BACKGROUND The effectiveness of surgery versus observation for men with localized prostate cancer detected by means of prostate-specific antigen (PSA) testing is not known. METHODS From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality. RESULTS During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P = 0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P = 0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P = 0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P = 0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death. CONCLUSIONS Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points. (Funded by the Department of Veterans Affairs Cooperative Studies Program and others; PIVOT ClinicalTrials.gov number, NCT00007644.)

Chronic pain hypersensitivity depends upon N-methyl-D-aspartate receptors (NMDARs). However, clinical use of NMDAR blockers is limited by side effects from suppressing physiological functions of these receptors. Here we report a means to suppress pain hypersensitivity without blocking NMDARs but rather by inhibiting the binding of a key enhancer of NMDAR function, the protein tyrosine kinase Src. We show that a peptide consisting of amino acids 40-49 of Src fused to the protein transduction domain of the HIV Tat protein (Src40-49Tat) prevented pain behaviors induced by intraplantar formalin and reversed pain hypersensitivity produced by intraplantar injection of complete Freund's adjuvant or by peripheral nerve injury. Src40-49Tat had no effect on basal sensory thresholds, acute nociceptive responses, or cardiovascular, respiratory, locomotor or cognitive functions. Thus, by targeting Src-mediated enhancement of NMDARs, inflammatory and neuropathic pain are suppressed without deleterious consequences of directly blocking NMDARs, an approach that may be of broad relevance to managing chronic pain.Chronic pain is categorized as inflammatory or neuropathic, each involving neuroplastic changes leading to hypersensitivity in peripheral and central nociceptive systems 1,2 . Multiple mechanisms including increased primary afferent excitability 3 , enhanced transmission in the dorsal horn 1 , changes in gene expression 4 , aberrant neuron-glia interactions 5,6 and neuronal apoptosis 7 are implicated in hypersensitivity in chronic pain models. Abundant pre-clinical evidence indicates that N-methyl-D-aspartate receptor (NMDARs) 8 are critically involved in pain hypersensitivity 9-11 . However, pharmacological blockade of these receptors in humans is deleterious because the activity of NMDARs is essential for many important physiological functions including breathing and locomotion 9,12,13 . A crucial signaling event for NMDAR-dependent neuroplasticity, including pain hypersensitivity 1,14 , is upregulation of NMDAR currents by mechanisms including relieving Mg 2+ blockade and receptor phosphorylation 15,16 . Thus, preferentially inhibiting mechanisms which upregulate NMDARs without affecting basal channel activity represents a strategy that may suppress pain hypersensitivity without impairing key physiological functions.