Summary Background Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies. In ...partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease. Methods Data from the comparator arms of four phase 3 clinical trials in first-line metastatic castration-resistant prostate cancer were obtained from Project Data Sphere, comprising 476 patients treated with docetaxel and prednisone from the ASCENT2 trial, 526 patients treated with docetaxel, prednisone, and placebo in the MAINSAIL trial, 598 patients treated with docetaxel, prednisone or prednisolone, and placebo in the VENICE trial, and 470 patients treated with docetaxel and placebo in the ENTHUSE 33 trial. Datasets consisting of more than 150 clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Data from ASCENT2, MAINSAIL, and VENICE were released publicly to be used as training data to predict the outcome of interest—namely, overall survival. Clinical data were also released for ENTHUSE 33, but data for outcome variables (overall survival and event status) were hidden from the challenge participants so that ENTHUSE 33 could be used for independent validation. Methods were evaluated using the integrated time-dependent area under the curve (iAUC). The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance. Further validation was done using data from a fifth trial—ENTHUSE M1—in which 266 patients with metastatic castration-resistant prostate cancer were treated with placebo alone. Findings 50 independent methods were developed to predict overall survival and were evaluated through the DREAM challenge. The top performer was based on an ensemble of penalised Cox regression models (ePCR), which uniquely identified predictive interaction effects with immune biomarkers and markers of hepatic and renal function. Overall, ePCR outperformed all other methods (iAUC 0·791; Bayes factor >5) and surpassed the reference model (iAUC 0·743; Bayes factor >20). Both the ePCR model and reference models stratified patients in the ENTHUSE 33 trial into high-risk and low-risk groups with significantly different overall survival (ePCR: hazard ratio 3·32, 95% CI 2·39–4·62, p<0·0001; reference model: 2·56, 1·85–3·53, p<0·0001). The new model was validated further on the ENTHUSE M1 cohort with similarly high performance (iAUC 0·768). Meta-analysis across all methods confirmed previously identified predictive clinical variables and revealed aspartate aminotransferase as an important, albeit previously under-reported, prognostic biomarker. Interpretation Novel prognostic factors were delineated, and the assessment of 50 methods developed by independent international teams establishes a benchmark for development of methods in the future. The results of this effort show that data-sharing, when combined with a crowdsourced challenge, is a robust and powerful framework to develop new prognostic models in advanced prostate cancer. Funding Sanofi US Services, Project Data Sphere.
Background Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare, autosomal-dominant disease secondary to germline-inactivating mutations of the tumor suppressor gene HRPT2/CDC73 . The aim of the ...present study was to determine the optimal operative approach to parathyroid disease in patients with HPT-JT. Methods A retrospective analysis of clinical and genetic features, parathyroid operative outcomes, and disease outcomes in 7 unrelated HPT-JT families. Results Seven families had 5 distinct germline HRPT2/CDC73 mutations. Sixteen affected family members (median age, 30.7 years) were diagnosed with primary hyperparathyroidism (PHPT). Fifteen of the 16 patients underwent preoperative tumor localization studies and uncomplicated bilateral neck exploration at initial operation; all were in biochemical remission at most recent follow-up. Of these patients, 31% had multiglandular involvement; 37.5% of the patients developed parathyroid carcinoma (median overall survival, 8.9 years; median follow-up, 7.4 years). Long-term follow-up showed that 20% of patients had recurrent PHPT. Conclusion Given the high risk of malignancy and multiglandular involvement in our cohort, we recommend bilateral neck exploration and en bloc resection of parathyroid tumors suspicious for cancer and life-long postoperative follow-up.
Depression is common in patients with heart failure (HF), prognostic for adverse outcomes and purportedly related to disease severity. Psychological and physiologic factors relevant to HF were ...assessed in HF-ACTION, a large randomized study of aerobic exercise training in patients with systolic HF. The relation of objective and subjective parameters was compared with scores on the Beck Depression Inventory (BDI) to examine the hypothesis that depressive symptoms are better associated with perception of disease severity than with objective markers of HF severity. At baseline, 2,322 of 2,331 subjects entered into HF-ACTION completed questionnaires to assess depression (BDI) and quality of life (Kansas City Cardiomyopathy Questionnaire KCCQ). Objective markers of HF severity included ejection fraction, B-type natriuretic peptide, and peak oxygen consumption (using cardiopulmonary exercise testing, with evaluation of duration and respiratory exchange ratio also performed). Measures more likely to be affected by perceived functional status included New York Heart Association (NYHA) classification and the 6-minute walk test. Objective assessments of disease severity were slightly related (peak oxygen consumption) or not related (B-type natriuretic peptide and ejection fraction) to BDI scores. Using multivariate analysis (KCCQ not included), only age, gender, cardiopulmonary exercise testing duration, NYHA class, 6-minute walk distance, and peak respiratory exchange ratio independently correlated with BDI scores. In conclusion, depression was minimally related to objective assessments of severity of disease in patients with HF, but was associated with patient (and clinician) perceptions of disease severity. Addressing depression might improve symptoms in patients with HF.
Objectives This study sought to ascertain causes of death and the incidence of percutaneous coronary intervention (PCI)-related mortality within 30 days. Background Public reporting of 30-day ...mortality after PCI without clearly identifying the cause may result in operator risk avoidance and affect hospital reputation and reimbursements. Death certificates, utilized by previous reports, have poor correlation with actual cause of death and may be inadequate for public reporting. Methods All patients who died within 30 days of a PCI from January 2009 to April 2011 at a tertiary care center were included. Causes of death were identified through detailed chart review using Academic Research Consortium consensus guidelines and compared with reported death certificates. The causes of death were divided into cardiac and noncardiac and PCI and non–PCI-related categories. Results Of the 4,078 PCI, 81 deaths (2%) occurred within 30 days. Of these, 58% died of cardiac and 42% of noncardiac causes. However, only 42% of 30-day deaths were attributed to PCI-related complications. Patients with non–PCI-related, compared with PCI-related, death presented with a higher incidence of cardiogenic shock (15 of 47 32% vs. 2 of 34 6%; p < 0.01) and cardiac arrest (19 of 47 40% vs. 1 of 34 3%; p < 0.01). Death certificates had only 58% accuracy (95% confidence interval: 45% to 72%) for classifying patients as experiencing cardiac versus noncardiac death. Conclusions Less than one-half of 30-day deaths are attributed to a PCI-related complication. Death certificates are inaccurate and do not report PCI-related deaths, which may represent a better marker of PCI quality.
There is a paucity of evidence on the impact of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) on long-term outcomes in patients with ejection fraction (EF) ...>40% after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (STEMI). We compared long-term all-cause mortality between patients with left ventricular ejection fraction (LVEF) >40% discharged on ACEi/ARB with patients who were discharged on neither of these agents. Patients discharged after percutaneous intervention for STEMI from our catheterization laboratories from January 2002 to December 2011 were considered for inclusion. Patients were excluded if they had LVEF <40% or chronic kidney disease or hypotension (systolic blood pressure <90 mm Hg any time after the procedure). Long-term mortality and discharge medications were determined using the Social Security Death Index and electronic medical record review, respectively. A total of 988 patients were included. The median follow-up duration was 4.6 years. Kaplan-Meier analysis showed no significant difference in long-term all-cause mortality in patients discharged on ACEi/ARB compared with those who were not discharged on these medications. The number needed to treat to prevent 1 death at 1 year was 714. In addition, multivariable Cox proportional hazard modeling failed to demonstrate any beneficial effect of ACEi/ARB similar to Kaplan-Meir analysis (hazard ratio 0.88, 95% confidence interval 0.57 to 1.36). In conclusion, we found no significant benefit in long-term mortality using ACEi/ARB in patients with LVEF >40% after primary percutaneous coronary intervention for STEMI.
Glycated hemoglobin (HbA1c) is an approved and widely used laboratory investigation for diagnosis of diabetes that is not affected by acute changes in blood glucose. Our aim was to analyze the extent ...to which routine HbA1c measurements diagnose unknown diabetes mellitus (DM) in patients presenting with ST-segment elevation myocardial infarction (STEMI). We also compared outcomes in patients with newly diagnosed DM, previously established DM and those without DM. Consecutive patients undergoing PCI for STEMI from January 2005 to December 2012 were included and routinely performed admission HbA1c was used to identify patients with previously undiagnosed DM (HbA1c ≥6.5 and no history of DM or DM therapy) and pre-DM (HbA1c 5.7% to 6.4%). Overall 1,686 consecutive patients underwent primary percutaneous coronary intervention for STEMI during the study period and follow-up data were available for 1,566 patients (90%). A quarter of the patients (24%, n = 405) had history of DM, 7% (n = 118) had previously undiagnosed DM, and 38.7% (n = 652) had pre-DM. Mortality was comparable in patients with known DM and newly diagnosed DM both in-hospital (11.1% vs 11.9%, p = 0.87) and at 3-year follow-up (27.3% and 24%). Patients with DM, including those who were newly diagnosed, had higher mortality at 3 years (26.5%) compared to those with pre-DM (12.1%) or no dysglycemia (11.2%, p <0.01). In conclusion, a substantial number of patients with STEMI have previously undiagnosed DM (7%). These patients have similar in-hospital and long-term mortality as those with known DM, and outcomes are inferior to patients without dysglycemia.
Abstract Background Few studies have explored percutaneous coronary intervention (PCI) in perioperative myocardial infarction (PMI), even though PMI is a major cause of mortality in patients ...undergoing urgent/emergent noncardiac surgery. Objectives This study sought to describe the angiographic characteristics and outcomes in patients presenting to the cardiac catheterization laboratory for myocardial infarction sustained after undergoing noncardiac surgery, with a detailed analysis of those undergoing PCI. Methods We included all patients presenting to the catheterization laboratory at our institution after PMI from 2003 to 2012, who had noncardiac surgery within the previous 7 days. Data from patients who underwent PCI were analyzed using both standard regression and time-to-event survival analysis. Results From 2003 to 2012, 1,093 patients with 3,832 person-years of follow-up underwent diagnostic coronary angiography, of whom 281 (40 ST-segment elevation myocardial infarction STEMI and 241 non-ST-segment elevation myocardial infarction NSTEMI cases) underwent PCI. Using Kaplan-Meier survival analysis, we found 30-day mortality was 5.2% and 1-year mortality was 15% in the overall population. In the PCI subpopulation, we estimated 30-day mortality to be 11.3%. The 30-day death rate in the STEMI cohort was 31.2% and 8.5% in the NSTEMI cohort of the PCI subpopulation. Stepwise logistic regression revealed the following factors as strong predictors of 30-day mortality after PCI: bleeding event after PCI (odds ratio OR: 4.33; 95% confidence limits (CL): 1.52 to 12.30), peak troponin T level (OR: 1.20; 95% CL: 1.08 to 1.34), and underlying peripheral vascular disease (OR: 4.86; 95% CL: 1.66 to 14.22). Cox proportional hazard analysis of survival data showed that increasing age (hazard ratio HR: 1.03; 95% CL: 1.01 to 1.04), bleeding after PCI (HR: 2.31; 95% CL: 1.61 to 3.32), renal insufficiency (HR: 2.26; 95% CL: 1.51 to 3.39), and vascular surgery (HR: 1.48; 95% CL: 1.02 to 2.15) were all significant predictors of long-term mortality after PCI. Conclusions Perioperative MI has a markedly high mortality rate, despite PCI. Bleeding event, peak troponin T level, and peripheral vascular disease predict mortality within 30 days of PCI in this patient population. Similarly, older age, vascular surgery, bleeding event, and renal dysfunction strongly predict long-term mortality after PCI in the setting of PMI.
Summary Wernicke-Korsakoff syndrome in patients with cancer is understudied. Much of what is known—that significant under-recognition and delays in treatment exist—comes from studies of alcohol ...misuse disorders or non-alcohol-related Wernicke-Korsakoff syndrome in patients. We investigated the frequency and associated features of cancer-related Wernicke-Korsakoff syndrome in the published literature. We included 90 articles reporting on 129 patients. Only 38 (30%) of 128 patients with data available exhibited the entire triad of classic features of Wernicke-Korsakoff syndrome: confusion, ataxia, and ophthalmoplegia or nystagmus. Diagnosis during life was missed altogether in 22 (17%) of 128 patients. The operational diagnostic criteria (at least two of the following: nutritional deficiency, ocular signs, cerebellar signs, and either altered mental status or mild memory impairment), which are considered more reliable than the classical triad, were used in only nine (7%) cases, yet 120 (94%) met the operational criteria for diagnosis at the time of presentation when applied retroactively. Complete recovery was reported in only 47 (36%) cases. Given that oncologists or haematologists accounted for only 17 (19%) first authors among the articles included, it is important that oncologists are aware of the risk factors for cancer-related Wernicke-Korsakoff syndrome, and that they are vigilant about diagnosing and treating the disease especially in the absence of alcohol misuse disorders.
Background Randomized trials have demonstrated progressive improvements in clinical and angiographic measures of restenosis with technologic iterations from balloon angioplasty to bare-metal stents ...and subsequently to drug-eluting stents (DES). However, the permanent presence of a metal stent prevents coronary vasomotion, autoregulation, and adaptive coronary remodeling. The limitations imposed by a permanent metal implant may be overcome with a bioresorbable scaffold. ABSORB III is a large-scale, multicenter, randomized trial designed to support US premarket approval of the ABSORB BVS platform and is the first study with sufficient size to allow valid examination of the relative clinical outcomes between metallic DES and bioresorbable scaffold. Design ABSORB III ( ClincalTrials.gov NCT01751906) will register approximately 2,262 patients and includes a lead-in phase (n = 50), the primary randomized analysis group (n = 2,000), an imaging cohort (n = 200), and a pharmacokinetic substudy (n = 12). In the primary analysis group, approximately 2,000 patients with up to 2 de novo native coronary artery lesions in separate epicardial vessels will be prospectively assigned in a 2:1 ratio to ABSORB BVS versus XIENCE everolimus-eluting stents (EES). The primary end point is target lesion failure (the composite of cardiac death, target vessel–related myocardial infarction, or ischemia-driven target lesion revascularization) at 1 year, powered for noninferiority of ABSORB BVS compared to XIENCE EES. Clinical follow-up will continue for 5 years. Enrollment has been completed, and the principal results will be available in the fall of 2015. Conclusions The large-scale ABSORB III randomized trial will evaluate the safety and effectiveness of ABSORB BVS compared to XIENCE EES in the treatment of patients with coronary artery disease.
PDF
