Miracle-dz/UniFAR-FTUs huggingface dataset:
Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

BACKGROUND Nivolumab combined with ipilimumab resulted in longer progression‐free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3‐year overall survival outcomes in this trial. METHODS We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD‐L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression‐free survival and overall survival in the nivolumab‐plus‐ipilimumab group and in the nivolumab group versus the ipilimumab group. RESULTS At a minimum follow‐up of 36 months, the median overall survival had not been reached in the nivolumab‐plus‐ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab‐plus‐ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment‐related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab‐plus‐ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group. CONCLUSIONS Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone. (Funded by Bristol‐Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.)
Tezacaftor–Ivacaftor in Residual‐Function Heterozygotes with Cystic Fibrosis

BACKGROUND Cystic fibrosis is an autosomal recessive disease caused by mutations in the CFTR gene that lead to progressive respiratory decline. Some mutant CFTR proteins show residual function and respond to the CFTR potentiator ivacaftor in vitro, whereas ivacaftor alone does not restore activity to Phe508del mutant CFTR. METHODS We conducted a randomized, double‐blind, placebo‐controlled, phase 3, crossover trial to evaluate the efficacy and safety of ivacaftor alone or in combination with tezacaftor, a CFTR corrector, in 248 patients 12 years of age or older who had cystic fibrosis and were heterozygous for the Phe508del mutation and a CFTR mutation associated with residual CFTR function. Patients were randomly assigned to one of six sequences, each involving two 8‐week intervention periods separated by an 8‐week washout period. They received tezacaftor–ivacaftor, ivacaftor monotherapy, or placebo. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from the baseline value to the average of the week 4 and week 8 measurements in each intervention period. RESULTS The number of analyzed intervention periods was 162 for tezacaftor–ivacaftor, 157 for ivacaftor alone, and 162 for placebo. The least‐squares mean difference versus placebo with respect to the absolute change in the percentage of predicted FEV1 was 6.8 percentage points for tezacaftor–ivacaftor and 4.7 percentage points for ivacaftor alone (P<0.001 for both comparisons). Scores on the respiratory domain of the Cystic Fibrosis Questionnaire–Revised, a quality‐of‐life measure, also significantly favored the active‐treatment groups. The incidence of adverse events was similar across intervention groups; most events were mild or moderate in severity, with no discontinuations of the trial regimen due to adverse events for tezacaftor–ivacaftor and few for ivacaftor alone (1% of patients) and placebo (<1%). CONCLUSIONS CFTR modulator therapy with tezacaftor–ivacaftor or ivacaftor alone was efficacious in patients with cystic fibrosis who were heterozygous for the Phe508del deletion and a CFTR residual‐function mutation. (Funded by Vertex Pharmaceuticals and others; EXPAND ClinicalTrials.gov number, NCT02392234.)
Tisagenlecleucel in Children and Young Adults with B‐Cell Lymphoblastic Leukemia

Background In a single‐center phase 1–2a study, the anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B‐cell acute lymphoblastic leukemia (ALL). Methods We conducted a phase 2, single‐cohort, 25‐center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B‐cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. Results For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event‐free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. Conclusions In this global study of CAR T‐cell therapy, a single infusion of tisagenlecleucel provided durable remission with long‐term persistence in pediatric and young adult patients with relapsed or refractory B‐cell ALL, with transient high‐grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849.)
Restrictive or Liberal Red‐Cell Transfusion for Cardiac Surgery

BACKGROUND The effect of a restrictive versus liberal red‐cell transfusion strategy on clinical outcomes in patients undergoing cardiac surgery remains unclear. METHODS In this multicenter, open‐label, noninferiority trial, we randomly assigned 5243 adults undergoing cardiac surgery who had a European System for Cardiac Operative Risk Evaluation (EuroSCORE) I of 6 or more (on a scale from 0 to 47, with higher scores indicating a higher risk of death after cardiac surgery) to a restrictive red‐cell transfusion threshold (transfuse if hemoglobin level was <7.5 g per deciliter, starting from induction of anesthesia) or a liberal red‐cell transfusion threshold (transfuse if hemoglobin level was <9.5 g per deciliter in the operating room or intensive care unit [ICU] or was <8.5 g per deciliter in the non‐ICU ward). The primary composite outcome was death from any cause, myocardial infarction, stroke, or new‐onset renal failure with dialysis by hospital discharge or by day 28, whichever came first. Secondary outcomes included red‐cell transfusion and other clinical outcomes. RESULTS The primary outcome occurred in 11.4% of the patients in the restrictive‐threshold group, as compared with 12.5% of those in the liberal‐threshold group (absolute risk difference, ‐1.11 percentage points; 95% confidence interval [CI], ‐2.93 to 0.72; odds ratio, 0.90; 95% CI, 0.76 to 1.07; P<0.001 for noninferiority). Mortality was 3.0% in the restrictive‐threshold group and 3.6% in the liberal‐threshold group (odds ratio, 0.85; 95% CI, 0.62 to 1.16). Red‐cell transfusion occurred in 52.3% of the patients in the restrictive‐threshold group, as compared with 72.6% of those in the liberal‐threshold group (odds ratio, 0.41; 95% CI, 0.37 to 0.47). There were no significant between‐group differences with regard to the other secondary outcomes. CONCLUSIONS In patients undergoing cardiac surgery who were at moderate‐to‐high risk for death, a restrictive strategy regarding red‐cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new‐onset renal failure with dialysis, with less blood transfused. (Funded by the Canadian Institutes of Health Research and others; TRICS III ClinicalTrials.gov number, NCT02042898.)
Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging

Background Thrombectomy is currently recommended for eligible patients with stroke who are treated within 6 hours after the onset of symptoms. Methods We conducted a multicenter, randomized, open‐label trial, with blinded outcome assessment, of thrombectomy in patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infarcted. Patients with proximal middle‐cerebral‐artery or internal‐carotid‐artery occlusion, an initial infarct size of less than 70 ml, and a ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or more were randomly assigned to endovascular therapy (thrombectomy) plus standard medical therapy (endovascular‐therapy group) or standard medical therapy alone (medical‐therapy group). The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at day 90. Results The trial was conducted at 38 U.S. centers and terminated early for efficacy after 182 patients had undergone randomization (92 to the endovascular‐therapy group and 90 to the medical‐therapy group). Endovascular therapy plus medical therapy, as compared with medical therapy alone, was associated with a favorable shift in the distribution of functional outcomes on the modified Rankin scale at 90 days (odds ratio, 2.77; P<0.001) and a higher percentage of patients who were functionally independent, defined as a score on the modified Rankin scale of 0 to 2 (45% vs. 17%, P<0.001). The 90‐day mortality rate was 14% in the endovascular‐therapy group and 26% in the medical‐therapy group (P=0.05), and there was no significant between‐group difference in the frequency of symptomatic intracranial hemorrhage (7% and 4%, respectively; P=0.75) or of serious adverse events (43% and 53%, respectively; P=0.18). Conclusions Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes than standard medical therapy alone among patients with proximal middle‐cerebral‐artery or internal‐carotid‐artery occlusion and a region of tissue that was ischemic but not yet infarcted. (Funded by the National Institute of Neurological Disorders and Stroke; DEFUSE 3 ClinicalTrials.gov number, NCT02586415.)
Durable Remissions with Ivosidenib in IDH1‐Mutated Relapsed or Refractory AML

Background Mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG‐120) is an oral, targeted, small‐molecule inhibitor of mutant IDH1. Methods We conducted a phase 1 dose‐escalation and dose‐expansion study of ivosidenib monotherapy in IDH1‐mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow‐up. Results Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment‐related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase‐chain‐reaction assay. No preexisting co‐occurring single gene mutation predicted clinical response or resistance to treatment. Conclusions In patients with advanced IDH1‐mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment‐related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839.)
Risks and benefits of direct-to-consumer genetic testing remain unclear.

FOR AS LITTLE AS ABOUT $400, A consumer can hire 1 of several companies to scan his or her entire genome for about a million genetic variations in hopes of identifying the presence of variants associated with an elevated risk of developing a disease. But lingering uncertainties about the validity and clinical implications of such results raise the question of whether marketing these tests to consumers is premature. The unprecedented speed with which high-throughput techniques for extracting genetic information are being translated into commercial products— bypassing traditional professional and regulatory gatekeepers—has left scientists and clinicians playing catch-up. But professional organizations and regulators are beginning to weigh in on how these products should be used, and scientists are launching efforts to systematically answer the questions raised by these tests.
Clopidogrel and Aspirin in Acute Ischemic Stroke and High‐Risk TIA

BACKGROUND Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population. METHODS In a randomized trial, we assigned patients with minor ischemic stroke or high‐risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time‐to‐event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days. RESULTS A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P=0.02). CONCLUSIONS In patients with minor ischemic stroke or high‐risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029.)
DNA Sequencing Predicts 1st-Line Tuberculosis Drug Susceptibility Profiles

BACKGROUND The World Health Organization recommends drug‐susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first‐line antituberculosis drugs has not been clear. METHODS We obtained whole‐genome sequences and associated phenotypes of resistance or susceptibility to the first‐line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole‐genome sequencing might direct first‐line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance. RESULTS A total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug‐susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profiles that were predicted to be pansusceptible, 3952 (97.9%) were correctly predicted. CONCLUSIONS Genotypic predictions of the susceptibility of M. tuberculosis to first‐line drugs were found to be correlated with phenotypic susceptibility to these drugs. (Funded by the Bill and Melinda Gates Foundation and others.)
Labor Induction versus Expectant Management in Low‐Risk Nulliparous Women

Background The perinatal and maternal consequences of induction of labor at 39 weeks among low‐risk nulliparous women are uncertain. Methods In this multicenter trial, we randomly assigned low‐risk nulliparous women who were at 38 weeks 0 days to 38 weeks 6 days of gestation to labor induction at 39 weeks 0 days to 39 weeks 4 days or to expectant management. The primary outcome was a composite of perinatal death or severe neonatal complications; the principal secondary outcome was cesarean delivery. Results A total of 3062 women were assigned to labor induction, and 3044 were assigned to expectant management. The primary outcome occurred in 4.3% of neonates in the induction group and in 5.4% in the expectant‐management group (relative risk, 0.80; 95% confidence interval [CI], 0.64 to 1.00). The frequency of cesarean delivery was significantly lower in the induction group than in the expectant‐management group (18.6% vs. 22.2%; relative risk, 0.84; 95% CI, 0.76 to 0.93). Conclusions Induction of labor at 39 weeks in low‐risk nulliparous women did not result in a significantly lower frequency of a composite adverse perinatal outcome, but it did result in a significantly lower frequency of cesarean delivery. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ARRIVE ClinicalTrials.gov number, NCT01990612.)
MRI‐Targeted or Standard Biopsy for Prostate‐Cancer Diagnosis

Background Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography–guided biopsy for prostate‐cancer detection in men with a raised prostate‐specific antigen level who have not undergone biopsy. However, comparative evidence is limited. Methods In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography–guided biopsy. Men in the MRI‐targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10‐to‐12–core, transrectal ultrasonography–guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer. Results A total of 500 men underwent randomization. In the MRI‐targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy. Clinically significant cancer was detected in 95 men (38%) in the MRI‐targeted biopsy group, as compared with 64 of 248 (26%) in the standard‐biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P=0.005). MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI‐targeted biopsy group than in the standard‐biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, ‐13 percentage points; 95% CI, ‐19 to ‐7; P<0.001). Conclusions The use of risk assessment with MRI before biopsy and MRI‐targeted biopsy was superior to standard transrectal ultrasonography–guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027.)