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1.
Neuro Oncol ; 25(1): 123-134, 2023 01 05.
Article in English | MEDLINE | ID: mdl-35419607

ABSTRACT

BACKGROUND: Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in patients with glioblastoma (GBM), but previous studies suggest that patients with tumors harboring an unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase III CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO) + RT compared with TMZ + RT in newly diagnosed GBM with unmethylated MGMT promoter. METHODS: Patients were randomized 1:1 to standard RT (60 Gy) + NIVO (240 mg every 2 weeks for eight cycles, then 480 mg every 4 weeks) or RT + TMZ (75 mg/m2 daily during RT and 150-200 mg/m2/day 5/28 days during maintenance). The primary endpoint was OS. RESULTS: A total of 560 patients were randomized, 280 to each arm. Median OS (mOS) was 13.4 months (95% CI, 12.6 to 14.3) with NIVO + RT and 14.9 months (95% CI, 13.3 to 16.1) with TMZ + RT (hazard ratio [HR], 1.31; 95% CI, 1.09 to 1.58; P = .0037). Median progression-free survival was 6.0 months (95% CI, 5.7 to 6.2) with NIVO + RT and 6.2 months (95% CI, 5.9 to 6.7) with TMZ + RT (HR, 1.38; 95% CI, 1.15 to 1.65). Response rates were 7.8% (9/116) with NIVO + RT and 7.2% (8/111) with TMZ + RT; grade 3/4 treatment-related adverse event (TRAE) rates were 21.9% and 25.1%, and any-grade serious TRAE rates were 17.3% and 7.6%, respectively. CONCLUSIONS: The study did not meet the primary endpoint of improved OS; TMZ + RT demonstrated a longer mOS than NIVO + RT. No new safety signals were detected with NIVO in this study. The difference between the study treatment arms is consistent with the use of TMZ + RT as the standard of care for GBM.ClinicalTrials.gov NCT02617589.


Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Temozolomide/therapeutic use , Glioblastoma/drug therapy , Glioblastoma/genetics , Nivolumab/therapeutic use , Disease-Free Survival , Progression-Free Survival , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Antineoplastic Agents, Alkylating/therapeutic use , DNA Modification Methylases/genetics , Tumor Suppressor Proteins/genetics , DNA Repair Enzymes/genetics
2.
Neurooncol Adv ; 4(1): vdac025, 2022.
Article in English | MEDLINE | ID: mdl-35402913

ABSTRACT

Background: The phase 1 cohorts (1c+1d) of CheckMate 143 (NCT02017717) evaluated the safety/tolerability and efficacy of nivolumab plus radiotherapy (RT) ± temozolomide (TMZ) in newly diagnosed glioblastoma. Methods: In total, 136 patients were enrolled. In part A (safety lead-in), 31 patients (n = 15, methylated/unknown MGMT promoter; n = 16, unmethylated MGMT promoter) received nivolumab and RT+TMZ (NIVO+RT+TMZ) and 30 patients with unmethylated MGMT promoter received NIVO+RT. In part B (expansion), patients with unmethylated MGMT promoter were randomized to NIVO+RT+TMZ (n = 29) or NIVO+RT (n = 30). Primary endpoint was safety/tolerability; secondary endpoint was overall survival (OS). Results: NIVO+RT±TMZ was tolerable; grade 3/4 treatment-related adverse events occurred in 51.6% (NIVO+RT+TMZ) and 30.0% (NIVO+RT) of patients in part A and 46.4% (NIVO+RT+TMZ) and 28.6% (NIVO+RT) in part B. No new safety signals were detected. In part A, median OS (mOS) with NIVO+RT+TMZ was 33.38 months (95% CI, 16.2 to not estimable) in patients with methylated MGMT promoter. In patients with unmethylated MGMT promoter, mOS was 16.49 months (12.94-22.08) with NIVO+RT+TMZ and 14.41 months (12.55-17.31) with NIVO+RT. In part B, mOS was 14.75 months (10.01-18.6) with NIVO+RT+TMZ and 13.96 months (10.81-18.14) with NIVO+RT in patients with unmethylated MGMT promoter. Conclusions: CheckMate 143 was the first trial evaluating immune checkpoint inhibition with first-line treatment of glioblastoma. Results showed that NIVO can be safely combined with RT±TMZ, with no new safety signals. Toxicities, including lymphopenia, were more frequent with NIVO+RT+TMZ. OS was similar with or without TMZ in patients with unmethylated MGMT promoter, and differences by MGMT methylation status were observed.

3.
BMC Res Notes ; 9: 211, 2016 Apr 12.
Article in English | MEDLINE | ID: mdl-27067839

ABSTRACT

BACKGROUND: Since the early 1980s, several school based anti-bullying interventions (SBABI) have been implemented and evaluated in different countries. Some meta-analyses have also drawn conclusions on the effectiveness of SBABIs. However, the relationship between time and effectiveness of SBABIs has not been fully studied. For this aim, a collaborative project, SET-Bullying, is established by researchers from Greece, Belgium, Norway and United Kingdom. Its primary objective is to further understand and statistically model the relationship between the time and the sustainability of the effectiveness of SBABI. The secondary objective of SET-Bullying is to assess the possibility of predicting the medium-term or long-term effectiveness using as key information the prior measurement and the short-term effectiveness of the intervention. RESULTS: Researchers and owners of potentially eligible databases were asked to participate in this effort. Two studies have contributed data for the purpose of SET-Bullying. This paper summarizes the main characteristics of the participating studies and provides a high level overview of the collaborative project. It also discusses on the extent to which both study and project characteristics may pose threats to the expected internal and external validity of the potential outcomes of the project. DISCUSSION: Despite these threats, this work represents the first effort to understand the impact of time on the observed effectiveness of SBABIs and assess its predictability, which would allow for better planning, implementation and evaluation of SBABIs.


Subject(s)
Bullying/prevention & control , International Cooperation , Program Evaluation/methods , Schools , Belgium , Greece , Humans , Models, Theoretical , Norway , Reproducibility of Results , Time Factors , United Kingdom
4.
Diabetes Care ; 38(3): 412-9, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25271207

ABSTRACT

OBJECTIVE: Insulin adjustments to maintain glycemic control in individuals with type 1 diabetes often lead to wide glucose fluctuations, hypoglycemia, and increased body weight. Dapagliflozin, an insulin-independent sodium-glucose cotransporter 2 (SGLT2) inhibitor, increases glucosuria and reduces hyperglycemia in individuals with type 2 diabetes. The primary objective of this study was to assess short-term safety of dapagliflozin in combination with insulin; secondary objectives included pharmacokinetic, pharmacodynamic, and efficacy parameters. RESEARCH DESIGN AND METHODS: A 2-week, dose-ranging, randomized, double-blind, placebo-controlled proof-of-concept study randomly assigned 70 adults with type 1 diabetes (HbA1c 7-10%), who were receiving treatment with stable doses of insulin, to one of four dapagliflozin doses (1, 2.5, 5, or 10 mg) or placebo. The insulin dose was not proactively reduced at randomization but could be adjusted for safety reasons. RESULTS: Sixty-two patients (88.6%) completed the study. Any hypoglycemia was common across all treatments (60.0-92.3%); one major event of hypoglycemia occurred with dapagliflozin 10 mg. No diabetic ketoacidosis occurred. Pharmacokinetic parameters were similar to those observed in patients with type 2 diabetes. Glucosuria increased by 88 g/24 h (95% CI 55 to 121) with dapagliflozin 10 mg and decreased by -21.5 g/24 h (95% CI -53.9 to 11.0) with placebo. Changes from baseline with dapagliflozin 10 mg by day 7 were as follows: -2.29 mmol/L (95% CI -3.71 to -0.87 [-41.3 mg/dL; 95% CI -66.9 to -15.7]) for 24-h daily average blood glucose; -3.77 mmol/L (95% CI -6.09 to -1.45 [-63.1 mg/dL; 95% CI -111.5 to -14.8]) for mean amplitude of glycemic excursion; and -16.2% (95% CI -29.4 to -0.5) for mean percent change in total daily insulin dose. Corresponding changes with placebo were as follows: -1.13 mmol/L (95% CI -3.63 to 1.37), -0.45 mmol/L (95% CI -4.98 to 4.08), and 1.7% (95% CI -22.8 to 33.9), respectively. However, for every efficacy parameter, the 95% CIs for all dapagliflozin doses overlapped those for placebo. CONCLUSIONS: This exploratory study of dapagliflozin in adults with type 1 diabetes demonstrated acceptable short-term tolerability and expected pharmacokinetic profiles and increases in urinary glucose excretion. Within the dapagliflozin groups, dose-related reductions in 24-h glucose, glycemic variability, and insulin dose were suggested, which provide hope that SGLT2 inhibition may prove in larger randomized controlled trials to be efficacious in reducing hyperglycemia in type 1 diabetes.


Subject(s)
Benzhydryl Compounds/administration & dosage , Diabetes Mellitus, Type 1/drug therapy , Glucosides/administration & dosage , Hypoglycemic Agents/administration & dosage , Insulin/administration & dosage , Sodium-Glucose Transporter 2 Inhibitors , Adolescent , Adult , Aged , Area Under Curve , Benzhydryl Compounds/pharmacokinetics , Blood Glucose/drug effects , Diabetes Mellitus, Type 1/blood , Double-Blind Method , Female , Glucosides/pharmacokinetics , Glycated Hemoglobin/drug effects , Glycosuria/chemically induced , Humans , Hyperglycemia/chemically induced , Hypoglycemia/chemically induced , Hypoglycemic Agents/pharmacokinetics , Insulin/pharmacokinetics , Male , Middle Aged , Pilot Projects , Treatment Outcome , Young Adult
5.
Diabetes Technol Ther ; 16(3): 137-44, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24237386

ABSTRACT

AIM: This randomized, double-blind, placebo-controlled parallel-group study assessed the effects of sodium glucose cotransporter 2 inhibition by dapagliflozin on insulin sensitivity and secretion in subjects with type 2 diabetes mellitus (T2DM), who had inadequate glycemic control with metformin (with or without an insulin secretagogue). SUBJECTS AND METHODS: Forty-four subjects were randomized to receive dapagliflozin 5 mg or matching placebo once daily for 12 weeks. Subjects continued stable doses of background antidiabetes medication throughout the study. Insulin sensitivity was assessed by measuring the glucose disappearance rate (GDR) during the last 40 min of a 5-h hyperinsulinemic, euglycemic clamp. Insulin secretion was determined as the acute insulin response to glucose (AIRg) during the first 10 min of a frequently sampled intravenous glucose tolerance test. Where noted, data were adjusted for baseline values and background antidiabetes medication. RESULTS: An adjusted mean increase from baseline in GDR (last observation carried forward), at Week 12, was observed with dapagliflozin (7.98%) versus a decrease with placebo (-9.99%). The 19.97% (95% confidence interval 5.75-36.10) difference in GDR versus placebo was statistically significant (P=0.0059). A change from baseline in adjusted mean AIRg of 15.39 mU/L min was observed with dapagliflozin at Week 12, versus -12.73 mU/L min with placebo (P=0.0598). Over 12 weeks, numerical reductions from baseline in glycosylated hemoglobin (HbA1c), fasting plasma glucose, and body weight were observed with dapagliflozin (-0.38%, -0.39 mmol/L, and -1.58%, respectively) versus slight numerical increases with placebo (0.03%, 0.26 mmol/L, and 0.62%, respectively). CONCLUSIONS: In patients with T2DM and inadequate glycemic control, dapagliflozin treatment improved insulin sensitivity in the setting of reductions in HbA1c and weight.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 2/drug therapy , Glucosides/administration & dosage , Glycated Hemoglobin/metabolism , Hypoglycemic Agents/administration & dosage , Insulin Resistance , Insulin/metabolism , Metformin/administration & dosage , Sodium-Glucose Transporter 2 Inhibitors , Adult , Aged , Benzhydryl Compounds , Blood Glucose/drug effects , C-Peptide/metabolism , Creatinine/metabolism , Diabetes Mellitus, Type 2/metabolism , Double-Blind Method , Drug Therapy, Combination , Female , Glucose Tolerance Test , Glycated Hemoglobin/drug effects , Humans , Insulin Secretion , Male , Middle Aged , Treatment Outcome
6.
J Am Coll Cardiol ; 52(11): 941-52, 2008 Sep 09.
Article in English | MEDLINE | ID: mdl-18772067

ABSTRACT

OBJECTIVES: This study was designed to investigate whether single nucleotide polymorphisms (SNPs) and haplotypes of the fibrinogen gene-cluster (fibrinogen chains alpha [FGA], beta [FGB], and gamma [FGG]) could explain the inter- and intraindividual variability of fibrinogen levels in patients with atherosclerosis. We also searched for genetic determinants affecting the responses of fibrinogen genes to proinflammatory stimulation. BACKGROUND: The mechanisms regulating fibrinogen levels are not fully understood, and they are likely to be regulated by complex gene-environment interactions. METHODS: In the AIRGENE study, 895 survivors of myocardial infarction from 5 European cities were followed prospectively for 6 to 8 months, and plasma fibrinogen, interleukin (IL)-6, and C-reactive protein levels were determined monthly. We analyzed 21 SNPs and the corresponding haplotypes in the 3 fibrinogen genes. RESULTS: Eight SNPs in FGA and FGB were significantly associated with fibrinogen levels. Similarly, 2 different haplotypes in FGA and 3 in FGB were also associated with mean fibrinogen levels. The IL-6 levels had a significant impact on the associations between SNPs/haplotypes in FGA/FGB and fibrinogen levels. We also identified SNPs and haplotypes in FGA and FGB with strong impact on the intraindividual variability of fibrinogen during the follow-up period. CONCLUSIONS: We identified common SNPs and haplotypes on FGA/FGB genes, explaining the interindividual and intraindividual variability of fibrinogen levels, in patients with a history of myocardial infarction. We have also identified for the first time, SNPs/haplotypes on FGA/FGB whose effects on fibrinogen expression are modified by the underlying IL-6 levels. These findings may have an impact on risk stratification and the design of genetically guided therapeutic approaches in patients with advanced atherosclerosis.


Subject(s)
C-Reactive Protein/metabolism , Fibrinogen/genetics , Interleukin-6/metabolism , Myocardial Infarction/genetics , Aged , Fibrinogen/metabolism , Genotype , Haplotypes , Humans , Male , Middle Aged , Myocardial Infarction/blood , Polymorphism, Single Nucleotide , White People/genetics
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