Summary Background Endogenous or iatrogenic antitumour immune responses can improve the course of follicular lymphoma, but might be diminished by immune checkpoints in the tumour microenvironment. ...These checkpoints might include effects of programmed cell death 1 (PD1), a co-inhibitory receptor that impairs T-cell function and is highly expressed on intratumoral T cells. We did this phase 2 trial to investigate the activity of pidilizumab, a humanised anti-PD1 monoclonal antibody, with rituximab in patients with relapsed follicular lymphoma. Methods We did this open-label, non-randomised trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Adult (≥18 years) patients with rituximab-sensitive follicular lymphoma relapsing after one to four previous therapies were eligible. Pidilizumab was administered at 3 mg/kg intravenously every 4 weeks for four infusions, plus eight optional infusions every 4 weeks for patients with stable disease or better. Starting 17 days after the first infusion of pidilizumab, rituximab was given at 375 mg/m2 intravenously weekly for 4 weeks. The primary endpoint was the proportion of patients who achieved an objective response (complete response plus partial response according to Revised Response Criteria for Malignant Lymphoma). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00904722. Findings We enrolled 32 patients between Jan 13, 2010, and Jan 20, 2012. Median follow-up was 15·4 months (IQR 10·1–21·0). The combination of pidilizumab and rituximab was well tolerated, with no autoimmune or treatment-related adverse events of grade 3 or 4. The most common adverse events of grade 1 were anaemia (14 patients) and fatigue (13 patients), and the most common adverse event of grade 2 was respiratory infection (five patients). Of the 29 patients evaluable for activity, 19 (66%) achieved an objective response: complete responses were noted in 15 (52%) patients and partial responses in four (14%). Interpretation The combination of pidilizumab plus rituximab is well tolerated and active in patients with relapsed follicular lymphoma. Our results suggest that immune checkpoint blockade is worthy of further study in follicular lymphoma. Funding National Institutes of Health, Leukemia and Lymphoma Society, Cure Tech, and University of Texas MD Anderson Cancer Center.
Summary Background The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination ...with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV. Methods For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800 000 IU/mL vs ≥800 000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov , number NCT01329978. Results We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5). In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77–96) in cohort A, 97 patients (89%, 82–94) in cohort B, and by 135 (87%, 81–92) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0·94), or in cohort C (p=0·78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug—anaemia and neutropenia—were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event. Interpretation Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis. Funding Gilead Sciences.
Atopic dermatitis is a chronic, pruritic inflammatory dermatosis that affects up to 25% of children and 2% to 3% of adults. This guideline addresses important clinical questions that arise in atopic ...dermatitis management and care, providing recommendations based on the available evidence. In this third of 4 sections, treatment of atopic dermatitis with phototherapy and systemic immunomodulators, antimicrobials, and antihistamines is reviewed, including indications for use and the risk-benefit profile of each treatment option.
Summary Background Peginterferon plus ribavirin achieves sustained virological response (SVR) in fewer than half of patients with genotype 1 chronic hepatitis C virus infection treated for 48 weeks. ...We tested the efficacy of boceprevir, an NS3 hepatitis C virus oral protease inhibitor, when added to peginterferon alfa-2b and ribavirin. Methods In part 1 of this trial, undertaken in 67 sites in the USA, Canada, and Europe, 520 treatment-naive patients with genotype 1 hepatitis C virus infection were randomly assigned to receive peginterferon alfa-2b 1·5 μg/kg plus ribavirin 800–1400 mg daily for 48 weeks (PR48; n=104); peginterferon alfa-2b and ribavirin daily for 4 weeks, followed by peginterferon alfa-2b, ribavirin, and boceprevir 800 mg three times a day for 24 weeks (PR4/PRB24; n=103) or 44 weeks (PR4/PRB44; n=103); or peginterferon alfa-2b, ribavirin, and boceprevir three times a day for 28 weeks (PRB28; n=107) or 48 weeks (PRB48; n=103). In part 2, 75 patients were randomly assigned to receive either PRB48 (n=16) or low-dose ribavirin (400–1000 mg) plus peginterferon alfa-2b and boceprevir three times a day for 48 weeks (low-dose PRB48; n=59). Randomisation was by computer-generated code, and study personnel and patients were not masked to group assignment. The primary endpoint was SVR 24 weeks after treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00423670. Findings Patients in all four boceprevir groups had higher rates of SVR than did the control group (58/107 54%, 95% CI 44–64, p=0·013 for PRB28; 58/103 56%, 44–66, p=0·005 for PR4/PRB24; 69/103 67%, 57–76, p<0·0001 for PRB48; and 77/103 75%, 65–83, p<0·0001 for PR4/PRB44; vs 39/104 38%, 28–48 for PR48 control). Low-dose ribavirin was associated with a high rate of viral breakthrough (16/59 27%), and a rate of relapse (six of 27 22%) similar to control (12/51 24%). Boceprevir-based groups had higher rates of anaemia (227/416 55% vs 35/104 34%) and dysgeusia (111/416 27% vs nine of 104 9%) than did the control group. Interpretation In patients with untreated genotype 1 chronic hepatitis C infection, the addition of the direct-acting antiviral agent boceprevir to standard treatment with peginterferon and ribavirin after a 4-week lead-in seems to have the potential to double the sustained response rate compared with that recorded with standard treatment alone. Funding Merck.
Objective To determine the effect of neonatal caffeine treatment on rates of developmental coordination disorder (DCD). Study design Children in the Caffeine for Apnea of Prematurity trial were ...assessed for motor performance (Movement Assessment Battery for Children MABC), clinical signs of cerebral palsy, and Full-Scale IQ at 5 years of age by staff who were unaware of the children's treatment group. DCD was defined as MABC <5th percentile in children with a Full-Scale IQ >69 who did not have a diagnosis of cerebral palsy. Results There were 1433 children with known MABC corrected-age percentile as well as known Full-Scale IQ at 5 years and cerebral palsy status, of whom 735 had been randomly assigned to caffeine and 698 to placebo therapy. The rate of DCD was lower in those treated with caffeine (11.3%) than in the placebo group (15.2%) (OR adjusted for center and baseline covariates, 0.71, 95% CI, 0.52-0.97; P = .032). Conclusions Neonatal caffeine therapy for apnea of prematurity reduces the rate of DCD at 5 years of age. As more children have DCD than have cerebral palsy, this is an important additional benefit from neonatal caffeine treatment.
Abstract Background It is unclear whether a positive skin patch test for metal allergy in patients with skin hypersensitivity to metals is associated with an increased risk of total knee arthroplasty ...(TKA) failure. Our aim was to determine whether patients with a history of metal allergy who had a positive skin patch test (SPT+) had worse outcomes after primary TKA compared with those with a negative skin patch test and compared with controls. Methods Over 12 years, 127 patients underwent 161 TKA after skin patch testing (SPT; 56 were positive). Cases were matched by age, gender, body mass index, American Society of Anesthesiologists score, implant type, and implant manufacturer to 161 control knee arthroplasties without any prior history of metal allergy and no SPT. Median follow-up was 5.3 years. Differences in outcome measures were assessed between groups. Results Patients with a SPT+ to metal did not have a higher complication, reoperation, or revision rates compared with patients with a SPT− and matched controls. Survivorship free of revision at 5 years was 98.1% for SPT+; 100% for SPT−; 97.6% for SPT+ controls, 99.0% for SPT− controls. There was no statistically significant difference in postoperative pain between SPT+ and SPT− patients and matched controls. Conclusion This study was designed to evaluate the effect of metal hypersensitivity on TKA outcomes and the role of SPT in patients before TKA. In this study, a SPT+ for metals was of little practical value in predicting the midterm outcome after TKA and cannot be strongly recommended as a method to guide the selection of implant type.
Background Hepatic resection is associated with substantial morbidity and resource use. To contain costs and improve outcomes, recent health care regulations focus on reducing hospital readmissions ...while using readmission rates as a quality measure. The goal of this investigation was to characterize the incidence, patterns, and risk factors for readmission after resection for hepatocellular carcinoma. Study design Patient demographics, operative factors, and perioperative outcomes of 245 patients undergoing hepatic resection at an academic center from 2000 to 2012 were reviewed retrospectively. Factors associated for readmission within 90 days of operation were identified through univariate and multivariate logistic regression analysis. Results Forty-six patients (18.7%) required hospital readmission. Univariate analysis identified American Society of Anesthesiologists class, preoperative Model for End-stage Liver Disease score and total bilirubin, preexisting vascular disease, acute renal failure, bile leak, peak postoperative total bilirubin, and intraabdominal infection as factors associated with readmission. Intraabdominal infection, postoperative renal failure, and a history of vascular disease were found to be significant on multivariate analysis. Overall, intraabdominal infection was the strongest predictor for readmission. Conclusion Early readmission after hepatectomy remains relatively common. Postoperative complications and patient comorbidities are the dominant factors in readmission, and we must be mindful of those patients at increased risk for readmission.
Fluticasone furoate (FF) is an inhaled corticosteroid (ICS) with 24-hour activity in development as a once-daily treatment for the long-term management of asthma.
To assess the efficacy and safety of ...4 doses of once-daily FF administered using a dry powder inhaler in patients (≥12 years) with moderate asthma, uncontrolled on low-dose ICS (fluticasone propionate FP 200 μg/day or equivalent).
This double-blind, placebo-controlled, dose-ranging study randomized 622 patients to 1 of 6 treatments: FF (100, 200, 300, or 400 μg) once daily in the evening, FP 250 μg twice daily (active control), or placebo for 8 weeks. The primary endpoint was the change from baseline in predose evening forced expiratory colume in 1 second (FEV1) at week 8.
At week 8, relative to placebo, all doses of FF once daily and FP twice daily demonstrated significantly (P < .001) greater increases from baseline and greater than 200-mL increases in predose FEV1. There was no evidence of a dose-response relationship between FF doses. Improvement with once-daily FF was similar to or greater than that for twice-daily FP. Secondary efficacy endpoint findings generally supported the efficacy of FF 100 to 400 μg once daily, although statistically significant improvements versus placebo in symptom-free 24-hour periods were only reported for FF 400 μg. There were few withdrawals due to lack of efficacy. Oral candidiasis was reported in 0 to 4% of patients; 24-hour urinary cortisol excretion ratios were similar across active treatment groups and not significantly different from placebo.
FF 100 to 400 μg once daily in the evening is effective and well tolerated in patients with asthma uncontrolled on low-dose ICS, with 100 μg and 200 μg, considered the most applicable doses in this asthma population.
clinicaltrials.gov Identifier: NCT00603278.
Background Inclusion of a measure of left ventricular diastolic dysfunction (LVDD) may improve risk prediction after cardiac surgery. Current LVDD grading guidelines rely on echocardiographic ...variables that are not always available or aligned to allow grading. We hypothesized that a simplified algorithm involving fewer variables would enable more patients to be assigned a LVDD grade compared with a comprehensive algorithm, and also be valid in identifying patients at risk of long-term major adverse cardiac events (MACE). Methods Intraoperative transesophageal echocardiography data were gathered on 905 patients undergoing coronary artery bypass graft surgery, including flow and tissue Doppler-based measurements. Two algorithms were constructed to categorize LVDD: a comprehensive four-variable algorithm, A, was compared with a simplified version, B, with only two variables—transmitral early flow velocity and early mitral annular tissue velocity—for ease of grading and association with MACE. Results Using algorithm A, only 563 patients (62%) could be graded, whereas 895 patients (99%) received a grade with algorithm B. Over the median follow-up period of 1,468 days, Cox modeling showed that LVDD was significantly associated with MACE when graded with algorithm B ( p = 0.013), but not algorithm A ( p = 0.79). Patients with the highest incidence of MACE could not be graded with algorithm A. Conclusions We found that an LVDD algorithm with fewer variables enabled grading of a significantly greater number of coronary artery bypass graft patients, and was valid, as evidenced by worsening grades being associated with MACE. This simplified algorithm could be extended to similar populations as a valid method of characterizing LVDD.
PDF
