Initial treatment and survival in Danish patients diagnosed with non-small-cell lung cancer (2005-2015): SCAN-LEAF study.

Aim: To describe initial treatment patterns and survival of patients diagnosed with non-small-cell lung cancer (NSCLC) in Denmark, before immune checkpoint inhibitor and later-generation tyrosine kinase inhibitor use. Patients & methods: Adults diagnosed with incident NSCLC (2005-2015; follow-up: 2016). Initial treatments and overall survival (OS) are reported. Results: 31,939 NSCLC patients (51.6% stage IV) were included. Increasing use of curative radiotherapy/chemoradiation for stage I, II/IIIA and IIIB NSCLC coincided with improved 2-year OS. Systemic anticancer therapy use increased for patients with stage IV non-squamous NSCLC (53.0-60.6%) but not squamous NSCLC (44.9-47.3%). 1-year OS improved in patients with stage IV non-squamous NSCLC (23-31%) but not squamous NSCLC (22-25%). Conclusion: Trends indicated improved OS as treatments evolved between 2005 and 2015, but the effect was limited to 1-year OS in stage IV disease.

Comparing Findings From a Friends of Cancer Research Exploratory Analysis of Real-World End Points With the Cancer Analysis System in England.

PURPOSE: This study compared real-world end points extracted from the Cancer Analysis System (CAS), a national cancer registry with linkage to national mortality and other health care databases in England, with those from diverse US oncology data sources, including electronic health care records, insurance claims, unstructured medical charts, or a combination, that participated in the Friends of Cancer Research Real-World Evidence Pilot Project 1.0. Consistency between data sets and between real-world overall survival (rwOS) was assessed in patients with immunotherapy-treated advanced non-small-cell lung cancer (aNSCLC). PATIENTS AND METHODS: Patients with aNSCLC, diagnosed between January 2013 and December 2017, who initiated treatment with approved programmed death ligand-1 (PD-[L]1) inhibitors until March 2018 were included. Real-world end points, including rwOS and real-world time to treatment discontinuation (rwTTD), were assessed using Kaplan-Meier analysis. A synthetic data set, Simulacrum, on the basis of conditional random sampling of the CAS data was used to develop and refine analysis scripts while protecting patient privacy. RESULTS: Characteristics (age, sex, and histology) of the 2,035 patients with immunotherapy-treated aNSCLC included in the CAS study were broadly comparable with US data sets. In CAS, a higher proportion (46.7%) of patients received a PD-(L)1 inhibitor in the first line than in US data sets (18%-30%). Median rwOS (11.4 months; 95% CI, 10.4 to 12.7) and rwTTD (4.9 months; 95% CI, 4.7 to 5.1) were within the range of US-based data sets (rwOS, 8.6-13.5 months; rwTTD, 3.2-7.0 months). CONCLUSION: The CAS findings were consistent with those from US-based oncology data sets. Such consistency is important for regulatory decision making. Differences observed between data sets may be explained by variation in health care settings, such as the timing of PD-(L)1 approval and reimbursement, and data capture.

Epidemiology and Survival Outcomes for Patients With NSCLC in Scandinavia in the Preimmunotherapy Era: A SCAN-LEAF Retrospective Analysis From the I-O Optimise Initiative.

INTRODUCTION: SCAN-LEAF, part of the I-O Optimise initiative, is a retrospective, longitudinal study investigating the epidemiology, clinical care, and outcomes for patients with NSCLC in Scandinavia. We report overall survival (OS) trends for patients diagnosed with NSCLC in Sweden and Denmark between 2005 and 2015. METHODS: Swedish and Danish cohorts were established by linking national registries. Data on all adults diagnosed with incident NSCLC from January 1, 2005, to December 31, 2015, were included. For temporal analyses of OS trends, patients were stratified by TNM stage and histology. RESULTS: Between 2005 and 2015, a total of 30,067 and 31,939 patients from Sweden and Denmark, respectively, were diagnosed with NSCLC; the most common histological subtype was nonsquamous cell carcinoma (56.9% and 53.0%) and 48.4% and 51.6% were diagnosed at stage IV. Over the study period, significant improvements in short-term survival (1 y) were observed for patients with nonsquamous cell carcinoma in both countries, regardless of disease stage at diagnosis; however, improvements in longer-term survival (5 y) were limited to patients with stage I and II disease only. Conversely, among patients with squamous cell histology, improvements in short-term survival were only observed for stage I disease in Sweden and stage IIIA disease in Denmark, while significant improvements in longer-term survival were seen only for stage IIIA NSCLC in both countries. CONCLUSIONS: Despite some survival improvements between 2005 and 2015, an unmet need remains for patients with advanced NSCLC, particularly those with squamous cell histology. Future analyses will evaluate the impact of newer treatments on OS in NSCLC.

Burden of dry eye disease in Germany: a retrospective observational study using German claims data.

PURPOSE: To evaluate the clinical and economic burden of dry eye disease (DED) among affected patients in Germany. METHODS: Adult patients (≥18 years) with ≥1 confirmed diagnosis of DED during the study period (2008-2015) were identified from the medical claims of ~3.6 million insured patients from Betriebskrankenkassen, a German statutory health insurance database. Prevalence (per 1000 patients) and incidence (per 1000 person-years at risk) were estimated, and demographic and clinical characteristics, treatment history (excluding over-the-counter tear supplements), healthcare resource use (HCRU) and costs were assessed. RESULTS: In this population, the prevalence of DED increased from 20.24 in 2008 to 23.13 per 1000 patients in 2014. Overall incidence was 6.24 per 1000 person-years at risk (2008-2015). Prevalence and incidence increased with age and were higher in women. Mean age at index was 63.4 years (incident cohort, n = 35 026). The most common ocular comorbidity was cataract (48.5%), and ~36% of patients were dispensed a reimbursed DED-specific medication during the postindex period - most commonly, corticosteroids alone (13.2%) or in combination with anti-infectives (21.8%). HCRU was high in patients with DED, mostly due to comorbidities. HCRU and associated costs were highest in patients ≥60 years. Total costs during the postindex period were higher in the DED cohort than among matched controls (€117 million versus €107 million; p < 0.001). CONCLUSION: This retrospective database analysis provides a better understanding of the epidemiology, clinical characteristics, real-world treatment patterns, HCRU and costs associated with DED in patients living in Germany.

Alcohol, pattern of drinking and all-cause mortality in Russia, Belarus and Hungary: a retrospective indirect cohort study based on mortality of relatives.

AIMS: To assess the relationship between alcohol intake frequency and mortality among males and females in three Eastern European populations, and to estimate the additional mortality risk posed by a combination of frequent drinking, binge drinking and other hazardous drinking habits. DESIGN: Retrospective cohort study; the cohort consisted of close relatives of survey participants. SETTING: Middle-sized settlements in Russia, Belarus and Hungary. PARTICIPANTS: A total of 124 150 subjects aged 35-69 years in 1998 and followed-up until 2013. MEASUREMENTS: Survey respondents provided information on their mothers, fathers, siblings and partners of female respondents. This information, including current vital status and dates of birth and death, was used to construct the cohort of relatives. Alcohol consumption indices, reported by survey participants, included drinking frequency, binge drinking and hazardous drinking [consuming non-beverage and/or illicitly-produced alcohol and/or heavy drinking over several days (zapoi in Russian)]. FINDINGS: Drinking frequency was associated positively with mortality in all three countries and both genders. At each drinking frequency level, mortality risk increased among those who also engaged in binge and/or hazardous drinking. Regular male drinkers who were also binge drinkers and hazardous drinkers had the highest risk of death; their hazard ratios (HR), compared with non-binge-non-hazardous occasional drinkers, were 2.56 [95% confidence interval (CI) = 2.27-2.88], 2.14 (95% CI = 1.84-2.48) and 2.11 (95% CI = 1.90-2.35) in Russia, Belarus and Hungary, respectively. In women, the corresponding HRs (using a lower frequency cut-off) were 2.86 (95% CI = 1.99-4.12) in Russia, 3.44 (95% CI = 2.17-5.44) in Belarus and 3.01 (95% CI = 2.26-4.01) in Hungary. CONCLUSIONS: Drinking frequency is associated positively with mortality among men and women in Russia, Belarus and Hungary. The mortality risk is higher among frequent drinkers who exhibit binge and hazardous drinking patterns.

Smoking and Mortality in Eastern Europe: Results From the PrivMort Retrospective Cohort Study of 177 376 Individuals.

Background: The estimated prevalence of smoking and proportion of deaths due to tobacco in Eastern European countries are among the highest in the world. Existing estimates of mortality attributable to smoking in the region are mostly indirect. The aim of this analysis was to calculate the proportion of tobacco-attributed deaths in three Eastern European countries using individual level cohort data. Methods: The PrivMort project established a cohort of relatives of participants in population sample surveys in Russia, Belarus and Hungary. Survey participants provided data on smoking habits and vital statistics of their close relatives between 1982 and 2013. Population attributable risk fractions (PARF) in men (n = 99528) and women (n = 77848) aged 40-79 years were calculated from the prevalence rates of smoking and hazard ratios of mortality for smokers versus non-smokers. Trends in PARF over four 8-year time periods (1982-1989, 1990-1997, 1998-2005, and 2006-2013) were examined. Results: In men in the most recent period (2006-2013), the proportions of deaths attributable to tobacco were 23% in Russia, 22% in Belarus, and 22% in Hungary. The respective estimates in women were lower (2%, 2%, and 13%), possibly due to underestimation of smoking prevalence. PARF estimates have declined slightly since the early 1990s in men but increased in women. Conclusions: Consistently with existing indirect estimates, our results based on individual level cohort data suggest that over one fifth of all deaths in men aged 40-79 years are attributable to tobacco. While these proportions are lower in women, the increasing trend is a major concern. Implications: This is the first large scale, individual-level cohort study that estimated the mortality attributable to tobacco smoking directly in Eastern European population samples. The results confirm previous indirect estimates and show that more than 20% of all deaths in Eastern European men can be attributed to tobacco. The study also confirms the increasing trend in smoking-related deaths among women. These findings emphasize the importance of targeted policy interventions in Eastern European countries.

The effect of rapid privatisation on mortality in mono-industrial towns in post-Soviet Russia: a retrospective cohort study.

BACKGROUND: Population-level data suggest that economic disruptions in the early 1990s increased working-age male mortality in post-Soviet countries. This study uses individual-level data, using an indirect estimation method, to test the hypothesis that fast privatisation increased mortality in Russia. METHODS: In this retrospective cohort study, we surveyed surviving relatives of individuals who lived through the post-communist transition to retrieve demographic and socioeconomic characteristics of their parents, siblings, and male partners. The survey was done within the framework of the European Research Council (ERC) project PrivMort (The Impact of Privatization on the Mortality Crisis in Eastern Europe). We surveyed relatives in 20 mono-industrial towns in the European part of Russia (ie, the landmass to the west of the Urals). We compared ten fast-privatised and ten slow-privatised towns selected using propensity score matching. In the selected towns, population surveys were done in which respondents provided information about vital status, sociodemographic and socioeconomic characteristics and health-related behaviours of their parents, two eldest siblings (if eligible), and first husbands or long-term partners. We calculated indirect age-standardised mortality rates in fast and slow privatised towns and then, in multivariate analyses, calculated Poisson proportional incidence rate ratios to estimate the effect of rapid privatisation on all-cause mortality risk. FINDINGS: Between November, 2014, and March, 2015, 21 494 households were identified in 20 towns. Overall, 13 932 valid interviews were done (with information collected for 38 339 relatives [21 634 men and 16 705 women]). Fast privatisation was strongly associated with higher working-age male mortality rates both between 1992 and 1998 (age-standardised mortality ratio in men aged 20-69 years in fast vs slow privatised towns: 1·13, SMR 0·83, 95% CI 0·77-0·88 vs 0·73, 0·69-0·77, respectively) and from 1999 to 2006 (1·15, 0·91, 0·86-0·97 vs 0·79, 0·75-0·84). After adjusting for age, marital status, material deprivation history, smoking, drinking and socioeconomic status, working-age men in fast-privatised towns experienced 13% higher mortality than in slow-privatised towns (95% CI 1-26). INTERPRETATION: The rapid pace of privatisation was a significant factor in the marked increase in working-age male mortality in post-Soviet Russia. By providing compelling evidence in support of the health benefits of a slower pace of privatisation, this study can assist policy makers in making informed decisions about the speed and scope of government interventions. FUNDING: The European Research Council.

Blood-Based Oxidative Stress Markers and Cognitive Performance in Early Old Age: The HAPIEE Study.

BACKGROUND/AIMS: Oxidative stress is involved in Alzheimer disease pathology, but its impact on cognitive function in community-dwelling older adults remains unknown. We estimated associations between serum oxidative stress markers and cognitive function in early old age. METHODS: Subjects aged 45-69 years recruited in urban centers in Central and Eastern Europe had memory, verbal fluency, and processing speed assessed at baseline (2002-2005) and 3 years later. Derivatives of reactive oxygen metabolites (d-ROMs), biological antioxidant potential (BAP), and total thiol levels (TTLs) were measured at baseline in a subsample. Linear regression was used to estimate associations of biomarkers with cognitive test scores cross-sectionally (n = 4,304) and prospectively (n = 2,882). RESULTS: Increased d-ROM levels were inversely associated with global cognition and verbal fluency cross-sectionally and in prospective analysis; observed effects corresponded to 3-4 years' higher age. TTL was inconsistently associated with memory. BAP was not related to cognitive function. CONCLUSION: This study found modest evidence for a relationship between serum d-ROMs and cognitive function in a population sample of older adults.

Mortality in Transition: Study Protocol of the PrivMort Project, a multilevel convenience cohort study.

BACKGROUND: Previous research using routine data identified rapid mass privatisation as an important driver of mortality crisis following the collapse of Communism in Central and Eastern Europe. However, existing studies on the mortality crisis relying on individual level or routine data cannot assess both distal (societal) and proximal (individual) causes of mortality simultaneously. The aim of the PrivMort Project is to overcome these limitations and to investigate the role of societal factors (particularly rapid mass privatisation) and individual-level factors (e.g. alcohol consumption) in the mortality changes in post-communist countries. METHODS: The PrivMort conducts large-sample surveys in Russia, Belarus and Hungary. The approach is unique in comparing towns that have undergone rapid privatisation of their key industrial enterprises with those that experienced more gradual forms of privatisation, employing a multi-level retrospective cohort design that combines data on the industrial characteristics of the towns, socio-economic descriptions of the communities, settlement-level data, individual socio-economic characteristics, and individuals' health behaviour. It then incorporates data on mortality of different types of relatives of survey respondents, employing a retrospective demographic approach, which enables linkage of historical patterns of mortality to exposures, based on experiences of family members. By May 2016, 63,073 respondents provided information on themselves and 205,607 relatives, of whom 102,971 had died. The settlement-level dataset contains information on 539 settlements and 12,082 enterprises in these settlements in Russia, 96 settlements and 271 enterprises in Belarus, and 52 settlement and 148 enterprises in Hungary. DISCUSSION: In addition to reinforcing existing evidence linking smoking, hazardous drinking and unemployment to mortality, the PrivMort dataset will investigate the variation in transition experiences for individual respondents and their families across settlements characterized by differing contextual factors, including industrial characteristics, simultaneously providing information about how excess mortality is distributed across settlements with various privatization strategies.

Serum folate, vitamin B-12 and cognitive function in middle and older age: The HAPIEE study.

BACKGROUND: Nutrient status of B vitamins, particularly folate and vitamin B-12, may be related to cognitive ageing but epidemiological evidence remains inconclusive. OBJECTIVE: The aim of this study was to estimate the association of serum folate and vitamin B-12 concentrations with cognitive function in middle-aged and older adults from three Central and Eastern European populations. METHODS: Men and women aged 45-69 at baseline participating in the Health, Alcohol and Psychosocial factors in Eastern Europe (HAPIEE) study were recruited in Krakow (Poland), Kaunas (Lithuania) and six urban centres in the Czech Republic. Tests of immediate and delayed recall, verbal fluency and letter search were administered at baseline and repeated in 2006-2008. Serum concentrations of biomarkers at baseline were measured in a sub-sample of participants. Associations of vitamin quartiles with baseline (n=4166) and follow-up (n=2739) cognitive domain-specific z-scores were estimated using multiple linear regression. RESULTS: After adjusting for confounders, folate was positively associated with letter search and vitamin B-12 with word recall in cross-sectional analyses. In prospective analyses, participants in the highest quartile of folate had higher verbal fluency (p<0.01) and immediate recall (p<0.05) scores compared to those in the bottom quartile. In addition, participants in the highest quartile of vitamin B-12 had significantly higher verbal fluency scores (ß=0.12; 95% CI=0.02, 0.21). CONCLUSIONS: Folate and vitamin B-12 were positively associated with performance in some but not all cognitive domains in older Central and Eastern Europeans. These findings do not lend unequivocal support to potential importance of folate and vitamin B-12 status for cognitive function in older age. Long-term longitudinal studies and randomised trials are required before drawing conclusions on the role of these vitamins in cognitive decline.

Alcohol, drinking pattern and all-cause, cardiovascular and alcohol-related mortality in Eastern Europe.

Alcohol has been implicated in the high mortality in Central and Eastern Europe but the magnitude of its effect, and whether it is due to regular high intake or episodic binge drinking remain unclear. The aim of this paper was to estimate the contribution of alcohol to mortality in four Central and Eastern European countries. We used data from the Health, Alcohol and Psychosocial factors in Eastern Europe is a prospective multi-centre cohort study in Novosibirsk (Russia), Krakow (Poland), Kaunas (Lithuania) and six Czech towns. Random population samples of 34,304 men and women aged 45-69 years in 2002-2005 were followed up for a median 7 years. Drinking volume, frequency and pattern were estimated from the graduated frequency questionnaire. Deaths were ascertained using mortality registers. In 230,246 person-years of follow-up, 2895 participants died from all causes, 1222 from cardiovascular diseases (CVD), 672 from coronary heart disease (CHD) and 489 from pre-defined alcohol-related causes (ARD). In fully-adjusted models, abstainers had 30-50% increased mortality risk compared to light-to-moderate drinkers. Adjusted hazard ratios (HR) in men drinking on average ≥60 g of ethanol/day (3% of men) were 1.23 (95% CI 0.95-1.59) for all-cause, 1.38 (0.95-2.02) for CVD, 1.64 (1.02-2.64) for CHD and 2.03 (1.28-3.23) for ARD mortality. Corresponding HRs in women drinking on average ≥20 g/day (2% of women) were 1.92 (1.25-2.93), 1.74 (0.76-3.99), 1.39 (0.34-5.76) and 3.00 (1.26-7.10). Binge drinking increased ARD mortality in men only. Mortality was associated with high average alcohol intake but not binge drinking, except for ARD in men.

Alcohol consumption, drinking patterns, and cognitive function in older Eastern European adults.

OBJECTIVE: To investigate associations of frequency, quantity, binge, and problem drinking with cognitive function in older Eastern European adults. METHODS: The investigation included 14,575 participants, aged 47 to 78 years at cognitive assessment in 2006-2008 from Novosibirsk (Russia), Krakow (Poland), and 6 Czech towns participating in the HAPIEE (Health, Alcohol, and Psychosocial Factors in Eastern Europe) prospective cohort study. Average response rates were 59% at baseline (2002-2005) and 63% in 2006-2008. Alcohol consumption was assessed at baseline and in 2006-2008. Cognitive tests included immediate and delayed word recall, semantic fluency (animal naming), and letter cancellation. Associations between alcohol indices and cognitive scores were analyzed cross-sectionally (all measures from 2006 to 2008) and prospectively (alcohol and covariates from 2002 to 2005 and cognition from 2006 to 2008). RESULTS: In cross-sectional analyses, nondrinkers had lower cognitive scores and female moderate drinkers had better cognitive performance than light drinkers. Heavy, binge, and problem drinking were not consistently associated with cognitive function. Few associations were replicated in prospective analyses. Participants who stopped drinking during follow-up had worse cognition than stable drinkers; in men, regression coefficients (95% confidence interval) ranged from -0.26 (-0.36, -0.16) for immediate recall to -0.14 (-0.24, -0.04) for fluency. CONCLUSION: Regular and episodic heavy drinking were not consistently associated with cognitive function. Worse cognition in participants who stopped drinking during follow-up suggests that inclusion of less healthy ex-drinkers may partly explain poorer cognition in nondrinkers.

A systematic review and meta-analysis of 130,000 individuals shows smoking does not modify the association of APOE genotype on risk of coronary heart disease.

BACKGROUND: Conflicting evidence exists on whether smoking acts as an effect modifier of the association between APOE genotype and risk of coronary heart disease (CHD). METHODS AND RESULTS: We searched PubMed and EMBASE to June 11, 2013 for published studies reporting APOE genotype, smoking status and CHD events and added unpublished data from population cohorts. We tested for presence of effect modification by smoking status in the relationship between APOE genotype and risk of CHD using likelihood ratio test. In total 13 studies (including unpublished data from eight cohorts) with 10,134 CHD events in 130,004 individuals of European descent were identified. The odds ratio (OR) for CHD risk from APOE genotype (ε4 carriers versus non-carriers) was 1.06 (95% confidence interval (CI): 1.01, 1.12) and for smoking (present vs. past/never smokers) was OR 2.05 (95%CI: 1.95, 2.14). When the association between APOE genotype and CHD was stratified by smoking status, compared to non-ε4 carriers, ε4 carriers had an OR of 1.11 (95%CI: 1.02, 1.21) in 28,789 present smokers and an OR of 1.04 (95%CI 0.98, 1.10) in 101,215 previous/never smokers, with no evidence of effect modification (P-value for heterogeneity = 0.19). Analysis of pack years in individual participant data of >60,000 with adjustment for cardiovascular traits also failed to identify evidence of effect modification. CONCLUSIONS: In the largest analysis to date, we identified no evidence for effect modification by smoking status in the association between APOE genotype and risk of CHD.

Alcohol consumption and cognitive performance: a Mendelian randomization study.

AIMS: To use Mendelian randomization to assess whether alcohol intake was causally associated with cognitive function. DESIGN: Mendelian randomization using a genetic variant related to alcohol intake (ADH1B rs1229984) was used to obtain unbiased estimates of the association between alcohol intake and cognitive performance. SETTING: Europe. PARTICIPANTS: More than 34 000 adults. MEASUREMENTS: Any versus no alcohol intake and units of intake in the previous week was measured by questionnaire. Cognitive function was assessed in terms of immediate and delayed word recall, verbal fluency and processing speed. FINDINGS: Having consumed any versus no alcohol was associated with higher scores by 0.17 standard deviations (SD) [95% confidence interval (CI) = 0.15, 0.20] for immediate recall, 0.17 SD (95% CI = 0.14, 0.19) for delayed recall, 0.17 SD (95% CI = 0.14, 0.19) for verbal fluency and 0.12 SD (95% CI = 0.09, 0.15) for processing speed. The minor allele of rs1229984 was associated with reduced odds of consuming any alcohol (odds ratio = 0.87; 95% CI = 0.80, 0.95; P = 0.001; R(2) = 0.1%; F-statistic = 47). In Mendelian randomization analysis, the minor allele was not associated with any cognitive test score, and instrumental variable analysis suggested no causal association between alcohol consumption and cognition: -0.74 SD (95% CI = -1.88, 0.41) for immediate recall, -1.09 SD (95% CI = -2.38, 0.21) for delayed recall, -0.63 SD (95% CI = -1.78, 0.53) for verbal fluency and -0.16 SD (95% CI = -1.29, 0.97) for processing speed. CONCLUSIONS: The Mendelian randomization analysis did not provide strong evidence of a causal association between alcohol consumption and cognitive ability.

Life course socioeconomic position and mid-late life cognitive function in Eastern Europe.

OBJECTIVES: To investigate whether the positive relation between socioeconomic position (SEP) across the life course and later life cognitive function observed in Western populations exists in former communist countries with apparently smaller income inequalities. METHOD: Structural equation modeling analysis of cross-sectional data on 30,846 participants aged 45-78 years in four Central and Eastern European centers: Novosibirsk (Russia), Krakow (Poland), Kaunas (Lithuania), and six Czech towns from the HAPIEE (Health, Alcohol, and Psychosocial factors In Eastern Europe) study. SEP was measured using self-reported childhood (maternal education, household amenities), adult (education), and older adult (current material circumstances) indicators. Latent variable for cognition was constructed from word recall, animal naming, and letter search. RESULTS: Associations between SEP measures over the life course and cognition were similar across study centers. Education had the strongest direct association with cognition, followed by current material circumstances. Indirect path from education to cognition, mediated by current SEP, was small. Direct path from mother's education to cognition was significant but modest, and partially mediated by later SEP measures, particularly education. DISCUSSION: In these Eastern European populations, late life cognition reflected life course socioeconomic trajectories similarly to findings in Western countries.