Donald F. Gleason

A phase 3, multicenter, open-label, randomized study of abarelix versus leuprolide acetate in men with prostate cancer.

OBJECTIVES To evaluate the levels of testosterone and other hormones in men with prostate cancer treated with abarelix versus leuprolide acetate. METHODS Patients (n = 269) were randomized to receive open-label abarelix 100 mg or leuprolide acetate 7.5 mg by intramuscular injection. The results of the first 84 days of the study are reported. The primary efficacy endpoints included avoidance of testosterone surge, castration on day 8, and achievement and maintenance of castration from days 29 through 85. The secondary endpoints included castration on days 2, 4, and 15; a reduction in prostate-specific antigen level; and measurements of other hormones. Patients were monitored for clinical adverse events and laboratory abnormalities. RESULTS No men in the abarelix group and 82% of men in the leuprolide acetate group experienced a testosterone surge (P <0.001). Abarelix caused rapid medical castration: 24% of men 1 day after treatment and 78% after 7 days compared with 0% of men treated with leuprolide acetate on either day. A comparable percentage of men achieved and maintained castration between days 29 and 85 in each group. Prostate-specific antigen had a statistically significant decrease for the first month in patients treated with abarelix. Dihydrotestosterone, luteinizing hormone, prostate-specific antigen, and follicle-stimulating hormone showed similar rapid reductions without an initial increase. The overall occurrence of adverse events was similar across the treatment groups, and most were sequelae of comorbid disorders. CONCLUSIONS Treatment with abarelix produced a higher percentage of patients who avoided a testosterone surge and had a more rapid time to testosterone suppression with a higher rate of medical castration 1 day after treatment and greater reductions in testosterone, luteinizing hormone, follicle-stimulating hormone, and dihydrotestosterone during the first 2 weeks of treatment compared with leuprolide acetate. The achievement and maintenance of castration was comparable between the two groups.

The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer.

PURPOSE We contrasted the endocrinological and biochemical efficacies of abarelix depot, a pure gonadotropin-releasing hormone antagonist, with a prospective concurrent control cohort receiving luteinizing hormone releasing hormone (LH-RH) agonists with or without antiandrogen for treatment of patients with prostate cancer receiving initial hormonal therapy. MATERIALS AND METHODS In this phase 2 open label study 242 patients with prostate cancer requiring initial hormonal treatment received abarelix depot (209) or LH-RH agonists (33) with or without antiandrogen. A total of 100 mg. abarelix depot was delivered intramuscularly every 28 days with an additional injection on day 15. LH-RH agonists with or without antiandrogen were administered according to the depot formulation used. Endocrine efficacy was measured by the absence of testosterone surge and rapidity of castration onset. The rate of prostate specific antigen decrease was assessed. RESULTS No patient treated with abarelix depot had testosterone surge during week 1 compared with 82% of those treated with LH-RH agonists. The concomitant administration of antiandrogen had no effect. During the first week of drug administration, in 75% of patients treated with abarelix depot and in 0% of those treated with LH-RH agonist medical castration was achieved. Prostate specific antigen decrease was faster, with no flare or surge in patients treated with abarelix depot. Abarelix depot was well tolerated. CONCLUSIONS Abarelix depot represents a new class of hormonal therapy, gonadotropin releasing hormone antagonists, that has rapid medical castration and avoids the testosterone surge characteristic of LH-RH agonists.

Competing Risk Analysis of Men Aged 55 to 74 Years at Diagnosis Managed Conservatively for Clinically Localized Prostate Cancer

CONTEXT The appropriate therapy for men with localized prostate cancer is uncertain. Until results of clinical trials are available, men and their physicians need guidance. OBJECTIVE To estimate survival based on a competing risk analysis stratified by age at diagnosis and histologic findings for men diagnosed as having clinically localized prostate cancer and who were managed conservatively. DESIGN Retrospective cohort study. SETTING Connecticut Tumor Registry. PATIENTS A total of 767 men with localized prostate cancer diagnosed between 1971 and 1984, aged 55 to 74 years at diagnosis, either not treated or treated with immediate or delayed hormonal therapy, and followed up for 10 to 20 years after diagnosis. MAIN OUTCOME MEASURES Estimates of the probability of dying from prostate cancer or other competing hazards. RESULTS Men with tumors that have Gleason scores of 2 to 4, 5, 6, 7, and 8 to 10 face a 4% to 7%, 6% to 11%, 18% to 30%, 42% to 70%, and 60% to 87% chance, respectively, of dying from prostate cancer within 15 years of diagnosis depending on their age at diagnosis. CONCLUSIONS Men whose prostate biopsy specimens show Gleason score 2 to 4 disease face a minimal risk of death from prostate cancer within 15 years of diagnosis. Conversely, men whose biopsy specimens show Gleason score 7 to 10 disease face a high risk of death from prostate cancer when treated conservatively, even when cancer is diagnosed as late as age 74 years. Men with Gleason score 5 or 6 tumors face a modest risk of death from prostate cancer that increases slowly over at least 15 years of follow-up.

Immunoelectron microscopic localization of prostatic-specific antigen in human prostate by the protein A-gold complex.

Human prostate specimens from 25 patients provided 15 normal, four benign prostatic hypertrophy (BPH), and seven adenocarcinoma samples which were studied using a polyclonal antibody against prostatic specific antigen (PSA) and protein A‐gold complex. Our study showed the presence of gold particles in cytoplasmic vesicles and granules, rough endoplasmic reticulum, and occasional lysosomal dense bodies in columnar or cuboidal cells of acini from normal, BPH and well‐differentiated cancerous specimens, but not in the acinar basal cells. Some moderately differentiated and most poorly differentiated tumors contained undifferentiated neoplastic cells in which PSA localizations often were associated with membranous structures since specific cytoplasmic organelles were not differentiated. In prostatic stroma, invasive cells which were of differentiated type localized gold particles. In addition, some neutrophils and macrophages also localized PSA suggesting their role in phagocytosis of extra‐cellularly released PSA in the stroma of BPH and cancerous samples. Thus far, the authors have not observed neutrophils and macrophages with gold particles in normal prostate. We suggest that neutrophils and macrophages were involved in transport of some extracellularly released PSA from the prostatic stroma or other metastatic sites to sera in BPH and cancer patients.

Complete Heart Block Complicating Bacterial Endocarditis

Among 142 cases of bacterial endocarditis (BE), complete heart block (CHB) was found in six cases (4%) and first-degree (1°) or second-degree (2°) A-V block in 14 cases (10%).The aortic valve was involved in 18 of 20 cases with atrioventricular (A-V) conduction disturbance, including all six cases of CHB.Anatomic observations (four autopsy, one operative) were made in five of the six cases of CHB. In these cases, a common finding, in addition to involvement of the aortic valve, was extension of the infection to adjacent structures resulting in cardioaortic fistulae. CHB likely resulted from extension of infection to the major conduction tissues.Five of the six patients with CHB died suddenly while in the hospital. One patient was treated with electric pacing while the infection was being controlled and, 38 days later, underwent successful replacement of the aortic valve. Conduction abnormalities are important possible complications of aortic valvular BE. Prompt pacing may be a lifesaving procedure, allowing eradication of infection as a prelude to surgical therapy.

Prediction of Pelvic Lymph Node Metastasis by the Ratio of Cathepsin B to Stefin A in Patients with Prostate Carcinoma

Pathologic grade and/or histologic score, extraprostatic extension indicated by invasion of the prostatic capsule, margin, and/or seminal vesicles by prostate cancer cells, serum total prostate‐specific antigen (PSA), free PSA, complexed PSA levels and/or their ratios, regional pelvic lymph node metastases, and clinical staging have been used to diagnose and monitor the treatment of prostate carcinoma (PC) patients. The Gleason grading system is also used to grade/score a patients stage of disease, with lower to higher scores indicating progression of PC. However, Gleasons system cannot be used to distinguish biologically aggressive PCs within a single Gleason score. Our objective was to identify subpopulations (or clones) of aggressive prostate cancers within an individual Gleason score by utilizing biological molecule(s) that also facilitate cancer cell invasion to prostatic stroma and metastasis to the lymph nodes.

Analysis of Fixation Effects on Immunohistochemical Localization of Prostatic Specific Antigen in Human Prostate

We studied human prostatic specific antigen (PSA) localization in human prostate to investigate the possibility that the previously reported variations in the intensity of antigen staining were due to fixation and embedding methods. We have evaluated the effects of physical and several chemical fixatives on prostate samples obtained immediately after prostatectomies and radical cystectomies. Our analysis of fixation effects and immunohistochemical staining of polyclonal antibody to PSA indicates that the formalin fixation and paraffin embedding methods used previously did provide optimum localization of the antigen and the variations in the intensity of PSA staining could not be attributed to the methodology. Although PSA staining was relatively uniform in the lower grade neoplastic tumors, the higher grade, moderately to poorly differentiated tumors showed intense-through-weak PSA localization or no PSA staining suggesting that PSA staining intensity was not uniformly related to tumor differentiation.

Codistribution of Procathepsin B and Mature Cathepsin B Forms in Human Prostate Tumors Detected by Confocal and Immunofluorescence Microscopy

Cathepsin B (CB) is involved in invasion and metastasis of a variety of solid organ tumors, including human prostate cancer. The tertiary structures of the proenzyme and mature forms of CB are related closely, as revealed by crystallographic studies. However, the cellular distributions of the CB forms have not been defined in human prostate and its tumors. Our objective was to investigate the distribution and codistribution of CB and procathepsin B (proCB) in human prostate tumors. Human prostate tissue samples that were obtained from 21 prostatectomy and/or cystectomy patients were collected immediately after surgery and processed for this study. We used a rabbit antihuman liver CB immunoglobulin G (IgG) that recognizes both mature CB and proCB and a mouse antipropeptide monoclonal antibody IgG that recognizes only proCB. Fluorescein isothiocyanate (FITC)‐conjugated donkey antirabbit IgG and indocarbocyanine (Cy3; rhodamine)‐conjugated donkey antimouse IgG were used to differentiate localization of the enzyme forms. Immunofluorescence of FITC and Cy3 was examined in prostate sections by using epifluorescence and confocal laser‐scanning microscopy. Because fluorescence is dependent on section thickness, time needed for study and photography, and the antigenic sites of proCB and mature CB localized by antibodies and by fluorescent markers (Cy3 vs. FITC), the cellular distributions and the relative intensity of fluorescence on cryostat sections were assessed qualitatively. Immunofluorescence of Cy3 for localizing proCB and of FITC for localizing mature CB were observed in prostatic epithelial cells and their tumors and in stromal connective tissue cells. By using confocal microscopy, colocalization of the enzyme forms in the same cells was indicated by yellow fluorescence. In stromal cells (such as smooth muscles, fibroblast, and macrophages), the distribution of proCB and relative fluorescence intensity was moderate to predominant in human prostate and its tumors. In neoplastic prostate, the cellular distributions of CB ranged from low to predominant levels. In some neoplastic glands, Cy3 fluorescence for proCB was absent, whereas the mature form of CB localized in cancer cells and in the subjacent extracellular matrix. Confocal microscopy showed a close association of CB with extracellular matrix surrounding neoplastic acini and invasive cells, indicating that the enzyme form was probably involved in degradation of the matrix proteins. The negative control study showed no specific immunofluorescence for proCB or CB in prostate cancer cases. We have shown a differential distribution of proenzyme and mature forms of CB in normal prostate, benign prostatic hyperplasia, and neoplastic prostate. The enzyme forms were assessed by determining the cellular distributions of CB and proCB. Our study indicates that the differential distribution of proCB and CB might provide clues into aggressiveness of prostate cancers within Gleason grades. However, we emphasize that our observation should be evaluated in a larger series of prostate samples before a definitive conclusion can be reached. This is the first report to show codistribution of proenzyme and mature forms of CB by using confocal microscopy. Anat. Rec. 252:281–289, 1998.

Antibody immunoglobulin G (IgG) against human prostatic specific antigen (PSA) as a carrier protein for chemotherapeutic drugs to human prostate tumors: Part 1. A double immunofluorescence analysis.

Adenocarcinoma of the prostate (CaP) is the second highest cause of cancer deaths in U.S. males. Current chemotherapeutic and/or endocrine treatments do not specifically and selectively target tumor cells of prostate cancer and benign prostatic hyperplasia (BPH). We hypothesized that because of the specific binding characteristics of antibody immunoglobulin G (IgG) to human prostatic‐specific antigen (PSA), PSA‐IgG could function as a carrier protein for conjugated chemotherapeutic drugs and that the immunoconjugate would selectively bind to prostatic epithelial cells and their tumors, but not to epithelial cells of unrelated organs. Our objective was to test the hypothesis using human prostatectomy specimens.

Nonantibody-mediated suppression of delayed hypersensitivity to human γ-globulin in mice☆

Abstract Development of delayed hypersensitivity (DHS) to human γ-globulin (HIgG) in mice was documented by histological analysis, by the kinetics of footpad swelling in animals exhibiting humoral or delayed responses, and by the failure of sera to transfer delayed reactions to normal, syngeneic recipients. Since cyclophosphamide (CY) treatment resulted in diminished humoral and augmented delayed reactions, we used this as a tool to explore the nature of the regulatory mechanisms which affect expression of this type of cell-mediated immunity. In order to evaluate the effect which the presence or absence of antigen-specific cells might exert on expression of DHS, we subjected mice to experimental regimes which would result in lymphocyte proliferation or depletion, respectively (see Bachvaroff, R., and Rapaport, F. T., Cell. Immunol. 15, 336, 1975). Cell proliferation was induced by injection of 80 μg of aqueous antigen on Day −4; this was followed by sensitization with HIgG-CFA (Freunds adjuvant) on Day 0, and footpad challenge on Day 13. These mice exhibited strong humoral reactivity; three of six died of anaphylaxis following footpad challenge, and the remaining three showed a diminished delayed response. Similarly treated mice that, in addition, received 6 mg of CY 3 days after injection of aqueous antigen and, therefore, would have antigen-specific cells present showed greatly diminished humoral reactivity, due to B-cell depletion. However, they also exhibited a marked diminution in delayed responsiveness. The data clearly demonstrate that a nonantibody-mediated, possibly cell-directed, regulatory influence is exerted on DHS where cell proliferation has occurred. We next examined the impact which the depletion of proliferating cells would exert on the expression of DHS. Cell depletion was attempted by giving one injection of aqueous antigen (Day 0) early in a regime of chronic CY administration (Days −1 through +3) ; antigen-induced proliferating cells would be susceptible to CY and, therefore, depleted under these conditions. The results show that mice receiving both aqueous antigen and CY have depressed humoral and markedly diminished delayed reactivity compared to animals that were injected with CY alone. Thus, the augmenting effect which CY exerts on DHS is abrogated by stimulation with aqueous antigen. One interpretation is that CY removes a regulatory cell population in the normal animal, thereby allowing enhanced expression of delayed responsiveness. Clearly, regulatory function cannot be attributed solely to bumoral antibody production.