Ryosuke Nemoto

Immunocytochemical Demonstration of S Phase Cells by Antlbromobeoxyuribine Monoclonal Antibody in Human Prostate Adenocarcinoma

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.

S Phase Fraction of Human Bladder Tumor Measured in Situ with Bromodeoxyuridine Labeling

A total of 18 patients with transitional cell bladder cancer was given a 0.5-hour intravenous infusion of bromodeoxyuridine at the time of endoscopic biopsy or transurethral resection 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 with anti-bromodeoxyuridine monoclonal antibody as the first antibody. The bromodeoxyuridine labeling index, S phase fraction, was determined by counting the number of bromodeoxyuridine-labeled cells in the tissue sections. All grade 1 tumors had an S phase fraction of lower than 10 per cent. The average S phase fractions for noninvasive (11 cases) and invasive (7) tumors were 9.8 and 20.0 per cent, respectively. Two distant metastatic bladder tumors showed an average S phase fraction of 25.3 and 30.0 per cent. Thus, transitional cell bladder cancers with an S phase fraction of greater than 10 per cent appears to grow faster and be more invasive more often than those with an S phase fraction of less than 10 per cent. The higher S phase fraction may indicate greater biological malignancy. Our preliminary results suggest that measurement of the bromodeoxyuridine labeling index in bladder tumors may be a new objective and quantitative assay of biological potential of individual tumors.

Immunohistochemical Detection of Proliferating Cell Nuclear Antigen (Pcna)/Cyclin in Human Prostate Adenocarcinoma

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 model of localized osteolysis induced by the MBT-2 tumor in mice and its responsiveness to etidronate disodium

SummaryA new experimental method to test the effect of drugs on tumor-induced osteolysis using a bladder tumor in mice has been designed. The method consistsed of inoculating MBT-2 tumor cells s.c. over the calvaria in mice, resulting in a local tumor causing fragmentation of the bone. This was accompanied by adjacent osteoplastic changes, which were evaluated by X-ray and histological examination. Etidronate disodium (EHDP), a diphosphonate derivative, at a dose of 3 mg/kg to 30 mg/kg s. c. protected the bone by decreasing the extent of osteolysis as judged by the same criteria. Therapy with EHDP prolonged the survival period. This inhibition was obtained with no apparent effect on the growth of the MBT-2 tumor.

Effects of a new bisphosphonate (AHBuBP) on osteolysis induced by human prostate cancer cells in nude mice.

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.

Establishment of a Model to Evaluate Inhibition of Bone Resorption Induced by Human Prostate Cancer Cells in Nude Mice

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.

Renal Autotransplantation for Localized Amyloidosis of the Ureter

Localized amyloidosis of the ureter is a relatively rare disease, causing at times ureteral stenosis with hydronephrosis and renal function impairment to various extent. Although it is not malignant nearly all reported cases have been treated by nephroureterectomy because it is clinically difficult to differentiate this entity from ureteral malignancy. We report a case in which the ipsilateral kidney was salvaged successfully by renal autotransplantation. To the best of our knowledge, this is the first case reported of renal autotransplantation for localized amyloidosis of the ureter in the English literature. We suggest that renal autotransplantation be considered in cases of localized ureteral amyloidosis.

Tumor-bone interaction induced by transplantable human tumors in nude mice

Tumor‐bone interactions were experimentally studied using four transplantable human urogenital tumors in nude mice. The method consisted of subcutaneously (SC) inoculating tumor cells over the calvaria in nude mice after the periosteum has been disrupted. This resulted in a local tumor causing fragmentation of the bone. The degree of tumor‐bone interaction also varied with the type of implanted tumors as shown in radiographic and histologic examinations. All tumors were associated with histologic patterns of classical bone remodeling, including bone destruction with osteoclast proliferation and reactive new bone formation. The evidence presented here suggests that the majority of tumor‐bone interaction showed a combination of both features, bone destruction and new bone formation, and the mechanisms whereby tumors interact with bone may vary with the biological properties of the tumor. Our new system would be suitable for studying the biology of local interaction between bone and tumor cells and searching out a method to protect the bone from cancer cells.

Experience with gleason histopathologic grading of prostatic cancer in Japan

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 Gleasons 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.

Long-term intra-arterial infusion chemotherapy with Adriamycin for advanced bladder cancer

SummaryLong-term intra-arterial infusion chemotherapy with Adriamycin (ADM) was performed in cases of bladder cancer prior to total cystectomy. This report describes the effects in 13 cases evaluated more than 3 weeks after infusion of 10 mg ADM once or twice weekly.An oblique skin incision approximately 10 cm long was made in the gluteal region to expose the gluteus maximus muscle. A teflon catheter was then inserted into the gluteal artery and fixed; the distal end was brought out from under the skin in the precordial region. A similar procedure was performed on the contralateral side.The catheter was inserted through the superior and inferior gluteal arteries in five and eight cases, respectively. In the former group, partial response was obtained in two cases, minimal response in two and no response in one, so that primary tumor remission was evident in 40% of the cases. In the latter group, all cases but one attained partial response, i.e., remission was seen in 87.5% of cases treated by inferior gluteal infusion.Skin erosion of the gluteal, perineal, and anal regions and sciatica-like pain were observed in some cases; however neither myocardial effect nor bone marrow suppression, which have been reported as side-effects of ADM, were observed in any of the cases.These results suggest that this therapeutic modality could be effective in the preoperative work-up of candidates for total cystectomy, and also that it could be useful in the treatment of patients in whom total cystectomy is contraindicated.