Kathrin Thöne

Risk of Stroke after Herpes Zoster – Evidence from a German Self-Controlled Case-Series Study

Background Herpes zoster (HZ) is caused by reactivation of the latent varicella-zoster virus (VZV). A severe complication of HZ is VZV vasculopathy which can result in ischemic or hemorrhagic stroke. The aims of our study were to assess the risk of stroke after the onset of HZ and to investigate the roles of stroke subtype, HZ location and the time interval between HZ onset and stroke. Methods A self-controlled case-series study was performed on a cohort of patients with incident stroke recorded in the German Pharmacoepidemiological Research Database (GePaRD), which covers about 20 million persons throughout Germany. We estimated adjusted incidence rate ratios (IRR) by comparing the rate of stroke in risk periods (i.e., periods following HZ) with the rate of stroke in control periods (i.e., periods without HZ) in the same individuals, controlling for both time-invariant and major potentially time-variant confounders. Results The cohort included 124,462 stroke patients, of whom 6,035 (5%) had at least one HZ diagnosis identified in GePaRD either as main hospital discharge diagnosis or as HZ treated with antivirals. The risk of stroke was about 1.3 times higher in the risk periods 3 months after HZ onset, than in the control periods (IRR: 1.29; 95% confidence interval: 1.16–1.44). An elevated risk of similar magnitude was observed for ischemic and unspecified stroke, but a 1.5-fold higher risk was observed for hemorrhagic stroke. A slightly stronger effect on the risk of stroke was also observed during the 3 months after HZ ophthalmicus (HZO) onset (1.59; 1.10–2.32). The risk was highest 3 and 4 weeks after HZ onset and decreased thereafter. Conclusions Our study corroborates an increased risk of stroke after HZ, which is highest 3 to 4 weeks after HZ onset. The results suggest that the risk is more pronounced after HZO and is numerically higher for hemorrhagic than for ischemic stroke.

Genistein and enterolactone in relation to Ki-67 expression and HER2 status in postmenopausal breast cancer patients

SCOPEnPhytoestrogens (PE) may improve breast cancer prognosis by modifying tumor prognostic markers, such as cell proliferation marker Ki-67 and human epidermal growth factor receptor 2 (HER2). Epidemiological evidence linking lignans and isoflavones to Ki-67 and HER2 is limited. We examined associations between the major metabolites of lignans and isoflavones - enterolactone (ENL) and genistein (GEN) - respectively, and Ki-67 expression and HER2 in tumor tissue of breast cancer patients.nnnMETHODS AND RESULTSnData from 1060 invasive breast cancer patients from the population-based MARIE study were used. Multivariate-adjusted linear (Ki-67 log-transformed) and quantile regression, and logistic regression analyses (HER2, Ki-67 dichotomized) were performed to calculate β estimates and ORs, respectively. Median post-diagnostic ENL and GEN concentrations were 19.5 and 4.8 nmol/L, respectively. Median Ki-67 was 12.0%, and 21.2% of the tumors were HER2+. After adjustment, there was an inverse association between GEN and Ki-67 at high expression levels (OR for Ki-67 ≥20% versus <20% of 0.93 (95%CI [0.87;0.99]) per 10 nmol/L GEN increment).nnnCONCLUSIONnOur findings indicate an inverse association between GEN and Ki-67 at high levels of Ki-67 expression. Additional investigations are recommended to confirm our findings and to further elucidate mechanisms linking PE metabolites to breast cancer survival.

Evaluation of vaccination herd immunity effects for anogenital warts in a low coverage setting with human papillomavirus vaccine—an interrupted time series analysis from 2005 to 2010 using health insurance data

BackgroundShortly after the human papillomavirus (HPV) vaccine recommendation and hence the reimbursement of vaccination costs for the respective age groups in Germany in 2007, changes in the incidence of anogenital warts (AGWs) were observed, but it was not clear at what level the incidence would stabilize and to what extent herd immunity would be present. Given the relatively low HPV vaccination coverage in Germany, we aimed to assess potential vaccination herd immunity effects in the German setting.MethodsA retrospective open cohort study with data from more than nine million statutory health insurance members from 2005 to 2010 was conducted. AGW cases were identified using ICD-10-codes. The incidence of AGWs was estimated by age, sex, and calendar quarter. Age and sex specific incidence rate ratios were estimated comparing the years 2009–2010 (post-vaccination period) with 2005–2007 (pre-vaccination period).ResultsIncidence rate ratio of AGWs for the post-vaccination period compared to the pre-vaccination period showed a u-shaped decrease among the 14- to 24-year-old females and males which corresponds well with the reported HPV vaccination uptake in 2008. A maximum reduction of up to 60% was observed for the 16- to 20-year-old females and slightly less pronounced (up to 50%) for the 16- and 18-year-old males. Age groups outside of the range 14–24xa0years demonstrated no decrease. The decrease of incidence occurred in both sexes early after the vaccine recommendation and stabilized at lower levels in 2009–2010.ConclusionsA relative reduction of up to 50% among males of approximately similar age groups as that of females receiving the HPV vaccination suggests herd protection resulting from assortative mixing by age. The early decrease among males can be reduced over time due to partner change.

Circulating enterolactone concentrations and prognosis of postmenopausal breast cancer: assessment of mediation by inflammatory markers: Enterolactone and breast cancer survival

Higher lignan exposure has been associated with lower all‐cause mortality (ACM) and breast cancer‐specific mortality (BCSM) for postmenopausal breast cancer patients. However, the biological mechanisms underpinning these associations are still unclear. We investigated for the first time whether and to what extent the association between enterolactone (ENL), the major lignan metabolite, and postmenopausal breast cancer prognosis is mediated by inflammatory biomarkers. Circulating concentrations of ENL and inflammatory markers were measured in a population‐based prospective cohort of 1,743 breast cancer patients recruited between 2002 and 2005 and followed‐up until 2009. Hazard ratios (HR) and 95% CIs were estimated using multivariable Cox regression. Mediation analysis was performed to estimate the percentage association between ENL (log2) and ACM, BCSM and distant disease‐free survival (DDFS), which is mediated by C‐reactive protein (CRP) (log2), as the strongest potential mediator, and also interleukin (IL)‐10. Median serum/plasma ENL and CRP concentrations for all patients, including 180 deceased patients, were 23.2 and 17.5 nmol/L, and 3.2 and 6.5 mg/l, respectively. ENL concentrations were significantly inversely associated with ACM, BCSM and DDFS (per doubling of ENL concentrations: HRs 0.93 [0.87, 0.99], 0.91 [0.84, 0.99] and 0.92 [0.87, 0.99]), after adjusting for prognostic factors and BMI. Estimated 18, 14 and 12% of the effects of ENL on ACM, BCSM and DDFS, respectively, were mediated through CRP. No mediational effect of IL‐10 was found. We provide first evidence that the proinflammatory marker CRP may partially mediate the association of ENL with postmenopausal breast cancer survival, which supports hormone‐independent mechanisms.

Non-Steroidal Anti-Inflammatory Drug Use and the Risk of Acute Myocardial Infarction in the General German Population: A Nested Case–Control Study

IntroductionUse of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with an increased relative risk of acute myocardial infarction (AMI), but the label warnings refer particularly to patients with cardiovascular risk factors. The magnitude of relative AMI risk for patients with and without cardiovascular risk factors varies between studies depending on the drugs and doses studied.ObjectivesThe aim of our study was to estimate population-based relative AMI risks for individual and widely used NSAIDs, for a cumulative amount of NSAID use, and for patients with and without a prior history of cardiovascular risk factors.MethodsBased on data from the German Pharmacoepidemiological Research Database (GePaRD) of about 17 million insurance members from four statutory health insurance providers, for the years 2004–2009, a nested case–control study was conducted within a cohort of 3,476,931 new NSAID users classified into current, recent, or past users. Up to 100 controls were matched to each case by age, sex, and length of follow-up using risk set sampling. Multivariable conditional logistic regression was applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Duration of NSAID use was calculated by the cumulative amount of dispensed defined daily doses (DDDs), and stratified analyses were conducted for potential effect modifiers.ResultsOverall, 17,236 AMI cases were matched to 1,714,006 controls. Elevated relative AMI risks were seen for current users of fixed combinations of diclofenac with misoprostol (OR 1.76, 95% CI 1.26–2.45), indometacin (1.69, 1.22–2.35), ibuprofen (1.54, 1.43–1.65), etoricoxib (1.52, 1.24–1.87), and diclofenac (1.43, 1.34–1.52) compared with past use. A low cumulative NSAID amount was associated with a higher relative AMI risk for ibuprofen, diclofenac, and indometacin. The relative risk associated with current use of diclofenac, fixed combinations of diclofenac with misoprostol, etoricoxib, and ibuprofen was highest in the younger age group (<60xa0years) and similar for patients with or without major cardiovascular risk factors.ConclusionRelative AMI risk estimates differed among the 15 investigated individual NSAIDs. Diclofenac and ibuprofen, the most frequently used NSAIDs, were associated with a 40–50% increased relative risk of AMI, even for low cumulative NSAID amounts. The relative AMI risk in patients with and without cardiovascular risk factors was similarly elevated.

Associations between adjuvant radiotherapy and different causes of death in a German breast cancer cohort

BACKGROUNDnStudies of cohorts of breast cancer (BC) patients diagnosed before 1990 showed radiotherapy (RT) to be associated with increased cardiovascular (CVD) and lung cancer mortality many years after diagnosis. In the late 1990s, improvements in RT planning techniques reduced radiation doses to normal tissues. Recent studies did not consistently report higher RT-related mortality for CVD and second cancers. Aim of the study was to analyze specific causes of death after 3D-conformal RT in a recent BC cohort.nnnMETHODSnStage I-III BC patients diagnosed 2001-2005 and enrolled in the population based MARIEplus study were followed-up for 11.9 years (median). Associations between adjuvant RT and cause-specific mortality were analyzed by using competing risks models, yielding subdistribution hazard ratios (SHR) for RT directly related to cumulative incidences. Models were adjusted for differences in baseline characteristics applying inverse-probability-of-treatment-weighting (IPTW).nnnRESULTSnOf the 2951 patients, 2439 (83.0%) received RT. No significant association of RT with lung cancer mortality (SHRIPTW 0.88, 0.35-2.12), other cancer mortality (SHRIPTW 1.04, 95% CI 0.62-1.73) or cardiac mortality was observed (SHRIPTW 1.57, 0.75-3.29). Mortality from lung and other diseases were significantly lower in irradiated women (SHRIPTW 0.39, 95% CI 0.17-0.90 and SHRIPTW 0.58, 95% CI 0.34-0.97, respectively).nnnCONCLUSIONnIn line with recent studies, 3D-conformal RT did not significantly increase mortality from non-BC causes in the German MARIEplus cohort. Since long-term data are still sparse and event rates low in BC-cohorts, who received modern RT, investigation of possible late RT effects on mortality beyond 14 years of follow-up is warranted.

Prognostic impact of surgery for early-stage invasive breast cancer on breast cancer-specific survival, overall survival, and recurrence risk: a population-based analysis

PurposeRecent cohort studies demonstrated better overall survival (OS) or breast cancer-specific survival (BCS) for breast-conserving therapy (BCT) followed by radiation (RT) compared to mastectomy alone (MT). This is the first observational study in which adjustments for a comprehensive set of prognostic factors, adjuvant therapies, mode of detection, and comorbidities were possible to investigate OS, BCS, as well as recurrence risk of patients undergoing BCTu2009+u2009RT, MTu2009+u2009RT, or MT.MethodsWomen aged 50–74xa0years at diagnosis of early-stage invasive breast cancer (I–IIIa) between 2001 and 2005 at the German population-based case–control study (MARIE study) were recruited and followed prospectively as a case cohort until 2015. Kaplan–Meier estimates and stepwise adjusted multivariable Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI).ResultsThe 2762 patients included were followed up for a median of 11.9xa0years (95% CI 11.8–12.0). 74.2% of patients underwent BCTu2009+u2009RT; 10.3% MTu2009+u2009RT and 15.6% MT alone. Compared to patients treated with MT alone, patients treated with BCTu2009+u2009RT showed non-statistically significant improved OS (HR 0.79, 95% CI 0.61–1.02), BCS (HR 0.79, 95% CI 0.55–1.12), and no difference in recurrence risks (HR 1.01, 95% CI 0.74–1.37). For patients treated with MTu2009+u2009RT, there were no differences in OS (HR 1.06, 95% CI 0.75–1.50), BCS (HR 1.17, 95% CI 0.75–1.82), or recurrence risk (HR 1.33, 95% CI 0.89–1.97).ConclusionsAmong patients with early-stage breast cancer, clinical outcomes more than 10xa0years after diagnosis did not differ between the primary treatment options BCTu2009+u2009RT, MTu2009+u2009RT versus MT alone after full adjustment.

Validation of inflammatory genetic variants associated with long-term cancer related fatigue in a large breast cancer cohort

BACKGROUNDnStudies to date have reported several associations between single nucleotide polymorphisms (SNPs) and cancer related fatigue (CRF), but have been limited by small sample sizes, missing adjustment for relevant covariates or multiple testing, as well as varying CRF definitions, i.e. time and method of assessment. This study aimed to validate previously reported associations using the largest independent breast cancer sample to date and to evaluate further functional cytokine variants in relation to total CRF and all relevant CRF subdomains (physical, cognitive, and affective CRF).nnnMETHODn45 candidate SNPs in inflammatory pathway genes were selected based on previous reports (16 SNPs) or regulatory function (29 SNPs). Breast cancer patients recruited between 2002 and 2005 provided information on CRF at first follow-up (FU1) (Nu202f=u202f1389) and second follow-up (FU2) (Nu202f=u202f950), a median of 6.2u202fyears and 11.7u202fyears respectively after diagnosis. SNP associations were assessed using linear regression models on CRF scores separately for FU1 and FU2. Additionally, patients with persistent fatigue (fatigued at both time-points) were compared to those never fatigued using logistic regression models (Nu202f=u202f684). All analyses were adjusted for relevant covariates. Secondary analyses were conducted for CRF subdomains.nnnRESULTSnFor total CRF none of the previously reported associations were confirmed after correction for multiple testing. The p-value distribution of all SNPs was not different than the one expected by chance. Analyses of CRF subdomains yielded a significant association between TNF-α rs3093662 and persistent physical CRF (Odds Ratio (OR)u202f=u202f3.23, 95% Confidence Interval (CI)u202f=u202f1.71-6.10, pu202f=u202f0.0003).nnnCONCLUSIONnWe were unable to confirm previously reported findings, suggesting that individual SNPs are unlikely to be of clinical utility. Further investigations in well powered studies are warranted, which consider genetic heterogeneity according to subdomains of CRF.