Viral neoplastic transformation of hamster prostate tissue in vitro.

Cultures of hamster prostatic tissues infected with simian virus 40 undergo transformation in vitro, and the transformed cells produce malignant tumors when injected into homologous hosts. Tartrate-inhibited acid phosphastase is found in the cultures of transformed cells and in the tumors they produce. Tartrate-inhibited acid phosphatase activity is elevated in the serum of tumor-bearing animals.

Synaptonemal complex complement of man in spreads of spermatocytes, with details of the sex chromosome pair.

Human pachytene chromosome pairs have been characterized electron microscopically in spread preparations on the basis of synaptonemal complex length, kinetochore position and attached nucleoli when present. The X and Y chromosomes can be followed by their filamentous axial cores from partial synapsis, through precocious disjuction and end-to-end attachment, to differentiation of a network in the sex chromosome pair.

Apical soft tissue biopsies predict biochemical failure in radical perineal prostatectomy patients with apical cancer involvement.

The aim of the study was to prospectively assess the role of apical soft tissue biopsies in radical perineal prostatectomy (RPP) patients with documented apical prostate cancer (PCA) involvement. Between June 1998 and May 1999, 77 consecutive men with localized PCA and documented invasion of the prostatic apex underwent RPP by a single surgeon. Soft tissue biopsies were systematically obtained from the prostatic fossa overlying the apex at the time of surgery. Time to biochemical failure was calculated using the Kaplan-Meier method. The rates of positive apical margins and positive apical soft tissue biopsies were 23.4% (18/77) and 15.6% (12/77). The sensitivity, specificity and positive predictive value of positive apical margins for residual apical disease as determined by apical soft tissue biopsy were 41.7, 80, and 28%, respectively. The overall biochemical failure rate was 28.6% (22/77) with a median follow-up of 51 months (range 3-73 months). The 36-month biochemical recurrence-free survival rate was 55.9+/-14.9% for patients with positive apical biopsies and 78.7+/-5.3% for those with negative biopsies (P=0.023). In conclusion, positive apical soft tissue biopsy is an independent predictor of biochemical failure in patients with apical PCA who undergo RPP. Positive apical surgical margins poorly predict residual apical disease that is frequently identifiable by apical soft tissue biopsy. Apical soft tissue biopsies should therefore be obtained in patients with known extensive apical cancer involvement at the time of RPP.

Detection of metastatic tumors in nude mice: brief communication.

Homozygous nude (nu/nu) mice were inoculated ip with either highly malignant human bladder transitional cell carcinoma or human prostate adenocarcinoma. These animals were subsequently given injections of normal human T-lymphocytes to restore the known T-lymphocyte deficiency present in homozygous nude mice. Metastatic spread of the prostate and bladder carcinomas was evident in mice given human T-lymphocytes. Although tumor growth was observed at the sites of tumor inoculation, no tumor spread was observed in mice not receiving T-lymphocytes.

Treatment of metastatic endocrine-unresponsive carcinoma of the prostate gland with multiagent chemotherapy: indicators of response to therapy.

Eighty-eight patients with metastatic and hormonally unresponsive carcinoma of the prostate gland were treated with a multiagent chemotherapy protocol. Because of the difficulty in evaluating the response of patients to therapy, data were collected in a prospective fashion and analyzed for clinical or laboratory changes that correlated with improved survivorship. Decrease of initially abnormal values of either acid or alkaline phosphotase into the normal range was associated with prolonged survival; weight gain of more than 10% was also associated with improved survival. Thirty-three patients demonstrated a fall of acid or alkaline phosphatase into the normal range or they increased their weight by at least 10%. The median survival time for this group of patients was 76.1 weeks as compared to 28.2 weeks for patients who failed to exhibit these changes. In future studies of the treatment of metastatic prostate cancer, these changes might be used as criteria of response to therapy.

Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen-metabolism gene glutathione S-transferase M1 (GSTM1) that increases susceptibility to bladder cancer.

BACKGROUND: Numerous studies have associated bladder cancer with exposure to carcinogens present in tobacco smoke and other environmental or occupational exposures. Approximately 50% of all humans inherit two deleted copies of the GSTM1 gene which encodes for the carcinogen-detoxification enzyme glutathione S-transferase M1. Recent findings suggest that the GSTM1 gene may modulate the internal dose of environmental carcinogens and thereby affect the risk of developing bladder cancer. PURPOSE: We investigated whether the absence of the GSTM1 gene affects bladder cancer risk and whether there are racial differences in GSTM1 genotype frequency. METHODS: Using a polymerase chain reaction (PCR)-based method, we examined the frequency of the homozygous deleted genotype (GSTM1 0/0) in 229 patients with transitional cell carcinoma of the bladder and 211 control subjects who were enrolled from the Urology Clinics at Duke University Medical Center and the University of North Carolina Hospitals. Control subjects were urology clinic patients who primarily presented with benign prostatic hypertrophy or impotence, who had no history of any cancer other than nonmelanoma skin cancer, and who were frequency matched to case patients on race, sex, and age (10-year age intervals). In order to explore racial differences in GSTM1 gene frequency, genotype was also determined in a community-based sample of 466 paid, healthy, unrelated volunteers from Durham and Chapel Hill, N.C. The presence or absence of the GSTM1 gene locus was determined by using a differential PCR, a semiquantitative technique in which multiple genes are coamplified. RESULTS: Overall, the GSTM1 0/0 genotype conferred a 70% increased risk of bladder cancer (odds ratio [OR] = 1.7; 95% confidence interval [CI] = 1.2-2.5; P = .004). Absence of the GSTM1 gene encoding the glutathione S-transferase M1 enzyme significantly increased risk to persons with exposure to the carcinogens in tobacco smoke (OR = 1.8; 95% CI = 1.2-3.0; P = .01) but poses little increased risk to persons without such exposure. Persons with smoking exposure of more than 50 pack-years who had the GSTM1 0/0 genotype had a sixfold greater risk relative to persons in the lowest risk group (i.e., nonsmokers who were GSTM1 +/+ or +/0). In the pooled clinic control and community sample groups (677 individuals), the GSTM1 0/0 genotype occurred less frequently among Blacks (35%) than among Whites (49%, P < .001). CONCLUSIONS: These findings support a protective role for the GSTM1 gene in bladder cancer. From these findings, it is estimated that 25% of all bladder cancer may be attributable to the at-risk GSTM1 0/0 genotype.

An in vitro assay procedure to test chemotherapeutic drugs on cells from human solid tumors.

An in vitro assay was developed to measure the chemotherapeutic drug susceptibility of cells from human tumors. The assay utilized live cells, freshly isolated from tumor tissue, which were incubated for a short period in vitro. The drug-induced inhibition of incorporation of radiolabeled precursor into DNA, RNA, and protein was measured. The assay is sensitive to concentrations of chemotherapeutic drugs in the therapeutic range and is reproducible when tested with replicates of the same tumor cell population.

Activation of cyclophosphamide for in vitro testing of cell sensitivity.

Two methods are described for the activation of cyclophosphamide by a liver microsome preparation. These procedures were applicable to an assay in vitro which tests the sensitivity of tumor cells to the drug. Satisfactory results were obtained either by pretreatment of the cyclophosphamide and removal of the microsomes before testing or by the somewhat simpler procedure of mixing drug, microsomes, and test cells for the assay. Microsome treatment of bleomycin gave a smaller increase in activity, and much smaller effects were seen on some other drugs.

Production of monoclonal antibody alpha Pro3 recognizing a human prostatic carcinoma antigen.

The monoclonal antibody alpha Pro3 recognizes an antigen concentrated in human primary prostatic carcinoma tissue removed surgically. Although the antigen was detectable in extracts of human normal and malignant nonprostatic tissue, as well as in benign prostate tissue, quantitative absorption analysis revealed a substantially greater quantity of the antigen in malignant prostate tissue. The antigen recognized by alpha Pro3 in primary prostatic carcinoma has an apparent nonreduced molecular weight of 175,000 and an apparent subunit molecular weight of 54,000. This antigen, p54, appears to be present on the surface of cultured prostatic tumor cells of the PC-3 cell line, but its location in vivo has not been defined. Successful competition between alpha Pro3 and prostatic carcinoma patient serum immunoglobulin for a Mr 54,000 antigen (reduced molecular weight) present in prostatic carcinoma tissue extract suggests that p54 may play a significant role in the immunobiology of prostatic carcinoma. alpha Pro3 has potential as a sensitive probe for an antigen relevant to human tumor biology.

Development and application of basic research techniques in bladder cancer research.

The growth of transitional epithelial cells with different growth media and growth supports was examined. Sephadex G-10, Bio-Gel P-20, Bio-Glas-1000, DEAE-Sephadex A-50, DEAE-cellulose, CM-Sephadex C-50, acid-soluble collagen, and immobilized collagen fibers were used to enhance plating efficiency. Acid-soluble collagen layers optimally increased the plating efficiency of primary cultures of bladder carcinoma. Media alterations with serial combinations of fetal calf, newborn calf, calf, bovine, and bull serum with minimum essential medium, Roswell Park Memorial Institute Tissue Culture Medium 1640, Connaught Medical Research Laboratories Medium 1066, Medium 199, Grand Island Biological, National Cancer Tissue Culture 135, 1415, McCoy's 5A, and National Cancer Institute medium were established. No promotion of cell division was noted with any one of these basic medium formulations.

Heterotransplantation of a human prostatic adenocarcinoma cell line in nude mice.

Nude mice of NIH/Swiss background were utilized for the heterotransplantation of a tissue culture cell line derived from a human prostate adenocarcinoma metastatic to the brain. These cells, which had been grown in vitro for 13 passages, formed solid tumors when injected s.c. into nude mice. The cell line DU 145 has been passaged 60 times in vitro over a period of 18 months. Tumors removed from the mice were serially transplanted to additional mice and reestablished in vitro. Light-microscopic analysis of the tumor grown in nude mice revealed a strong similarity to the patient's metastatic tumor. The ultrastructure of the tumor cells propagated in nude mice was compared to that of the original human tumor cells and to the tissue culture cells, both before and after passage in nude mouse. No major differences were detected. Karyotypic analysis of the tumor cells grown in vitro before mouse passage, grown in nude mouse, and grown in vitro after mouse passage indicated chromosomal identity and consistent marker chromosomes: three large acrocentric chromosomes and metacentric minute chromosomes.

Early onset baldness and prostate cancer risk.

Prostatic carcinoma is the leading cancer among American men, yet few risk factors have been established. Although increased androgen levels have long been associated with both prostatic carcinoma and baldness, to date no studies have shown an association between hair patterning and prostate cancer risk. A lack of standardized instruments to assess baldness or the assessment of hair patterning during uninformative periods of time may have precluded the ability of previous studies to detect an association. We hypothesized that baldness, specifically vertex baldness, should be assessed using standardized instruments and during early adulthood if an association with prostate cancer risk is to be found. To test this hypothesis, we included identical items related to hair patterning in surveys that were administered in two distinct prostate cancer case-control studies (Duke-based study, n = 149; 78 cases; 71 controls and community-based study, n = 130; 56 cases; 74 controls). In each, participants were provided with an illustration of the Hamilton Scale of Baldness and asked to select the diagrams that best represented their hair patterning at age 30 and again at age 40. From these data, the following five categories were created and compared: not bald (referent group); vertex bald early onset (by age 30); vertex bald later onset (by age 40); frontal bald early onset (by age 30); frontal bald later onset (by age 40); and frontal (at age 30) to vertex bald (at age 40). Separate analyses of the two studies are consistent and suggest an association between vertex baldness and prostate cancer [vertex bald early onset odds ratios, 2.44 [confidence interval (CI), 0.57-10.46)] and 2.11 (CI, 0.66-6.73), respectively; vertex bald later onset odds ratios, 2.10 (CI, 0.63-7.00) and 1.37 (CI, 0.47-4.06), respectively]. Although statistical significance was not achieved in either one of these studies, the concordance between the data suggests a need for future studies to determine whether early onset vertex baldness serves as a novel biomarker for prostate cancer and whether androgen production, metabolism, or receptor status differs among these men when compared to those who exhibit other types of hair patterning.

Correlation of apparent molecular weight and antigenicity of viral proteins: an SDS-page separation followed by acrylamide-agarose electrophoresis and immunoprecipitation.

A simple method is described which combines a sodium dodecyl sulfate polyacrylamide gel electrophoresis (SOS-PAGE) in the first demension with a second electrophoresis, at right angles to the first, into an agarose matrix. The proteins, separated by SDS-PAGE, are exposed to appropriate antisera after the second stage electrophoresis and immunoprecipitates form in the agarose corresponding to the relative electrophoretic mobilities of proteins in the first stage SDS-PAGE separation. The method thus provides a simple, reproducible means for correlating antigenicity with apparent molecular weight of proteins. The technique is qualtitative, but requires smaller quantities of antisera than more conventional immunoelectrophoretic methods such as rocket electrophoresis.

Overview of first-line amikacin therapy for urologic infections.

Severe infections in urologic patients are frequently and effectively treated with aminoglycoside medications. Because of the frequency of nosocomial gram-negative infections in urologic patients, antimicrobial therapy with broad-spectrum antibiotics, such as aminoglycosides, is an integral part of management of urinary infections. Amikacin, because of its activity against infections caused by Pseudomonas, Serratia, and other frequently resistant bacteria, as well as its ability to achieve high blood and tissue levels, provides a significant advantage over other aminoglycoside agents in hospitalized urologic patients with suspected nosocomial infections. Although amikacin remains the most expensive of the aminoglycoside agents, its use is prudent in infections in which the causative organism is suspected but not definitively identified and when treatment must be started before specific culture and sensitivity information is available. In these situations, the most potent antibiotic agent with the broadest spectrum for eliminating infections caused by suspect organisms must be chosen, and amikacin is an ideal choice.

Management of metastatic prostatic cancer.

Current management techniques for metastatic prostatic cancer have given rise to controversies regarding the optimal timing, form, and degree of androgen deprivation. Low-dose diethylstilbestrol (DES) or orchiectomy decrease serum testosterone levels while posing less cardiovascular risk than high-dose DES. LH-RH analogues, such as leuprolide or buserelin, also inhibit testosterone production. Some studies suggest that some tumor cells may be relatively, rather than absolutely, androgen dependent. This has been the rationale for the combined use of a pure antiandrogen and an LH-RH agonist. Unfortunately, while this combination has been found effective in previously untreated patients, it has not been equally effective in those who have undergone prior therapy and demonstrated disease progression.

Staging lymphadenectomy should not be an antecedent to treatment in localized prostatic carcinoma.

The current controversy focusing on regional node evaluation in patients with prostatic carcinoma has been engendered by the enhanced biologic risk created by regional lymph node extension. The data indicate that node-positive disease is a systemic disorder and, as such, is not controlled by local treatment, such as lymphadenectomy combined with either radical removal of the primary malignancy or local radiation therapy. If lymphadenectomy is only prognostic and not therapeutic, it is reasonable to argue that any form of anatomic staging that permits the identification of nodal extension is a replacement for staging lymphadenectomy.

Oxybutynin chloride in control of post-trasurethral vesical pain and spasm.

Oxybutynin chloride (Ditropan) and placebo were randomized in a double-blind trial to determine the effectiveness of the test agent in controlling post-transurethral pain and spasm. Oxybutynin chloride was found effective in controlling pain and spasm; no significant side effects were noted.

Comparison of cinoxacin and nalidixic acid in patients with cystitis.

A single-blind comparative study was undertaken in 95 patients with cystitis. Each patient received either cinoxacin. 250 mg. qid or nalidixic acid, 1 Gm. qid for seven to fourteen days. Fifty-five patients fulfilled all the criteria for efficacy evaluations; in the cinoxacin-treated group, 26 patients (93 per cent) had a satisfactory symptomatic response, and in the nalidixic acid group there were 25 patients (93 per cent) with a satisfactory symptomatic response. The bacteriologic response was also similar in both groups. One patient in each group became reinfected with a new pathogen and in 1 patient, who received conoxacin, the causative pathogen was not eliminated. four female patients in the cinoxacin group had seven adverse drug reactions, compared with 9 patients in the nalidixic acid group who had 18 adverse reactions. It is concluded that cinoxacin has advantages over nalidixic acid for the treatment of patients with cystitis due to susceptible organisms.

Renal cystic disease.

Renal cystic disorders have long represented an area of diagnostic confusion. We have attempted to correlate renal microdissection findings with clinically established renal cystic disorders by examining each disorder in sequential fashion. The clinical presentation of a child with a multicystic kidney is followed by a review of the cystic diseases with emphasis on clinical presentation, distinguishing factors, course, and prognosis.

Postoperative prostate-specific antigen as a prognostic indicator in patients with margin-positive prostate cancer, undergoing adjuvant radiotherapy after radical prostatectomy.

OBJECTIVES: To identify a population of patients within the group with positive surgical margins after radical prostatectomy who would benefit in terms of improved local control of disease by the administration of adjuvant radiation therapy to the prostate bed. METHODS: Postoperative prostate-specific antigen (PSA) values were evaluated in 45 patients with margin-positive (MP) disease who underwent adjuvant radiotherapy within 6 months of surgery. All patients were clinically T1-2 MO, and pNO. A cutoff of 0.5 ng/mL or less was used as the level below which PSA was considered undetectable. The mean follow-up time from date of radiation was 33 months. RESULTS: In 30 of 45 (67%) patients, PSA levels did drop to undetectable levels postoperatively. In 15 of 45 (33%) patients postoperative PSA levels did not drop to undetectable levels. In the group with detectable postoperative PSA, 12 of 15 (80%) failed adjuvant radiotherapy as determined by a progressive increase in PSA levels in a mean time of 0.95 years (range, 4 months to 2.02 years; median, 0.92 years). When postoperative PSA reached undetectable levels, only 10 of 30 (33%) failed treatment, with a mean time to failure of 2.1 years (range, 4 months to 7.8 years; median, 3.31 years). CONCLUSIONS: The data would suggest that patients who are MP, but attain an undetectable PSA level postoperatively accompanied by a progressive delayed increase in PSA, probably represent a group with local disease recurrence in the prostate fossa, whereas patients whose PSA levels are detectable postoperatively may represent a group with microscopic metastatic disease or a combination of local recurrence and distant disease or large volume local persistent disease. It is in the group of patients in whom the postoperative PSA decreased to undetectable levels that adjuvant radiotherapy may be effective in controlling local progression of prostate cancer through improved local control, as indicated by a durable decrease in PSA values to undetectable levels in roughly two thirds of these patients. Longer follow-up of these patients will be required to determine whether this improved local control will translate into improved survival.