Summary Background Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF ...inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma. Methods In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAFV 600 mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov , number NCT01721746. Findings Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5–40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5–23·1) of 47 patients in the ICC group. Grade 3–4 adverse events related to nivolumab included increased lipase (three 1% of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two 1% each); for ICC, these included neutropenia (14 14% of 102), thrombocytopenia (six 6%), and anaemia (five 5%). We noted grade 3–4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred. Interpretation Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need. Funding Bristol-Myers Squibb.
Background The Universal Definition of Myocardial Infarction recommends the 99th percentile concentration of cardiac troponin in a normal reference population as part of the decision threshold to ...diagnose type 1 spontaneous myocardial infarction. Adoption of this recommendation in contemporary worldwide practice is not well known. Methods We performed a cohort study of 276 hospital laboratories in 31 countries participating in the National Heart, Lung, and Blood Institute sponsored International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial. Each hospital laboratory's troponin assay manufacturer and model, the recommended assay's 99th percentile upper reference limit (URL) from the manufacturer's package insert, and the troponin concentration used locally as the decision level to diagnose myocardial infarction was ascertained. Results Twenty-one unique troponin assays from 9 manufacturers were used by the surveyed hospital laboratories. The ratio of the troponin concentration used locally to diagnose myocardial infarction to the assay manufacturer-determined 99th percentile URL was <1 at 19 (6.6%) laboratories, equal to 1 at 91 (31.6%) laboratories, >1 to ≤5 at 101 (35.1%) laboratories, >5 to ≤10 at 34 (11.8%) laboratories and >10 at 43 (14.9%) laboratories. The variability in troponin decision level for myocardial infarction relative to the assay 99th percentile URL was present for laboratories in and outside of the United States, as well as for high- and standard-sensitivity assays. Conclusions There is substantial hospital level variation in the troponin threshold used to diagnose myocardial infarction; only one-third of hospital laboratories currently follow the Universal Definition of Myocardial Infarction consensus recommendation for use of troponin concentration at the 99th percentile of a normal reference population as the decision level to diagnose myocardial infarction. This variability across laboratories has important implications both for the diagnosis of myocardial infarction in clinical practice as well as adjudication of myocardial infarction in clinical trials.
Pancreatic ductal adenocarcinoma is an aggressive malignancy with a high mortality rate. Proper determination of the extent of disease on imaging studies at the time of staging is one of the most ...important steps in optimal patient management. Given the variability in expertise and definition of disease extent among different practitioners as well as frequent lack of complete reporting of pertinent imaging findings at radiologic examinations, adoption of a standardized template for radiology reporting, using universally accepted and agreed on terminology for solid pancreatic neoplasms, is needed. A consensus statement describing a standardized reporting template authored by a multi-institutional group of experts in pancreatic ductal adenocarcinoma that included radiologists, gastroenterologists, and hepatopancreatobiliary surgeons was developed under the joint sponsorship of the Society of Abdominal Radiologists and the American Pancreatic Association. Adoption of this standardized imaging reporting template should improve the decision-making process for the management of patients with pancreatic ductal adenocarcinoma by providing a complete, pertinent, and accurate reporting of disease staging to optimize treatment recommendations that can be offered to the patient. Standardization can also help to facilitate research and clinical trial design by using appropriate and consistent staging by means of resectability status, thus allowing for comparison of results among different institutions.
Objective Analysis of congenital heart surgery results requires a reliable method of estimating the risk of adverse outcomes. Two major systems in current use are based on projections of risk or ...complexity that were predominantly subjectively derived. Our goal was to create an objective, empirically based index that can be used to identify the statistically estimated risk of in-hospital mortality by procedure and to group procedures into risk categories. Methods Mortality risk was estimated for 148 types of operative procedures using data from 77,294 operations entered into the European Association for Cardiothoracic Surgery (EACTS) Congenital Heart Surgery Database (33,360 operations) and the Society of Thoracic Surgeons (STS) Congenital Heart Surgery Database (43,934 patients) between 2002 and 2007. Procedure-specific mortality rate estimates were calculated using a Bayesian model that adjusted for small denominators. Each procedure was assigned a numeric score (the STS–EACTS Congenital Heart Surgery Mortality Score 2009) ranging from 0.1 to 5.0 based on the estimated mortality rate. Procedures were also sorted by increasing risk and grouped into 5 categories (the STS–EACTS Congenital Heart Surgery Mortality Categories 2009) that were chosen to be optimal with respect to minimizing within-category variation and maximizing between-category variation. Model performance was subsequently assessed in an independent validation sample (n = 27,700) and compared with 2 existing methods: Risk Adjustment for Congenital Heart Surgery (RACHS-1) categories and Aristotle Basis Complexity scores. Results Estimated mortality rates ranged across procedure types from 0.3% (atrial septal defect repair with patch) to 29.8% (truncus plus interrupted aortic arch repair). The proposed STS–EACTS score and STS–EACTS categories demonstrated good discrimination for predicting mortality in the validation sample (C-index = 0.784 and 0.773, respectively). For procedures with more than 40 occurrences, the Pearson correlation coefficient between a procedure's STS–EACTS score and its actual mortality rate in the validation sample was 0.80. In the subset of procedures for which RACHS-1 and Aristotle Basic Complexity scores are defined, discrimination was highest for the STS–EACTS score (C-index = 0.787), followed by STS–EACTS categories (C-index = 0.778), RACHS-1 categories (C-index = 0.745), and Aristotle Basic Complexity scores (C-index = 0.687). When patient covariates were added to each model, the C-index improved: STS–EACTS score (C-index = 0.816), STS–EACTS categories (C-index = 0.812), RACHS-1 categories (C-index = 0.802), and Aristotle Basic Complexity scores (C-index = 0.795). Conclusion The proposed risk scores and categories have a high degree of discrimination for predicting mortality and represent an improvement over existing consensus-based methods. Risk models incorporating these measures may be used to compare mortality outcomes across institutions with differing case mixes.
Objective Microbial invasion of the amniotic cavity (MIAC) is common in early preterm labor and is associated with maternal and neonatal infectious morbidity. MIAC is usually occult and is reliably ...detected only with amniocentesis. We sought to develop a noninvasive test to predict MIAC based on protein biomarkers in cervicovaginal fluid (CVF) in a cohort of women with preterm labor (phase 1) and to validate the test in an independent cohort (phase 2). Study Design This was a prospective study of women with preterm labor who had amniocentesis to screen for MIAC. MIAC was defined by positive culture and/or 16S ribosomal DNA results. Nine candidate CVF proteins were analyzed by enzyme-linked immunosorbent assay. Logistic regression was used to identify combinations of up to 3 proteins that could accurately classify the phase 1 cohort (N = 108) into those with or without MIAC. The best models, selected by area under the curve (AUC) of the receiver operating characteristic curve in phase 1, included various combinations of interleukin (IL)-6, chemokine (C-X-C motif) ligand 1 (CXCL1), alpha fetoprotein, and insulin-like growth factor binding protein-1. Model performance was then tested in the phase 2 cohort (N = 306). Results MIAC was present in 15% of cases in phase 1 and 9% in phase 2. A 3-marker CVF model using IL-6 plus CXCL1 plus insulin-like growth factor binding protein-1 had AUC 0.87 in phase 1 and 0.78 in phase 2. Two-marker models using IL-6 plus CXCL1 or alpha fetoprotein plus CXCL1 performed similarly in phase 2 (AUC 0.78 and 0.75, respectively), but were not superior to CVF IL-6 alone (AUC 0.80). A cutoff value of CVF IL-6 ≥463 pg/mL (which had 81% sensitivity in phase 1) predicted MIAC in phase 2 with sensitivity 79%, specificity 78%, positive predictive value 38%, and negative predictive value 97%. Conclusion High levels of IL-6 in CVF are strongly associated with MIAC. If developed into a bedside test or rapid laboratory assay, cervicovaginal IL-6 might be useful in selecting patients in whom the probability of MIAC is high enough to warrant amniocentesis or transfer to a higher level of care. Such a test might also guide selection of potential subjects for treatment trials.
To evaluate efficacy and safety of a novel device that combines an inferior vena cava (IVC) filter and central venous catheter (CVC) for prevention of pulmonary embolism (PE) in critically ill ...patients.
In a multicenter, prospective, single-arm clinical trial, the device was inserted at the bedside without fluoroscopy and subsequently retrieved before transfer from the intensive care unit (ICU). The primary efficacy endpoint was freedom from clinically significant PE or fatal PE 72 hours after device removal or discharge, whichever occurred first. Secondary endpoints were incidence of acute proximal deep venous thrombosis (DVT), catheter-related thrombosis, catheter-related bloodstream infections, major bleeding events, and clinically significant thrombus (occupying > 25% of volume of filter) detected by cavography before retrieval.
The device was placed in 163 critically ill patients with contraindications to anticoagulation; 151 (93%) were critically ill trauma patients, 129 (85%) had head or spine trauma, and 102 (79%) had intracranial bleeding. The primary efficacy endpoint was achieved for all 163 (100%) patients (95% confidence interval CI, 97.8%-100%, P < .01). Diagnosis of new or worsening acute proximal DVT was time dependent with 11 (7%) occurring during the first 7 days. There were no (0%) catheter-related bloodstream infections. There were 5 (3.1%) major bleeding events. Significant thrombus in the IVC filter occurred in 14 (8.6%) patients. Prophylactic anticoagulation was not initiated for a mean of 5.5 days ± 4.3 after ICU admission.
This novel device prevented clinically significant and fatal PE among critically ill trauma patients with low risk of complications.
Summary Background The Placement of Aortic Transcatheter Valves (PARTNER) trial showed that mortality at 1 year, 2 years, and 3 years is much the same with transcatheter aortic valve replacement ...(TAVR) or surgical aortic valve replacement (SAVR) for high-risk patients with aortic stenosis. We report here the 5-year outcomes. Methods We did this randomised controlled trial at 25 hospitals, in Canada (two), Germany (one), and the USA (23). We used a computer-generated randomisation sequence to randomly assign high-risk patients with severe aortic stenosis to either SAVR or TAVR with a balloon-expandable bovine pericardial tissue valve by either a transfemoral or transapical approach. Patients and their treating physicians were not masked to treatment allocation. The primary outcome of the trial was all-cause mortality in the intention-to-treat population at 1 year, we present here predefined outcomes at 5 years. The study is registered with ClinicalTrials.gov , number NCT00530894. Findings We screened 3105 patients, of whom 699 were enrolled (348 assigned to TAVR, 351 assigned to SAVR). Overall mean Society of Thoracic Surgeons Predicted Risk of Mortality score was 11·7%. At 5 years, risk of death was 67·8% in the TAVR group compared with 62·4% in the SAVR group (hazard ratio 1·04, 95% CI 0·86–1·24; p=0·76). We recorded no structural valve deterioration requiring surgical valve replacement in either group. Moderate or severe aortic regurgitation occurred in 40 (14%) of 280 patients in the TAVR group and two (1%) of 228 in the SAVR group (p<0·0001), and was associated with increased 5-year risk of mortality in the TAVR group (72·4% for moderate or severe aortic regurgitation vs 56·6% for those with mild aortic regurgitation or less; p=0·003). Interpretation Our findings show that TAVR as an alternative to surgery for patients with high surgical risk results in similar clinical outcomes. Funding Edwards Lifesciences.
Background Pulmonary arterial hypertension (PAH) is a devastating illness of pulmonary vascular remodeling, right-sided heart failure, and limited survival. Whether strain-based measures of right ...ventricular (RV) systolic function predict future right-sided heart failure and/or death is untested. Methods RV longitudinal systolic strain and strain rate were evaluated by echocardiography in 80 patients with World Health Organization group 1 pulmonary hypertension (PH) (72% were functional class FC III or IV). Survival status was assessed over 4 years. Results All patients had a depressed RV systolic strain (−15% ± 5%) and strain rate (−0.80 ± 0.29 s−1 ). Of the parameters assessed, average RV free wall systolic strain worse than −12.5% identified a cohort with greater severity of disease (82% were FC III/IV), greater RV systolic dysfunction (RV stroke volume index 26 ± 9 mL/m2 ), and higher right atrial pressure (12 ± 5 mm Hg). Patients with an RV free wall strain worse than −12.5% were associated with a greater degree of disease progression within 6 months, a greater requirement for loop diuretics, and/or a greater degree of lower extremity edema, and it also predicted 1-, 2-, 3-, and 4-year mortality (unadjusted 1-year hazard ratio, 6.2; 2.1–22.3). After adjusting for age, sex, PH cause, and FC, patients had a 2.9-fold higher rate of death per 5% absolute decline in RV free wall strain at 1 year. Conclusions Noninvasive assessment of RV longitudinal systolic strain and strain rate independently predicts future right-sided heart failure, clinical deterioration, and mortality in patients with PAH.
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