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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.

Objectives: This study was undertaken to determine the clinical usefulness of nuclear matrix protein 22 (NMP22) as a novel urine marker for urothelial cancer, particularly, to substitute for voided-urine cytology., Methods: NMP22 values were determined for 280 patients and 20 healthy volunteers by NMP22 Test Kit based on an enzyme-linked immunosorbent assay., Results: When the cut-off value was set at 10 U/ml, the positive rate of urinary NMP22 for urothelial cancer was 80.9% (38/47), whereas that for posttreatment cases and benign diseases was 35.7% (74/207). When urinary NMP22 and voided-urine cytology were compared, the test for urinary NMP22 showed higher sensitivity than cytology in patients with urothelial cancer. When urinary NMP22 values were determined pre- and postoperatively in patients with urothelial cancer, the postoperative value decreased in all patients, and were below the cut-off value in all except one patient., Conclusions: Urinary NMP22 is a useful diagnostic marker as a substitute for voided-urine cytology for the surveillance of urothelial cancer.

Between July 1991 and December 1994 at Tsukuba Gakuen Hospital, we treated 19 consecutive men with advanced adenocarcinoma of the prostate (five at stage C, four at stage D1 and 10 at stage D2). Of these, 14 patients underwent castration (two patients) or received LH-RH analogue (12 patients) plus chlormadinone acetate for combined androgen blockade. We report three representative cases of sequential prostate specific antigen (PSA) elevation following initial response to this combined androgen blockade. Discontinuation of chlormadinone acetate resulted in decline of the serum PSA level. This suggests that trial chlormadinone acetate withdrawal in patients showing increasing levels of PSA during combined androgen blockade should be considered before initiation of alternative treatment.

M-VAC therapy (methotrexate, vinblastine, Adriamycin, and cisplatin) has improved the treatment results of urothelial cancer patients. However, it is sometimes complicated by drug toxicities, including bone marrow suppression. We analyzed the relative dose intensity in each patient undergoing M-VAC chemotherapy in relation to the chemotherapeutic effect and survival. In addition, the role of granulocyte colony-stimulating factor (G-CSF) in the dose intensity of M-VAC therapy was analyzed. Between June 1988 and March 1993, 29 patients with advanced urothelial cancer were treated with M-VAC therapy in our institution. Of 18 patients with evaluable lesions, 2 (11.1%) showed a complete response (CR) and 7 (38.9%) showed a partial response (PR), and the overall response rate was 50.0%. The median follow-up period for these 18 patients was 14.6 months and the median survival was 8.7 months, with 12 of the 18 patients being alive at the time of analysis. The relative dose intensity (RDI) for these 18 patients was 0.81 for methotrexate, 0.80 for vinblastine, 0.92 for Adriamycin, and 0.91 for cisplatin, for a mean RDI of 0.87. There was no correlation between the chemotherapeutic effect and the RDI. When we calculated the RDI for all 29 patients who underwent M-VAC therapy, G-CSF increased the RDI of Adriamycin significantly. The results of this retrospective study indicate that a dose intensity for M-VAC therapy in the range of 0.61-1.00 is unlikely to correlate with the chemotherapeutic effect, although G-CSF contributes to increasing the RDI of Adriamycin.

It has been shown that molecular cytogenetics in interphase nuclei is applicable to paraffin embedded sections from formarin-fixed materials utilizing in situ hybridization (ISH). This allows precise identification of numerical abnormalities of chromosome in tumor cells without disruption of tumor morphology. Thirteen cases of bladder cancer and twenty six cases of prostate adenocarcinoma were evaluated for numerical aberrations of chromosome 1, 7, 10, 11, 17, 18, X and Y utilizing biotinylated probes specific for the alpha satellite region. In two cases from total prostatectomy, one case from total cystectomy and two cases from TUR-P specimen, hybridized chromosomes could not be detected in individual tumor cells. With respect to the appearance of the ISH signal, optical concentration and time for the digestion enzyme has to be established essentially. This technique can now be applied on the detection of biological activity in various types of urological cancer.

Histopathological comparison of clinical prostatic adenocarcinoma between Japan and the United States (US) has been made with retrospective analyses on 1,037 and 987 cases, respectively. All cases were histologically evaluated by the same pathologist (M.H.) without previous knowledge of clinical information according to application of the Japanese General Rules for Prostatic Cancer (JGRPC) based on the predominant degree of histological differentiation, the nuclear grading by WHO classification and the Gleason grading systems. The age distribution of the patients was slightly different among both groups. However, this difference appeared not to be essential, because there existed difference of the date on diagnosis between two groups. Even though considering this time difference on registration, much more cases from Japan had stage D disease. The observed incidence of the histological differentiation classified by JGRPC among over-all cases did not show significant difference, however, the incidence among the cases with same stage between two groups differed with some statistical significance. Much more cases from the US fell in well differentiated adenocarcinoma and frequency of moderately differentiated adenocarcinoma was higher in the Japanese even in the cases diagnosed at advanced stages. The observed incidence of nuclear grade 3 was also higher in the Japanese. Gleason primary and secondary grade 5 and score 9-10 appeared more frequently in the cases from Japan.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

Tissue specimens from 12 patients with adenocarcinoma of the prostate and 7 patients with benign prostate hypertrophy were stained by an indirect immunoperoxidase method using antiproliferating cell nuclear antigen (PCNA) monoclonal antibody. The PCNA labeling index was determined by counting the number of PCNA-labeled cells in the tissue sections. Average PCNA labeling index of the benign prostate hypertrophy was 1.2 +/- 0.5%. Poorly differentiated tumors averaged 7.6 +/- 3.9% labeling versus 4.6 +/- 1.3% in moderately differentiated tumors, and well differentiated tumor in the series had a PCNA labeling index of 2.5 +/- 0.9%. The PCNA labeling indices for atypical hyperplasia were 1.9, and 4.1%, respectively. Our preliminary results suggest that the measurement of PCNA labeling index in prostate cancer may prove to be a new objective and quantitative assay of biological potential of individual tumor.

A total of 75 prostate cancer and 67 lung cancer patients with positive bone scintigrams were studied. The patterns of spread in the axial skeleton and pelvis were different between the groups. The differences in the distribution of bony metastases between prostate and lung are explained by the role of Batson's vertebral venous plexus. We developed an animal model of spinal bone metastasis to prove this route. As suspension of tumor cells was injected into the tail vein of mice with vena caval occlusion. This procedure reproducibly resulted in metastatic tumor growth in the lumbar region of the vertebral column. The prevalence of spinal bone metastasis is attributed to passage of tumor cells via the vertebral venous plexus.

A new bisphosphonate, 4-amino-1-hydroxybutylidene-1, 1-bisphosphonate (AHBuBP), was compared with 3-amino-1-hydroxypropylidene-1, 1-bisphosphonate (AHPrBP) and 1-hydroxyethylidene-1, 1-bisphosphonate (HEBP) assessing their effects on tumor induced osteolysis using human prostate adenocarcinoma cells in nude mice. The method consisted of inoculating transplantable human prostate cancer cells subcutaneously over the calvaria in nude mice resulting in a local tumor causing fragmentation of the bone. The parameters included assessing the extent of decreased osteolysis in bone as judged by X-ray and histological examination. The results showed the following sequence of potency: AHBuBP greater than AHPrBP greater than HEBP. 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 tumor. This inhibition was obtained with no apparent effect on the growth of the tumor. AHBuBP appears to be an interesting new bisphosphonate for future clinical use.

Forty-six patients with adenocarcinoma of the prostate were given an intravenous infusion of the thymidine analogue, bromodeoxyuridine (BrdU), 200 mg/m2, at the time of needle biopsy or transurethral resection to label tumor cells in the DNA synthesis phase. The tumor specimens were stained by an indirect immunoperoxidase method with anti-BrdU monoclonal antibody. The BrdU labeling index, S-phase fraction, was determined by counting the number of BrdU-labeled cells in the tissue sections. S-phase fraction correlates with the results of histologic tumor grade, Gleason score, and growth patterns. The higher S-phase fraction may indicate biologic malignancy. Moreover, the degree of heterogeneity concerning S-phase fraction distribution within prostate cancer tissue could be evaluated and the findings compared with the morphologic appearance. The authors results suggest that the measurement of BrdU labeling index in prostate cancer may prove to be a new objective and quantitative assay for biologic potential of individual tumors.

Reported is a case of 67-year-old man with a recurrent gastric carcinoma that was associated with a possible lymphatic metastasis to the scrotum. Seven years earlier (October, 1980), since an adenocarcinoma of the stomach was present, a subtotal gastrectomy was performed. At that time, a IIc-like advanced tumor with a ul-III, measuring 32 x 28 mm in size, was noted on the anterior wall of the corpus near the greater curvature of the stomach, on macroscopical examination of the resected specimen. Microscopic findings showed a poorly differentiated adenocarcinoma with an involvement of the serosa but without a lymph node metastasis (H0, P0, n0, se, stage III). In July 1987, a tumor in the right scrotum was found and the patient underwent surgery. The resected specimen revealed a histologically cancerous involvement of the testis, the epididymis, the tunica vaginalis testis, and the spermatic cord. The cancerous cells showed the same poorly differentiated adenocarcinoma which had been observed in the primary locus of the stomach. Judging from these findings, this case was diagnosed as a recurrent gastric carcinoma with a lymphatic metastasis to the scrotum.

A new epithelial cell line, TSU-Pr1, from a human prostatic adenocarcinoma metastatic to lymph node has been established in long term tissue culture. The cultured cells show loss of contact inhibition, rapid growth in vitro and growth in athymic nude mice. Karyotypic analysis demonstrated an aneuploid karyotype with a modal chromosome number of 80 including a Y-chromosome and at least 10 marker chromosomes. The cells produced only a small amount of prostatic acid phosphatase, and heterotransplanted tumors did not have nuclear androgen receptors.

A simplified classification for primary urethral tumors is proposed. The T stage for tumors of male or female and of the upper or lower urethra has been combined into a single system. The system has been applied to 104 cases of urethral tumors. Although the cases were not necessarily very well qualified, a retrospective survival study demonstrated a general trend to a poorer prognosis in higher stages. Such a unified system might be useful for a simple classification of urethral tumors, a rare neoplasm with various clinical manifestations depending on sex or tumor site.

Surgery has been considered to be a main treatment of urogenital cancer. However, surgery alone could not completely cure these patients. The prognosis was poor. Multi-disciplinary treatment has been adopted to improve these results. However, there are many problems to be solved, such as combination of these regimens. In addition, the criteria for evaluation of the therapy should be considered. Nevertheless, multi-disciplinary treatment has been one of the most potent procedures for these malignancies.

Using a monoclonal antibody to bromodeoxyuridine and immunohistochemistry, we measured the incorporation of this thymidine analogue into the deoxyribonucleic acid of human prostate adenocarcinoma cells exposed in situ. Fifteen patients with prostate cancer were given an intravenous infusion of 500 mg. bromodeoxyuridine at needle biopsy to label tumor cells in the deoxyribonucleic acid synthesis phase (S phase). The tumor specimens were fixed with 70 per cent ethanol, embedded in paraffin, sectioned and stained by an indirect immunoperoxidase method using anti-bromodeoxyuridine monoclonal antibody as the first antibody. The results showed that this method demonstrated bromodeoxyuridine-labeled nuclei satisfactorily in tissue section. The bromodeoxyuridine labeling index, S phase fraction, was determined by counting the number of bromodeoxyuridine-labeled cells in the tissue sections. Grade 3 tumors averaged 4.37 +/- 0.48 per cent labeling versus 2.41 +/- 0.49 per cent in grade 2 tumors, and grade 1 tumor in the series had an S phase fraction of 1.36 +/- 0.39 per cent. The average S phase fractions for single gland, cribriform, fused and medullary were 1.16, 2.30, 3.74 and 4.95 per cent, respectively. The results obtained with S phase fraction measured with bromodeoxyuridine labeling proved to be comparable to the results of histological grade and growth pattern. Thus, the higher S phase fraction may indicate biological malignancy. Moreover, the degree of heterogeneity concerning S phase fraction distribution within prostate cancer tissue could be compared to the morphological appearance. Our preliminary results suggest that the measurement of bromodeoxyuridine labeling index in prostate cancer may prove to be a new objective and quantitative assay of biological potential of individual tumor.

The incidence of incidental carcinoma of the prostate in Japan is reported, and a retrospective study of 60 incidental carcinoma of the prostate is presented on the basis of tumor size and histological features. As the tumor progressed in size, there was a corresponding increase in its malignant potential. The survival rate according to tumor size and histological grade showed a significant difference between A1 (less than 10 mm diameter and low grade) and A2 (greater than or equal to 10 mm diameter or moderate to high-grade tumor).

Histologic characteristics of prostate cancer in Japan were evaluated in a retrospective analysis of 267 cases. These specimens were graded by the Gleason histopathologic grading system, and the proportional distribution of histologic features and the death rate were compared with those of Gleason's results in the literature. The system demonstrates significant correlation with mortality rates for each grade group in our cases, and it was also found that the death rates as obtained by our figures were comparable to those of Gleason in each category. The results help to provide the basis for future comparative multinational trials of prostate cancer.

Renal cell carcinoma in a solitary kidney is rather rare. We present a case of this condition occurring in a 50-year-old man. He was treated by partial nephrectomy and temporary hemodialysis for postoperative acute renal failure. Perusal of the literature reveals that in situ partial nephrectomy, if possible, seems to be a reasonable treatment of choice for renal cell carcinoma in a solitary kidney. This is the fifth case ever reported in Japan.

A model system of human prostate carcinoma in nude mice for searching out a method to protect the bone from cancer cells is described, in which the transplanted human prostate cancer cells were inoculated subcutaneously over the calvaria in nude mice after the periosteum wa disrupted. The tumor induced osteolysis associated with osteoclast proliferation accompanied with reactive new bone formation. This osteolysis was evaluated by measuring the increased area of bone resorption by its reduced opacity to X-ray, and histology. Etidronate disodium, a diphosphonate derivative, at a dose of three mg./kg. and 10 mg./kg. s.c. protected the bone by decreasing the extent of osteolysis as judged by the above criteria. This inhibition was obtained with no apparent effect on the growth of the tumor. These results are discussed in light of recent clinical work, showing that this animal model is a useful tool to test the effect of new drugs against osteolysis of cancer as well as to study the biology of local interaction between bone and cancer cell.