Summary Background Concurrent administration of the immune checkpoint inhibitors nivolumab and ipilimumab has shown greater efficacy than either agent alone in patients with advanced melanoma, albeit ...with more high-grade adverse events. We assessed whether sequential administration of nivolumab followed by ipilimumab, or the reverse sequence, could improve safety without compromising efficacy. Methods We did this randomised, open-label, phase 2 study at nine academic medical centres in the USA. Eligible patients (aged ≥18 years) with unresectable stage III or IV melanoma (treatment-naive or who had progressed after no more than one previous systemic therapy, with an Eastern Cooperative Oncology Group performance status of 0 or 1) were randomly assigned (1:1) to induction with intravenous nivolumab 3 mg/kg every 2 weeks for six doses followed by a planned switch to intravenous ipilimumab 3 mg/kg every 3 weeks for four doses, or the reverse sequence. Randomisation was done by an independent interactive voice response system with a permuted block schedule (block size four) without stratification factors. After induction, both groups received intravenous nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary endpoint was treatment-related grade 3–5 adverse events until the end of the induction period (week 25), analysed in the as-treated population. Secondary endpoints were the proportion of patients who achieved a response at week 25 and disease progression at weeks 13 and 25. Overall survival was a prespecified exploratory endpoint. This study is registered with ClinicalTrials.gov , number NCT01783938 , and is ongoing but no longer enrolling patients. Findings Between April 30, 2013, and July 21, 2014, 140 patients were enrolled and randomly assigned to nivolumab followed by ipilimumab (n=70) or to the reverse sequence of ipilimumab followed by nivolumab (n=70), of whom 68 and 70 patients, respectively, received at least one dose of study drug and were included in the analyses. The frequencies of treatment-related grade 3–5 adverse events up to week 25 were similar in the nivolumab followed by ipilimumab group (34 50%; 95% CI 37·6–62·4 of 68 patients) and in the ipilimumab followed by nivolumab group (30 43%; 31·1–55·3 of 70 patients). The most common treatment-related grade 3–4 adverse events during the whole study period were colitis (ten 15%) in the nivolumab followed by ipilimumab group vs 14 20% in the reverse sequence group), increased lipase (ten 15% vs 12 17%), and diarrhoea (eight 12% vs five 7%). No treatment-related deaths occurred. The proportion of patients with a response at week 25 was higher with nivolumab followed by ipilimumab than with the reverse sequence (28 41%; 95% CI 29·4–53·8 vs 14 20%; 11·4–31·3). Progression was reported in 26 (38%; 95% CI 26·7–50·8) patients in the nivolumab followed by ipilimumab group and 43 (61%; 49·0–72·8) patients in the reverse sequence group at week 13 and in 26 (38%; 26·7–50·8) and 42 (60%; 47·6–71·5) patients at week 25, respectively. After a median follow-up of 19·8 months (IQR 12·8–25·7), median overall survival was not reached in the nivolumab followed by ipilimumab group (95% CI 23·7–not reached), whereas over a median follow-up of 14·7 months (IQR 5·6–23·9) in the ipilimumab followed by nivolumab group, median overall survival was 16·9 months (95% CI 9·2–26·5; HR 0·48 95% CI 0·29–0·80). A higher proportion of patients in the nivolumab followed by ipilimumab group achieved 12-month overall survival than in the ipilimumab followed by nivolumab group (76%; 95% CI 64–85 vs 54%; 42–65). Interpretation Nivolumab followed by ipilimumab appears to be a more clinically beneficial option compared with the reverse sequence, albeit with a higher frequency of adverse events. Funding Bristol-Myers Squibb.
Summary Background In the Step Study, the MRKAd5 HIV-1 gag/pol/nef vaccine did not reduce plasma viraemia after infection, and HIV-1 incidence was higher in vaccine-treated than in placebo-treated ...men with pre-existing adenovirus serotype 5 (Ad5) immunity. We assessed vaccine-induced immunity and its potential contributions to infection risk. Methods To assess immunogenicity, we characterised HIV-specific T cells ex vivo with validated interferon-γ ELISPOT and intracellular cytokine staining assays, using a case–cohort design. To establish effects of vaccine and pre-existing Ad5 immunity on infection risk, we undertook flow cytometric studies to measure Ad5-specific T cells and circulating activated (Ki-67+/BcL-2lo ) CD4+ T cells expressing CCR5. Findings We detected interferon-γ-secreting HIV-specific T cells (range 163/106 to 686/106 peripheral blood mononuclear cells) ex vivo by ELISPOT in 77% (258/354) of people receiving vaccine; 218 of 354 (62%) recognised two to three HIV proteins. We identified HIV-specific CD4+ T cells by intracellular cytokine staining in 58 of 142 (41%) people. In those with reactive CD4+ T cells, the median percentage of CD4+ T cells expressing interleukin 2 was 88%, and the median co-expression of interferon γ or tumor necrosis factor α (TNFα), or both, was 72%. We noted HIV-specific CD8+ T cells (range 0·4–1·0%) in 117 of 160 (73%) participants, expressing predominantly either interferon γ alone or with TNFα. Vaccine-induced HIV-specific immunity, including response rate, magnitude, and cytokine profile, did not differ between vaccinated male cases (before infection) and non-cases. Ad5-specific T cells were lower in cases than in non-cases in several subgroup analyses. The percentage of circulating Ki-67+BcL-2lo /CCR5+CD4+ T cells did not differ between cases and non-cases. Interpretation Consistent with previous trials, the MRKAd5 HIV-1 gag/pol/nef vaccine was highly immunogenic for inducing HIV-specific CD8+ T cells. Our findings suggest that future candidate vaccines have to elicit responses that either exceed in magnitude or differ in breadth or function from those recorded in this trial. Funding National Institute of Allergy and Infectious Diseases, US National Institutes of Health; and Merck Research Laboratories.
Background We previously reported that transfusion of 1 to 2 units of red blood cells (RBCs) confers a 16% increased hazard of late death after cardiac surgical treatment. We explored whether a ...similar effect existed among octogenarians. Methods We enrolled 17,026 consecutive adult patients undergoing cardiac operations from 2001 to 2008 in northern New England. Patients receiving more than 2 units of RBCs or undergoing emergency operations were excluded. Early (to 6 months) and late (to 3 years, among those surviving longer than 6 months) survival was confirmed using the Social Security Death Index. We estimated the relationship between RBCs and survival, and any interaction by age (<80 years versus ≥ 80 years) or procedure. We calculated the adjusted hazard ratio (HR), and plotted adjusted survival curves. Results Patients receiving RBCs had more comorbidities irrespective of age. Patients 80 years of age or older underwent transfusion more often than patients younger than 80 years (51% versus 30%; p < 0.001). There was no evidence of an interaction by age or procedure ( p > 0.05). Among patients younger than 80 years, RBCs significantly increased a patient's risk of early death HR, 2.03; 95% confidence interval CI, 1.47, 2.80 but not late death 1.21 (95%CI, 0.88, 1.67). RBCs did not increase the risk of early HR, 1.47; 95% CI, 0.84, 2.56 or late (HR, 0.92 95% CI, 0.50, 1.69) death in patients 80 years or older. Conclusions Octogenarians receive RBCs more often than do younger patients. Although transfusion of 1 to 2 units of RBCs increases the risk of early death in patients younger than 80 years, this effect was not present among octogenarians. There was no significant effect of RBCs in late death in either age group.
Stroke is the third-leading cause of death in the United States, Canada, Europe, and Japan. According to the American Heart Association and the American Stroke Association, 750,000 new strokes occur ...each year, resulting in 200,000 deaths (or 1 of every 16 deaths) per year in the United States alone. Endovascular therapy for patients with acute ischemic stroke is an area of intense investigation. The American Stroke Association has given a qualified endorsement of intra-arterial (IA) thrombolysis in selected patients. IA thrombolysis has been studied in 2 randomized trials and numerous case series. Although 2 devices have been granted FDA 3 approval with an indication for mechanical stroke thrombectomy, none of these devices has demonstrated efficacy in improving patient outcomes. This report defines what constitutes adequate training to perform neuroendovascular procedures in patients with acute ischemic stroke and identifies the performance standards that should be adopted to assess outcomes. These guidelines have been written and approved by multiple neuroscience societies that historically have been directly involved in the medical, surgical, and endovascular care of patients with acute stroke, including the Neurovascular Coalition and its participating societies: the Society of NeuroInterventional Surgery; American Academy of Neurology; American Association of Neurological Surgeons, Cerebrovascular Section; and Society of Vascular & Interventional Neurology.
Background Smoking is the most important risk factor for COPD and accelerates its progression. Despite the health implications, a large proportion of patients with COPD continue to smoke, so finding ...effective smoking cessation interventions for this population is paramount. To our knowledge, this is the first randomized clinical trial to compare the efficacy and safety of varenicline tartrate vs placebo in smokers with mild to moderate COPD. Methods In a 27-center, double-blind, multinational study, 504 patients with mild to moderate COPD (postbronchodilator FEV1 /FVC, < 70%; FEV1 percent predicted normal value, ≥ 50%) and without known psychiatric disturbances were randomized to receive varenicline (n = 250) or placebo (n = 254) for 12 weeks, with a 40-week nontreatment follow-up. The primary end point was carbon monoxide-confirmed continuous abstinence rate (CAR) for weeks 9 to 12. A secondary end point was CAR for weeks 9 to 52. Results CAR for weeks 9 to 12 was significantly higher for patients in the varenicline group (42.3%) than for those in the placebo group (8.8%) (OR, 8.40; 95% CI, 4.99-14.14; P < .0001). CAR in the patients treated with varenicline remained significantly higher than in those treated with placebo through weeks 9 to 52 (18.6% vs 5.6%) (OR, 4.04; 95% CI, 2.13-7.67; P < .0001). Nausea, abnormal dreams, upper-respiratory tract infection, and insomnia were the most commonly reported adverse events (AEs) for patients in the varenicline group. Serious AEs were infrequent in both treatment groups. Two patients in the varenicline group and one patient in the placebo group died during the study. Reports of psychiatric AEs were similar for both treatment groups. Conclusions Varenicline was more efficacious than placebo for smoking cessation in patients with mild to moderate COPD and demonstrated a safety profile consistent with that observed in previous trials. Trial registry ClinicalTrials.gov ; No.: NCT00285012 ; URL: www.clinicaltrials.gov
Background Practice guidelines reflect published literature. Because of the ever changing literature base, it is necessary to update and revise guideline recommendations from time to time. The ...Society of Thoracic Surgeons recommends review and possible update of previously published guidelines at least every three years. This summary is an update of the blood conservation guideline published in 2007. Methods The search methods used in the current version differ compared to the previously published guideline. Literature searches were conducted using standardized MeSH terms from the National Library of Medicine PUBMED database list of search terms. The following terms comprised the standard baseline search terms for all topics and were connected with the logical ‘OR’ connector—Extracorporeal circulation (MeSH number E04.292), cardiovascular surgical procedures (MeSH number E04.100), and vascular diseases (MeSH number C14.907). Use of these broad search terms allowed specific topics to be added to the search with the logical ‘AND’ connector. Results In this 2011 guideline update, areas of major revision include: 1) management of dual anti-platelet therapy before operation, 2) use of drugs that augment red blood cell volume or limit blood loss, 3) use of blood derivatives including fresh frozen plasma, Factor XIII, leukoreduced red blood cells, platelet plasmapheresis, recombinant Factor VII, antithrombin III, and Factor IX concentrates, 4) changes in management of blood salvage, 5) use of minimally invasive procedures to limit perioperative bleeding and blood transfusion, 6) recommendations for blood conservation related to extracorporeal membrane oxygenation and cardiopulmonary perfusion, 7) use of topical hemostatic agents, and 8) new insights into the value of team interventions in blood management. Conclusions Much has changed since the previously published 2007 STS blood management guidelines and this document contains new and revised recommendations.
Highlights • Ventilator-associated pneumonia prevention is standard care in the intensive care unit, but not yet in the emergency department. • Ventilator-associated pneumonia occurs frequently in ...emergency department intubated patients who may remain in the emergency department for many hours. • Starting ventilator-associated pneumonia prevention in the emergency department results in decreased overall and early ventilator-associated pneumonia for these patients. • High rates of compliance with an emergency department–based ventilator-associated pneumonia bundle can be achieved. • Bundle compliance is improved with a registered nurse (RN) champion.
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