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Objectives: In January 2018, the European Union (EU) approved ocrelizumab in relapsing multiple sclerosis (RMS) and as the first disease-modifying therapy (DMT) for patients with primary progressive multiple sclerosis (PPMS) with efficacy proven in a phase 3 randomised controlled trial. Eleven months prior to the European regulatory approval, a compassionate use programme (CUP) made ocrelizumab available to 489 patients with PPMS in Germany, thereby for the first time providing a therapeutic option to patients with PPMS who could not participate in ocrelizumab studies. Here, we report real-world patient characteristics and short-term safety data of patients with PPMS treated with ocrelizumab in this CUP., Patients and Methods: This CUP was initiated in February 2017 - shortly before US Food and Drug administration approval in March 2017 - and ended in January 2018, following ocrelizumab approval in the EU. Adult patients (age ≥18 years) with PPMS who had a positive benefit/risk ratio according to the treating physician were eligible for inclusion at German treatment centres. The main exclusion criteria were current/recent treatment with other immune therapies and unresolved/chronic/active infections. Patients received methylprednisolone and an antihistamine before treatment with intravenous ocrelizumab in 6-month cycles. The first ocrelizumab dose was a 300 mg infusion followed by a second 300 mg infusion 2 weeks later; subsequent doses were delivered as a single 600 mg infusion. Adverse events were reported immediately., Results: Of 580 requests received from 104 centres, 525 patients met the eligibility criteria. Thirty-five patients did not participate due to withdrawal by the treating physician, and one due to death prior to treatment. A total of 489 patients received at least one 600 mg dose of ocrelizumab (administered as two 300 mg infusions) and 51 received a second dose. Due to termination of the CUP upon marketing authorisation, the maximum follow-up period was 12 months. Median patient age was 52 years (range: 24-73), and 49% were female. Previous immunomodulatory or immunosuppressive therapies had been received by 41% of patients, with the most commonly used being glucocorticoids, mitoxantrone, interferon-β and glatiramer acetate. Patients with a previous malignancy, serious disease or infection (42 patients, 9%) had recovered from this prior to the CUP. Nine serious adverse events and 70 non-serious adverse events were reported in 40 patients. Adverse event categories were generally consistent with the known safety profile of ocrelizumab; one patient had carry-over progressive multifocal leukoencephalopathy (PML) due to previous natalizumab treatment., Conclusion: This CUP provides first real-world observations of ocrelizumab for the treatment of PPMS in a large patient cohort in Germany, supporting that ocrelizumab is generally well-tolerated in clinical practice. Physicians should be vigilant for early symptoms of PML, as to date, 9 PML cases that were all confounded have been reported in patients treated with ocrelizumab worldwide, with 8 carry-over cases from a prior DMT., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: There is inadequate evidence to determine whether there is an effect of alcohol consumption on lung cancer risk. We conducted a pooled analysis of data from the International Lung Cancer Consortium and the SYNERGY study to investigate this possible association by type of beverage with adjustment for other potential confounders., Methods: Twenty one case-control studies and one cohort study with alcohol-intake data obtained from questionnaires were included in this pooled analysis (19,149 cases and 362,340 controls). Adjusted odds ratios (OR) or hazard ratios (HR) with corresponding 95% confidence intervals (CI) were estimated for each measure of alcohol consumption. Effect estimates were combined using random or fixed-effects models where appropriate. Associations were examined for overall lung cancer and by histological type., Results: We observed an inverse association between overall risk of lung cancer and consumption of alcoholic beverages compared to non-drinkers, but the association was not monotonic. The lowest risk was observed for persons who consumed 10-19.9 g/day ethanol (OR vs. non-drinkers = 0.78; 95% CI: 0.67, 0.91), where 1 drink is approximately 12-15 g. This J-shaped association was most prominent for squamous cell carcinoma (SCC). The association with all lung cancer varied little by type of alcoholic beverage, but there were notable differences for SCC. We observed an association with beer intake (OR for ≥20 g/day vs nondrinker = 1.42; 95% CI: 1.06, 1.90)., Conclusions: Whether the non-monotonic associations we observed or the positive association between beer drinking and squamous cell carcinoma reflect real effects await future analyses and insights about possible biological mechanisms., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Evidence of an inverse association between serum vitamin D and mortality from epidemiological studies has prompted efforts to reduce mortality by vitamin D supplementation, either in targeted interventions for people with vitamin D insufficiency or deficiency, or in untargeted interventions regardless of baseline vitamin D status. Objective: We aimed to assess the expected impact of the 2 different approaches on effect sizes and power of intervention studies. Methods: Serum concentrations of 25-hydroxyvitamin D [25(OH)D] were measured in 9579 participants aged 50-75 y in the German Epidemiologische Studie zu Chancen der Verhütung, Früherkennung und optimierten Therapie chronischer Erkrankungen in der älteren Bevölkerung (ESTHER) study who were followed for mortality for a median of 12.4 y. We estimated adjusted HRs of mortality from all causes, cardiovascular disease, and cancer for defined increases in serum 25(OH)D by Cox regression, both across the full range of 25(OH)D concentrations and for those with vitamin D insufficiency [30 nmol/L ≤ 25(OH)D < 50 nmol/L] or deficiency [25(OH)D <30 nmol/L] only, and we calculated the power of intervention studies achieving those effect sizes. Results: An inverse association between serum 25(OH)D and mortality was observed only for participants with vitamin D insufficiency or deficiency and was strongest for the latter. Accordingly, the expected effects were much stronger and the expected power was much higher for interventions that targeted these groups than for untargeted interventions. For example, a targeted intervention study with 10,000 older adults (age 50-75 y) with serum 25(OH)D <50 nmol/L that increases serum 25(OH)D concentrations by 20 nmol/L in the intervention group ( n = 5000) would be expected to yield a 26% reduction of all-cause mortality that could be detected with 89% power within 5 y of follow-up compared with a 10% mortality reduction and 20% power in an untargeted intervention study of the same size. Conclusions: Vitamin D supplementation trials aimed at reducing mortality in older adults have much higher power when focused on those with low serum 25(OH)D concentrations., Competing Interests: Author disclosures: HB, LJ, K-US, BH, and BS, no conflicts of interest., (© 2017 American Society for Nutrition.)

Objective: A patient's risk for anticholinergic adverse effects is frequently estimated by instruments evaluating the drugs included in his medication profile. It remains unknown, however, which characteristics should be included in such an assessment instrument aiming to reliably predict adverse anticholinergic outcomes., Design: Cross-sectional study., Setting: ESTHER cohort (Germany)., Participants: Home-dwelling participants (N = 2,761) aged between 60 and 87 years., Measurements: The association between anticholinergic load calculated with nine different instruments and four anticholinergic adverse outcomes was investigated in univariate and multivariate analyses. Therefore, linear models complemented with Kendall's tau rank correlation coefficients (ԏ) were applied for continuous outcomes and generalized linear models were used to derive odds ratios (ORs) with 95% confidence intervals (CIs) for binary endpoints., Results: Based on the respective identification criteria for anticholinergic drugs, the nine instruments identified between 245 (9%) and 866 (31%) anticholinergic drug users (mean age ± SD: 73 ± 6 years; Mini-Mental State Examination [MMSE] score: 28.3 ± 2.07; Barthel Index: 97.1 ± 7.5; 291 reporting falls; 29 taking laxatives [surrogate for constipation]). In the multivariate analysis, only two instruments indicated a significant association between anticholinergic load and all four outcomes. The instrument considering the prescribed dose showed the strongest association with MMSE scores (ԏ = -0.10), falls (OR: 2.30; 95% CI: 1.50-3.52), and the use of laxatives (OR: 3.11; 95% CI: 1.04-9.36)., Conclusions: Instruments most reliably predicted anticholinergicadverse events if they were either based on the drugs' serum anticholinergic activity and the suggestions of clinician experts or considered the actual prescribed dose., (Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Epigenome-wide profiling of DNA methylation pattern with respect to tobacco smoking has given rise to a new measure of smoking exposure. We investigated the relationships of methylation markers with both cotinine, an established marker of internal smoking exposure, and self-reported smoking., Methods: Blood DNA methylation levels across the genome and serum cotinine were measured in 1000 older adults aged 50-75 years. Epigenome-wide scans were performed to identify methylation markers associated with cotinine. The inter-dose-response relationships between the number of cigarettes smoked per day, cotinine concentration, and DNA methylation were modeled by restricted cubic spline regression., Results: Of 61 CpGs that passed the genome-wide significance threshold (p<1.13×10(-7)), 40 CpGs in 25 chromosomal regions were successfully replicated, showing 0.2-3% demethylation per 10ng/ml increases in cotinine. The strongest associations were observed for several loci at AHRR, F2RL3, 2q37.1, 6p21.33, and GFI1 that were previously identified to be related to self-reported smoking. One locus at RAB34 was newly discovered. Both cotinine and methylation markers exhibited non-linear relationships with the number of cigarettes smoked per day, where the highest rates of increase in cotinine and decreases in methylation were observed at low smoking intensity (1-15 cigarettes/day) and plateaued at high smoking intensity (>15-20 cigarettes/day). A clear linear relationship was observed between cotinine concentration and methylation level. Both cotinine and methylation markers showed similar accuracy in distinguishing current from never smoker, but only methylation markers distinguished former from never smoker with high accuracy., Conclusions: Our study corroborates and expands the list of smoking-associated DNA methylation markers. Methylation levels were linearly related to cotinine concentration and provided accurate measures for both current and past smoking exposure., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Despite high curability, some testicular cancer (TC) patient groups may have increased mortality. We provide a detailed age- and histology-specific comparison of population-based relative survival of TC patients in Europe and the USA. Design Using data from 12 European cancer registries and the USA Surveillance, Epidemiology and End Results 9 database, we report survival trends for patients diagnosed with testicular seminomas and nonseminomas between 1993-1997 and 2003-2007. Additionally, a model-based analysis was used to compare survival trends and relative excess risk (RER) of death between Europe and the USA adjusting for differences in age and histology., Results: In 2003-2007, the 5-year relative survival of patients with testicular seminoma was at least 98% among those aged <50 years, survival of patients with nonseminoma remained 3%-6% units lower. Despite improvements in the relative survival of nonseminoma patients aged ≥ 50 years by 13%-18% units, survival remained markedly lower than the survival of seminoma patients of the same age. Model-based analyses showed increased RERs for nonseminomas, older, and European patients., Conclusions: There remains little room for survival improvement among testicular seminoma patients, especially for those aged <50 years. Older TC patients remain at increased risk of death, which seems mainly attributable to the lower survival among the nonseminoma patients.