Migraine or any headaches and white matter hyperintensities and their progression in women and men.

BACKGROUND: Cross-sectional and longitudinal studies have been conducted to investigate the association between migraine and any headache and white matter hyperintensities (WMH). However, studies are inconsistent regarding the strength of the association and its clinical significance. The aim of our study was to investigate the association between headache and its subtypes (migraine with aura (MigA+), migraine without aura (MigA-), non-migraine headache (nonMigHA)) and WMH and its course in the population-based 1000BRAINS study using state-of-the-art imaging techniques and migraine classification according to modified international classification of headache disorders. METHODS: Data from 1062 participants (45% women, 60.9 ± 13.0 years) with ever or never headache (neverHA) and complete quantitative (WMH volume) and qualitative (Fazekas classification) WMH data at first imaging and after 3.7 ± 0.7 years (393 participants) were analyzed. The sex-specific association between headache and its subtypes and WMH volume and its change was evaluated by linear regression, between headache and its subtypes and Fazekas score high vs. low (2-3 vs. 0-1) by log-binomial regression, adjusted for confounders. RESULTS: The lifetime prevalence of headache was 77.5% (10.5% MigA+, 26.9% MigA-, 40.1% nonMigHA). The median WMH volume was 4005 (IQR: 2454-6880) mm3 in women and 4812 (2842-8445) mm3 in men. Women with any headaches (all headache types combined) had a 1.23 [1.04; 1.45]-fold higher WMH volume than women who reported never having had a headache. There was no indication of higher Fazekas grading or more WMH progression in women with migraine or any headaches. Men with migraine or any headaches did not have more WMH or WMH progression compared to men without migraine or men who never had headache. CONCLUSIONS: Our study demonstrated no increased occurrence or progression of WMH in participants with mgiraine. But, our results provide some evidence of greater WMH volume in women with headache of any type including migraine. The underlying pathomechanisms and the reasons why this was not shown in men are unclear and require further research.

Associations of metabolically healthy obesity with prevalence and progression of coronary artery calcification: Results from the Heinz Nixdorf Recall Cohort Study.

BACKGROUND AND AIMS: There is controversy on the potentially benign nature of metabolically healthy obesity (MHO), i.e., obese persons with few or no metabolic abnormalities. So far, associations between MHO and coronary artery calcification (CAC), a measure of subclinical atherosclerosis, have mainly been studied cross-sectionally in Asian populations. We assessed cross-sectional and longitudinal MHO CAC associations in a Caucasian population. METHODS AND RESULTS: In the Heinz Nixdorf Recall Study, a population-based cohort study in Germany, CAC was assessed by electron-beam tomography at baseline and at 5-year follow-up. For cross-sectional and longitudinal analyses, we included 1585 participants free of coronary heart disease at baseline, with CAC measurements at baseline and at follow-up, and with either normal weight (BMI 18.5-24.9 kg/m2) or obesity (BMI ≥30.0 kg/m2) at baseline. We used four definitions of MHO. In our main analysis, we defined obese persons as metabolically healthy if they met ≤1 of the NCEP ATP III criteria for the definition of the metabolic syndrome - waist circumference was not taken into account because of collinearity with BMI. Persons with MHO had a higher prevalence of CAC than metabolically healthy normal weight (MHNW) persons (prevalence ratio = 1.59 (95% confidence interval 1.38-1.84) for the main analysis). Persons with MHO had slightly larger odds of CAC progression than persons with MHNW (odds ratios ranged from 1.17 (0.69-1.99) to 1.48 (1.02-2.13) depending on MHO definition and statistical approach). CONCLUSION: Our analyses on MHO CAC associations add to the evidence that MHO is not a purely benign health condition.

Incidence and mortality for cutaneous squamous cell carcinoma: comparison across three continents.

BACKGROUND: Population-based incidence and mortality studies of cutaneous squamous cell carcinoma (SCC) have been few owing to the commonness of the disease, and rare deaths making accurate mortality statistics difficult. OBJECTIVES: Our aim was to summarize SCC incidence and mortality in populations across three continents, exemplified by Australia, the United States (US) and Germany. METHODS: We estimated age-specific and age-standardized (Australian Standard 2001 Population) incidence and mortality rates per 100 000 person-years. RESULTS: Squamous cell carcinoma incidence is plateauing or falling in Australia, stable in the United States (2013-2015) and rising in Germany (2007-2015). Current incidence estimates in men and women are 341 and 209, 497 and 296, and 54 and 26, respectively, for the three countries. Incidence increases strongly with age in all countries. Mortality of non-melanoma skin cancer appears to be increasing in Germany and stable in Australia (unavailable for the US population). CONCLUSIONS: Squamous cell carcinoma is an important health issue, particularly among older men, with incidence exceeding most other cancers. More precise and uniform population-based studies of incidence and mortality are needed to better quantify the impact of SCC on healthcare systems worldwide and to gauge the effect of new treatments such as anti-PD1 therapy on mortality.

[Some Caveats in the Interpretation of Population Attributable Risks]. / Stolpersteine bei der Interpretation des populationsattributablen Risikos.

Population attributable risks (PARs) are often used in health sciences because they offer an apparently easy answer to the question as to the proportion of disease cases that could be prevented in a population if one or more risk factors were eliminated. We discuss some problems in the interpretation of PARs that result from the fact that diseases have more than one cause. Moreover, requirements are discussed which have to be met before PARs can give a realistic idea of the proportion of cases of illness that can be avoided.

[Public Health: Setting Goals, Establishing Structures and Improving Health for All]. / Public Health ­ mehr Gesundheit für alle.

Public health is a population- and system-based approach that is needed to improve the health of societies and to decrease health inequalities. In the face of global challenges, the public health approach is essential. In Germany, the importance of public health is only partly reflected by its institutions and institutional arrangements. This applies equally to research, teaching and training, as well as to the public health service. Furthermore, the public health perspective is not sufficiently considered in cross-sectional topics that are relevant for health.There have been several initiatives to overcome structural deficits which can partly be traced back to historical circumstances. The White Paper presented here should encourage discussions about future policy options in public health. The authors represent public health in practice, research, and teaching in Germany.

Single center experience of endoscopic submucosal dissection (ESD) in early Barrett's adenocarcinoma.

BACKGROUND: Endoscopic mucosal resection (EMR) or radical surgical resection are the standard treatment options for patients with early Barrett's adenocarcinoma (EBAC). Endoscopic submucosal dissection (ESD) is a new endoscopic technique, which allows--in contrast to EMR--endoscopic en-bloc resection of neoplastic lesions greater than 2 cm with complete histological evaluation of the resected specimen. In contrast to Western countries, Barrett's esophagus is less common in Asia indicating the low volume of published data of ESD in EBAC in Japanese series. Therefore, the aim of the present study is to describe the results of ESD in patients with EBAC performed in a German tertiary referral center. METHODS: Between November 2009 and April 2014 ESDs were performed in 22 patients with histologically proven EBAC. Data were given for the en-bloc, the R0, the R0 en-bloc, and the curative resection rate as well as for the complication and the local recurrence rate. RESULTS: ESD was technically possible in all of the 22 patients. 20 of the resected EBAC were mucosal carcinomas, whereas in two patients the tumor showed submucosal invasion. The en-bloc, R0, R0 en-bloc, and curative resection rates were 95.5, 81.8, 81.8 %, and 77.3 %, resp. Complication rate was 27.3 % (perforation n = 1, bleeding n = 2, stenosis n = 3). In case of curative tumor resection, only one local tumor recurrence (5.9 %) occurred after a medium follow-up of 1.6 years. CONCLUSIONS: Despite the small number of patients and a relatively short follow-up, the present data underline the value of ESD, especially in case of curative resections in the definite and less invasive therapy of EBAC. Attention should be drawn toward subsquamous extension of EBAC requiring a sufficient safety margin as an obligate condition for curative R0 resections. Due to the required learning curve and the management of potential complications, ESD should be restricted to greater endoscopic centers.

The role of phenotype, body mass index, parental and sun exposure factors in the prevalence of melanocytic nevi among schoolchildren in Lithuania.

BACKGROUND: The occurrence and number of melanocytic nevi (MN) are among the most important known risk factors for the development of cutaneous melanoma (CM). OBJECTIVES: To estimate the prevalence of MN among schoolchildren and its relationship with phenotype, body mass index (BMI), parental and sun exposure factors. METHODS: A cross-sectional study was conducted on N = 1277 schoolchildren aged 7-19 years old in Kaunas city, Lithuania. Subjects were interviewed using a self-administered questionnaire and were assessed by a dermatologist. MN of all sizes and ≥2 mm in diameter were counted; phenotypic features and skin phototype were defined. BMI and body surface area (BSA) were calculated. Whole-body MN counts were expressed both as totals and as counts per unit of BSA - MN density (MND). Biological parents completed questionnaires regarding nevus counts, family history of skin cancer and CM. RESULTS: The numbers of all sizes and ≥2 mm MN increased according to age, respectively, from median values of 44 (IQR 28, 60) and 5 (IQR 2, 8) at the age of 7-9 years to 85 (IQR 55, 128) and 16 (IQR 8, 30) at the age of 16-19 years. A higher MND was found in children with light skin colour (P < 0.001), I-II skin phototype (P < 0.001), extensive facial freckling (P < 0.005) and multiple nevi on the father's and mother's arms (P < 0.05). 20.2% of pupils were overweight or obese, 130 males and 118 females. Overweight and obese children had a higher all sizes MND (P = 0.033, P = 0.044). Acquired suntan at the end of summer was associated with a higher all sizes MND (P < 0.05), outdoor activities at midday - with a higher ≥2 mm MND (P = 0.047) respectively. CONCLUSIONS: The prevalence of MN among schoolchildren is age-dependent and strongly determined by skin colour, skin phototype, facial freckling and BMI. Parental nevus numbers, acquired suntan and outdoor activities at midday must be considered.

Breast cancer survival in Ethiopia: a cohort study of 1,070 women.

There is little information on breast cancer (BC) survival in Ethiopia and other parts of sub-Saharan Africa. Our study estimated cumulative probabilities of distant metastasis-free survival (MFS) in patients at Addis Ababa (AA) University Radiotherapy Center, the only public oncologic institution in Ethiopia. We analyzed 1,070 females with BC stage 1-3 seen in 2005-2010. Patients underwent regular follow-up; estrogen receptor-positive and -unknown patients received free endocrine treatment (an independent project funded by AstraZeneca Ltd. and facilitated by the Axios Foundation). The primary endpoint was distant metastasis. Sensitivity analysis (worst-case scenario) assumed that patients with incomplete follow-up had events 3 months after the last appointment. The median age was 43.0 (20-88) years. The median tumor size was 4.96 cm [standard deviation (SD) 2.81 cm; n = 709 information available]. Stages 1, 2 and 3 represented 4, 25 and 71%, respectively (n = 644). Ductal carcinoma predominated (79.2%, n = 1,070) as well as grade 2 tumors (57%, n = 509). Median follow-up was 23.1 (0-65.6) months, during which 285 women developed metastases. MFS after 2 years was 74% (69-79%), declining to 59% (53-64%) in the worst-case scenario. Patients with early stage (1-2) showed better MFS than patients with stage 3 (85 and 66%, respectively). The 5-year MFS was 72% for stages 1 and 2 and 33% for stage 3. We present a first overview on MFS in a large cohort of female BC patients (1,070 patients) from sub-Saharan Africa. Young age and advanced stage were associated with poor outcome.

The prevalence and risk factors of adolescent acne among schoolchildren in Lithuania: a cross-sectional study.

BACKGROUND: Acne is one of the most common chronic inflammatory dermatological diseases among adolescents. OBJECTIVES: We sought to estimate the prevalence of acne among schoolchildren and its association with puberty, body mass index (BMI), acne history of parents, nutritional habits, smoking and alcohol consumption. METHODS: A cross-sectional study was conducted on 1277 pupils aged 7-19 years. Children were interviewed with self-administered questionnaires, and were subsequently examined by one specially trained dermatologist. To evaluate the onset of puberty, girls provided details about their menarche and boys--about their facial hair growth. RESULTS: The overall response rate of the study was 51.4%. The prevalence of acne among respondents was 82.9%, and was strongly age-dependent with highest rates in the age groups of 13-15 and 16-19 years. The prevalence of pre-pubertal acne among participating girls and boys was 69.9% and 73.6% respectively. The main risk factors of acne were facial hair growth in boys (OR = 4.9), menarche in girls (OR = 3.1), overweight/obesity (BMI ≥ 25 kg/m(2) at 18 years of age) (OR = 2.6), acne history from both parents (OR = 2.6) and from mother alone (OR = 2.1). We did not find any associations between acne and nutritional habits, smoking or alcohol consumption. The self-reported prevalence of acne among children who refused to take part in the study was lower than that among participants of the study. CONCLUSIONS: The overall prevalence of acne among schoolchildren is high and age-dependent. The onset of puberty, overweight/obesity and history of acne from both parents are the top risk factors for acne.

[Single centre experience of endoscopic submucosal dissection (ESD) in premalignant and malignant gastrointestinal neoplasia]. / Single-Center-Erfahrung mit der Endoskopischen Submukosa-Dissektion (ESD) bei prämalignen und malignen gastrointestinalen Neoplasien.

INTRODUCTION: Worldwide endoscopic submucosal dissection (ESD) of early GI cancers or premalignant neoplasia is becoming increasingly important. In Germany ESD is restricted to larger endoscopic institutions and only a few literature reports are available. The aim of the present study is to describe the results of 46 ESDs conducted in a German endoscopic centre. MATERIAL AND METHODS: Between June 2007 and May 2012 46 ESDs in 45 patients (33 men, 12 women, mean age 66.1 years) were performed in the oesophagus (n = 17), stomach (n = 23) and rectum (n = 6). Data were collected for the en-bloc, R0 and R0 en-bloc resection rates as well as for complications, the curative resection and the local recurrence rates. In order to demonstrate a learning curve, results were evaluated for two periods (June 2007 to November 2010 vs. December 2010 to May 2012). RESULTS: ESD was technically possible in 93.5%. En-bloc, R0, R0 en-bloc and curative resection rates were 90.7%, 74.4%, 67.4% and 65.1%, respectively. The complication rate was 13%. In the second period en-bloc and R0 en-bloc resection rates increased from 81% to 100% and, respectively, from 52.4% to 81.8%. After a medium follow-up of 11.4 months, local tumour recurrence occurred in 10%. In cases of curative R0 en bloc resection of malignant tumours no tumour recurrence occurred. DISCUSSION: Despite the small number of patients, the present data underline the value of ESD, especially in cases of R0 en-bloc resections in the therapy for premalignant and early malignant GI tumours. Due to the required learning curve, ESD should be restricted to larger endoscopic centres in Germany.

Gonadal and extragonadal germ cell tumours in the United States, 1973-2007.

Germ cell tumours (GCTs) most often arise in the gonads, but some develop extragonadally. The aim of this study was to examine gender- and race-specific trends in incidence and survival of gonadal (GGCTs) and extragonadal GCTs (EGCTs) in the US from 1973 to 2007. We also examined the topographical distribution of EGCTs by race and gender. We estimated age-specific and age-standardized incidence rates and 5-year relative survival rates (RSR) of GCTs using the Surveillance, Epidemiology and End Results (SEER) Program (SEER nine registries). GCTs and their topographical sites were identified using ICD-O morphology and topography codes. Of 21,170 GCTs among males, 5.7% were extragonadal (Whites 5.5%; Blacks 16.3%). Of 2093 GCTs among females, 39.3% were extragonadal (Whites, 36.9%; Blacks 51.0%). The incidence of GGCT was much higher among White (56.3/1,000,000) than Black males (10.0/1,000,000), while there was no difference in incidence between White and Black females (3.2/1,000,000). The rates of EGCT among men and women of both races were similar (range:1.9-3.4/1,000,000). The most frequent extragonadal sites were mediastinum among males and placenta among females. The 5-year RSR of testicular GCT was higher among Whites (97%) than Blacks (90%), as was the 5-year RSR of ovarian GCT (Whites, 92%; Blacks 85%). In general, the 5-year RSRs of EGCTs were lower than the 5-year RSRs of GGCTs. The different incidence trends of GGCTs and EGCTs and distinct age-specific incidence patterns by anatomical site of EGCTs suggest that GGCTs and EGCTs may have different aetiologies.

Prognostic and predictive value of CA 19-9 in locally advanced pancreatic cancer treated with multiagent induction chemotherapy: results from a prospective, multicenter phase II trial (NEOLAP-AIO-PAK-0113).

BACKGROUND: The prognostic and predictive value of carbohydrate antigen 19-9 (CA 19-9) in locally advanced pancreatic cancer (LAPC) has not yet been defined from prospective randomized controlled trials (RCTs). PATIENTS AND METHODS: A total of 165 LAPC patients were treated within the NEOLAP RCT for 16 weeks with multiagent induction chemotherapy [ICT; either nab-paclitaxel/gemcitabine alone or nab-paclitaxel/gemcitabine followed by FOLFIRINOX (combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin)] followed by surgical exploration of all patients without evidence of disease progression. CA 19-9 was determined at baseline and after ICT and correlated with overall survival (OS) and secondary R0 resection rate. RESULTS: From the NEOLAP study population (N = 165) 133 patients (81%) were evaluable for CA 19-9 at baseline and 81/88 patients (92%) for post-ICT CA 19-9 response. Median OS (mOS) in the CA 19-9 cohort (n = 133) was 16.2 months [95% confidence interval (CI) 13.0-19.4] and R0 resection (n = 31; 23%) was associated with a significant survival benefit [40.8 months (95% CI 21.7-59.8)], while R1 resected patients (n = 14; 11%) had no survival benefit [14.0 (95% CI 11.7-16.3) months, hazard ratio (HR) 0.27; P = 0.001]. After ICT most patients showed a CA 19-9 response (median change from baseline: -82%; relative decrease ≥55%: 83%; absolute decrease to ≤50 U/ml: 43%). Robust CA 19-9 response (decrease to ≤50U/ml) was significantly associated with mOS [27.8 (95% CI 18.4-37.2) versus 16.5 (95% CI 11.7-21.2) months, HR 0.49; P = 0.013], whereas CA 19-9 baseline levels were not prognostic for OS. Multivariate analysis demonstrated that a robust CA 19-9 response was an independent predictive factor for R0 resection. Using a CA 19-9 decrease to ≤61 U/ml as optimal cut-off (by receiver operating characteristic analysis) yielded 72% sensitivity and 62% specificity for successful R0 resection, whereas CA 19-9 nonresponders (<20% decrease or increase) had no chance for successful R0 resection. CONCLUSIONS: CA 19-9 response after multiagent ICT provides relevant prognostic and predictive information and is useful in selecting LAPC patients for explorative surgery. CLINICAL TRIAL NUMBER: ClinicalTrials.govNCT02125136; https://clinicaltrials.gov/ct2/show/NCT02125136; EudraCT 2013-004796-12; https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004796-12/results.

Impact of classification of mixed germ-cell tumours on incidence trends of non-seminoma.

Seminomas and non-seminomas [embryonal carcinomas, yolk sac tumours, teratomas, choriocarcinomas, mixed germ-cell tumours (MGCT)] are the major histological types of testicular germ-cell tumours (TGCT). TGCTs composed of both seminomatous and non-seminomatous elements have been coded as their non-seminoma component in the World Health Organization classification. In the late 1980s, a provisional International Classification of Diseases for Oncology (ICD-O) morphology code for MGCT was introduced. Using data from the Surveillance, Epidemiology and End Results Program and two population-based German cancer registries, we examined the impact of MGCT classification on TGCT trends. Cases were identified using ICD-O topography (ICD-9: 186; ICD-10: C62) and morphology codes (seminoma=9060-9062, 9064; embryonal carcinoma=9070; yolk sack tumour=9071; teratoma=9080-9084, 9102; choriocarcinoma=9100, 9101; MGCT=9085; all non-seminoma=9065-9102). As MGCTs and teratoma are often grouped as a single histological group, we analysed teratoma both including and excluding MGCTs. Between 1988 and 2007, incidence rates of MGCT in the US increased 407%. Rates of teratoma including MGCT increased 80%, whereas rates of teratoma excluding MGCT decreased 71%. Rates of embryonal carcinoma [-40%] and choriocarcinoma [-22%] also declined, suggesting that the code for MGCT is now being used for any mixed histology. Similar declines in incidence were observed in the German comparison populations. The declines in incidence of teratoma (excluding MGCT), embryonal carcinoma and choriocarcinoma in the US data since 1988 are likely in part because of increases in classifying any TGCT with mixed histology as MGCT. These results suggest that analysis of trends in specific histological types of non-seminoma should be interpreted cautiously.

Micrographic surgery of skin cancer in German hospitals 2005-2006.

BACKGROUND/OBJECTIVE: Surgical therapy of skin cancer includes conventional wide excision and micrographic surgery (MS). Little is known about the population-wide spread of MS for the treatment of skin cancer. The aim was to estimate the in-hospital use of MS for the treatment of skin cancer in Germany. METHODS: We used nationwide DRG data from 2005 through 2006. We identified hospitalizations with a main diagnosis of cutaneous malignant melanoma (CMM) (ICD-10: C43) or non-melanoma skin cancer (NMSC) (ICD-10: C44). MS was identified by OPS procedure codes including 5-895.1, 5-895.3, 5-212.1, 5-181.1, 5-181.4, 5-181.6, 5-182.1, 5-091.1, or 5-091.3. RESULTS: We identified 52 660 and 98 484 hospitalizations with a primary diagnosis of CMM and NMSC respectively; 54.6% and 36.5% of NMSC and CMM-related admissions with local skin cancer treatment included MS. The relative frequency of MS varied by anatomic subsite of the skin cancer and by region of the hospital. Local infections were the most frequent complications after MS with 3.2-4.0% for NMSC and 2.3-2.9% for CMM followed by haemorrhages. Dehiscence of the operation wound is a rare event with risks ranging between 0.1% and 0.3%. CONCLUSIONS: Micrographic surgery is frequently used for the local treatment of NMSC and varies considerably across Federal States of Germany. It is difficult to speculate how many MS might be performed in private or ambulatory settings in Germany. As MS requires surgical expertise, technical support and dermatopathology, we speculate that MS is much less frequently undertaken in private practices in Germany.

Incidentally detected splenic lesions in ultrasound: does contrast-enhanced ultrasonography improve the differentiation of benign hemangioma/hamartoma from malignant lesions?

PURPOSE: The aim of the study was to identify and validate enhancing features for differentiating benign vascular neoplasms of the hemangioma/hamartoma type from malignant splenic lesions on contrast-enhanced ultrasonography (CEUS). MATERIALS AND METHODS: 136 splenic lesions (58 benign vascular neoplasms, 78 malignant) in 136 patients underwent baseline US and pulse-inversion CEUS after sulfur hexafluoride-filled microbubble injection. Two on-site readers assessed lesion enhancement features during arterial and parenchymal phase in consensus. Best predicting CEUS features for lesion diagnosis were identified through univariate and multivariate analyses. Two blinded off-site readers independently issued a confidence rating for lesion diagnosis in baseline US and CEUS using extracted diagnostic CEUS features. Diagnostic performance, receiver operating curves (Az-value), and interreader agreement were calculated. The reference standards were histopathology or CT and/or MR imaging with clinical follow-up.  RESULTS: Multivariate analysis outlined arterial hyperenhancement or isoenhancement to be an independent CEUS predictor of benign vascular neoplasms (odds ratio, 3.558; p < 0.0017). Within the subgroup of isoechoic or hypoechoic lesions, arterial hyperenhancement was virtually diagnostic for benign vascular neoplasm (odds ratio, 21.333; p < 0.001). The diagnostic accuracy and confidence (Az-value) of the two readers was 63.2 % and 70.6 % (0.785 and 0.818) for baseline US, which improved significantly to 87.5 % and 88.2 % (0.915 and 0.908) for CEUS (p < 0.001). Interreader agreement also increased with CEUS (қ = 0.88) compared to baseline US (қ = 0.52). CONCLUSION: Sulfur hexafluoride-enhanced CEUS improves differentiation between benign vascular and malignant splenic tumors and may be especially useful in clinical scenarios in which the incidental hypoechoic splenic lesion is unclear on conventional US.

[Causality and confounding in epidemiology]. / Kausalität und Confounding in der Epidemiologie.

In theory, a cause of an effect in an individual and a group can be defined. However, in empirical studies the requirements of this definition cannot be fulfilled with certainty: an individual or a group of people cannot be exposed and unexposed at the same point in time. Therefore, substitute populations are used to answer what the risk of an outcome would have been, if the actually exposed group would not have been exposed (or vice versa). If the substitute population is not able to deliver this information, confounding is present according to the counterfactual definition. The so-called collapsibility definition of confounders suffers from five limitations and therefore does not appear to be acceptable. The classical theory of confounders is a special case of directed acyclic graphs (DAGs), where only one extraneous variable might be a potential confounder. In contrast to previous theories on confounding, DAGs are able to show when adjustment for covariates produces bias. Furthermore, DAGs are able to use also information on relations among confounders.

[Directed acyclic graphs (DAGs) - the application of causal diagrams in epidemiology]. / Directed Acyclic Graphs (DAGs) - Die Anwendung kausaler Graphen in der Epidemiologie.

Causal graphs such as directed acyclic graphs (DAGs) are a novel approach in epidemiology to conceptualize confounding and other sources of bias. DAGs visually encode the causal relations based on a priori knowledge among the exposure of interest and the outcome while considering several covariates. The application of formal rules on these diagrams enables the identification of the causal and non-causal structures in the DAG. The causal effects are of interest and require no adjustment. Whereas the non-causal effects have to be checked for confounding and for which covariates adjustment is necessary. The identification of the adjustment set depends on the causal relations among the variables. The consideration of these relations is valuable because adjusting for more variables increases the risk of introducing bias. Considering every single path of a DAG allows the systematic identification of the causal structures in the DAG, and the determination of minimally sufficient adjustment sets for estimating the causal effect of the exposure on the outcome based on the underlying DAG. The aim of this paper is to provide an introduction to the basic assumptions as well as the steps for drawing and applying a DAG.

Automated analysis of DNA damage in the high-throughput version of the comet assay.

Recently a high-throughput version of the comet assay was developed using a special 96-well multichamber plate (MCP) [1]. In this version, the electrophoresis is performed directly on the MCP, which makes transferring of cells to microscope slides unnecessary. In order to facilitate the scoring procedure we adapted an automated slide-scanning system (Metafer MetaCyte with CometScan) to enable unattended analysis of comets on the MCP. The results of the system were compared with the data obtained with two interactive comet-assay analysis systems. For induction of DNA damage in human fibroblasts methylmethane sulfonate (MMS) or H2O2 was used. The three systems revealed similar, concentration-dependent results for all parameters tested: tail moment (tm), % DNA-in-tail and olive tail moment. Near the detection limit of 5-6% DNA-in-tail a significant difference with the untreated control was obtained by use of four parallel samples (p=0.01). With the newly developed automated analysis system, the evaluation of either 50 or 100 comets yielded similar standard errors for either treatment with MMS or H2O2, thus showing that the method is suitable to reveal the crucial low-dose effects with high precision. The results also show that the time needed for automated evaluation of comets on the MCP was reduced by a factor of 10 when compared with the time required for interactive evaluation. In summary, the high-throughput version of the comet assay combined with the automated evaluating system increased the output by a factor up to 180 compared with the standard method.

[Harmless: fact or fiction?]. / "Gesundheitlich unbedenklich": Fakt oder Fiktion?

The aim of this article is to critically discuss what conclusions can be drawn about health risks or innocuousness of exposures from an epistemiological point of view. For the interpretation of the epidemiological evidence of health risks, several assumptions have to be met--some of them cannot be empirically checked. Replication of study findings does not necessarily imply causation. However, it is possible to falsify hypotheses based on emipirical studies. This falsification principle can also be used for the interpretation of a single study. If we are able to falsify all non-causal hypotheses, the causal hypothesis is the only hypothesis that has survived and therefore should be taken seriously. Regardless of the number and kind of empirical studies, we cannot logically prove that an exposure has a harmful effect or not. Therefore, a hypothesis that could not be falsified until now should be used for political or other decisions even if there is a chance that this hypothesis will be falsified in the future when based on more appropriate trials of falsification.

Unresectable Hepatic Metastasis of Uveal Melanoma: Hepatic Chemosaturation with High-Dose Melphalan-Long-Term Overall Survival Negatively Correlates with Tumor Burden.

INTRODUCTION: Percutaneous hepatic perfusion with melphalan (PHP-M) for hepatic metastasis of uveal melanoma (LMUM) achieves high local response rates, but the individual clinical benefit is poorly defined. We aimed to determine cofactors of response and clinical outcomes including the probability of long-term (5-years) overall survival (OS) in PHP-M-treated patients with LMUM. Patients and Methods. We retrospectively reviewed clinicopathological, radiological, and outcome data of 19 patients with unresectable LMUM treated with 43 PHP-M (median 2 PHP-M) between 2014 and 2019. Tumor response and adverse events were evaluated using RECIST 1.1 and the Clavien-Dindo classification. Kaplan-Meier methods and Cox regression hazard proportional models were used. RESULTS: Of 19 patients, 10 (53%) achieved a partial response (PR) and 9 (47%) had stable disease (SD). There was no progressive disease (PD) and no adverse events exceeding Clavien-Dindo grade IV. Median OS was 16.7 months after the first PHP-M treatment and 26.4 months after initial diagnosis. Low hepatic tumor volume (median of 10 mL vs. 150 mL) was an independent predictor of favorable OS (hazard ratio (95% confidence interval): 0.190 (0.041, 0.893); p < 0.05), and female patients were at a lower risk compared with males (0.146 (0.017, 1.240)). Estimates of the overall survival were 0.213 (0.0449, 1) from first imaging (95% confidence interval) to 5 years and 0.793 (0.609, 1) and 0.604 (0.380, 0.960) for 1 and 2 years after chemosaturation, respectively. Discussion. PHP-M for nonresectable LMUV provides a safe and locally efficient liver-directed procedure that offers patients a chance for long-term OS, especially for patients with a low hepatic tumor burden.