Cancer-related fatigue: Towards a more targeted approach based on classification by biomarkers and psychological factors.

Cancer-related fatigue is a frequent, burdensome and often insufficiently treated symptom. A more targeted treatment of fatigue is urgently needed. Therefore, we examined biomarkers and clinical factors to identify fatigue subtypes with potentially different pathophysiologies. The study population comprised disease-free breast cancer survivors of a German population-based case-control study who were re-assessed on average 6 (FU1, n = 1871) and 11 years (FU2, n = 1295) after diagnosis. At FU1 and FU2, we assessed fatigue with the 20-item multidimensional Fatigue Assessment Questionnaire and further factors by structured telephone-interviews. Serum samples collected at FU1 were analyzed for IL-1ß, IL-2, IL-4, IL-6, IL-10, TNF-a, GM-CSF, IL-5, VEGF-A, SAA, CRP, VCAM-1, ICAM-1, leptin, adiponectin and resistin. Exploratory cluster analyses among survivors with fatigue at FU1 and no history of depression yielded three clusters (CL1, CL2 and CL3). CL1 (n = 195) on average had high levels of TNF-α, IL1-ß, IL-6, resistin, VEGF-A and GM-CSF, and showed high BMI and pain levels. Fatigue in CL1 manifested rather in physical dimensions. Contrarily, CL2 (n = 78) was characterized by high leptin level and had highest cognitive fatigue. CL3 (n = 318) did not show any prominent characteristics. Fatigued survivors with a history of depression (n = 214) had significantly higher physical, emotional and cognitive fatigue and showed significantly less amelioration of fatigue from FU1 to FU2 than survivors without depression. In conclusion, from the broad phenotype "cancer-related fatigue" we were able to delineate subgroups characterized by biomarkers or history of depression. Future investigations may take these subtypes into account, ultimately enabling a better targeted therapy of fatigue.

The Healthy Participant Effect: insights and results from a population-based case-control study on breast cancer.

Agreement to participate in case-control studies has become low. Healthy participant bias resulting from differential response proportions in cases and controls can distort results; however, the magnitude of bias is difficult to assess. We investigated the effect in a large population-based case-control study on breast cancer, with a participation rate of 43.4% and 64.1% for controls and cases. We performed a mortality follow-up in 2020 for 3,813 cases and 7,335 controls recruited between 2002-2005. Standardized mortality ratios (SMR) for overall mortality and selected causes of death were estimated. The mean age at recruitment was 63.1 years. The overall mortality for controls was 0.66 times lower (95%CI 0.62-0.69) than for the reference population. For causes of death other than breast cancer, SMRs were similar in cases and controls (0.70 and 0.64). Higher education was associated with lower SMRs in both cases and controls. Options for adjusting the healthy participant bias are limited if the true risk factor distribution in the underlying population is unknown. However, a relevant bias in this particular case-control study is considered unlikely since a similar healthy participant effect was observed for both controls and cases.

Social relationships and their impact on health-related quality of life in a long-term breast cancer survivor cohort.

BACKGROUND: Health-related quality of life (HRQOL) has become increasingly important for breast cancer survivors, but clinically relevant declines often persist for many years after treatment. This study aimed to investigate whether social relationships can mitigate or prevent this decline in HRQOL. METHODS: Data were used from the German population-based Mamma Carcinoma Risk Factor Investigation (MARIE) cohort of 2022 breast cancer cases with follow-up information for more than 15 years after diagnosis. Correlations between social integration, social support, and global health status (GHS) as an overall measure of HRQOL were analyzed, and linear regression analysis was performed with structural equation modeling. RESULTS: The majority of participants reported high levels of social integration and social support and moderate levels of GHS. Social integration 5 years after diagnosis was associated with GHS 5 years after diagnosis (ß = 1.12; 95% CI, 0.25-1.99), but no longitudinal effects were found. Social support 5 years after diagnosis was associated with better GHS 5 years (ß = 0.42; 95% CI, 0.36-0.48) and 10 years after diagnosis (ß = 0.12; 95% CI, 0.02-0.22), whereas social support 10 years after diagnosis was associated with GHS 10 years (ß = 0.29; 95% CI, 0.20-0.39) and 15 years after diagnosis (ß = 0.10; 95% CI, 0.01-0.21). CONCLUSIONS: These results confirm that social relationships positively influence HRQOL in long-term breast cancer survivors and that their association should receive more attention clinically and beyond routine care.

Does breast cancer modify the long-term relationship between lifestyle behaviors and mortality? A prospective analysis of breast cancer survivors and population-based controls.

BACKGROUND: Modifiable lifestyle factors are known to impact survival. It is less clear whether this differs between postmenopausal women ever diagnosed with breast cancer and unaffected women. METHODS: Women diagnosed with breast cancer and unaffected women of comparable age were recruited from 2002 to 2005 and followed up until 2020. Using baseline information, a lifestyle adherence score (range 0-8; categorized as low [0-3.74], moderate [3.75-4.74], and high [≥4.75]) was created based on the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations. Cox regression and competing risks analysis were used to analyze the association of adherence to WCRF/AICR lifestyle recommendations with overall mortality and with death due to cardiovascular diseases and cancer, respectively. RESULTS: A total of 8584 women were included (2785 with breast cancer and 5799 without). With a median follow-up of 16.1 years there were 2006 total deaths. Among the deaths of known causes (98.6%), 445 were cardiovascular-related and 1004 were cancer-related. The average lifestyle score was 4.2. There was no differential effect of lifestyle score by case-control status on mortality. After adjusting for covariates, moderate (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.57-0.76) and high (HR, 0.54; 95% CI, 0.47-0.63) adherence to WCRF/AICR lifestyle recommendations were significantly associated with a decrease in overall mortality. Similarly, in competing risks analysis, moderate and high adherence were associated with decreased mortality from cardiovascular diseases and from cancer. CONCLUSIONS: A healthy lifestyle can substantially reduce mortality risk in women. With low adherence to all WCRF/AICR guidelines in about a third of study participants, health interventions are warranted.

Childhood and adolescence factors and multiple sclerosis: results from the German National Cohort (NAKO).

BACKGROUND: Multiple Sclerosis (MS) represents the most common inflammatory neurological disease causing disability in early adulthood. Childhood and adolescence factors might be of relevance in the development of MS. We aimed to investigate the association between various factors (e.g., prematurity, breastfeeding, daycare attendance, weight history) and MS risk. METHODS: Data from the baseline assessment of the German National Cohort (NAKO) were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the association between childhood and adolescence factors and risk of MS. Analyses stratified by sex were conducted. RESULTS: Among a total of 204,273 participants, 858 reported an MS diagnosis. Male sex was associated with a decreased MS risk (HR 0.48; 95% CI 0.41-0.56), while overweight (HR 2.03; 95% CI 1.41-2.94) and obesity (HR 1.89; 95% CI 1.02-3.48) at 18 years of age compared to normal weight were associated with increased MS risk. Having been breastfed for ≤ 4 months was associated with a decreased MS risk in men (HR 0.59; 95% CI 0.40-0.86) compared to no breastfeeding. No association with MS risk was observed for the remaining factors. CONCLUSIONS: Apart from overweight and obesity at the age of 18 years, we did not observe considerable associations with MS risk. The proportion of cases that can be explained by childhood and adolescence factors examined in this study was low. Further investigations of the association between the onset of overweight and obesity in childhood and adolescence and its interaction with physical activity and MS risk seem worthwhile.

Changes in physical activity and sedentary behavior during the first COVID-19 pandemic- restrictions in Germany: a nationwide survey : Running head: physical activity during the COVID-19 restrictions.

BACKGROUND: The COVID-19 pandemic restrictions posed challenges to maintaining healthy lifestyles and physical well-being. During the first mobility restrictions from March to mid-July 2020, the German population was advised to stay home, except for work, exercise, and essential shopping. Our objective was to comprehensively assess the impact of these restrictions on changes in physical activity and sedentary behavior to identify the most affected groups. METHODS: Between April 30, 2020, and May 12, 2020, we distributed a COVID-19-specific questionnaire to participants of the German National Cohort (NAKO). This questionnaire gathered information about participants' physical activity and sedentary behavior currently compared to the time before the restrictions. We integrated this new data with existing information on anxiety, depressive symptoms, and physical activity. The analyses focused on sociodemographic factors, social relationships, physical health, and working conditions. RESULTS: Out of 152,421 respondents, a significant proportion reported altered physical activity and sedentary behavioral patterns due to COVID-19 restrictions. Over a third of the participants initially meeting the WHO's physical activity recommendation could no longer meet the guidelines during the restrictions. Participants reported substantial declines in sports activities (mean change (M) = -0.38; 95% CI: -.390; -.378; range from -2 to + 2) and reduced active transportation (M = -0.12; 95% CI: -.126; -.117). However, they also increased recreational physical activities (M = 0.12; 95% CI: .117; .126) while engaging in more sedentary behavior (M = 0.24; 95% CI: .240; .247) compared to pre-restriction levels. Multivariable linear and log-binomial regression models indicated that younger adults were more affected by the restrictions than older adults. The shift to remote work, self-rated health, and depressive symptoms were the factors most strongly associated with changes in all physical activity domains, including sedentary behavior, and the likelihood to continue following the physical activity guidelines. CONCLUSIONS: Mobility patterns shifted towards inactivity or low-intensity activities during the nationwide restrictions in the spring of 2020, potentially leading to considerable and lasting health risks.

[Effects of high thermal stress on health-a nationwide analysis based on statutory health insurance routine data between 2012 and 2021]. / Auswirkungen thermischer Belastungen auf die Gesundheit ­ eine bundesweite Analyse auf Grundlage von GKV-Routinedaten zwischen 2012­2021.

BACKGROUND: The extent to which statutory health insurance (SHI) data can be used to map associations between thermal stress and heat-related diseases is still unclear. The aim of this study is to analyse the association between climate variability and heat-associated diseases using insurance data. METHODS: The study is based on claims data (outpatient and stationary) from health insurance companies in Germany for the years 2012-2021, covering approximately 11 million people with statutory health insurance. Four heat-related ICD-10 diagnoses were considered: T67 (heat and sun damage), E86 (volume depletion), N17 (acute renal failure) and N19 (renal insufficiency). Thermal conditions were quantified using meteorological variables. The evaluation was carried out on a federal state-specific basis for the second and third quarters (Q2, Q3) using descriptive methods and correlation analyses with repeated measurements. RESULTS: The years 2016, 2018 and 2020 were characterised by high temperatures. Compared with Q2, Q3 was associated with higher thermal stress and more heat-related diagnoses on average during the entire observational period. Nationally, diagnoses of heat and sun damage (outpatient) correlated with the number of hot days (rmw = 0.86 [0.81; 0.90]). Although heat stress is lower in the second quarter, a similar correlation is found here (rmw = 0.76 [0.68; 0.82]). This striking association was also maintained when analysing the federal states specifically. DISCUSSION: The article shows that associations between thermal stress and morbidity can also be found in routine SHI data. Against the background of an increase in high thermal stress due to climate change, this article highlights the need for adaptation measures.

Postdiagnosis circulating osteoprotegerin and TRAIL concentrations and survival and recurrence after a breast cancer diagnosis: results from the MARIE patient cohort.

BACKGROUND: Experimental studies suggest a role for osteoprotegerin (OPG) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in mammary tumor development and progression. These biomarkers have been minimally investigated with respect to outcomes in breast cancer patients. METHODS: OPG and TRAIL were evaluated in blood samples collected from 2459 breast cancer patients enrolled in the MARIE study, a prospective population-based patient cohort, at median of 129 days after diagnosis. Participants were between ages 50 and 74 at diagnosis and recruited from 2002 to 2005 in two regions of Germany. Follow-up for recurrence and mortality was conducted through June 2015. Delayed-entry Cox proportional hazards regression was used to assess associations between OPG and TRAIL with all-cause and breast cancer-specific mortality, and recurrence, both overall and by tumor hormone receptor status. RESULTS: Median follow-up time was 11.7 years, with 485 deaths reported (277 breast cancer-specific). Higher OPG concentrations were associated with a higher risk of all-cause mortality (hazard ratio for 1-unit log2-transformed concentration (HRlog2) = 1.24 (95% confidence interval 1.03-1.49). Associations were observed in women diagnosed with ER-PR- tumors or discordant hormone receptor status (ER-PR-, HRlog2 = 1.93 (1.20-3.10); discordant ERPR, 1.70 (1.03-2.81)), but not for women with ER + PR + tumors (HRlog2 = 1.06 (0.83-1.35)). OPG was associated with a higher risk of recurrence among women with ER-PR- disease (HRlog2 = 2.18 (1.39-3.40)). We observed no associations between OPG and breast cancer-specific survival, or for TRAIL and any outcome. CONCLUSIONS: Higher circulating OPG may be a biomarker of a higher risk of poor outcome among women diagnosed with ER- breast cancer. Further mechanistic studies are warranted.

The impact of cardiovascular disease on all-cause and cancer mortality: results from a 16-year follow-up of a German breast cancer case-control study.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death worldwide. The aim of this study was to examine if CVD affects the mortality of women after a breast cancer diagnosis and population controls differently. METHODS: The analysis included a total of 3,555 women, diagnosed with primary stage 1-3 breast cancer or in situ carcinoma between 2002 and 2005 and 7,334 controls breast cancer-free at recruitment, all aged 50-74 years, who were followed-up in a German breast cancer case-control study until June, 30 2020. Kaplan-Meier and cumulative incidence function were calculated for all-cause mortality and mortality from any cancer, stratified for case-control status and CVD, separately for women aged < 65 and ≥ 65 years. Cox regression and Fine-Gray subdistribution hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between case-control-status, CVD and mortality from all causes/any cancer. RESULTS: The median follow-up was 16.1 years. In total, 1,172 cases (33.0%) and 1,401 initial controls (19.1%) died. CVD prevalence at recruitment was 15.2% in cases and controls. Cases with CVD had the highest and controls without CVD the lowest mortality during the entire observation period in both age groups (< 65 and ≥ 65 years). CVD was identified as a risk factor for all-cause mortality in both cases and controls aged < 65 years (HR 1.22, 95%CI 0.96-1.55 and HR 1.79, 95%CI 1.43-2.24) as well as at ages of ≥ 65 years (HR 1.44, 95%CI 1.20-1.73 and HR 1.59, 95%CI 1.37-1.83). A significant association of CVD and cancer mortality was found only for cases aged ≥ 65 years. CONCLUSION: CVD was significantly associated with all-cause mortality of both cases and controls and CVD was identified as a risk factor for cancer mortality of cases aged ≥ 65 years at recruitment. Therefore, attention should be paid on monitoring and preventing CVD in breast cancer patients, especially in those diagnosed at older ages.

Endogenous estrogen receptor modulating oxysterols and breast cancer prognosis: Results from the MARIE patient cohort.

BACKGROUND: 27-hydroxycholesterol (HC) and 25-HC were identified as endogenous selective estrogen receptor modulators (SERMs) and estrogen receptor (ER) modulators, respectively. They are hypothesized to play a role in multiple physiologic processes and pathologies, including breast cancer development and progression. METHODS: We evaluated circulating 27-HC and 25-HC, and outcomes following a breast cancer diagnosis in 2282 women from the MARIE study over median follow-up of 11.6 years. 27-HC and 25-HC were quantified by liquid chromatography-mass spectrometry. We calculated hazard ratios (HR) and 95% confidence intervals [CI] using multivariable Cox Proportional Hazards regression. RESULTS: We observed no associations between 27-HC and breast cancer prognosis overall. Associations between 27-HC and survival differed by circulating estradiol concentrations and endocrine therapy, but not by hormone receptor status. Among women with estradiol levels below the median (0.08 nM), 27-HC was associated with higher risk of all-cause mortality (HRlog2 = 1.80 [1.20-2.71]) and breast cancer-specific mortality (HRlog2 = 1.95 [1.14-3.31]). No associations were observed in women with estradiol levels above the median. Higher 25-HC levels were associated with lower risk of recurrence (HRlog2 = 0.87 [0.77-0.98]). CONCLUSION: Associations between 27-HC and breast cancer prognosis varied by circulating estradiol levels and endocrine therapy. Less consistent results were observed for 25-HC.

Circulating oxysterols and prognosis among women with a breast cancer diagnosis: results from the MARIE patient cohort.

BACKGROUND: Breast cancer is the most commonly diagnosed cancer in women worldwide, and underlying mechanistic pathways associated with breast cancer-specific and non-breast cancer-related deaths are of importance. Emerging evidence suggests a role of oxysterols, derivates of cholesterol, in multiple chronic diseases including breast cancer and coronary artery diseases. However, associations between oxysterols and survival have been minimally studied in women diagnosed with breast cancer. In this large breast cancer patient cohort, we evaluated associations between a panel of circulating oxysterols and mortality and recurrence outcomes. METHODS: Concentrations of 13 circulating oxysterols representing different pathways of cholesterol metabolism were quantified using liquid-chromatography mass-spectrometry. Associations between baseline levels of oxysterols and cause-specific mortality outcomes and recurrence following a breast cancer diagnosis were assessed in 2282 women from the MARIE study over a median follow-up time of 11 years. We calculated hazard ratios (HR) and 95% confidence intervals (CI) using multivariable Cox proportional hazard models and competing risks models. RESULTS: We observed no associations for circulating oxysterols and breast cancer-specific outcomes. Higher levels of six oxysterols were associated with an increased risk of cardiovascular disease death, including 24S-hydroxycholesterol (alternative bile acid pathway, HRlog2 = 1.73 (1.02, 2.93)), lanosterol (cholesterol biosynthesis pathway, HRlog2 = 1.95 (1.34, 2.83)), 7-ketocholesterol (HRlog2 = 1.26 (1.03, 1.55)), 5α,6α-epoxycholesterol (HRlog2 = 1.34 (1.02-1.77)), and 5a,6ß-dihydroxycholestanol (HRlog2 = 1.34 (1.03, 1.76)). After adjusting for multiple comparisons, none of the associations were statistically significant. CONCLUSION: We provide first evidence on a range of circulating oxysterols and mortality following a breast cancer diagnosis, contributing to a better understanding of associations between different pathways of cholesterol metabolism and prognosis in women with a breast cancer diagnosis. The findings of this study suggest circulating oxysterols may be associated with cardiovascular mortality among women diagnosed with breast cancer. Further studies are needed to evaluate these oxysterols as potential markers of risk for cardiovascular mortality among women with a breast cancer diagnosis as well as their clinical potential.

Association of circulating free and total oxysterols in breast cancer patients.

OBJECTIVES: Oxysterols, a family of oxidized cholesterol derivates, are of increasing interest due to their role in cancer development and progression. Some oxysterols are estrogen receptor modulators and thus of particular interest in breast cancer research. In human studies, two forms of circulating oxysterols are commonly evaluated: "free" (unesterified) and "total" (esterified and unesterified). However, associations between free and total oxysterols are not well established. We addressed this knowledge gap in a pilot study by evaluating correlations between the free and the total form of each of the circulating oxysterols (free vs. total), and pairwise associations within the panel of total oxysterols (total vs. total) and the panel of free oxysterols (free vs. free). METHODS: Concentrations of oxysterols and other non-cholesterol sterols were quantified in blood samples of 27 breast cancer patients from the MARIE breast cancer patient cohort using liquid chromatography mass spectrometry. We used Spearman rank correlations to assess associations. Overall, 12 oxysterols (including 27-hydroxycholesterol (HC), 25-HC, 24S-HC, 7a-HC, 5a6a-epoxycholesterol) and five sterols (including lanosterol and desmosterol) were analyzed. RESULTS: Strong correlations (r≥0.82) were observed for seven circulating free and total oxysterols/sterols. The free and total form of 27-HC (r=0.63), 25-HC (r=0.54), and two more oxysterols were weaker correlated. Correlation patterns in the panel of total oxysterols/sterols and the panel of free oxysterols/sterols were similar. CONCLUSIONS: These findings demonstrate that concentrations of most free and total oxysterols/sterols are strongly correlated. We provide further insight into the interrelationships between oxysterols in breast cancer patients.

Investigating people's attitudes towards participating in longitudinal health research: an intersectionality-informed perspective.

BACKGROUND: Increasing evidence suggests that participation proportions in longitudinal health research vary according to sex/gender, age, social class, or migration status. Intersectionality scholarship purports that such social categories cannot be understood in isolation and makes visible the co-dependent nature of the social determinants of health and illness. This paper uses an intersectionality-informed approach in order to expand the understanding of why people participate in health research, and the impact of intersecting social structures and experiences on these attitudes. METHODS: A sample of 80 respondents who had previously either accepted or declined an invitation to participate in the German National Cohort (NAKO) participated in our interview study. Interviews were semi-structured and contained both narrative elements and more structured probes. Data analysis proceeded in two steps: first, the entire data set was analysed thematically (separately for participants and non-participants); second, key themes were compared across self-reported sex/gender, age group and migration status to identify differences and commonalities. RESULTS: Respondents' attitudes towards study participation can be categorised into four themes: wanting to make a contribution, seeking personalised health information, excitement and feeling chosen, and seeking social recognition. Besides citing logistical challenges, non-participants narrated adverse experiences with or attitudes towards science and the healthcare system that deterred them from participating. A range of social experiences and cultural value systems shaped such attitudes; in particular, this includes the cultural authority of science as an arbiter of social questions, transgressing social categories and experiences of marginalisation. Care responsibilities, predominantly borne by female respondents, also impacted upon the decision to take part in NAKO. DISCUSSION: Our findings suggest that for participants, health research constitutes a site of distinction in the sense of making a difference and being distinct or distinguishable, whereas non-participants inhabited an orientation towards science that reflected their subjective marginalisation through science. No clear relationship can thereby be presumed between social location and a particular attitude towards study participation; rather, such attitudes transgress and challenge categorical boundaries. This challenges the understanding of particular populations as more or less disadvantaged, or as more or less inclined to participate in health research.

Polymorphisms in genes of melatonin biosynthesis and signaling support the light-at-night hypothesis for breast cancer.

Light-at-night triggers the decline of pineal gland melatonin biosynthesis and secretion and is an IARC-classified probable breast-cancer risk factor. We applied a large-scale molecular epidemiology approach to shed light on the putative role of melatonin in breast cancer. We investigated associations between breast-cancer risk and polymorphisms at genes of melatonin biosynthesis/signaling using a study population of 44,405 women from the Breast Cancer Association Consortium (22,992 cases, 21,413 population-based controls). Genotype data of 97 candidate single nucleotide polymorphisms (SNPs) at 18 defined gene regions were investigated for breast-cancer risk effects. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CI) by logistic regression for the main-effect analysis as well as stratified analyses by estrogen- and progesterone-receptor (ER, PR) status. SNP-SNP interactions were analyzed via a two-step procedure based on logic regression. The Bayesian false-discovery probability (BFDP) was used for all analyses to account for multiple testing. Noteworthy associations (BFDP < 0.8) included 10 linked SNPs in tryptophan hydroxylase 2 (TPH2) (e.g. rs1386492: OR = 1.07, 95% CI 1.02-1.12), and a SNP in the mitogen-activated protein kinase 8 (MAPK8) (rs10857561: OR = 1.11, 95% CI 1.04-1.18). The SNP-SNP interaction analysis revealed noteworthy interaction terms with TPH2- and MAPK-related SNPs (e.g. rs1386483R ∧ rs1473473D ∧ rs3729931D: OR = 1.20, 95% CI 1.09-1.32). In line with the light-at-night hypothesis that links shift work with elevated breast-cancer risks our results point to SNPs in TPH2 and MAPK-genes that may impact the intricate network of circadian regulation.

Breastfeeding and Risk of Multiple Sclerosis: A Systematic Review and Meta-Analysis of Observational Studies.

INTRODUCTION: The causes of multiple sclerosis (MS) are not fully understood, yet. Genetic predisposition, environmental and lifestyle factors as well as an interplay thereof constitute relevant factors in the development of MS. Especially early-life risk factors such as having been breastfed may also be of relevance. Breast milk provides the newborn not only with essential nutrients and vitamins but also with numerous immune-active molecules, metabolites, oligosaccharides, and microbial components that are important for the development of the immune system. We present a systematic review and meta-analysis on the influence of having been breastfed during infancy on the risk of developing MS. METHODS: The databases MEDLINE, Cochrane Library, and Web of Science were systematically searched for studies on breastfeeding and MS published between database inception and May 18, 2022. Observational studies comparing persons with MS to healthy controls with regard to having been breastfed during the first 2 years of life were eligible for inclusion. A random effects meta-analysis was calculated to estimate pooled effect sizes using the Mantel-Haenszel method for dichotomous outcomes. The Newcastle-Ottawa Scale was used for quality analysis. RESULTS: 15 studies (13 case-control, 2 cohort) were included of which 12 were rated as high quality. The meta-analysis of crude odds ratios (ORs) yielded a risk estimate of ORcrude = 0.82 (95% confidence interval [CI]: 0.70-0.96) for MS in breastfed versus non-breastfed individuals with substantial heterogeneity (I2 = 68.2%). Using adjusted OR, when available, reduced heterogeneity (I2 = 48.9%) and resulted in an ORadjusted = 0.86 (95% CI: 0.75-0.99). Restricting the analysis to studies with high-quality scores (i.e., ≥6/9 points) resulted in a combined ORcrude of 0.79 (95% CI: 0.66-0.94) and an ORadjusted = 0.83 (95% CI: 0.71-0.98), respectively. DISCUSSION/CONCLUSION: The meta-analysis showed a small protective effect of having been breastfed on MS risk. This adds to the knowledge that breastfeeding is beneficial for the immunological health of a child. Future studies on the influence of having been breastfed on MS risk should apply a uniform definition of breastfeeding and investigate possible sex-specific aspects.

Postdiagnosis weight change is associated with poorer survival in breast cancer survivors: A prospective population-based patient cohort study.

More women are surviving after breast cancer due to early detection and modern treatment strategies. Body weight also influences survival. We aimed to characterize associations between postdiagnosis weight change and prognosis in postmenopausal long-term breast cancer survivors. We used data from a prospective population-based patient cohort study (MARIE) conducted in two geographical regions of Germany. Breast cancer patients diagnosed 50 to 74 years of age with an incident invasive breast cancer or in situ tumor were recruited from 2002 to 2005 and followed up until June 2015. Baseline weight was ascertained at an in-person interview at recruitment and follow-up weight was ascertained by telephone interview in 2009. Delayed entry Cox proportional hazards regression was used to assess associations between relative weight change and all-cause mortality, breast cancer mortality, and recurrence-free survival. In total, 2216 patients were included. Compared to weight maintenance (within 5%), weight loss >10% increased risk of all-cause mortality (HR 2.50, 95% CI 1.61, 3.88), breast cancer mortality (HR 3.07, 95% CI 1.69, 5.60) and less so of recurrence-free survival (HR 1.43, 95% CI 0.87, 2.36). Large weight gain of >10% also increased all-cause mortality (HR 1.64, 95% CI 1.02, 2.62) and breast cancer mortality (HR 2.25, 95% CI 1.25, 4.04). Weight maintenance for up to 5 years in long-term breast cancer survivors may help improve survival and prognosis. Postdiagnosis fluctuations in body weight of greater than 10% may lead to increased mortality. Survivors should be recommended to avoid large deviations in body weight from diagnosis onwards to maintain health and prolong life.

Comorbidity burden in long-term breast cancer survivors compared with a cohort of population-based controls from the MARIE study.

BACKGROUND: The number of elderly cancer survivors is growing because of increasing survival rates. A high comorbidity burden in the elderly can affect their quality of life and survival. The aim of this study was to examine whether breast cancer survivors and population-based controls have a different comorbidity burden after long-term follow-up. METHODS: This study used data from a German breast cancer case-control study, which initially comprised 3813 breast cancer cases aged 50 to 74 years who were diagnosed between 2002 and 2005 and 7341 population-based controls. Participants were followed up in 2014/2016. A modified Charlson Comorbidity Index (mCCI) was calculated to quantify severe comorbidities. Negative binomial regression was performed to estimate rate ratios (RRs) with 95% confidence intervals (CIs) for the association between case-control status and mCCI (dependent variable) for the baseline population and for those who participated at follow-up, with adjustments made for relevant lifestyle factors. RESULTS: In total, 1925 cases and 3674 controls participated in the follow-up 12 years after recruitment. In the baseline population 35% had at least 1 comorbid condition.In long-term survivors this proportion was 52%. No difference was found in the mCCI between breast cancer cases and controls at baseline (RR, 1.05; 95% CI, 0.98-1.11) or between long-term survivors of the 2 groups at baseline (RR, 1.07; 95% CI, 0.97-1.18) or at follow-up (RR, 1.00; 95% CI, 0.91-1.10). CONCLUSIONS: The comorbidity burden of long-term breast cancer survivors and controls increased over time; however, it remained similar in both groups after 12 years of follow-up.

Prevalence and clinical prediction of mitochondrial disorders in a large neuropediatric cohort.

Neurological symptoms are frequent and often a leading feature of childhood-onset mitochondrial disorders (MD) but the exact incidence of MD in unselected neuropediatric patients is unknown. Their early detection is desirable due to a potentially rapid clinical decline and the availability of management options. In 491 children with neurological symptoms, a comprehensive diagnostic work-up including exome sequencing was performed. The success rate in terms of a molecular genetic diagnosis within our cohort was 51%. Disease-causing variants in a mitochondria-associated gene were detected in 12% of solved cases. In order to facilitate the clinical identification of MDs within neuropediatric cohorts, we have created an easy-to-use bedside-tool, the MDC-NP. In our cohort, the MDC-NP predicted disease conditions related to MDs with a sensitivity of 0.83, and a specificity of 0.96.

Prognostic associations of circulating phytoestrogens and biomarker changes in long-term survivors of postmenopausal breast cancer.

Lignans are associated with improved postmenopausal breast cancer (BC) survival, but whether these associations, particularly with enterolactone (major lignan metabolite), persist over time is unclear. Little is known about other phytoestrogens on prognosis in long-term survivors. The study examines associations of prognosis with 1) circulating postdiagnosis enterolactone, 2) eight circulating phytoestrogen metabolites, and 3) changes in enterolactone and genistein. In a German cohort of 2,105 postmenopausal BC patients with blood samples collected at recruitment 2002-2005 (baseline) and re-interview in 2009 (follow-up), delay-entry Cox proportional hazards regression was used. Landmark analysis showed that circulating enterolactone (log2) associations with 5-year survival changed over time, with strongest hazard ratios of 0.89 (95% CI, 0.80-0.99) at blood draw (BD) and 0.86 (0.77-0.97) at 2 years post-BD for BC mortality, and 0.87 (0.80-0.95) at BD and 0.84 (0.76-0.92) at 3 years post-BD for all-cause mortality, which attenuated thereafter. In long-term survivors, increasing concentrations of genistein (1.17, 1.01-1.36), resveratrol (1.19, 1.02-1.40), and luteolin (1.96, 1.07-3.58) measured in follow-up blood samples were associated with poorer subsequent prognosis. Neither enterolactone at follow-up nor changes in enterolactone/genistein were associated with prognosis. Large long-term longitudinal studies with multiple phytoestrogen measurements are required to understand long-term effects of phytoestrogens after BC.

[Self-reported cancer in the German National Cohort (NAKO Gesundheitsstudie): assessment methods and first results]. / Selbstberichtete Krebserkrankungen in der NAKO Gesundheitsstudie: Erfassungsmethoden und erste Ergebnisse.

BACKGROUND: In the German National Cohort (NAKO Gesundheitsstudie), the largest prospective cohort study in Germany, data on self-reported cancer diagnoses are now available for the first half of participants. OBJECTIVES: Description of the methods to assess self-reported cancer diagnoses and type of cancer in the NAKO and presentation of first results. MATERIALS AND METHODS: In a computer-assisted, standardized personal interview, 101,787 participants (54,526 women, 47,261 men) were asked whether they had ever been diagnosed with cancer (malignant tumors including in situ) by a physician and how many cancer diagnoses they had. The type of cancer was classified with a list. Absolute and relative frequencies of self-reported cancer diagnoses and types of cancer were calculated and compared with cancer registry data. RESULTS: A physician-diagnosed cancer was reported by 9.4% of women and 7.0% of men. Of the participants who reported a cancer diagnosis, 88.3% reported to have had only one cancer diagnosis. In women, the most frequent malignancies were breast cancer, cervical cancer, and melanoma. In men, the most frequent malignancies were prostate cancer, melanoma, and colorectal cancer. Comparing the frequencies of cancer diagnoses reported by 45- to 74-year-old NAKO participants within the last five years to cancer registry-based 5­year prevalences, most types of cancer were less frequent in the NAKO, with the exception of melanoma in men and women, cervical cancer and liver cancer in women, and bladder cancer and breast cancer in men. CONCLUSIONS: The NAKO is a rich data basis for future investigations of incident cancer.