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A 1280×960 floating diffusion storage global shutter image sensor is implemented in a 3D stacked back illuminated indirect time of flight sensor (iToF). The sensor, achieves 18,000e- full well capacity and 32% quantum efficiency (QE) with a pyramid surface for diffraction (PSD) structure [1], utilizing a 3.5µm pixel. Low power consumption is also achieved, due to low leakage current for the iToF pixel and low resistance Cu-Cu connection metal wiring. These device architectures enable high resolution and wide dynamic range 3D depth sensing for both near and far objects.

The recommended treatment for medically fit patients with muscle-invading bladder cancer is usually radical cystectomy. However, transurethral resection of the tumor, partial cystectomy, irradiation and systemic chemotherapy are each effective in some patients. These latter treatments allow bladder preservation and cure as an alternative to radical cystectomy although when used unselectively the survival rates are inferior to those of radical cystectomy. The updated results of conservative surgery, radiation therapy and systemic chemotherapy as monotherapy, as well as strategies of combined modality treatment were reviewed. Based on this review many areas of consensus were reached which include: 1. The primary goal of any treatment for a patient with muscle-invading bladder cancer is survival; bladder preservation in the interest of quality of life is a secondary objective. 2. Only a small proportion of carefully selected patients may be cured by transurethral surgery alone, or by partial cystectomy alone. 3. Radiation therapy is currently the standard bladder-preserving therapy against which all other bladder-preserving methods must be compared. 4. Systemic chemotherapy as monotherapy is inadequate and cannot be recommended. 5. The addition of cisplatin-containing systemic chemotherapy to radiation therapy or conservative surgery appears to improve local control. While no multi-modality therapeutic regimen has yet been shown to be clearly optimal with regard to local efficacy and minimizing toxicity, monotherapy for bladder preservation is probably not desirable as a routine approach. 6. Deferring the patient from immediate cystectomy does not appear to compromise survival, nor does the addition of primary systemic chemotherapy appear to significantly increase the morbidity of cystectomy or radiotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

To examine the precise localization of lysosomal cysteine proteinases, cathepsins B, H, and L in rat epididymal epithelial cells, immunohistochemistry and enzyme assay were applied to the epididymal tissue. Granular immunodeposits for cathepsins B and H were detected in epididymal epithelial cells, whereas faint or no immunoreactivity for cathepsin L was found. Moreover, immunoreactivity for cathepsin B appeared mainly in principal cells and was more intense in the head of the epididymis than in the tail, whereas that for cathepsin H appeared in both principal and clear cells and was more intense in the tail than the head. By enzyme assay, activities of cathepsins B and H showed a similar distribution to that of the immunoreactivity. The cathepsin L-specific activity was distributed evenly in each part of the epididymis and was also detected in epididymal fluids obtained from the body and tail parts. By immunoblotting, proforms of cathepsins B, H, and L were present in the seminal fluid. The results suggest that cathepsins B and H are involved in the intracellular degradation system of epididymal epithelial cells, and proforms of cathepsins B, H, and L may be secreted into the epididymal duct lumen.

A new bisphosphonate, disodium dihydrogen (cycloheptylamino) methylene bisphosphonate monohydrate (YM175), was compared with 3-amino-1-hydroxypropylidene-1, 1-bisphosphonate (AHPrBP) and 1-hydroxyethylidene-1,1-bisphosphonate (HEBP) in terms of its effect on tumour induced osteolysis using a bladder tumour in mice (MBT-2). The method consisted of inoculating tumour cells subcutaneously (SC) over the calvaria in mice, resulting in a local tumour causing fragmentation of the bone. The compounds were active not only when administered preventively before establishment of bone resorption, but also in an inhibitory fashion once the variables were already under the influence of the tumour. This osteolysis was evaluated by measuring the increased area of bone resorption in reduced opacity to radiograph and histology. The results showed the following sequence of potency: YM175 > AHPrBP = HEBP. This inhibition was obtained with no apparent effect on the growth of the MBT-2 tumour. YM175 appears to be an interesting new bisphosphonate with possible clinical application. Images Figure 1

Histopathological characteristics of stage A prostatic adenocarcinoma from Japan (137 cases) and the United States (51 cases) were comparatively evaluated by retrospective analysis. All cases were examined by one referee pathologist (MH) using classification based on Japanese General Rules for Prostatic Cancer (JGRPC), nuclear grading by Mostofi-WHO system and Gleason grading. The incidences of the cases with well differentiated, low nuclear anaplasia and Gleason grade 1 or 2 on primary and secondary grades as well as histologic score 2-4 were much more higher in the cases from Japan as compared with those from the US. In the cases from the US proportion of the cases with moderately differentiated adenocarcinoma and grade 2 nuclear anaplasia exceeded those with well differentiated and grade 1 anaplasia. Adenocarcinomas with Gleason grade 3 in primary and secondary grade and 6-8 of histologic score were also more frequently observed in the cases from the US. No different distribution of each histologic grade could be obtained among the Japanese cases classified stage A2 and entire cases from the US. These results suggest that much more stage A adenocarcinoma in the US might fall into A2 if strict criteria was applied for subcalssification of stage A, which may reflected in the remarkable difference in the incidence of clinical prostatic carcinoma.

First, we will describe the concept and implementation issues of our "Dynamically Extendible Museum", a system which enables the users to create their favorite virtual spaces dynamically and incrementally from databases in order to present the objects retrieved by the user's queries. Second, we propose a mechanism to incrementally formulate user's query by letting the user select objects in a virtual space. We also discuss implementation issues of our prototype systems using museum metaphors to demonstrate our ideas.

The authors propose the idea of associating and presenting metadata (attribute information) of digital archive objects in a virtual space. In the presentation using a virtual space, we introduce two methods. One is called InfoLOD, which dynamically associates and controls metadata (attribute information) with archive objects (2D/3D images) in the 3D space. We propose to control the level of detail (LOD) of attribute information based on orientation and distance. We extend this idea to control the LOD of hierarchically-described metadata (such as XML data) based on distance, orientation, and differentiation. LOD control based on differentiation compares the hierarchical data of spatial objects visible from one's viewpoint in 3D space, and presents the dissimilarities in the objects having similar data. The other method is called passive viewing, and it realizes users to watch and listen automatic presentation of 3D objects and their metadata. Some of our implementations are shown to illustrate our ideas.

Pharmacodynamics (PD), anti-tumor effects, safety and pharmacokinetics of a 3-month formulation of goserelin (Zoladex LA 10.8 mg depot: "10.8 mg depot") were investigated in a collaborative multicenter study. Study participants were 40 Japanese patients with prostate cancer comprising 20 untreated patients and 20 switch patients who had been receiving Zoladex 3.6 mg depot for 3 months or longer. Serum testosterone levels, serum LH levels, prostate-specific antigen (PSA) levels and drug concentrations were measured until 12 weeks after a single subcutaneous dose of 10.8 mg depot. Anti-tumor effects were evaluated by means of changes in the tumor lesions and the PSA levels at 12 weeks. After administration to the untreated patients, 10.8 mg depot reduced serum testosterone to the castrate range within 4 weeks and the reduction was maintained for up to 12 weeks. In the switch patients, serum testosterone suppression that had been produced by previous treatment with Zoladex 3.6 mg depot was maintained for up to 12 weeks following 10.8 mg depot administration. The anti-tumor effect at 12 weeks was 90.0% including partial response cases. The ratio of PSA normalization at 12 weeks was 75.0%. Fifty-seven adverse reactions were observed in 27 of the 40 patients (67.5%), but none were clinically significant. Although a disease flare presented as urinary retention in 1 of the untreated patients, all patients completed the study. Serum goserelin was detected up to 12 weeks after the administration of 10.8 mg depot. In conclusion a single dose of 10.8 mg depot showed a satisfactory PD-effect and brought about clinical efficacy persisting for at least 12 weeks and was well tolerated in patients with prostate cancer.

This study was conducted to examine the efficacy of administration of tamsulosin hydrochloride alone or in combination with chlormadinone acetate (CMA) against lower urinary tract symptoms for a period of 52 weeks in 33 patients with benign prostatic hyperplasia. The patients were randomly allocated into a group administered tamsulosin alone and a group administered tamsulosin in combination with CMA. Based on the assessment of the total I-PSS (International Prostate Symptom Score), significant symptomatic improvement was noted 4 weeks after the commencement of drug administration in the tamsulosin + CMA group, whereas no significant improvement was observed in the tamsulosin group. Both irritative and obstructive bladder symptoms improved significantly at any time of assessment after 4 weeks of drug administration in the tamsulosin + CMA group; however, significant improvement was noted only at week 16 and week 52 for irritative symptoms and at week 16 for obstructive symptoms in the tamsulosin group. In particular, obstructive symptoms showed significant improvement at week 4 in the tamsulosin + CMA group, as compared with that in the tamsulosin group. The average value of peak urinary flow rate was significantly increased in the tamsulosin + CMA group (10.4 ml/s to 15.6 ml/s) as compared with that in the tamsulosin group (8.5 ml/s to 10.5 ml/s). These findings indicate that combined administration of tamsulosin and CMA resulted in early improvement of lower urinary tract symptoms in these patients. Long-term combined administration of tamsulosin and CMA thus appears to be a promising treatment strategy for the improvement of obstructive symptoms and peak urinary flow rate, particularly, 16 weeks onward after administration in patients with benign prostatic hyperplasia.

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 prospective randomized joint study was conducted to evaluate the usefulness of UFT 1) as a postoperative adjuvant therapy in patients with invasive bladder cancer who had undergone curative combination therapy with operation and/or chemotherapy and/or radiation therapy, 2) as an endocrine chemotherapy in patients with newly diagnosed stage C/D prostate cancer, for a period of 3 years from January, 1992. For bladder cancer, of 36 patients with invasive bladder cancer, clinically cured by combination therapy, 20 patients were treated with UFT as an adjuvant chemotherapy over 12 months, and they were compared to 16 patients with no adjuvant therapy. After excluding 10 inappropriate patients, 12 patients in the UFT treatment group and 14 patients with no adjuvant treatment group were observed. For prostate cancer, of 29 patients with clinically stage C/D prostate cancer, 13 were treated with endocrine therapy in combination with UFT, and 16 patients were treated with endocrine therapy alone. After excluding 7 inappropriate patients, 10 patients with endocrine chemotherapy and 12 patients with hormonal therapy were observed. The non-recurrence rate, survival rate and side effects of UFT were evaluated. In the study of bladder cancer, neither a significant difference of non-recurrent rate nor of survival rate was seen between the two groups. In the study of prostate cancer, neither a significant difference of non-recurrent rate nor of survival rate was seen between the two groups. These findings suggest UFT is less useful as an adjuvant therapy for the invasive bladder cancer and as an endocrine chemotherapy for newly diagnosed advanced prostate cancer.

The BTA test is a latex agglutination assay for the qualitative detection in the urine of analytes that are associated with bladder tumor. We compared the results of the BTA test with those of voided urine cytology (VUC) in patients with bladder cancer.A multicenter trial was performed at 6 institutions. A total of 132 patients with histologically diagnosed bladder cancer were enrolled. Urine samples were split for BTA and VUC testing.The sensitivities of the BTA test and VUC were 57.6% and 37.9%, respectively; this difference was significant (P0.001). The BTA test had much higher sensitivity for small, solitary, superficial tumors than did VUC.The BTA test is simple to perform, gives rapid results, and is far more sensitive than VUC for detection of bladder cancer. The BTA test has the potential to become an additional tool for detecting bladder cancer.

This study was undertaken to determine the clinical usefulness of NMP22 (Nuclear Matrix Protein 22) as a urinary marker for the screening of urothelial cancer in patients with microscopic hematuria, especially in comparison with that of voided urine cytology. Urinary NMP22 values were determined for 183 patients with microscopic hematuria by use of a UNMP22 Test kit, which is based on an enzyme-linked immunosorbent assay. All patients were entered in this study before cystoscopy was performed, and were evaluated for NMP22 values and voided urine cytology simultaneously from the same urine samples. Of the 183 patients with microscopic hematuria, 14 cases of urothelial cancer were detected. For the other cases, 65 were of benign diseases and 104 were designated NED (No Evidence of Disease). The median NMP22 values for urothelial cancer, benign diseases, and NED were 26.5 U/ml (95% CI: 18.5-228.2; 4.9 U/ml (95% CI: 3.6-8.3), and 5.9 U/ml (95% CI: 4.8-6.5), respectively. The urinary NMP22 value for urothelial cancer was significantly higher than for benign diseases and NED. When the cut-off value of urinary NMP22 was set at 12 U/ml, the positive rate of NMP22 for urothelial cancer was 85.7%, significantly higher than the 50% positive rate by voided urine cytology. This study indicates that urinary NMP22 is a useful tool for the screening of urothelial cancer in patients with microscopic hematuria.

This study was undertaken to determine the clinical usefulness of NMP22 (Nuclear Matrix Protein 22) as a urinary marker for the surveillance of bladder cancer, especially in comparison with that of voided urine cytology. Urinary NMP22 values were determined for 144 patients with histologically diagnosed bladder cancer, 65 patients with other urological cancers, and 171 healthy volunteers by use of a UNMP22 Test kit, which is based on an enzyme-linked immunosorbent assay. All bladder cancer patients were evaluated for urinary NMP22 values and voided urine cytology simultaneously from the same urine samples. Based on the data from the bladder cancer patients and the healthy volunteers, the cut-off value was set at 12 U/ml. The median urinary NMP22 value for the bladder cancer patients was 17.8 U/ml (95% CI: 13.1-29.0). The sensitivities of urinary NMP22 and voided urine cytology were 61.1% (88/144) and 33.8% (48/144), respectively, a significant difference (p0.00001). Multivariate analysis revealed that tumor size affected the urinary NMP22 values. The positive rate by tumor size was 42.3%, 59.1%, and 85.0% for tumors of10 mm, 10-30 mm, and30 mm, respectively. Urinary NMP22 values decreased postoperatively in 82.9% of the patients. The median NMP22 values for prostate cancer and renal cancer were 4.4 U/ml (95% CI: 2.2-6.7) and 6.2 U/ml (95% CI: 3.6-12.5). The positive rates were 24.2% and 31.3%, respectively, both of which were significantly lower than for bladder cancer. Our multicenter study indicates that urinary NMP22 test is more sensitive than voided urine cytology test for the surveillance of bladder cancer.

Loss of E-cadherin-mediated adhesion is an important step in the progression of many carcinomas. In model systems, it has been shown that cadherin function requires not only proper E-cadherin expression but also its linkage to the cytoskeleton through catenins. Hence, defects in catenins may cause defective E-cadherin function, and catenins as well as E-cadherin might constitute prognostic indicators. Here, we extend our previous study on E-cadherin in bladder cancer (Cancer Res., 53: 3241-3245, 1993). We have evaluated the expression of E-cadherin-associated cytoplasmic molecules (alpha-, beta-, and gamma-catenins and p120cas) to clarify whether or not the pattern of their expression could provide additional prognostic information beyond that from E-cadherin alone. Forty-eight frozen bladder tumor specimens and 9 samples of normal urothelium were studied by immunohistochemistry. A discrepancy between the E-cadherin and catenin expression pattern was seen in 20.8% of cases. Abnormal expression of each molecule is significantly correlated with tumor grade (P0.01) and stage (P0.01). Reduced expression of all of the molecules correlates with poor survival (P0.01 for each variable). Proportional hazard regression analysis showed that beta-catenin, E-cadherin, and alpha-catenin have strong predictive value, whereas plakoglobin and p120cas have a somewhat lower predictive value. Within patients with invasive tumors, those with a normal staining for either E-cadherin, alpha-catenin, or beta-catenin show a trend toward better survival. However, the difference in survival is significant only for E-cadherin (P0.05). Thus, beta-catenin, E-cadherin, and alpha-catenin have similar prognostic values. Therefore, from a practical point of view, the expression of any of these proteins can be of prognostic value for patients with bladder cancer.

We performed mass screening for prostate diseases in the village of Satomi-mura, in Ibaraki Prefecture for males between 40 and 79 years old (participation rate; 21%). The findings were compared to those obtained by mass screening in the village of Shimamaki-mura, in Hokkaido Prefecture, conducted by the same examiners in a consistent manner (participation rate; 47%). When we considered the difference in biopsy rates between the two sites, the detection rate of prostate cancer in Satomi-mura was similar to that in Shimamaki-mura. There were no apparent differences in distribution of prostate volume, the International Prostate Symptom Score (I-PSS) and maximum flow rate between the two sites for each 10-year-age group. Our findings suggested that there was little site difference in the detection rate of prostate cancer and voiding condition between the two villages.

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.

A cross-over clinical trial was carried out to compare the antiemetic effect and safety between granisetron alone (40 micrograms/kg) and the combination of granisetron and methylprednisolone (MP: 10 mg/kg) in urological cancer patients treated with cisplatin. Forty-eight courses were given with granisetron alone and 47 courses with both granisetron and MP. The antiemetic effect of nausea and vomiting was evaluated in the acute emetic phase. during the 24 hours following the CDDP administration, and in the delayed emetic phase, 2 to 7 days after the administration. Combination therapy of granisetron and MP demonstrated a greater antiemetic effect during the 72 hours following the CDDP administration than by granisetron alone. But there was no significant difference in antiemetic effect between combination therapy and granisetron alone after the 3rd day. Combination therapy also demonstrated more efficacy in complete antiemetic effect, with no emesis and less than moderate nausea, than by granisetron alone. Both treatments showed no side effects and were safe.

Evaluation of prognostic significance of nucleolar organizer regions (NORs) in renal cell carcinoma (RCC).Nuclear organizer regions were quantified in a series of 59 cases of RCC by the silver colloid method, and the NOR index was obtained from the ratio between mean NOR counts in each neoplastic nucleus and in normal nucleus. The patients were staged pathologically and divided into 2 groups by average NOR index of all cases, which was 0.76. Correlations between the NOR index and other parameters were statistically analyzed, and the prognostic value of the NOR index was also examined.The NOR indices from each group were correlated with the survival curve. In low stage tumors (pT1 or 2 N0M0), the low NOR index group had a survival rate of almost 100 per cent while in those patients with higher NOR indices, there was a significantly increased mortality (p0.01). In patients presenting with high stage tumors (excluding pT1 and 2 N0M0), the survival rate was significantly improved in those patients with a low NOR index (p0.01). On the other hand, the patients with a low NOR index have a better prognosis than those with a high NOR index within each tumor grade (p0.01). Statistical analysis by the log rank test indicated NORs to be a significant predictor of survival over the whole series within low and high pathological stages and within each tumor grade. Analysis of the data with Cox's proportional hazard model showed that NOR index had a stronger hazard ratio than grade or stage of tumor (p = 0.0005).Our study has demonstrated that NOR index is a new prognostic indicator for patients with RCC (p = 0.0005).

Because treatment of testicular cancer has improved dramatically during the past 15 years, about 70% of the patients can be relieved of this disease today. Although this can be attributed to the availability of various tumor markers, better imaging diagnosis and improvement of surgical techniques, the improvement of chemotherapy, mainly based on cisplatin, has made the largest contribution. Hopefully, more powerful chemotherapy regimens will be available for patients who fail to respond to primary chemotherapy or relapse within a short period after primary chemotherapy. Supportive therapy, such as bone marrow transplantation, will serve to enhance the treatment for testicular cancer. On the other hand, milder therapy will given, if it is determined sufficient to treat the patient with an excellent response to the present therapeutic regimen. In the future, more therapeutic regimens will be prescribed to meet the exact needs of individual patients according to their prognoses.

We examined nucleolar organizer region (NOR) indices on 13 bladder tumors on both squash-prepared specimens and paraffin embedded specimens stained by silver-colloid method. It was noted that; 1. The nuclear size was enlarged by squashing, 2. Aggregated NOR dots were dispersed, 3. Uniformity of microscopic phase of the dots was obtained, 4. Squash specimens had more precise countabilities than the paraffin embedded sections for avoidance of nuclear resection. NOR indices (mean +/- S.D.) of those bladder tumors on squash-preparation and paraffin section were 8.64 +/- 4.32 and 6.13 +/- 1.58, respectively, and the former showed good correlation with the tumor stage. When we prepare the squashed specimen from the surgically resected bladder tumor tissue, embedding and sectioning processes which are inevitable for preparation of paraffin embedded section, could be eliminated. Thus, squash-smear technique was considered to be better than the method using paraffin embedded section on the point of shorter duration of examination and accurate countability of the NOR dots.

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.

Combination effect of UFT and leucovorin against the rat prostatic carcinoma (R-3327) was evaluated by the subrenal capsular assay (SRCA) using nude mice. Anticancer effect of UFT was augmented by co-administration of both low and high dose leucovorin. These results suggest a clinical usefulness of UFT administration with leucovorin for the patients with hormonally refractory advanced prostatic carcinoma.

The number of elderly patients with urological cancer is increasing, and it is becoming very difficult for urologists to decide on an appropriate treatment modality for each patient. Physical and socioeconomical problems make it impossible for the patients to accept a standard treatment for their disease. Between 1987 and 1992, 498 patients with urological cancer were hospitalized in our institute. Among them, 51 patients (10%) were 80 years of age or older. The average age of these older patients was 83.2 (80-93) years. There were 41 men, and 10 women. These older patients included 30 with bladder cancer, 15 with prostate cancer, three with renal cancer, and three with renal pelvic and ureteral cancer. The incidence of patients aged 80 or older was 18.5% for prostate cancer and 15.9% for bladder cancer. Eighty percent of these patients had complications such as cardiovascular disease, and fewer patients could be adapted treatment because of their physical condition. The median survival period was 21.6 months, with only 18 of the patients still living at the time of the analysis. Only 11 of the initial 51 patients (22%) still received follow-up treatment in the outpatient clinic of our institute, 10 of whom were lost during the follow-up. Our observations indicate that we should consider both the medical aspects and quality of life when we choose the suitable type of treatment.

For management of muscle-invading bladder cancer (clinical stages T2 to T4), combined treatment of definitive radiotherapy (RT) and intraarterial (IA) administration of chemotherapy was carried out for local cure and bladder preservation.Between 1987 and 1990, a pilot study (Protocol-1) was initially conducted in 16 patients to investigate the efficacy of chemoradiotherapy where RT was combined with TURB and continuous IA infusion of cisplatin. We then performed a regimen of possible bladder-preservation treatment (Protocol-2) in which 19 patients were treated with combination of TURB, full-dose RT and one-shot IA infusion of cisplatin and methotrexate. In RT small pelvis irradiation was performed with x-rays followed by proton beam boost irradiation to the original tumor site.Among patients treated on Protocol-1, a tumor-free bladder was observed in 50% (2/4) after 50-76 Gy but only 8% (1/14) after 30-40 Gy. In this regimen, planned cystectomy was performed in 10 patients and 13 patients (81%) are alive. Among 19 patients treated on Protocol-2, 17 patients (89%) are alive and 13 patients (68%) retained intact bladders without any recurrence. There were 3 cystectomies performed because of persistent tumors. Using a conformal mode of proton beam irradiation, a total dose of 60-80 Gy was safely administered with acceptable morbidities.In the light of good complete response and survival rates achieved in the patients treated on Protocol-2, the combined treatment of definitive RT and IA administration of chemotherapy is considered as an effective bladder-preserving strategy.

Two cases of Fibroepithelial polyp in 47-and 74-year-old males complaining of gross hematuria are described. In the foreign literature, this polyp most commonly occurs in infancy and childhood in the first decade of life, but rarely occurs in aged male. Ten cases of this disease could be accumulated in the Japanese literatures, in which this polyp more commonly occurs in older generation compared with younger one. Urethral polyp should be considered in the differential diagnosis of gross hematuria.

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

A 40-year-old man was admitted to our hospital with a fat-density extrarenal tumor and intrarenal nodules which were detected by ultrasonography (US) and CT scan obtained the general health check. After his admission, US, CT, MRI and angiography were performed. As the final diagnostic procedure, we performed a US-guided percutaneous needle biopsy of the extrarenal tumor, because this tumor was difficult to distinguish from liposarcoma and angiomyolipoma (AML). The pathological study revealed a well-differentiated liposarcoma, and the extrarenal tumor and the left kidney were removed en bloc. Pathologically, the tumor not only invaded into the renal parenchyma directly but also have metastasized independently to the intrarenal region. Postoperatively, he received a tumor dose of irradiation of 50 Gy. Liposarcoma arising in the perirenal space should be considered in the differential diagnosis of exophytic AML. If radiological studies can not confirm the appropriate diagnosis, we consider that biopsy of the tumor should be selected as an alternative diagnostic approach. And, we think that this is the first case report dealing with intrarenal metastases of liposarcoma.

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.

Two cases of prostatic cancer accompanied by monoclonal gammopathy of undetermined significance (MGUS) are reported. Both cases presented IgG-lambda type hyperimmunoglobulinemia and Bence Jones protein (BJP) in the urine. A characteristic of both cases was significant multiple bone metastasis, and one case also demonstrated a severe immunological disorder. During the treatment, one patient recovered from MGUS. We recommend that elderly male patients manifesting MGUS be examined for prostatic cancer.

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.

Combination effect of UFT and CDDP against the rat prostatic carcinoma (R3327) was evaluated by the subrenal capsule assay in nude mice. The tumor growth of R3327 was inhibited in proportion to the UFT concentration. Anticancer effect of UFT was elevated by co-administration of CDDP. These data suggest a clinical usefulness of UFT administration with CDDP for hormonally refractory advanced prostatic carcinoma.

To avoid confusion between serum prostate-specific antigen (PSA) values among various assay systems, clinical studies on the possibility of conversion among detection values were performed. The assay kits used for the PSA comparisons were MARKIT-F PA, MARKIT-M PA, EIKEN PA, PA test WAKO, Ball ELSA PSA, E-Test Tosoh II PA, PROS-CHECK PSA, DELFIA PSA and TANDEM-R PSA. Using each kit, the standards attached to each assay system were detected, and 142 sera samples from benign hypertrophies or prostate cancers were assayed for serum PSA values. By detecting the standards for each kit, slopes were obtained which were almost identical to those obtained from original assay system. The coefficients of correlation among the PSA detection systems, using patients' sera, were very high, and linear regression lines were also obtained. The results suggest that almost identical serum PSA values may be detected either by multiplying by a coefficient to bring it to the standard or using the conversion formula.

The combination therapy with natural type human tumor necrosis factor (n-TNF; MHR-24) and human lymphoblastoid interferon-alpha (n-IFN-alpha; MOR-22) was investigated for antitumor effect against renal cell carcinoma in a multiclinic cooperative study throughout Japan. The "Response criteria of Japan Society for Cancer Therapy" were followed for the handling of subjects and the evaluation of antitumor effect. MHR-24 was administered at a daily dosage of 5,000-10,000 JRU by intravenous drip and MOR-22 at a dosage of 5,000,000 IU daily was administered intramuscularly at the same time. Both drugs were administered for 4 weeks or longer. A total of 36 patients were enrolled as subjects in the study. None of them were classified as ineligible. Five patients, were classified as imperfectly evaluable, and 31, as evaluable for the results of treatment. The responses in the evaluable patients were partial response (PR) in 4 patients, minor response (MR) in 3 patients, no change (NC) in 14 patients and progressive disease (PD) in 10 patients, with a response rate of 12.9%. Adverse reactions to the therapy were investigated in all 36 patients. The frequent subjective and objective reactions that occurred were fever, rigors and shivering, anorexia, and generalized malaise, and the frequent abnormal laboratory findings were leukopenia, thrombocytopenia, elevation of GOT, and elevation of GPT.

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.

To identify the specific regulatory mechanism associated with the events following unilateral nephrectomy, we measured the levels of mRNA encoding for extracellular matrix (ECM) constituents, for protooncogenes, and for proliferating cell nuclear antigen (PCNA) in renal cortex and glomeruli. One hour after left nephrectomy, c-jun and c-fos mRNA levels in renal cortex increased rapidly and then decreased rapidly to the control level, whereas c-myc and PCNA mRNA levels showed a slower and more sustained increase, with a peak at 6 h after nephrectomy, and then decreased to the control level after 7 days. mRNA levels for basement membrane components including alpha 1-chain of type IV collagen, laminin B1 and B2 chains, and heparan sulfate proteoglycan core protein were significantly increased in renal cortex at 12 h after nephrectomy, whereas those for interstitial collagens including alpha 1-chains of type I and type III collagen were unchanged following nephrectomy. On the other hand, the glomerular expression of all genes examined in this study showed little change during the experimental period. These results suggest that the time course of mRNA expression of ECM constituents is different from that of growth-related proteins in renal cortex and that glomerular mRNA levels for these components may not be associated with renal hypertrophy in the early stages following unilateral nephrectomy.

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)