How Well do Polygenic Risk Scores Identify Men at High Risk for Prostate Cancer? Systematic Review and Meta-Analysis.

OBJECTIVES: Genome-wide association studies have revealed over 200 genetic susceptibility loci for prostate cancer (PCa). By combining them, polygenic risk scores (PRS) can be generated to predict risk of PCa. We summarize the published evidence and conduct meta-analyses of PRS as a predictor of PCa risk in Caucasian men. PATIENTS AND METHODS: Data were extracted from 59 studies, with 16 studies including 17 separate analyses used in the main meta-analysis with a total of 20,786 cases and 69,106 controls identified through a systematic search of ten databases. Random effects meta-analysis was used to obtain pooled estimates of area under the receiver-operating characteristic curve (AUC). Meta-regression was used to assess the impact of number of single-nucleotide polymorphisms (SNPs) incorporated in PRS on AUC. Heterogeneity is expressed as I2 scores. Publication bias was evaluated using funnel plots and Egger tests. RESULTS: The ability of PRS to identify men with PCa was modest (pooled AUC 0.63, 95% CI 0.62-0.64) with moderate consistency (I2 64%). Combining PRS with clinical variables increased the pooled AUC to 0.74 (0.68-0.81). Meta-regression showed only negligible increase in AUC for adding incremental SNPs. Despite moderate heterogeneity, publication bias was not evident. CONCLUSION: Typically, PRS accuracy is comparable to PSA or family history with a pooled AUC value 0.63 indicating mediocre performance for PRS alone.

Cost-Effectiveness of Lower Extremity Nerve Decompression Surgery in the Prevention of Ulcers and Amputations: A Markov Analysis.

BACKGROUND: The costs and health effects associated with lower extremity complications in diabetes mellitus are an increasing burden to society. In selected patients, lower extremity nerve decompression is able to reduce symptoms of neuropathy and the concomitant risks of diabetic foot ulcers and amputations. To estimate the health and economic effects of this type of surgery, the cost-effectiveness of this intervention compared to current nonsurgical care was studied. METHODS: To estimate the incremental cost-effectiveness of lower extremity nerve decompression over a 10-year period, a Markov model was developed to simulate the onset and progression of diabetic foot disease in patients with diabetes and neuropathy who underwent lower extremity nerve decompression surgery, compared to a group undergoing current nonsurgical care. Mean survival time, health-related quality of life, presence or risk of lower extremity complications, and in-hospital costs were the outcome measures assessed. Data from the Rotterdam Diabetic Foot Study were used as current care, complemented with information from international studies on the epidemiology of diabetic foot disease, resource use, and costs, to feed the model. RESULTS: Lower extremity nerve decompression surgery resulted in improved life expectancy (88,369.5 life-years versus 86,513.6 life-years), gain of quality-adjusted life-years (67,652.5 versus 64,082.3), and reduced incidence of foot complications compared to current care (490 versus 1087). The incremental cost-effectiveness analysis was -€59,279.6 per quality-adjusted life-year gained, which is below the Dutch critical threshold of less than €80,000 per quality-adjusted life-year. CONCLUSIONS: Decompression surgery of lower extremity nerves improves survival, reduces diabetic foot complications, and is cost saving and cost-effective compared with current care, suggesting considerable socioeconomic benefit for society.

Validation of cardiovascular outcomes and risk factors in the Clinical Practice Research Datalink in the United Kingdom.

PURPOSE: Strategies to identify and validate acute myocardial infarction (AMI) and stroke in primary-care electronic records may impact effect measures, but to an unknown extent. Additionally, the validity of cardiovascular risk factors that could act as confounders in studies on those endpoints has not been thoroughly assessed in the United Kingdom Clinical Practice Research Datalink's (CPRD's) GOLD database. We explored the validity of algorithms to identify cardiovascular outcomes and risk factors and evaluated different outcome-identification strategies using these algorithms for estimation of adjusted incidence rate ratios (IRRs). METHODS: First, we identified AMI, stroke, smoking, obesity, and menopausal status in a cohort treated for overactive bladder by applying computerized algorithms to primary care medical records (2004-2012). We validated these cardiovascular outcomes and risk factors with physician questionnaires (gold standard for this analysis). Second, we estimated IRRs for AMI and stroke using algorithm-identified and questionnaire-confirmed cases, comparing these with IRRs from cases identified through linkage with hospitalization/mortality data (best estimate). RESULTS: For AMI, the algorithm's positive predictive value (PPV) was >90%. Initial algorithms for stroke performed less well because of inclusion of codes for prevalent stroke; algorithm refinement increased PPV to 80% but decreased sensitivity by 20%. Algorithms for smoking and obesity were considered valid. IRRs based on questionnaire-confirmed cases only were closer to IRRs estimated from hospitalization/mortality data than IRRs from algorithm-identified cases. CONCLUSIONS: AMI, stroke, smoking, obesity, and postmenopausal status can be accurately identified in CPRD. Physician questionnaire-validated AMI and stroke cases yield IRRs closest to the best estimate.

Author Correction: Introducing PIONEER: a project to harness big data in prostate cancer research.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Introducing PIONEER: a project to harness big data in prostate cancer research.

Prostate Cancer Diagnosis and Treatment Enhancement Through the Power of Big Data in Europe (PIONEER) is a European network of excellence for big data in prostate cancer, consisting of 32 private and public stakeholders from 9 countries across Europe. Launched by the Innovative Medicines Initiative 2 and part of the Big Data for Better Outcomes Programme (BD4BO), the overarching goal of PIONEER is to provide high-quality evidence on prostate cancer management by unlocking the potential of big data. The project has identified critical evidence gaps in prostate cancer care, via a detailed prioritization exercise including all key stakeholders. By standardizing and integrating existing high-quality and multidisciplinary data sources from patients with prostate cancer across different stages of the disease, the resulting big data will be assembled into a single innovative data platform for research. Based on a unique set of methodologies, PIONEER aims to advance the field of prostate cancer care with a particular focus on improving prostate-cancer-related outcomes, health system efficiency by streamlining patient management, and the quality of health and social care delivered to all men with prostate cancer and their families worldwide.

Validation of Cancer Cases Using Primary Care, Cancer Registry, and Hospitalization Data in the United Kingdom.

BACKGROUND: In the United Kingdom, hospital or cancer registry data can be linked to electronic medical records for a subset of general practices and years. METHODS: We used Clinical Practice Research Datalink data (2004-2012) from patients treated for overactive bladder. We electronically identified provisional cases of 10 common cancers in General Practitioner Online Database data and validated them by medical profile review. In practices with linkage to Hospital Episodes Statistics and National Cancer Data Repository (2004-2010), we validated provisional cancer cases against these data sources. This linkage also let us identify additional cancer diagnoses in individuals without cancer diagnosis records in the General Practitioner Online Database. RESULTS: Among 50,840 patients, 1,486 provisional cancer cases were identified in the General Practitioner Online Database for 2004-2012. Medical profile review confirmed 93% of 661 cases in nonlinked practices (range, 100% of non-Hodgkin lymphomas and uterine cancer to 77% of skin melanomas) and 96% of 825 cases in linked practices (100% of kidney and uterine cancers to 92% of melanomas). In the subset of linked practices, for 2004-2010, 720 cases were confirmed, of which 68% were identifiable in the General Practitioner Online Database (range, 90% of breast to 36% of kidney cancers). CONCLUSIONS: Most cases of cancer identified electronically in the General Practitioner Online Database were confirmed. A substantial proportion of cases, especially of cancer types not typically managed by general practitioners, would be missed without Hospital Episodes Statistics and National Cancer Data Repository data (and are likely missed in nonlinked practices). See video abstract at, http://links.lww.com/EDE/B315. REGISTRATION (BEFORE STUDY CONDUCT): European Union electronic Register of Post-Authorisation Studies (EU PAS Registry) number EUPAS5529, http://www.encepp.eu/encepp/viewResource.htm?id=11107.

Epidemiological features of invasive mold infections among solid organ transplant recipients: PATH Alliance® registry analysis.

Epidemiological characteristics of 333 proven and probable invasive mould infections (IMIs) among solid organ transplant recipients (SOTRs) identified between 2004 and 2008 from the Prospective Antifungal Therapy Alliance (PATH) registry are presented. Liver transplant recipients (LTRs) had the lowest median time to IMIs (109 days; interquartile range [IQR] 24-611 days), the highest rate of disseminated disease (n/N = 18/33; 55%), and highest mortality (n/N = 21/33; 64%). Lung transplant recipients had highest median time to IMIs (486 days; IQR 117-1358 days) and lowest mortality (n/N = 31/184; 17%). Complete or partial response at week 12 in patients with invasive aspergillosis (IA) was 67% (n/N = 189/281), and 41% (n/N = 9/22) in mucormycosis patients. In the composite outcome of death or no response to therapy, LTRs had the worst outcome. Higher suspicion of mold infection and institution of appropriate antifungal prophylactic strategies are warranted, especially in high risk LTRs.

Alpha blocker monotherapy versus combination therapy with antimuscarinics in men with persistent LUTS refractory to alpha-adrenergic treatment: patterns of persistence.

INTRODUCTION: Patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) often present with voiding and storage symptoms, which may require combination therapy with an alpha blocker and an antimuscarinic (AM). This study compared treatment persistence in LUTS/BPH patients on alpha blocker monotherapy with those using combination alpha blocker and AM therapy (AB/AM). MATERIALS AND METHODS: Retrospective analysis of anonymized patient longitudinal prescription reimbursement claims data. All patients who had claims for any of four alpha blocker medications and six AM agents during an index period from April 1, 2011 to March 31, 2012 were included. For the combination therapy group, the effect of adherence with the AM medication on persistence to the alpha blocker was examined. RESULTS: Patients on AB/AM combination therapy remained on alpha blockers for longer than those on alpha blocker monotherapy (p = 0.04); 92.4% were persistent at 3 months versus 89.0%, and at 1 year 50.8% were persistent versus 49.6%, respectively. The highest number of days on therapy was reported for tamsulosin plus solifenacin. As confirmed by multivariate analysis, patients with the highest adherence to AM medication (= 80%) persisted on alpha blockers for longer than those with the lowest (< 50%) adherence (p < 0.05). CONCLUSIONS: Patients taking an AM in combination with an alpha blocker showed greater persistence with alpha blocker treatment over a 1 year period. When an AM is combined with an alpha blocker in patients with LUTS/BPH, the additional medication burden does not have a negative impact on persistence and may even improve it.

Efficacy outcomes by baseline prostate-specific antigen quartile in the AFFIRM trial.

BACKGROUND: Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer (PCa) after docetaxel in the randomised, phase 3, double-blind, placebo-controlled, multinational Patients with Progressive Castration-Resistant Prostate Cancer Previously Treated with Docetaxel-Based Chemotherapy (AFFIRM) trial (NCT00974311). Prostate-specific antigen (PSA) is commonly used as a marker of PCa disease burden, and the relationship of baseline PSA level to consequent treatment effect is of clinical interest. OBJECTIVE: Exploratory analysis to evaluate any differences in patient characteristics and efficacy outcomes by baseline PSA level in the AFFIRM trial. DESIGN, SETTING, AND PARTICIPANTS: Post hoc subanalysis of all randomised patients (n=1199) from the AFFIRM trial. INTERVENTION: Participants were randomly assigned in a two-to-one ratio to receive oral enzalutamide 160 mg/d or placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The major clinical efficacy end points were overall survival (OS), radiographic progression-free survival (rPFS), and time to PSA progression (TTPP) versus placebo; baseline characteristics, treatment duration, and subsequent antineoplastic therapy were compared by baseline PSA quartile. RESULTS AND LIMITATIONS: Baseline PSA quartiles corresponded to the following PSA groups: <40 ng/ml (n=299), 40 to <111 ng/ml (n=300), 111 to <406 ng/ml (n=300), and ≥406 ng/ml (n=300). Enzalutamide consistently improved OS, rPFS, and TTPP compared with placebo across all subgroups, regardless of baseline PSA level. Hazard ratios for improvements in OS were 0.55 (95% confidence interval [CI], 0.36-0.85), 0.69 (95% CI, 0.47-1.02), 0.73 (95% CI, 0.53-1.01), and 0.53 (95% CI, 0.39-0.73) for PSA groups 1-4, respectively. The post hoc design of this analysis was not statistically powered to assess the relationship between baseline PSA and clinical efficacy outcomes. CONCLUSIONS: This post hoc analysis of the AFFIRM trial demonstrates consistent benefits in OS, rPFS, and TTPP with enzalutamide regardless of baseline disease severity, as assessed by PSA. PATIENT SUMMARY: Exploratory post hoc analysis of the AFFIRM trial showed that enzalutamide improves overall survival, radiographic progression-free survival, and time to prostate-specific antigen progression compared with placebo regardless of baseline disease severity, as assessed by prostate-specific antigen. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00974311.

Enzalutamide in European and North American men participating in the AFFIRM trial.

OBJECTIVE: To explore any differences in efficacy and safety outcomes between European (EU) (n = 684) and North American (NA) (n = 395) patients in the AFFIRM trial (NCT00974311). PATIENTS AND METHODS: Phase III, double-blind, placebo-controlled, multinational AFFIRM trial in men with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel. Participants were randomly assigned in a 2:1 ratio to receive oral enzalutamide 160 mg/day or placebo. The primary end point was overall survival (OS) in a post hoc analysis. RESULTS: Enzalutamide significantly improved OS compared with placebo in both EU and NA patients. The median OS in EU patients was longer than NA patients in both treatment groups. However, the relative treatment effect, expressed as hazard ratio and 95% confidence interval, was similar in both regions: 0.64 (0.50, 0.82) for EU and 0.63 (0.47, 0.83) for NA. Significant improvements in other end points further confirmed the benefit of enzalutamide over placebo in patients from both regions. The tolerability profile of enzalutamide was comparable between EU and NA patients, with fatigue and nausea the most common adverse events. Four EU patients (4/461 enzalutamide-treated, 0.87%) and one NA patient (1/263 enzalutamide-treated, 0.38%) had seizures. The difference in median OS was related in part to the timing of development of mCRPC and baseline demographics on study entry. CONCLUSION: This post hoc exploratory analysis of the AFFIRM trial showed a consistent OS benefit for enzalutamide in men with mCRPC who had previously progressed on docetaxel in both NA- and EU-treated patients, although the median OS was higher in EU relative to NA patients. Efficacy benefits were consistent across end points, with a comparable safety profile in both regions.

Epidemiology and outcomes of invasive candidiasis due to non-albicans species of Candida in 2,496 patients: data from the Prospective Antifungal Therapy (PATH) registry 2004-2008.

This analysis describes the epidemiology and outcomes of invasive candidiasis caused by non-albicans species of Candida in patients enrolled in the Prospective Antifungal Therapy Alliance (PATH Alliance) registry from 2004 to 2008. A total of 2,496 patients with non-albicans species of Candida isolates were identified. The identified species were C. glabrata (46.4%), C. parapsilosis (24.7%), C. tropicalis (13.9%), C. krusei (5.5%), C. lusitaniae (1.6%), C. dubliniensis (1.5%) and C. guilliermondii (0.4%); 111 infections involved two or more species of Candida (4.4%). Non-albicans species accounted for more than 50% of all cases of invasive candidiasis in 15 of the 24 sites (62.5%) that contributed more than one case to the survey. Among solid organ transplant recipients, patients with non-transplant surgery, and patients with solid tumors, the most prevalent non-albicans species was C. glabrata at 63.7%, 48.0%, and 53.8%, respectively. In 1,883 patients receiving antifungal therapy on day 3, fluconazole (30.5%) and echinocandins (47.5%) were the most frequently administered monotherapies. Among the 15 reported species, 90-day survival was highest for patients infected with either C. parapsilosis (70.7%) or C. lusitaniae (74.5%) and lowest for patients infected with an unknown species (46.7%) or two or more species (53.2%). In conclusion, this study expands the current knowledge of the epidemiology and outcomes of invasive candidiasis caused by non-albicans species of Candida in North America. The variability in species distribution in these centers underscores the importance of local epidemiology in guiding the selection of antifungal therapy.

Treatment and outcomes of invasive fusariosis: review of 65 cases from the PATH Alliance(®) registry.

Invasive Fusarium infections occur in immunosuppressed patients, especially those with haematological malignancies. We conducted a descriptive analysis of data from patients with invasive fusariosis identified in the Prospective Antifungal Therapy Alliance registry, which collected data on invasive fungal infections in the United States and Canada from 2004 to 2008. In this series of 65 patients with proven (83.1%) and probable (16.9%) invasive fusariosis, the most common underlying condition was haematological malignancy, in which neutropenia and corticosteroid usage frequently occurred. Seven patients with invasive Fusarium infections had cross-reactive galactomannan assay results. The survival rate for all patients at 90 days was 44%, which was an improvement compared with historical data. Disseminated disease occurred frequently (35.4%), and patients with and without disseminated disease had survival rates of 33% and 50%, respectively. Posaconazole and voriconazole were the most frequently employed therapies and may be linked to the improved survival rate observed in this patient series. In summary, patients with invasive Fusarium infections continue to have high fatality rates, especially those with disseminated disease. Fusarium infections should be strongly considered in the absence of Aspergillus isolation in patients at high risk of mould infections with positive galactomannan assay test results.

Prospective antifungal therapy (PATH) alliance(®) : focus on mucormycosis.

Mucormycosis is increasingly encountered in immunosuppressed patients, such as those with haematological malignancies or stem cell transplantation. We present a descriptive analysis of 121 cases of mucormycosis from the Prospective Antifungal Therapy Alliance(®) registry (July 2004 to December 2008). Patients with proven or probable mucormycosis were enrolled and followed prospectively for 12 weeks. The most common underlying disease and site of infection were haematologic malignancy (61.2%) and lungs (46.3%) respectively. Rhizopus (n = 63; 52.1%) was the most commonly isolated species, followed by Mucor (n = 28; 23.1%), other or unknown (n = 17; 14.0%), Rhizomucor (n = 9; 7.4%) and Lichtheimia (n = 4; 3.3%). The 12-week Kaplan-Meier survival probability for all patients was 0.41; however, there was large variation in survival probabilities between species, with highest survival probability observed for Lichtheimia (0.5), followed by Rhizopus (0.47), Mucor (0.40), unknown Mucormycetes species (0.40), other Mucormycetes species (0.17) and Rhizomucor (0.15). Prior use of voriconazole decreased 12-week survival probability. Survival probability was higher in patients receiving amphotericin B by Day 3 (0.72) vs. those who started amphotericin B therapy after Day 3 (0.33). The low survival probability observed underscores the importance of further studies of mucormycosis. Optimal treatment selection and timing may improve prognosis.

Effect of caffeine on SPECT myocardial perfusion imaging during regadenoson pharmacologic stress: rationale and design of a prospective, randomized, multicenter study.

BACKGROUND: Caffeine attenuates the coronary hyperemic response to adenosine by competitive A2(A) receptor blockade. This study aims to determine whether oral caffeine administration compromises diagnostic accuracy in patients undergoing vasodilator stress myocardial perfusion imaging (MPI) with regadenoson, a selective adenosine A(2A) agonist. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study includes patients with suspected coronary artery disease who regularly consume caffeine. Each participant undergoes three SPECT MPI studies: a rest study on day 1 (MPI-1); a regadenoson stress study on day 3 (MPI-2), and a regadenoson stress study on day 5 with double-blind administration of oral caffeine 200 or 400 mg or placebo capsules (MPI-3; n = 90 per arm). Only participants with ≥ 1 reversible defect on the second MPI study undergo the subsequent stress MPI test. The primary endpoint is the difference in the number of reversible defects on the two stress tests using a 17-segment model. Pharmacokinetic/pharmacodynamic analyses will evaluate the effect of caffeine on the regadenoson exposure-response relationship. Safety will also be assessed. CONCLUSION: The results of this study will show whether the consumption of caffeine equivalent to 2-4 cups of coffee prior to an MPI study with regadenoson affects the diagnostic validity of stress testing (ClinicalTrials.gov number, NCT00826280).

Differences in heart rate response to adenosine and regadenoson in patients with and without diabetes mellitus.

BACKGROUND: Adenosine and regadenoson increase heart rate (HR) when used as stress agents to produce coronary hyperemia due to direct sympathetic stimulation. We hypothesized that the HR response will be lower in patients with than in those without diabetes mellitus (DM). METHODS: We studied the HR response (percentage maximal increase) in 2,000 patients in The ADenoscan Versus regAdenosoN Comparative Evaluation for Myocardial Perfusion Imaging (ADVANCE MPI 1 and 2) Trials with known DM status. RESULTS: There were 643 patients with a history of DM (65.4 +/- 0.4 years, 32% women) and 1,357 patients with no DM (65.5 +/- 0.3 years, 29% women). Compared with non-DM, the DM group had higher HR at baseline (68.4 +/- 0.48 vs 65.2 +/- 0.31 beat/min, P < .001) and smaller HR response after adenosine or regadenoson administration (29.4% +/- 0.64% vs 36.1% +/- 0.54%, P < .001). Insulin therapy was associated with further blunting in the HR response (25.9% +/- 1.0% vs 31.2% +/- 0.8%, P < .001). After adjusting for beta-blocker intake, baseline HR, age, gender, renal function, systolic blood pressure, and left ventricular systolic function, DM independently accounted for a decrease in the HR response. CONCLUSIONS: The HR response to adenosine and regadenoson in patients with DM is blunted. If additional studies confer an agreement between traditional tests for determination of autonomic neuropathy and this measure, then examination of HR response to these agents during myocardial perfusion imaging might add prognostic power.