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Biomedical subjects

Michael K Brawer

Publications and source records attributed to Michael K Brawer.

At least 19 recordsLinked to original sources
PubMed2006

Hormonal therapy for prostate cancer.

Updates on hormonal therapy in the treatment of prostate cancer are presented. The most common therapy is to reduce testosterone to castrate levels. A dosage of 1 mg diethylstilbestrol daily prolonged survival in patients with advanced prostate cancer. The leuteinizing hormone-releasing hormone agonists have essentially replaced surgical orchiectomy in the vast majority of clinical settings; however, a major problem with the leuteinizing hormone- releasing hormone agonists has been the surge and flare of testosterone levels. If hormonal therapy is initiated early, the risk of major complications is significantly decreased. Combined androgen blockade is better than monotherapy, although there is only a small clinical benefit. When androgen deprivation is used for a short time and the normal androgen milieu is re-established, the side effects and toxicity of androgen deprivation are decreased. The major complications of androgen deprivation include hot flushes, reduction of bone mineral density, osteoporosis, and anemia. Intermittent androgen blockade might have the same benefits of total androgen suppression with fewer side effects, increased duration of androgen dependence, and less cost. The 10 steps to take when advising patients about initiation of androgen deprivation therapy are reviewed.

Journal Article↗
PubMed2005

Observed effect of age and body mass index on total and complexed PSA: analysis from a national screening program.

OBJECTIVES: To assess the effect of aging and body mass index (BMI) on both serum total prostate-specific antigen (tPSA) and complexed PSA (cPSA) from the results of the 2003 Prostate Cancer Awareness Week national screening database. METHODS: A total of 12,943 men were screened for prostate cancer. Of these, 4458 men had simultaneous measurements of tPSA and cPSA. Height and weight were used to calculate the BMI. The subjects were grouped by decade of age and categorized as either obese or nonobese with a cutoff BMI of 30 kg/m2. The rates of increase in mean tPSA and cPSA between consecutive decades were compared. The relationship among BMI, PSA, and cPSA was also analyzed using multivariate regression analysis. RESULTS: The median age of those screened was 60 years. The median PSA and cPSA was 1.10 and 0.69 ng/dL, respectively. Both serum tPSA and cPSA levels showed an exponential increase with advancing age. The ratio of cPSA/tPSA remained relatively constant at 0.6. Compared with the nonobese cohort, men with a BMI of 30 kg/m2 or more had significantly lower tPSA and cPSA levels across all age groups (P <0.01). The overall odds ratio for all age groups was 1.8 (95% confidence interval 1.2 to 2.3). CONCLUSIONS: Both tPSA and cPSA levels increased with age. Across age groups, men with a greater BMI had significantly lower cPSA and tPSA levels. The clinical significance of age-adjusted cutoff levels for PSA in obese men for the diagnosis of prostate cancer should be explored further in future prospective clinical trials.

Age Factors↗
PubMed2005

Prostatic intraepithelial neoplasia: an overview.

Prostatic intraepithelial neoplasia (PIN) is the most established precursor of prostatic carcinoma. The presence of prominent nucleoli within an existing duct structure is an easy way to identify the disorder. Four main patterns of high-grade PIN (HGPIN) have been described: tufting, micropapillary, cribriform, and flat. In addition to exhibiting similar cytologic features, both HGPIN and prostatic carcinoma are associated with increased incidence and severity with age, and with high rates of occurrence in the peripheral zone of the prostate. HGPIN and prostate cancer share genetic and molecular markers as well, with PIN representing an intermediate stage between benign epithelium and invasive malignant carcinoma. The clinical significance of HGPIN is that it identifies patients at risk for malignancy. With the increased use of extended biopsy protocols, clinicians are more likely to identify HGPIN and less likely to miss concurrent carcinoma. Androgen deprivation therapy decreases the prevalence and extent of PIN, and may play a role in chemoprevention. Preliminary studies suggest that selective estrogen receptor modulators may also prevent the progression of HGPIN to prostate cancer.

Journal Article↗
PubMed2005

A Multicenter Study on the Efficacy and Safety of Interstitial Laser Coagulation Versus alpha-Blockade in Subjects With Symptomatic Benign Prostatic Hyperplasia: Preliminary Results.

Significant efforts have been made to develop minimally invasive surgical approaches to the treatment of benign prostatic hyperplasia, both to lessen the morbidity of the standard operative procedures and to avoid the need for continued drug therapy throughout the patient's life. Interstitial laser coagulation (ILC) is a minimally invasive procedure that can be performed with local, regional, or general anesthesia. With this operator-dependent procedure, the surgeon can selectively control placement of the laser fiber to achieve the optimum destruction of tissue. Preliminary (6-month) data from a randomized trial comparing alpha-blockade with ILC demonstrate that treatment with ILC is associated with a clinically significant decrease in American Urological Association symptom scores, a result superior to that achieved with an alpha-blocker.

Journal Article↗
PubMed2005

Lonidamine: basic science and rationale for treatment of prostatic proliferative disorders.

Normal and hyperplastic prostatic tissues concentrate citrate within the epithelium; however, a unique biochemical property within prostate epithelial cells renders them dependent on glycolysis, rather than the citric acid cycle, for energy production. Lonidamine, an orally administered small molecule that inhibits glycolysis by the inactivation of hexokinase, may represent a unique and novel approach to the treatment of benign prostatic hyperplasia (BPH). Results of a phase II trial of lonidamine in BPH (described elsewhere in this supplement) are encouraging. Lonidamine is already used in the treatment of several cancers in other countries. Its target-specific nature renders it a safe compound for administration; in cancer therapy, patients have been treated with 40 times the daily dose used in the BPH trial, with negligible toxicity.

Journal Article↗
PubMed2004

Complexed prostate specific antigen (PSA) reduces unnecessary prostate biopsies in the 2.6-4.0 ng/mL range of total PSA.

OBJECTIVE: To compare the performance of complexed prostate-specific antigen (cPSA) to total PSA (tPSA) and percentage free PSA (f/tPSA) in the diagnosis of prostate cancer for the tPSA range 2.6-4.0 ng/mL. PATIENTS AND METHODS: Consecutive men scheduled for prostate biopsy were enrolled prospectively at 14 different sites in two multicentre studies in Europe and the USA. Serum obtained before biopsy was tested with the ACS:180 and Immuno 1 tPSA and cPSA assays (Bayer Diagnostics, Tarrytown, NY, USA) and the Access fPSA and tPSA assays (Beckman, Inc., San Diego, CA, USA). Receiver operating characteristics (ROC) curves were generated to compare the diagnostic performance of tPSA, cPSA and f/tPSA. RESULTS: Of 316 men with a tPSA of 2.6-4.0 ng/mL, 82 (26%) were diagnosed with prostate cancer on biopsy. ROC analysis of all 316 men showed an area under the curve (AUC) for cPSA of 0.63, significantly greater than the AUC for tPSA of 0.56 (P = 0.008). At a sensitivity of 95%, threshold values of 2.3 ng/mL for cPSA and 2.73 ng/mL for tPSA provided specificities of 20.1% and 9.8%, respectively. f/tPSA was only available for 205 of the 316 (65%) men and the AUC for cPSA was 0.63, and did not significantly differ from the f/tPSA AUC of 0.64 (P = 0.58). CONCLUSIONS: As a single test, cPSA provides improved specificity over tPSA and comparable specificity to f/tPSA for detecting prostate cancer, and may reduce the number of unnecessary prostate biopsies in the 2.6-4.0 ng/mL tPSA range.

Adult↗
PubMed2004

High-grade prostatic intraepithelial neoplasia.

High-grade prostatic intraepithelial neoplasia is considered the most likely precursor of prostatic carcinoma. The only method of detection is biopsy; prostatic intraepithelial neoplasia (PIN) does not significantly elevate serum prostate-specific antigen concentration and cannot be detected by ultra-sonography. The incidence of PIN in prostate biopsies averages 9% (range, 4%-16%), representing 115,000 new cases of PIN diagnosed each year in United States. PIN has a high predictive value as a marker for adenocarcinoma, and its identification warrants repeated biopsy for concurrent or subsequent invasive carcinoma. Carcinoma will develop in most patients with PIN within 10 years. PIN is associated with progressive abnormalities of phenotype and genotype that are intermediate between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis. Androgen deprivation therapy decreases the prevalence and extent of PIN, suggesting that this form of treatment may play a role in chemoprevention.

Journal Article↗
PubMed2004

Testosterone replacement therapy for a man with prostate cancer.

A 52-year-old male with elevated serum prostate-specific antigen (PSA) level, moderate lower urinary tract symptoms (LUTS), and negative family history of prostate cancer is found to have adenocarcinoma of the prostate with negative bone scan. Following radical retropubic prostatectomy and satisfactory postoperative recovery, heretofore undetectable serum PSA level rose 35 months later. Digital rectal examination (DRE) and bone scan were negative. Adjuvant external beam radiation preceded by a 3-month injection of goserelin was initiated. Radiation was well tolerated, although the patient reported significant loss of libido, hot flashes, and depression warranting antidepressant medication. Failure to respond to this intervention led to initiation of supplemental testosterone; 1 month later, the patient reported significant relief of symptoms. The patient is currently successfully tapering use of supplemental testosterone in order to decrease andropause symptoms and to permit restoration of intrinsic testosterone.

Case Reports↗
PubMed2004

Testosterone replacement in men with andropause: an overview.

Serum testosterone levels decline progressively as men age, with resulting pathophysiological changes. Because the onset of andropause is gradual and many of its symptoms mirror those associated with medications or disease states common in the elderly, a clinical diagnosis can be difficult to make. Additionally, because of a lack of established normal testosterone levels for different age groups, as well as confusion regarding what subset of testosterone to measure, simply testing testosterone levels is inadequate. Although clinical studies have shown testosterone supplementation to be safe, no long-term placebo-controlled trials have been performed. Among the possible side effects of testosterone replacement therapy is an increased risk of prostate cancer. While there is no evidence that supplemental testosterone will initiate prostate cancer or cause clinically significant progression of an established occult malignancy, the initial evaluation of patients prior to administration of testosterone requires screening for prostatic carcinoma. A number of formulations of testosterone are currently available; transdermal gels, although expensive, are the preferred modality because of their ease of administration.

Journal Article↗
PubMed2004

Challenges with luteinizing hormone-releasing hormone agonists: flare and surge.

Although the mechanism behind the role of circulating androgens in the development and progression of prostatic carcinoma is not totally clear, androgen deprivation therapy remains a mainstay of treatment for this cancer. As surgical orchiectomy has fallen out of favor and the use of estrogens has been associated with cardiac toxicity, pharmacologic approaches have become even more common, namely, the use of luteinizing hormone-releasing hormone (LHRH) agonists. These agents, however, are not without side effects; the primary ones are the "flare" phenomenon, which stems from an initial surge in testosterone level and can include increased pain at metastatic sites, spinal cord compression, and even sudden death. Some studies have reported increased morbidity with the use of LHRH agonists, and while the significance of flare is not entirely known at this point, data seem to indicate that, at least in men with advanced disease, avoiding flare may be prudent.

Journal Article↗
PubMed2003

A neurocomputational model for prostate carcinoma detection.

BACKGROUND: Current guidelines for prostate carcinoma screening rely primarily on the digital rectal examination (DRE) and prostate specific antigen (PSA). Well described patient risk factors for prostate carcinoma also include age, ethnicity, family history, and complexed PSA. However, due to the nonlinear relation of each of these variables with prostate carcinoma, it is difficult to predict reliably each patient's risk based on linear univariate analysis. The authors investigated a neural network to model the risk of prostate carcinoma by seven readily available clinical features. METHODS: The database for the current study comprised 3268 men recently evaluated for the early detection of prostate carcinoma. The seven clinical features evaluated included age, race, family history, International Prostate Symptom Score (IPSS), DRE, and total and complexed PSA. Three hundred forty-eight subjects in the dataset included men with determined prostate biopsy outcomes and for whom at least 6 of 7 features were available. The dataset was divided randomly into a training set (60%) and a test set (40%), with n1/n2 cross-validation used to evaluate model accuracy, and was modeled with linear and quadratic discriminant function analysis and a neural computational system. After a model with acceptable goodness of fit was achieved, reverse regression analysis using Wilks's generalized likelihood ratio test was performed to evaluate the statistical significance of each input variable. RESULTS: The receiving operating characteristic (ROC) area for the neural computational system in the test set was 0.825, whereas total PSA and complexed PSA alone had ROC areas of 0.678 and 0.697, respectively. The ROC area of logistic regression in the test set was 0.510, linear discriminant function analysis was 0.674, and quadratic discriminant function analysis was 0.011. All were significantly less than the ROC area of the neural computational model (all Ps < 0.002). Reverse regression based on Wilks's generalized likelihood ratio test demonstrated each input feature to be highly significant to the model (all Ps << 0.000001). CONCLUSIONS: The authors modeled a combination of well described patient risk factors for prostate carcinoma using a neural computational system with acceptable goodness of fit. They demonstrated that each of the seven variates on which the model was based was critically significant to model performance. The authors presented this model for clinical use and suggested that clinicians use it in deciding to perform prostate biopsy.

Age Factors↗
PubMed2003

Volume indexes of total, free, and complexed prostate-specific antigen enhance prediction of extraprostatic disease extension in men with nonpalpable prostate cancer.

OBJECTIVES: To analyze the ability of volume-adjusted total, complexed, and free prostate-specific antigen (PSA) to predict organ-confined cancer at radical prostatectomy in patients with nonpalpable disease. METHODS: Collected sera were assayed for total PSA (tPSA), complexed PSA (cPSA), and free PSA (fPSA) in 78 men who underwent radical prostatectomy with nonpalpable prostate cancer. The pathologic results (organ-confined versus extraprostatic extension [EPE]), tPSA, cPSA, fPSA/tPSA ratio, cPSA/tPSA ratio, fPSA/cPSA ratio, tPSA density (tPSAD), cPSA density (cPSAD), and fPSA density (fPSAD) were compared by the Mann-Whitney U test and receiver operating characteristic curves. RESULTS: Fifteen men (19.2%) had pathologic EPE. After stratifying the patients on the basis of the Beckman tPSA, the cPSAD, tPSAD, and fPSAD were significant predictors of EPE when comparing their respective medians in individuals with tPSA greater than 4.0 ng/mL. Statistically significant differences were noted between patients with and without EPE for tPSAD (P = 0.0015), cPSAD (P = 0.0018), and fPSAD (P = 0.0022), but not for the fPSA/tPSA, cPSA/tPSA, and fPSA/cPSA ratios. The area under the receiver operating characteristic curve was similar for tPSA (0.539) and cPSA (0.542), as it was for tPSAD (0.708), cPSAD (0.700), and fPSAD (0.731). The specificity and diagnostic accuracy of tPSAD, cPSAD, and fPSAD were significantly greater than those of tPSA and cPSA (specificity P <0.001; diagnostic accuracy P <0.05). CONCLUSIONS: In men with nonpalpable prostate cancer, the density parameters of tPSA, cPSA, and fPSA performed equivalently and appeared to enhance the predictability of EPE.

Adenocarcinoma↗
PubMed2003

Study design of the Medical Therapy of Prostatic Symptoms (MTOPS) trial.

Alpha-blockers and 5-alpha-reductase inhibitors are medical therapies that are being used as alternatives to surgical interventions to relieve symptoms of benign prostatic hyperplasia (BPH). Taken as monotherapy, alpha-blockers and 5-alpha-reductase inhibitors have each been shown to provide relief from BPH symptoms. Treatment with finasteride over 4 years has been shown to reduce both BPH symptoms and the likelihood of acute urinary retention and the need for surgery. Direct comparison of the alpha-blocker terazosin with finasteride has been done, but only for a period of 1 year. The Medical Therapy of Prostatic Symptoms (MTOPS) trial is a multicenter, randomized, placebo-controlled, double-masked clinical trial designed to evaluate the long-term efficacy of the alpha-blocker doxazosin and the 5-alpha-reductase inhibitor finasteride, whether taken as a monotherapy or in combination, in preventing or delaying the progression of BPH. We describe in this paper the design of the MTOPS trial, the concept of BPH progression, the definition and methods of determining the primary outcome events and the proposed statistical analysis methods. A unique feature of MTOPS is the inclusion of prostate biopsies on a subgroup of randomized participants. Volunteers among randomized participants are to undergo a biopsy of the prostate at predetermined time points during the trial. Studies that will be conducted using the tissue specimens collected in MTOPS can potentially provide information at the molecular level on the natural history of BPH among medically treated and untreated men with moderate to severe symptoms of BPH.

Data Collection↗
PubMed2003

Complexed prostate specific antigen improves specificity for prostate cancer detection: results of a prospective multicenter clinical trial.

PURPOSE: Complexed (c) prostate specific antigen (PSA) has been shown to enhance specificity for prostate cancer (CaP) detection over total PSA (tPSA), although a large multi-institutional prospective evaluation was required to confirm these findings. We compared the clinical performance of cPSA with tPSA as a first line test for CaP detection and secondarily to determine if PSA ratios, namely percent free PSA (fPSA) and percent cPSA, can provide further enhancement in diagnostic performance over cPSA or tPSA. MATERIALS AND METHODS: Consecutive men scheduled for initial biopsy of the prostate were enrolled prospectively at each of 7 university centers and community based urology practices. Serum was collected and tested with the Immuno 1 (Bayer Diagnostics, Tarrytown, New York), tPSA and cPSA, and Access (Beckman, Inc., San Diego, California) fPSA and tPSA methods. RESULTS: A total of 831 patients were evaluated, of whom 313 (37.5%) were diagnosed with CaP. ROC curve analysis performed from the results of all samples and those within the clinically relevant cPSA ranges of 1.5 to 3.2, 1.5 to 5.1, 1.5 to 8.3 and 3.2 to 8.3 ng/ml (tPSA 2 to 4, 2 to 6, 2 to 10 and 4 to 10 ng/ml, respectively) indicated a significant improvement in the AUC ROC curve for cPSA compared with tPSA (p < or =0.001). Using cutoff points that provide a sensitivity of 80% to 95% for CaP detection within the 1.5 to 8.3 ng/ml cPSA range cPSA provided a statistically significant enhancement in specificity over tPSA of 6.2% to 7.9%. Within the cPSA range of 1.5 to 3.2 ng/ml using a cutoff point of 2.5 ng/ml for tPSA and 2.2 ng/ml for cPSA provided a specificity of 21.2% and 35%, respectively, and 85% sensitivity for CaP detection. PSA ratios provided no further enhancement in specificity over cPSA within these ranges. CONCLUSIONS: The use of cPSA as a single test provided improved specificity over tPSA. Percent fPSA and percent cPSA offered little to no additional benefit in the differentiation of benign and malignant disease at clinically relevant cPSA concentrations.

Aged↗
PubMed2003

Androgen supplementation and prostate cancer risk: strategies for pretherapy assessment and monitoring.

Since in men androgen levels decrease with age and result in symptoms of hypogonadism, the use of testosterone supplementation to treat symptoms resulting from hypogonadism is increasing. One potential complication of this treatment is the possibility of an increased risk of prostate cancer. Although most authorities agree that androgen is involved in the exacerbation of existing carcinoma of the prostate, the action of androgens on the carcinogenic process is not well understood. Attempts to demonstrate a correlation between hormone levels and prostate cancer have yielded inconsistent results. No clear evidence exists that androgen supplementation to restore physiologic levels produces any deleterious effects on the prostate. It is highly doubtful that when testosterone therapy is administered to middle-aged or older men, any potential prostate cancer promotion effect will be clinically manifested in the absence of already established cancer. It is, however, imperative that existing or developing prostate cancer be ruled out before initiation and during androgen replacement therapy. As with any therapeutic regimen, careful monitoring of the patient receiving treatment is recommended and constitutes good medical care.

Journal Article↗
PubMed2003

Assays for complexed prostate-specific antigen and other advances in the diagnosis of prostate cancer.

This review discusses advances in the area of serum and tissue markers for prostate cancer. A recently developed assay for complexed prostate-specific antigen (PSA) has been found to have better specificity than that afforded by assay of total PSA. Researchers in Austria have found that lowering the PSA cutoff point for a diagnosis of prostate cancer resulted in a significant increase in identifying men with cancer at a favorable pathologic stage. Difficulties in pathologic interpretation of tissue specimens can result in both under- and over-diagnosis of prostate cancer. When in doubt, referral to a pathologist who specializes in prostate cancer is warranted. Epidermal growth factor receptor is emerging as an important therapeutic approach not only to prostate cancer but also to breast and colon cancers.

Journal Article↗