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Objective The aim of the present study was to examine the association between subjects with self-awareness of fast eating and diagnostic components of metabolic syndrome in Japanese middle-aged male and female. Patients and methods Subjects consisted of 3208 males (average age 50.6 years) and 2055 females (average age 50.0 years). Associations between subjects with self-awareness of fast eating and multiple components of metabolic syndrome (waist circumference, body mass index [BMI], blood pressure, and related blood sample tests) were evaluated. Results Significantly more males (57.7%) acknowledged themselves as "fast eater" than females (46.5%). Self-reported fast eaters showed significantly elevated body weight, BMI, and waist circumference in both genders. However, only male self-reported fast eaters showed high levels of blood pressure, fasting blood glucose, uric acid, and low-density lipoprotein (LDL)-cholesterol. Conclusion Fast eating is associated with diagnostic components of metabolic syndrome. The effect of acknowledging themselves as fast eater presents a higher impact on males than on females in the middle-aged Japanese population. The present study indicates that finding subjects with self-awareness of fast eating may lead to the prevention of developing metabolic syndrome.

Orthostatic hypotension is a hallmark of diabetic autonomic neuropathy and is associated with increased mortality. The serum level of adiponectin is elevated in patients with heart failure or renal failure. In the present study, we measured serum levels of total and high molecular weight adiponectin in patients with Type 2 diabetes and orthostatic hypotension. We also investigated the relationship between the presence of orthostatic hypotension and various clinical variables in patients with Type 2 diabetes.We studied 105 patients with Type 2 diabetes. Orthostatic hypotension was defined as a decrease of 20 mmHg or more in systolic blood pressure and/or 10 mmHg in diastolic blood pressure when blood pressure was measured for 3 min while standing. The brachial-ankle pulse-wave velocity was also measured as an index of arterial stiffness.Orthostatic hypotension was found in 30 patients with diabetes (28.6%). The haematocrit and estimated glomerular filtration rate were significantly lower in patients with orthostatic hypotension than in those without it. Brachial-ankle pulse-wave velocity and serum total and high molecular weight adiponectin were significantly higher in patients with orthostatic hypotension than in those without. Furthermore, the high molecular weight/total adiponectin ratio was higher in patients with orthostatic hypotension than in those without and hypertension was more common in patients with orthostatic hypotension. Plasma prothrombin F1 + 2, a coagulation maker, was higher in patients with orthostatic hypotension than in those without, while there were no differences of fibrinolytic markers between the two groups. Multivariate analysis showed that HDL cholesterol, haematocrit, F1 + 2, brachial-ankle pulse-wave velocity and a decline of systolic blood pressure on standing were independent determinants of high molecular weight adiponectin.Patients with Type 2 diabetes and orthostatic hypotension had an elevated serum level of high molecular weight adiponectin, which was associated with the simultaneous presence of renal dysfunction, anaemia, arterial stiffness and hypercoagulability.

We proposed a new classification of pheochromocytomas according to DNA ploidy patterns. Proliferation index (PI = S% + 4C%) might be an alternative to 4C% which was used as a critical marker of DNA nonaneuploid histograms. The follow-up survey revealed that DNA tetraploid with minimum increase of PI could not rule out the substantial possibility of malignancy and the comparison of DNA diploid histograms disclosed that 22 and 0% showed significant increase of the ratio of 4C% to S% under PI and 4C% criteria, respectively. In conclusion, 4C% was more effective and reliable than PI in order to classify DNA nonaneuploid pheochromocytomas.

The main purpose of the study was to investigate the association between vascular endothelial function and diabetic microangiopathy (nephropathy, retinopathy and neuropathy) in patients with type 2 diabetes. In addition, the association between endothelial function and macroangiopathy evaluated by intimal-medial complex thickness (IMT) was also investigated. Endothelial function was evaluated non-invasively by the measurement of flow-mediated vasodilatation (FMD) of the brachial artery. Diabetic nephropathy and neuropathy were assessed by urinary albumin excretion (UAE) and motor or sensory nerve conduction velocity (MCV, SCV), respectively, and retinopathy was evaluated by an ophthalmologist using the Davis classification. FMD was measured in 102 patients with type 2 diabetes and in 20 control subjects, and showed a tendency to be lower in the diabetic patients. There was a significant decrease in FMD in patients with proliferative diabetic retinopathy, compared with those in patients with no diabetic retinopathy. FMD showed significant positive correlations with MCV and SCV, and significant negative correlations with log UAE, systolic blood pressure and diabetic duration, but no correlation was obtained between FMD and IMT. In stepwise regression analysis, MCV alone showed a significant association with FMD. In conclusion, our results show that in patients with type 2 diabetes FMD is closely associated with all types of microangiopathy, with neuropathy being most strongly associated with FMD; however, FMD is not associated with macroangiopathy evaluated by IMT.

It is recognized that QTc intervals reflect autonomic nerve function. To investigate the clinical usefulness of corrected QT intervals (QTc) in assessing autonomic nerve function in type 2 diabetes, we measured QTc intervals using Bazett's formula in 58 type 2 diabetic patients and 20 age-matched healthy subjects.We examined relationships between QTc intervals and the coefficient of variation of RR intervals (CV(RR)), systolic blood pressure response to standing, and sympathetic skin response (SSR) whose tests reflect autonomic nerve function. We also studied the correlation between QTc and blood pressure or serum lipid concentrations.QTc intervals in diabetic patients were significantly longer than those in healthy subjects and showed a significant but weak negative correlation with CV(RR), as well as systolic blood pressure response to standing. No significant difference in QTc intervals was observed between patients with and without a detectable SSR. QTc intervals showed a significant positive correlation with systolic and diastolic blood pressure although it did not correlate with serum lipid concentrations. QTc also tended to be long in obese diabetic subjects (body mass index25).QTc intervals might also be affected by other factors such as arteriosclerotic macroangiopathy and obesity, and not only autonomic nerve function. Therefore it might be considered as an overall index for complications, and not for pure autonomic impairment.

We investigated the change in low-density lipoprotein receptor activity following the administration of estrogen to patients with hypercholesterolemia (HC). Studies were conducted in 16 patients with HC (total cholesterol (TC)220 mg/dL) and 133 healthy control subjects. LDL-R activity was measured by fluorocytometry. Three of sixteen patients with HC showed low LDL-R activity below 80% together with extremely high serum levels of TC and LDL cholesterol (LDL-C). LDL-R activity showed an inverse correlation with serum levels of TC and LDL-C (p0.05, respectively). Two women with initially low LDL-R activity who showed a marked increase in LDL-R activity exhibited a normalized activity at four and eight weeks after estriol administration, proportional to the reduction in serum levels of TC and LDL-C. One man with an initially extremely low LDL-R activity showed no abnormality at the sites of exons 7, 14, 17 and intron 12 by the PCR-DGGE method, which are common sites for point-mutations of LDL-R among Japanese patients with HC. Estrogen reduced serum levels of TC and LDL-C in patients with HC, at least in part, via an increase in the LDL-R activity of patients with HC and an initially low LDL-R activity.

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.

The effects of preoperative androgen deprivation were explored in the patients who received radical prostatectomy and subsequent adjuvant endocrine therapy for prostate cancer.Stage A2, B or C prostate cancers were randomized to one of two groups: (i) group I (n=90), who received androgen deprivation (leuploride and chlormadinone acetate) for 3 months preoperatively followed by radical prostatectomy and adjuvant endocrine therapy (leuploride only); and (ii) group II (n=86), who underwent the surgery followed by 3 month androgen deprivation and subsequent adjuvant endocrine therapy. The effects of preoperative androgen deprivation on clinical relapse (serum prostate specific antigen (PSA)1.98 ng/mL, local recurrence or distant metastasis) and PSA relapse (PSA0.2ng/mL) were evaluated at 2 years after randomization.There was no significant difference in clinical or PSA relapse-free survival and quality of life measures between the two groups, although relapses occurred significantly more frequently in patients who had more advanced stages, higher pretreatment PSA values or lower histologic differentiation in either group. Subgroup analysis indicated that clinical relapse-free survival in stage C cancer tended to be better in patients with preoperative androgen deprivation than in those patients without it (P0.1).Preoperative androgen deprivation may be beneficial for stage C prostate cancer patients receiving radical prostatectomy and adjuvant endocrine therapy over the 2 year observation period. A longer follow up is needed to clarify the exact extent of benefit in terms of survival and quality of life.

A 52-year-old Japanese male complained of palpitations and excessive sweating. He showed evidence of hyperthyroidism, but without suppression of the serum thyroid-stimulating hormone (TSH). On admission, the serum level of the alpha-subunit of TSH was elevated, but tests for thyroid autoantibodies were negative. The TSH response to thyrotropin-releasing hormone (TRH) was blunted. Imaging studies revealed a pituitary tumor 2 cm in diameter. Administration of methimazole lowered the serum levels of thyroid hormones, and elevated the serum level of TSH. These findings led to the diagnosis of a thyrotropin-secreting pituitary tumor. Immunohistochemical analysis and electron microscopic findings verified the diagnosis.

Objective To examine the usefulness of serum immunosuppressive acidic protein (IAP) as a predictor for staging renal cell carcinoma (RCC), using receiver-operator characteristic (ROC) analysis, and to compare IAP with other tumour markers. Patients and methods From September 1983 to December 1995, serum IAP was measured in 133 untreated patients with RCC (mean age 60.1 years, sD 11.4, range 31-84). The erythrocyte sedimentation rate (ESR), the levels of fibrinogen, C-reactive protein (CRP), and α2-globulin were also measured. To compare these markers as predictors of local involvement of the renal capsule, lymph node and distant metastasis, the area under the corresponding ROC curve was calculated. Tumour size at the time of resection was added in this analysis for comparison with the levels of these tumour markers. Results The final pathological stage was T1 or T2 in 101 patients and T3 or T4 in 32, while it was NO in 122 patients, N1-3 in seven, M0 in 114 patients and M1 in 19. The area of the ROC curve for tumour size was greatest (0.843) for staging of the local extent (T1/T2 versus T3/T4) and that for IAP was 0.714, similar to the values for fibrinogen, ESR and CRP. For predicting lymph node metastasis, IAP and fibrinogen were the most important (0.864). However, IAP alone (0.894) was the most important predictor of distant metastasis. Using an IAP threshold of 600

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.

Intravesical instillation therapy of Bacillus Calmette-Guérin (BCG) has become a standard treatment for carcinoma in situ (CIS) of the urinary bladder. However, there have been few reports concerning the direct effect of BCG on existing tumors classified as Ta or T1. In the first stage of this clinical study, 157 patients were treated with BCG intravesical instillation (Tokyo 172 strain [BCG Co. Ltd., Tokyo, Japan]; 80 mg weekly for eight times) by our Study Group. The efficacy on existing tumors was a complete response (CR) rate of 84.4% and 66.4% and a partial response (PR) of 6.3% and 20.8% for 32 cases of CIS and 125 cases of Ta or T1 tumors, respectively.In the second stage of this study, the authors investigated the outcome of the 138 patients who had achieved CR or PR in the first stage. One hundred twenty (87.0%) of the patients were followed fully. Of those patients, 52 were randomized to receive prophylactic (maintenance) therapy consisting of BCG of 40 mg monthly for 12 times (Group A), whereas 55 were randomized to an untreated control group (Group B). Thirteen other patients refused to be randomized and were followed without prophylactic instillation.The median follow-up period was 48 months for Group A and 42 months for Group B. In Groups A and B, the beneficial effect of the BCG therapeutic instillation persisted for a long time, and the 3-year nonrecurrence rate was 77.6% in Group A and 74.2% in Group B. Disease progression was observed rarely.For patients in whom transurethral resection of tumors of the bladder (TUR-Bt) alone is unlikely to eliminate the tumor, intravesical BCG is potentially the treatment of choice.

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

In recent years renal cell carcinomas have been diagnosed as incidental findings. The tumors are usually associated with low stage and good prognosis. To find out if they might have a different malignant potential from suspected tumors, we retrospectively compared 56 cases of incidentally detected tumors with 84 cases of suspected tumors, with regard to tumor stage, nuclear grade, tumor size and DNA ploidy pattern as evaluated by flow cytometry. The incidentally detected tumors were lower in stage (P0.01), smaller in size (P0.01) and higher in probability of survival (P0.02) than the suspected tumors, as other studies have reported. Meanwhile, there was no difference in nuclear grade, DNA ploidy pattern and survival in stage I tumors between the two groups of renal cancers. The results suggest that the better prognosis in incidental renal cancer might be due to early detection rather than lower malignant potential of this specific type of renal cancer.

Age-related changes in the lower urinary tract function were investigated by means of symptomatology and urodynamics. In the symptom study subjectively normal 168 males and 101 females aged over 30 were administered a questionnaire regarding urinary symptoms. The prevalence of symptoms gradually advanced with age and nocturia more than 2 times was dramatically increased up to a half in those aged over 70. In the urodynamic study involving 65 males and 51 females with low symptom scores, significant reduction with advancing age was noted for maximum flow rate in both sexes (males: r = -0.295, p0.05, females: r = -0.591, p0.01) and maximum detrusor pressure in females (r = -0.513, p0.01). There was a significant increase in residual urine in males (r = 0.473, p0.05); otherwise no consistent changes in cystometry and urethral pressure profile related to aging were detected. These results indicate that urinary symptoms and urodynamic variables may change with age even in "normal" subjects, and warrant a careful interpretation of them in the elderly subjects.

An analysis has been undertaken to determine chronological changes that have occurred in the clinical features and treatments of advanced renal cell carcinomas. To accomplish this, 96 renal cell carcinoma cases, handled by the authors' department and at the branch hospital, were divided into two groups: 48 patients treated between 1975 and 1983 (group 1) and 48 patients treated between 1984 and 1991 (group 2). Between the two groups, no differences were seen in the sex ratio, the mean age, and the ratio of those who were found to be advanced cases at the time of diagnosis and those whose cancers had advanced after undergoing a nephrectomy. Concerning treatment, interferon (IFN) and UFT were more frequently used in treating group 2 than group 1, and chemotherapy, radiotherapy, and endocrine therapy less frequently used. No differences were seen in the prognosis between the two groups; however, in those who had advanced after nephrectomy, group 2 cases survived for a significantly longer period than did group 1 cases. Patients who survived for 5 years or longer accounted for two cases in group 1 and 5 cases in group 2 and combination therapies involving surgery, IFN, UFT, or similar medications were used for their treatments. These results suggest that adjuvant therapies, such as surgery, IFN, and UFT, have possibly contributed to prolonging survival, especially for cases that advanced after nephrectomy.

We have conducted a double-blind comparative study of flutamide and chlormadinone acetate (CMA) on patients with stage C or D prostatic cancer and with no prior experience of hormone therapy. This is believed to be the first such trial entered in the medical literature, fifty-four patients were randomly selected to undergo flutamide (p.o.) monotherapy at a daily dose of 375 mg, which was determined as the optimal dose in Japan in our previous phase II study. Forty-nine others were randomly selected to undergo CMA (p.o.) monotherapy at a daily dose of 100 mg, which is the most commonly used dosage in Japan for patients with prostatic cancer. Ultimately, 47 patients from the flutamide group and 40 patients from the CMA group were judged eligible, with efficacy being evaluated after 12 weeks of treatment. Similar objective responses were seen in both groups: 48.9% (95% confidence limits 34.1-63.9%) in the flutamide group, 45% (95% confidence limits 29.3-61.5%) in the CMA group. The response at each organ site was also similar between the groups. Serum prostatic specific antigen decreased by more than 50% of the abnormal pretreatment level in 87.5% of the flutamide group and in 85.7% of the CMA group. Serum luteinizing hormone, follicle-stimulating hormone, testosterone and 5 alpha-dihydrotestosterone decreased significantly in the CMA group, but increased significantly in the flutamide group. The serum testosterone level after 12 weeks of treatment was 0.955 +/- 0.13 ng/ml in the CMA group and 6.64 +/- 0.38 ng/ml in the flutamide group. The serum estradiol level also increased significantly in patients in the flutamide group. The serum prolactin level decreased significantly in the flutamide group, but increased significantly in the CMA group. Eight patients on flutamide manifested gynecomastia. Diarrhea and hepatic toxicity were observed in both groups, but only rarely, and were well tolerated. We have thus concluded that flutamide is as effective as CMA in maintaining libido and potency without decreasing testosterone levels.

The phase II study of flutamide, a pure anti-androgen, was performed to estimate the clinical doses on 165 hormone untreated or treated patients with prostatic cancer. The hormone-untreated patients were given orally flutamide of 90, 375, 750 or 1,125 mg/day in three divided doses daily for 12 weeks. Responses were not observed at the 90 mg/day dose except for improvement of clinical symptoms. However, an objective response rate of 48.8-46.7% was obtained at 375-1,125 mg/day doses. In hormone-treated patients including cases refractory to the previous hormonal treatment, the objective response rates were 13.3 and 8.3% in 375 and 750 mg/day flutamide groups, respectively. Side effects such as gynecomastia, nausea, vomiting, diarrhea, and abnormal laboratory findings such as the elevation of hepatic transaminases were observed. The incidence increased dose-dependently. Determinations of serum hormone levels revealed an increase in testosterone levels by the use of flutamide. In conclusion 375 mg/day of flutamide is the optimal dose in monotherapy for hormone-untreated patients with prostatic cancer, where the quality of life can be maintained compared with therapies involving testosterone suppression. This dose is also expected to show some efficacy in cases refractory to hormone treatment.

A phase I study of orally administered flutamide (a pure anti-androgen) was performed in 26 patients with prostatic cancer. No side effects were observed in 11 patients receiving single doses of either 125, 250, 375 or 500 mg. However, in the daily dosing schedule of 375, 750, 1125 and 1,500 mg/day doses, where medication was taken in three divided doses, discomfort in the stomach, nausea, vomiting and anorexia were experienced in one of the four patients receiving the highest dose of 1,500 mg. Nine patients receiving the other doses did not complain of toxic symptoms. Laboratory values did not change in the three patients receiving the lowest 375 mg/day dose, but elevation of transaminase was observed in five of the nine patients given higher doses. This elevation was observed in all the three patients receiving 1,500 mg/day dose. Among the serum hormone levels, significant increases of luteinizing hormone were observed. As for efficacy, objective responses were observed in two of the three patients in each of the four daily dosing groups. Improvement of pain, voiding obstruction symptoms, and performance status were also observed. Flutamide was found to be absorbed rapidly and to exist as a hydroxylated form (hydroxy-flutamide) in the plasma. The half-life of hydroxy-flutamide was similar in the single and daily administration, but the peak concentration and area under the concentration versus time curve in the daily administration became greater than those in the single administration. In conclusion, flutamide should be examined for efficacy and safety using doses of 375 to 1,125 mg/day in the phase II study.

The results of clinical use of an extracorporeal shock wave lithotripter (Biolithos MARK III) are presented. From May 1991 through February 1992, a total of 50 sessions were carried out on 33 patients with upper urinary tract stones. Treatments were performed on an outpatient basis, and none of the patients needed anesthesia or analgesia. One month after the last session, 18 patients (54.5%) were free from stone fragments and 6 (18.2%) had stone fragments equal to or smaller than 4 mm. The over-all successful rate obtained by these categories was 72.7%. After treatment no serious complications were observed. Although gross hematuria appeared in almost all patients, pain was noted in only 5 patients. Laboratory data after treatments showed slight and transient changes. It is concluded that Biolithos MARK III is useful and safe in the management of upper urinary tract stones on an outpatient basis.

The results of long-term administration of leuprorelin acetate depot (TAP-144-SR), a sustained-release preparation of luteinising hormone-releasing hormone (LH-RH) agonist, to 40 stage D prostate cancer patients who had had no previous hormonal therapy, have been analyzed. The drug was administered by subcutaneous injection once every four weeks at a dose of 3.75 or 7.5 mg. The mean duration of treatment was 480 (141-1,266) days, and treatment continued for more than one year for 60% of the 40 patients. Objective response was evaluated in accordance with Japanese Response Criteria. The best objective response in the overall evaluation was a partial response in 68.6% of the total patient group (3.75 mg, 64.3%; 7.5 mg, 71.4%). During the administration period, 21 patients were diagnosed as having progressive disease (PD), and the mean time to onset of PD was 308 days. The earliest diagnoses of PD were made on bone metastases (17 cases) and prostatic acid phosphatase levels (12 cases). The survival rate, as determined by Kaplan-Meier's method, was 81.2% (3.75 mg, 80.5%; 7.5 mg, 81.3%) two years after starting the regimen and 66.0% (3.75 mg, 65.1%; 7.5 mg, 66.0%) after three years. There was no dose dependency between either of the two drug doses, which we adopted as functions of the objective response rate, and patients' survival. Serum levels of testosterone, LH and follicle-stimulating hormone (FSH) were monitored from the first-dose until the 148th week of administration. In all patients receiving the drug as scheduled, the testosterone level was maintained at less than 1 ng/ml, and the LH and FSH levels were maintained at levels lower than their respective upper normal limits. There were no particular adverse reactions specific to the long-term administration subsequent to the foregoing 12-week administration study. In conclusion, LH-RH analogue treatment is thought to be a long-lasting, effective, palliative measure for patients with previously-untreated, advanced, prostatic cancer.

We evaluated the efficacy and safety of recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with leukopenia after chemotherapy for urogenital cancers. Recombinant human G-CSF was administered at 100 micrograms./m.2 intravenously in 36 patients and at 75 micrograms. per body weight subcutaneously in 37 for 8 days after methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) therapy or for 14 days after other chemotherapies. Cycle 1 of chemotherapy was given without recombinant human G-CSF, while at cycle 2, recombinant human G-CSF was given additionally. Therefore, cycle 1 of the regimen served as a control to cycle 2 in each patient. An elevation in the median white blood cell nadir was noted: 1,500 versus 3,200 (intravenous) and 2,100 versus 3,200 (subcutaneous) on M-VAC therapy, and 1,800 versus 2,100 (intravenous) and 1,700 versus 2,500 (subcutaneous) on other chemotherapeutic regimens. A shortening of the leukopenic period was observed in cycle 2. There were no significant adverse side effects attributed to the use of recombinant human G-CSF. The results indicate that recombinant human G-CSF may be safely and effectively used against leukopenia after chemotherapy for urogenital cancer. This remedy will become useful for completion of the schedule and dose intensification of chemotherapy in the future. Subcutaneous administration is considered to be the more preferable route.

We investigated the effects of intravesical instillation of BCG Tokyo 172 strain on patients with superficial bladder cancer and CIS of the bladder for tumor ablation and prophylaxis. This is the first controlled multicenter study for governmental approval of BCG Tokyo 172 strain for the treatment of superficial bladder cancer and CIS of the bladder. One hundred-fifty-seven patients (125 with Ta or T1, and 32 with CIS) were treated by 80 mg of BCG diluted in 40 ml of saline, once a week for 8 weeks. The dose and interval adopted in this multicenter study was determined by the previous Phase II study conducted by the same Study Group. Out of 125 superficial tumor Ta, T1, 83 (66.4%) showed complete disappearance of the tumor (CR) and 26 (20.8%) partial disappearance (PR), and out of 32 CIS, 27 (84.4%) showed CR and 2 (6.3%) PR. Among those patients showing CR, and PR who were treated with additional TUR-Bt, 98 patients were randomised for a controlled study of prophylactic BCG instillation. Prophylactic treatment consisted of 40 mg of BCG diluted in 40 ml of saline, monthly for 12 months. Forty-two patients were assigned to the treatment group, whereas the remaining 56 to the control group without any prophylactic instillation. Three cases showed tumor recurrence during the prophylactic phase. Twenty-five cases could not be treated for the whole course of prophylactic instillation mainly due to bladder irritable symptoms. Recurrent free curves were compared till 1050 days after the initiation of the study. However, there was no significant difference between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized controlled study was conducted in patients with superficial bladder cancer in order to investigate the safety of an orally administered (3 g/day) Lactobacillus preparation, biolactis powder (BLP), and its preventive effect on the recurrence after transurethral resection of the bladder tumor (TUR-Bt). Of 58 cases enrolled in the study 23 cases in the BLP group and 25 cases in the control group completed the study. There were no significant differences in the patient characteristics for the complete cases between the two groups. Comparison of the disease-free duration by the Kaplan-Meier method revealed that the 50% recurrence-free interval after TUR-Bt was prolonged by BLP treatment (350 days) to 1.8 times that in the control group (195 days). A significant difference between the groups was detected by the long-rank test (p = 0.03). No adverse side effect was observed. The results suggest that oral administration of BLP is useful for the prevention of the recurrence of superficial bladder cancer.

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

Localization of ferritin in testicular tumors was studied by the immunohistochemical method and the usefulness of ferritin was evaluated compared with the clinical course. Seven cases of seminoma and 9 cases of non-seminoma were used for the study. Formalin-fixed, paraffin-embedded tissue sections were stained by the avidin-biotin complex method. Commercial rabbit anti-human ferritin polyclonal antibody in 1/100 dilution was allowed to react at room temperature for one hour. In normal testicular tissues, the epithelium in germinal cells was not stained for ferritin. In seminomas, some tumor nests were stained for ferritin. Interstitial cells, especially histiocytes, were also stained for ferritin. In stained tumor cells, cytoplasm was stained uniformly. Necrotic cells were not stained. The same findings were obtained in non-seminomas. In metastatic lesions and tumor thrombi in the vessels, some tumor cells were stained as intensely as in the origin. A case was calculated positive if more than 5% of the tumor cells in the specimen were stained. The positive rate in ferritin immunostaining was significantly higher than that of human chorionic gonadotropin (beta-HCG), alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) immunostaining with the same materials. The specimens from cases with abnormally high serum ferritin level, were stained more intensely than those from cases with normal serum ferritin level. The result suggests that ferritin might be a useful tumor marker in some of testicular tumors.

We carried out a randomized multi-center study comparing cefpirome (CPR) 0.5 g b.i.d. (1 g group), 1.0 g b.i.d. (2 g group) and ceftazidime (CAZ) 1.0 g b.i.d. (CAZ group) in the treatment of complicated urinary tract infections. Patients who were over 16 years old and had underlying urinary tract disease, with bacteriuria of more than 10(4) cells ml or more and pyuria of more than 5 WBCs/hpf (x 400) or more were randomly allocated to receive either 0.5 g of CPR, 1.0 g of CPR or 1.0 g of CAZ twice a day for 5 days by intravenous drip infusion. The overall clinical efficacy of the treatment was evaluated by the criteria of the Japanese UTI Committee as excellent, moderate or poor, on the basis of the changes in pyuria and bacteriuria. A total of 530 patients were treated. Of these, 141 patients in the 1 g group, 136 in the 2 g group, and 140 in the CAZ group were evaluable for clinical efficacy. No significant differences in background characteristics were observed among the treatment groups. The overall clinical efficacy rate of the 1 g group, the 2 g group and the CAZ group was 80.1%, 76.5% and 71.4%, respectively. The differences were not statistically significant. The overall bacteriological eradication rate of the 1 g group, the 2 g group and the CAZ group was 81.0%, 88.1% and 83.8%. The differences were not statistically significant either. Against the enterococcus group, however, eradication rates were higher significantly in the 1 g and 2 g groups than in the CAZ group. The incidence of adverse reactions was 2.2% in the 1 g group, 0.6% in the 2 g group and 2.9% in the CAZ group. Abnormal laboratory data after medication were observed in 10.8% of the 1 g group, 12.1% of the 2 g group and 10.2% of the CAZ group, the difference not being statistically significant. There were no serious untoward reactions to medication. From the results obtained in this study, we consider that CPR is at least as useful as CAZ in the treatment of complicated urinary tract infections.

A randomized controlled phase III clinical trial comparing TAP-144-SR (TAP) and diethylstilbestrol diphosphate was conducted for patients with prostatic cancer. Patients with Stage B, C, or D disease, who were previously untreated, were enrolled. TAP-144-SR 3.75 mg was administered subcutaneously at 4-week intervals for 12 weeks (a total of 3 injections) in the TAP-144-SR group, while 100 mg of diethylstilbestrol diphosphate was administered orally three times a day (before meals) for 12 weeks in the control group. A total of 141 patients were enrolled using a centralized telephone registration system. Four of these patients were ineligible, and there were 3 drop-outs who never received drugs because they withdrew their consents to participate in the trial. These 7 were excluded from the evaluation, and as a result, 134 patients (66 in the TAP group and 68 in the control group) were evaluable in safety and efficacy. Between the two groups, there were no significant differences in patient characteristics, except the age distribution. Clinical response rates (CR+PR) in evaluable patients according to the criteria of Japanese Prostatic Cancer Study Group were 54.5% in the TAP group and 47.1% in the control group. In addition, the rates according to the criteria for Evaluating the Direct Response to Chemotherapy in Solid Carcinomas and NPCP criteria were 7.6% in the TAP group and 8.8% in the control group and 18.2% in the TAP group and 20.6% in the control group, respectively. Using any of the three criteria, there were no significant differences in response rate between the two groups. The incidence of side effects was 64.1% in the TAP group and 95.4% in the control group; the incidence being significantly higher in the control group (p less than 0.001; chi 2-test). Therefore, the overall safety was significantly greater in the TAP group than in the control group (p less than 0.001; chi 2-test). On the basis of the efficacy and safety the clinical usefulness rate of TAP-144-SR was significantly higher than that of diethylstilbestrol diphosphate (p = 0.038; U-test). In conclusion, TAP-144-SR was confirmed to be more useful than diethylstilbestrol diphosphate as a standard drug for hormonal therapy of prostatic cancer.

TAP-144-SR is a sustained release formulation of an LH-RH agonist, leuprorelin acetate (TAP-144), that has been newly developed in Japan. As a phase I study, a single subcutaneous dose of TAP-144-SR was given to 15 patients with prostatic cancer to investigate the safety, endocrinological effects, and serum levels of the drug. The patients were divided into four groups according to the dosage levels of 1.88 mg, 3.75mg, 7.5 mg and 15 mg. No serious side effects were noted in any of the patients treated with any dose. No patients exhibited signs of a local reaction at the site of injection. In two patients transient exacerbation of clinical symptoms owing to "flare up" was observed. Serum testosterone levels decreased to the castration level (less than 1.0 ng/ml) in all of the patients, although the time required to attain the castration level tended to be longer in the patients receiving 1.88 mg. Serum TAP-144 levels increased on the first day and gradually decreased thereafter. In the groups of patients that received 3.75 mg or more of TAP-144-SR, TAP-144 was detected in the serum up to 4 weeks after administration. Based on the results of the phase I study, 3.75 mg and 7.5 mg of TAP-144-SR were selected as the doses for the phase II study. The phase II study was carried out as a multi-center open trial. Patients with stage B-D prostatic cancer received subcutaneously either 3.75 mg (3.75 mg group) or 7.5 mg (7.5 mg group) of TAP-144-SR once every 4 weeks for a total of 3 doses over a period of 12 weeks. TAP-144-SR 3.75 mg was administered to 51 patients and 7.5 mg to 50 patients. Both of these doses were adequate to suppress serum LH and FSH levels. Serum testosterone was decreased to the castration level within 22 days after the first dose, and this suppression was maintained throughout the treatment period. Clinical response rate (CR + PR) was 21% in the 3.75 mg group and 22-24% in the 7.5 mg group according to the Criteria for Evaluating the Direct Response to Chemotherapy in Solid Carcinomas and NPCP criteria. The response rate by the criteria of Japanese Prostatic Cancer Study Group was 51% in the 3.75 mg group and 62% in the 7.5 mg group. Adverse reactions were noted in 26% of patients in the 3.75 mg group and 34% in the 7.5 mg group.(ABSTRACT TRUNCATED AT 400 WORDS)

The therapeutic utility of bunazosin hydrochloride was evaluated by a multi-center (67 hospitals) double-blind controlled study in patients who complained of voiding disturbances due to neurogenic bladder. For means of comparison, bethanechol chloride and placebo were used as reference drugs. Bunazosin hydrochloride was orally administered 1.5 mg per day for the first week and 3.0 mg per day for two weeks thereafter (Group E). Bethanechol chloride 15 mg (Group B) and placebo (Group P) were orally administered three times daily for three weeks. Three hundred and twenty-three cases were subjected to this study. The global improvement rating was analyzed for 244 cases (83 in Group E, 78 in Group B and 83 in Group P). The global utility rating (GUR) was analyzed for 252 cases (84 in Group E, 81 in Group B and 87 in Group P). Three hundred and twenty cases (107 in Group E, 104 in Group B and 109 in Group P) were analyzed with respect to overall safety rating (OSR). The global improvement ratings (excellent and good) were 32.5% in Group E, 28.2% in Group B and 21.2% in Group P. In the evaluation of GUR, Group E was superior to Group P. In addition, the incidence judged to be useless in Group E was significantly lower than that in Group B. There were no differences in OSR among these three groups. In the total evaluation of the subjective symptoms, the rates of improvement were not different among these three groups. In the total evaluation of the objective findings, the improvement rate in Group E was significantly higher than that in Group P. In addition, the deterioration rate in Group E was significantly lower than that in Group B. In objective findings before and after administration of bunazosin hydrochloride (Group E), the volume of residual urine, the rate of residual urine and the average flow rate improved significantly However, the bladder capacity, the maximum resting bladder pressure and the maximum urethral pressure did not change significantly. Bunazosin hydrochloride improved the objective findings regardless of the bladder capacity and the maximum resting bladder pressure. These significant improvements were marked in the neurogenic bladder patients who were able to urinate and in the patients whose urethral pressure was high. There were no differences in the incidence of side effects or in the appearance of abnormal values of laboratory findings in these three groups. Neither specific signs nor serious clinical side effects except those reported previously were observed.(ABSTRACT TRUNCATED AT 400 WORDS)

A recently synthesized alpha 1-blocker, (R)(-)-5-[2-[[2-(o-ethoxyphenoxy)ethyl]amino]propyl]-2- methoxybenzenesulfonamide hydrochloride (YM617), was evaluated in 270 patients with benign prostatic hypertrophy in a double-blind study. After 2 weeks on placebo the patients were assigned at random to 4 groups: group P--placebo, group L--0.1 mg., group M--0.2 mg. and group H--0.4 mg. of YM617. Comparing the placebo to the treatment period, subjective symptoms, such as nocturia and urgency, were significantly decreased in group H (p less than 0.01). The sensation of incomplete voiding was significantly improved in groups M and H (p less than 0.01). However, the differences among the groups were statistically insignificant. Residual urine volume was significantly decreased in groups L, M and H after instillation of saline into the bladder (p less than 0.01) but not in group P. The maximum and average flow rates were significantly increased in groups L, M and H (p less than 0.01) but not in group P. Average flow rate showed significant differences between groups M or H versus group P. Neither orthostatic hypotension nor a decrease in blood pressure was noted. Adverse side effects and changes in laboratory data were all slight and disappeared when the second tests were performed. In summary, the irritative and obstructive symptoms caused by benign prostatic hypertrophy were decreased and urodynamic studies were markedly improved by the alpha 1-blocker, YM617. The drug seems to be useful in the treatment of patients with benign prostatic hypertrophy.

The clinical efficacy and safety of 3.75 or 7.5 mg leuprorelin acetate depot given subcutaneously once every 4 weeks was evaluated in a collaborative study of 81 patients with untreated prostatic cancer. Efficacy of treatment was assessed using criteria based on a meeting of the Prostatic Cancer Study Group funded by the Japanese Ministry of Health and Welfare and using National Prostatic Cancer Project criteria. Japanese criteria enabled evaluation of individual parameters, unlike the National Prostatic Cancer Project system which classified a patient as unevaluable if one evaluation parameter was unavailable. Leuprorelin acetate depot suppressed serum luteinizing hormone, follicle stimulating hormone and testosterone concentrations. Objective response rates of the prostate, bone metastases, serum prostatic acid phosphatase and soft tissue metastases, and subjective dysuria and pain responses were comparable to those found with conventional hormone therapy. Leuprorelin acetate depot was well tolerated, with no significant differences in response to the two doses.

Extended surgery was divided into 4 types per below. (1) Extended local resection (1 case). Resection of descending colon and splenectomy were performed in a case with invading left renal cancer. The patient died of cancer in 9 months. Three other cases with locally invading renal cancer were inoperable because of multiple metastases or poor general condition. (2) Thrombectomy in vena cava inferior (6 cases). Successful thrombectomy was carried out in 5 of our 6 cases. All the cases died of metastases of cancer within 4 years. In the literature, long survival is reported after complete resection of thrombus. (3) Resection of distant metastases (11 cases). Palliative surgery was performed in 5 cases with symptomatic brain metastases. After radical resection of solitary metastases, 2 died of cancer, 2 are alive with cancer and the remaining 2 are alive with no evidence of disease (NED). (4) Surgery for contralateral kidney (4 cases). Partial nephrectomy or enucleation of tumor was undertaken in 3 cases (2 NED, 1 death). In the 4th case, as the tumor appeared to invade deeply in the renal parenchyma, ex vivo partial nephrectomy followed by autotransplantation was done (NED). The results indicate that the minimum requirement for radicality should be complete extirpation of the tumor mass and that the indication for radical extended surgery includes presumably resectable intracaval thrombus, solitary metastases and contralateral renal tumor.

Recently, a new antibiotic of cephamycins, cefmetazole (CMZ) has been developed. In our clinic, CMZ was used to examine its clinical effect and adverse reactions, and the results were herein reported. The CMZ was administered to 8 patients for the prevention of postoperative infections, 7 with genitourinary infections and 1 with maxillitis complicated with uremia. For these patients, a daily dose of 1 to 6 g of CMZ was intravenously given for a period of 4 to 12 days. Among the 8 patients who received CMZ for the prevention of postoperative infections, there were 1 case with urinary tract infection, 1 with wound infection and 2 with fever of over 38 degrees C, but they had no serious infections. In the clinical observations on 3 cases with pyelonephritis, the CMZ showed marked effectiveness in 2 cases and effectiveness in 1 case. It must be noted that CMZ was proved to be markedly effective for pyelonephritis caused by Serratia marcescens. In the cases with acute epididymitis and prostatitis, a good effect of CMZ was obtained. Similarly in the case with maxillitis complicated with uremia, the maxillitis was improved by the effect of CMZ and hemodialysis. No cases with hepatic or renal dysfunction were observed after using CMZ. It is concluded that satisfactory effect of CMZ was obtained clinically.

From November 1985 through September 1986, 20 cases of upper urinary tract calculi (14 kidney, 7 ureter) were treated by the one-stage procedure percutaneous nephrolithotripsy. Renal and ureteral calculi were successfully removed in all 20 cases (100%). After the procedure, a few small stone fragments remained in 3 cases (the rate of remnant stone : 14%). High fever was noted in 7 patients but did not last longer than 3 days. No patients required blood transfusion. The one-stage percutaneous procedure was considered a more efficient procedure to remove the upper urinary tract calculi, than open surgery or two stage percutaneous nephrolithotripsy. In one-stage percutaneous nephrolithotripsy, however, serum sodium concentration was lowered significantly after the procedure, although the hematocrit remained unchanged throughout. This should be carefully corrected by the supplement of irrigation fluid and intravenous infusion during the procedure.

Ultrasonically guided puncture of the prostate was carried out in 10 patients with prostatic disease. Biopsy of the aiming portion of the prostate was performed with more certainty and safety by this method than the conventional blind procedure. In the 15 cases having the suspicion of seminal vesicle disorder, the seminal vesicle was punctured under ultrasound control. By this procedure, the seminal vesicle fluid was safely and accurately obtained.

A Phase II clinical trial of a new anthracycline, (2''R)-4'-0-tetrahydropyranyladriamycin (THP), was performed in 137 patients with urological malignancies. Out of them, 111 patients were evaluated for tumor responses and 125 patients were evaluated for adverse effects. In cases of intravenous administration, overall response rate was 18.5% (22.2% for bladder cancer, 30.0% for tumors of the renal pelvis and ureter, and 6.7% for prostatic cancer). In the case of intra-arterial administration, overall response rate was 42.9% (50.0% for bladder cancer). For 50 patients with superficial bladder cancer intravesical chemotherapy with THP was performed. Sixteen patients showed complete disappearance of the tumor, 2 patients showed more than 90% tumor regression and 12 patients showed more than 50% tumor regression, respectively. Overall response rate was 60%. Cardiotoxicity was minimal. Alopecia was noted in a total of 16 patients, but this was minimal. Leukocytopenia was the major adverse effect among patients undergoing systemic THP administration. In conclusion, THP was most effective against transitional cell carcinoma of the urinary tract.

Renal autotransplantation has been a treatment of choice for renovascular hypertension, renal artery aneurysm, complicated staghorn calculi, ureteral disorders and others. The paper reports 5 cases of extensively damaged ureter and discusses the indication and the results of operation. There were three cases of postoperative extensive ureteral stricture. One patient had postoperative ureteral injury with retroperitoneal abscess. The last one showed renal foreign body calculi with recurrent pyelonephritis after ureterocutaneostomy. The postoperative course of four patients had been uneventful revealing well functioning autotransplanted kidneys without hydronephrosis and infection during the follow-up period of 22 to 42 months. However, the patient with the ureteral injury and retroperitoneal abscess died of bleeding from renal vein anastomosis on the 15th postoperative day, since the renal pedicle showed marked inflammatory change including renal vein wall. Subsequently, autotransplantation is contraindicated in the cases with marked inflammation in the renal pedicle. In cases of various other ureteral lesions including long distance ureteral stricture, this procedure is recommended when neither the end to side ureteral anastomosis, Boari's bladder flap operation nor bladder hitch operation is feasible.

Allylestrenol at the daily dose of 50 mg was administered to 45 patients with benign prostatic hypertrophy. The treatment was performed for more than 12 weeks in 40 patients, and improvements, marked and moderate, were observed in 22 patients (55%) in the overall judgement. As side effects of this drug, decrease of potency was observed in 3 cases, decrease of libido in 1 case, pigmentation on breasts in 2 cases, palpitation in 2 cases, short breath in 1 case, and gastrointestinal symptoms in 1 case. However, these side effects were not serious. Our trial suggests that the treatment of benign prostatic hypertrophy with allylestrenol can be useful in urological clinics.

Since the adrenal or parathyroid cancer is a clinically rare entity. We often have difficulty in its diagnosis and treatment. The adrenocortical cancer is usually classified into two categories--endocrinologically functioning or non-functioning. The incidence is not different between them. It is often found in an advanced stage as it does not show clinical manifestation before it has grown up to a large tumor. Only an effective agent for the adrenal cancer is op'-DDD so far. Recently, cisplatin, VP-16 (etoposide) and others are administered as trial use. Most of malignant pheochromocytomas are endocrinologically active and they often cause hypertension leading to death. Therefore it is important to control hypertension in malignant pheochromocytoma. Chemotherapy and irradiation are not effective for it. Recently, 131I-MIBG (metaiodobenzylguanidine) is found to be useful not only for diagnosis but also treatment of malignant pheochromocytoma. 131I-MIBG is accumulated specifically in the chromaffin cells and with helpful to find out metastatic foci. It is also used in a large amount as a specific irradiation therapy for this malignancy. Parathyroid cancer is found in approximately 3 percent of primary hyperparathyroidism. Clinically it usually reveal serum calcium level higher than 14 mg/dl, bone lesions and renal dysfunction in addition to palpable cervical tumors adhering with skin. Sometimes it is difficult to differentiate malignancy from adenoma in histology. Most cases develop local recurrences and distant metastases in due course and dies of hypercalcemia. It is very important to control hypercalcemia in inoperable cases. As both chemotherapy and radiation therapy render no effect on this malignancy. Surgery is a sole strategy for it.