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Notes: Summary To obtain more accurate information on the prevalence of stage A prostatic cancer (incidental or latent carcinoma), a prospective collaborative study was set up in Japan and the Netherlands. A total of 859 specimens were submitted for routine histological examination (Japan: 343 specimens; the Netherlands: 516 specimens). All specimens were obtained from patients more than 50 years of age showing clinical signs of obstructive benign prostatic disease. The overall prevalence of stage A cancer in both countries was almost equal (Japan 13% vs the Netherlands 14%). A relatively large number of incidental tumors were found in subcapsular prostatectomy specimens in the Netherlands. Increasing prevalence of stage A disease in subsequent age decades was not found in the Netherlands, where the highest prevalence was observed in the 70–79 age-group. Subdivision of stage A disease into A1 and A2 tumors did not reveal any significant difference in prevalence between the two countries. Of particular interest is that the number of A2 lesions found in the Netherlands was not higher than that found in Japan. In both countries almost all A1 lesions were identified as G1 tumors in stage A1 disease. Both G2 and G3 lesions were present in Japan and the Netherlands in 79% and 72% of the A2 cases respectively. Results are discussed and especially related to their possible impact upon the differences in mortality rate between the two countries.

Notes: Summary Many human tumors such as bladder carcinoma that are initially responsive to chemotherapy eventually fail to respond to treatment. For most drugs, dose escalation that may be required for a cure cannot be achieved because sensitive tissues such as bone marrow limit cytotoxic therapy. Approaches to prevent or circumvent myelosuppression are therefore a high priority of research on dose intensification protocols. One such strategy is to protect bone marrow cells by virtue of expression of the multidrug-resistance (MDR1) gene encoding for P-glycoprotein. In our first set of experiments, we transplanted bone marrow cells derived from transgenic mice that constitutively express MDR1 to lethally irradiated recipients (n=36). From 6 weeks to 10 months after the transplant, all animals contained MDR1 DNA in spleen and bone marrow specimens as indicated by Southern-blot analysis and expressed MDR1 RNA in bone marrow samples as detected by slot-blot analysis. In addition, these animals were resistant to the myelosuppressive effect of doxorubicin, daunomycin, taxol, vinblastine, vincristine, etoposide, and actinomycin D, whereas control animals that were reconstituted with normal bone marrow reacted with a significant decrease in their white blood counts. In a second set of experiments, we retrovirally transfected a construct consisting of a murine long-terminal repeat (LTR) promoter and the human MDR1 gene into CD34-positive bone marrow stem cells from rhesus monkeys using the same technique as in the ongoing clinical ADA gene-therapy protocol. Upon transplantation, high-level and long-lasting expression of the human MDR1 gene was observed in recipient monkeys. On the basis of this preclinical analysis, we have, in close cooperation with the Dutch Gene Therapy Group, submitted clinical protocols designed to test myeloprotection afforded by MDR1 gene transfer to intensify chemotherapy in otherwise incurable human cancer for institutional and state approval. The Department of Urology will investigate metastatic, refractory bladder carcinoma using the multidrug-resistance (MDR)-related drugs vinblastine and doxorubicin for myeloablative support of bone marrow transplantation, selection of MDR-positive clones, and dose escalation of chemotherapy in patients. The objectives of these phase I/II studies are to test the feasibility and toxicity of transplanting retrovirally transfected MDR-bone marrow stem cells and, eventually, to determine the efficacy of this innovative approach.

Notes: Summary Of 39 human kidney carcinoma transplanted to nude mice, four tumor lines were maintained on nude mice by serial transplantation. The established tumor cell lines were used to determine the assay evaluability of three different drug-testing systems: the subrenal capsule assay (SRC), the in vitro assay with labeled DNA precursor (L-DNA-P) and the stem cell assay (STC). Tumor cell lines were used because they allowed us to perform the different assays with the same tumor. Criteria for assay evaluability were measurable growth of the transplanted tumor fragment (histologically proved) in the SRC-assay, the amount of thymidine incorporation in relation to the number of cells in vitro and time of incubation in the L-DNA-P-assay, and a mean colony count for the sixfold plated cells of 50 or greater in the STC-assay. The criteria for evaluability were fulfilled when athymic or irradiated immunocompetent mice were used for the SRC-assay. However, in immunocompetent, non-irradiated mice, remarkable incursion of host cells was found. In the L-DNA-P-assay, optimal incorporation was reached after different times of culture, with different cell numbers. Therefore the technique of assaying with labeled DNA precursor lacks optimally defined assay conditions. The tumor cell lines examined in the stem cell assay demonstrated excellent growth; they therefore may be useful for pharmacological studies of drug interactions.

Notes: Summary Naturally occurring glycosaminoglycans (GAGs) and other, semisynthetic, sulphated polysaccharides are thought to play an important role in urolithiasis. Processes involved in urinary stone formation are crystallization and crystal retention. Oxalate transport and renal tubular cell injury are determining factors in these processes. In this article experimental results concerning the possible mechanisms of action of GAGs and other sulphated polysaccharides are reviewed. GAGs are inhibitors of crystal growth and agglomeration and possibly also of nucleation. They can prevent crystal adherence, correct an abnormal oxalate flux and prevent renal tubular cell damage.

Notes: Summary Since 1980, a total of 55 patients with previously untreated prostatic carcinoma have been managed by castration and were followed regularly by means of transrectal ultrasonometry of the prostate. During the period of the study, distant metastases occurred in 20 patients; 10 showed progression after less than 1 year and 10 after more than 1 year. All patients showed a decrease of prostatic volume following castration. In the group of 10 patients who progressed within 1 year after castration, the initial volume reduction of the prostate was significantly smaller than in the rest of the patients. In patients whose prostatic volume decreased to at least 50% of the pretreatment volume after 3 months, none developed distant progression within 1 year. Of those patients whose prostatic volume did not decrease to at least 70% of the pretreatment volume after 3 months, 78% developed distant progression before or after 1 year. There was no significant difference in the volume decrease observed in patients who showed progression later than 1 year after initiation of treatment as compared to those patients who did not show progression at all. This prognostic information was compared to the impact of other commonly used prognostic factors, such as T-category, N- and M-status and grading. None of these factors reproduced the predictive value of the volume changes of the primary tumor. It therefore seems that transrectal ultrasonometry of the primary tumor has a place in monitoring the effects of endocrine management. The prediction of progression in 78% of the patients with prostatic volume 〉70% may be of limited clinical value now, but will be of greater importance as soon as effective treatment for hormone-unresponsive prostatic carcinoma becomes available.

Notes: Summary Serum acid phosphatase activity is known to be elevated in a number of patients with metastatic prostatic carcinoma. Prostatic acid phosphatase (PAP) can be specifically measured by immunological methods. In this study we evaluated an enzyme-immunoassay of the sandwich type utilizing monoclonal antibodies. Immunoassayable PAP decreased after storage at room temperature for 72 h and also after repeated freezing and thawing, although not evident in all samples. PAP levels were measured in 88 newly diagnosed prostatic carcinoma patients, in 124 patients with histologically proven benign prostatic hypertrophy (BPH) and in 124 elderly hospitalized male patients without urological complaints. The upper limit of normal, as determined in the control group, was 2.3 μg/l. Of the BPH patients, 17% had elevated PAP levels (range 2.4–27 μg/l). We found a positive correlation between prostate volume (grams of tissue removed during TUR) and preoperative PAP values (r=0.26, N=121, P〈0.01). Elevated PAP levels were found in 3% of BPH patients with a prostate volume of less than 20 g (N=63), in contrast with 55% of patients with a prostate volume above 50 g (N=18). The sensitivity of this PAP assay for detecting the clinical stages of prostatic carcinoma was 13% for category To (N=15), 30% for category T1–2 (N=20), 71% for category T3–4 (N=24), and 83% for category M1 or N1–4 (N=29). The upper limit of normal (2.3 μg/l) as calculated from a large group of controls with a mean age of 62 years is rather similar to the value found in younger controls. In BPH patients, however, elevated PAP levels may be found which are seen more frequently in patients with a large prostate. Thus, for the calculation of the normal range, it is not recommended to include the results from BPH patients. The sensitivity of this enzyme-immunoassay with monoclonal antibodies in detecting prostatic cancer, at a specificity of 98%, is comparable to other immunoassays for PAP.

Notes: Summary A retrospective study of 55 patients with incidental prostatic carcinoma with long term follow-up is presented. All patients were treated with total perineal prostatectomy, 43 received some form of endocrine treatment after the initial diagnosis was made. In order to contribute to the establishment of low and high risk groups which do not or do require agressive treatment, a careful histological analysis of the 39 patients was carried out on whom total prostatectomy slides with tumor were available. The amount of tumor, grade and parameters commonly used to establish grading were determined and correlated with corrected survival. The findings indicate that a small amount of tumor, grade 1, the presence of small, intermediate or large glands (but not cribriform and/or solid tumor) and the presence of slight but not moderate or marked variation in size and shape of the nucleus are strong predictors of not dying from prostatic carcinoma. There is agreement with the literature, where similar groups of patients not further treated after the initial diagnosis had been established showed a comparably low number of progressions. It is concluded that small, well differentiated prostatic carcinomas (category T0pT1NxM0G1, stage A1) do not require an aggressive diagnostic work-up or further treatment. A group of 11 patients (27%) showed more extensive but well differentiated tumors. Only two of these patients died of prostatic carcinoma. The natural history of this entity is not sufficiently known to make definite treatment decisions. Staging, radical prostatectomy, radiotherapy or deferred treatment may be indicated. Grade 3 carcinoma or the presence of cribriform and/or solid tumor were strong predictors of progression and death from prostatic carcinoma. Seven of 14 patients with these characteristics died of their disease. It is concluded that at least the experience in this series does not show radical prostatectomy to be an optimal treatment in this group of patients. Smaller rates of progression are however described in the literature. Endocrine management does not seem to have any beneficial effect, reports on radiotherapy are scarce. The optimal treatment for this group of patients with a high risk of dying from their tumor and a significantly shortened overall survival is not known.

Notes: Summary Between 1973 and 1979, 130 patients with pTa noninvasive bladder carcinoma were treated either by TUR plus intravesical chemotherapy with a single dose of Epodyl on the following day (60 patients), or by TUR only (70 patients). There was no significant difference between the two treatment groups as to time until first recurrence. However, the recurrence rate with Epodyl was significantly lower than that with no adjuvant treatment (P〈0.01). The incidence of increase in T-category was lower among patients who received Epodyl (P〈0.01). Thus single dose intravesical chemotherapy following TUR appeared to be beneficial.