Association of Rapid Eye Movement Sleep With Mortality in Middle-aged and Older Adults.

Importance: Rapid eye movement (REM) sleep has been linked with health outcomes, but little is known about the relationship between REM sleep and mortality. Objective: To investigate whether REM sleep is associated with greater risk of mortality in 2 independent cohorts and to explore whether another sleep stage could be driving the findings. Design, Setting, and Participants: This multicenter population-based cross-sectional study used data from the Outcomes of Sleep Disorders in Older Men (MrOS) Sleep Study and Wisconsin Sleep Cohort (WSC). MrOS participants were recruited from December 2003 to March 2005, and WSC began in 1988. MrOS and WSC participants who had REM sleep and mortality data were included. Analysis began May 2018 and ended December 2019. Main Outcomes and Measures: All-cause and cause-specific mortality confirmed with death certificates. Results: The MrOS cohort included 2675 individuals (2675 men [100%]; mean [SD] age, 76.3 [5.5] years) and was followed up for a median (interquartile range) of 12.1 (7.8-13.2) years. The WSC cohort included 1386 individuals (753 men [54.3%]; mean [SD] age, 51.5 [8.5] years) and was followed up for a median (interquartile range) of 20.8 (17.9-22.4) years. MrOS participants had a 13% higher mortality rate for every 5% reduction in REM sleep (percentage REM sleep SD = 6.6%) after adjusting for multiple demographic, sleep, and health covariates (age-adjusted hazard ratio, 1.12; fully adjusted hazard ratio, 1.13; 95% CI, 1.08-1.19). Results were similar for cardiovascular and other causes of death. Possible threshold effects were seen on the Kaplan-Meier curves, particularly for cancer; individuals with less than 15% REM sleep had a higher mortality rate compared with individuals with 15% or more for each mortality outcome with odds ratios ranging from 1.20 to 1.35. Findings were replicated in the WSC cohort despite younger age, inclusion of women, and longer follow-up (hazard ratio, 1.17; 95% CI, 1.03-1.34). A random forest model identified REM sleep as the most important sleep stage associated with survival. Conclusions and Relevance: Decreased percentage REM sleep was associated with greater risk of all-cause, cardiovascular, and other noncancer-related mortality in 2 independent cohorts.

Urodynamic factors associated with the large capacity bladder and incomplete emptying after prolapse repair (2009-2015).

AIMS: To identify the clinical and urodynamic factors associated with the large capacity bladder and incomplete bladder emptying after prolapse repair. METHODS: We identified 592 women who underwent anterior and/or apical prolapse repair at our institution from 2009 to 2015. Women were stratified by urodynamic capacity. The primary outcome was incomplete emptying at the longest follow-up (postvoid residual [PVR] > 200 mL). Data were analyzed in the Statistical Analysis System software. RESULTS: Two hundred and sixty-six women (mean age, 61 years) had preoperative urodynamic tracings available for review. After surgery, there were 519 PVRs in 239 women recorded at up to 2949 days (mean, 396) and nine time points (median, 2; IQR, 1-3). The receiver operator curve for predicted probability of longest follow-up PVR greater than 200 mL (area under curve = 0.67) identified the 600 mL cutpoint which defined large capacity bladder. Large capacity bladders (capacity, >600 mL [n=79] vs ≤600 mL, [n=160]) had a mean: detrusor pressure at maximum flow (21 vs 22 cm H2 O; P = 0.717), maximum flow rate (19 vs 17 mL/s; P = 0.148), significantly elevated PVR (202 vs 73 mL; P < 0.001), and significantly lower voiding efficiency (VE) (74 vs 82%, P < 0.05). Following prolapse repair, elevated PVR was associated with large capacity (PVR 101 vs 49 mL, P < 0.05). Large bladders had a two- to three-fold risk of longest follow-up PVR greater than 200 mL (14.3%-20.3% [capacity, >600 mL] vs 4.1%-7.0% [capacity, ≤600 mL]). VE was similar after surgery regardless of the capacity (87% vs 88%, P = 0.772). CONCLUSIONS: The decision to pursue prolapse repair should be individualized and take into account, the bladder capacity and goals for PVR improvement after surgery.

How and why studies disagree about the effects of education on health: A systematic review and meta-analysis of studies of compulsory schooling laws.

Rich literatures across multiple disciplines document the association between increased educational attainment and improved health. While quasi-experimental studies have exploited variation in educational policies to more rigorously estimate the health effects of education, there remains disagreement about whether education and health are causally linked. The aim of this study was to conduct a systematic review and meta-analysis to characterize this literature, with a focus on quasi-experimental studies of compulsory schooling laws (CSLs). Articles from 1990 to 2015 were obtained through electronic searches and manual searches of reference lists. We searched for English-language studies and included manuscripts if: (1) they involved original data analysis; (2) outcomes were health-related; and (3) the primary predictor utilized variation in CSLs. We identified 89 articles in 25 countries examining over 25 health outcomes, with over 600 individual point estimates. We systematically characterized heterogeneity on key study design features and conducted a meta-analysis of studies with comparable health outcome and exposure variables. Within countries, studies differed in terms of birth cohorts included, the measurement of health outcomes within a given category, and the type of CSL variation examined. Over 90% of manuscripts included multiple analytic techniques, such as econometric and standard regression methods, with as many as 31 "primary" models in a single study. A qualitative synthesis of study findings indicated that educational attainment has an effect on the majority of health outcomes-most beneficial, some negative-while the meta-analysis demonstrated small beneficial effects for mortality, smoking, and obesity. Future work could focus on inconsistent findings identified by this study, or review the health effects of other types of educational policies.

An epigenetic marker panel for detection of lung cancer using cell-free serum DNA.

PURPOSE: We investigated the feasibility of detecting aberrant DNA methylation of some novel and known genes in the serum of lung cancer patients. EXPERIMENTAL DESIGN: To determine the analytic sensitivity, we examined the tumor and the matched serum DNA for aberrant methylation of 15 gene promoters from 10 patients with primary lung tumors by using quantitative methylation-specific PCR. We then tested this 15-gene set to identify the more useful DNA methylation changes in the serum of a limited number of lung cancer patients and controls. In an independent set, we tested the six most promising genes (APC, CDH1, MGMT, DCC, RASSF1A, and AIM1) for further elucidation of the diagnostic application of this panel of markers. RESULTS: Promoter hypermethylation of at least one of the genes studied was detected in all 10 lung primary tumors. In majority of cases, aberrant methylation in serum DNA was accompanied by methylation in the matched tumor samples. In the independent set, using a single gene that had 100% specificity (DCC), 35.5% (95% CI: 25-47) of the 76 lung cancer patients were correctly identified. For patients without methylated DCC, addition of a logistic regression score that was based on the five remaining genes improved sensitivity from 35.5% to 75% (95% CI: 64-84) but decreased the specificity from 100% to 73% (95% CI: 54-88). CONCLUSION: This approach needs to be evaluated in a larger test set to determine the role of this gene set in early detection and surveillance of lung cancer.

High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease.

Because of its potent immunosuppressive yet stem cell-sparing activity, high-dose cyclophosphamide was tested as sole prophylaxis of graft-versus-host disease (GVHD) after myeloablative allogeneic bone marrow transplantation (alloBMT). We treated 117 patients (median age, 50 years; range, 21-66 years) with advanced hematologic malignancies; 78 had human leukocyte antigen (HLA)-matched related donors and 39 had HLA-matched unrelated donors. All patients received conventional myeloablation with busulfan/cyclophosphamide (BuCy) and T cell-replete bone marrow followed by 50 mg/kg/d of cyclophosphamide on days 3 and 4 after transplantation. The incidences of acute grades II through IV and grades III through IV GVHD for all patients were 43% and 10%, respectively. The nonrelapse mortality at day 100 and 2 years after transplantation were 9% and 17%, respectively. The actuarial overall survival and event-free survivals at 2 years after transplantation were 55% and 39%, respectively, for all patients and 63% and 54%, respectively, for patients who underwent transplantation while in remission. With a median follow-up of 26.3 months among surviving patients, the cumulative incidence of chronic GVHD is 10%. These results suggest that high-dose posttransplantation cyclophosphamide is an effective single-agent prophylaxis of acute and chronic GVHD after BuCy conditioning and HLA-matched BMT (clinicaltrials.gov no. NCT00134017).

Sensitive digital quantification of DNA methylation in clinical samples.

Analysis of abnormally methylated genes is increasingly important in basic research and in the development of cancer biomarkers. We have developed methyl-BEAMing technology to enable absolute quantification of the number of methylated molecules in a sample. Individual DNA fragments are amplified and analyzed either by flow cytometry or next-generation sequencing. We demonstrate enumeration of as few as one methylated molecule in approximately 5,000 unmethylated molecules in DNA from plasma or fecal samples. Using methylated vimentin as a biomarker in plasma samples, methyl-BEAMing detected 59% of cancer cases. In early-stage colorectal cancers, this sensitivity was four times more than that obtained by assaying serum-carcinoembryonic antigen (CEA). With stool samples, methyl-BEAMing detected 41% of cancers and 45% of advanced adenomas. In addition to diagnostic and prognostic applications, this digital quantification of rare methylation events should be applicable to preclinical assessment of new epigenetic biomarkers and quantitative analyses in epigenetic research.

Phase II study of risk-adapted therapy of newly diagnosed, aggressive non-Hodgkin lymphoma based on midtreatment FDG-PET scanning.

In newly diagnosed aggressive non-Hodgkin lymphoma (NHL), a positive midtreatment fluorine-18 fluorodeoxyglucose positron emission tomography (PET) scan often carries a poor prognosis, with reported 2-year event-free survival (EFS) rates of 0% to 30% after standard therapy. To determine the outcome of early treatment intensification for midtreatment PET-positive disease, a phase II trial of risk-adapted therapy was conducted. Fifty-nine newly diagnosed patients, 98% with B cell lymphoma, had PET/CT performed after 2 or 3 cycles of first-line chemotherapy. Those with negative PET on semiquantitative visual interpretation completed standard therapy. Those with positive PET received platinum-based salvage chemotherapy, high-dose therapy, and autologous stem cell transplantation (ASCT). Midtreatment PET was positive in 33 (56%); 28 received ASCT with an actuarial 2-year EFS of 75% (95% confidence interval, 60%-93%). On intention-to-treat analysis, 2-year EFS was 67% (53%-86%) in all PET-positive patients and 89% (77%-100%) in PET-negative patients. No association was found between the International Prognostic Index category and the midtreatment PET result. The favorable outcome achieved here in historically poor-risk patients warrants further, more definitive investigation of treatment modification based on early PET scanning.

RNAi-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy.

Nuclear factor erythroid-2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that regulates the expression of electrophile and xenobiotic detoxification enzymes and efflux proteins, which confer cytoprotection against oxidative stress and apoptosis in normal cells. Loss of function mutations in the Nrf2 inhibitor, Kelch-like ECH-associated protein (Keap1), results in constitutive activation of Nrf2 function in non-small cell lung cancer. In this study, we show that constitutive activation of Nrf2 in lung cancer cells promotes tumorigenicity and contributes to chemoresistance by up-regulation of glutathione, thioredoxin, and the drug efflux pathways involved in detoxification of electrophiles and broad spectrum of drugs. RNAi-mediated reduction of Nrf2 expression in lung cancer cells induces generation of reactive oxygen species, suppresses tumor growth, and results in increased sensitivity to chemotherapeutic drug-induced cell death in vitro and in vivo. Inhibiting Nrf2 expression using naked siRNA duplexes in combination with carboplatin significantly inhibits tumor growth in a subcutaneous model of lung cancer. Thus, targeting Nrf2 activity in lung cancers, particularly those with Keap1 mutations, could be a promising strategy to inhibit tumor growth and circumvent chemoresistance.

Systematic review: gene expression profiling assays in early-stage breast cancer.

BACKGROUND: Three gene expression-based prognostic breast cancer tests have been licensed for use. PURPOSE: To summarize evidence on the validity and utility of 3 gene expression-based prognostic breast cancer tests: Oncotype DX (Genomic Health, Redwood City, California), MammaPrint (Agendia BV, Amsterdam, the Netherlands), and H/I (AvariaDX, Carlsbad, California). DATA SOURCES: MEDLINE, EMBASE, and Cochrane databases (from 1990 through January 2007), Web sites of test manufacturers, and discussion with the manufacturers. STUDY SELECTION: Original data studies published in English that addressed prognostic accuracy and discrimination or treatment benefit prediction of any of the 3 tests in women with breast cancer. DATA EXTRACTION: Information was extracted about the clinical characteristics of the study population (particularly clinical and therapeutic homogeneity), tumor characteristics, and whether the marketed test or underlying signature was evaluated. DATA SYNTHESIS: The tests are based on distinct gene lists, using 2 different technologies. Overall, the body of evidence showed that this new generation of tests may improve prognostic and therapeutic prediction, but the tests are at different stages of development. Evidence shows that the tests offer clinically relevant, improved risk stratification over standard predictors. Oncotype DX has the strongest evidence, closely followed by MammaPrint and H/I (which is still maturing). LIMITATIONS: For all tests, the relationship of predicted to observed risk in different populations and their incremental contribution over conventional predictors, optimal implementation, and relevance to patients receiving current therapies need further study. CONCLUSION: Gene expression technologies show great promise to improve predictions of prognosis and treatment benefit for women with early-stage breast cancer. More information is needed on the extent of improvement in prediction, characteristics of women in whom the tests should be used, and how best to incorporate test results into decision making about breast cancer treatment.

Tissue inhibitor of metalloproteinases-3 promoter methylation is an independent prognostic factor for bladder cancer.

PURPOSE: TIMP-3 (tissue inhibitor of metalloproteinases-3) is 1 of 4 members of a family of proteins that were originally classified according to their ability to inhibit matrix metalloproteinases. We analyzed TIMP-3 methylation in 175 urine sediment DNA samples from patients with bladder cancer with well characterized clinicopathological parameters, including patient outcome. MATERIALS AND METHODS: We examined urine sediment DNA for aberrant methylation of 9 genes, including TIMP-3, by quantitative fluorogenic real-time polymerase chain reaction. RESULTS: Using an optimal cutoff value by TaqMan(R) quantitation we found that the risk of death was statistically significantly higher in patients with higher TIMP-3 and ARF methylation (HR 1.99, 95% CI 1.12 to 3.27, p = 0.01 and HR 1.66, 95% CI 1.00 to 2.76, p = 0.05, respectively) than in patients without/lower TIMP3 and ARF methylation in urine. A significant correlation was also seen between the risk of death and stage 3 tumor (HR 2.73, 95% CI 1.58 to 4.72, p = 0.003) and metastasis (HR 3.32, 95% CI 1.98 to 5.57, p = 0.0001). Multivariate analysis subsequently revealed that TIMP-3 methylation was an independent prognostic factor for bladder cancer survival with stage and metastasis (p = 0.001 and 0.02, respectively). CONCLUSIONS: These results suggest that TIMP-3 promoter methylation could be a clinically applicable marker for bladder cancer progression.

Purpose and benefits of early phase cancer trials: what do oncologists say? What do patients hear?

CANCER PATIENTS OVERESTIMATE BENEFITS of early phase trials but studies have not reported what oncologists say to patients about trials. We audiotaped oncologists talking to cancer patients about Phase I or II trials and interviewed patients about the purpose and expected outcomes of trials presented to them. Oncologists gave mixed messages, saying Phase I trials measure safety and dosing, yet referring to trials as treatment with uncertain therapeutic effects. Seventeen percent of Phase I respondents said the trial's purpose related to safety/dosing (p = 0.017); 17% of Phase I respondents said the purpose was "to cure my cancer." Patients may find it important to believe trials offer significant benefit. Oncologists, while respecting patients' hopes, should be precise in their language, particularly regarding Phase I trials, distinguishing early stages of research from treatment.

Impact of gene expression profiling tests on breast cancer outcomes.

OBJECTIVES: To assess the evidence that three marketed gene expression-based assays improve prognostic accuracy, treatment choice, and health outcomes in women diagnosed with early stage breast cancer. REVIEW METHODS: We evaluated the evidence for three gene expression assays on the market; Oncotype DX, MammaPrint and the Breast Cancer Profiling (BCP or H/I ratio) test, and for gene expression signatures underlying the assays. We sought evidence on: analytic performance of tests, clinical validity (i.e., prognostic accuracy and discrimination), clinical utility (i.e., prediction of treatment benefit), harms, impact on clinical decision making and health care costs. RESULTS: Few papers were found on the analytic validity of the Oncotype DX and MammaPrint tests, but these showed reasonable within-laboratory replicability. Pre-analytic issues related to sample storage and preparation may play a larger role than within-laboratory variation. For clinical validity, studies differed according to whether they examined the actual test that is currently being offered to patients or the underlying gene signature. Almost all of the Oncotype DX evidence was for the marketed test, the strongest validation study being from one arm of a randomized controlled trial (NSABP-14) with a clinically homogeneous population. This study showed that the test, added in a clinically meaningful manner to standard prognostic indices. The MammaPrint signature and test itself was examined in studies with clinically heterogeneous populations (e.g., mix of ER positivity and tamoxifen treatment) and showed a clinically relevant separation of patients into risk categories, but it was not clear exactly how many predictions would be shifted across decision thresholds if this were used in combination with traditional indices. The BCP test itself was examined in one study, and the signature was tested in a variety of formulations in several studies. One randomized controlled trial provided high quality retrospective evidence of the clinical utility of Oncotype DX to predict chemotherapy treatment benefit, but evidence for clinical utility was not found for MammaPrint or the H/I ratio. Three decision analyses examined the cost-effectiveness of breast cancer gene expression assays, and overall were inconclusive. CONCLUSIONS: Oncotype DX is furthest along the validation pathway, with strong retrospective evidence that it predicts distant spread and chemotherapy benefit to a clinically relevant extent over standard predictors, in a well-defined clinical subgroup with clear treatment implications. The evidence for clinical implications of using MammaPrint was not as clear as with Oncotype DX, and the ability to predict chemotherapy benefit does not yet exist. The H/I ratio test requires further validation. For all tests, the relationship of predicted to observed risk in different populations still needs further study, as does their incremental contribution, optimal implementation, and relevance to patients on current therapies.

Quantitation of promoter methylation of multiple genes in urine DNA and bladder cancer detection.

BACKGROUND: The noninvasive identification of bladder tumors may improve disease control and prevent disease progression. Aberrant promoter methylation (i.e., hypermethylation) is a major mechanism for silencing tumor suppressor genes and other cancer-associated genes in many human cancers, including bladder cancer. METHODS: A quantitative fluorogenic real-time polymerase chain reaction (PCR) assay was used to examine primary tumor DNA and urine sediment DNA from 15 patients with bladder cancer and 25 control subjects for promoter hypermethylation of nine genes (APC, ARF, CDH1, GSTP1, MGMT, CDKN2A, RARbeta2, RASSF1A, and TIMP3) to identify potential biomarkers for bladder cancer. We then used these markers to examine urine sediment DNA samples from an additional 160 patients with bladder cancers of various stages and grades and from an additional 69 age-matched control subjects. Data were analyzed on the basis of a prediction model and were internally validated using a jacknife procedure. All statistical tests were two-sided. RESULTS: For all 15 patients with paired DNA samples, the promoter methylation pattern in urine matched that in the primary tumors. Four genes displayed 100% specificity. Of the 175 bladder cancer patients, 121 (69%, 95% confidence interval [CI] = 62% to 76%) displayed promoter methylation in at least one of these genes (CDKN2A, ARF, MGMT, and GSTP1), whereas all control subjects were negative for such methylation (100% specificity, 95% CI = 96% to 100%). A logistic prediction model using the methylation levels of all remaining five genes was developed and internally validated for subjects who were negative on the four-gene panel. This combined, two-stage predictor produced an internally validated ROC curve with an overall sensitivity of 82% (95% CI = 75 % to 87%) and specificity of 96% (95% CI = 90% to 99%). CONCLUSION: Testing a small panel of genes with the quantitative methylation-specific PCR assay in urine sediment DNA is a powerful noninvasive approach for the detection of bladder cancer. Larger independent confirmatory cohorts with longitudinal follow-up will be required in future studies to define the impact of this technology on early detection, prognosis, and disease monitoring before clinical application.

Ethical issues in evidence-based surgery.

Evidence-based medicine, although ostensibly concerned with the research evidence underlying claims of efficacy for surgical procedures,has a direct connection with the ethics of surgical decision making. Questions of whether new procedures should ever be performed on patients outside of a formal research protocol, what the patient should be told about the uncertainties inherent in the use of nonvalidated innovative procedures, when formal evaluation is necessary, what form that evaluation should take, and how the burdens and results of such research can be distributed fairly all involve balancing competing ethical principles. Good ethics requires good facts, and evidence from well-controlled experiments provides best information upon which to base decisions in these areas and to build ethical surgical practice.

Phase I study of low-dose interleukin-2, fludarabine, and cyclophosphamide for previously untreated indolent lymphoma and chronic lymphocytic leukemia.

PURPOSE: Fludarabine and cyclophosphamide is an effective combination but increases the risk of opportunistic infections due to depressed lymphocyte counts. In an attempt to preserve CD4 counts, we conducted a phase I, double-blind, placebo-controlled trial of recombinant interleukin-2 (IL-2) added to fludarabine and cyclophosphamide in patients with treatment-naive indolent lymphomas or chronic lymphocytic leukemia. EXPERIMENTAL DESIGN: Subcutaneous IL-2 (days 1-21 of each 28-day cycle) was combined with cyclophosphamide (600 mg/m2, day 8) and fludarabine (20 mg/m2, days 8-12) at four dose levels: 0.8, 1.0, 1.2, and 1.4 x 10(6) IU/m2/d. IL-2 dose was escalated in cohorts of four to six patients, with one patient per cohort receiving placebo. RESULTS: Twenty-three patients, median age 50, were enrolled, of whom 30% had chronic lymphocytic leukemia/small lymphocytic lymphoma and 52% had follicular lymphomas. The combination was generally well tolerated, with mainly hematologic toxicities. CD4 counts typically declined substantially during the early weeks of treatment and remained suppressed for months afterward. In the 18 evaluable patients who received IL-2, the mean absolute CD4 count was 999 cells/microL (range, 97-3,776) pretreatment, 379 cells/microL (range, 54-2,599) at day 14, and 98 cells/microL (range, 17-291) at end of treatment. In longitudinal linear models, the changes in CD4 counts were not significantly different across IL-2 dose levels. CONCLUSIONS: The addition of low-dose IL-2 to fludarabine and cyclophosphamide does not seem immunoprotective. New approaches are needed to reduce the cellular immunosuppression and infectious complications associated with purine analogues.

Detection and quantification of mutations in the plasma of patients with colorectal tumors.

The early detection of cancers through analysis of circulating DNA could have a substantial impact on morbidity and mortality. To achieve this goal, it is essential to determine the number of mutant molecules present in the circulation of cancer patients and to develop methods that are sufficiently sensitive to detect these mutations. Using a modified version of a recently developed assay for this purpose, we found that patients with advanced colorectal cancers consistently contained mutant adenomatous polyposis coli (APC) DNA molecules in their plasma. The median number of APC DNA fragments in such patients was 47,800 per ml of plasma, of which 8% were mutant. Mutant APC molecules were also detected in >60% of patients with early, presumably curable colorectal cancers, at levels ranging from 0.01% to 1.7% of the total APC molecules. These results have implications for the mechanisms through which tumor DNA is released into the circulation and for diagnostic tests based on this phenomenon.

Role and limitations of epidemiology in establishing a causal association.

Cancer risk assessment is one of the most visible and controversial endeavors of epidemiology. Epidemiologic approaches are among the most influential of all disciplines that inform policy decisions to reduce cancer risk. The adoption of epidemiologic reasoning to define causal criteria beyond the realm of mechanistic concepts of cause-effect relationships in disease etiology has placed greater reliance on controlled observations of cancer risk as a function of putative exposures in populations. The advent of molecular epidemiology further expanded the field to allow more accurate exposure assessment, improved understanding of intermediate endpoints, and enhanced risk prediction by incorporating the knowledge on genetic susceptibility. We examine herein the role and limitations of epidemiology as a discipline concerned with the identification of carcinogens in the physical, chemical, and biological environment. We reviewed two examples of the application of epidemiologic approaches to aid in the discovery of the causative factors of two very important malignant diseases worldwide, stomach and cervical cancers. Both examples serve as paradigms of successful cooperation between epidemiologists and laboratory scientists in the pursuit of the understanding of cancer etiology.

Quantitative GSTP1 methylation and the detection of prostate adenocarcinoma in sextant biopsies.

Hypermethylation of the 5' promoter region of the glutathione S-transferase pi gene (GSTP1) occurs at a very high frequency in prostate adenocarcinoma. We compared the results of blinded histologic review of sextant biopsy samples from 72 excised prostates with those obtained using a quantitative methylation-specific polymerase chain reaction assay (QMSP) for GSTP1. Formal surgical pathologic review of the resected prostates was used to determine the number of patients with (n = 61) and without (n = 11) prostate cancer. Histology alone detected prostate carcinoma with 64% sensitivity (95% confidence interval [CI] = 51% to 76%) and 100% specificity (95% CI = 72% to 100%), whereas the combination of histology and GSTP1 QMSP at an assay threshold greater than 10 detected prostate carcinoma with 75% sensitivity (95% CI = 63% to 86%) and 100% specificity (95% CI = 72% to 100%), an 11% improvement (95% CI = 5% to 22%) in sensitivity over histology alone. The combination of histology and GSTP1 QMSP at an assay threshold greater than 5 detected prostate adenocarcinoma with 79% sensitivity (95% CI = 68% to 89%), a 15% improvement (95% CI = 7% to 26%) over histology alone. Thus, GSTP1 QMSP improved the sensitivity of histologic review of random needle biopsies for prostate cancer diagnosis. Further studies should determine whether detection of GSTP1 hypermethylation in a biopsy sample with normal histology indicates the need for an early repeat biopsy at the same site.