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A new modality is necessary to prevent recurrence of superficial bladder cancer after complete transurethral resection (TUR) because of the high recurrence rate even with current prophylaxis protocols. Prostaglandins (PGs) are known to be produced more in transitional cell carcinoma, and etiologically bladder cancer risk is negatively associated with the intake of non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX), the rate-limiting enzyme of the PG production. We have shown the chemopreventive effect of piroxicam, an NSAID, on the N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced rat bladder cancer model. To avoid gastrointestinal side effects of regular NSAIDs, we also showed the chemopreventive effect of nimesulide, a selective inhibitor of the second isoform of COX, COX-2, which does not affect COX-l house-keeping activity in gastrointestinal mucosa on the same model. We also observed induction of COX-2 protein in the rat bladder tumor. In this study, we screened COX-2 protein expression in primary superficial bladder cancer tissues, to elucidate if COX-2 selective inhibitors can be a candidate chemopreventive agent for bladder cancer recurrence. Five and 6 samples of superficial bladder cancer cases with and without recurrence after complete TUR were examined by immunohistochemical analysis. We found more COX-2 protein positive samples in the cases with recurrence than in cases without recurrence. Even though the number of cases examined is small, this result supports our hypothesis that COX-2 contributes to superficial bladder cancer recurrence, thus, selective COX-2 inhibitors can be a candidate chemopreventive agent for the recurrence.

Our previous study demonstrated the clear detection of MN/CA9 mRNA in peripheral blood samples from RCC patients. However, approximately 30 % of control blood samples from healthy volunteers showed MN/CA9 expression. We have developed a new primer set and optimized the PCR conditions, now resulting in a specificity of 100 %. In tissue samples, all clear cell type carcinomas but none of the spindle cell type and pleomorphic cell type tumors expressed the MN/CA9 message. Analysis of MN/CA9 messages in peripheral blood samples from RCC patients gave positive results for 0/2, 1/9, 0/4 and 4/12 of stage I, II, III and IV cases, respectively. RT-PCR analysis using preoperative renal venous blood samples resulted in clear detection of MN/CA9 positive cells in 2/4, 3/13, 2/6 and 1/1 of stage I, II, III and IV cases, respectively. Our results suggest that assessment of MN/CA9 expression by RT-PCR is a promising method for detecting cancer cells in the circulation of patients with RCC.

To compare the efficacy and safety of an incremental-dose regimen of terazosin (1-2 mg daily) and a fixed-dose regimen of tamsulosin (0.2 mg daily), on Japanese patients with symptomatic benign prostatic hyperplasia (BPH).This multicentre, single-blind, randomized trial compared terazosin and tamsulosin over 4 weeks, in 61 patients with symptomatic BPH randomly assigned to terazosin (n = 31) or tamsulosin (n = 30). Terazosin 0.5 mg twice daily was administered for 2 weeks, followed by 1 mg twice daily for 2 weeks. Tamsulosin (0.2 mg) was administered once daily for 4 weeks. Symptoms were evaluated using the International Prostate Symptom Score (IPSS), and quality of life (QOL) was assessed subjectively before treatment, and again after 2 and 4 weeks of treatment. Objective measurements taken before and after the treatment period were the maximum (Qmax) and average (Qave) urinary flow rates, and the percentage residual urine volume. Improvement was defined as a 25% decrease from baseline in IPSS,1 point increase in QOL score, and2.5 mL/s increase in Qmax. Adverse reactions potentially related to the study drugs were recorded throughout the treatment period.Both terazosin and tamsulosin produced statistically significant improvements in subjective and objective variables. Neither treatment affected systolic or diastolic blood pressure or pulse rate. Adverse reactions were noted in four patients (three in the terazosin group and one in the tamsulosin group). However, there was no statistically significant difference in the incidence of adverse effects between the groups.Despite the limitations of small sample size and relatively short treatment periods, terazosin and tamsulosin were equally effective in the treatment of symptomatic BPH in Japanese patients, using relatively lower doses than those used in Western countries.

The aims of this randomized, controlled study were to investigate the efficacy and safety of long-term monotherapy with the luteinizing hormone-releasing hormone agonist goserelin acetate compared with both short- and long-term combined androgen blockade.Patients with advanced prostate cancer (n = 371) were randomized to treatment with goserelin acetate alone or a combination of goserelin acetate plus either long-term or short-term antiandrogen (chlormadinone acetate) or short-term estrogen (diethylstilbestrol diphosphate).There were no significant differences between the treatment groups with respect to objective progression, overall survival or disease-specific survival. Nevertheless, subgroup analysis suggested that patients with minimal disease or a good prognosis might benefit more from combined androgen blockade than other patients. Combined androgen blockade significantly reduced the incidence of disease flare compared with goserelin acetate treatment alone.Neither short- nor long-term combined androgen blockade had a survival advantage over goserelin acetate alone.

A follow-up investigation was conducted on a Late Phase II clinical study of bropirimine for carcinoma in situ (CIS) of the bladder. We previously reported that 48 patients were enrolled and 17 patients achieved complete remission (CR) in the Late Phase II study. Of the 17 CR patients, 5 had recurrence, but 9 were recurrence free for a year and 5 have remained so for more than 2 years (median follow-up: 29.1 +/- 4.2 months). The 1-year and 2-year recurrence-free rates calculated using the Kaplan-Meier method were 70.3% and 61.5% respectively. Of all the 47 bropirimine-treated patients, 11 underwent total cystectomy (median follow-up: 31.8 +/- 5.2 months). The rates of bladder preservation after 1 year, 2 years, and 3 years calculated using the Kaplan-Meier method were 87.2%, 80.7%, and 74.0% respectively. Of the 39 patients who did not respond to bropirimine or suffered from recurrence after bropirimine treatment, 19 received subsequent intravesical bacillus Calmette-Guerin (BCG) therapy and 13 achieved CR (68.4%). This suggests that bropirimine does not decrease the efficacy of BCG therapy. In the present study, the prognosis was confirmed to be favorable after bropirimine therapy. Bropirimine would thus seem to be a useful oral anticancer agent for bladder CIS.

The present investigation was conducted to examine the effects of intra-arterial chemotherapy (IAC) for patients with invasive bladder cancer. A total of 37 patients were treated with IAC at Nara Medical University and its affiliated hospitals between January, 1993 and August, 1997. There were 27 patients in the poor risk group. The remaining 10 patients underwent anti-tumor IAC. Thirty of the 37 patients received chemotherapeutic agents via a reservoir, and the remaining 7 patients received a one-shot injection of agents followed by transcatheter arterial embolization (TAE). In the reservoir group, there were 18 patients who received IAC in combination with radiation therapy. As a result, reduction of tumor size was noted in 53%, and the 3-year cause-specific survival rate was 54% in all cases. There was a significant difference in the 3-year survival rate between the radiation-treated group and the group without radiation. The adverse events included anemia, leukopenia, thrombocytopenia and gastrointestinal symptoms, but none of them were severe. The results of the present study indicate that IAC is useful in the treatment of invasive bladder cancer for poor risk patients.

The E-cadherin–catenin complex plays an important role in establishing and maintaining intercellular connections and morphogenesis and reduced expression of its constituent molecules is associated with invasion and metastasis. In the present study, we examined E-cadherin and α-, β- and γ-catenin levels in tumour tissues obtained by radical prostatectomy in order to investigate the relationship with histopathological tumour invasion. Immunohistochemical findings for 45 prostate cancer specimens demonstrated aberrant expression of each molecule to be associated with dedifferentiation and, in addition, alteration of staining patterns for the three types of catenin was significantly correlated with capsular but not lymphatic or vascular invasion. The data thus suggest that three types of catenin may be useful predictive markers for biological aggressiveness of prostate cancer. © 1999 Cancer Research Campaign

The chemopreventive potential of a selective cyclooxygenase-2 inhibitor, nimesulide (NIM), against the development of rat superficial urinary bladder carcinomas after initiation with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was examined. Six-week-old Fischer 344 male rats were given 0.05% BBN in their drinking water for 8 weeks, followed by diets supplemented with 0, 100, 200, or 400 ppm NIM for 12 weeks, and they were then sacrificed. NIM decreased, in a dose-dependent manner, the incidence of transitional cell carcinoma (TCC) to 12 of 20 (60.0%), 8 of 16 (50.0%), and 5 of 19 (26.3%) and the multiplicity of TCCs to 0.75 +/- 0.79, 0.56 +/- 0.63, and 0.37 +/- 0.78 per rat at 100, 200, and 400 ppm, respectively, as compared with the BBN alone group values of 18 of 20 (90.0%) and 2.35 +/- 1.23. NIM did not significantly affect the cell differentiation or invasiveness of TCCs. These results indicate clear chemopreventive potential of a selective cyclooxygenase-2 inhibitor against postinitiation development of superficial rat urinary bladder carcinomas.

A 7-center cooperative clinical study with a new formulation of epirubicin hydrochloride injectable solution (Epirubicin-RTU) was conducted in patients with superficial bladder carcinoma. Epirubicin-RTU at the dose of 60 mg/30 ml was administered by intravesical instillation once daily for three (3) consecutive days and a 4-day drug-free interval followed; then the above intravesical instillation of Epirubicin-RTU was repeated for three consecutive days. All 20 registered cases were eligible, and 18 cases completed the whole course of the study. In 18 completers, CR was observed in 12 cases and PR was observed in one (1) case, for an efficacy rate of 72.2%. The primary adverse reaction was bladder irritation including pollakiuria 85.0% (17/20), miction pain 85.0% (17/20), and hematuria 80.0% (16/20), which were all reversible and tolerable. In urinalysis, urinary sediment showed leukocytes and erythrocytes, and proteinuria was observed. All were reversible. From the above results, this new formulation of Epirubicin-RTU was considered useful for the treatment of superficial bladder carcinoma.

The objective of this report is to evaluate the upper urinary tract changes of the patients with spina bifida who have been followed up for more than 10 years.We analyzed 228 patients (97 males and 131 females) of spina bifida. Mean patient age was 18.7 years (10 to 51 years) and follow up period ranged from 10 to 27 years (mean 13.4 years). Upper urinary tract deterioration (Hydroureter and/or hydronephrosis), vesicoureteral reflux (VUR) and bladder deformity were investigated by excretory urography and voiding cystourethrography. We compared these 3 parameters in the initial and final examinations.In the initial examinations, upper urinary tract deterioration, VUR and bladder deformity were observed in 32.9%, 33.3% and 40.0%, respectively. During the follow up period, upper urinary tract was improved in 47.3% and VUR in 80.0%. Bladder deformity was disappeared in 14.4%. On the other hand, upper urinary tract was deteriorated in 9.3%. VUR and bladder deformity was newly developed or progressed in 8.0% and 29.3%, respectively. Finally, upper urinary tract deterioration, VUR and bladder deformity were observed in 31.3%, 18.2% and 52.0%, respectively.These results revealed that upper urinary tract and VUR were relatively controlled, however, bladder deformity was increased in its frequency. To prevent upper urinary tract deterioration, further analysis of sequential changes of urinary tract conditions should be demanded.

Tetraplegic women who underwent a cutaneous vesicostomy in our institutions were studied to evaluate long-term urinary complications and their quality of life (QOL). A total of 5 patients (C4, C5 and C6 injuries in one patient each and C7 injury in 2) were followed for 98 to 125 months (mean 107 months). Autonomic hyperreflexia disappeared after surgery in all patients. None of the patients showed deterioration of the upper urinary tract. Urinary tract infections were noted in 3 of 5 patients, but not severe. Bladder stones developed in 2 patients and a stomal stricture in 1. A questionnaire survey showed the patients to be satisfied with the operation, which had improved their QOL. These findings suggest that a cutaneous vesicostomy is an excellent surgical procedure for tetraplegic women.

To evaluate the usefulness of total androgen blockade (TAB) therapy, we retrospectively studied 45 patients with prostate cancer who received TAB therapy as the first-line treatment. The clinical stage was A2 in 1 patient, B1 in 10, B2 in 9, C in 6, D1 in 3 and D2 in 16. Seven, 25 and 13 patients had well, moderately and poorly differentiated adenocarcinomas, respectively. The patients were placed on 1 of 3 TAB regimens: Luteinizing hormone-releasing hormone (LH-RH) agonist and flutamide (group 1), LH-RH agonist and chlormadinone acetate (group 2) and a surgical castration and flutamide (or chlormadinone acetate) (group 3). The therapeutic effect was evaluated at 12 weeks according to the response criteria in the general rules for clinical and pathological studies on prostatic cancer. The overall response was partial response (PR) in 35 patients (77.8%), no change (NC) in 6 (13.3%) and progressive disease (PD) in 4 (8.9%). PR was obtained in 81.3, 79.2 and 60% of the patients in groups 1, 2 and 3, respectively. One patient with PD responded briefly to flutamide withdrawal. None of the patients developed any severe adverse effects. In conclusion, the first-line TAB therapy is effective for prostate cancer with a lower risk than estrogens. Relapsed cases should be followed for flutamide withdrawal syndrome during TAB therapy.

We summarized here the urological emergency status accompanied by cancer, such as urinary obstruction, bleeding and renal failure. Hydronephrosis occurs due to obstructive change and post-renal failure finally results after complete obstruction of bilateral ureters. Patients with obstructive disease are treated with percutaneous nephrostomy or indwelling double-J catheter. Bladder tamponade develops after bleeding of the urinary tract. Patients with bleeding are treated by bladder irrigation or transcatheter arterial embolization. Acute renal failure (ARF) includes pre-renal ARF, renal ARF and post-renal ARF, necessitating emergency hemodialysis. The emergency status can be often observed simultaneously, so careful examination and rapid treatment are necessary.

The present investigation was conducted to examine the effects of granisetron alone and a combination of granisetron plus steroids on CDDP-based combination chemotherapy-induced emesis by multi-institutional randomized comparative trial using a central registration method. A total of 62 patients with urological cancer enrolled this study were randomized into two groups: granisetron (40 micrograms/kg) only group and granisetron (40 micrograms/kg) plus steroids (500 mg of methylprednisolone or 8 mg of dexamethasone) group. There were 31 patients eligible in the granisetron only group and 28 in the combination group. The same anti-emetic treatments were given in the recycling courses of chemotherapeutic regimens. Therefore, eligible patients of the second and the third cycle numbered 31 (17 in the granisetron only group, 14 in the combination group) and 21 (11 in the granisetron only group and 10 in the combination group). Significant inhibition of acute emesis in combination group was observed when compared with the granisetron only group in each cycle. Delayed emesis was also significantly inhibited in the combination group on Day 2 and 3 of the first cycle and on Day 2 of the second and third cycle. In addition, appetite loss was significantly reduced in the combination group on Day 2 and 3 of the first and second cycle. No adverse events were seen in either group. These results suggested that a combination of granisetron and steroids was useful for preventing CDDP-based combination chemotherapy-induced emesis.

Late Phase II clinical study with bropirimine (U-54461S), a novel oral antitumor agent that has interferon inducing and anti-proliferative activities, was conducted in patients with bladder CIS at 38 institutions nationwide. To investigate the efficacy and safety of the treatment, bropirimine was administered to the patients at the dose of 750 mg every two hours, three times a day, for three consecutive days with four-day drug withdrawal, based on the results of the preceding clinical studies up to early phase II. Among the 48 patients registered, 41 patients were evaluable for antitumor efficacy. Complete response (CR) was observed in 17 of them, no change (NC) in 18 patients, and progressive disease (PD) in 6 patients; so the efficacy rate was 41.5%. Classified by patient background, the efficacy rates were 58.3% (7/12) in patients with primary bladder CIS, 34.5% (10/29) in those with secondary bladder CIS, 45.5% (10/22) in those with Grade 3, and 23.8% (5/21) in those previously given chemotherapeutic agents or BCG by intravesical or other routes. Adverse drug reactions frequently observed were influenza-like symptoms such as fever and generalized malaise and gastrointestinal symptoms like anorexia and nausea/vomiting; these symptoms were all Grade 2 or milder. Abnormalities in laboratory tests, such as an elevation in GOT/GPT, neutropenia, and leukopenia were observed. These adverse effects were all tolerated by the patients. From the above results, bropirimine was considered to be a useful oral agent for the treatment of bladder CIS.

Since April 1986, a prospective clinical trial for testicular cancer has been underway by our Nara Uro-Oncology Research Group. One hundred and forty-eight cases of germ cell tumor were entered into this study between April, 1986 and August, 1995. They included 99 cases (66.9%) of seminoma and 49 cases (33.1%) of non-seminomatous germ cell tumor (NSGCT). The mean age of seminoma cases (39.7 yrs) was higher than that (30.2 yrs) of NSGCT cases. One hundred and twenty-three cases were treated according to our protocol. In the treatment group, one patient with stage I seminoma died of other diseases and one patient each with stage II and stage III seminoma died of cancer. Three patients with stage III NSGCT died of cancer. The 5-year survival rate was 100% for stage I seminoma, and stage I and stage II NSGCT, 75.0% for stage II seminoma, 0% for stage III seminoma and 66.7% for stage III NSGCT. These findings suggest that new treatment modalities should be introduced into our protocol in the future.

The number of cases of prostate carcinoma (PCA) is steadily inceasing in Japan. The clinical application of a reliable tumor marker, prostate specific antigen (PSA) for the diagnosis, as well as the increasing elderly population in Japan may account for this increase. The subjects were patients at the Nara Medical University and its affiliated hospitals; 1) 687 cases without PCA were evaluated for age-specific PSA and the incidence of abnormal PSA following urological manipulations, 2) 135 cases with histological proven BPH by transurethral resection of prostate (TUR-P) were examined for PSA density (PSAD) and positive PSA rate in BPH, 3) 135 cases receiving a needle biopsy with suspicion of PCA were examined for the efficacy of PSA and PSAD and other parameters, and 4) 459 PCA cases treated between 1988 and 1994, were examined for specific PSA and PSAD values by stage and degree of cell differentiation. The PSA assay used in this study was MARKIT-M PA (normal rangeor = 3.6 ng/ml). The PSA was decreased gradually with age in non-PCA patients, and abnormal PSA was found in 5.5% of these patients following manipulations. The average PSA was 2.95 +/- 2.03 ng/ml in 130 BPH patients (mean age: 71.1 +/- 7.0 years old. and average prostate volume: 32.9 +/- 16.1 ml). And abnormal PSA level (more than 3.61 ng/ml) was found in 22.3%. The mean PSAD was 0.1.0 +/- 0.06, and PSAD was below 0.15 in 86.1% of these BPH cases. Among the 135 cases receiving a needle biopsy, 33 cases had PSA values between 3.61 and 10.0 ng/ml. Of these cases, PCA was found in 18.5% of the 27 cases with a PSAD below 1.5, and in 33.3% of the 6 cases with a PSAD over 1.5. PSA and PSAD were proportionally increased with stage, and a significant difference in the PSA value was observed between stage B1 and B2, and stage C and D (P0.05). However, PSA and PSAD values were not significantly correlated with the cell differentiation in PCA stage A2-C. In total, PSA was 18.1 ng/ml in well, 23.9 ng/ml in moderately and 35.9 ng/ml in poorly differentiated type PCA. The positive rate of PSA was 22.3, 65.4 and 83.5%, that of prostate acid phosphatase (PAP) was 10.0, 17.8 and 45.8%, and that of GSM was 25.0, 14.7 and 68.4%, in BPH, stage A PCA and stage BPCA, respectively. In conclusion, PSA is the most reliable tool in the diagnosis of localized PCA. However, the differential diagnosis of BPH and localized PCA is difficult when the PSA value is between 3.61 and 10.0 ng/ml, and accurate staging of localized PCA is difficult with PSA or PSAD alone. At present, it is necessary to use all possible tools for the early detection of localized PCA, and to perform the needle biopsy in all PCA-suspicious cases.

Screening was performed on 102 patients aged 60 years or older who visited the Outpatient Department of Internal Medicine in Tane General Hospital between June 1994 and May 1995. Of those screened, 36 patients (35.3%) had elevated prostate specific antigen (PSA) values, and 20 of them visited the Urological Department, and underwent digital rectal examination (DRE) and transrectal ultrasonography (TRUS) for further screening. Of the 16 patients who underwent ultrasound guided biopsies of the prostate, 7 patients were found to have prostate cancer. Therefore, the cancer detection rate was 6.9%, which was about 4 times higher than that of mass-screening examinations previously reported in the Japanese literature. These findings suggested that the screening using PSA in outpatients of Internal Medicine may be useful for the early detection of prostate cancer.

The effects of a colchicine-induced M-phase block of regeneration after partial hepatectomy on early-stage liver carcinogenesis were studied in rats. When administered 1 or 3 days after N-diethylnitrosamine initiation and partial hepatectomy, colchicine increased the mitotic index of regenerating hepatocytes at days 4-6 without evidence of liver cell necrosis. When the protocol was combined with a selection procedure (E. Cayama et al., Nature (Lond.), 275: 60-62, 1978), a significant increase in the size but not number of gamma-glutamyltranspeptidase-positive foci at week 5 was observed in a colchicine dose-dependent manner. This was associated with an elevated incorporation of 5-bromo-2-deoxyuridine into the gamma-glutamyltranspeptidase-positive cells. In a longer-term experiment, the numbers, sizes, and 5-bromo-2-deoxyuridine labeling index of persistent nodules were increased significantly in colchicine-treated rats at week 9. This was associated with significant increases in the incidences and numbers of hepatocellular carcinomas at week 42. The above results raise the interesting possibility that a cell cycle disturbance in the early stage of liver carcinogenesis provides a persisting growth advantage for initiated cells, resulting in enhanced growth of foci and persistent nodules that evolve into hepatocellular carcinomas.

The concentrations of pyridinoline (Pyr), a novel marker of bone resorption, were simultaneously measured in both serum and urine samples by ion-paired high-performance liquid chromatography in 27 patients with predialysis chronic renal failure. The patients consisted of 19 males and 8 females, whose creatinine clearance (Ccr) ranged from 2.5 to 47.6 ml/min. The influence of residual renal function on serum Pyr and the clinical significance of serum and urinary Pyr were analyzed in patients with predialysis chronic renal failure. There were significant correlations between serum Pyr and serum Cr (r = 0.76) and between Pyr clearance and Ccr (r = 0.70). In addition, significant correlations were observed serum and urinary Pyr (r = 0.64) and between both serum and urinary Pyr and HS-PTH (r = 0.96 and r = 0.61, respectively) and osteocalcin (r = 0.80 and r = 0.73, respectively). However, serum bone alkaline phosphatase isoenzyme (ALP3) was correlated with neither serum nor urinary Pyr. There was no correlation between the ratio of serum Pyr/serum Cr and the metabolic bone markers (HS-PTH, osteocalcin and ALP3). There was a correlation between Ccr and urinary Pyr, although it was statistically significant (p0.1). These date led to the following conclusions: (1) serum Pyr in patients with oredialysis chronic renal failure is influenced by reduced renal function and (2) urinary pyr shows a state of bone resorption when an adegvafe level of renal function is maintained. This suggests that patients with an advanced stage of renal osteodystrophy are included among cases of predialysis chronic renal failure.

Recently, it has been noted that radical molecules participate in the pathogenesis of some of the complications associated with long-term dialysis therapy, such as amyloidosis. Since allantoin is produced from uric acid almost exclusively by the hydroxy radical, we investigated the plasma concentrations of allantoin in 71 patients with chronic renal failure who were on maintenance hemodialysis. Our specific objective was to investigate the relation of allantoin to the plasma concentrations of beta2-microglobulin and methylguanidine to evaluate the potential of allantoin as a significant parameter of the radical reaction. Although plasma allantoin was not detected in 15 healthy controls, plasma concentrations of allantoin increased markedly in all of the hemodialysis patients (42.6 +/- 37.7 nmol/mL) and wide variation was observed from 4.3 to 185.2 nmol/mL. In addition, we confirmed significant correlations between plasma concentrations of allantoin and beta2-microglobulin as well as serum concentrations of methylguanidine/creatinine and hyaluronic acid (r - 0.456, p0.0005, r = 0.313, p0.005, r = 0.368, p0.01, respectively). Although evidence for a direct link between plasma allantoin levels and amyloidosis was not obtained, the increase in the plasma concentrations of allantoin suggested its clinical significance as a parameter of the radical reaction that is thought to participate closely in the pathogenesis of dialysis-related amyloidosis. From a practical point of view, the measurement of plasma allantoin can be expected to become a significant method of measuring radical members which may be useful in the prophylaxis of some of the complications induced by free radicals.

Androgen ablative treatments for advanced prostatic cancer have achieved great progress with new concepts of therapy in the last decade such as chemical castration with LH-RH analogue and total androgen ablation. However, in treatment for hormone-refractory or relapsing prostatic cancer it remains controversial whether cytotoxic chemotherapy is acceptable or palliative, and whether there is an alternative treatment for this incurable disease. The current status of cytotoxic chemotherapy for advanced prostatic cancer patients in Nara Medical University since 1980 is reported in this paper with the some review of recent advances in hormone-independent prostatic cancer treatment. The overall objective response rate of CDDP-based multi-drug regimens including CDDP monotherapy was 49.6% (CR 0% + PR 49.6%). Response rate of primary chemotherapy group constituted with untreated patient was 67.2%, against 23.9% in the hormone refractory or relapse group. Five-year survival rate was 61.1% in the primary chemotherapy group, 35.5% in the hormone refractory group and 40.6% in the relapse group. Basically, there was no significant difference in response rates and survival rates among the groups of CDDP monotherapy, CDDP+bleomycin+vinblastine, CDDP+cyclophosphamide+adriamycin or CDDP+etoposide. The different response rates among the regimens seemed mainly to depend on the population of refractory or relapsing cases in each group. The important problems remaining unsolved in the research of chemotherapy for prostatic cancer are that there is no effective breakthrough agent and the lack of the harmonization in response criteria. The new agents are under development based on the cellular biology of hormone-refractory prostatic cancer, and there is a bright future in the treatment of this intractable disease.

To investigate the efficacy and safety of bicalutamide (Casodex) with its clinically recommended dose, the randomized early phase II study was performed in 124 patients with prostatic cancer (stage C, D). The patients were given 50, 80 or 100 mg of bicalutamide orally once a day in fixed doses for 12 weeks; 122 patients were eligible for evaluation. The overall response rate was 50.0% (20/40), 61.0% (25/41) and 53.7% (22/41) in the 50 mg, 80 mg and 100 mg groups, respectively. The response rate in prostate lesion, bone and lymph node metastases was slightly higher in the 80 mg group than in the 50 mg and 100 mg groups. The proportion of patients showing a response with regard to serum PSA (CR and PR) was 84.2, 92.7 and 97.6% in the 50, 80 and 100 mg groups, respectively. The incidence of adverse reactions was 65.0, 61.0 and 61.0% in the 50, 80 and 100 mg groups, respectively, and there was no significant difference in overall safety rating in the three groups. Frequent adverse reactions were gynecomastia and breast pain. Only one patient in the 80 mg group was withdrawn due to shortness of breath. Serum concentrations of LH, testosterone and estradiol increased significantly after treatment. Bicalutamide was concluded to be effective and well tolerated in patients with prostatic cancer, and its recommended dose was 80 mg once daily.

A phase I study (open trial) of bicalutamide (Casodex), a non-steroidal antiandrogen, was conducted on 16 patients with prostatic cancer (stage C to D). The patients were given 10, 30, 50, 80 or 100 mg of bicalutamide orally daily for 12 weeks. Adverse reactions were observed in 8 out of 16 patients, but almost all were mild. Breast pain, gynecomastia and hot flushes were observed in 6 patients. Adverse reactions regarding liver function tests were observed in 3 patients. These were increased glutamic-oxalacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), alkaliphosphatase (AL-P) or gamma guanosine 5'-triphosphate (gamma-GTP). However, during or after the treatment period the elevated values were reversed to the pretreatment level. In terms of efficacy, anti-tumor effect was observed in 1 or 2 patients at each dose. Serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and estradiol increased during treatment. Plasma concentrations of the R (-) enantiomer, which has antiandrogenic activity, reached the steady state 6-8 weeks after the initiation of treatment; its apparent plasma elimination half-life observed following repeated administration was 8.4 +/- 1.1 days. In conclusion, bicalutamide (10-100 mg od) is considered to be tolerated well enough to be administered to patients with prostatic cancer and has shown evidence of anti-tumor effect.

Ninety-five paraffin blocks of renal cell carcinomas (RCCs) and background normal tissue were obtained from patients in Nara Medical University Hospital and used for studying silver-binding nucleolar organizer regions (AgNORs), proliferating cell nuclear antigen (PCNA) and nm23 oncogenes. The RCCs were grouped by size (or = 30,30 andor = 50,50 mm of average diameter) and grade according to the General Rules for Clinical and Pathological Studies of Renal Cell Carcinoma, Japan. Numbers of cases were 17 in theor = 30-mm group, 36 in the30- andor = 50-mm group, and 42 in the50-mm group. AgNOR scores were 4.68 +/- 1.22, 3.91 +/- 1.31 and 3.01 +/- 1.05, respectively, with significant intergroup differences. Frequencies of PCNA-positive cells per 500 cells were 33.8 +/- 23.5, 39.4 +/- 13.8 and 45.9 +/- 38.8. nm23-H1 immunohistochemical staining proved strongly positive in 21 of 24 areas of normal proximal convoluted tubules, 4 of 8 dysplasia cases, 2 of 17 in theor = 30-mm group RCCs, 1 of 36 in the30- andor = 50-mm group RCCs and none of 42 in the50-mm RCCs. nm23-H2 in contrast was weakly positive in 3/24, 2/8, 12/17, 30/36 and 20/42 of the cases, respectively. The results indicated an inverse relationship between tumor size and score of AgNOR without any variation in PCNA labeling and contrasting expression of nm23-H1 and nm23-H2 linked to the size of RCCs.

Since Kock et al. reported a low pressure continent reservoir using detubularized ileal segment as urinary diversion following cystectomy, continent urinary diversion including neobladder has been focused upon. On the other hand, ureterocutaneostomy, or ileal conduit as an incontinent urinary diversion is still commonly used, and especially the latter form is usually performed in many hospitals. These facts suggest that it is difficult to conclude that continent urinary diversion regarded as an excellent operation with good quality of life (QOL) is a generally acceptable method and that there are still some problems to decide the indication for urinary diversion. We discuss the problems about the postoperative complications and care of urinary diversion after cystectomy and our opinion about the selection of these operations.

A series of 180 patients treated with ileal conduit urinary diversion at Nara Medical University and its affiliated hospitals were reviewed. The patients ages at the time of operation ranged from 21 to 79 years old with an average of 60.9 years old and the average postoperative follow-up period was 44.2 months. Early complications occurred in 60 patients (33.3%) and 9 (5.0%) of them resulted in post-operative deaths. Late complications were noticed in 54 (31.6%) of the 171 patients. Frequent late complications included peristomal dermatitis (37.3%), ureteroileal stenosis (17.9%) and urolithiasis (11.9%), for the latter two of which endourological treatments seemed to be effective. To be emphasized is that more attentive care should be paid to the condition of the peristomal skin during follow-up.

Serum concentration of the pyridinium cross-links, pyridinoline (Pyr) and deoxypyridinoline (Dpyr), which are markers of bone resorption, was measured by high-performance liquid chromatography in 56 patients on maintenance hemodialysis. The following analyses were conducted: 1) correlation with known markers of bone metabolism, 2) correlation with findings on bone changes on plain X-ray film, 3) elimination rates by hemodialysis, and 4) increment per day in pyridinoline after hemodialysis (delta Pyr/day). There was a very close correlation found between serum Pyr and Dpyr (r = 0.861). Both serum Pyr and Dpyr showed correlations with known markers of bone metabolism: C-PTH (r = 0.806 and r = 0.747, respectively), M-PTH (r = 0.766 and r = 0.749), osteocalcin (r = 0.717 and r = 0.693), Alp-3 (r = 0.523 and r = 0.441) and tartrateresistant acid phosphatase (r = 0.549 and r = 0.548). In addition, a correlation between the duration of hemodialysis and serum Pyr and Dpyr was observed (r = 0.426 and r = 0.318, respectively). When comparing the mean values of serum Pyr or Dpyr in three groups of patients divided according to bone changes seen on plain X-ray film, there were statistically significant differences between the group without bone changes and the remaining two groups with some bone changes (p0.05). A mean of 45.3% of serum Pyr was removed by hemodialysis. The serum Pyr level returned almost to the original concentration by the following hemodialysis. delta Pyr/day showed a close correlation with C-PTH (r = 0.656).(ABSTRACT TRUNCATED AT 250 WORDS)

A case of congenital patent urachus is reported. A 12-month-old boy was referred to our outpatient clinic with the complaint of watery discharge from the navel. A cystography revealed the communication between the dome of the urinary bladder and the umbilicus. Excretion from the umbilicus of indigocarmine solution instilled into the urinary bladder was recognized. There were no complicated abnormalities in other organs. The patient underwent radical operation. Herein, we collected 164 cases of urachal disorders reported in Japan and reviewed the incidence, clinical symptoms, diagnosis and treatment. The classifications of the disease were briefly discussed.

Between October 1990 and June 1993, 112 patients underwent fine needle aspiration cytology and core needle biopsy of the prostate under transrectal ultrasonographic guidance. They were suspected of having prostatic cancer from the prostatic antigen level, digital rectal examination and/or transrectal ultrasonography. Twenty seven of the 112 cases (24%) were diagnosed with prostatic cancer. Their cytological diagnoses showed 22 class IV or V, 2 class III, and 3 class I or II. Efficiency, false negative rate and false positive rate were 86%, 11% and 0% in fine needle aspiration cytology. We could obtain sufficient samples for fine needle aspiration cytology in all cases. No severe complication was observed. However, we missed 3 patients, in fine needle aspiration cytology, who were strongly suspected of having prostatic cancer, and reexamination or additional core needle biopsy would have been necessary on 15 of the 112 patients (13%) who showed false negative or class III cytological results, if we had screened prostatic cancer only by fine needle aspiration cytology. In conclusion, fine needle aspiration cytology may not be as useful as core needle biopsy to screen prostatic cancer.

A case of asymptomatic synchronous bilateral granulomatous orchitis in a 79-year-old male patient is described. He was diagnosed with asymptomatic microhematuria, and referred to our outpatient clinic. In the physiological examination, there were stone-hard indurations in his bilateral testes. There were multiple hypoechoic areas in the scrotal ultrasonography. Bilateral testicular tumor was suspected. However, histological findings after bilateral orchidectomy revealed granulomatous orchitis. Abdominal computed tomography revealed swelling of the paraaortic lymph nodes postoperatively. However no malignant origin was detected. Differential diagnosis between testicular tumor and granulomatous orchitis is very difficult in any examination except by histological findings. Conservative therapy is usually not effective, and most cases are treated by orchidectomy. Bilateral cases of this entity are relatively rare, but in young cases, it is necessary to distinguish the granulomatous orchitis from the testicular tumor before surgical intervention.

A total of 70 patients with renal trauma were treated at the Department of Urology, Nara Medical University and Nara Prefectural Hospital, including Life-Saving Emergency center, from January 1982 to June 1993. They were between 3 and 79 years old (mean 30.0) and preponded to the younger generation. The main cause of injury was traffic accident in 46 cases (65.7%). According to the Classification of Renal Injury by the Japanese Association for the Surgery of Trauma in Japan, there were 31 cases (44.3%) of type I (subcapsular injury), 18 cases (25.7%) of type II (superficial injury), 15 cases (21.4%) of type III (deep injury), and 6 cases (8.6%) of type IV (pedicle injury). Surgical treatment was performed in 17 cases (24.2%). The major associated injuries were bone fracture in 32 cases (45.7%), lung injury in 17 cases (24.2%), and liver injury in 15 cases (21.4%). Furthermore, hydronephrosis and ureteral tumors were incidentally found in 4 and 1 patient during the course of treatment for renal trauma. Post-traumatic plasma renin activities (PRA) in types III and IV were significantly higher than those in types I and II. Hypertension developed in 1 case of types I and II and 4 cases of types III and IV. The mean level of PRA was significantly decreased 2 years after renal injury in both groups. We should bear in mind that renal trauma may be associated with other urological diseases such as hydronephrosis and urological malignancies, and post-traumatic PRA should be followed carefully.

The current status of treatments for advanced transitional cell carcinoma of the urinary tract with metastasis is reported. A total of 62 patients were treated in Nara Medical University Hospital and its affiliated hospitals between January, 1980 and June, 1993. All patients were divided into two categories; cases in which local recurrence and/or distant metastasis had developed during the followup study (group 1) (n = 32) and fresh cases with distant metastasis (group 2) (n = 30). Most of the metastatic sites were treated with chemotherapy alone or combination therapy including chemotherapy. As for clinical response of each case, CR + PR rate in group 1 (34%) was higher than that in group 2 (13%) (p0.1). As for prognosis, the survival rate in group 1 was significantly higher than that in group 2 (p0.05). In group 1, the survival of CR was significantly higher than that of the non-responders. No adjuvant therapy for invasive bladder cancer and post-operative adjuvant therapy for renal pelvic and/or ureteral cancer can be recommended to prevent local recurrence or distant metastasis. In addition, supporting therapy and dose intensified chemotherapy would lead to good prognosis in advanced urothelial cancer patients.

In clinical trials in advanced urogenital cancer with metastasis there are cases showing a poor clinical response and poor prognosis. The cure of advanced urogenital cancer still remains a major problem in management. The present paper is a summary of 8 articles presented at the symposium on "Management of advanced urogenital cancer: Treatment of metastasis" in the 43th Annual Meeting of Center Section of Japanese Urological Association in November, 1993. The present status, problems and future conception of treatment modalities for advanced urogenital cancer were discussed.

We report a unique case of a patient with synchronous renal cell carcinoma, hepatocellular carcinoma and squamous cell carcinoma of the oral floor. All three tumors were resected during a single operation. The patient was a 75-year-old man with masses in the liver and right kidney discovered by ultrasound examination during a routine checkup. Further examination also revealed a squamous cell carcinoma of the oral floor. The patient underwent a simultaneous radical nephrectomy, enucleation of the liver tumor and resection of the tumor of the oral floor. The diagnoses were histopathologically confirmed. The number of patients with multiple cancers has recently been increasing. The possibility of a second or third malignant lesion should be considered, not only in patients with a known malignancy but also in those without malignancy. The importance of screening procedures in the early detection of malignancy before the appearance of clinical symptoms should be emphasized.

Ultrasound-guided percutaneous puncture of renal cysts replaced by CO2 was performed on 9 renal cysts of 6 patients from May 1993 through September 1993. Puncture and aspiration of cysts was performed using a 5.5 Fr one-step fluid drain kit (pig tail stent) under ultrasonography inspection. Aspirated volume of cyst contents was 15-292ml (mean 115 ml), and the instilled CO2 volume was 15-150 ml (mean 73 ml). All patients were checked by CT scan. In one month, the reduction rate of cyst volume was 46-84% (mean 69%) and lumbago, their chief complaint, was improved in all patients. No complications were observed in patients treated by CO2 instillation. Although long-term followup is needed to draw a definite conclusion, this therapy may be useful for benign renal cystic lesions.

Cyclosporine A (CYA) a new immunosuppressive drug, has greatly improved the outcome of solid graft transplantation. The nephrotoxicity of CYA, however, is a serious problem, and constitutes the major obstacle limiting the use of CYA as an immunosuppressive agent for renal transplantation. On the other hand, the newly described atrial natriuretic peptide (ANP) hormonal system in both humans and animals appears to play an important role in sodium and water excretion. The present study examined the nephrotoxicity of CYA and the effect of recombinant-ANP (r-ANP) on the damaged kidneys in three groups. Group 1 consisted of rats with 45 minutes warm ischemic left kidney and right nephrectomy [WI rats]; Group 2 consisted of WI rats with oral administration of CYA (100mg/kg/day) for 2 weeks [WI+CYA rats]; Group 3 consisted of WI+CYA rats with intraperitoneal administration of r-ANP (10ng/kg/day) for 2 weeks. Group 2 had lower glomerular filtration rates (GFR) and renal plasma flow (RPF) than Group 1, but Group 3 had significantly higher GFR and RPF than Group 2. Additionally, in order to demonstrate the change in renal viability among the three groups, the adenosine triphosphoric acid level (ATP) and adenylate energy charge ratio (EC) of renal parenchymal tissue were measured by high performance liquid chromatography (HPLC). Group 2 had lower ATP and EC than Group 1, and Group 3 had higher ATP and EC than Group 2. The results of this study suggest that r-ANP is efficacious on rat kidney damage induced by CYA and WIT.

The preliminary results of a multi-institutional prospective randomized study of the prophylaxis of superficial bladder cancer using epirubicin (protocol NUORG SBT-003) are reported. The subjects were 129 patients with untreated superficial bladder cancer (or = T1b,or = G2) who were randomized into 2 groups: a transurethral resection (TUR)-alone group (63 patients) and a TUR + intravesical epirubicin (20 mg/40 ml, 30 times/2 years) group (66 patients). The nonrecurrence rate observed in the epirubicin group was significantly higher than that seen in the control group. To unify the pathological diagnosis, a central pathology laboratory (CPL) was set up for extramural review. The correspondence of the pathological diagnosis of TUR-Bt specimens between the CPL and the local pathology laboratory (LPL) was 70.5% in grading and 51.9% in staging. There was a tendency for overdiagnosis by the LPL for both the grade and the stage of tumors. However, differing interpretations by pathologists seem to exert little influence on the nonrecurrence rate at interim analysis. Further observation will be necessary to clarify the prophylactic efficacy of low-dose, long-term periodic intravesical epirubicin instillation and the influence of the disagreement in pathological findings between the CPL and the LPL on the analysis of the results.

Rhodamine 123 (Rh123) is a red fluorescence dye, which is accumulated more and retained longer in the mitochondria of malignant transformed cells. In this study, the suppressive effects on the growth of cultured urogenital carcinoma cells (PC-3 and LNCaP from prostate carcinoma, T-24 from bladder cancer, and SV-HUC-1 human ureteral transitional cell transformed by SV virus in vitro, ACHN, YCR-1 and RCF213 from renal cell carcinoma) were examined. The cell growth of PC-3, LNCaP, T-24 and SV-HUC-1 was suppressed significantly in a dose dependent manner, but that of cells derived from renal cell carcinoma was not suppressed. The uptake and elimination of Rh123 in PC-3, ACHN and YCR-1 were not significantly different. When administered with verapamil and buthionine sulfoximine, which are reported to be chemical modulators of anticancer agents, Rh123 suppressed the growth of ACHN and YCR-1 significantly. Rh123 seems to have an anticancer effect against the urogenital carcinomas, and the role of Rh123 with hyperthermia, photodynamic therapy and chemotherapy requires further investigation.

A series of 32 patients with spina bifida, representing 50 renal units with vesicoureteral reflux (VUR), was treated with antireflux operation. All but one patient underwent ureteral reimplantation with Cohen's technique. Another patient was treated with bilateral Politano-Leadbetter's technique. The overall success rates were 92.0% by renal unit and 87.5% by case, with a mean follow-up period of 42.5 months. These results were comparable to those in the recent literature. Failure included recurrence of VUR in 3 patients. Another patient who had undergone unilateral reimplantation developed new occurrence of reflux in the contralateral ureter. Possible masking of contralateral VUR should be taken into consideration in patients with unilateral high grade VUR. We also emphasize the importance of continuing clean intermittent catheterization in a proper manner to be free of VUR postoperatively.

Augmentation cystoplasty is evolving into a common method of surgical treatment for a low capacity and/or low compliance neurogenic bladder. Although an increasing number of successful results have been recently reported, the operative indication of augmentation cystoplasty is yet to be established. Herein, we report two cases of neurogenic bladder due to spina bifida which required abandonment of augmentation cystoplasty. The first case was in a 23-year-old female with a severely deformed bladder and right vesicoureteral reflux (VUR). She refused to undergo ileocystoplasty because we could not assure her of postoperative conception which she eagerly anticipated. The second case was in a 19-year-old male with a severely deformed bladder and right VUR. He experienced recurrent episodes of ventriculoperitoneal shunt (V-P shunt) difficulty which required exchanging the shunt tube each time, and each exchange proved to be very difficult or nearly impossible. Based on lengthy neurosurgical consultation, we came to the conclusion that ileocystoplasty was not a preferable treatment of choice for the correction of his disease due to the possibility of V-P shunt infection, which could be fatal. Alternatively, both cases were treated with Cohen's ureteral reimplantation, which resulted in the recurrence of VUR. These cases presented still unresolved issues concerning the operative indication of augmentation cystoplasty in spina bifida patients.

Current studies have reported that free radical molecules had anticipated intimately with the pathogenesis of some complications specific for a long term hemodialysis. Among substances generated by free radical reaction, methylguanidine (MG) had been well known as most popular parameter in hemodialyzed patient, but allantoin (Alt) had been reported to be generated from uric acid by hydroxyradical, too. In this study, we measured serum level of Alt in long term hemodialyzed patient and analysed in the comparison with serum level of sialic acid, MG, and MG/Cr value. Serum level of Alt in patients group varied from 2.6 to 105.9 nmol/ml, which was significantly higher as compared with exclusively undetectable level in normal volunteers (n = 15). Serum level of Alt in each patient showed a significant correlation with serum level of a sialic acid (r = 0.400 p0.02). Furthermore, although serum level of Alt failed to show a significant correlation with serum level of MG, but showed a significant correlation with MG/Cr value. (r = 0.485 p0.01). In addition, higher level could be found in patient group having higher serum level of MG or MG/Cr value. Based upon those results, we proposed that a measurement of serum level of Alt could be of value in detection of free radical reaction in long term hemodialyzed patient.

Extramedullary plasmacytoma (EMP) is a very rare disease and mainly arises in the head and neck area. We herein reported a case of EMP arising in the retroperitoneal space. A 46-year-old man was referred to our outpatient clinic in November 1989 with the complaint of flank pain on the left side. Radiological examinations showed a tumor formation in the retroperitoneal space, which involved the left kidney, spleen and pancreas. Immunoelectrophoresis showed an elevation of serum IgG level and a spike of M-protein was detected in the serum protein electrophoresis. No bone lesions were detected, and bone marrow aspiration showed no abnormal cells. US-guided needle biopsy of the tumor led to the histological diagnosis as plasmacytoma of the IgG-kappa type. Following three cycles of preoperative chemotherapy (a THP-COP regimen), which resulted in a size reduction of the tumor by 40%, extensive resection of the tumor including extirpation of the left kidney, spleen, and tail of pancreas was performed. Because of tumor extension into the posterior wall of the stomach, however, the surgery resulted in incomplete resection. A total of 11 cycles of postoperative chemotherapy (THP-COP) was performed periodically for the residual tumor in the stomach. Rapid tumor spreading in addition to re-elevation of the serum IgG level, however, developed after the 11th postoperative chemotherapy, which extensively involved the stomach and intestines. The patient died of the disease 33 months after the initiation of treatment.

Thirty-one patients (26 male and 5 female patients) of non-hypercalciuric Ca stone formers were studied concerning their bone metabolism. We measured plasma free gamma-carboxyglutamic acid, plasma hydroxyproline, urinary free gamma-carboxyglutamic acid and urinary hydroxyproline as markers of bone metabolism. Plasma free gamma-carboxyglutamic acid level showed significantly higher in stone formers than normal controls (1.01 +/- 0.37 nmol/ml vs 0.39 +/- 0.13 nmol/ml). But no significant difference were observed in plasma hydroxyproline level (1.99 +/- 0.73 micrograms/ml vs 2.27 +/- 0.92 micrograms/ml), urinary free gamma-carboxyglutamic acid (52.0 +/- 17.6 nmol/mg.Cr vs 45.7 +/- 9.8 nmol/mg.Cr), and urinary hydroxyproline (3.87 +/- 2.02 micrograms/mg.Cr vs 3.33 +/- 1.63 micrograms/mg.Cr). In conclusion, these results suggest that abnormality of bone metabolism may be not a primary event in causing stone formation in these patients.

The current status and controversy of the treatment for renal cell carcinoma are reported. From 1980 to 1990, a total of 283 patients with renal cell carcinoma were treated in Nara Medical University and its affiliated hospitals. All patients were divided into two groups: M0 group (n = 217) and M1 group (n = 66). In addition, the M0 group patients were divided into two groups according to the followup study: M0--M0 group (n = 194) and M0--M1 group (n = 23). There was a significant difference between the survival of the M0 group and that of the M1 group (p0.001). A significant difference was also seen between the survival of M0--M0 group and that of the M0--M1 group (p0.001). The clinical and pathological factors which might be related to prognosis were analyzed. In the M1 group, high stage, high grade, non-surgical treatment for primary site and metastatic sites other than the lungs were found to be poor prognostic factors. In the M0--M1 group, no prognostic factor was seen. These findings indicated that surgical treatment for the primary site in M1 patients should be performed. In addition, development of effective treatment for metastatic sites other than the lungs and effective postoperative adjuvant treatment would be necessary.