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Background Black men in the United States have markedly higher rates of prostate cancer than the general population. National guidelines for prostate-specific antigen (PSA) screening do not provide clear guidance for this high-risk population. The purpose of this study is to estimate the benefit and harm of intensified PSA screening in Black men. Methods Two microsimulation models of prostate cancer calibrated to incidence from the Surveillance, Epidemiology, and End Results program among Black men project the impact of different screening strategies (varying screening intervals, starting and stopping ages, and biopsy utilization following an abnormal PSA) on disease-specific mortality and overdiagnosis. Each strategy induces a mean lead time (MLT) for detected cases. A longer MLT reduces mortality according to estimates combining the US and European prostate cancer screening trials but increases overdiagnosis. Results Under historical population screening, Black men had similar MLT to men of all races and similar mortality reduction (range between models = 21%-24% vs 20%-24%) but a higher frequency of overdiagnosis (75-86 vs 58-60 per 1000 men). Screening Black men aged 40-84 years annually would increase both mortality reduction (29%-31%) and overdiagnosis (112-129 per 1000). Restricting screening to ages 45-69 years would still achieve substantial mortality reduction (26%-29%) with lower overdiagnosis (51-61 per 1000). Increasing biopsy utilization to 100% of abnormal tests would further reduce mortality but substantially increase overdiagnosis. Conclusions Annual screening in Black men is expected to reduce mortality more than that estimated under historical screening. Limiting screening to men younger than 70 years is expected to help reduce overdiagnosis.

Dynamic prediction methods incorporate longitudinal biomarker information to produce updated, more accurate predictions of conditional survival probability. There are two approaches for obtaining dynamic predictions: (1) a joint model of the longitudinal marker and survival process, and (2) an approximate approach that specifies a model for a specific component of the joint distribution. In the case of a binary marker, an illness-death model is an example of a joint modeling approach that is unified and produces consistent predictions. However, previous literature has shown that approximate approaches, such as landmarking, with additional flexibility can have good predictive performance. One such approach proposes using a Gaussian copula to model the joint distribution of conditional continuous marker and survival distributions. It has the advantage of specifying established, flexible models for the marginals for which goodness-of-fit can be assessed, and has easy estimation that can be implemented in standard software. In this article, we provide a Gaussian copula approach for dynamic prediction to accommodate a binary marker using a continuous latent variable formulation. We compare the predictive performance of this approach to joint modeling and landmarking using simulations and demonstrate its use for obtaining dynamic predictions in an application to a prostate cancer study.

Background Surgical patients are vulnerable to opioid dependency and related risks. Clinical-translational data suggest that caffeine may enhance postoperative analgesia. This trial tested the hypothesis that intraoperative caffeine would reduce postoperative opioid consumption. The secondary objective was to assess whether caffeine improves neuropsychological recovery postoperatively. Methods This was a single-center, randomized, placebo-controlled trial. Participants, clinicians, research teams, and data analysts were all blinded to the intervention. Adult (≥18 years old) surgical patients (n = 65) presenting for laparoscopic colorectal and gastrointestinal surgery were randomized to an intravenous caffeine citrate infusion (200 mg) or dextrose 5% in water (40 mL) during surgical closure. The primary outcome was cumulative opioid consumption through postoperative day 3. Secondary outcomes included subjective pain reporting, observer-reported pain, delirium, Trail Making Test performance, depression and anxiety screens, and affect scores. Adverse events were reported, and hemodynamic profiles were also compared between the groups. Results Sixty patients were included in the final analysis, with 30 randomized to each group. The median (interquartile range) cumulative opioid consumption (oral morphine equivalents, milligrams) was 77 mg (33-182 mg) for caffeine and 51 mg (15-117 mg) for placebo (estimated difference, 55 mg; 95% confidence interval [CI], -9 to 118; P = .092). After post hoc adjustment for baseline imbalances, caffeine was associated with increased opioid consumption (87 mg; 95% CI, 26-148; P = .005). There were otherwise no differences in prespecified pain or neuropsychological outcomes between the groups. No major adverse events were reported in relation to caffeine, and no major hemodynamic perturbations were observed with caffeine administration. Conclusions Caffeine appears unlikely to reduce early postoperative opioid consumption. Caffeine otherwise appears well tolerated during anesthetic emergence.

Objective Many studies suggest a strong familial component to fibromyalgia (FM). However, those studies have nearly all been confined to individuals with primary FM, i.e., FM without any other accompanying disorder. The current 2011 and 2016 criteria for diagnosing FM construct a score using a combination of the number of painful body sites and the severity of somatic symptoms (FM score). This study was undertaken to estimate the genetic heritability of the FM score across sex and age groups to identify subgroups of individuals with greater heritability, which may help in the design of future genetic studies. Methods We collected data on 26,749 individuals of European ancestry undergoing elective surgery at the University of Michigan (Michigan Genomics Initiative study). We estimated the single-nucleotide polymorphism-based heritability of FM score by age and sex categories using genome-wide association study data and a linear mixed-effects model. Results Overall, the FM score had an estimated heritability of 13.9% (SE 2.9%) (P = 1.6 × 10-7 ). Estimated FM score heritability was highest in individuals ≤50 years of age (23.5%; SE 7.9%) (P = 3.0 ×10-4 ) and lowest in individuals >60 years of age (7.5%; SE 8.1%) (P = 0.41). These patterns remained the same when we analyzed FM as a case-control phenotype. Even though women had an ~30% higher average FM score than men across age categories, FM score heritability did not differ significantly by sex. Conclusion Younger individuals appear to have a much stronger genetic component to the FM score than older individuals. Older individuals may be more likely to have what was previously called "secondary FM." Regardless of the cause, these results have implications for future genetic studies of FM and associated conditions.

Background The Timing Of Androgen Deprivation (TOAD) trial found an overall survival benefit for immediate vs delayed androgen deprivation therapy (ADT) for prostate-specific antigen (PSA)–relapsed or noncurable prostate cancer. However, broad eligibility criteria allowed entry of a heterogeneous participant group, including those with prior ADT exposure, raising concerns about subsequent androgen sensitivity. For these reasons, we completed previously specified subgroup analyses to assess if prior ADT was associated with ADT timing efficacy after PSA relapse. Methods We examined TOAD trial patient-level data for participants with PSA relapse after local therapy. We performed Kaplan-Meier analyses for overall survival stratified by prior ADT and randomized treatment arm (immediate or delayed ADT). We compared group characteristics using Mann-Whitney U and Fisher exact tests. All hypothesis tests were 2-sided. Results We identified 261 patients with PSA relapse, 125 of whom received prior ADT. Patients with prior ADT had higher PSA at presentation (12.1 vs 9.0 ng/mL; P Conclusions The survival benefit demonstrated in the TOAD trial may be driven by patients who received ADT prior to trial entry. We provide possible explanations for this finding with implications for treatment of PSA-relapsed prostate cancer and future study planning.

Recent studies show decreasing prostate-specific antigen utilization and increasing incidence of metastatic prostate cancer in the United States after national recommendations against screening in 2012. Yet, whether the increasing incidence of metastatic prostate cancer is consistent in magnitude with the expected impact of decreased screening is unknown. We compared observed incidence of metastatic prostate cancer from the Surveillance, Epidemiology, and End Results program and published effects of continued historical screening and discontinued screening starting in 2013 projected by 2 models of disease natural history, screening, and diagnosis. The observed rate of new metastatic prostate cancer cases in 2017 was 44%-60% of the projected increase under discontinued screening relative to continued screening. Thus, the observed increase in incident metastatic prostate cancer is consistent with the expected impact of reduced screening. Although this comparison does not establish a causal relationship, it highlights the plausible role of decreased screening in the observed trend.

Adrenal vein sampling (AVS) is required to distinguish unilateral from bilateral aldosterone sources in primary aldosteronism (PA), and cortisol is used for AVS data interpretation, but cortisol has several pitfalls. In this study, we present the utility of several other steroids in PA subtyping, both during AVS, as well as in peripheral serum. We included patients with PA who underwent AVS at University of Michigan between 2012 and 2018. We used mass spectrometry to simultaneously quantify 17 steroids in adrenal veins (AV) and periphery, both at baseline and after cosyntropin administration. PA was classified as unilateral or bilateral based on a lateralization index ≥ or P

Study objective We evaluated a strategy to increase use of the test (Dix-Hallpike’s test [DHT]) and treatment (canalith repositioning maneuver [CRM]) for benign paroxysmal positional vertigo in emergency department (ED) dizziness visits. Methods We conducted a stepped-wedge randomized trial in 6 EDs. The population was visits with dizziness as a principal reason for the visit. The intervention included educational sessions and decision aid materials. Outcomes were DHT or CRM documentation (primary), head computed tomography (CT) use, length of stay, admission, and 90-day stroke events. The analysis was multilevel logistic regression with intervention, month, and hospital as fixed effects and provider as a random effect. We assessed fidelity with monitoring intervention use and semistructured interviews. Results We identified 7,635 dizziness visits during 18 months. The DHT or CRM was documented in 1.5% of control visits (45/3,077; 95% confidence interval 1% to 1.9%) and 3.5% of intervention visits (159/4,558; 95% confidence interval 3% to 4%; difference 2%, 95% confidence interval 1.3% to 2.7%). Head CT use was lower in intervention visits compared with control visits (44.0% [1,352/3,077] versus 36.9% [1,682/4,558]). No differences were observed in admission or 90-day subsequent stroke risk. In fidelity evaluations, providers who used the materials typically reported positive clinical experiences but provider engagement was low at facilities without an emergency medicine residency program. Conclusion These findings provide evidence that an implementation strategy of a benign paroxysmal positional vertigo–focused approach to ED dizziness visits can be successful and safe in promoting evidence-based care. Absolute rates of DHT and CRM use, however, were still low, which relates in part to our broad inclusion criteria for dizziness visits.

Objective While psychosocial factors have been associated with poorer outcomes after knee and hip arthroplasty, we hypothesized that augmented pain perception, as occurs in conditions such as fibromyalgia, may account for decreased responsiveness to primary knee and hip arthroplasty. Methods A prospective, observational cohort study was conducted. Preoperative phenotyping was conducted using validated questionnaires to assess pain, function, depression, anxiety, and catastrophizing. Participants also completed the 2011 fibromyalgia survey questionnaire, which addresses the widespread body pain and comorbid symptoms associated with characteristics of fibromyalgia. Results Of the 665 participants, 464 were retained 6 months after surgery. Since individuals who met criteria for being classified as having fibromyalgia were expected to respond less favorably, all primary analyses excluded these individuals (6% of the cohort). In the multivariate linear regression model predicting change in knee/hip pain (primary outcome), a higher fibromyalgia survey score was independently predictive of less improvement in pain (estimate −0.25, SE 0.044; P

BACKGROUND Molecular stratification of prostate cancer (PCa) based on genetic aberrations including ETS or RAF gene-rearrangements, PTEN deletion, and SPINK1 over-expression show clear prognostic and diagnostic utility. Gene rearrangements involving ETS transcription factors are frequent pathogenetic somatic events observed in PCa. Incidence of ETS rearrangements in Caucasian PCa patients has been reported, however, occurrence in Indian population is largely unknown. The aim of this study was to determine the prevalence of the ETS and RAF kinase gene rearrangements, SPINK1 over-expression, and PTEN deletion in this cohort. METHODS In this multi-center study, formalin-fixed paraffin embedded (FFPE) PCa specimens (n = 121) were procured from four major medical institutions in India. The tissues were sectioned and molecular profiling was done using immunohistochemistry (IHC), RNA in situ hybridization (RNA-ISH) and/or fluorescence in situ hybridization (FISH). RESULTS ERG over-expression was detected in 48.9% (46/94) PCa specimens by IHC, which was confirmed in a subset of cases by FISH. Among other ETS family members, while ETV1 transcript was detected in one case by RNA-ISH, no alteration in ETV4 was observed. SPINK1 over-expression was observed in 12.5% (12/96) and PTEN deletion in 21.52% (17/79) of the total PCa cases. Interestingly, PTEN deletion was found in 30% of the ERG-positive cases (P = 0.017) but in only one case with SPINK1 over-expression (P = 0.67). BRAF and RAF1 gene rearrangements were detected in ∼1% and ∼4.5% of the PCa cases, respectively. CONCLUSIONS This is the first report on comprehensive molecular profiling of the major spectrum of the causal aberrations in Indian men with PCa. Our findings suggest that ETS gene rearrangement and SPINK1 over-expression patterns in North Indian population largely resembled those observed in Caucasian population but differed from Japanese and Chinese PCa patients. The molecular profiling data presented in this study could help in clinical decision-making for the pursuit of surgery, diagnosis, and in selection of therapeutic intervention. Prostate 75:1051–1062, 2015. © 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc.

Background and Objectives Facet interventions for spine pain have high failure rates, and preprocedural prediction of response is nearly impossible. A potential explanation may be aberrant central pain processing as that existing in conditions like fibromyalgia. To test this hypothesis, we conducted a retrospective study investigating the impact of having characteristics of fibromyalgia on the acute analgesic response to a first diagnostic medial branch block (MBB). Methods We evaluated the analgesic responses of 187 patients that underwent MBB. Patients were categorized as “fibromyalgia-positive” or “fibromyalgia-negative” using the 2011 fibromyalgia survey criteria. Preprocedural and postprocedural pain scores and patient-completed pain diaries up to 24 hours postprocedure were collected. A linear mixed model was used to study longitudinal effects of MBB on pain responses. Results Fibromyalgia-positive patients had a worse preprocedural pain phenotype (ie, greater pain severity, higher levels of depressive and anxiety symptoms, reduced function). Binary categorization of fibromyalgia status was not associated with a difference in immediate postprocedural pain relief; however, the longitudinal analgesic response across time varied significantly between groups (P = 0.0005). Fibromyalgia-negative subjects showed the expected steep decline in pain scores, followed by gradual return to baseline, whereas a more aberrant pattern was noted in the fibromyalgia-positive group. Pain scores for fibromyalgia-negative patients were also lower by −1.07 (SE = 0.37) on average after the MBB (P = 0.005). Conclusions Characteristics of fibromyalgia may indicate pain that is more centralized in nature, a factor that may explain the aberrant analgesic response to this peripheral intervention. This may have implications for future prediction of treatment response, although prospective studies are needed.

Objective Fibromyalgia is a chronic pain condition with few effective treatments. Many fibromyalgia patients seek acupuncture for analgesia; however, its efficacy is limited and not fully understood. This may be due to heterogeneous pathologies among participants in acupuncture clinical trials. We hypothesized that pressure pain tenderness would differentially classify treatment response to verum and sham acupuncture in fibromyalgia patients. Design Baseline pressure pain sensitivity at the thumbnail at baseline was used in linear mixed models as a modifier of differential treatment response to sham versus verum acupuncture. Similarly, needle-induced sensation was also analyzed to determine its differential effect of treatment on clinical pain. Methods and Patients A cohort of 114 fibromyalgia patients received baseline pressure pain testing and were randomized to either verum (N = 59) or sham (N = 55) acupuncture. Participants received treatments from once a week to three times a week, increasing in three-week blocks for a total of 18 treatments. Clinical pain was measured on a 101-point visual analog scale, and needle sensation was measured by questionnaire throughout the trial. Results Participants who had higher pain pressure thresholds had greater reduction in clinical pain following verum acupuncture while participants who had lower pain pressure thresholds showed better analgesic response to sham acupuncture. Moreover, patients with lower pressure pain thresholds had exacerbated clinical pain following verum acupuncture. Similar relationships were observed for sensitivity to acupuncture needling. Conclusions These findings suggest that acupuncture efficacy in fibromyalgia may be underestimated and a more personalized treatment for fibromyalgia may also be possible.

The ERSPC (European Randomized Study of Screening for Prostate Cancer) found that screening reduced prostate cancer mortality, but the PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) found no reduction.To evaluate whether effects of screening on prostate cancer mortality relative to no screening differed between the ERSPC and PLCO.Cox regression of prostate cancer death in each trial group, adjusted for age and trial. Extended analyses accounted for increased incidence due to screening and diagnostic work-up in each group via mean lead times (MLTs), which were estimated empirically and using analytic or microsimulation models.Randomized controlled trials in Europe and the United States.Men aged 55 to 69 (ERSPC) or 55 to 74 (PLCO) years at randomization.Prostate cancer screening.Prostate cancer incidence and survival from randomization; prostate cancer incidence in the United States before screening began.Estimated MLTs were similar in the ERSPC and PLCO intervention groups but were longer in the PLCO control group than the ERSPC control group. Extended analyses found no evidence that effects of screening differed between trials (P = 0.37 to 0.47 [range across MLT estimation approaches]) but strong evidence that benefit increased with MLT (P = 0.0027 to 0.0032). Screening was estimated to confer a 7% to 9% reduction in the risk for prostate cancer death per year of MLT. This translated into estimates of 25% to 31% and 27% to 32% lower risk for prostate cancer death with screening as performed in the ERSPC and PLCO intervention groups, respectively, compared with no screening.The MLT is a simple metric of screening and diagnostic work-up.After differences in implementation and settings are accounted for, the ERSPC and PLCO provide compatible evidence that screening reduces prostate cancer mortality.National Cancer Institute.

Rationale and Objectives To assess whether left atrial (LA) volume, function, and diameter as determined by multidetector computed tomography (MDCT) are associated with the presence and chronicity of atrial fibrillation (AF). Materials and Methods A total of 232 subjects, 156 with AF (43 with chronic and 113 with paroxysmal) and 76 normal subjects, formed the study population. AF subjects underwent MDCT of the pulmonary veins and LA, and normal subjects underwent coronary computed tomography (CT), on which LA volume, function, and diameter were measured. Associations between each MDCT LA parameter and presence and chronicity of AF were assessed using logistic regression analysis. Results The indexed LA maximum volume (odds ratio [OR] = 2.42; 95% confidence interval [CI], 1.43–4.08; P = .0009) was significantly associated with chronicity and presence of AF (OR = 1.06; 95% CI, 1.03–1.10; P = .0003) after adjustment for traditional risk factors. The LA function was associated with presence of AF (OR = 0.93; 95% CI, 0.89–0.97; P = .0005), but not with AF chronicity (OR = 1.12; 95% CI, 0.93–1.33; P = .21). Conclusions Decreased LA function is associated with presence of AF, and increased LA maximum volume is associated with presence and chronicity of AF, independent of traditional risk factors.

Papillary renal cell carcinoma (P-RCC) is the second most common type of malignant renal epithelial tumor and can be subclassified into type 1, which demonstrates simple cuboidal low-grade epithelium and type 2, which demonstrates pseudostratified high-grade epithelium with abundant eosinophilic cytoplasm. Despite this clinically useful subclassification, P-RCCs exhibit considerable histomorphologic diversity, with many cases having features differing from classically described type 1 and type 2 tumors. To our knowledge, there has been no recent study that has methodically evaluated the histomorphologic features of a series of P-RCCs. To address this, we evaluated a cohort of P-RCCs diagnosed between 1997 and 2004 with long-term clinical follow-up data (n = 56). Histomorphologic features previously described in the spectrum of type 1 and type 2 P-RCCs were recorded for each tumor, including nuclear grade, complete tumor capsule, and cytoplasmic eosinophilia as well as several other features. The current TNM staging (American Joint Committee on Cancer, seventh edition) was assigned to all cases. Histomorphologic features were diverse, demonstrating classic type 1 P-RCC and classic type 2 P-RCC morphology and several tumors with nonclassic features. Four patients in this cohort had distant metastasis. The primary tumor was equally divided between type 1 (2 cases) and type 2 (2 cases) morphology in the cases with metastasis. All P-RCC cases with metastases demonstrated presence of high nuclear grade and high tumor stage in the primary tumor. Cluster analysis using staging parameters and histomorphologic features divided tumors into 2 primary clusters. All primary tumors associated with metastasis were in the same cluster.

Prostate cancer is considered a disease of older men (aged >65 years), but today over 10% of new diagnoses in the USA occur in young men aged ≤55 years. Early-onset prostate cancer, that is prostate cancer diagnosed at age ≤55 years, differs from prostate cancer diagnosed at an older age in several ways. Firstly, among men with high-grade and advanced-stage prostate cancer, those diagnosed at a young age have a higher cause-specific mortality than men diagnosed at an older age, except those over age 80 years. This finding suggests that important biological differences exist between early-onset prostate cancer and late-onset disease. Secondly, early-onset prostate cancer has a strong genetic component, which indicates that young men with prostate cancer could benefit from evaluation of genetic risk. Furthermore, although the majority of men with early-onset prostate cancer are diagnosed with low-risk disease, the extended life expectancy of these patients exposes them to long-term effects of treatment-related morbidities and to long-term risk of disease progression leading to death from prostate cancer. For these reasons, patients with early-onset prostate cancer pose unique challenges, as well as opportunities, for both research and clinical communities. Current data suggest that early-onset prostate cancer is a distinct phenotype-from both an aetiological and clinical perspective-that deserves further attention.

The use of self-report questionnaires to detect characteristics of altered central pain processing, as seen in centralized pain disorders such as fibromyalgia, allow for the epidemiological studies of pain patients. Here, we assessed the relationship between reporting high levels of pain while taking opioids and the presence of characteristics associated with centralized pain.We evaluated 582 patients taking opioid medications using validated measures of clinical pain, neuropathic pain symptoms, mood, and functioning. A multivariate linear regression model was used to assess the association between levels of pain while taking opioids and presenting with characteristics consistent with having centralized pain.We found that 49% of patients taking opioids continued to report severe pain (≥ 7/10). In multivariate analysis, factors associated with having higher levels of pain in opioid users included higher fibromyalgia survey scores (P = 0.001), more neuropathic pain symptoms (P0.001), and higher levels of depression (P = 0.002). Although only 3.2% were given a primary diagnosis of fibromyalgia by their physician, 40.8% met American College of Rheumatology survey criteria for fibromyalgia.Our findings suggest that patients with persistently high pain scores despite opioid therapy are more likely than those with lower levels of pain to present with characteristics associated with having centralized pain. This study cannot determine whether these characteristics were present before (fibromyalgia-like patient) or after the initiation of opioids (opioid-induced hyperalgesia). Regardless, patients with a centralized pain phenotype are thought to be less responsive to opioids and may merit alternative approaches.

Context: Patients with 21-hydroxylase deficiency (21OHD) have long-term complications, resulting from poor disease control and/or glucocorticoid overtreatment. Lack of optimal biomarkers has made it challenging to tailor therapy and predict long-term outcomes. Objective: To identify biomarkers of disease control and long-term complications in 21OHD. Setting and Participants: Cross-sectional study of 114 patients (70 males), ages 2 to 67 years (median, 15 years), seen in a tertiary referral center. Methods: We correlated a mass-spectrometry panel of 23 steroids, obtained before first morning medication, with bone age advancement (children), adrenal volume (adults), testicular adrenal rest tumors (TART), hirsutism, menstrual disorders, and pituitary hormones. Results: Total adrenal volume correlated positively with 18 steroids, most prominently 21-deoxycortisol and four 11-oxygenated-C19 (11oxC19) steroids: 11β-hydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11ketoA4), 11β-hydroxytestosterone (11OHT), and 11-ketotestosterone (11ketoT) (r ≈ 0.7, P < 0.0001). Nine steroids were significantly higher (P ≤ 0.01) in males with TART compared with those without TART, including 11OHA4 (6.8-fold), 11OHT (4.9-fold), 11ketoT (3.6-fold), 11ketoA4 (3.3-fold), and pregnenolone sulfate (PregS; 4.8-fold). PregS (28.5-fold) and 17-hydroxypregnenolone sulfate (19-fold) levels were higher (P < 0.01) in postpubertal females with menstrual disorders. In males, testosterone levels correlated positively with all 11oxC19 steroids in Tanner stages 1 and 2 (r ≈ 0.7; P < 0.001) but negatively in Tanner stage 5 (r = −0.3 and P < 0.05 for 11ketoA4 and 11ketoT). In females, testosterone level correlated positively with all four 11oxC19 steroids across all Tanner stages (r ≈ 0.8; P < 0.0001). Conclusion: 11oxC19 steroids and PregS might serve as clinically useful biomarkers of disease control and long-term complications in 21OHD., Using LC-MS/MS, we show 11-oxygenated 19-carbon steroids and pregnenolone sulfate are biomarkers of disease control and long-term complications in adults and children with 21-hydroxylase deficiency.

Objective This double-blind randomized controlled trial aimed to test the efficacy of self-administered acupressure for pain and physical function improvement for older adults with knee osteoarthritis (OA). Methods Participants were community-dwelling adults with symptomatic knee OA (n = 150, mean age 73 years), randomized to 1 of 3 groups: verum acupressure, sham acupressure, or usual care. Participants in the verum and sham groups, but not those in the usual care group, were taught to self-apply acupressure once daily, 5 days/week for 8 weeks. Assessments were collected during center visits at baseline, and at 4 and 8 weeks. In addition, pain level was assessed weekly by phone using a numeric rating scale (NRS). Outcomes included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale (primary), and subjective and objective physical function measures and the NRS and physical function measures (secondary). Linear mixed regression analysis was conducted to test between-group differences in mean changes from baseline for the outcomes at 8 weeks. Results Compared with usual care, both verum and sham acupressure participants experienced significant improvements in WOMAC pain (mean difference -1.27 units [95% confidence interval (95% CI) -1.95, -0.58] and -1.24 units [95% CI -1.92, -0.55], respectively), NRS pain (-0.74 units [95% CI -1.24, -0.24] and -0.51 units [95% CI -1.01, -0.01], respectively), and WOMAC function (-4.83 units [95% CI -6.99, -2.67] and -4.21 units [95% CI -6.37, -2.04], respectively) at 8 weeks. There were no significant differences between the verum and sham acupressure groups on any of the outcomes. Conclusion Self-administered acupressure is superior to usual care in pain and physical function improvement for older adults with knee OA. The reason for the benefits is unclear, and the placebo effect may play a role.

To assess the feasibility of a study to evaluate the efficacy of self-administered acupressure in pain and related symptom management for older people with symptomatic knee osteoarthritis. Feasibility with regard to (1) sample recruitment and retention, (2) treatment fidelity and adherence, and (3) tolerability and adverse events was examined.The study was a randomized controlled trial. Community-living older adults were recruited and randomly assigned to one of three groups: verum acupressure, sham acupressure, and usual care. Participants in the first two groups learned their respective acupressure protocol during their first center visit and from a set of materials. They were asked to practice the protocol at home once daily, 5 days a week, for 8 weeks. Participants attended three center visits and received weekly phone calls from a research assistant in an 8-week study period. Both quantitative and qualitative data collected from center visits and weekly phone calls were used to examine study feasibility.A total of 150 participants (mean age, 73 years; 38% men) were enrolled; 83% completed all three center visits. Among those assigned to verum and sham acupressure groups, 94% passed a fidelity check at the second visit, more than 80% reported performing self-administered acupressure as instructed most of the time, and about 10% reported discomfort from performing the acupressure. Thirty adverse events were reported; most were related to pre-existing health conditions.It is feasible to conduct a study of self-administered acupressure for symptom management in community-living older adults with knee osteoarthritis, although sample recruitment may be challenging.

Introduction We examine the trajectory of adult smoking prevalence in the United States over the period 1990-2014 to investigate whether the smoking cessation rate has changed during this period. Methods We employ a dynamic model of smoking prevalence, and data from the National Health Interview Survey (NHIS) and the National Survey on Drug Use and Health (NSDUH), to estimate the adult cessation rate in 6-year intervals. We use weighted nonlinear least squares to perform the estimation. We then employ a meta-regression model to test whether the cessation rate has increased. Results The annual cessation rate has increased from 2.4% in 1990 to 4.5% in 2014 according to the NHIS data, and from 3.2% in 2002 to 4.2% in 2014 according to the NSDUH data. The increasing trend is statistically significant (p value = 1.57×10-6) and the two independent surveys produced nearly identical results, which makes it unlikely that our findings are a product of chance. Conclusions Our analysis finds that the smoking cessation rate in the United States has almost doubled since 1990. This increase is responsible for at least 2 million fewer smokers in 2014. If current conditions persist, by the year 2020 the increase in cessation rates will be responsible for 3.5 million fewer smokers. Our findings can assist in predicting the future path of the smoking epidemic and determining the correct allocation of resources to eradicate it. Implications We show that the adult smoking cessation rate has greatly increased since 1990. We demonstrate this by studying prevalence trajectories from two independent population surveys, which yielded nearly identical results. Different from other studies, we focus on permanent quit rates (net of relapses) which we estimate from a dynamic model of prevalence. Our results do not stem from self-reported quitting behavior, but from the analysis of observed prevalence and its inherent variability. Our findings can contribute to predicting the future path of the smoking epidemic and to determining the optimal allocation of resources to eradicate it.

To quantify the extent to which a clinically significant prostate cancer mortality reduction due to screening could have been masked by control arm screening (contamination) in the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial.We used three independently developed models of prostate cancer natural history to conduct a virtual PLCO trial. Simulated participants underwent pre-trial screening based on population patterns. The intervention arm followed observed compliance during the trial then resumed population screening. A contaminated control arm followed observed contamination during the trial then resumed population screening, while an uncontaminated control arm discontinued screening upon entry. We assumed a clinically significant screening benefit, applied population treatments and survival patterns, and calculated mortality rate ratios relative to the contaminated and uncontaminated control arms.The virtual trial reproduced observed incidence, including stage and grade distributions, and control arm mortality after 10 years of complete follow-up. Under the assumed screening benefit, the three models found that contamination increased the mortality rate ratio from 0.68-0.77 to 0.86-0.91, increased the chance of excess mortality in the intervention arm from 0-4 % to 15-28 %, and decreased the power of the trial to detect a mortality difference from 40-70 % to 9-25 %.Our computer simulation models indicate that contamination substantially limited the ability of the PLCO to identify a clinically significant screening benefit. While the trial shows annual screening does not reduce mortality relative to population screening, contamination prevents concluding whether screening reduces mortality relative to no screening.

Background: Making an informed decision about treating a prostate cancer detected after a routine prostate-specific antigen (PSA) test requires knowledge about disease natural history, such as the chances that it would have been clinically diagnosed in the absence of screening and that it would metastasize or lead to death in the absence of treatment. Methods: We use three independently developed models of prostate cancer natural history to project risks of clinical progression events and disease-specific deaths for PSA-detected cases assuming they receive no primary treatment. Results: The three models project that 20%–33% of men have preclinical onset; of these 38%–50% would be clinically diagnosed and 12%–25% would die of the disease in the absence of screening and primary treatment. The risk that men age less than 60 at PSA detection with Gleason score 2–7 would be clinically diagnosed in the absence of screening is 67%–93% and would die of the disease in the absence of primary treatment is 23%–34%. For Gleason score 8 to 10 these risks are 90%–96% and 63%–83%. Conclusions: Risks of disease progression among untreated PSA-detected cases can be nontrivial, particularly for younger men and men with high Gleason scores. Model projections can be useful for informing decisions about treatment. Impact: This is the first study to project population-based natural history summaries in the absence of screening or primary treatment and risks of clinical progression events following PSA detection in the absence of primary treatment. Cancer Epidemiol Biomarkers Prev; 20(5); 740–50. ©2011 AACR.

The efficacy and safety of consuming high-dose isoflavone supplements for prostate cancer is not clear. A double-blind, placebo controlled, randomized trial was conducted in 53 men with prostate cancer enrolled in an active surveillance program. The treatment group consumed a supplement containing 450 mg genistein, 300 mg daidzein, and other isoflavones daily for 6 mo. Prostate-specific antigen (PSA) was measured in both groups at baseline, 3 mo, and 6 mo, and serum concentrations of genistein, daidzein, and equol were assessed at baseline and 6 mo in the treatment group. Following the completion of the 6-mo double-blind study, men were enrolled in a 6-mo open label trial with the same isoflavone-rich supplement, and PSA was measured at 3 and 6 mo. PSA concentrations did not change in either group after 6 mo or after 12 mo when the open-label study was included. The 6 mo serum concentrations of genistein and daidzein (39.85 and 45.59 μmol/l, respectively) were significantly greater than baseline values and substantially higher than levels previously reported in other studies. Equol levels did not change. Although high amounts of aglycone isoflavones may result in significantly elevated serum concentrations of genistein and daidzein, these dietary supplements alone did not lower PSA levels in men with low-volume prostate cancer.

Purpose We studied the incidence, risk factors, treatment, and outcomes of post-transplantation lymphoproliferative disorder (PTLD) that occurred at the University of Michigan since 1964. Patients and Methods We identified 7,040 patients who received solid organ transplantation (SOT) and post-transplantation immunosuppressive therapy. Seventy-eight patients developed PTLD. Results Diffuse large B-cell lymphoma (n = 43), polymorphic PTLD (n = 10), Hodgkin's lymphoma (n = 7), Burkitts lymphoma (n = 6), plasmacytoma (n = 5), and mucosa-associated lymphoid tissue lymphoma (n = 3) were all over-represented in the SOT population compared with a population sample from the Surveillance, Epidemiology, and End Results (SEER) database; follicular lymphoma (n = 0) was underrepresented. Negative pretransplantation Epstein-Barr virus (EBV) serology was a risk factor for PTLD. Available histologic analysis of tumor tissue showed that 75% were CD20 positive and that 62% were EBV positive; EBV-positive tumors occurred sooner after SOT than EBV-negative tumors (mean, 29 v 66 months). Extralymphatic disease (79%), poor performance status (68%), elevated lactate dehydrogenase (LDH; 71%), and advanced stage (68%) disease were all common at the time of lymphoma diagnosis. Two thirds of patients had a complete response when treated with cyclophosphamide, doxorubicin, vincristine, and prednisone–like chemotherapy (either with or without rituximab). Median overall survival in all patients with PTLD was 8.23 years (95% CI, 2.28 to 30.0 years). Conclusion EBV-naïve patients who receive a donor organ from an EBV-infected donor are in the highest-risk situation for PTLD development. Most of these lymphomas are CD20 positive. Follicular lymphoma is unusual. With treatment, survival of patients with PTLD was indistinguishable from that of the SEER population sample.

Objective. We attempted to identify psychological comorbidities that are associated with the propensity for prescription opioid abuse. Interventions. Patients presenting to an emergency department seeking opioid refills for chronic pain were evaluated with five validated self-report instruments and structured clinical interviews. The potential for prescription opioid abuse was modeled with multiple regression analysis using depression, anxiety disorders, personality disorder, and addiction as independent variables. Results. Of the 113 patients studied, 91 (81%) showed a propensity for prescription opioid abuse as determined by scores on the Screener and Opioid Assessment for Patients with Pain instrument. Depression, anxiety, and a history of substance were common and panic attacks, posttraumatic stress disorder, and personality disorders were also found, albeit less frequently. Panic attacks, trait anxiety, and the presence of a personality disorder accounted for 38% of the variance in the potential for prescription opioid abuse. Conclusions. Patients in chronic pain should be assessed for psychological and addiction disorders because they are at increased risk for abusing opioids. They should also be referred for psychosocial treatment as part of their care, where appropriate.

ETS gene fusions have been characterized in a majority of prostate cancers; however, the key molecular alterations in ETS-negative cancers are unclear. Here we used an outlier meta-analysis (meta-COPA) to identify SPINK1 outlier expression exclusively in a subset of ETS rearrangement-negative cancers ( approximately 10% of total cases). We validated the mutual exclusivity of SPINK1 expression and ETS fusion status, demonstrated that SPINK1 outlier expression can be detected noninvasively in urine, and observed that SPINK1 outlier expression is an independent predictor of biochemical recurrence after resection. We identified the aggressive 22RV1 cell line as a SPINK1 outlier expression model and demonstrate that SPINK1 knockdown in 22RV1 attenuates invasion, suggesting a functional role in ETS rearrangement-negative prostate cancers.

We evaluated the recognition of osteoporosis in the veteran male population through a computer-based review of chest X-ray (CXR) reports in the Veterans Affairs Northern California Health Care System database, looking for unrecognized vertebral fractures. All CXR reports between January 1, 2000 and December 31, 2001, were scanned for the terms "compression" or "wedg (where the "" indicates a wild card search encompassing such terms as "wedge" or "wedging")". During this time, 26,994 CXR examinations were performed on 18,069 patients. 22,494 (83.3% of the total) CXR examinations were done in 14,561 men >or=50 years of age. 780 CXR reports (3.5%) encompassing 664 men (4.5%) contained at least one key phrase suggesting osteoporosis. Three years later, 495 of these 664 men were still living. 99 of these (20%) had been diagnosed with osteoporosis, 72 (15%) had a dual-energy X-ray absorptiometry (DXA) scan, and 89 (18%) had ever been prescribed a bisphosphonate. Overall, only 126 (25%) men had chart documentation indicating some recognition by the provider of the abnormality reported on CXR. We conclude that a significant fraction of men >50 years old may have unrecognized osteoporosis severe enough to result in vertebral fracture. We conclude that computerized screening of CXR reports may represent an effective strategy to aid clinicians in identifying men at risk for further debilitating fractures.

Although prostate-specific antigen (PSA) serum level is currently the standard of care for prostate cancer screening in the United States, it lacks ideal specificity and additional biomarkers are needed to supplement or potentially replace serum PSA testing. Emerging evidence suggests that monitoring the noncoding RNA transcript PCA3 in urine may be useful in detecting prostate cancer in patients with elevated PSA levels. Here, we show that a multiplex panel of urine transcripts outperforms PCA3 transcript alone for the detection of prostate cancer. We measured the expression of seven putative prostate cancer biomarkers, including PCA3, in sedimented urine using quantitative PCR on a cohort of 234 patients presenting for biopsy or radical prostatectomy. By univariate analysis, we found that increased GOLPH2, SPINK1, and PCA3 transcript expression and TMPRSS2:ERG fusion status were significant predictors of prostate cancer. Multivariate regression analysis showed that a multiplexed model, including these biomarkers, outperformed serum PSA or PCA3 alone in detecting prostate cancer. The area under the receiver-operating characteristic curve was 0.758 for the multiplexed model versus 0.662 for PCA3 alone (P = 0.003). The sensitivity and specificity for the multiplexed model were 65.9% and 76.0%, respectively, and the positive and negative predictive values were 79.8% and 60.8%, respectively. Taken together, these results provide the framework for the development of highly optimized, multiplex urine biomarker tests for more accurate detection of prostate cancer. [Cancer Res 2008;68(3):645–9]

To quantify the plausible contribution of prostate-specific antigen (PSA) screening to the nearly 30% decline in the US prostate cancer mortality rate observed during the 1990s.Two mathematical modeling teams of the US National Cancer Institute's Cancer Intervention and Surveillance Modeling Network independently projected disease mortality in the absence and presence of PSA screening. Both teams relied on Surveillance, Epidemiology, and End Results (SEER) registry data for disease incidence, used common estimates of PSA screening rates, and assumed that screening, by shifting disease from distant to local-regional clinical stage, confers a corresponding improvement in disease-specific survival.The teams projected similar mortality increases in the absence of screening and decreases in the presence of screening after 1985. By 2000, the models projected that 45% (Fred Hutchinson Cancer Research Center) to 70% (University of Michigan) of the observed decline in prostate cancer mortality could be plausibly attributed to the stage shift induced by screening.PSA screening may account for much, but not all, of the observed drop in prostate cancer mortality. Other factors, such as changing treatment practices, may also have played a role in improving prostate cancer outcomes.

OBJECTIVES Fibromyalgia (FM) characteristics can be evaluated using a simple, self-reported measure that correlates with postoperative opioid consumption after lower-extremity joint arthroplasty. The purpose of this study was to determine whether preoperative pain history and the FM survey score can predict postoperative outcomes after shoulder arthroscopy, which may cause moderate to severe pain. MATERIALS AND METHODS In this prospective study, 100 shoulder arthroscopy patients completed preoperative validated self-report measures to assess baseline quality of recovery score, physical functioning, depression, anxiety, and neuropathic pain. FM characteristics were evaluated using a validated measure of widespread pain and comorbid symptoms on a 0 to 31 scale. Outcomes were assessed on postoperative day 2 (opioid consumption [primary], pain, physical functioning, quality of recovery score), and day 14 (opioid consumption, pain). RESULTS FM survey scores ranged from 0 to 13. The cohort was divided into tertiles for univariate analyses. Preoperative depression and anxiety (P

To estimate the ability of bedside information to risk stratify stroke in acute dizziness presentations.Surveillance methods were used to identify patients with acute dizziness and nystagmus or imbalance, excluding those with benign paroxysmal positional vertigo, medical causes, or moderate to severe neurologic deficits. Stroke was defined as acute infarction or intracerebral hemorrhage on a clinical or research MRI performed within 14 days of dizziness onset. Bedside information comprised history of stroke, the ABCD(2) score (age, blood pressure, clinical features, duration, and diabetes), an ocular motor (OM)-based assessment (head impulse test, nystagmus pattern [central vs other], test of skew), and a general neurologic examination for other CNS features. Multivariable logistic regression was used to determine the association of the bedside information with stroke. Model calibration was assessed using low (5%), intermediate (5% to10%), and high (≥10%) predicted probability risk categories.Acute stroke was identified in 29 of 272 patients (10.7%). Associations with stroke were as follows: ABCD(2) score (continuous) (odds ratio [OR] 1.74; 95% confidence interval [CI] 1.20-2.51), any other CNS features (OR 2.54; 95% CI 1.06-6.08), OM assessment (OR 2.82; 95% CI 0.96-8.30), and prior stroke (OR 0.48; 95% CI 0.05-4.57). No stroke cases were in the model's low-risk probability category (0/86, 0%), whereas 9 were in the moderate-risk category (9/94, 9.6%) and 20 were in the high-risk category (20/92, 21.7%).In acute dizziness presentations, the combination of ABCD(2) score, general neurologic examination, and a specialized OM examination has the capacity to risk-stratify acute stroke on MRI.

Summary Misclassified causes of failures are a common phenomenon in competing risks survival data such as cancer mortality. We propose new estimating equations for a semiparametric proportional hazards (PH) model with misattributed causes of failures. Unlike other methods, the estimator does not require any parametric assumptions on baseline cause-specific hazard rates. It is shown that the estimators for regression coefficients are consistent and asymptotically normal. Simulation results support the theoretical analysis in finite samples. The methods are applied to analyze prostate cancer survival.

Background. Asians and Pacific Islanders (APIs) are important populations nationally and globally. So we assessed cumulative tobacco smoke overexposure (smoke overload)/cancer mortality associations across states, ethnicities, years, and genders among API-Americans. Methods. Death rates were adjusted to the 2000 United States age standard, lung cancer death rates used as a smoke overload bio-index, and lung/non-lung cancer death rate linear regressions run. Cancer death rate smoking-attributable fractions (SAFs) are equal to 1 − estimated unexposed rate/observed rate. Results. The two lowest smoke overload and non-lung cancer death rates were in South Asian (Indo)-Californian females and males. The highest were in Korean-Californian males. Non-lung cancer death rates were tightly and steeply associated with smoke overload across ethnicity, state, year, or gender. Cancer death rate smoking-attributable fractions ranged from 0 in female and 6% in male Indo-Californians, to 39% in female and 57% in male API-Americans in 2002, to 71% in Korean-Californian and 69% in API Hawaiian males. Discussion. Many API American cancer death rate disparities across genders, ethnicities, states, or years can be explained by smoke overload disparities. Tobacco control may greatly reduce cancer death rates and disparities among API-Americans and, likely, others.

Introduction of screening for prostate cancer using the prostate-specific antigen (PSA) marker of the disease led to remarkable dynamics of the incidence of the disease observed in the last two decades. A statistical model is used to provide a link between dissemination of PSA and the observed transient population responses. The model is used to estimate lead time, overdiagnosis and other relevant characteristics of prostate cancer screening.

Purpose Familial melanoma patients are reported to present with thinner melanomas, to be younger at the time of diagnosis, and to have a greater likelihood of developing multiple primary tumors. We sought to determine whether melanomas that occur in a familial setting demonstrate different prognostic and survival statistics relative to sporadic melanoma. Patients and Methods This population-based study used the Utah Cancer Registry and Utah Population Database to objectively evaluate prognostic and survival statistics of the familial melanoma population. From 1973 to 1999, there were 7,785 cases of invasive melanoma identified through the Utah Cancer Registry. These were linked to the Utah Population Database, resulting in 2,659 subjects with family-history information from which a familiality score could be calculated. Cases scored in the top ninth percentile were assigned as high familial risk, and the remaining 91% were considered low familial risk. Results Multivariate logistic-regression analysis found no association between sex, Breslow depth, Clark level, or survival and the familial status. Age at first diagnosis of invasive melanoma was slightly lower in the high-familial-risk group (57 v 60 years; P = .03). High-familial-risk subjects had more melanomas diagnosed at age 30 or younger (12% v 6%; P < .001). A significant difference in the overall number of individuals with two or more primary malignant melanomas was not detected among the groups (P = .2). Conclusion These data suggest that melanomas occurring in the context of an underlying inherited susceptibility do not have a significantly different biologic behavior.

Polymorphisms of glutathione S-transferase (GST) enzymes have been correlated with altered risk of several cancers, as well as altered response and toxicity from cancer chemotherapy. We report a low cost, highly reproducible and specific PCR-based high-throughput assay for genotyping different GSTs designed for use in large clinical trials. In comparison to an alternative genotyping method (single nucleotide extension), the sensitivity and specificity of the high throughput assay was shown to be 92 and 97%, respectively, depending on the source of genomic DNA. Using the high-throughput assay, we demonstrate by multivariate analysis an increased risk of acute lymphoblastic leukemia, glial brain tumors, and osteosarcoma for patients carrying nonnull alleles of GSTM1 and/or GSTT1.

Asthma, a family of airway disorders characterized by airway inflammation, has an increasing incidence worldwide. Platelet-activating factor (PAF) may play a role in the pathophysiology of asthma. Its proinflammatory actions are antagonized by PAF acetylhydrolase. A missense mutation (V279F) in the PAF acetylhydrolase gene results in the complete loss of activity, which occurs in 4% of the Japanese population. We asked if PAF acetylhydrolase deficiency correlates with the incidence and severity of asthma in Japan. We found that the prevalence of PAF acetylhydrolase deficiency is higher in Japanese asthmatics than healthy subjects and that the severity of this syndrome is highest in homozygous-deficient subjects. We conclude that the PAF acetylhydrolase gene is a modulating locus for the severity of asthma.

Background and Objectives Research suggests that the addition of dexmedetomidine to local anesthetics can prolong peripheral nerve blocks; however, clinical safety data are limited, and interscalene blocks have not been studied. The present study was designed to test the hypothesis that dexmedetomidine added to ropivacaine would safely enhance the duration of analgesia without adverse effects when compared with ropivacaine alone. Methods We conducted a single-center, prospective, randomized, triple-blind, controlled trial of 62 patients undergoing elective shoulder surgery under general anesthesia with an interscalene block. Patients underwent ultrasound-guided interscalene blocks using either 12 mL of 0.5% ropivacaine or 0.5% ropivacaine plus 150-µg dexmedetomidine. The primary outcomes were self-reported duration of the nerve block and safety assessment (adverse effects and neurological sequelae). Data were analyzed in a blinded fashion. Results The median duration of the nerve block was 18 hours (95% confidence interval, 18–20) in the dexmedetomidine group and 14 hours (95% confidence interval, 14–16) in the ropivacaine group (P = 0.0001). Dexmedetomidine also lowered pain scores for the first 14 hours postoperatively and significantly hastened the time to sensory (P = 0.04) and motor (P = 0.002) block onset. Dexmedetomidine lowered heart rate but blood pressures were stable. Plasma levels of ropivacaine were not different between groups, and plasma dexmedetomidine levels were relatively low. There were no adverse events or neurological sequelae. Conclusions Dexmedetomidine added to ropivacaine for interscalene blocks increased the duration of the nerve block and improved postoperative pain. These additional efficacy and safety data should encourage further study of peripheral perineural dexmedetomidine in humans.

The current gold standard for diagnosis of hepatic fibrosis and cirrhosis is the traditional invasive liver biopsy. It is desirable to assess hepatic fibrosis with noninvasive means. Targeted proteomic techniques allow an unbiased assessment of proteins and might be useful to identify proteins related to hepatic fibrosis. We utilized selected reaction monitoring (SRM) targeted proteomics combined with an organ-specific blood protein strategy to identify and quantify 38 liver-specific proteins. A combination of protein C and retinol-binding protein 4 in serum gave promising preliminary results as candidate biomarkers to distinguish patients at different stages of hepatic fibrosis due to chronic infection with hepatitis C virus (HCV). Also, alpha-1-B glycoprotein, complement factor H and insulin-like growth factor binding protein acid labile subunit performed well in distinguishing patients from healthy controls.

BACKGROUND: Prostate cancer mortality rates in the United States declined by >40% between 1991 and 2005. The impact of changes in primary treatment and adjuvant and neoadjuvant hormone therapy on this decline is unknown. METHODS: The authors applied 3 independently developed models of prostate cancer natural history and disease detection under common assumptions about treatment patterns, treatment efficacy, and survival in the population. Primary treatment patterns were derived from the Surveillance, Epidemiology, and End Results registry; data on the frequency of hormone therapy were obtained from the CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) database; and treatment efficacy was based on estimates from randomized trials and comparative effectiveness studies of treatment alternatives. The models projected prostate cancer mortality without prostate-specific antigen screening and in the presence and absence of treatment benefit. The impact of primary treatment was expressed as a fraction of the difference between observed mortality and projected mortality in the absence of treatment benefit. RESULTS: The 3 models projected that changes in treatment explained 22% to 33% of the mortality decline by 2005. These contributions were accounted for mostly by surgery and radiation therapy, which increased in frequency until the 1990s, whereas hormone therapies contributed little to the mortality decline by 2005. Assuming that treatment benefit was less for older men, changes in treatment explained only 16% to 23% of the mortality decline by 2005. CONCLUSIONS: Changes in primary treatment explained a minority of the observed decline in prostate cancer mortality. The remainder of the decline probably was because of other interventions, such as prostate-specific antigen screening and advances in the treatment of recurrent and progressive disease. Cancer 2012;118:5955-63. V C 2012 American Cancer Society.

Several authors have indicated that incorrectly classified cause of death for prostate cancer survivors may have played a role in the observed recent peak and decline of prostate cancer mortality. Motivated by the suggestion we studied a competing risks model where other cause of death may be misattributed as a death of interest. We first consider a naive approach using unconstrained nonparametric maximum likelihood estimation (NPMLE), and then present the constrained NPMLE where the survival function is forced to be monotonic. Surprising observations were made as we studied their small-sample and asymptotic properties in continuous and discrete situations. Contrary to the common belief that the non-monotonicity of a survival function NPMLE is a small-sample problem, the constrained NPMLE is asymptotically biased in the continuous setting. Other isotonic approaches, the supremum (SUP) method and the Pooled-Adjacent-Violators (PAV) algorithm, and the EM algorithm are also considered. We found that the EM algorithm is equivalent to the constrained NPMLE. Both SUP method and PAV algorithm deliver consistent and asymptotically unbiased estimator. All methods behave well asymptotically in the discrete time setting. Data from the Surveillance, Epidemiology and End Results (SEER) database are used to illustrate the proposed estimators.

In bladder cancer, clinical grade and stage fail to capture outcome. We developed a clinically applicable quantitative PCR (QPCR) gene signature to predict progression in non–muscle-invasive bladder cancer. Comparative metaprofiling of 12 DNA microarray data sets (comprising 631 samples and 241,298 probe sets) identified 96 genes, which showed differential expression in seven clinical outcome categories, or were identified as outliers, historic markers, or housekeeping genes. QPCR was done to determine mRNA expression from 96 bladder tumors. Fifty-seven genes differentiated T2 from non-T2 tumors (P < 0.05). Principal components analysis and Cox regression models were used to predict probability of T2 progression for non-T2 patients, placing them into high- and low-risk groups based on their gene expression. At 2 years, high-risk patients exhibited greater T2 progression (45% for high-risk patients versus 12% for low-risk patients; P = 0.003, log-rank test). This difference remained significant within T1 tumors (61% for high-risk patients versus 22% for low-risk patients; P = 0.02) and Ta tumors (29% for high-risk patients versus 0% for low-risk patients; P = 0.03). The best multivariate Cox model included stage and gender, and this signature provided predictive improvement over both (P = 0.002, likelihood ratio test). Immunohistochemistry was done for two genes in the signature not previously described in bladder cancer, ACTN1 and CDC25B, corroborating their up-regulation at the protein level with disease progression. Thus, we identified a 57-gene QPCR panel to help predict progression of non–muscle-invasive bladder cancers and delineate a systematic, generalizable approach to converting microarray data into a multiplex assay for cancer progression. [Cancer Res 2009;69(9):3810–8]

Background The time by which prostate-specific antigen (PSA) screening advances prostate cancer diagnosis, called the lead time, has been reported by several studies, but results have varied widely, with mean lead times ranging from 3 to 12 years. A quantity that is closely linked with the lead time is the overdiagnosis frequency, which is the fraction of screen-detected cancers that would not have been diagnosed in the absence of screening. Reported overdiagnosis estimates have also been variable, ranging from 25% to greater than 80% of screen-detected cancers. Methods We used three independently developed mathematical models of prostate cancer progression and detection that were calibrated to incidence data from the Surveillance, Epidemiology, and End Results program to estimate lead times and the fraction of overdiagnosed cancers due to PSA screening among US men aged 54-80 years in 1985-2000. Lead times were estimated by use of three definitions. We also compared US and earlier estimates from the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) that were calculated by use of a microsimulation screening analysis (MISCAN) model. Results The models yielded similar estimates for each definition of lead time, but estimates differed across definitions. Among screen-detected cancers that would have been diagnosed in the patients' lifetimes, the estimated mean lead time ranged from 5.4 to 6.9 years across models, and overdiagnosis ranged from 23% to 42% of all screen-detected cancers. The original MISCAN model fitted to ERSPC Rotterdam data predicted a mean lead time of 7.9 years and an overdiagnosis estimate of 66%; in the model that was calibrated to the US data, these were 6.9 years and 42%, respectively. Conclusion The precise definition and the population used to estimate lead time and overdiagnosis can be important drivers of study results and should be clearly specified.

Objective. The emergency department (ED) can be a particularly challenging environment in which to offer care for chronic pain. This study tried to determine if beliefs held by patients and providers about noncancer-related chronic pain affect evaluation and management of pain in ED. Intervention. We surveyed 103 patients presenting to the ED with chronic pain, 34 ED physicians, and 44 ED nurses to assess the influence of 15 possible barriers to managing chronic pain in the ED. Results. Patients were significantly more likely than providers to believe that their pain had to have a diagnosed physical component to be treated. Providers were significantly more likely than patients to believe that patients came to the ED because they lacked a primary care physician. All agreed that chronic pain treatment was not a priority in the ED and the potential for addiction, dependence, diversion, and forged prescriptions was low. Conclusions. Patients in chronic pain may need to be reassured that their pain will be treated, even in the absence of objective signs or magnified symptoms. Providers may wrongly believe that lack of a primary care physician brings these patients to the ED. Providers and patients appear to believe that treating chronic pain in the ED has a low priority. Both groups may underestimate the problems inherent with prescribing opioids in this setting.

To determine if pain perception is affected by an extreme bout of exercise that causes ongoing exercise-related pain.Repeated-measures design.Pre-race registration area and finish area of an endurance race.Twenty-one competitors in the 2005 Western States 100 Mile Endurance Run and 11 control subjects who were assisting at the race but not running.Not applicable.Overall pain and pain ratings on a pressure pain test before and after the event.Mean overall pain +/- standard deviation on a 100-mm scale increased (P.05) from 3+/-6mm before the run to 39+/-28mm after the run among the runners. The faster runners showed a mean reduction (P.05) in pain ratings after the race of 15+/-20mm (on a 100-mm scale), whereas there was no change for the slower runners and controls. Findings were confirmed by model-based analysis.The faster runners in a 100-mile (161-km) running race experience a modest temporary reduction in pressure pain perception that does not appear to be augmented by ongoing pain related to the exercise. The lack of a reduction in pain perception among the slower runners may be because an extreme bout of exercise of this nature can "exhaust" the systems responsible for exercise-induced analgesia in all but the most well-trained of runners, or that these systems were not activated because the slower runners were unable to maintain a high enough exercise intensity during the later stages of the race.

Hepatic steatosis is a recognized problem in patients after orthotopic liver transplant (OLT). However, de novo development of nonalcoholic fatty liver disease (NAFLD) has not been well described. The aim of this study was to determine the prevalence and predictors of de novo NAFLD after OLT. A retrospective analysis was performed on 68 OLT patients with donor liver biopsies and posttransplantation liver biopsies. Individual medical charts were reviewed for demographics, indication for OLT, serial histology reports, genotypes for hepatitis C, comorbid conditions, and medications. Liver biopsies were reviewed blindly and graded according to the Brunt Scoring System. Multivariate logistic regression analysis was used to study the risk factors for developing NAFLD. The interval time from OLT to subsequent follow-up liver biopsy was 28 ± 18 months. A total of 12 patients (18%) developed de novo NAFLD, and 6 (9%) developed de novo NASH. The regression model indicated that the use of angiotensin-converting enzyme inhibitors (ACE-I) was associated with a reduced risk of developing NAFLD after OLT (odds ratio, 0.09; 95% confidence interval, 0.010-0.92; P = 0.042). Increase in body mass index (BMI) of greater than 10% after OLT was associated with a higher risk of developing NAFLD (odds ratio, 19.38; 95% confidence interval, 3.50-107.40; P = 0.001). In conclusion, de novo NAFLD is common in the post-OLT setting, with a significant association with weight gain after transplant. The use of an ACE-I may reduce the risk of developing post-OLT NAFLD. Liver Transpl, 2006. © 2006 AASLD.

Estimates that smoking contributes 38-72% of the United States (US) Black male cancer death rate leave a wide range of uncertainty. This paper uses additional and regional data, and refined methods, to reassess that range.This study uses lung cancer rates as an exposure index, linear regression, age adjusted US 1950-2001 and US regional 1969-2001 death rates (rates), and the formula: smoking-attributable fraction (SAF)=(1-((rate in the unexposed) / (rate in the exposed))). Estimated lung cancer rates in the unexposed range between rates predicted for a population with no smoking-attributable lung cancers to rates seen in "nonsmokers."Lung cancer death rates predicted 99.9% and 99.8% of the variances in non-lung non-stomach cancer death rates from 1950-1980 and 1950-1988, respectively (each P0.0001). That suggests 2001 all-sites cancer death SAFs of 63% (sensitivity range 60-66%) nationally and from 43% in the Northeast to 67% in the South.Smoking may cause most premature cancer deaths and temporal and regional cancer death rate disparities in Black men.

Since 1980, electron arc irradiation of the postmastectomy chest wall has been the preferred radiotherapy technique at the University of Utah for patients with advanced breast cancer. We report the results of this technique in 156 consecutive Stage IIA-IIIB patients treated from 1980 to 1998.CT treatment planning was used in all patients to identify chest wall thickness and internal mammary lymph node depth. Computerized dosimetry was used to deliver total doses of 50 Gy in 5-1/2 weeks to the chest wall and the internal mammary lymph nodes with electron arc therapy. Patients were assessed for local, regional, and distant control of disease and for survival. Univariate and multivariate proportional hazards were modeled using a hierarchical nonproportional semiparametric model testing the following prognostic factors: age, stage, tumor size, number of positive lymph nodes, estrogen receptor status, and dose. End points evaluated included disease-free survival, cause-specific survival, and overall survival.Eighty-one percent of patients were at high risk for local-regional failure because ofT2 primary tumor or3 positive axillary lymph nodes. The median number of positive lymph nodes was 5, and the median tumor size was 3.5 cm. Actuarial 10-year local-regional control and overall survival were 95% and 52%, respectively. In multivariate analysis, the only factor prognostic for disease-free survival, cause-specific survival, and overall survival was the number of positive lymph nodes (p0.001). The 10-year rates of local-regional control for patients with 0, 1-3, 4-9, andor = 10 involved lymph nodes were 100%, 98%, 93%, and 89%, respectively. The only rates of acute and chronic radiotherapy toxicityor = 2 by RTOG/EORTC criteria were skin related and observed in 44% and 10% for acute and late reactions, respectively.These data demonstrate excellent local-regional control rates with electron arc therapy of the postmastectomy chest wall in patients with advanced breast cancer. Our 20-year experience with electron arc radiotherapy has demonstrated the safety and efficacy of this technique. The advantage of this technique is that the internal mammary lymph node chain can be easily encompassed while the dose to heart and lung is minimized; it also obviates match lines in areas of high risk.