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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.

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.

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: 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 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 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.

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%.

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.

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.

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.

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.

A randomized clinical trial of neoadjuvant endocrine therapy followed by either surgery or irradiation and a resumption of endocrine therapy for stages B2 and C prostate cancer has been in progress since 1989. A hundred patients entered the trial between 1989 and 1993, and 95 cases were evaluated. Forty-six patients received surgery and 49 were treated with irradiation. Neoadjuvant endocrine therapy for two months resulted in prostate shrinkage and prostate specific antigen lowering. Except for two patients, one dying of a progression of disease and the other of another concurrent cancer, all are alive with an average follow-up term of 25 (range 3-53) months. The good prognostic results obtained from both treatment groups at present seem to be due in part to the neoadjuvant endocrine therapy; but in order to reach a final conclusion further comparisons need to be made.

The distribution of bone metastases on a bone scan has not been duly considered when assessing the prognosis of metastatic prostate cancer.The medical records of 76 patients with newly diagnosed, untreated metastatic prostate cancer were reviewed. According to the distribution of bone metastases on the initial bone scan, we divided the patients into three groups: Group I (having bone metastases exclusively within the pelvis and the lumbar spine), Group II (having bone metastases exclusively outside these bones), and Group III (having bone metastases in both areas).Among the responders to androgen deprivation, those in Group I survived significantly longer than did those in Groups II or III. Because the extent of the disease and the distribution of histologic differentiation in Groups I and II were similar, the results indicate that the presence of bone metastases outside the pelvis and the lumbar spine is predictive of short survival time. This prediction was not possible when the extent of disease (EOD) grading system was used.The distribution of bone metastases on the initial bone scan should be considered as a variable for the prognostic stratification of patients with metastatic prostate cancer.

The results of treatment by orchiectomy and radiotherapy for stage I testicular seminoma are excellent with cure rates exceeding 95% and relapse rates less than 5%. However, after the development of successful surveillance programs for stage I nonseminomatous testicular cancers, the role of radiotherapy has been questioned by some authors and they proposed a "surveillance policy" for these patients. The purpose of this study was to determine the percentage of patients cured by orchiectomy alone, percentage who ultimately required therapy for occult metastases, site of recurrence, and over-all cure rate and treatment morbidity. And these data were compared with those of adjuvant radiotherapy group retrospectively. Twenty seven patients were treated with adjuvant radiotherapy (RT group). Since 1986, 23 patients with stage I testicular seminoma entered the "surveillance only" protocol at our institution (S group) with a follow-up between 14 and 70 months (median 43 months). Informed consent for the policy of surveillance was obtained. Follow up consisted of physical examination, determination of serum tumor markers and chest X-ray bimonthly for 2 years, every 3 months for 1 year, every 6 months for 2 years and annually thereafter to 10 years. CT scans were performed every 4 months for 3 years, every 6 months for 2 years. Two patients in S group (8.7%) relapsed at 4 and 7 months after orchiectomy with nonbulky retroperitoneal disease (less than 5 cm in diameter), whereas only 1 (3.7%) irradiated patients did so after 4 months.

A multicentric randomised trial was conducted for the purpose of investigating the efficacy of intravesical chemoprophylaxis of superficial bladder cancers. A total of 443 patients (number of evaluable patients, 284) were registered from July 1987 to December 1989 and randomised into 3 groups. Group A received 21 intravesical instillations of Adriamycin (ADM) at 20 mg/40 ml physiological saline for 2 years after undergoing transurethral resection (TUR); group B was given the same dose as group A but received 6 intravesical instillations for 2 weeks before undergoing TUR; and group C served as a control and underwent TUR only. Better prophylactic effects were obtained in group A. The overall non-recurrence rates calculated for groups A and B differed significantly (P less than 0.05) on day 240, and those determined for groups A and C were also significantly different (P less than 0.01) on day 480. No benefit was obtained using intravesical instillation prior to TUR (group B). The major side effects encountered were pollakisuria and miction pain, which occurred in 32% of the patients in group A and in 52% of those in group B.

Human lymphoblastoid interferon-alpha was administered intramuscularly at a dose of 5 x 10(6) units/day to 20 metastatic renal cell carcinoma patients. For potentiating the antitumor effect of interferon, cimetidine was also given to them orally at a dose of 800 mg/day. The combination therapy obtained a complete response in three patients (15%) and a partial response in three (15%). Nine patients (45%) had stable disease and five (25%), progressive disease. All six patients who responded to the combination therapy had been nephrectomized and had pulmonary metastases. Two of them also had metastases to other sites (mediastinal lymph nodes and bone). The pulmonary metastases were significantly more receptive to interferon therapy than those at the other sites. The average times before a response was obtained were 2.2 months for a minor response, 2.7 months for a partial response and 3.0 months for a complete response, and the average duration of response was 26 months. The six patients who responded survived for a significantly longer period than the 14 non-responding patients treated with interferon in combination with cimetidine. The major toxicities encountered were fever, fatigue and anorexia due to interferon, and the combination therapy was well tolerated except in three patients. The results suggest that interferon-alpha and cimetidine combination therapy may be of use in the management of patients with metastatic renal cell carcinoma.

The effects of recombinant granulocyte colony-stimulating factor (rG-CSF) on the myelosuppression, especially neutropenia, induced by cancer chemotherapy in patients with urogenital cancer were investigated in a randomized, controlled clinical study. In this study, rG-CSF was given subcutaneously at a dose of 2 micrograms/kg per day for 14 consecutive days. Changes in neutrophil counts were compared between the first (no rG-CSF) and second cycles (rG-CSF treatment period) of chemotherapy. rG-CSF administration was found to be effective in reducing the duration of neutropenia, in elevating the neutrophil nadir, and in reducing recovery time. Based on comparisons between the randomized rG-CSF treatment group (with rG-CSF) and the control group, treatment with rG-CSF resulted in the moderation or prevention of neutropenia and the acceleration of recovery. These results demonstrate that in chemotherapy of patients with urogenital cancer, in which neutropenia is a dose- or schedule-limiting factor, the concomitant use of rG-CSF may enable an increase in the dose (higher single dose or increased dose per unit of time) or shorten the chemotherapy period.

Histological effects of endocrine therapy were evaluated in one hundred and four prostatic cancer patients by new criteria presented by the committee of "General Rule for Clinical and Pathological Studies on Prostatic Cancer". Route and time of biopsy, clinical stage and histological grade were related to histological effects. Biopsy specimens taken within three months from the start of the therapy tended to score rather low marks and this tendency is especially apparent with low grade cancers. Histological effects evaluated by the present method correlated well with prognosis in localized stages (stage B, C and D1). In metastatic cases, however, local effects were not related to the prognosis.

We treated in total 795 patients with primary transitional cell carcinoma of the urinary bladder between April, 1964 and December, 1988. Eighteen patients of them had upper urothelial cancer during the follow-up period. Thirteen of the 18 patients had received transurethral resection for the initial bladder cancer, while 3 total cystectomy and 2 segmental resection. The over-all incidence of bladder cancer patients who subsequently developed upper urinary tract tumors was 2.3 per cent. The interval between initial treatment of the bladder cancer and treatment for the upper urinary tract tumor ranged from 2 to 74 months (median 20 months). The five-year survival rate after treatment for the upper urinary tract tumor was 31.7 per cent. We conclude that the following are high risk patients for development of upper urinary tract recurrences: 1) patients with bladder cancer near orifices, 2) patients with recurrent bladder cancer under bladder preserving treatment for a long time, 3) patients with G2 multifocal bladder cancer.

Background : Follow-up strategies after cystectomy for carcinoma of the bladder should be determined according to the risk of recurrence, which is stage dependent. We aimed to develop follow-up protocol for monitoring patients with carcinoma of the bladder for tumor recurrence and diverted urinary tract complications after radical cystectomy. Methods: The records of 351 patients with carcinoma of the bladder who underwent cystectomy between 1979 and 1999 were reviewed for dates and presenting symptoms of local and distant recurrences. The results of imaging studies and blood tests were also reviewed. Based on the division of patients into pathological stages of pT1 and lower, pT2, and pT3 and higher groups, we proposed a new follow-up schedule for carcinoma of the bladder. Results: The risk of metastasis was related to the pathological stage of the primary tumor. Recurrence developed in 10 of 124 patients (8%) with pT1 or lower, 17 of 101 patients (17%) with pT2, and 55 of 101 patients (54%) with pT3 or higher disease at a median of 11 (range 6–186), 10 (1–40) and 7 (1–76) months, respectively. Recurrences in patients with pT3 or higher were found earlier and more frequently than those with pT2 or lower. Of 82 patients with metastases, 54 initially were symptomatic, and three of pT1 or lower, six of pT2, and 19 of pT3 or higher were asymptomatic. Based on these results we proposed a stage specific follow-up protocol. Conclusions: A stage-driven follow-up strategy for monitoring patients after radical cystectomy can reduce medical expenses while efficiently detecting recurrences and complications.

A cell line, designated as OS-RC-2, has been established from a renal cell carcinoma in a 52-yr-old Japanese male patient and maintained for 23 mo. through 60 in vitro passages. The OS-RC-2 formed monolayers of polygonal epithelial cells and lacked contact inhibition. Doubling time of cells was about 60 h at the 30th passage. Electron microscopic findings indicated numerous long microvilli on the cell surface and many glycogen granules in the cytoplasm of this cell line, which are characteristic structures of renal cell carcinoma. Chromosomal analysis revealed that a small portion of this cell line had a hypodiploid modal number of 40 and a large portion had a hypotetraploid modal number of 75. The characteristics of the karyotype were one detected marker chromosome and the translocation between the Chromosomes 2 and 13. Cell line OS-RC-2 was serially transplantable into nude mice, and histopathological findings of heterotransplanted tumor showed a close similarity to those of the original tumor. Histocompatibility antigens of OS-RC-2 were HLA-A9, Bw52, which were identical to those of the peripheral blood lymphocytes of the patient.

Analyses of hormone receptors in cytosols from 41 renal cell carcinoma specimens were performed by the dextran-coated charcoal technique, using estradiol, synthetic progestin R5020 and synthetic androgen R1881. Binding data were calculated according to the method of Scatchard. Of 41 renal cell carcinomas estradiol receptor was detected in 11, R5020 receptor in 11 and R1881 receptor in 13. No significant correlation between histopathological findings and hormone receptors was observed. Patients were classified into those positive and negative for receptors. The clinical response of endocrine therapy for 17 with advanced residual or metastatic lesions after nephrectomy was studied in regard to the survival rates. Although there was no complete or partial regression in tumor size, the survival rate of patients with 1 or more receptors was significantly higher than that of patients negative for receptors (p less than 0.01). In conclusion, hormonal manipulation in patients with renal cell carcinoma cannot induce an antitumor effect but seems to increase survival in patients with receptors.

Total prostatectomy is an effective mode of therapy for early carcinoma of the prostate. This report deals with 74 patients who underwent total retropubic prostatectomy at our hospitals during a 23-year period. The 5-year survival rates of patients with stages A and B, C, and D carcinomas were 84.1, 40.1, and 12.7% respectively. The total 5-year survival rate was 56.1%. The 10-year survival rates compare favorably with those of any other mode of therapy. The histological grade was highly significant with respect to prognosis. Combined orchiectomy with total prostatectomy was effective. Operative mortality was 4.05% (3 patients), and the main complication was incontinence. We strongly believe that total prostatectomy is the only curative treatment for early carcinoma of the prostate. This procedure should be utilized more frequently.

Stop-flow analysis was performed before and after parathyroidectomy in 7 kidneys which appeared to be normal in urogram in the patients with primary hyperparathyroidism. The main functional change in the kidney, which was induced by excess of parathyroid hormone, seemed to occur at the proximal tubules. This change was similar to that of the result in animal experiment. The functional damage in the tubules might be reversible, since the normal stop-flow pattern was obtained immediately after parathyroidectomy. No remarkable changes were found in the stop-flow patterns in 3 patients with urolithiasis due to other causes, as in the normal kidneys of 2 control patients.

Thirty-three patients with advanced transitional cell carcinoma of the urinary tract (23 bladder cases, 8 ureter cases, and 2 renal pelvis cases) were treated by three-drug combination chemotherapy using two protocols (protocol I: Adriamycin 50 mg/m2, cyclophosphamide 500 mg/m2, and 5-fluorouracil 500 mg/m2, protocol II: Adriamycin 50 mg/m2, cyclophosphamide 500 mg/m2, and cis-platinum 50 mg/m2). Protocol I induced responses in three of 19 patients (16%), (1 complete response, 2 partial responses), and protocol II (I complete response, 4 partial responses) in five of 14 patients (36%). The overall response rate was 24%. The duration of response was relatively short (median duration 5.1 months). The combination therapy was relatively well tolerated except in three patients, including two mortalities. In our study, three-drug combination chemotherapy with Adriamycin, especially that including cis-platinum, was effective against transitional cell carcinoma of the urinary tract, but the results were not completely satisfactory.

The Japanese Urological Cancer Research Group has conducted three randomized clinical studies on intravesical chemoprophylaxis of superficial bladder cancers. This paper presents a comparative analysis of the first and second of these. The protocol used in the first study was a so-called short-term schedule in which drugs (for group A, ADM 30 mg/30 ml; group B, ADM 20 mg/40 ml; group C, MMC 20 mg/40 ml; and group D, control) were administered twice a week for 4 weeks after transurethral resection (TUR), and in the second study a long-term schedule was used, in which drugs (for group E, ADM 30 mg/30 ml; group F, ADM 20 mg/40 ml; group G, MMC 20 mg/40 ml; and group H, control) were administered twice a week for 1 week, every 2 weeks for 7 weeks, monthly for 8 months, and finally once every 3 months for 1 year. In the first study 575 patients were evaluated and followed up for 5 years. The second study started 28 months later, and 607 patients were evaluated. A generally good prophylactic effect was obtained in the second study when the patients' backgrounds were adjusted in combination with the history and number of the tumors. The second study did not reveal any promoting or inhibitory effect on the progression of the recurrent tumors. There were no significant side effects in either study. The indications and the schedule for prophylactic intravesical chemotherapy should be more carefully studied.

Thirteen evaluable patients with germinal testicular cancers failing to be cured with first-line therapy (refractory) were treated by salvage chemotherapy. Ten patients received salvage chemotherapy with VM-26 (50 mg/m2, twice a week X 6 weeks) and cisplatin (CDDP, 20 mg/m2 for 5 consecutive days every 3 weeks for 3-4 times) (P-VM), 3 patients were also treated by radiation therapy, and 3 patients received VP-16 (100 mg/m2) and CDDP (20 mg/m2) (P-VP), all given daily for 5 consecutive days every 3-4 weeks for 4-5 courses. Of 13 evaluable patients, 6 (46%) had complete response (CR) (three cases were also treated with radiation therapy), 4 (31%) achieved partial response (PR), and 3 (23%) had no response. Limited to 7 patients treated with only P-VM therapy, there were 3 (43%) CR and 4 (57%) PR. Nine patients (69%) remained alive and were continuously disease free 18 to 84 months (median 48 months). Hematologic toxicity was severe, but with no death related to sepsis. Salvage chemotherapy with VM-26 or VP-16 and cisplatin offers potentially curative treatment to patients with refractory testicular cancer. The addition of radiation therapy to salvage chemotherapy was also effective.

Lactate dehydrogenase (LDH) activity and isoenzyme were determined in 27 human renal carcinoma (RC) tissues. Although LDH-1 and LDH-2 were predominant in the normal kidney, a completely inverted isoenzyme pattern was observed in 16 carcinomas. The others, however, showed either a normal or an incompletely inverted pattern. The LDH activity in the tumours with a completely inverted pattern was significantly higher than the activity of incompletely inverted or normal kidney pattern. It was also found that the isoenzyme pattern was more closely correlated with cell type than the grade of malignancy of the tumour, 14 out of the 16 cases of the completely inverted pattern being of the clear cell type, and 9 out of the 11 cases of incompletely inverted or normal kidney pattern being of either granular cell or mixed cell type. These results seemed to well substantiate an opinion that in clear cells anaerobic glycolysis provides a major energy source, whereas granular cells seek energy source primarily in TCA cycle and subsequent oxidative phosphorylation.

In order to determine the significance of androgen receptor (AR) gene mutations for Japanese prostate cancers, we examined the entire coding region, from exon A to H, in 36 primary lesions. Five in stage A, 12 in stage B, six in stage C and 13 in stage D were subjected to PCR-SSCP analysis for genomic DNA and nucleotide sequencing. Mutations were detected in five samples (14%). Two in stage D and refractory to anti-androgen treatment showed mis-sense mutations. The other three showed changes in the length of the CAG repeat in exon A, with an expansion or a contraction of one repeat unit. However, no association with changes in AR function was indicated because they had not been refractory to hormone therapy. Since these latter three tumors were associated with microsatellite instability, the changes might have been the result of an impairment of mismatch repair. This study indicates that AR gene mutations play a role, in only a subset of prostate cancer patients, in a treatment-refractory state.