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Background Prostate tumor heterogeneity and biopsy undersampling pose challenges to accurate, individualized risk assessment for men with localized disease. Objective To identify and validate a biopsy-based gene expression signature that predicts clinical recurrence, prostate cancer (PCa) death, and adverse pathology. Design, setting, and participants Gene expression was quantified by reverse transcription-polymerase chain reaction for three studies - a discovery prostatectomy study (n = 441), a biopsy study (n = 167), and a prospectively designed, independent clinical validation study (n = 395) - testing retrospectively collected needle biopsies from contemporary (1997-2011) patients with low to intermediate clinical risk who were candidates for active surveillance (AS). Outcome measures and statistical analysis The main outcome measures defining aggressive PCa were clinical recurrence, PCa death, and adverse pathology at prostatectomy. Cox proportional hazards regression models were used to evaluate the association between gene expression and time to event end points. Results from the prostatectomy and biopsy studies were used to develop and lock a multigene-expression-based signature, called the Genomic Prostate Score (GPS); in the validation study, logistic regression was used to test the association between the GPS and pathologic stage and grade at prostatectomy. Decision-curve analysis and risk profiles were used together with clinical and pathologic characteristics to evaluate clinical utility. Results and limitations Of the 732 candidate genes analyzed, 288 (39%) were found to predict clinical recurrence despite heterogeneity and multifocality, and 198 (27%) were predictive of aggressive disease after adjustment for prostate-specific antigen, Gleason score, and clinical stage. Further analysis identified 17 genes representing multiple biological pathways that were combined into the GPS algorithm. In the validation study, GPS predicted high-grade (odds ratio [OR] per 20 GPS units: 2.3; 95% confidence interval [CI], 1.5-3.7; p < 0.001) and high-stage (OR per 20 GPS units: 1.9; 95% CI, 1.3-3.0; p = 0.003) at surgical pathology. GPS predicted high-grade and/or high-stage disease after controlling for established clinical factors (p < 0.005) such as an OR of 2.1 (95% CI, 1.4-3.2) when adjusting for Cancer of the Prostate Risk Assessment score. A limitation of the validation study was the inclusion of men with low-volume intermediate-risk PCa (Gleason score 3 + 4), for whom some providers would not consider AS. Conclusions Genes representing multiple biological pathways discriminate PCa aggressiveness in biopsy tissue despite tumor heterogeneity, multifocality, and limited sampling at time of biopsy. The biopsy-based 17-gene GPS improves prediction of the presence or absence of adverse pathology and may help men with PCa make more informed decisions between AS and immediate treatment. Patient summary Prostate cancer (PCa) is often present in multiple locations within the prostate and has variable characteristics. We identified genes with expression associated with aggressive PCa to develop a biopsy-based, multigene signature, the Genomic Prostate Score (GPS). GPS was validated for its ability to predict men who have high-grade or high-stage PCa at diagnosis and may help men diagnosed with PCa decide between active surveillance and immediate definitive treatment. © 2014 European Association of Urology.

OBJECTIVE: Sulfonylureas have historically been analyzed as a medication class, which may be inappropriate given the differences in properties inherent to the individual sulfonylureas (hypoglycemic risk, sulfonylurea receptor selectivity, and effects on myocardial ischemic preconditioning). The purpose of this study was to assess the relationship of individual sulfonylureas and the risk of overall mortality in a large cohort of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A retrospective cohort study was conducted using an academic health center enterprise-wide electronic health record (EHR) system to identify 11,141 patients with type 2 diabetes (4,279 initiators of monotherapy with glyburide, 4,325 initiators of monotherapy with glipizide, and 2,537 initiators of monotherapy with glimepiride), >or=18 years of age with and without a history of coronary artery disease (CAD) and not on insulin or a noninsulin injectable at baseline. The patients were followed for mortality by documentation in the EHR and Social Security Death Index. Multivariable Cox models were used to compare cohorts. RESULTS: No statistically significant difference in the risk of overall mortality was observed among these agents in the entire cohort, but we did find evidence of a trend toward an increased overall mortality risk with glyburide versus glimepiride (hazard ratio 1.36 [95% CI 0.96-1.91]) and glipizide versus glimepiride (1.39 [0.99-1.96]) in those with documented CAD. CONCLUSIONS: Our results did not identify an increased mortality risk among the individual sulfonylureas but did suggest that glimepiride may be the preferred sulfonylurea in those with underlying CAD. [ABSTRACT FROM AUTHOR]

Background: It has been demonstrated that multivariate prediction models predict cancer outcomes more accurately than cancer stage; however, the effects of these models on clinical management are unclear. The objective of the current study was to determine whether a previously published multivariate prediction model for bladder cancer ("bladder nomogram") improved medical decision making when referral for adjuvant chemotherapy was used as a model.Methods: Data were analyzed from an international cohort study of 4462 patients who underwent cystectomy without chemotherapy from 1969 to 2004. The number of patients eligible for chemotherapy was determined using pathologic stage criteria (lymph node-positive disease or pathologic T3 [pT3] or pT4 tumor classification) and for 3 cutoff levels on the bladder nomogram (10%, 25%, and 70% risk of recurrence with surgery alone). The number of recurrences was calculated by applying a relative risk reduction to the baseline risk among eligible patients. Clinical net benefit was then calculated by combining recurrences and treatments and weighting the latter by a factor related to drug tolerability.Results: A nomogram cutoff outperformed pathologic stage for chemotherapy in every scenario of drug effectiveness and tolerability. For a drug with a relative risk of 0.80, with which clinicians would treat Conclusions: The authors concluded that referring patients who undergo cystectomy to adjuvant chemotherapy on the basis of a multivariate model is likely to lead to better patient outcomes than the use of pathologic stage. Further research is warranted to evaluate the clinical effects of multivariate prediction models. [ABSTRACT FROM AUTHOR]

Current prostate cancer screening relies heavily upon PSA measurements and DRE findings, but many other factors can affect a patient's risk of having cancer. Limitations in study design have kept the use of prediction models from becoming standard practice. With current studies using saturation biopsies, prediction models may soon be developed to enhance the effectiveness of screening guidelines. [ABSTRACT FROM AUTHOR]

Phase 2 clinical trials are undertaken to provide evidence of treatment efficacy and safety. A test statistic that accounts for individual patient risk in the patient population is proposed and applied to a phase 2 clinical trial for castrate metastatic prostate cancer. The test statistic is computed to compare, for each patient, the observed 2-year survival outcome to the predicted 2-year survival probability. A logistic regression model, developed using historical data in the same patient population, is used to adjust for patient risk in predicting the 2-year survival probability. Goodness-of-fit procedures are performed to ensure that a proper model is fit to the data. The test result is compared to the score test, the binomial exact test, and Fisher's exact test, all of which use the average 2-year survival probability in the population as the parameter of interest. The results demonstrate the benefit of risk adjustment in determining treatment efficacy in a single-arm phase 2 trial. By adjusting for patient risk, this method can provide a more precise assessment of phase 2 treatment efficacy, thereby improving the decision whether to proceed to a phase 3 clinical trial. [ABSTRACT FROM AUTHOR]

Hot flashes are a common problem in men who undergo orchiectomy or treatment with androgen ablation therapy for prostate cancer. The analysis of this symptom has relied on the use of subjective tools such as patient diaries, but such approaches have been associated with problems in validity and reliability. Although developed to measure the impact of hot flashes in breast cancer survivors, the Hot Flash Related Daily Interference Scales (HFRDIS) exhibited high internal consistency and validity; its use should be considered in men who experience hot flashes. Additional reliable tools are needed to subjectively and objectively evaluate the impact of hot flashes in patients who receive androgen suppression therapy. [ABSTRACT FROM AUTHOR]

PURPOSE: To evaluate the effect of preference assessment method on treatment recommended by an individualized decision-analytic model for early prostate cancer. METHODS: Health state preferences were elicited by time tradeoff, rating scale, and a power transformation of the rating scale from 63 men ages 55 to 75. The authors used these values in a Markov model to determine whether radical prostatectomy or watchful waiting yielded the greater quality-adjusted life expectancy. RESULTS: Time tradeoff and transformed rating scale recommendations differed widely. Time tradeoff and transformed rating scale utilities differed in their treatment recommendation for 21% to 52% of men, and the mean difference in quality-adjusted life years varied from less than 0.5 to greater than 1.0. CONCLUSIONS: Treatment recommendations from the prostate cancer decision model were sensitive to the method of preference assessment. If decision analysis is used to counsel individual patients, careful consideration must be given to the method of preference elicitation. [ABSTRACT FROM AUTHOR]

BACKGROUND: Quality of life is often best estimated by standard gamble techniques. However, these techniques usually require time-consuming and expensive interviews or computer-directed questionnaires. Paper Standard Gamble (PSG) is a paper questionnaire that has previously been shown to accurately represent standard gambles elicited by computer. The authors sought to demonstrate its test-retest reliability in comparison to other, paper-based measures of quality of life. METHODS: The authors used a longitudinal cohort design with duplicate assessments of quality of life by PSG, the Dermatology Life Quality Index, and the Mental and Physical Component Summary scores of the SF-12 in stable dermatology out-patients. Baseline measures were performed by mail 1 to 2 weeks before a scheduled dermatology clinic visit. Follow-up measures were performed in the waiting room before being seen by the dermatologist. The authors calculated the coefficient of variation and the Spearman rank correlation coefficient for each of the instruments. RESULTS: 74 patients with stable skin conditions participated. The coefficient of variation of PSG (0.47%) was smaller than the other instruments (4.26%-5.22%); PSG's correlation was higher (0.97 v. 0.65-0.80). CONCLUSION: PSG, a 1-page paper questionnaire, is a reliable measure of patient utility suitable for use in postal surveys. [ABSTRACT FROM AUTHOR]

Objective: To compare the cost-effectiveness of interferon-alpha with that of hydroxyurea as initial therapy for patients with chronic myelogenous leukemia (CML) in the chronic phase.Design: A decision analysis and Markov model that described the natural history of the therapeutic process. The Markov model contained two treatment arms (interferon-alpha and hydroxyurea) and eight states of health (complete hematologic remission with cytogenetic response, complete hematologic remission without cytogenetic response, partial hematologic remission, chronic phase without hematologic remission, accelerated phase, blast crisis, bone marrow transplantation, and death). Probabilities, costs, and utilities were obtained from published clinical studies and clinical investigators.Measurement: Quality-adjusted years of life saved and costs and qualities discounted at 5% per year.Setting: University medical centers in North America and Europe.Patients: Meta-analysis of results from patients studied in clinical trials.Results: The model's predictions of median survival (69 months with interferon-alpha therapy and 58 months with hydroxyurea therapy) were derived from data in the recent literature. In patients 50 years of age, interferon-alpha improved life expectancy over hydroxyurea by approximately 18 months. The marginal cost-effectiveness of interferon-alpha (incremental discounted cost of interferon-alpha compared with that of conventional therapy) was $34800 per quality-adjusted year of life saved. The model was sensitive to the monthly cost of interferon-alpha therapy (if the cost of interferon-alpha is reduced by one third, the cost-effectiveness becomes $19300 per quality-adjusted year of life saved) but was not particularly sensitive to the costs associated with blast crisis or bone marrow transplantation. The other significant variable was quality of life during therapy with interferon-alpha; when this measure was varied from 70% to 100% of the quality of life during hydroxyurea therapy, cost-effectiveness changed from $123200 to $25620 per quality-adjusted year of life saved. When the quality of life associated with interferon-alpha was less than 62% of the quality of life associated with hydroxyurea, the discounted quality-adjusted life expectancy with interferon-alpha was less than that with hydroxyurea.Conclusion: Compared with hydroxyurea, interferon-alpha is, in most clinical scenarios, a cost-effective initial therapy for patients with chronic-phase CML who can tolerate the drug. [ABSTRACT FROM AUTHOR]

Objective: To report the relative incidence of the perceived reduction in penile size across prostate cancer treatment modalities and to describe its effect on quality of life and treatment regret.Materials and Methods: The incidence of patient complaints about reduced penile size was calculated for 948 men in the Comprehensive, Observational, Multicenter, Prostate Adenocarcinoma (COMPARE) registry who experienced biochemical failure (per registry definition) and were assessed a median of 5.53 years after prostatectomy or radiotherapy (RT) consisting of either external beam RT or brachytherapy, with or without androgen deprivation therapy (ADT). Multivariate logistic regression analysis was used to determine the factors associated with treatment regret and interference with emotional relationships.Results: Of 948 men, 25 (2.63%) complained of a reduced penile size. The incidence of reduced penile size stratified by treatment was 3.73% for surgery (19 of 510), 2.67% for RT plus ADT (6 of 225), and 0% for RT without ADT (0 of 213). The surgery (P=.004) and RT plus ADT (P=.016) groups had significantly more shortened penis complaints than the RT alone group. The rate of a shortened penis after surgery and after RT plus ADT was similar (P=.47). On multivariate analysis adjusting for age, treatment type, and baseline comorbidity, a perceived reduction in penile size was associated with interference with close emotional relationships (odds ratio 2.36, 95% confidence interval 1.02-8.26; P=.04) and increased treatment regret (odds ratio 3.37, 95% confidence interval 1.37-8.26; P=.0079).Conclusion: Complaints about a reduced penile size were more common with RT plus ADT or surgery than RT alone and were associated with greater interference with close emotional relationships and increased treatment regret. Physicians should discuss the possibility of this rarely mentioned side effect with their patients to help them make more informed treatment choices. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy (ADT) is a standard mode of therapy for patients with metastatic prostate cancer. Controversy exists, however, as to the optimal timing of initiation of ADT, as well as whether this form of therapy imparts a survival benefit to patients with advanced disease. Side effects of ADT are not minimal and can seriously compromise a patient's quality of life. Additionally, ADT eventually results in hormone-refractory prostate cancer (HRPC). Despite new chemotherapeutic regimens and hormonal agents, overall survival in these patients remains universally low. Nonetheless, it is valuable to gauge a patient's prognosis to assist in decision making when considering treatment options. Contemporary series analyzing patients with HRPC have identified several factors prognostic of survival outcomes, such as lactate dehydrogenase (LDH), alkaline phosphatase (ALK), hemoglobin (Hgb), and serum prostate specific antigen (PSA) level. Nomograms have been developed that utilize these pretreatment clinical variables to predict clinical outcomes, including 1-year, 2-year, and median survival times in patients with HRPC. These instruments are capable of more accurately predicting survival outcomes than traditional tables of multivariate results or simple analysis of prognostic factors. We believe these nomograms will become indispensable tools for patient counseling and clinical trial design in patients with HRPC. [ABSTRACT FROM AUTHOR]

Bcl-2 antagonizes p53-induced apoptosis and may contribute to chemoresistance. In renal cell carcinoma (RCC), the role of bcl-2 is not well-defined, though its expression is reportedly low in primary tumors and lacks prognostic value. This study evaluates patterns of bcl-2 expression in high-risk (pT(3)) primary tumors and in matched patient metastases. Immunohistochemical analysis of bcl-2 was performed on 149 cases of conventional (clear cell) RCC (112 pT(3) primaries, 37 metastases). Paraffin-embedded tissues were obtained from nephrectomies and metastatic resections. Median follow up was 48 months in the entire cohort and 69 months in living patients. We evaluated associations between bcl-2 expression and tumor recurrence or patient survival with the Cox regression test, and used the t-test and Pearson correlation methods to evaluate bcl-2 expression in primary and metastatic cases. Bcl-2 expression was observed at a higher frequency in metastases (21/37 cases; 57%) compared to primary tumors (24/112 cases; 21%; P < 0.001). The percentage of cells stained was greater in metastases than primary tumors (P = 0.003). This finding was also noted when expression in metastatic cases was compared with matched primaries (P = 0.05). Bcl-2 expression did not predict disease-free (P = 0.30), disease-specific (P = 0.90), or overall (P = 0.51) survival. Most RCC primary tumors have low-to-absent levels of bcl-2 protein, whereas most RCC metastases display greater protein levels. Bcl-2 expression in primary tumors does not predict clinical outcome. However, expression of bcl-2 protein occurs at a high frequency in RCC metastases when compared to primary tumors. It may be reasonable to target RCC patients displaying altered bcl-2 levels for molecular therapies, such as anti-bcl2, should metastatic disease develop. [ABSTRACT FROM AUTHOR]