NextGEM: Next-Generation Integrated Sensing and Analytical System for Monitoring and Assessing Radiofrequency Electromagnetic Field Exposure and Health.

The evolution of emerging technologies that use Radio Frequency Electromagnetic Field (RF-EMF) has increased the interest of the scientific community and society regarding the possible adverse effects on human health and the environment. This article provides NextGEM's vision to assure safety for EU citizens when employing existing and future EMF-based telecommunication technologies. This is accomplished by generating relevant knowledge that ascertains appropriate prevention and control/actuation actions regarding RF-EMF exposure in residential, public, and occupational settings. Fulfilling this vision, NextGEM commits to the need for a healthy living and working environment under safe RF-EMF exposure conditions that can be trusted by people and be in line with the regulations and laws developed by public authorities. NextGEM provides a framework for generating health-relevant scientific knowledge and data on new scenarios of exposure to RF-EMF in multiple frequency bands and developing and validating tools for evidence-based risk assessment. Finally, NextGEM's Innovation and Knowledge Hub (NIKH) will offer a standardized way for European regulatory authorities and the scientific community to store and assess project outcomes and provide access to findable, accessible, interoperable, and reusable (FAIR) data.

A nested case-control study on radiation dose-response for cardiac events in breast cancer patients in Germany.

BACKGROUND: Previous studies with the majority of breast cancer (BC) patients treated up to 2000 provided evidence that radiation dose to the heart from radiotherapy (RT) was linearly associated with increasing risk for long-term cardiac disease. RT techniques changed substantially over time. This study aimed to investigate the dose-dependent cardiac risk in German BC patients treated with more contemporary RT. METHODS: In a cohort of 11,982 BC patients diagnosed in 1998-2008, we identified 494 women treated with 3D-conformal RT who subsequently developed a cardiac event. Within a nested case-control approach, these cases were matched to 988 controls. Controls were patients without a cardiac event after RT until the index date of the corresponding case. Separate multivariable conditional logistic regression models were used to assess the association of radiation to the complete heart and to the left anterior heart wall (LAHW) with cardiac events. RESULTS: Mean dose to the heart for cases with left-sided BC was 4.27 Gy and 1.64 Gy for cases with right-sided BC. For controls, corresponding values were 4.31 Gy and 1.66 Gy, respectively. The odds ratio (OR) per 1 Gy increase in dose to the complete heart was 0.99 (95% confidence interval (CI): 0.94-1.05, P = .72). The OR per 1 Gy increase in LAHW dose was 1.00 (95% CI: 0.98-1.01, P = .68). CONCLUSIONS: Contrary to previous studies, our study provided no evidence that radiation dose to the heart from 3D-conformal RT for BC patients treated between 1998 and 2008 was associated with risk of cardiac events.

Environmental Risk Factors for Childhood Acute Lymphoblastic Leukemia: An Umbrella Review.

Leukemia is the most common type of cancer among children and adolescents worldwide. The aim of this umbrella review was (1) to provide a synthesis of the environmental risk factors for the onset of childhood acute lymphoblastic leukemia (ALL) by exposure window, (2) evaluate their strength of evidence and magnitude of risk, and as an example (3) estimate the prevalence in the German population, which determines the relevance at the population level. Relevant systematic reviews and pooled analyses were identified and retrieved through PubMed, Web of Science databases and lists of references. Only two risk factors (low doses of ionizing radiation in early childhood and general pesticide exposure during maternal preconception/pregnancy) were convincingly associated with childhood ALL. Other risk factors including extremely low frequency electromagnetic field (ELF-MF), living in proximity to nuclear facilities, petroleum, benzene, solvent, and domestic paint exposure during early childhood, all showed some level of evidence of association. Maternal consumption of coffee (high consumption/>2 cups/day) and cola (high consumption) during pregnancy, paternal smoking during the pregnancy of the index child, maternal intake of fertility treatment, high birth weight (≥4000 g) and caesarean delivery were also found to have some level of evidence of association. Maternal folic acid and vitamins intake, breastfeeding (≥6 months) and day-care attendance, were inversely associated with childhood ALL with some evidence. The results of this umbrella review should be interpreted with caution; as the evidence stems almost exclusively from case-control studies, where selection and recall bias are potential concerns, and whether the empirically observed association reflect causal relationships remains an open question. Hence, improved exposure assessment methods including accurate and reliable measurement, probing questions and better interview techniques are required to establish causative risk factors of childhood leukemia, which is needed for the ultimate goal of primary prevention.

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.

Mortality risk among 5-year survivors of childhood cancer in Germany-Results from the CVSS study (Cardiac and Vascular late Sequelae in long-term Survivors of childhood cancer study).

The growing population of long-term childhood cancer survivors is at increased risk for severe, therapy-related late effects and premature mortality. The cardiac and vascular late sequelae in long-term survivors of childhood cancer (CVSS) study is a cohort of patients from Germany diagnosed with a neoplasia prior to 15 years of age in the time period 1980 to 1990. Late mortality was evaluated in a total of 4505 individuals who survived 5 years or more after the initial diagnosis (5-year survivors). Survivors with a second primary tumor were excluded. Standardized mortality ratios (SMRs) were calculated. By December 2014, 400 patients had died. Available cause of death information from 188 individuals was used to estimate cause-specific mortality for all deceased persons. Compared to the population of (former) West Germany, we observed an excess overall mortality risk (SMR = 9.53, 95% confidence interval [CI] = 8.62-10.51). After correcting for missing cause of death information, an increased cancer mortality (SMR = 43.50, 95% CI = 25.79-73.50) in the 5-year survivors was detected. Cardiac death was ascertained in 14 individuals, resulting in an SMR of 10.85 (95% CI = 2.80-32.02) after correcting for missing values. In conclusion, childhood cancer survivors diagnosed in Germany in 1980 to 1990 have a higher mortality risk overall and an elevated risk of dying from cancer and cardiac causes in particular. The results are consistent with those of international cohort studies. However, the reported results are based on few cases and individuals with secondary cancers were excluded.

The effect of exposure to radiofrequency fields on cancer risk in the general and working population: A protocol for a systematic review of human observational studies.

BACKGROUND: The World Health Organization (WHO) has an ongoing project to assess potential health effects of exposure to radiofrequency electromagnetic fields (RF-EMF) in the general and working population. Here we present the protocol for a systematic review of the scientific literature on cancer hazards from exposure to RF-EMF in humans, commissioned by the WHO as part of that project. OBJECTIVE: To assess the quality and strength of the evidence provided by human observational studies for a causal association between exposure to RF-EMF and risk of neoplastic diseases. ELIGIBILITY CRITERIA: We will include cohort and case-control studies investigating neoplasia risks in relation to three types of exposure to RF-EMF: near-field, head-localized, exposure from wireless phone use (SR-A); far-field, whole body, environmental exposure from fixed-site transmitters (SR-B); near/far-field occupational exposures from use of handheld transceivers or RF-emitting equipment in the workplace (SR-C). While no restriction on tumour type will be applied, we will focus on selected neoplasms of the central nervous system (brain, meninges, pituitary gland, acoustic nerve) and salivary gland tumours (SR-A); brain tumours and leukaemias (SR-B, SR-C). INFORMATION SOURCES: Eligible studies will be identified through Medline, Embase, and EMF-Portal. RISK-OF-BIAS ASSESSMENT: We will use a tailored version of the OHAT's tool to evaluate the study's internal validity. DATA SYNTHESIS: We will consider separately studies on different tumours, neoplasm-specific risks from different exposure sources, and a given exposure-outcome pair in adults and children. When a quantitative synthesis of findings can be envisaged, the main aims of the meta-analysis will be to assess the strength of association and the shape of the exposure-response relationship; to quantify the degree of heterogeneity across studies; and explore the sources of inconsistency (if any). When a meta-analysis is judged inappropriate, we will perform a narrative synthesis, complemented by a structured tabulation of results and appropriate visual displays. EVIDENCE ASSESSMENT: Confidence in evidence will be assessed in line with the GRADE approach. FUNDING: This project is supported by the World Health Organization. Co-financing was provided by the New Zealand Ministry of Health; the Istituto Superiore di Sanità in its capacity as a WHO Collaborating Centre for Radiation and Health; ARPANSA as a WHO Collaborating Centre for Radiation Protection. REGISTRATION: PROSPERO CRD42021236798.

Sensitivity and Specificity of Human Papillomavirus (HPV) 16 Early Antigen Serology for HPV-Driven Oropharyngeal Cancer: A Systematic Literature Review and Meta-Analysis.

Antibodies against HPV16 early proteins have been shown to be promising biomarkers for the identification of HPV-driven oropharyngeal cancer (HPV-OPC) among OPC cases in multiple studies. A systematic literature search was performed to identify original research articles comparing HPV early antigen serology with established reference methods to determine molecular HPV tumor status. Random-effects models were used to calculate summary estimates for sensitivity and specificity of HPV16 E2, E6 and E7 serology for HPV-OPC. Subgroup analyses were performed to explore heterogeneity across studies and describe variables associated with test performance. We identified n = 23 studies meeting all eligibility criteria and included these in the meta-analysis. E6 serology showed the best performance with pooled sensitivity and specificity estimates of 83.1% (95% confidence interval (CI) 72.5-90.2%) and 94.6% (95% CI 89.0-97.4%), respectively, while E2 and E7 serological assays were highly specific (E2: 92.5% (95% CI 79.1-97.6%); E7: 88.5% (95% CI 77.9-94.4%)) but moderately sensitive (E2: 67.8% (95% CI 58.9-75.6%); E7: 67.0% (95% CI 63.2-70.6%)). Subgroup analyses revealed increased pooled sensitivity for bacterially (89.9% (95% CI 84.5-93.6%)) vs. in vitro expressed E6 antigen (55.3% (95% CI 41.0-68.7%)), while both showed high specificity (95.2% (95% CI 93.0-96.7%) and 91.1% (95% CI 46.6-99.2%), respectively). Pooled specificity estimates for HPV16 E2, E6 and E7 serology were significantly lower in studies utilizing HPV DNA PCR as the only molecular reference method compared to those using a combination of any two reference methods (HPV DNA, RNA, in situ hybridization (ISH), p16 immunohistochemistry (IHC)), or histopathological reference methods (ISH or p16 IHC) as stand-alone marker. In conclusion, HPV16 E6 seropositivity is a highly sensitive and specific biomarker for HPV-OPC. However, its performance differs between serological assays and depends on molecular reference methods.

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.

Exposure To Extremely Low-Frequency Magnetic Fields In Low- And Middle-Income Countries: An Overview.

To compare extremely low-frequency magnetic field (ELF-MF) exposure in the general population in low- and middle-income countries (LMICs) with high-income countries (HIC), we carried out a systematic literature search resulting in 1483 potentially eligible articles; however, only 25 studies could be included in the qualitative synthesis. Studies showed large heterogeneity in design, exposure environment and exposure assessment. Exposure assessed by outdoor spot measurements ranged from 0.03 to 4µT. Average exposure by indoor spot measurements in homes ranged from 0.02 to 0.4µT. Proportions of homes exposed to a threshold of ≥0.3µT were many times higher in LMICs compared to HIC. Based on the limited data available, exposure to ELF-MF in LMICs appeared higher than in HIC, but a direct comparison is hampered by a lack of representative and systematic monitoring studies. Representative measurement studies on residential exposure to ELF-MF are needed in LMICs together with better standardisation in the reporting.

Second follow-up of a German cohort on childhood cancer incidence after exposure to postnatal diagnostic x-ray.

Studies on children exposed to ionising radiation by computed tomography (CT) indicate an increased risk of leukemia and central nervous system (CNS) tumors. Evidence of the risks associated with diagnostic x-ray examinations, the most frequent examination in pediatric radiology, in which the radiation dose is up to 750 times lower compared to CT examinations, is less clear. This study presents results of the second follow-up for the risk of childhood cancer in a cohort of children (<15 years) with diagnostic x-ray exposure at a large German hospital during 1976-2003 followed for additional 10 years until 2016. With a latency period of 6 months, 92 998 children contributed 794 549 person-years. The median effective dose was 7 µSv. Hundred incident cancer cases were identified: 35 leukemia, 13 lymphomas, 12 CNS tumors, 15 blastomas, 15 sarcomas and 10 other solid tumors, consisting of six germ cells tumors, three thyroid cancers and one adrenocortical carcinoma. For all cancer cases combined the standardised incidence ratio (SIR) was 1.14 (95% confidence interval (CI) 0.93-1.39), for leukemia 1.15 (95% CI 0.63-1.61), for lymphomas 1.03 (95% CI 0.55-1.76), for CNS tumors 0.65 (95% CI 0.34-1.14), for blastomas 1.77 (95% CI 0.91-2.91), for sarcomas 1.28 (95% CI 0.71-2.11) and for other solid tumors 2.38 (95% CI 1.14-4.38). Dose-response analysis using Poisson regression revealed no significant trend for dose groups. Results did not differ substantially with a latency period of 2 years for all cancer entities and 5 years for solid tumors in sensitivity analyses. Overall, the null results of the first follow-up were confirmed. Although an association between radiation exposure and a risk for certain solid tumors like thyroid cancer is known, the significantly increased SIR in the group of other solid tumors must be critically interpreted in the context of the small number of cases and the very low doses of radiation exposure in this group.

Radiotherapy for childhood cancer and subsequent thyroid cancer risk: a systematic review.

Most of the pooled analyses and reviews reported an association between radiotherapy for childhood cancer and an increased thyroid cancer risk. Up to now this article presents the first systematic literature review on this association combined with a critical assessment of the methodological quality of the included articles. PubMed and Web of Science databases were searched for relevant articles until May 2016. We included peer-reviewed cohort and case-control studies that investigated an association between radiotherapy for childhood cancer and the occurrence of subsequent thyroid cancer. A systematic overview is presented for the included studies. We identified 17 retrospective cohort studies, and four nested case-control studies, representing 100,818 subjects. The age range at first cancer diagnosis was 0-25.2 years. Considerable variability was found regarding study sizes, study design, treatment strategies, dose information, and follow-up periods. 20 of the 21 identified studies showed increased thyroid cancer risks associated with childhood radiation exposure. The large majority showed an increased relative risk or odds ratio confirming the association between radiotherapy and thyroid cancer although the variation in results was large. Additionally to a pooled analysis that has been published recently, we systematically included 17 further studies, which allowed us to cover information from countries that were not covered by large-scale childhood cancer survivor studies. The methodological limitations of existing studies and inconsistencies in findings across studies yielded a large study heterogeneity, which made a detailed comparison of study results difficult. There is a need to strengthen standardisation for reporting.