.744-1.722). Conclusions Although modified bRFS data did not demonstrate noninferiority for arm 2, intermittent adjuvant ADT after EBRT with 14 months of neoadjuvant and short-term adjuvant ADT is a promising treatment strategy, especially in a population of responders after 6 months of ADT for locally advanced PCa.

PURPOSE To clarify the optimal duration and methods for adjuvant endocrine therapy after external beam radiation therapy (EBRT) in patients with locally advanced prostate cancer. MATERIALS AND METHODS Between 2001 and 2003, 215 patients with locally advanced prostate cancer were enrolled in the study. Patients were registered as primary candidates of the study and were treated with 6 months of LHRH agonist, with short-term of antiandrogen treatment for flare-up prevention. Patients with PSA levels below 10 ng/ml after the 6-month endocrine treatment were randomly divided into two arms. Then, a total dose of 72 Gy was given to the prostate. After 14 months of the protocol treatment, patients were treated with continuous androgen ablation (arm 1) or intermittent androgen ablation (arm 2). RESULTS A total of 188 cases (87%) remained in the protocol. The median PSA level at entry was 25.3 ng/ml. The Gleason score was 2–6 in 32 cases (16%), 7 in 94 cases (48%), and 8–10 in 68 cases (35%). The median PSA level showed a remarkable decrease to 1.1, 0.2, and 0.1 ng/ml, after 6, 8, and 14 months of the protocol treatment, respectively. Of the 157 cases treated with EBRT, 153 cases (97.5%) had no biochemical failure in the mean follow-up of 17.3 months. CONCLUSIONS The present study may reveal the possibilities of intermittent endocrine therapy after EBRT. However, the follow-up interval is short and little can be said about the results observed so far, exception of acute tolerance and patient acceptance of the protocol. © 2004 Wiley-Liss, Inc.

Objectives: We compared the prophylactic efficacy and safety of epirubicin (EPI) in primary superficial bladder cancer. Methods: The major inclusion criteria were primary superficial bladder tumour (Ta, T1, G1, G2) and new cases of primary multiple tumours, or recurrent cases. The major exclusion criteria were Tis or G3 tumours. Group A received 17 doses of EPI 20mg/40ml over a period of 12 months for a total dose of 340mg. In contrast, Group B received 12 doses of EPI 30mg/40ml over a period of 7 months, while Group C received 9 doses of EPI 40mg/40ml over a period of 4 months, both for a total dose of 360mg. This study enrolled a total of 622 patients diagnosed as having primary superficial bladder cancer during the period from June 1994 through November 1996 at the 118 institutions. Follow-up of the patients was conducted through October 1999. Results: The relationship between the EPI concentration and the recurrence-free rate was evaluated by Tarone's test, and it was found that the recurrence-free rate became significantly higher as the drug concentration increased ( p =0.0375). In the safety evaluation, with regard to adverse drug reactions, pollakiuria and pain on urination occurred at significantly higher incidences as the concentration of the EPI solution increased. Conclusions: The greatest effect of intravesical instillation of EPI after TUR-BT was shown by the regimen using the highest concentration of the drug solution which was administered during a short period of time.

BACKGROUND Only 20–30% of patients with refractory or recurrent germ cell tumors (GCT) are cured by salvage chemotherapy. Irinotecan, a new derivative of camptothecin, is a potent anticancer agent against a variety of solid cancers. The current pilot study investigated the efficacy of salvage chemotherapy with irinotecan in combination with cisplatin (CDDP) or nedaplatin (NDP), a derivative of cisplatin, for GCT. METHODS The combination chemotherapy consisted of 100–150 mg/m2 irinotecan on Days 1 and 15 or 200–300 mg/m2 on Day 1 in combination with 20 mg/m2 CDDP on Days 1–5 or 100 mg/m2 NDP on Day 1 every 4 weeks. Patients with refractory GCT, ranging in age from 17 to 43 years, received 2–11 cycles of the combination chemotherapy. The median duration of follow-up is 28 months (8–140 months). RESULTS Twenty patients entered this study, 18 of whom were assessed for response and toxicity. The response rate was 50 % (two complete responses and seven partial responses). Nine patients remain alive without disease. However, six patients died of the disease and one patient died of a brain glioma. The 5-year survival rate was approximately 53%. Myelosuppression was the major toxicity, but was manageable. CONCLUSIONS This pilot study demonstrates that the chemotherapy with irinotecan in combination with CDDP or NDP showed significant anticancer activity for patients with refractory GCT, without serious side effects. Although this study comprised only a few patients, these findings suggest that the combination chemotherapy may be one of the options of salvage chemotherapy for patients with refractory GCT. Cancer 2002;95:1879–85. © 2002 American Cancer Society. DOI 10.1002/cncr.10918

Introduction: A kind of lactic acid bacteria, Lactobacillus casei strain Shirota, shows antitumor activity in experimental animals. One clinical trial using L. casei showed a significant decrease in the recurrence of superficial bladder cancer. So, to assess the preventive effect of the intake of L. casei, widely taken as fermented milk products in Japan, against bladder cancer, we conducted a case-control study. Methods: A total of 180 cases (mean age: 67 years, SD 10) were selected from 7 hospitals, and 445 population-based controls matched by gender and age were also selected. Interviewers asked them 81 items. The conditional logistic regression was used to estimate adjusted odds ratios (OR). Results: The OR of smoking was 1.61 (95% confidence interval: 1.10–2.36). Those of previous (10–15 years ago) intake of fermented milk products were 0.46 (0.27–0.79) for 1–2 times/week and 0.61 (0.38–0.99) for 3–4 or more times/week, respectively. Conclusion: It was strongly suggested that the habitual intake of lactic acid bacteria reduces the risk of bladder cancer.

Human lymphoblastoid interferon (IFN)-alpha was administered intramuscularly at doses of 5 megaunits/day 5 to 7 days a week to 32 advanced renal cell carcinoma patients. To augment the antitumor effect of IFN, cimetidine was also administered orally in doses oi 800 mg/day. This combination therapy resulted in a complete response (CR) in 6 patients (19%), a partial response (PR) in 7 (22%), a stable disease (SD) in 11 (34%), and a progressive disease (PD) in 8 (25%). The response rate (CR+PR) was 41%. The pulmonary metastases were more receptive to IFN therapy than those at other sites. The median times to response were 2 months for PR, and 4.5 months for CR. The survival of the responder patients was significantly longer than the nonresponder patients. These results suggest that IFN-alpha and cimetidine combination therapy may be of use in the management of advanced renal cell carcinoma.

BACKGROUND Nephron-sparing surgery for incidentally detected small renal tumors has been performed. The main objection to such surgery concerns the incidence rate of satellite renal tumors. In this study, the authors analyzed the rate of incidence and proliferative potential of satellite renal tumors. METHODS The tumors of 124 renal cell carcinoma patients with a clinically identified unilateral and single tumor measuring ≤90 mm who were examined between November 1991 and May 1997 were analyzed prospectively. The authors determined whether these specimens obtained by radical nephrectomy had satellite tumors, and whether the satellite tumors were reactive with a monoclonal antibody (MoAb), MIB-1, to assess their proliferative potential. RESULTS Satellite renal cell carcinomas were detected in 8 of the 124 patients (6.5%). None of the pathologic variables examined (tumor grade, tumor stage, main tumor size, cell pattern, and vascular invasion) were found to be predictive of the presence of satellite tumors. Of these eight tumors, two main tumor specimens and three satellite tumor specimens reacted with the MIB-1 MoAb. The reactivity of MIB-1 correlated with the tumor grade. The satellite tumors were observed to have a proliferative potential compared with the main tumors. Among 86 kidney specimens from patients with urothelial tumors after total nephroureterectomy, 2 (2.3%) contained small renal cell carcinoma but did not show positive staining with the MoAb MIB-1. CONCLUSIONS The incidence rate of satellite tumors among 124 renal cell carcinoma patients was 6.5% and the presence of satellite tumors was not predictable. Some of these satellite tumors showed positive staining with the MIB-1 MoAb, but small renal tumors detected in kidney specimens with urothelial tumors did not. Cancer 1999;86:2331–6. © 1999 American Cancer Society.

BACKGROUND The effect of intravesical instillation of doxorubicin or epirubicin after transurethral resection (TUR) was estimated from the data of five randomized clinical trials in Japan. The authors provided the estimated hazard function plots with a smoothing technique, to evaluate the prophylactic effect of an intravesical therapy over time and to estimate the natural history of superficial bladder carcinoma. METHODS Data on a total of 1732 patients from 5 studies of the Japanese Urological Cancer Research Group who were eligible to receive doxorubicin and epirubicin were analyzed. The patients were divided into four subgroups based on their background characteristics. Their tumors were categorized as “primary and solitary,” “primary and multiple,” “recurrent and solitary,” or “recurrent and multiple.” RESULTS Multivariate analysis revealed that intravesical instillation reduced the risk of recurrence to about one-half to two-thirds compared with the controls. The shapes of the graphs that estimated the hazard function for patients with no prophylaxis indicated that multiple tumors showed an earlier peak of recurrence than solitary tumors and recurrent tumors had a higher hazard of recurrence than primary tumors. Graphic presentation of the hazard function in each subgroup suggested that the effect of prophylaxis continued for 500 days after TUR but not for longer. CONCLUSIONS This analysis indicated that there are two patterns of tumor recurrence of superficial bladder carcinoma after TUR, namely, early phase and late phase. Intravesical chemotherapy may be effective mainly in reducing the hazard for recurrence in the early phase. Cancer 1999;86:1818–26. © 1999 American Cancer Society.

Objectives. To improve the treatment of locally advanced prostate cancer (Stages B2 and C), a prospective randomized trial was conducted to compare radical prostatectomy versus external beam radiotherapy with the combination of endocrine therapy in both modalities. Methods. One hundred patients were enrolled and 95 were evaluated. Forty-six patients underwent radical prostatectomy with pelvic lymph node dissection, and 49 were treated with radiation by linear accelerator with 40 to 50 Gy to the whole pelvis and a 20-Gy boost to the prostatic area. For all patients, endocrine therapy was initiated 8 weeks before surgery or radiation, and continued thereafter. The living patients were asked to respond to a quality-of-life questionnaire. Results. The follow-up period ranged from 6.0 to 94.4 months (median 58.5). The progression-free and cause-specific survival rates at 5 years were 90.5% and 96.6% in the surgery group and 81.2% and 84.6% in the radiation group, respectively. The surgery group had better progression-free and cause-specific survival rates ( P = 0.044 and 0.024, respectively). More patients in the surgery group complained of urinary incontinence. The questionnaire revealed that quality of life was less disturbed in the radiation group. Conclusions. Radical prostatectomy combined with endocrine therapy may contribute to the survival benefit of patients with locally advanced prostate cancer. External beam radiotherapy in combination with endocrine therapy can be used in selected patients because of its low morbidity.

Purpose: The aim of the present study was to determine the clinical usefulness of nuclear matrix protein 22 (NMP22) as a new urinary marker for the screening of urothelial cancer in patients with microscopic hematuria, especially in comparison with that of voided urine cytology. Methods: Patients with microscopic hematuria detected at a health examination, who were advised by a consulted urologist to have a cystoscopical examination, were asked to enter this study. Urine samples were collected before cystoscopy and divided into two portions for a NMP22 test and voided urine cytology. Results: Of the 309 patients with microscopic hematuria, 22 cases (7.1%) of urothelial cancer and one case of prostate cancer were detected. For the other cases, 128 (41.4%) were of benign diseases and 158 (51.1%) were designated as having no evidence of disease (NED). The median NMP22 values for urothelial cancer, other diseases and NED were 35.5, 6.7 and 6.0 U/mL, respectively, with 95% confidence intervals of 19.9–228.2, 5.1–9.3 and 5.4–7.2, respectively. The sensitivity of the NMP22 test for urothelial cancer was 90.9% (20/22), whereas the sensitivity of voided urine cytology was only 54.5% (12/22). Conclusions: The present study indicates that urinary NMP22 is a useful tool for the screening of urothelial cancer in patients with microscopic hematuria.

Background: A multicenter cooperative study to evaluate clinical usefulness of recombinant human granulocyte colony stimulating factor (rG-CSF; lenograstim) in the treatment of neutropenia associated with cancer chemotherapy was conducted in patients with urothelial cancer. Methods: Therapeutic responses were compared within each patient between the observation and study treatment phases. Results: Treatment with rG-CSF raised the nadir of the neutrophil count (343 to 3015/mm3), reduced the duration of neutropenia (6.2 to 0.4 days) and hastened recovery from the neutropenic state (23.5 to 5.5 days). Febrile neutropenia was encountered in 12 patients during the observation phase alone and in only one patient during the study treatment phase alone. The mean duration of febrile neutropenia was also shortened (0.39 to 0.12 days). In addition, the duration of antibiotic therapy was significantly reduced during treatment. The percentage of patients completing the chemotherapeutic regimens of combination M-VAC therapy was markedly increased to 81.0% as a result of rG-CSF therapy compared with 44.8% in the observation phase. Adverse reactions were observed in four patients and abnormal laboratory values were found in nine patients. None of these adverse events was of a serious nature. Conclusions: These results indicate that rG-CSF is a useful drug for the treatment of neutropenia associated with chemotherapy in urothelial cancer.

BACKGROUND In the TNM classification of renal cell carcinoma released in 1997, T1 tumors were defined as organ-confined tumors 7.0 cm or less in size, and T2 as those larger than 7.0 cm. The consideration of tumor size should be predicated on its prognostic value in predicting survival, because the goal of clinical staging is to separate patients into similar classes of survival based on the extent of disease at presentation. The authors examined the impact of tumor size on the clinical outcomes of patients with Robson Stage I disease to determine a size cutoff that would maximize the predictive value of the TNM staging system. METHODS Between 1962 and 1995, 382 patients with renal cell carcinoma were treated at the Department of Urology at the Osaka Medical Center for Cancer and Cardiovascular Diseases in Osaka, Japan, and the TNM staging of 350 of those patients was recorded. Of 350 patients, 157 (45%) were at TNM Stage I, 47 (13%) at Stage II, 65 (19%) at Stage III, and 81 (23%) at Stage IV, according to the TNM stages defined in 1997. Robson Stage I includes TNM Stages I and II, and 204 patients in these stages were analyzed in this study. This study group included 146 men and 58 women with a mean age of 57.8 years (range, 26–84 years). The mean follow-up period was 5.4 years. RESULTS The patient survival periods were not significantly different for those with TNM Stages I and II. This finding indicated that the tumor size cutoff of 7.0 cm was not useful in predicting the prognosis. The patients at TNM Stages I and II were then divided into two groups at each size cutoff, from 2.5 cm to 9.0 cm, at 0.5-cm intervals. The tumor size cutoff of 5.5 cm was most predictive of patient survival (P = 0.0121). None of other patient characteristics varied significantly between the two groups at this dichotomous point. Tumor size and microscopic intrarenal venous invasion, but not grade or infiltration pattern, were found in univariate and multivariate analyses to be significantly predictive of the survival of Robson Stage I patients after radical nephrectomy. CONCLUSIONS The current data indicate that the tumor size cutoff of 5.5 cm was most significantly predictive of the survival of Robson Stage I patients after radical nephrectomy. The tumor size cutoff of 5.5 cm was also shown to be significant in univariate and multivariate analyses. Cancer 1999;85:689–95. © 1999 American Cancer Society.

Background: To evaluate the antitumor activity in patients with T3b, T4 or metastatic urothelial carcinoma treated with MEC or M-VAC chemotherapy, by performing a multi-center randomized prospective study. Methods: From 1991 to 1995, 89 patients with T3b, T4 or metastatic urothelial carcinoma were randomly allocated to a methotrexate, epirubicin and cisplatin chemotherapy group (arm 1: S-MEC therapy; n = 29), a dose-intensified MEC therapy combined with G-CSF group (arm 2: I-MEC therapy; n =30) or a methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy (arm 3: M-VAC therapy; n = 30). At the registration center, the patients were stratified into previously untreated patients and patients with recurrence after radical operation and then randomly allocated to the treatment groups. In each arm, two or more courses of chemotherapy (4-weekcycles) were performed. Results: Of the 88 eligible patients, four treated with S-MECtherapy andtwo treated with I-MEC therapy showed CR.The response rates (CR+ PR) were 52% (15/29) with S-MEC therapy, 76% (22/29) with I-MECtherapy and 47% (14/30) with M-VAC therapy. The response rate with I-MEC therapy was significantly higherthan that with M-VAC therapy (P= 0.02). Although the incidence of leukopenia was low with I-MEC therapy, the incidence of thrombocytopenia was high with this therapy. Conclusion: MEC therapy used in this study is promising in terms of the antitumor effects.

Background: Excellent treatment results are obtained for stage I testicular seminoma treated with orchiectomy and prophylactic radiotherapy. In patients with stage I nonseminomatous testicular tumors, surveillance alone is successful, however, this treatment option for stage I testicular seminomas is controversial. There have been few reports of long-term follow-up of surveillance alone for patients with stage I testicular seminoma. Methods: To assess the appropriateness of this treatment option, a retrospective survey of stage I testicular seminoma was undertaken. Twenty-seven patients who underwent prophylactic radiation therapy (RT group) and 41 patients followed only by surveillance (S group) after high orchiectomy were evaluated. Their follow-up consisted of frequent clinical examinations, abdominal CT scans, chest x-rays and serum tumor markers. Results: In the RT group, with a median follow-up period of 15 years, 1 patient (3.6%) had a recurrence in the lung at 4 months after orchiectomy and died, but the remaining 26 are alive with no evidence of disease (NED). In the S group, with a median follow-up period of 7.3 years, 5 (12.2%) relapsed in the retroperitoneal lymph nodes, but all are alive with NED following chemotherapy. The remaining 36 are all alive without recurrence (follow-up period, 38 to 132 months). Although the relapse rate in the S group was relatively higher than in the RT group, there was no significant difference between the 2 groups. Conclusion: If a frequent follow-up protocol is administered and followed by the patient, surveillance alone may be a recommended management for stage I testicular seminoma.

Background: This study examines the minimally required imaging protocol needed for detection and staging of renal cell carcinoma (RCC). Methods: In 81 patients (21 women, 60 men; mean age = 62 years) with 85 RCCs, T1-weighted (T1WI), contrast-enhanced T1-weighted (Gd-T1WI), T2-weighted (T2WI), and gradient recalled echo–fast low flip angle shot (GRE/FLASH) images were evaluated alone and in combination. Surgical–pathological findings were available in all patients and were considered the standard of reference. Results: Tumor detection for lesions smaller than 3 cm was better on Gd-T1WI than on any other sequence, but only the comparison with noncontrast T1WI and GRE/FLASH was statistically significant (detection: T1WI = 33%, Gd-TIWI = 80%, T2WI = 60%, GRE = 47%). The respective accuracies of T1WI, Gd-T1WI, T2WI, and GRE/FLASH images were 81%, 78%, 71%, and 62% for evaluating local tumor extension; 90%, 88%, 89%, and 85% for lymphadenopathy; and 89%, 81%, 91%, and 95% for renal vein thrombus. The combination of T1WI and GRE sequences rendered the highest overall staging accuracy. Conclusion: For tumor detection, contrast-enhanced T1WI is necessary for lesions smaller than 3 cm. For tumor staging, although the addition of GRE results in significant improvement in the evaluation of venous thrombus, any combination of two sequences will result in similar accuracy, and the use of multiple sequences is not necessary.

A 74-year-old man was admitted to our hospital. Diagnosis of invasive bladder cancer was made and a total cystectomy was performed on January, 30, 1980. Histological examination showed transitional cell carcinoma, grade 2, pT1 is N0M0. After 16 years, when he suffered left femur, he had right inguinal lymphnode swelling. On the biopsy of the inguinal mass, histology was transitional cell carcinoma. The urethral washing cytology was positive. Lung CT scan dem onstrated multiple lesions. He was diagnosed of the urethral recurrence, right inguinal lymphnode metastasis and lung metastasis of bladder cancer. This case is the 5th case of urethral recurrence of bladder cancer following cystectomy in our hospital.

Prognostic factors related to the recurrence and progression of superficial primary bladder cancers were analyzed by Cox's proportional hazards regression model. We followed 75 patients (stage Ta, 49 cases; T1, 26 cases; grade G1, 42 cases; G2, 29 cases; G3, 4 cases) after transurethral resection for 10 to 74 months (median 38 months). The antibodies reactive with the products of oncogenes [anti-c-myc oncoprotein (MYC-1); anti-c-erbB-2 oncoprotein], tumor suppressor gene [anti-p53 mutant protein (BP53-12)], growth factor receptor [anti-transferrin receptor (HBT-2)], proliferation [anti-proliferatioe nuclear antigen (Ki-67)], and malignant transformation (B1.4) were used for immunohistochemical staining. The reactivities of mAb B1.4, HBT2, and BP53-12 were significantly increased according to the grade, and those of mAb Ki-67, MYC-1, and c-erbB-2 were not. The reactivities of all antibodies were not significantly different between stages Ta and T1. As prognostic factors, stage, grade, tumor number, urinary cytology, and reactivities of the above six antibodies were used for the analysis. Urinary cytology, multifocality, and the reactivity of mAb Ki-67 showed a relative but significant high risk for recurrence, and the reactivities of mAb HBT2, mAb B1.4, and mAb Ki-67 showed a significant high risk for progression in the multivariate analysis. These results suggest that mAb B1.4 may be useful as a new prognostic factor for the progression of superficial bladder cancer.

A double-blind trial was conducted in 138 patients with superficial transitional cell carcinoma of the bladder following transurethral resection to evaluate the prophylaxis of recurrence by an oral Lactobacillus casei preparation (BLP). Patients were stratified into the following 3 subgroups: (A) with primary multiple tumors; (B) with recurrent single tumors, and (C) with recurrent multiple tumors. In each group, patients were randomly allocated to receive BLP or placebo. BLP showed a better prophylactic effect in subgroups A and B than placebo, whereas no significant difference was observed in subgroup C. Cox multivariate analysis showed that the outcome with BLP was significantly better than with placebo (p = 0.01). Slight and tolerable adverse reactions occurred in 3 patients receiving BLP and in 3 of the placebo-treated patients. Oral administration of BLP was thus safe and effective for preventing recurrence of superficial bladder cancer.

Immunohistochemical analysis by indirect immunoperoxidase staining demonstrated that monoclonal antibody (mAb) B1.4 derived from a mouse immunized with a bladder cancer cell line EJ‐1 was reactive with a high proportion of high‐grade and invasive bladder tumors, but not with the majority of low‐grade and superficial bladder tumors, or normal urinary epithelium. Among 71 primary bladder tumors classified by pathological grading, positive stainings were observed in 1 of 34 tumors (3%) of grade 1, 8 of 20 tumors (40%) of grade 2 and 14 of 17 tumors (82%) of grade 3. When the tumors were classified by pathological staging, positive stainings were observed in only 8 of 54 (15%) superficial tumors of stages Ta and T1, but in 15 of 17 (88%) invasive tumors of stages T2 and T3. mAb B1.4 showed restricted positive stainings with normal tissues including renal glomerulus, vascular endothelium, squamous epithelium of esophagus, glandular epithelium of prostate, and epithelium of pancreatic acinar gland and minute duct, while positive stainings were observed in a range of tumor tissues other than bladder tumor. Mixed hemadsorption assays with a panel of cell cultures showed also that the antigen recognized by mAb B1.4 was expressed on a range of tumor cell lines. These findings suggest that the antigen recognized by mAb B1.4 may appear after malignant transformation, and be an indicator of malignant potential of bladder cancer.

A total of 20 patients with primary invasive bladder cancer who underwent radical cystectomy received postoperative adjuvant chemotherapy using a CAP (cyclophosphamide, doxorubicin, and cisplatin) or modified M-VAC (methotrexate, vinblastine, pirarubicin, and cisplatin) regimen. In all, 16 of the patients were treated with CAP and 4 received the modified M-VAC regimen. Of the 20 patients, 17 had transitional-cell carcinoma with or without non-transitional-cell elements. All of the patients had tumors with a histological grade of G2 (6 cases) or G3 (14 cases). As for lymph-node metastasis, there were ten N0 cases, three N1 cases, six N2 cases, and one N3 case. Adjuvant chemotherapy was usually commenced 2 weeks after the surgery and was given every 3-4 weeks for two or three cycles. The 5-year survival rate of these 20 patients was 65.9%, whereas that of 49 patients who did not receive any adjuvant chemotherapy was 30.2%. Regarding toxicity, both of the adjuvant chemotherapy regimens used in this study were generally well tolerated. The most common toxic effects were gastrointestinal symptoms, alopecia, and myelosuppression. Another 19 patients with invasive transitional-cell carcinoma of the bladder received 2 or 3 cycles of neoadjuvant chemotherapy using the modified M-VAC or MEC (methotrexate, epirubicin, and cisplatin) regimen. Of 18 pathologically evaluable patients who underwent radical cystectomy or partial cystectomy, the stage was pT0 in 3 cases (17%), pTis in 3 (17%), pT1 in 3 (17%), and pT2 or higher in 9 (50%). The 4-year survival rate of 18 patients who received neoadjuvant chemotherapy was 71.5%. Regarding toxicity, one patient died of a bowel complication after surgery, and the complication was suggested to be drug-induced.

The antitumor effect of recombinant human tumor necrosis factor (rHu-TNF) on 2 human testicular tumors (embryonal carcinoma, TTSC-1, and teratocarcinoma, TTSC-4) heterotransplanted in nude mice was studied. Therapeutic antitumor effect was observed more evidently in TTSC-1 than TTSC-4 when more than 5 x 10(3) U/mouse of rHu-TNF was administered intratumorally. Complete tumor regression was observed in both TTSC-1 and TTSC-4 after intratumoral administration of rHu-TNF. Histological findings correlated well with the decrease in tumor volume of treated tumors. In contrast to these data, little antitumor effect was observed when the same dose of rHu-TNF was administered intravenously to nude mice bearing these tumors. In conclusion, intratumoral administration of rHu-TNF was a more effective and safe method than intravenous administration against human testicular tumors heterotransplanted in nude mice.

The Japanese Urological Cancer Research Group for Adriamycin has conducted a series of clinical trials to investigate the efficacy and safety of prophylactic intravesical chemotherapy for superficial bladder cancer. In the third trial, reported herein, patients with recurrent bladder cancer or multiple primary cancer were selected and randomized to one of four groups using the envelope method after complete resection of the original tumors. Group A was given Adriamycin alone, group B received oral 5-fluorouracil (5-FU), group C was given Adriamycin and oral 5-FU, and group D served as the control group. Of the 544 patients registered, 331 were evaluable for the purpose of this study. The administration of 5-FU (group B) failed to prevent the recurrence of bladder tumors. Although group C (both Adriamycin and 5-FU) did not fare better than group A (Adriamycin only), Adriamycin was effective in preventing the recurrence of tumors, especially in high-risk patients with recurrent and multiple tumors. The risk of recurrence was reduced to 0.21 (95% confidence interval, 0.10–0.44) relative to the control group. There was no indication of a synergistic effect between 5-FU and Adriamycin. As side effects, cystitis syndrome was observed in 23%–30% of the patients in the Adriamycin groups and mild myelosuppression was observed in the 5-FU groups.

The involvement of p53 mutations in prostate cancers in Japan was investigated. To evaluate any possible clinicopathological significance, p53 mutations in 40 samples from 36 Japanese prostate cancers of different stages (five cases of latent tumors, three of stage A cancers, 10 of stage B, five of stage C and 13 of stage D), including four lymph node metastases of stage D cases, were examined by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and sequencing. Mutations were detected in five of 40 samples (12.5%); four were in primary cancers and the other in a lymph node metastasis from one of them. All mutation-positive cases were in stage D, and the mutation frequency in stage D cases was 31%. This result indicates that p53 mutations may play a role in the progression of a subgroup of prostate cancers in Japanese, as observed for Americans and Europeans. However, a difference was noted between Japanese and Americans in the p53 mutational spectrum (at CpG site), presumably arising from variation in the underlying etiologic factors.

Neoadjuvant therapy for prostatic cancer might be important to increase cure rates of the disease and preservability of the organs. There were 43 cases in a period of 1975-1990 in which total prostatectomy were performed after neoadjuvant therapy. According to the clinical stage, there were 14 cases in B, 23 in C, 4 in D1 and 2 in D2. The median duration of neoadjuvant therapy was 4 months. Clinical response of the prostate in 37 evaluable cases was as follows; 6 cases were PR (16%), 12 cases were MR (32%) and 19 cases were NC (52%). Histopathological effect was as follows; 5 cases were grade 0a (12%), 12 cases were grade 0b (28%), 16 cases were grade 1 (37%), 8 cases were grade 2 (19%) and 2 cases were grade 3 (5%). In 2 cases with histopathological effect of grade 3, lymph node metastases were thought to have obviously disappeared. Histopathological effect seemed related to clinical response. In cases given neoadjuvant therapy for less than 2 months, no adequate clinicopathological effect was obtained. Cases that could achieve downstaging were 8; 1 in grade 0a, 2 in grade 1, 3 in grade 2 and 2 in grade 3. These results suggest that neoadjuvant therapy plays an important role in advanced prostatic cancer.

It is a fact that there are few effective drugs available except for interferon for that treatment of renal cell carcinoma, and the efficacy rate of interferon is less than 10% even if multiple drug regimens are included. We have experienced a case of renal cell carcinoma in whom interferon therapy was successful in reducing the primary lesion and tumor thrombus extending into the inferior vena cava. A 57-year-old man was admitted to our department with a complaint of macroscopic hematuria. Computed tomography and magnetic resonance imaging revealed a right renal tumor and the tumor thrombus. Because of the past history of his myocardial infarction, a radical operation was considered risky. So we started interferon therapy. Four months after the start of interferon therapy, the primary lesion and the tumor thrombus markedly reduced in their size, and the clinical response was evaluated as partial response by response criteria for urological cancer treatment. Therefore, radical nephrectomy and tumor thrombectomy were performed with extracorporeal circulation. Histopathologically, necrosis and lymphocyte infiltration into the cancer cell focus were seen, and these immunologic reactions were considered at the affection of interferon. In some case, interferon therapy is a useful and safe in the treatment of the primary lesion of renal cell carcinoma, and further investigation must be studied.

Assessing the QOL in cancer clinical trials is becoming increasingly important. However, a suitable device of assessment of QOL has not been developed yet for prostate cancer patients in Japan. We tried to assess the QOL of prostate cancer patients using the EORTC questionnaire translated in Japanese, and examined its validity and reliability. Thirty-six patients filled in a questionnaire. The reliability of this device was confirmed by the results of test-retest reproducibility. Good correlation was shown between the results and patients performance status, and between the results and clinical stages, which support the validity of the device. As for the results of assessment of QOL, these patients were severely damaged in sexuality. Those factors of functional status, physical symptoms and fatigue/malaise were closely related to disease activity and clinical stage.

下大静脈内進展を伴う後腹膜腫瘍6例 (腎細胞癌4例, 副腎癌1例, 睾丸腫瘍1例) に対して常温完全体外循環を用いて外科治療を行った. 腎細胞癌の2例を除く4例では術前肺あるいは骨への遠隔転移を認めた. 6例中5例は, 術後追跡期間1年から7年 (平均3年3か月) で, 健在である. 睾丸腫瘍および副腎癌の症例ではいずれも術前遠隔転移を有したが, 術後の放射線および化学療法にて転移巣の消失を認めた. 腎細胞癌に関して術前遠隔転移を有した2例中1例が術後6か月で死亡したが, その死因は周辺臓器への浸潤によるのであり, 体外循環中の腫瘍細胞の播種によるものではなかった. 2例で体外循環回路内のフィルターおよび回路血液の細胞診を行ったが, いずれも陰性であった. 術後遠隔成績および体外循環回路の細胞診の成績からは, 術中の腫瘍細胞の播種の可能性は低く, 下大静脈内進展を伴う後腹膜腫瘍に対して常温完全体外循環を用いた外科治療は有用である.

A multicenter cooperative study was conducted to evaluate the clinical efficacy and safety ofcis-diammine(glycolato)platinum (254-S), a second-generation anticancer platinum complex, in the treatment of genitourinary cancers. 254-S was given i. v. at 100 mg/m2 at 4-week intervals. As a result, 2 complete responses (CRs) and 8 partial responses (PRs) were obtained in 35 patients with transitional-cell carcinoma (TCC) of the urinary bladder or pyeloureter, 3 PRs were obtained in 16 subjects with prostatic cancer, and 6 CRs and 6 PRs were obtained in 15 patients with testicular cancer, generating objective response rates of 28.6% [95% confidence interval (CI), 14.6%–46.3%], 18.8% (95% CI, 4.0%–45.6%), and 80.0% (95% CI, 51.9%–95.7%), respectively. Bone marrow suppression was the dose-limiting toxicity, although it was reversible. Although no hydration was performed in approx. 40% of the patients, the incidence of nephrotoxic effects was low and most of those encountered were mild, the exception being one patient who showed severe renal insufficiency after the first treatment. Nausea and vomiting occurred in approx. 70% of the patients, but most gastrointestinal toxicities were controlled without antiemetic treatment. In addition, liver-function impairment was rarely observed. We conclude that 254-S is a promising cisplatin analogue for the treatment of genitourinary cancers and is worthy of further investigation in large-scale, randomized comparative studies with other platinum derivatives in both single-agent and combination regimens.

Long-term results were analyzed in terms of tumor progression and survival in patients with superficial bladder cancer who were enrolled in the second intravesical chemoprophylactic study of the Japanese Urological Cancer Research Group for Adriamycin, which was started in July 1982. This study was a prospective, randomized, controlled trial conducted on primary tumors treated with a long-term instillation regimen that involved control versus intravesical instillations of Adriamycin or mitomycin C given once a week for the first 2 weeks, once every other week for 14 weeks, once a month for 8 months, and once every 3 months for 1 year, for a total of 21 instillations in 2 years. An analysis of the prophylactic effects of such treatment on bladder tumors after TUR has previously been performed, and the results have been published elsewhere. The present study represents a follow-up of the above trial. Of the 671 cases previously analyzed with regard to tumor prophylaxis, 158 cases (23.5%) were eligible to be followed for tumor progression and survival. A detailed comparison of the background factors between these 158 patients and the other 513 cases revealed no statistically significant difference. Thus, the 158 evaluable cases might reasonably be considered to represent all patients enrolled in the second study, and the results were thought to be reasonable enough to reflect the long-term efficacy of the long-term instillation regimen adopted in this study. The median follow-up for these 158 cases was 6.6 years. Tumor progression in terms of the disease stage and/or grade occurred in 43 of 127 patients who received prophylactic instillations and in 12 of 31 control cases. No significant difference in the incidence of tumor progression was found between the treatment and the control groups. In addition, no difference in survival was observed between the treatment group and the control group. Survival was also compared between patients who showed tumor progression and those who did not. All patients whose tumors did not progress survived, whereas the 7-year survival of those exhibiting tumor progression was less than 90%.

In a cooperative study of the Japanese Urological Cancer Research Group for Adriamycin, the usefulness of chemotherapy with methotrexate, vinblastine, Adriamycin, and cisplatin (M-VAC therapy) in treating advanced or recurrent bladder cancer was examined. Evaluation of the clinical responses obtained in 86 evaluable patients revealed 13 complete responses, 29 partial responses, 4 minor responses, 19 cases of no change, and 21 cases of progressive disease. The overall response rate was 48.8% (42/86). The rate of response to M-VAC therapy at each disease site was as low as 21.4% (3/14) in bone lesions but exceeded 40% in the primary lesion, the lymph nodes, the lung, the liver, and other lesions. The clinical response to M-VAC therapy was not significantly influenced by the performance status of the patients, the dose intensity, or previous therapy. The median duration of response for the 42 responders was 22.7 weeks (range, 8.1–134.1 weeks), and the median duration of survival for the 86 evaluable patients was 9.8 months. Side effects were frequently encountered; the patients experienced anorexia, nausea, vomiting, malaise, alopecia, and leukopenia, but all of these symptoms were tolerable.

In the urological field, one of the most effective drugs is doxorubicin. A cooperative phase II study on pirarubicin (THP), a new anthracycline with less cardiotoxicity than doxorubicin, was performed in 14 institutions for treating urological tumors. THP was administered intravenously 3 or more times (as one course, 30-40 mg/m2 once a week, every 3 weeks or 20 mg/m2 2 consecutive days a week every 3 weeks). Fifty-four of the 63 patients included in this study were evaluable. An overall efficacy rate was 18.5% (10/54), consisting of transitional cell carcinoma 24.3% (9/37; bladder cancer 6/27 (22.2%), tumors of the renal pelvis and ureter 3/10 (30.0%), and prostatic cancer 1/15 (6.7%). Adverse effects were mostly slight especially alopecia (15.9%, WHO grade 1:7 patients and grade 2:3 patients), and there was no problem attributable to cardiotoxicity of THP. Leukocytopenia was seen for 65.1% (grade 1:14 patients, grade 2:13 patients, grade 3:13 patients, and grade 4:1 patients). The nadir was observed about 2 weeks later and it took about 2 weeks for the recovery. Thus, it can be concluded that the usefulness of THP in treating urological tumors is comparable to or better than that reported for doxorubicin. Based on the above results, a combination regimen including THP has been investigated in Japan.

Ten patients with refractory germ-cell tumors were treated with a chemotherapy regimen consisting of teniposide and cisplatin (VM-26 and CDDP; P-VM therapy). Three patients (30%) achieved a complete remission (CR) after chemotherapy alone, and another three subjects (30%) attained a CR following chemotherapy and radiation therapy. Three of the six complete responders relapsed but were rendered disease-free by re-salvage therapy. Among the responders, six patients (60%) are alive and remain disease-free after follow-up periods ranging from 18 to 84 months (median, 48 months). However, the toxicity of P-VM therapy was high, with severe myelosuppression being observed in nine patients; nevertheless, all side effects were reversible. We concluded that the P-VM regimen seems to be effective in the treatment of refractory testicular cancers.

Point mutations of c‐ras genes at codons 12, 13 and 61 were analyzed in 26 cases of bladder cancer and 16 cases of kidney cancer. DNA prepared from either frozen tissues or 10% formalin‐fixed, paraffin‐embedded tissues were amplified by means of polymerase chain reaction methods, and mutations were analyzed by dot blot hybridization assays with oligonucleotide probes. In three cases of bladder cancer c‐ras mutations were found, at codons 13 and 61 of c‐Ha‐ras and at codon 61 of c‐Ki‐ras, while no mutation was found in kidney cancer. No mutation was found in normal bladder epithelial tissues from the same patients. Our findings, taken together, may indicate relative scarcity of c‐ras mutations in these types of human cancer. The results of dot blot hybridization assays and DNA sequencing showed a G‐to‐C transition of the first nucleotide at codon 13 of c‐Ha‐ras. This is the first time that such a point mutation has been detected in human cancer tissues.

Purpose: In a preliminary non-randomized study, combination therapy with natural (i.e. non-recombinant) interferon-alpha plus cimetidine obtained a high response rate in patients with advanced renal cell carcinoma. We conducted a prospective randomized phase III trial to determine whether combination therapy with natural interferon-alpha plus cimetidine is superior to natural interferon-alpha alone in patients with advanced renal cell carcinoma with pulmonary metastasis. Methods: Patients received 5 million units (MU) natural interferon-alpha per day, five times a week, or the 5 MU natural interferon-alpha regimen plus a daily oral cimetidine. The primary and secondary end points were the response rate, and the time to progression (TTP), respectively. Results: Between April 1998 and March 2002, 71 patients from 32 institutions were randomly assigned to the 2 treatment groups. One patient in each group did not receive any natural interferon-alpha whatsoever. Two patients in the natural interferon-alpha alone group stopped treatment: on day 9 and on day 10, respectively. In the intent-to-treat analysis, 1 complete response (CR), 4 partial responses (PRs), 16 no changes (NCs), and 12 progressive diseases (PDs) were observed among the 36 patients in the interferon-alpha alone group with a response rate of 13.9%. Of the 35 patients in the natural interferon-alpha plus cimetidine group, there were two CRs, 8 PRs, 13 NCs, and 11 PDs, yielding a response rate of 28.6% (P=0.13). TTP ranged from 9 to 845 days (median 112 days) in the natural interferon-alpha-alone group, and from 31 to 1,568 days (median 125 days) in the natural interferon-alpha plus cimetidine group (P=0.87). Conclusions: Combined treatment with natural interferon-alpha plus cimetidine for advanced renal cell carcinoma did not result in a significant improvement in response rates or TTP compared to natural interferon-alpha therapy alone.

A patient with left testicular cancer and metastases to retroperitoneal lymph nodes, lung, and brain was treated by chemotherapy, radiotherapy and surgery, and obtained the state of no evidence of disease, but 10 years after radiotherapy, a glioblastoma multiforme tumor appeared in the brain. This is the first report of a glioma appearing after radiotherapy in a testicular cancer patient.

Reports of primary small intestine malignancies are rare. Even more uncommon is primary carcinoma in an ileal conduit. Here, we report a case of primary adenocarcinoma in an ileal conduit that developed 14 years after radical cystectomy and diversion to an ileal conduit for transitional cell carcinoma of the bladder. To our knowledge, only one case of primary adenocarcinoma developing in an ileal conduit after a radical surgery for bladder cancer has been reported previously.

We report a patient with synchronous bilateral adrenal metastases from renal cell carcinoma who underwent left radical nephrectomy and right adrenalectomy.

Intravesical Bacillus Calmette-Guérin (BCG) is now a standard treatment for Ta, T1 carcinoma and carcinoma in situ (CIS) of the urinary bladder. In Japan, however, only BCG Tokyo 172 strain is commercially available. We therefore designed a clinical study of PMCJ-9 (BCG Connaught strain) for obtaining approval from Japanese Ministry of Health, Labor and Welfare.In the phase I-II study, PMCJ-9 40.5, 81 (standard dose overseas) or 121.5 mg in saline was instilled into the bladder of patients with Ta, T1 or CIS once weekly for 8 weeks. The recommended dose was decided and similarly administered in the late phase II study.In the phase I-II study, 49 patients were evaluable for efficacy. The complete response (CR) rates were 60.0% (9/15), 68.2% (15/22) and 75.0% (9/12) in the 40.5, 81 and 121.5 mg groups. The incidence of adverse drug reactions (ADRs) was similar in all groups, but four 121.5 mg group patients developed severe ADRs. Thus, 81 mg was the recommended dose for the late phase II study. In that study, 39 patients were evaluable, showing CR rates of 71.8% (28/39) overall and 61.5% (16/26) and 92.3% (12/13) for the Ta, T1 and CIS cases. The safety was assessed in 42 patients and three (7.1%) were discontinued owing to ADRs.The recommended dose for the BCG Connaught strain was decided as 81 mg. PMCJ-9 administration at this dose level weekly for 8 weeks showed a clear antitumor effect and good safety profile against Ta, T1 and CIS transitional cell carcinoma of the bladder.

A randomized, multicenter, double-blind, parallel-group study was conducted in order to evaluate the hormonal kinetics, pharmacokinetics, efficacy and safety of TAP-144-SR (3M) a three-month sustained-release injectable preparation of leuprorelin acetate, a highly active luteinizing hormone-releasing hormone (LH-RH) derivative by comparing the treatment with two subcutaneous doses of the test medication TAP-144-SR (3M) and the treatment with six subcutaneous doses of the reference medication TAP-144-SR (1M), a 1-month sustained-release injectable preparation. Study participants were 103 patients with prostate cancer in whom a stable anti-tumor effect had been obtained with Leuplin Injection 3.75. The hormonal kinetics revealed that the proportion of the patients "maintaining the castration level of serum testosterone (maximum serum testosterone level during treatment below the castration level [100 ng/dl])" was 100% in both treatment groups. With regard to the efficacy, the proportions of the patients in whom the anti-tumor effects (or = Stable) of the baseline treatment prior to the initiation of the treatment with the study medication were maintained during the study treatment period (6 months) were comparable; 84.0% with TAP-144-SR (1M) and 80.4% with TAP-144-SR (3M). On evaluation of the pharmacokinetics, the mean value of AUC1-12w of the serum TAP-144 concentration (including the metabolite M-I) for the treatment with TAP-144-SR (3M) was 77.0% that of the treatment with TAP-144-SR (1M). Adverse events were similar in the subjects on TAP-144-SR (3M) and in those on TAP-144-SR (1M). There existed no big differences in kind, incidence or time of occurrence of adverse events between two groups. TAP-144-SR (3M) showed no clinically relevant findings in particular. These results indicate that one dose of TAP-144-SR (3M) is comparable to three doses of the already approved Leuplin injection 3.75 in serum testosterone level-inhibitory effect, efficacy and safety. Hence, it is considered that TAP-144-SR (3M) is a drug suitable for treatment of prostate cancer over a prolonged period of time.

A total of 465 patients with primary and multiple or recurrent, stages Ta and T1 superficial bladder cancer were included in this randomized multicenter trial to compare the prophylactic effect by 17 times instillation of 40 mg doxorubicin or 40 mg epirubicin with no instillation after transurethral resection of tumor(s). The primary endpoint was first recurrence after transurethral resection. Endoscopic examination as well as urinary cytology was performed in each case every three months. It became evident that the recurrence rate in the doxorubicin or epirubicin instillation arm was lower that in the no instillation arm. Toxicity was mainly restricted to bladder irritation in about 10% of patients in each instillation arm.

Background: Thecurrent histological evaluation of the effects of endocrine therapy hasdifficulty in distinguishing pathologic degeneration caused by androgen ablation from residual poorly differentiated tumor. Therefore, we examined the changes in cell proliferation and apoptosis before and afterendocrine therapy andanalyzed whether they correlated with pathologic effects and histological differentiation. Methods: Between January 1986andDecember 1995, 52 patients with clinical stage B2 and C prostate cancer underwent radical prostatectomy after neoadjuvant endocrine therapy (median duration 3.8 months). Proliferative andapoptotic activities of pretreatment biopsy specimens and radical prostatectomy specimens were analyzed with MIB-1 monoclonal antibody and in situ end-labeling of fragmented DNA. Results: The mean proliferative index (PI) of radical prostatectomy specimens was significantly lowerthan thatof biopsy specimens (P = 0.000 003) andthedecrease in PIafterendocrine therapy was significantly related to histological differentiation (P = 0.014). There was a weakrelationship between the decrease in PI after endocrine therapy and pathologic effects (P = 0.054), while in pathologically effective cases (Grades 2 and 3), three out of 16 (19%) showed a

BACKGROUND We studied the clinical significance of serum prostate-specific antigen bound to alpha1-antichymotrypsin (PSA-ACT) values determined with a newly developed enzyme immunoassay. METHODS Serum PSA-ACT values were determined in a total of 652 sera. Clinical utility for the diagnosis of prostate cancer was compared to that of Tandem-R PSA and gamma-seminoprotein (gamma-Sm). The new enzyme immunoassay is based on the use of the Stanford reference as an international standard for PSA assays. RESULTS Serum PSA-ACT values ranged from less than 0.10 to 1.4 ng/mL in healthy males (n = 100) while values in patients with benign prostatic hyperplasia (n = 155) averaged 3.4 +/- 3.8 ng/mL (mean +/- SD). In patients with prostate cancer, serum PSA-ACT values increased significantly with progression of the clinical stage and there were statistically significant differences between benign prostatic hyperplasia and each stage of prostate cancer except for stage A. Using BPH levels as controls (4.8 ng/mL for PSA-ACT, 7.2 ng/mL for PSA, 3.8 ng/mL for gamma-Sm, and 2.4 ng/mL for the complexed/free PSA ratio of PSA-ACT/gamma-Sm), specificity was 80%. The sensitivity of prostate cancer detection was 79% for PSA-ACT, 77% for PSA, 57% for gamma-Sm, and 46% for the ratio between PSA-ACT/gamma-Sm. CONCLUSION Although the determination of serum PSA-ACT showed essentially the same utility as that of PSA for the diagnosis of prostate cancer, PSA-ACT may allow prediction of the clinical stage. The PSA-ACT assay may therefore replace PSA in the detection of prostate cancer.

Mutations of the p53 gene are related to development of human cancers and their frequencies and spectra, the latter representing fingerprints left by carcinogens, provide information about the molecular epidemiology of the disease. Prostate cancer is the most common neoplasm in American males and although its incidence is still relatively low in Japanese people, it has recently been increasing with the westernization of life style. To assess the frequency and spectrum of p53 gene mutations in Japanese prostate cancers, we examined a series of 90 lesions using polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) analysis. The patients' mean age was 69.3 years (range 57-87). Of the total, six were well-, 34 moderately- and 50 poorly-differentiated adenocarcinomas, and the median Gleason score was 7.9. Eleven of the 90 cases (12%) had mutations in exons 2-11 of the p53 gene: none of the five clinical-stage A, one of 25 stage B (4%), three of 35 stage C (9%) and seven of 25 stage D (28%) cancers. The correlation with an advanced stage was statistically significant. One insertion and 10 base pair substitutions were encountered, comprising six transversions (55%) and four transitions (36%). Two of the latter involved methylated cytosine-guanine (CpG). These 11 mutations were combined with 18 other mutations in previous reports concerning Japanese prostate cancers to facilitate comparison of the p53 gene mutational spectrum with those reported for American and European prostate cancers. In the latter, 61% were transitions and 33% were transversions. The greater proportion of transversions in the Japanese population suggests that there are different factors responsible for carcinogenesis of the prostate glands in the various countries.

We examined whether cimetidine could augment the efficacy of interferon-alpha therapy for advanced renal cell carcinoma.Of 31 male and 6 female patients treated with interferon-alpha and cimetidine 21 had metastases at diagnosis and 15 had a recurrence after nephrectomy. One patient had a primary tumor with thrombus in the inferior vena cava. Lymphoblastoid interferon-alpha was administered at 5 megaunits daily intramuscularly 5 to 7 days a week for at least 8 weeks, and cimetidine was administered orally at 800 mg. daily in 4 divided doses. The evaluable tumors included 30 in the lung, 6 lymph nodes, 5 bone, 4 kidney and 1 inferior vena cava.Combined therapy with interferon-alpha and cimetidine resulted in a complete response in 7 patients, a partial response in 8, stable disease in 12 and progression in 10. The objective response rate was 41%. The lung metastasis showed the best response to combined therapy. The 5-year survival rates for patients with and without response, and overall were 74, 20 and 41%, respectively. Histopathologically, high grade tumors had a better response to combined therapy than did low grade tumors.Combined therapy with interferon-alpha and cimetidine for advanced renal cell carcinoma resulted in a definitively good response. A prospective randomized trial should be performed to elucidate the efficacy of the combined therapy.

Objective: The antitumor effect of CPT-11, a camptothecin derivative, on two human testicular embryonal carcinomas (TTSC-2 and TTSC-3) heterotransplanted into nude mice was studied. Materials and Methods: Tumor-bearing nude mice were given daily intraperitoneal injections of the anticancer drugs in 0.1 ml saline 3 times at 3-day intervals. At the end of the experiments tumors were resected and subjected to light-microscopic observation. Results: When 10, 30 and 50 mg/kg of CPT-11 was administered to tumor-bearing mice intraperitoneally, the antitumor effect of CPT-11 was observed dose-dependently in both TTSC-2 and TTSC-3. When 30 mg/kg of CPT-11 was administered in combination with CDDP, complete tumor regression was observed in both TTSC-2 and TTSC-3 tumors. Histological findings correlated well with the decrease in tumor volume of treated tumors. No mice died after treatment with CPT-11 in a single-agent and combination chemotherapy. Conclusion: Chemotherapy with CPT-11 was an effective and safe method against human testicular tumors heterotransplanted in nude mice.

Background: In a recent study by the Casodex Combination Study Group, USA, patients in a flutamide (750mg/day) plus LH-RH agonist group showed a high treatment failure rate, mainly due to flutamide-induced diarrhea and hepatotoxicity. Our current study was conducted to determine the optimal dose of flutamide for use in this type of Combination therapy. Methods: In a randomized, multicenter study, 30 patients (hormone untreated; stage C or D) were divided into 2 groups: flutamide 250mg (125mg × 2; 14 patients) and flutamide 375mg (125mg × 3; 16 patients), and each dose combined with either goserelin acetate (3.6 mg every 4 weeks) or leuprolide acetate (3.75 mg every 4 weeks). Goserelin and leuprolide were administered to patients in a 1:1 ratio. Flutamide monotherapy at a daily dose of 375 mg was determined to be the optimal dose in Japan in our previous phase II study. The endpoints of this pilot study were the objective response and adverse events during the 12-week treatment. Results: The objective response rate was 83.3% in the flutamide 250mg group and 85.7% in the flutamide 375 mg group according to the Japanese response criteria for prostate cancer. Elevated PSA levels fell to within the normal range in 83.3% of the patients in the former group and in 93.3% of the patients in the latter group. One patient administered 250 mg of flutamide experienced diarrhea, while the serum GOT and/or GPT were elevated in 3 patients administered 250 mg of flutamide and 4 patients administered 375 mg of flutamide. Conclusions: Based on the findings of this pilot study of maximal androgen-depletion therapy for advanced prostate cancer, 375mg/day of flutamide is recommended in combination with an LH-RH agonist. Assessment of the effects of our recommended regimen on longer term survival, quality of life and antiandrogen withdrawal syndrome of patients treated requires additional patients and time for foIIow-up.

Recently, there has been increased interest in the application of preoperative endocrine therapy prior to radical prostatectomy for locally advanced cancer in order to enhance surgical curability and increase survival. Between 1986 and 1993, 40 patients with prostate cancer were given endocrine therapy before radical prostatectomy. Fifteen patients had stage B2 disease and 25 stage C. The median duration of preoperative endocrine therapy was 3.8 months, and all the patients subsequently underwent radical prostatectomy, pelvic lymphadenectomy and castration. There was an average 25.5% (0-71.8%) decreases in the maximal cross-sectional area of the prostate gland as determined by transrectal ultrasonography. Twenty-four of 25 patients with elevated levels of serum prostate-specific antigen (PSA) showed normal values after preoperative endocrine therapy. Evaluation of treatment-related histological effects, divided into three grades, revealed that 17 patients had pronounced, 11 moderate and 12 poor or no regression. Thirteen of the 40 patients (33%) demonstrated pathological downstaging of disease status from the diagnosis made at the initial clinical examination. After a median follow-up period of 36 months (3-100 months), 36 of the 40 patients are disease-free; two died of cancer 43 and 50 months after surgery, respectively. These results suggest that preoperative endocrine therapy may play an important role in the management of locally advanced prostatic cancer.

Immunohistochemical analysis by indirect immunoperoxidase staining demonstrated that monoclonal antibody (mAb) K2.7, derived from a mouse immunized with a renal cell carcinoma (RCC) cell line OS-RC-2, reacted with 89 of 95 renal cancer tissues (94%). Only 1 gastric and uterine cancer tissue showed positive staining among 87 cancer specimens from 9 different organs. Among normal human tissues, the renal tubule, testis, epithelium of the uterine endometrial gland and Fallopian tube, grey matter of cerebrum and cerebellum, and foreskin showed positive staining. Serological analysis by protein A mixed hemadsorption (PA) assay demonstrated that mAb K2.7 reacted with 25 of 31 RCC cell lines (81%), but with only 2 of 50 other cell lines from different organs. The specific antitumor activities of mAb K2.7 against RCC cell lines were investigated in vitro by complement dependent cytotoxicity (CDC) and antibody dependent cell-mediated cytotoxicity (ADCC) assays. In the CDC assay, all of the 9 RCC cell lines reactive serologically with mAb K2.7 were killed by mAb K2.7 with normal human serum, and the killing activity of mAb K2.7 correlated well with the reactivity of mAb K2.7 in the PA assay. mAb K2.7 showed the same killing activity against each of 3 RCC cell lines with sera from 9 patients with low and high stage renal cancers, as well as with normal human serum. In the ADCC assay, mAb K2.7 with peripheral blood leukocytes (PBLs) from 4 healthy donors showed cytotoxic activity against RCC cell lines. Peripheral blood leukocytes from the same 9 renal cancer patients also showed significant killing activity against the 3 RCC cell lines. These findings suggest the potential utility of mAb K2.7 for specific immunotherapy of renal cancer.