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Abstract An under-recognised aspect of the current humanitarian catastrophe in Gaza is the impact of the war on the environment and the associated risks for human health. This commentary contextualises these impacts against the background of human suffering produced by the overwhelming violence associated with the use of military force against the general population of Gaza. In calling for an immediate cessation to the violence, the authors draw attention to the urgent need to rebuild the health care system and restore the physical and human infrastructure that makes a liveable environment possible and promotes human health and well-being, especially for the most vulnerable in the population. Environmental remediation should therefore form one of the most important parts of international efforts to assist reconstruction, through which we hope Palestinians and Israelis will achieve lasting peace, health, and sustainable development, all as part of accepted international human rights obligations.

Malignant mesothelioma (MM) is a highly aggressive and difficult-to-diagnose tumor that is almost always caused by asbestos or other asbestiform fibers. Chapter 2 in the Fourth (2015) and Fifth (2021) Editions of the WHO/IARC Classification of Tumours is devoted to the classification and pathologic diagnosis of MM. The authors of these Chapters state that most of the cases of MM in females do not show asbestos as the cause when, in fact, the epidemiologic literature shows that the risk of MM in females exposed to asbestos approaches that in males. While it is correct that the overall incidence of MM in females is lower than in males, the view that MM in females is not caused by asbestos is unsupported. This view results from an inadequate occupational history, the failure to recognize the importance of environmental exposures, and the misrepresentation of published literature by the selection of limited literature and biased bibliographies, often by authors with financial conflicting interests. In this article, we present an example of the institutional failure (1) to protect the public health by permitting the publication of inaccurate statements about the adverse health effects of exposure to asbestos among females, and (2) to make suggested corrections that more accurately reflect reality. Responsibility for correcting the misinformation lies, in our assessment, both with the authors of the erroneous statements and with the editors and publisher of the books that contain these statements. At issue is nothing less than scientific accuracy, the fate of at-risk females for whom early diagnosis could result in improved health outcome, a missed opportunity to promote primary and secondary prevention, and the social injustice of the loss of compensation for females so affected. We describe the steps that we took to correct the inaccuracies, and to expose the dereliction of duty among responsible parties based, at least in part, on what we believe to be undisclosed conflicting interests. Our efforts failed.

Introduction: The asbestos industry began its operations in Colombia in 1942 with the establishment of an asbestos-cement facility in Sibaté, located in the Department of Cundinamarca. Despite extensive asbestos use and production in Colombia, the country lacks a reliable epidemiological surveillance system to monitor the health effects of asbestos exposure. The Colombian health information system, known as SISPRO, did not report mesothelioma cases diagnosed in the municipality, posing a significant challenge in understanding the health impacts of asbestos exposure on the population of Sibaté. Methods: To address this issue, an active surveillance strategy was implemented in Sibaté. This strategy involved conducting door-to-door health and socioeconomic structured interviews to identify Asbestos-Related Diseases (ARDs). Validation strategies included a thorough review of medical records by a panel of physicians, and the findings were communicated to local, regional, and national authorities, as well as the general population. Results: The active surveillance strategy successfully identified a mesothelioma cluster in Sibaté, revealing the inadequacy of the existing health information system in monitoring asbestos-related diseases. The discovery of this cluster underscores the critical importance of implementing active surveillance strategies in Colombia, where governmental institutions and resources are often limited. Conclusion: The findings of this study emphasize the urgent need for Colombia to establish a reliable epidemiological surveillance system for asbestos-related diseases (ARDs). Active surveillance strategies can play a crucial role in identifying mesothelioma clusters and enhancing our understanding of the health effects of asbestos exposure in low- and middle-income countries.

Abstract Background The Italian mesothelioma registry (ReNaM) estimates mesothelioma incidence and addresses its etiology by assessing cases’ exposures but cannot provide relative risk estimates. Objectives i) To estimate pleural mesothelioma relative risk by industry and occupation and by ReNaM categories of asbestos exposure; and ii) to provide quantitative estimates of the exposure–response relationship. Methods A population-based mesothelioma case–control study was conducted in 2012–2014 in five Italian regions. Cases and age and gender frequency-matched controls were interviewed using a standard ReNaM questionnaire. Experts coded work histories according to international standard classifications of industries/occupations and assigned asbestos exposure according to ReNaM categories. Job codes were further linked to SYN-JEM, a quantitative job-exposure matrix. Cumulative exposure (CE, f/mL-years) was computed by summing individual exposures over lifetime work history. Unconditional logistic regression analyses adjusted by gender, centre and age were fitted to calculate odds ratios (OR) and 95% confidence intervals (CI). Results Among men we observed increased risks of mesothelioma in many industries and associated occupations, including: asbestos-cement (OR = 3.43), manufacture of railroad equipment (OR = 8.07), shipbuilding and repairing (OR = 2.34), iron and steel mills (OR = 2.15), and construction (OR = 1.94). ORs by ReNaM exposure categories were as follows: definite/probable occupational exposure (OR = 15.8, men; OR = 8.80, women), possible occupational (OR = 2.82, men; OR = 3.70, women), sharing home with an exposed worker (OR = 2.55, men; OR = 10.3, women), residential (OR = 2.14, men; OR = 3.24, women). Based on SYN-JEM, mesothelioma risk increased by almost 30% per f/mL-year (OR = 1.28, CI 1.16–1.42). Conclusions Out study involved five regions with historically different types and levels of industrial development, encompassing one third of the Italian population and half of Italian mesothelioma cases. As expected, we found increased pleural mesothelioma risk in the asbestos industry and in trades with large consumption of asbestos materials. Clear associations were found using both qualitative (ReNaM classifications) and quantitative estimates (using SYN-JEM) of past asbestos exposure, with clear evidence of an exposure–response relationship.

Parental occupational exposures around conception (father) or during pregnancy (mother) have been hypothesized as potential predisposing factors for childhood leukaemia. We investigated parental exposure to several known occupational carcinogens and childhood leukaemia risk. We conducted a pooled analysis using case-control data from four European countries (3362 childhood leukemia cases and 6268 controls). Parental occupational exposures to polycyclic aromatic hydrocarbons (PAH), diesel engine exhaust (DEE), chromium, nickel, crystalline silica, and asbestos were assessed by a general population job-exposure matrix. We estimated odd ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression models for all childhood leukaemia combined, by leukaemia type (ALL and AML) and by ALL subtype (B-lineage and T-lineage). We found an association between high paternal occupational exposure to crystalline silica and childhood ALL (OR 2.20, CI 1.60–3.01) with increasing trend from no exposure to high exposure (P =

Abstract Background The International Agency for Research on Cancer (IARC) recently classified glyphosate, the most used herbicide worldwide, as a probable human carcinogen. We inquired into the association between occupational exposure to glyphosate and risk of lymphoma subtypes in a multicenter case-control study conducted in Italy. Methods The Italian Gene-Environment Interactions in Lymphoma Etiology (ItGxE) study took place in 2011–17 in six Italian centres. Overall, 867 incident lymphoma cases and 774 controls participated in the study. Based on detailed questionnaire information, occupational experts classified duration, confidence, frequency, and intensity of exposure to glyphosate for each study subject. Using unconditional regression analysis, we modelled risk of major lymphoma subtypes associated with exposure to glyphosate adjusted by age, gender, education, and study centre. Results Very few study subjects (2.2%) were classified as ever exposed to glyphosate. Risk of follicular lymphoma (FL) was elevated 7-fold in subjects classified as ever exposed to glyphosate with medium-high confidence, 4.5-fold in association with medium-high cumulative exposure level, 12-fold with medium-high exposure intensity, and 6-fold with exposure for 10 days or more per year. Significant upward trends were detected with all the exposure metrics, but duration. The overall p-value for an upward trend with four independent metrics was 1.88 × 10− 4. There was no association with risk of lymphoma (any subtype), Non Hodgkin Lymphoma, B-cell lymphoma, or the major lymphoma subtypes other than FL. Conclusions Our findings provide limited support to the IARC decision to classify glyphosate as Group 2A human carcinogen.

OBJECTIVES: The purposes of this study are to describe the epidemiology of pericardial and tunica vaginalis testis mesothelioma and assess the role of asbestos exposure for these rare diseases. METHODS: Based on incident pericardial and tunica vaginalis testis mesothelioma cases collected from the Italian national mesothelioma registry (ReNaM) in the period 1993–2015, incidence rates, survival median period and prognostic factors have been evaluated. A case–control study has been performed to analyze the association with asbestos exposure (occupational and non-occupational) for these diseases. RESULTS: Between 1993 and 2015, 58 pericardial (20 women and 38 men) and 80 tunica vaginalis testis mesothelioma cases have been registered with a mean annual standardized (world standard population as reference) incidence rates of 0.049 (per million) in men and 0.023 in women for the pericardial site, and 0.095 for tunica vaginalis testis mesothelioma. Occupational exposure to asbestos was significantly associated with the risk of the diseases [odds ratio (OR) 3.68, 95% confidence interval (CI) 1.85–7.31 and OR 3.42, 95% CI 1.93–6.04 in pericardial and tunica vaginalis testis mesothelioma, respectively]. The median survival was 2.5 months for pericardial and 33.0 months for tunica vaginalis testis mesotheliomas. Age was the main predictive factor for survival for both anatomical sites. CONCLUSIONS: For the first time in an analytical study, asbestos exposure was associated with pericardial and tunica vaginalis testis mesothelioma risk, supporting the causal role of asbestos for all anatomical sites. The extreme rarity of the diseases, the poor survival and the prognostic role of age have been confirmed based on population and nationwide mesothelioma registry data.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with a dismal prognosis. Early therapeutic interventions could improve patient outcomes. We aimed to identify a pattern of microRNAs (miRNAs) as potential early non-invasive markers of MPM. In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition cohort, we screened the whole miRNome in serum extracellular vesicles (EVs) of preclinical MPM cases. In a subgroup of 20 preclinical samples collected five years prior MPM diagnosis, we observed an upregulation of miR-11400 (fold change (FC) = 2.6, adjusted p-value = 0.01), miR-148a-3p (FC = 1.5, p-value = 0.001), and miR-409-3p (FC = 1.5, p-value = 0.04) relative to matched controls. The 3-miRNA panel showed a good classification capacity with an area under the receiver operating characteristic curve (AUC) of 0.81 (specificity = 0.75, sensitivity = 0.70). The diagnostic ability of the model was also evaluated in an independent retrospective cohort, yielding a higher predictive power (AUC = 0.86). A signature of EV miRNA can be detected up to five years before MPM; moreover, the identified miRNAs could provide functional insights into the molecular changes related to the late carcinogenic process, preceding MPM development.

Mezei et al’s letter (1) is an opportunity to provide more details about our study on pericardial and tunica vaginalis testis (TVT) mesothelioma (2), which is based on the Italian national mesothelioma registry (ReNaM): a surveillance system on mesothelioma, with individual asbestos exposure assessment. Incidence of pericardial mesothelioma has been estimated around 0.5 and 0.2 cases per 10 million person-years in men and women, respectively, and around 1 case for TVT mesothelioma. ReNaM collected 138 cases thanks to its long period of observation (1993–2015) and national coverage. Conducting a population-based case–control study with incidence-density sampling of controls across Italy and over a 23 year time-span should have been planned in 1993 and would have been beyond feasibility and ReNaM scope. We rather exploited two existing series of controls (3). The resulting incomplete time- and spatial matching of cases and controls is a limitation of our study and has been acknowledged in our article. The analysis of case–control studies can nevertheless be accomplished in logistic models accounting for the variables of interest, in both individually and frequency matched studies (4). Furthermore, analyses restricted to (i) regions with enrolled controls, (ii) cases with definite diagnosis, (iii) incidence period 2000–2015, and (iv) subjects born before 1950 have been provided in the manuscript, confirming the strength of the association with asbestos exposure (supplemental material tables S4–7). Following Mezei et al’s suggestion, we performed further sensitivity analyses by restriction to regions with controls and fitting conditional regression models using risk-sets made of combinations of age and year of birth categories (5-year classes for both). We confirmed positive associations with occupational exposure to asbestos of pericardial mesothelioma, with odds ratios (OR) (adjusted for region) of 9.16 among women [95% confidence interval (CI) 0.56–150] and 5.63 (95% CI 1.02–31.0) among men; for TVT mesothelioma the OR was 7.70 (95% CI 2.89–20.5). Using risk sets of age categories and introducing year of birth (5-year categories) as a covariate (dummy variables) the OR were similar: OR (adjusted for region) of 9.17 among women (95% CI 0.56–150) and 5.76 (95% CI 1.07–31.0) among men; for TVT the OR was 9.86 (95% CI 3.46–28.1). Possible bias from incomplete geographical overlap between cases and controls has been addressed in the paper (table S4) and above. In spatially restricted analyses, OR were larger than in those including cases from the whole country, indicating that bias was towards the null. Mezei et al further noted that “the regional distribution of controls is different from that of person-time observed”. This objection is not relevant because the above analyses were adjusted by region. Our controls were provided by a population-based study on pleural mesothelioma (called MISEM) and a hospital-based study on cholangiocarcinoma (called CARA). In MISEM, the response rate was 48.4%, a low but not unexpected rate as participation among population controls is usually lower and has been declining over time (5). It is important to underline that ReNaM applied the same questionnaire that was used for interviews and carried out the same exposure assessment as both MISEM and CARA. As repeatedly stated in ReNaM papers (6–7), each regional operating center assesses asbestos exposure based on the individual questionnaire, other available information, and knowledge of local industries. Occupational exposure to asbestos is classified as definite, probable or possible. Occupational exposure is (i) definite when the subject`s work was reported or otherwise known to have involved the use of asbestos or asbestos-containing materials (MCA); (ii) probable when subjects worked in factories where asbestos or MCA were used, but their personal exposure could not be documented; and (iii) possible when they were employed in industrial activities known to entail the use of asbestos or MCA. Hence, the definite and probable categories are closer to one another and were combined in our analyses. In any case, restricting analyses to subjects with definite occupational exposure and using each set of controls separately, as suggested by Mezei et al, yielded elevated OR for TVT and pericardial mesothelioma among men using both the above described modelling strategies; the OR could not be calculated for women. There were 70 (25 pericardial and 45 TVT) occupationally exposed mesothelioma cases. In population-based studies, analyses by occupation are limited by the low prevalence of most specific jobs. As briefly reported in our paper, for purely descriptive purposes, the industrial activity of exposure (cases may have multiple exposures), were construction (22 exposures, 7 and 15 for pericardial and TVT mesotheliomas, respectively), steel mills and other metal working industries (4 and 11), textile industries (2 and 3), and agriculture (2 and 5); other sectors had lower exposure frequencies. The absence of industries like asbestos-cement production, shipbuilding and railway carriages production/repair should not be surprising and had already been observed (7). In the Italian multicenter cohort study of asbestos workers (8), given the person-years of observation accrued by workers employed in these industries and gender- and site-specific crude incidence rates, approximately 0.1 case of pericardial and 0.2 of TVT mesothelioma would have been expected from 1970 to 2010. Even increasing ten-fold such figures to account for higher occupational risks among these workers would not change much. Asbestos exposure in agriculture has been repeatedly discussed in ReNaM reports (9: pages 70, 73, 128, 164 and 205). Exposure opportunities included the presence of asbestos in wine production, reuse of hessian bags previously containing asbestos, or construction and maintenance of rural buildings. Similarly, mesothelioma cases and agricultural workers exposed to asbestos have been noted in France (10). In conclusion, the additional analyses we performed according to Mezei et al’s suggestions confirm the association between asbestos exposure and pericardial and TVT mesothelioma, supporting the causal role of asbestos for all mesotheliomas. ReNaM`s continuing surveillance system with national coverage is a precious platform for launching analytical studies on pleural and extra pleural mesothelioma. References 1. Mezei G, Chang ET, Mowat FS, Moolgavkar SH. Comments on a recent case-control study of malignant mesothelioma of the pericardium and the tunica vaginalis testis Scand J Work Environ Health. 2021;47(1):85–86. https://doi.org/10.5271/3909 2. Marinaccio A, Consonni D, Mensi C, Mirabelli D, Migliore E, Magnani C et al.; ReNaM Working Group. Association between asbestos exposure and pericardial and tunica vaginalis testis malignant mesothelioma: a case-control study and epidemiological remarks. Scand J Work Environ Health. 2020;46(6):609–617. https://doi.org/10.5271/sjweh.3895. 3. Greenland S. Control-initiated case-control studies. Int J Epidemiol 1985 Mar;14(1):130–4. https://doi.org/10.1093/ije/14.1.130. 4. Pearce N. Analysis of matched case-control studies. BMJ 2016 Feb;352:i969. https://doi.org/10.1136/bmj.i969. 5. Bigert C, Gustavsson P, Straif K, Pesch B, Brüning T, Kendzia B et al. Lung cancer risk among cooks when accounting for tobacco smoking: a pooled analysis of case-control studies from Europe, Canada, New Zealand, and China. J Occup Environ Med 2015 Feb;57(2):202–9. https://doi.org/10.1097/JOM.0000000000000337. 6. Marinaccio A, Binazzi A, Marzio DD, Scarselli A, Verardo M, Mirabelli D et al.; ReNaM Working Group. Pleural malignant mesothelioma epidemic: incidence, modalities of asbestos exposure and occupations involved from the Italian National Register. Int J Cancer 2012 May;130(9):2146–54. https://doi.org/10.1002/ijc.26229. 7. Marinaccio A, Binazzi A, Di Marzio D, Scarselli A, Verardo M, Mirabelli D et al. Incidence of extrapleural malignant mesothelioma and asbestos exposure, from the Italian national register. Occup Environ Med 2010 Nov;67(11):760–5. https://doi.org/10.1136/oem.2009.051466. 8. Ferrante D, Chellini E, Merler E, Pavone V, Silvestri S, Miligi L et al.; the working group. Italian pool of asbestos workers cohorts: mortality trends of asbestos-related neoplasms after long time since first exposure. Occup Environ Med 2017 Dec;74(12):887–98. https://doi.org/10.1136/oemed-2016-104100. 9. ReNaM VI Report. Available from: https://www.inail.it/cs/internet/docs/alg-pubbl-registro-nazionale-mesoteliomi-6-rapporto.pdf. Italian 10. Marant Micallef C, Shield KD, Vignat J, Baldi I, Charbotel B, Fervers B et al. Cancers in France in 2015 attributable to occupational exposures. Int J Hyg Environ Health 2019 Jan;222(1):22–9. https://doi.org/10.1016/j.ijheh.2018.07.015.

Germline mutations in the tumor suppressor gene BRCA1-associated protein-1 (BAP1) lead to BAP1 tumor predisposition syndrome (BAP1-TPDS), characterized by high susceptibility to several tumor types, chiefly melanoma, mesothelioma, renal cell carcinoma, and basal cell carcinoma. Here, we present the results of our ten-year experience in the molecular diagnosis of BAP1-TPDS, along with a clinical update and cascade genetic testing of previously reported BAP1-TPDS patients and their relatives. Specifically, we sequenced germline DNA samples from 101 individuals with suspected BAP1-TPDS and validated pathogenic variants (PVs) by assessing BAP1 somatic loss in matching tumor specimens. Overall, we identified seven patients (7/101, 6.9%) carrying six different germline BAP1 PVs, including one novel variant. Consistently, cascade testing revealed a total of seven BAP1 PV carriers. In addition, we explored the mutational burden of BAP1-TPDS tumors by targeted next-generation sequencing. Lastly, we found that certain tumors present in PV carriers retain a wild-type BAP1 allele, suggesting a sporadic origin of these tumors or a functional role of heterozygous BAP1 in neoplastic development. Altogether, our findings have important clinical implications for therapeutic response of BAP1-TPDS patients.

Abstract Background Despite the available information on cancer risk, asbestos is used in large areas in the world, mostly in the production of asbestos cement. Moreover, questions are raised regarding the shape of the dose response relation, the relation with time since exposure and the association with neoplasms in various organs. We conducted a study on the relationship between cumulative asbestos exposure and mortality from asbestos related diseases in a large Italian pool of 21 cohorts of asbestos-cement workers with protracted exposure to both chrysotile and amphibole asbestos. Methods The cohort included 13,076 workers, 81.9% men and 18.1% women, working in 21 Italian asbestos-cement factories, with over 40 years of observation. Exposure was estimated by plant and period, and weighted for the type of asbestos used. Data were analysed with consideration of cause of death, cumulative exposure and time since first exposure (TSFE), and by gender. SMRs were computed using reference rates by region, gender and calendar time. Poisson regression models including cubic splines were used to analyse the effect of cumulative exposure to asbestos and TSFE on mortality for asbestos-related diseases. 95% Confidence Intervals (CI) were computed according to the Poisson distribution. Results Mortality was significantly increased for ‘All Causes’ and ‘All Malignant Neoplasm (MN)’, in both genders. Considering asbestos related diseases (ARDs), statistically significant excesses were observed for MN of peritoneum (SMR: men 14.19; women 15.14), pleura (SMR: 22.35 and 48.10), lung (SMR: 1.67 and 1.67), ovary (in the highest exposure class SMR 2.45), and asbestosis (SMR: 507 and 1023). Mortality for ARDs, in particular pleural and peritoneal malignancies, lung cancer, ovarian cancer and asbestosis increased monotonically with cumulative exposure. Pleural MN mortality increased progressively in the first 40 years of TSFE, then reached a plateau, while peritoneal MN showed a continuous increase. The trend of lung cancer SMRs also showed a flattening after 40 years of TSFE. Attributable proportions for pleural, peritoneal, and lung MN were respectively 96, 93 and 40%. Conclusions Mortality for ARDs was associated with cumulative exposure to asbestos. Risk of death from pleural MN did not increase indefinitely with TSFE but eventually reached a plateau, consistently with reports from other recent studies.

Statistical models used to forecast malignant pleural mesothelioma (MPM) trends often do not take into account historical asbestos consumption, possibly resulting in less accurate predictions of the future MPM death toll. We used the distributed lag non-linear model (DLNM) approach to predict future MPM cases in Italy until 2040, based on past asbestos consumption figures. Analyses were conducted using data on male MPM deaths (1970–2014) and annual asbestos consumption using data on domestic production, importation, and exportation. According to our model, the peak of MPM deaths is expected to occur in 2021 (1122 expected cases), with a subsequent decrease in mortality (344 MPM deaths in 2039). The exposure–response curve shows that relative risk (RR) of MPM increased almost linearly for lower levels of exposure but flattened at higher levels. The lag-specific RR grew until 30 years since exposure and decreased thereafter, suggesting that the most relevant contributions to the risk come from exposures which occurred 20–40 years before death. Our results show that the Italian MPM epidemic is approaching its peak and underline that the association between temporal trends of MPM and time since exposure to asbestos is not monotonic, suggesting a lesser role of remote exposures in the development of MPM than previously assumed.

Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for noninvasive tests aimed at an MPM risk assessment tool that might improve life expectancy. Three hundred asbestos-exposed subjects (163 MPM cases and 137 cancer-free controls), from the same geographical region in Italy, were recruited. The evaluation of asbestos exposure was conducted considering the frequency, the duration and the intensity of occupational, environmental and domestic exposure. A genome-wide methylation array was performed to identify novel blood DNA methylation (DNAm) markers of MPM. Multiple regression analyses adjusting for potential confounding factors and interaction between asbestos exposure and DNAm on the MPM odds ratio were applied. Epigenome-wide analysis (EWAS) revealed 12 single-CpGs associated with the disease. Two of these showed high statistical power (99%) and effect size (>0.05) after false discovery rate (FDR) multiple comparison corrections: (i) cg03546163 in FKBP5, significantly hypomethylated in cases (Mean Difference in beta values (MD) = −0.09, 95% CI = −0.12|−0.06, p = 1.2 × 10−7), and (ii) cg06633438 in MLLT1, statistically hypermethylated in cases (MD = 0.07, 95% CI = 0.04|0.10, p = 1.0 × 10−6). Based on the interaction analysis, asbestos exposure and epigenetic profile together may improve MPM risk assessment. Above-median asbestos exposure and hypomethylation of cg03546163 in FKBP5 (OR = 20.84, 95% CI = 8.71|53.96, p = 5.5 × 10−11) and hypermethylation of cg06633438 in MLLT1 (OR = 11.71, 95% CI = 4.97|29.64, p = 5.9 × 10−8) genes compared to below-median asbestos exposure and hyper/hypomethylation of single-CpG DNAm, respectively. Receiver Operation Characteristics (ROC) for Case-Control Discrimination showed a significant increase in MPM discrimination when DNAm information was added in the model (baseline model, BM: asbestos exposure, age, gender and white blood cells); area under the curve, AUC = 0.75; BM + cg03546163 at FKBP5. AUC = 0.89, 2.1 × 10−7; BM + cg06633438 at MLLT1. AUC = 0.89, 6.3 × 10−8. Validation and replication procedures, considering independent sample size and a different DNAm analysis technique, confirmed the observed associations. Our results suggest the potential application of DNAm profiles in blood to develop noninvasive tests for MPM risk assessment in asbestos-exposed subjects.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with median survival of 12 months and limited effective treatments. The scope of this study was to study the relationship between blood DNA methylation (DNAm) and overall survival (OS) aiming at a noninvasive prognostic test. We investigated a cohort of 159 incident asbestos exposed MPM cases enrolled in an Italian area with high incidence of mesothelioma. Considering 12 months as a cut-off for OS, epigenome-wide association study (EWAS) revealed statistically significant (p value = 7.7 × 10−9) OS-related differential methylation of a single-CpG (cg03546163), located in the 5′UTR region of the FKBP5 gene. This is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Cases with DNAm < 0.45 at the cg03546163 had significantly poor survival compared with those showing DNAm ≥ 0.45 (mean: 243 versus 534 days; p value< 0.001). Epigenetic changes at the FKBP5 gene were robustly associated with OS in MPM cases. Our results showed that blood DNA methylation levels could be promising and dynamic prognostic biomarkers in MPM.

The authors would like to publish this addendum to their recent publication [...]

Background: Magnesium is involved in a wide variety of physiological processes including direct relaxation of smooth muscle. A magnesium imbalance can be considered the primary cause or consequence of many pathophysiological conditions. The smooth muscle tissue of the uterus, i.e., the myometrium, undergoes numerous physiological changes during life, fundamental for uterine activities, and it receives proven benefits from magnesium supplementation. However, magnesium supplements have poor absorption and bioavailability. Furthermore, no data are available on the direct interaction between intestinal absorption of magnesium and relaxation of the myometrium. Methods: Permeability in human intestinal cells (Caco-2 cells) and direct effects on myometrial cells (PHM1-41 cells) of two different forms of magnesium, i.e., sucrosomial and bisglycinate, were studied in order to verify the magnesium capacity of modulate contractility. Cell viability, reactive oxygen species (ROS) and nitric oxide (NO) production, magnesium concentration, contractility, and pathways involved were analyzed. Results: Data showed a better influence of buffered chelate bisglycinate on intestinal permeability and myometrial relaxation over time with a maximum effect at 3 h and greater availability compared to the sucrosomial form. Conclusions: Magnesium-buffered bisglycinate chelate showed better intestinal absorption and myometrial contraction, indicating a better chance of effectiveness in human applications.

Background: The association between circulating levels of vitamin D and the incidence of chronic diseases is known. The identification of vitamin D as a biomarker of physiological/pathological ageing could contribute to expanding current knowledge of its involvement in healthy ageing. Methods: According to PRISMA guidelines, a systematic review was conducted on cohorts studying the role of 25OH-Vitamin D [25(OH)D] and 1,25(OH)2-Vitamin D [1,25(OH)2D] concentrations as biomarkers of healthy ageing. We consulted MedLine, Scopus, and Web of Science to search for studies on the association between vitamin D status in populations of originally healthy adults, and outcomes of longevity, illness, and physical and cognitive functionality. The quality of the studies was assessed using the Newcastle Ottawa scale. Results: Twenty cohorts from 24 articles were selected for this review. Inverse associations were found between low 25(OH)D levels and all-cause mortality, respiratory and cardiovascular events, as well as markers relating to hip and non-vertebral fractures. Associations between 1,25(OH)2D and healthy ageing outcomes gave similar results, although of lower clinical significance. Conclusions: This systematic review pinpoints peculiar aspects of vitamin D as a multidimensional predictor of ill health in the ageing process. Further well-designed controlled trials to investigate whether vitamin D supplement results in superior outcomes are warranted in the future.

BackgroundAlpha-synuclein is a constituent of Lewy bodies and mutations of its gene cause familial Parkinson’s disease (PD). A previous study showed that a variant of the alpha-synuclein gene (SNCA), namely the 263 bp allele of Rep1 was associated with faster motor progression in PD. On the contrary, a recent report failed to detect a detrimental effect of Rep1 263 on both motor and cognitive outcomes in PD. Aim of this study was to evaluate the influence of the Rep1 variants on disease progression in PD patients.MethodsWe recruited and genotyped for SNCA Rep1 426 PD patients with age at onset ≥40 years and disease duration ≥4 years. We then analyzed frequency and time of occurrence of wearing-off, dyskinesia, freezing of gait, visual hallucinations, and dementia using a multivariate Cox’s proportional hazards regression model.ResultsSNCA Rep1 263 carriers showed significantly increased risk of both dementia (HR = 3.03) and visual hallucinations (HR = 2.69) compared to 263 non-carriers. Risk of motor complications did not differ in the two groups.ConclusionSNCA Rep1 263 allele is associated with a worse cognitive outcome in PD.

In the past, increases in childhood cancer incidence were reported in Europe and North America. The aim of this study is to show updated patterns of temporal behavior using data of the Childhood Cancer Registry of Piedmont (CCRP), a region with approximately 4.5 million inhabitants in North-West Italy. CCRP has been recording incident cases in children (0-14 years) since 1967 and in adolescents (15-19) since 2000. Time trends were estimated as annual percent change (APC) over the 1976-2011 period for children, and over 2000-2011 for both children and adolescents. CCRP registered 5020 incident cases from 1967 to 2011. Incidence rates were 157 per million person-years for children (1967-2011) and 282 for adolescents (2000-2011). From 1976-2011, increasing trends were observed in children for all neoplasms (APC 1.1, 95%CI: 0.8; 1.5) and for both embryonal and non-embryonal tumors: 1.1%, (0.5; 1.6) and 1.2%, (0.7; 1.6), respectively. Increases were observed in several tumor types, including leukemia, lymphoma, central nervous system tumors and neuroblastoma. In 2000-2011, incidence rates showed mostly non statistically significant variations and large variability. The observation of trends over a long period shows that the incidence of most tumors has increased, and this is only partially explained by diagnostic changes. Large rate variability hampers interpretation of trend patterns in short periods. Given that no satisfying explanation for the increases observed in the past was ever found, efforts must be made to understand and interpret this peculiar and still ununderstood pattern of childhood cancer incidence.

The objective of this paper is to investigate mortality among 1247 male asbestos-cement workers employed in an asbestos-cement plant located in Naples. The cohort included 1247 men hired between 1950 and 1986. The follow-up began on January 1st 1965. The vital status and causes of death were ascertained up to December 31 2005. Cause-specific mortality rates of the Campania Region population were used as reference. Relative risks were estimated using Standardized Mortality Ratios (SMRs), and the confidence intervals were calculated at a 95% level (95% CI). A significant increase in mortality was observed for respiratory disease (81 deaths; SMR = 187; 95% CI = 149-233), particularly for pneumoconiosis (42 deaths; SMR = 13 313; 95% CI = 9595-17 996) of which 41 deaths for asbestosis (SMR = 43 385; 95% CI = 31 134-58 857), for pleural cancer (24 deaths; SMR = 2617; 95% CI = 1677-3893), for lung cancer (84 deaths; SMR=153; 95% CI = 122-189) and for peritoneal cancer (9 deaths; SMR = 1985; 95% CI = 908-3769). Non-significant increases were also observed for rectum cancer (6 deaths; SMR = 157; 95% CI = 58-342). In conclusion, consistently with other mortality studies on asbestos-cement workers performed in different countries, an increased mortality from asbestosis, lung cancer, pleural and peritoneal mesothelioma was detected in the present cohort.

The relation between disease risk and a point source of pollution is usually investigated using distance from the source as a proxy of exposure. The analysis may be based on case-control data or on aggregated data. The definition of the function relating risk of disease and distance is critical, both in a classical and in a Bayesian framework, because the likelihood is usually very flat, even with large amounts of data. In this paper we investigate how the specification of the function relating risk of disease with distance from the source and of the prior distributions on the parameters of the function affects the results when case-control data and Bayesian methods are used. We consider different popular parametric models for the risk distance function in a Bayesian approach, comparing estimates with those derived by maximum likelihood. As an example we have analyzed the relationship between a putative source of environmental pollution (an asbestos cement plant) and the occurrence of pleural malignant mesothelioma in the area of Casale Monferrato (Italy) in 1987-1993. Risk of pleural malignant mesothelioma turns out to be strongly related to distance from the asbestos cement plant. However, as the models appeared to be sensitive to modeling choices, we suggest that any analysis of disease risk around a putative source should be integrated with a careful sensitivity analysis and possibly with prior knowledge. The choice of prior distribution is extremely important and should be based on epidemiological considerations.

BackgroundVitamin D status during pregnancy is related to neonatal vitamin D status. Vitamin D deficiency has been associated with an increased risk of rickets in children and osteomalacia in adults. Aim of this study was to investigate 25OHD levels in maternal serum and in neonatal blood spots in native and migrant populations living in Novara (North Italy, 45°N latitude).Methods and findingsWe carried out a cross sectional study from April 1st 2012 to March 30th 2013, in a tertiary Care Center. Maternal blood samples after delivery and newborns' blood spots were analyzed for 25OHD levels in 533 pairs. Maternal country of origin, skin phototype, vitamin D dietary intake and supplementation during pregnancy were recorded. Multivariate regression analysis, showed a link between neonatal and maternal 25OHD levels (R-square:0.664). Severely deficient 25OHD values (ConclusionsVitamin D insufficiency in pregnancy and in newborns is frequent especially among migrants. A prevention program in Piedmont should urgently be considered and people identified as being at risk should be closely monitored. Vitamin D supplementation should be taken into account when considering a preventative health care policy.

BACKGROUND:Parental smoking and exposure of the mother or the child to environmental tobacco smoke (ETS) as risk factors for Acute non-Lymphocytic Leukemia (AnLL) were investigated. METHODS:Incident cases of childhood AnLL were enrolled in 14 Italian Regions during 1998-2001. We estimated odds ratios (OR) and 95% confidence intervals (95%CI) conducting logistic regression models including 82 cases of AnLL and 1,044 controls. Inverse probability weighting was applied adjusting for: age; sex; provenience; birth order; birth weight; breastfeeding; parental educational level age, birth year, and occupational exposure to benzene. RESULTS:Paternal smoke in the conception period was associated with AnLL (OR for ≥ 11 cigarettes/day = 1.79, 95% CI 1.01-3.15; P trend 0.05). An apparent effect modification by maternal age was identified: only children of mothers aged below 30 presented increased risks. We found weak statistical evidence of an association of AnLL with maternal exposure to ETS (OR for exposure>3 hours/day = 1.85, 95%CI 0.97-3.52; P trend 0.07). No association was observed between AnLL and either maternal smoking during pregnancy or child exposure to ETS. CONCLUSIONS:This study is consistent with the hypothesis that paternal smoke is associated with AnLL. We observed statistical evidence of an association between maternal exposure to ETS and AnLL, but believe bias might have inflated our estimates.

Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, only 5-17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs) in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia. Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene-ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes), causing at most a 2-3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14). Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC) of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52-95.28). These results showed that genetic risk factors may play an additional role in the development of MPM, and that these should be taken into account to better estimate individual MPM risk in individuals who have been exposed to asbestos.

In spite of the common belief of Europe as reasonably homogeneous at genetic level, advances in high-throughput genotyping technology have resolved several gradients which define different geographical areas with good precision. When Northern and Southern European groups were considered separately, there were clear genetic distinctions. Intra-country genetic differences were also evident, especially in Finland and, to a lesser extent, within other European populations. Here, we present the first analysis using the 125,799 genome-wide Single Nucleotide Polymorphisms (SNPs) data of 1,014 Italians with wide geographical coverage. We showed by using Principal Component analysis and model-based individual ancestry analysis, that the current population of Sardinia can be clearly differentiated genetically from mainland Italy and Sicily, and that a certain degree of genetic differentiation is detectable within the current Italian peninsula population. Pair-wise F(ST) statistics Northern and Southern Italy amounts approximately to 0.001 between, and around 0.002 between Northern Italy and Utah residents with Northern and Western European ancestry (CEU). The Italian population also revealed a fine genetic substructure underscoring by the genomic inflation (Sardinia vs. Northern Italy = 3.040 and Northern Italy vs. CEU = 1.427), warning against confounding effects of hidden relatedness and population substructure in association studies.

Background The aim of this study was to describe the patterns of marriage and parenthood in a cohort of childhood cancer survivors included in the Off-Therapy Registry maintained by the Italian Association of Pediatric Hematology and Oncology.Design and Methods We analyzed a cohort of 6,044 patients diagnosed with cancer between 1960 and 1998, while aged 0 to 14 years and who were 18 years old or older by December 2003. They were followed up through the regional vital statistics registers until death or the end of follow up (October 30, 2006), whichever occurred first, and their marital status and date of birth of their children were recorded. The cumulative probabilities of being married and having a first child were computed by gender and compared by tumor type within the cohort. Marriage and fertility rates (the latter defined as the number of live births per woman-year) were compared with those of the Italian population of the same age, gender, area of residence and calendar period by means of the observed to expected (O/E) ratios.Results During the follow-up period, 4,633 (77%) subjects had not married. The marriage O/E ratios were 0.56 (95% CI: 0.51–0.61) and 0.70 (95% CI: 0.65–0.76) among men and women, respectively. Overall, 263 men had 367 liveborn children, and 473 women had 697 liveborn children. The female fertility O/E ratio was 0.57 (95% CI: 0.53–0.62) overall, and 1.08 (95% CI: 0.99–1.17) when analyses were restricted to married/cohabiting womenConclusions Childhood cancer survivors are less likely to marry and to have children than the general population, confirming the life-long impact of their previous disease on their social behavior and choices. The inclusion of counseling in the strategies of management and long-term surveillance of childhood cancer patients could be beneficial to survivors as they approach adulthood.

The total number of children with incident cancer in Italy has never been specifically estimated. Specialized population-based Childhood Cancer Registries have only been operating in Piedmont (CCRP) and in the Marche region, while general population cancer registries cover about 20% of the Italian population. The number of expected cases of childhood cancer (0–14 years) in Italy in the period 2001–2015 has been estimated using CCRP incidence rates and annual percentage changes. The expected number of cases of all cancer types were 8,132, 8,672 and 8,944 in the periods 2001–2005, 2006–2010 and 2011–2015 respectively. These figures help evaluate the allocation of resoures for the care of child cancer patients in Italy, and to estimate the number of cases expected to enter clinical trials.