The 11-year long-term follow-up study from the randomized BENEFIT CIS trial

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Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials

BACKGROUND: Treatment of multiple sclerosis (MS) with interferon β can lead to the development of antibodies directed against interferon β that interfere with treatment efficacy. Several observational studies have proposed different HLA alleles and genetic variants associated with the development of antibodies against interferon β. OBJECTIVE: To validate the proposed genetic markers and to identify new markers. METHODS: Associations of genetic candidate markers with antibody presence and development were examined in a post hoc analysis in 941 patients treated with interferon β-1b in the Betaferon® Efficacy Yielding Outcomes of a New Dose (BEYOND) and BEtaseron®/BEtaferon® in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) prospective phase III trials. All patients were treated with interferon β-1b for at least 6 months. In addition, a genome-wide association study was conducted to identify new genetic variants. RESULTS: We confirmed an increased risk for carriers of HLA-DRB1*04:01 (odds ratio (OR) = 3.3, p = 6.9 × 10-4) and HLA-DRB1*07:01 (OR = 1.8, p = 3.5 × 10-3) for developing neutralizing antibodies (NAbs). Several additional, previously proposed HLA alleles and genetic variants showed nominally significant associations. In the exploratory analysis, variants in the HLA region were associated with NAb development at genome-wide significance (OR = 2.6, p = 2.30 × 10-15). CONCLUSION: The contribution of HLA alleles and HLA-associated single-nucleotide polymorphisms (SNPs) to the development and titer of antibodies against interferon β was confirmed in the combined analysis of two multi-national, multi-center studies

Establishment and characterization of a new human pancreatic adenocarcinoma cell line with high metastatic potential to the lung

<p>Abstract</p> <p>Background</p> <p>Pancreatic cancer is still associated with devastating prognosis. Real progress in treatment options has still not been achieved. Therefore new models are urgently needed to investigate this deadly disease. As a part of this process we have established and characterized a new human pancreatic cancer cell line.</p> <p>Methods</p> <p>The newly established pancreatic cancer cell line PaCa 5061 was characterized for its morphology, growth rate, chromosomal analysis and mutational analysis of the K-<it>ras</it>, EGFR and p53 genes. Gene-amplification and RNA expression profiles were obtained using an Affymetrix microarray, and overexpression was validated by IHC analysis. Tumorigenicity and spontaneous metastasis formation of PaCa 5061 cells were analyzed in pfp^-/-/rag2^-/-mice. Sensitivity towards chemotherapy was analysed by MTT assay.</p> <p>Results</p> <p>PaCa 5061 cells grew as an adhering monolayer with a doubling time ranging from 30 to 48 hours. M-FISH analyses showed a hypertriploid complex karyotype with multiple numerical and unbalanced structural aberrations. Numerous genes were overexpressed, some of which have previously been implicated in pancreatic adenocarcinoma (GATA6, IGFBP3, IGFBP6), while others were detected for the first time (MEMO1, RIOK3). Specifically highly overexpressed genes (fold change > 10) were identified as EGFR, MUC4, CEACAM1, CEACAM5 and CEACAM6. Subcutaneous transplantation of PaCa 5061 into pfp^-/-/rag2^-/-mice resulted in formation of primary tumors and spontaneous lung metastasis.</p> <p>Conclusion</p> <p>The established PaCa 5061 cell line and its injection into pfp^-/-/rag2^-/-mice can be used as a new model for studying various aspects of the biology of human pancreatic cancer and potential treatment approaches for the disease.</p

Sodium intake and multiple sclerosis activity and progression in BENEFIT

To assess whether a high-salt diet, as measured by urinary sodium concentration, is associated with faster conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and MS activity and disability.status: publishe

Body mass index as a predictor of MS activity and progression among participants in BENEFIT

Background: There is a lack of studies on the association between obesity and conversion from a clinically isolated syndrome (CIS) to multiple sclerosis (MS). Objective: The aim of this study was to determine whether obesity predicts disease activity and prognosis in patients with CIS. Methods: Body mass index (BMI) at baseline was available for 464 patients with CIS in BENEFIT. Obesity was defined as BMI ⩾ 30 kg/m2 and normal weight as 18.5 ⩽ BMI < 25. Patients were followed up for 5 years clinically and by magnetic resonance imaging. Hazard of conversion to clinically definite (CDMS) or to 2001 McDonald criteria (MDMS) MS, annual rate of relapse, sustained progression on Expanded Disability Status Scale (EDSS), change in brain and lesion volume, and development of new brain lesions were evaluated. Results: Obese individuals were 39% more likely to convert to MDMS (95% CI: 1.02–1.91, p = 0.04) and had a 59% (95% CI: 1.01–2.31, p = 0.03) higher rate of relapse than individuals with normal weight. No associations were observed between obesity and conversion to CDMS, sustained progression on EDSS or magnetic resonance imaging (MRI) outcomes, except for a larger reduction of brain volume in obese smokers as compared to normal weight smokers (−0.82%; 95% CI: −1.51 to −0.12, p = 0.02). Conclusion: Obesity was associated with faster conversion to MS (MDMS) and a higher relapse rate

Sodium intake and multiple sclerosis activity and progression in BENEFIT.

OBJECTIVE To assess whether a high-salt diet, as measured by urinary sodium concentration, is associated with faster conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and MS activity and disability. METHODS BENEFIT was a randomized clinical trial comparing early versus delayed interferon beta-1b treatment in 465 patients with a CIS. Each patient provided a median of 14 (interquartile range = 13-16) spot urine samples throughout the 5-year follow-up. We estimated 24-hour urine sodium excretion level at each time point using the Tanaka equations, and assessed whether sodium levels estimated from the cumulative average of the repeated measures were associated with clinical (conversion to MS, Expanded Disability Status Scale [EDSS]) and magnetic resonance imaging (MRI) outcomes. RESULTS Average 24-hour urine sodium levels were not associated with conversion to clinically definite MS over the 5-year follow-up (hazard ratio [HR] = 0.91, 95% confidence interval [CI] = 0.67-1.24 per 1g increase in estimated daily sodium intake), nor were they associated with clinical or MRI outcomes (new active lesions after 6 months: HR = 1.05, 95% CI = 0.97-1.13; relative change in T2 lesion volume: -0.11, 95% CI = -0.25 to 0.04; change in EDSS: -0.01, 95% CI = -0.09 to 0.08; relapse rate: HR = 0.78, 95% CI = 0.56-1.07). Results were similar in categorical analyses using quintiles. INTERPRETATION Our results, based on multiple assessments of urine sodium excretion over 5 years and standardized clinical and MRI follow-up, suggest that salt intake does not influence MS disease course or activity. Ann Neurol 2017;82:20-29

Long-term Impact of Early MS Treatment with Interferon Beta-1b (IFNB-1b): Clinical, MRI, Employment, and Patient-Reported Outcomes (PROs) at the 11-Year Follow-up of BENEFIT (BENEFIT 11) (P7.012)

International audienceOBJECTIVE:To study long-term outcomes in patients treated with IFNB-1b after clinically isolated syndrome (CIS). BACKGROUND:In BENEFIT, patients with CIS were randomized to IFNB-1b or placebo (PL) treatment. After the second clinical event or after 2 years, all patients were treated with IFNB-1b. Mean delay of IFNB-1b in PL was 1.33 years. Comprehensive clinical, MRI, and PROs at 11 years post-randomization are reported. DESIGN/METHODS:All originally randomized patients were asked to undergo clinical, MRI, laboratory, and PRO assessments 11 years after randomization. RESULTS:281 patients were identified (60[percnt] of originally randomized, 72.6[percnt] of eligible patients at participating sites); 278 enrolled. Baseline characteristics were similar to the original BENEFIT population. At Year 11, patients randomized to IFNB-1b still had lower overall annualized relapse rate (p=0.0018) and longer time to first relapse (p=0.0005) and clinically definite MS (p=0.0012). Median EDSS score was 2.0 (change from baseline 0.5) in both groups. PASAT scores remained high (overall median 56 [IQR 10]). Of the 81.3[percnt] working at CIS start, 73.4[percnt] were still employed (64.4[percnt] fulltime). 12.2[percnt] retired early or were on long-term disability (2.9[percnt] at baseline). 64.0[percnt] did not report any sick leave during the past 12 months. Health-related quality of life remained stable (median [IQR] change from baseline EQ-5D: 0.000 [0.209], FAMS TOI: -7.54 [27.17]. Median (IQR) fatigue (FSMC) score: 45.00 (40.00), 46[percnt] of patients without fatigue (cut-off score\textless43), median (IQR) depression (CES-D) score: 9.00 (15.00). MRI findings were similar across groups: 86.4[percnt] had no gadolinium-enhancing lesions; median (IQR) number of new T2 lesions since 5-year MRI: 2.0 (6.0), T2 volume: 1760.0mm³ (3963.0mm³), cortical lesions: 2.0 (5.0), brain volume 1519.0cm³ (152.0mm³), mean cortical thickness 2.64mm³ (0.56mm³). CONCLUSIONS:Results from BENEFIT11 support a long-term impact of early treatment with IFNB-1b on clinical measures, including cognition and fatigue, and health economic and MRI outcomes. Study Supported by:Bayer HealthCare Pharmaceuticals Disclosure: Dr. Edan has received personal compensation for activities with LFB, Biogenidec, speaking from Serono, Inc., Sanofi, Teva, and Bayer Pharmaceuticals Corporation as a consultant and/or scientific advisory board member. Dr. Freedman has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Chugai, EMD Canada, Genzyme, Novartis, Sanofi-Aventis, and Teva Canada Innovation. Dr. Montalban has received personal compensation for activities with Bayer, Biogen Idec, EMD, Genentech, Genzyme, Merck Serono, Neurotec, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, and Almirall. Dr. Miller has received personal compensation for activities with UCL Institute of Neurology, Biogen Idec, GlaxoSmithKline Inc., Novartis, Merck & Co. Inc., Chugai, and Mitsubishi Pharma. Dr. Miller has received personal compensation in an editorial capac Dr. Hartung has holds stock and/or stock options from Opexa Therapeutics. Dr. Hemmer has received personal compensation for activities with Roche, Novartis, Bayer Schering, Merck Serono, Biogen Idec, GlaxoSmithKline, Chugai Pharmaceutical, Micromet, and Genzyme as a scientific advisory board member. Dr. Fox has received personal compensation for activities Acorda Therapeutics, Bayer Pharmaceuticals Corporation, Biogen Idec, Eli Lilly & Company, EMD Serono, Genzyme Corporation, GlaxoSmithKline, and Novartis. Dr. Barkhof has received personal compensation for activities with Bayer Schering Pharma, Sanofi, Genzyme, Biogen Idec, Teva, Merck Serono, Novartis, Roche, Synthon BV, and Janssen Research as a consultant. Dr. Schippling has received personal compensation for activities with Novartis. Dr. Schippling has received research support from Bayer Schering and Biogen Idec. Dr. Schulze has received personal compensation for activities with PAREXEL International as an employee. Dr. Pleimes has received personal compensation for activities with Myelo Therapeutics GmbH as an employee, and with Bayer Pharmaceuticals Corp. as an employee and consultant. Dr. Pohl has received personal compensation for activities with Bayer Pharmaceuticals Corporation as an employee. Dr. Pohl owns stock and/or stock options in Bayer Pharmaceuticals Corporation. Dr. Sandbrink has received personal compensation for activities with Bayer Pharmaceuticals Corporation as an employee. Dr. Sandbrink holds stock and/or stock options in Bayer Pharmaceuticals Corporation. Dr. Suarez has received personal compensation for activities with Bayer Pharmaceuticals Corporation as an employee. Dr. Wicklein has received personal compensation for activities with Bayer Pharmaceuticals Corporation as an employee. Dr. Kappos has received personal compensation for activities with Actelion Pharmaceutical

The 11-year long-term follow-up study from the randomized BENEFIT CIS trial

To assess outcomes for patients treated with interferon beta-1b immediately after clinically isolated syndrome (CIS) or after a short delay.status: publishe

Long-term safety of interferon beta-1b (IFNB-1b) treatment in early multiple sclerosis ( MS): The 11-year follow-up of BENEFIT (BENEFIT-11)

International audienceMeeting Abstract: P028 - ACTRIMS Forum, New Orleans, LA, feb 201