Subsequent primary neoplasms after childhood cancer therapy - design and description of the German nested case-control study STATT-SCAR.

BACKGROUND: Subsequent primary neoplasms (SPN) are among the most severe late effects and the second most frequent cause of death in childhood cancer patients. In this paper we introduce method and properties of the STATT-SCAR study (Second Tumor After Tumor Therapy, Second Cancer After Radiotherapy), which is a joint nested matched case-control study to evaluate the impact of chemotherapy (STATT) as well as radiotherapy (SCAR) on the risk of developing a SPN. METHODS: Based on the cohort of the German childhood cancer registry (GCCR), we selected patients diagnosed with a first neoplasm before age 15 or younger between 1980 and 2014. We selected those with a SPN at least half a year after the first neoplasm, and matched up to four controls to each case. Therapy data were acquired from various sources, including clinical study centers and treating hospitals. To analyze the impact of radiotherapy, organ doses were estimated by using reconstructed treatment plans. The effect of chemotherapy was analyzed using substance groups summarized after isotoxic dose conversion. RESULTS: 1244 cases with a SPN were identified and matched with 4976 controls. Treatment data were acquired for 83% of all match groups (one case and at least one control). Based on preliminary analyses, 98% of all patients received chemotherapy and 54% of all patients were treated with radiotherapy. CONCLUSIONS: Based on our data, detailed analyses of dose response relationships and treatment element combinations are possible, leading to a deeper insight into SPN risks after cancer treatments. TRIAL REGISTRATION: The study is registered at the German clinical trial register (DRKS) under number DRKS00017847 [45].

Brain cancer after radiation exposure from CT examinations of children and young adults: results from the EPI-CT cohort study.

BACKGROUND: The European EPI-CT study aims to quantify cancer risks from CT examinations of children and young adults. Here, we assess the risk of brain cancer. METHODS: We pooled data from nine European countries for this cohort study. Eligible participants had at least one CT examination before age 22 years documented between 1977 and 2014, had no previous diagnosis of cancer or benign brain tumour, and were alive and cancer-free at least 5 years after the first CT. Participants were identified through the Radiology Information System in 276 hospitals. Participants were linked with national or regional registries of cancer and vital status, and eligible cases were patients with brain cancers according to WHO International Classification of Diseases for Oncology. Gliomas were analysed separately to all brain cancers. Organ doses were reconstructed using historical machine settings and a large sample of CT images. Excess relative risks (ERRs) of brain cancer per 100 mGy of cumulative brain dose were calculated with linear dose-response modelling. The outcome was the first reported diagnosis of brain cancer after an exclusion period of 5 years after the first electronically recorded CT examination. FINDINGS: We identified 948 174 individuals, of whom 658 752 (69%) were eligible for our study. 368 721 (56%) of 658 752 participants were male and 290 031 (44%) were female. During a median follow-up of 5·6 years (IQR 2·4-10·1), 165 brain cancers occurred, including 121 (73%) gliomas. Mean cumulative brain dose, lagged by 5 years, was 47·4 mGy (SD 60·9) among all individuals and 76·0 mGy (100·1) among people with brain cancer. A significant linear dose-response relationship was observed for all brain cancers (ERR per 100 mGy 1·27 [95% CI 0·51-2·69]) and for gliomas separately (ERR per 100 mGy 1·11 [0·36-2·59]). Results were robust when the start of follow-up was delayed beyond 5 years and when participants with possibly previously unreported cancers were excluded. INTERPRETATION: The observed significant dose-response relationship between CT-related radiation exposure and brain cancer in this large, multicentre study with individual dose evaluation emphasises careful justification of paediatric CTs and use of doses as low as reasonably possible. FUNDING: EU FP7; Belgian Cancer Registry; La Ligue contre le Cancer, L'Institut National du Cancer, France; Ministry of Health, Labour and Welfare of Japan; German Federal Ministry of Education and Research; Worldwide Cancer Research; Dutch Cancer Society; Research Council of Norway; Consejo de Seguridad Nuclear, Generalitat de Catalunya, Spain; US National Cancer Institute; UK National Institute for Health Research; Public Health England.

Incidence of childhood leukemia before and after shut down of nuclear power plants in Germany in 2011: A population-based register study during 2004 to 2019.

The association between leukemia and proximity to nuclear-power-plants (NPPs) has been assessed in several countries with inconsistent results. A case-control study from Germany had shown an increased risk for childhood leukemia (diagnoses 1980-2003) near NPPs. Germany began shutting down nuclear reactors in 2011, following the Fukushima disaster. We tested whether the previously observed association between leukemia and proximity to NPP persisted despite the shutdown. We used an ecological study design to investigate the incidence of leukemia during 2004 to 2019 in children aged 0 to 14 years living near NPPs where at least one reactor was shut down in 2011. We defined study and control areas as municipalities whose surface area was at least 75% within 10 km or between 10 and 50 km of NPPs, respectively. We calculated age-standardized rates and incidence rate ratios (IRR) using control-areas as the reference. We also computed standardized incidence ratios (SIR) separately for each NPP using incidence rates of the German population as a reference. IRR decreased from 1.20 (95% confidence interval: 0.81-1.77) in 2004 to 2011 to 1.12 (0.75-1.68) in 2012 to 2019. Analyses of single plants showed an excess of childhood leukemia during 2004 to 2019 for the Unterweser-NPP, based only on three cases, and the Krümmel-NPP (n = 14; SIR: 1.98, 1.17-3.35). We found slightly decreasing of leukemia incidence rate ratios after the shutdown of nuclear reactors in 2011. Due to the small number of cases, risk estimates have large uncertainty. Further research including a longer follow-up is warranted. The consistent excess of incidence cases around Krümmel may require analytical epidemiological analysis.

Gene expression variability in long-term survivors of childhood cancer and cancer-free controls in response to ionizing irradiation.

BACKGROUND: Differential expression analysis is usually adjusted for variation. However, most studies that examined the expression variability (EV) have used computations affected by low expression levels and did not examine healthy tissue. This study aims to calculate and characterize an unbiased EV in primary fibroblasts of childhood cancer survivors and cancer-free controls (N0) in response to ionizing radiation. METHODS: Human skin fibroblasts of 52 donors with a first primary neoplasm in childhood (N1), 52 donors with at least one second primary neoplasm (N2 +), as well as 52 N0 were obtained from the KiKme case-control study and exposed to a high (2 Gray) and a low dose (0.05 Gray) of X-rays and sham- irradiation (0 Gray). Genes were then classified as hypo-, non-, or hyper-variable per donor group and radiation treatment, and then examined for over-represented functional signatures. RESULTS: We found 22 genes with considerable EV differences between donor groups, of which 11 genes were associated with response to ionizing radiation, stress, and DNA repair. The largest number of genes exclusive to one donor group and variability classification combination were all detected in N0: hypo-variable genes after 0 Gray (n = 49), 0.05 Gray (n = 41), and 2 Gray (n = 38), as well as hyper-variable genes after any dose (n = 43). While after 2 Gray positive regulation of cell cycle was hypo-variable in N0, (regulation of) fibroblast proliferation was over-represented in hyper-variable genes of N1 and N2+. In N2+, 30 genes were uniquely classified as hyper-variable after the low dose and were associated with the ERK1/ERK2 cascade. For N1, no exclusive gene sets with functions related to the radiation response were detected in our data. CONCLUSION: N2+ showed high degrees of variability in pathways for the cell fate decision after genotoxic insults that may lead to the transfer and multiplication of DNA-damage via proliferation, where apoptosis and removal of the damaged genome would have been appropriate. Such a deficiency could potentially lead to a higher vulnerability towards side effects of exposure to high doses of ionizing radiation, but following low-dose applications employed in diagnostics, as well.

Changes in the probability of hysterectomy in the city of Mainz and Mainz-Bingen region, Germany.

BACKGROUND: To assess the hysterectomy probability by calendar period and age, the overall and the age-specific prevalence of hysterectomy in women aged 30-65 years. METHODS: Baseline data (2005-2007) from the population-based MARZY study conducted in Mainz and Mainz-Bingen, Germany, were analysed. 6429 women aged 30-65 years were asked whether they had undergone a hysterectomy and the date and indication of the procedure. We calculated the 5-year age-specific prevalence of hysterectomy and estimated the probability of undergoing a hysterectomy combining two approaches: 1) Kaplan-Meier and 2) Inverse probability weighting (IPW). We assessed potential changes over calendar periods by simulating survival curves, having hysterectomy as the event, employing a Cox proportional hazard model. RESULTS: Data on hysterectomy were available for 4719 women. Of these, 961 (20.4%) had undergone a hysterectomy between 1960 and 2006. The hysterectomy prevalence was highest among the 60-64 year-olds (40.7%). The IPW-corrected probability of having a hysterectomy up to the age of 65 years was 36.4%. The age-specific probability of hysterectomy increased from 0.1% (20-24 years), peaking at 45-49 years (7.8%) and declining thereafter to less than 5% among women aged 50 and older. Over time, women were hysterectomised at an increasingly older age. Most hysterectomies (86.7%) were done due to benign disease. CONCLUSIONS: A shift to older age at hysterectomy with an advancing calendar period likely reflects changes in clinical practice in Germany. TRIAL REGISTRATION: Landesärztekammer Rheinland-Pfalz: 837.438.03 (4100).

Cardiac late effects after modern 3D-conformal radiotherapy in breast cancer patients: a retrospective cohort study in Germany (ESCaRa).

PURPOSE: Radiotherapy (RT) was identified as a risk factor for long-term cardiac effects in breast cancer patients treated until the 1990s. However, modern techniques reduce radiation exposure of the heart, but some exposure remains unavoidable. In a retrospective cohort study, we investigated cardiac mortality and morbidity of breast cancer survivors treated with recent RT in Germany. METHODS: A total of 11,982 breast cancer patients treated between 1998 and 2008 were included. A mortality follow-up was conducted until 06/2018. In order to assess cardiac morbidity occurring after breast cancer treatment, a questionnaire was sent out in 2014 and 2019. The effect of breast cancer laterality on cardiac mortality and morbidity was investigated as a proxy for radiation exposure. We used Cox Proportional Hazards regression analysis, taking potential confounders into account. RESULTS: After a median follow-up time of 11.1 years, there was no significant association of tumor laterality with cardiac mortality in irradiated patients (hazard ratio (HR) for left-sided versus right-sided tumor 1.09; 95% confidence interval (CI) 0.85-1.41). Furthermore, tumor laterality was not identified as a significant risk factor for cardiac morbidity (HR = 1.05; 95%CI 0.88-1.25). CONCLUSIONS: Even though RT for left-sided breast cancer on average incurs higher radiation dose to the heart than RT for right-sided tumors, we found no evidence that laterality is a strong risk factor for cardiac disease after contemporary RT. However, larger sample sizes, longer follow-up, detailed information on individual risk factors and heart dose are needed to assess clinically manifest late effects of current cancer therapy.

Association of allergic diseases and epilepsy with risk of glioma, meningioma and acoustic neuroma: results from the INTERPHONE international case-control study.

We investigated the association of allergic diseases and epilepsy with risk of brain tumours, in Interphone, a 13-country case-control study. Data were obtained from 2693 glioma cases, 2396 meningioma cases, and 1102 acoustic neuroma cases and their 6321 controls. Conditional logistic regression models were used to estimate pooled odds ratios (ORs) and their respective 95% confidence intervals (CIs), adjusted for education and time at interview. Reduced ORs were observed for glioma in relation to physician-diagnosed asthma (OR = 0.73; CI 0.58-0.92), hay fever (OR 0.72; CI 0.61-0.86), and eczema (OR 0.78, CI 0.64-0.94), but not for meningioma or acoustic neuroma. Previous diagnosis of epilepsy was associated with an increased OR for glioma (2.94; CI 1.87-4.63) and for meningioma (2.12; CI 1.27-3.56), but not for acoustic neuroma. This large-scale case-control study adds to the growing evidence that people with allergies have a lower risk of developing glioma, but not meningioma or acoustic neuroma. It also supports clinical observations of epilepsy prior to the diagnosis of glioma and meningioma.

Colposcopy non-attendance following an abnormal cervical cancer screening result: a prospective population-based cohort study.

BACKGROUND: A considerable proportion of cervical cancer diagnoses in high-income countries are due to lack of timely follow-up of an abnormal screening result. We estimated colposcopy non-attendance, examined the potential factors associated and described non-attendance reasons in a population-based screening study. METHODS: Data from the MARZY prospective cohort study were analysed. Co-test screen-positive women (atypical squamous cells of undetermined significance or worse [ASC-US+] or high-risk human papillomavirus [hrHPV] positive) aged 30 to 65 years were referred to colposcopy within two screening rounds (3-year interval). Women were surveyed for sociodemographic, HPV-related and other data, and interviewed for non-attendance reasons. Logistic regression was used to examine potential associations with colposcopy attendance. RESULTS: At baseline, 2,627 women were screened (screen-positive = 8.7%), and 2,093 again at follow-up (screen-positive = 5.1%; median 2.7 years later). All screen-positives were referred to colposcopy, however 28.9% did not attend despite active recall. Among co-test positives (ASC-US+ and hrHPV) and only hrHPV positives, 19.6% were non-attendees. Half of only ASC-US+ screenees attended colposcopy. Middle age (adjusted odds ratio [aOR] = 1.55, 95% CI 1.02, 4.96) and hrHPV positive result (aOR = 3.04, 95% CI 1.49, 7.22) were associated with attendance. Non-attendance was associated with having ≥ 3 children (aOR = 0.32, 95% CI 0.10, 0.86). Major reasons for non-attendance were lack of time, barriers such as travel time, need for childcare arrangements and the advice against colposcopy given by the gynaecologist who conducted screening. CONCLUSIONS: Follow-up rates of abnormal screening results needs improvement. A systematic recall system integrating enhanced communication and addressing follow-up barriers may improve screening effectiveness.

[Explaining the age-adjusted excess mortality with COVID-19-attributed deaths from January 2020 to July 2021]. / Erklärbarkeit der altersadjustierten Übersterblichkeit mit den COVID-19-attribuierten Sterbefällen von Januar 2020 bis Juli 2021.

BACKGROUND: Estimating COVID-19 mortality is impeded by uncertainties in cause of death coding. In contrast, age-adjusted excess all-cause mortality is a robust indicator of how the COVID-19 pandemic impacts public health. However, in addition to COVID-19 deaths, excess mortality potentially also reflects indirect negative effects of public health measures aiming to contain the pandemic. OBJECTIVES: The study examines whether excess mortality in Germany between January 2020 and July 2021 is consistent with fatalities attributed to COVID-19 or may be partially due to indirect effects of public health measures. METHODS: Excess mortality trends for the period from January 2020 to July 2021 were checked for consistency with deaths attributed to COVID-19 in both the German federal states and districts of Rhineland-Palatinate. The expected monthly mortality rates were predicted based on data from 2015-2019, taking into account the population demographics, air temperature, seasonal influenza activity, and cyclic and long-term time trends RESULTS: COVID-19-attributed mortality was included in the 95% prediction uncertainty intervals for excess mortality in 232 of 304 (76.3%) month-state combinations and in 607 of 684 (88.7%) month-district combinations. The Spearman rank correlation between excess mortality and COVID-19-attributed mortality across federal states was 0.42 (95% confidence interval [0.31; 0.53]) and 0.21 (95% confidence interval [0.13; 0.29]) across districts. CONCLUSIONS: The good agreement of spatiotemporal excess mortality patterns with COVID-19 attributed mortality is consistent with the assumption that indirect adverse effects from public health interventions to contain the COVID-19 pandemic did not substantially contribute to excess mortality in Germany between January 2020 and July 2021.

Gender specific excess mortality in Italy during the COVID-19 pandemic accounting for age.

Since the beginning of the COVID-19 pandemic, data have been accumulated to examine excess mortality in the first half of 2020. Mortality in the preceding year or years is used to calculate the expected number of deaths, which is then compared with the actual number of deaths in 2020. We calculated weekly age- and sex-specific mortality rates for 93.1% of the Italian municipalities for the years 2015-2019 and for the first 26 weeks in 2020. We assumed the mortality experience during 2015-2019 as the reference period to calculate standardised mortality ratios. Furthermore, in order to compare the mortality experience of males and females, we calculated sex- and age- specific weekly direct standardised mortality rates and differences between the observed and expected number of deaths. We observed considerable changes in the demographics in the Italian population between the years 2015 and 2020, particularly among people 60 years and older and among males. The population is aging and the proportion of elderly males has increased, which was not reflected adequately in previous estimates of excess mortality. Standardized excess mortality results show that in Italy between the 8th and 26th weeks in 2020, there were 33,035 excess deaths, which is only 643 fewer deaths than the official COVID-19 death toll for this time period. A comparative increase in the mortality rates was observed in March among both sexes, but particularly for males. Comparisons with recently published data show considerably higher excess deaths, but these data were either not covering the complete country or did not account for age and sex. Neglecting the demographic changes in a region, even over a short time span, can result in biased estimates.

Association of COVID-19 mortality with COVID-19 vaccination rates in Rhineland-Palatinate (Germany) from calendar week 1 to 20 in the year 2021: a registry-based analysis.

Vaccination is among the measures implemented by authorities to control the spread of the COVID-19 pandemic. However, real-world evidence of population-level effects of vaccination campaigns against COVID-19 are required to confirm that positive results from clinical trials translate into positive public health outcomes. Since the age group 80 + years is most at risk for severe COVID-19 disease progression, this group was prioritized during vaccine rollout in Germany. Based on comprehensive vaccination data from the German federal state of Rhineland-Palatinate for calendar week 1-20 in the year 2021, we calculated sex- and age-specific vaccination coverage. Furthermore, we calculated the proportion of weekly COVID-19 fatalities and reported SARS-CoV-2 infections formed by each age group. Vaccination coverage in the age group 80 + years increased to a level of 80% (men) and 75% (women). Increasing vaccination coverage coincided with a reduction in the age group's proportion of COVID-19 fatalities. In multivariable logistic regression, vaccination coverage was associated both with a reduction in an age-group's proportion of COVID-19 fatalities [odds ratio (OR) per 5 percentage points = 0.89, 95% confidence interval (CI) = 0.82-0.96, p = 0.0013] and of reported SARS-CoV-2 infections (OR per 5 percentage points = 0.82, 95% CI 0.76-0.88, p < 0.0001). The results are consistent with a protective effect afforded by the vaccination campaign against severe COVID-19 disease in the oldest age group.

Returning to work in lung cancer survivors-a multi-center cross-sectional study in Germany.

PURPOSE: To investigate the work situation of lung cancer survivors and to identify the factors associated with their returning to work. METHODS: Descriptive analysis and logistic regression were used to evaluate study population characteristics and independent factors of subsequently returning to work. To analyze time to return to work, Cox regression was used. RESULTS: The study sample included 232 lung cancer survivors of working age from 717 enrolled participants in the multi-center cross-sectional LARIS (Quality of Life and Psychosocial Rehabilitation in Lung Cancer Survivors) study. About 67% of the survivors were not employed during the survey. More than 51% of the survivors who were employed before their illness did not return to their work. The survivors who had returned to their careers were younger, associated with higher household income, lower fatigue score, and stable relationship and vocational training. Patients who received social service counseling showed a higher chance of regaining their career. CONCLUSIONS: Lung cancer survivors were found to be associated with a high risk of unemployment and very low professional reintegration after interruption due to illness. More comprehensive studies are needed to support lung cancer survivors and targeting of patients in need of special attention in rehabilitation that would benefit from the findings in the present study.

Occupational Exposure to Extremely Low-Frequency Magnetic Fields and Risk of Amyotrophic Lateral Sclerosis: Results of a Feasibility Study for a Pooled Analysis of Original Data.

Previous meta-analyses have suggested an increased risk of amyotrophic lateral sclerosis (ALS) associated with occupational exposure to extremely low-frequency magnetic fields (ELF-MF). However, results should be interpreted with caution since studies were methodologically heterogeneous. Here, we assessed the feasibility of a pooling study to harmonize and re-analyze available original data. A systematic literature search was conducted. Published epidemiological studies were identified in PubMed and EMF-Portal from literature databases' inception dates until January 2019. The characteristics of all studies were described, including exposure metrics, exposure categories, and confounders. A survey among the principal investigators (PI) was carried out to assess their willingness to provide their original data. The statistical power of a pooling study was evaluated. We identified 15 articles published between 1997 and 2019. Studies differed in terms of outcome, study population, exposure assessment, and exposure metrics. Most studies assessed ELF-MF as average magnetic flux density per working day; however, exposure categories varied widely. The pattern of adjustment for confounders was heterogeneous between studies, with age, sex, and socioeconomic status being most frequent. Eight PI expressed their willingness to provide original data. A relative risk of ≥1.14 for ALS and occupational exposure to ELF-MF can be detected with a power of more than 80% in a pooled study. The pooling of original data is recommended and could contribute to a better understanding of ELF-MF in the etiology of ALS based on a large database and reduced heterogeneity due to a standardized analysis protocol with harmonized exposure metrics and exposure categories. Bioelectromagnetics. © 2021 Bioelectromagnetics Society.

Environmental assessment of interventions to restrain the impact of industrial pollution using a quasi-experimental design: limitations of the interventions and recommendations for public health policy.

BACKGROUND: In an industrial area, the asymmetry between the weights of the economic interests compared to the public-health needs can determine which interests are represented in decision-making processes. This might lead to partial interventions, whose impacts are not always evaluated. This study focuses on two interventions implemented in Taranto, Italy, a city hosting one of the largest steel plants in Europe. The first intervention deals with measures industrial plants must implement by law to reduce emissions during so called "wind days" in order to reduce PM10 and benzo [a] pyrene concentrations. The second one is a warning to the population with recommendations to aerate indoor spaces from 12 pm to 6 pm, when pollutant concentrations are believed to be lower. METHODS: To analyse the impact of the first intervention, we analysed monthly PM10 data in the period 2009-2016 from two monitoring stations and conducted an interrupted-time-series analysis. Coefficients of time-based covariates are estimated in the regression model. To minimise potential confounding, monthly concentrations of PM10 in a neighbourhood 13 km away from the steel plant were used as a control series. To evaluate the second intervention, hourly concentrations of PM10, SO2 and polycyclic-aromatic-hydrocarbons (PAHs) were analysed. RESULTS: PM10 concentrations in the intervention neighbourhood showed a peak just a few months before the introduction of the law. When compared to the control series, PM10 concentrations were constantly higher throughout the entire study period. After the intervention, there was a reduction in the difference between the two time-series (- 25.6%). During "wind days" results suggested no reduction in concentrations of air pollutants from 12 pm to 18 pm. CONCLUSION: Results of our study suggest revising the warning to the population. Furthermore, they evidence that in complex highly industrialised areas, air quality interventions cannot focus on only a single pollutant, but rather should consider the complex relationships between the different contaminants. Environmental interventions should be reviewed periodically, particularly when they have implications for social constraints. While the results of our study can be related only to the specific situation reported in the article, the methodology applied might be useful for the environmental management in industrial areas with similar features.

Methodological considerations for interrupted time series analysis in radiation epidemiology: an overview.

Interrupted time series analysis (ITSA) is a method that can be applied to evaluate health outcomes in populations exposed to ionizing radiation following major radiological events. Using aggregated time series data, ITSA evaluates whether the time trend of a health indicator shows a change associated with the radiological event. That is, ITSA checks whether there is a statistically significant discrepancy between the projection of a pre-event trend and the data empirically observed after the event. Conducting ITSA requires one to consider specific methodological issues due to unique threats to internal validity that make ITSA prone to bias. We here discuss the strengths and limitations of ITSA with respect to bias and confounding, data quality, and statistical aspects. We provide recommendations to strengthen the robustness of ITSA studies and reduce their susceptibility to producing spurious results as a consequence of arbitrary modelling decisions.

Comparison of time and dose dependent gene expression and affected pathways in primary human fibroblasts after exposure to ionizing radiation.

BACKGROUND: Exposure to ionizing radiation induces complex stress responses in cells, which can lead to adverse health effects such as cancer. Although a variety of studies investigated gene expression and affected pathways in human fibroblasts after exposure to ionizing radiation, the understanding of underlying mechanisms and biological effects is still incomplete due to different experimental settings and small sample sizes. Therefore, this study aims to identify the time point with the highest number of differentially expressed genes and corresponding pathways in primary human fibroblasts after irradiation at two preselected time points. METHODS: Fibroblasts from skin biopsies of 15 cell donors were exposed to a high (2Gy) and a low (0.05Gy) dose of X-rays. RNA was extracted and sequenced 2 h and 4 h after exposure. Differentially expressed genes with an adjusted p-value < 0.05 were flagged and used for pathway analyses including prediction of upstream and downstream effects. Principal component analyses were used to examine the effect of two different sequencing runs on quality metrics and variation in expression and alignment and for explorative analysis of the radiation dose and time point of analysis. RESULTS: More genes were differentially expressed 4 h after exposure to low and high doses of radiation than after 2 h. In experiments with high dose irradiation and RNA sequencing after 4 h, inactivation of the FAT10 cancer signaling pathway and activation of gluconeogenesis I, glycolysis I, and prostanoid biosynthesis was observed taking p-value (< 0.05) and (in) activating z-score (≥2.00 or ≤ - 2.00) into account. Two hours after high dose irradiation, inactivation of small cell lung cancer signaling was observed. For low dose irradiation experiments, we did not detect any significant (p < 0.05 and z-score ≥ 2.00 or ≤ - 2.00) activated or inactivated pathways for both time points. CONCLUSIONS: Compared to 2 h after irradiation, a higher number of differentially expressed genes were found 4 h after exposure to low and high dose ionizing radiation. Differences in gene expression were related to signal transduction pathways of the DNA damage response after 2 h and to metabolic pathways, that might implicate cellular senescence, after 4 h. The time point 4 h will be used to conduct further irradiation experiments in a larger sample.

Cohort study of occupational cosmic radiation dose and cancer mortality in German aircrew, 1960-2014.

OBJECTIVES: To determine cancer mortality compared with the general population and to examine dose-response relationships between cumulative occupational radiation dose and specific cancer outcomes in the German aircrew cohort. METHODS: For a cohort of 26 846 aircrew personnel, standardised mortality ratios (SMR) were calculated. Dose-response analyses were carried out using Poisson regression to assess dose-related cancer risks for the period 1960-2014. Exposure assessment comprises recently available dose register data for all cohort members and newly estimated retrospective cabin crew doses for 1960-2003. RESULTS: SMR for all-cause, specific cancer groups and most individual cancers were reduced in all aircrew groups. The only increases were seen for brain cancer in pilots (n=23, SMR 2.01, 95% CI 1.15 to 3.28) and for malignant melanoma (n=10, SMR 1.88, 95% CI 0.78 to 3.85). Breast cancer mortality among female cabin crew was similar to the general population (n=71, SMR 1.06, 95% CI 0.77 to 1.44). Overall median cumulative effective dose was 34.2 mSv (max: 116 mSv) for 1960-2014. No dose-response associations were seen in any of the models. For brain cancer, relative risks were elevated across dose categories. An indicative negative trend with increasing dose category was seen for large intestine cancer in female cabin crew (n=23). CONCLUSIONS: There was no evidence for significant dose-response patterns for the considered cancer types. Interpretation of results remains difficult as cumulative dose is closely related to age. Future work should focus on investigating radiation jointly with other risk factors that may contribute to risks for specific cancers among aircrew.

[Contact Investigation in Active Tuberculosis and Management of Latent TB Infection: 5-year Analysis at a German City Health Authority]. / Kontaktuntersuchungen bei aktiver Tuberkulose und Management latenter Tuberkulose: 5 Jahres-Analyse an einem deutschen Großstadt Gesundheitsamt.

BACKGROUND: As part of the German TB control program, health authorities conduct investigations among contacts of patients with active tuberculosis based on the infection prevention legislation, to identify potential infections among these persons. The aim of this study was to analyze retrospectively procedures of the city health authority Cologne, in cases of newly diagnosed latent TB infection (LTBI) over a 5-year period. METHODS: Data from the Cologne City Health Authority on contact investigations of TB cases between July 1st 2012 und December 31st 2016 were analyzed. In the absence of signs for active TB and a positive result of the interferon gamma release assay (QFT), LTBI was diagnosed in contact persons. Those with positive test results aged 16 and above and registered in Cologne were included. RESULTS: Out of 3859 contact persons, 430 met the inclusion criteria: in 174/430 cases chemo-preventive therapy (CPT) was recommended and 65 (35.1 %) actually took the course of CPT; in 117 cases, no records of CPT were found in the files and 22/430 persons with LTBI developed active TB within the observation period. CONCLUSION: If the full potential of LTBI treatment on the basis of the recommendations of WHO's "End TB-Strategy" is to be realized, the present study reveals the need to continuously improve documentation and management of LTBI in this setting.

Validation of Semantic Analyses of Unstructured Medical Data for Research Purposes.

HINTERGRUND: In Sekundärdaten existieren oftmals unstrukturierte Freitexte. In dieser Arbeit wird ein Text-Mining-System validiert, um unstrukturierte medizinische Daten für Forschungszwecke zu extrahieren. METHODEN: Aus einer radiologischen Klinik wurden aus 7102 CT-Befunden 1000 zufällig ausgewählt. Diese wurden von 2 Medizinern manuell in definierte Befundgruppen eingeteilt. Zur automatisierten Verschlagwortung und Klassifizierung wurde die Textanalyse-Software Averbis Extraction Platform (AEP) eingesetzt. Besonderheiten des Systems sind u. a. eine morphologische Analyse zur Zerlegung zusammengesetzter Wörter sowie die Erkennung von Nominalphrasen, Abkürzungen und negierten Aussagen. Anhand der extrahierten standardisierten Schlüsselwörter werden Befundberichte mithilfe maschineller Lernverfahren den vorgegebenen Befundgruppen zugeordnet. Zur Bewertung von Reliabilität und Validität des automatisierten Verfahrens werden die automatisierten und 2 unabhängige manuelle Klassifizierungen in mehreren Durchläufen auf Übereinstimmungen hin verglichen. ERGEBNISSE: Die manuelle Klassifizierung war zu zeitaufwendig. Bei der automatisierten Verschlagwortung stellte sich in unseren Daten die Klassifizierung nach ICD-10 als ungeeignet heraus. Ebenfalls zeigte sich, dass die Stichwortsuche keine verlässlichen Ergebnisse liefert. Computerunterstütztes Textmining in Kombination mit maschinellem Lernen führte zu verlässlichen Klassifizierungen. Die Inter-Rater-Reliabilität der beiden manuellen Klassifizierungen, sowie der maschinellen und der manuellen Klassifizierung war sehr hoch. Beide manuelle Klassifizierungen stimmten in 93% aller Befunde überein. Der Kappa-Koeffizient beträgt 0,89 [95% Konfidenzintervall (KI) 0,87-0,92]. Die automatische Klassifizierung stimmte in 86% aller Befunde mit der unabhängigen, zweiten manuellen Klassifizierung überein (Kappa-Koeffizient 0,79 [95% KI 0,75-0,81]). DISKUSSION: Die Klassifizierung der Software AEP war sehr gut. In unserer Studie folgte sie allerdings einem systematischen Muster. Die meisten falschen Zuordnungen finden sich in Befunden, die auf ein erhöhtes Krebsrisiko hinweisen. Die Freitextstruktur der Befunde lässt Bedenken hinsichtlich der Machbarkeit einer rein automatisierten Analyse aufkommen. Die Kombination aus menschlichem Intellekt und einer intelligenten, lernfähigen Software erscheint als zukunftsweisend, um unstrukturierte aber wichtige Textinformationen der Forschung zugänglich machen zu können.

Use of psychosocial services by lung cancer survivors in Germany : Results of a German multicenter study (LARIS).

PURPOSE: Little is known about the use of psychosocial services in lung cancer survivors and patients who have survived the diagnosis for at least one year. We investigated the frequency of use, stratified by radiation therapy received, its associated factors, and the reasons for non-use of those services. METHODS: We performed a multicenter (n = 6 hospitals) cross-sectional study using data from medical records, patient reported questionnaires, and computer-assisted telephone interviews. Odds ratios (OR) for factors potentially associated with the use of any type of psychosocial services were calculated using multivariable logistic regression. RESULTS: We included 604 lung cancer patients/survivors. Of them, 60% (69% of those who had received radiotherapy) had used some kind of psychological and/or social service in the past (47% psychological, 42% social); 39% had used inpatient care, 24% outpatient care (cancer counselling center, general counselling center, psychological counselling by family doctor, psychotherapy, patient support group, pastoral work). Of those who visited a rehabilitation clinic, 66% received psychosocial care there. Factors associated with using psychosocial services in general were female gender (OR 1.96, 95% CI 1.32-2.93), poor emotional functioning (per unit decrease: OR 0.99, 95% CI 0.98-0.996), and younger age (per year decrease: OR 0.95, 95% CI 0.93-0.97). CONCLUSIONS/IMPLICATIONS: The high proportion of psychosocial care users among lung cancer survivors in Germany indicates that patients are interested in using it and that an unmet need exists. The creation of a broad spectrum of easily accessible services with high quality is important to enable and facilitate use.