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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.

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.

Background: Biliary tract cancer (BTC) encompasses a group of rare and heterogeneous malignancies with poor prognosis, including gallbladder cancer, ampulla of Vater cancer, intrahepatic cholangiocarcinoma (iCCA), and extrahepatic cholangiocarcinoma (eCCA), with the latter further subdivided into perihilar (pCCA) and distal (dCCA). Unfortunately, potentially curative surgical resection is possible in approximately the 25% of BTC patients at diagnosis, and even following radical surgery, relapse rates remain high. The aim of this research was to evaluate the impact of an intensive follow-up program in BTC patients who had received surgical resection with curative intent at a tertiary referral hospital. Methods: Medical records of all consecutive BTC patients treated with curative intent surgery at S. Orsola Malpighi Hospital, Bologna, Italy, from January 2000 to November 2020, were retrospectively reviewed. The BTC-specific overall survival (OS) and disease-free survival (DFS) status were determined by the Kaplan-Meier method; univariate and multivariate analysis were performed to assess the impact of covariates on survival. Results: A total of 398 BTC patients receiving surgery with curative intent were included in the analysis. Macroscopic residual tumor was observed in 29 patients, while 329 BTCs underwent R0 (n¼222; 67%) or R1 (n¼107; 33%) surgery. Among these, 278 patients started a follow-up program at our institution based on physical examination, serum CEA and CA19-9 and abdominal/chest CT scan every 3-4 months in the first two years and every 6 months from the third to the fifth year; 80% of this group (222/278) started follow-up after adjuvant chemotherapy (in case of R0 surgery) or chemoradiotherapy (in R1 resection). The median age of the follow-up group was 63 years (range 31-85 years) and 164 (49.5%) were females. Overall, 116 (32.5%) and 126 (38.6%) patients had iCCA and eCCA (78 pCCAs and 48 dCCAs), respectively. At a median follow-up of 37.4 months, median OS was 50.8 and 35 months in R0 and R1 patients, respectively (p¼0.04); similarly, median DFS was 16.4 and 12.3 months in the same groups (p¼0.02). No relapse was observed in 129 out of 329 BTCs (39%), while the 61% of R0/R1 patients (200/329) experienced disease relapse, including 39% of iCCA and 38% of eCCA; liver was the most frequent site of relapse (78%) followed by peritoneum and locoregional lymph nodes. In terms of treatment at the relapse, 15% (30/200) of patients underwent second surgery (R0¼14, R1¼6, R2¼3, exploratory laparotomy¼7) while 20% (40/200) received a locoregional approach, the most frequent of which was radiofrequency ablation (n¼22). None of the 14 BTC patients receiving second surgery with R0 experienced disease relapse. Overall, 127 BTCs received first-line chemotherapy following relapse, with gemcitabine-cisplatin as the most commonly used regimen (52%). Conclusions: Based on the results of our 20-year, single-center experience of 278 BTC patients, an intensive follow-up after surgical resection with curative intent could help in the identification of disease relapse, leading to early treatment and prolonged survival in selected cases, as reported in BTCs treated with second surgical resection with negative margins.

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Biliary tract cancer (BTC) patients usually have poor prognosis. Whereas combination chemotherapy has been shown to improve survival in the frontline setting, second-line treatment is subject to a lot of debate in the scientific community. Recent data of the ABC-06 trial has provided slight evidence for the use of second-line chemotherapy after progression on cisplatin plus gemcitabine combination. In this study, mFOLFOX plus active symptom control (ASC) improved overall survival (OS) after progression on cisplatin-gemcitabine combination compared with ASC alone, with an increase in 6- and 12-month OS rate. Although genomic studies have paved the way for a new age in cancer management, the “Precision Medicine Era” in BTC is still limited to intrahepatic cholangiocarcinoma and primarily focused on isocitrate dehydrogenase (IDH) and fibroblast growth factor receptor (FGFR) targeted therapies. We herein review recent published data regarding the use of second-line treatment after failure of standard first-line therapies in BTC patients, with a particular focus on ongoing active and recruiting clinical trials.

Introduction. Doping is an important public health problem widespread not only among elite athletes, but also among amateur and recreational athletes and the general population. In Italy the introduction of doping prevention within the Essential Levels of Care (LEA) with the DPCM 12/1/2017 represents a crucial step towards the implementation of education and health promotion interventions. In this context, the Departments of Prevention (DP) of the Local Health Authorities (LHA) have to play a fundamental role, becoming the cultural and operational reference on this issue. As part of the "Doping prevention: development of a permanent educational tool coordinated by the National Health Service Prevention Departments" project, funded by the Italian Ministry of Health, a survey was conducted on the activities carried out by the DP regarding doping prevention and improper use and abuse of drugs and food supplements in sports and physical activities, as a basis for the harmonization of organizational structures and prevention programs and the creation of a collaboration network at a regional and national level. Methods. A semi-structured questionnaire consisting of 11 questions, prepared on an electronic platform, was sent to the DP of all the Italian LHA. Results. A total of 38 DP out of 131 (29%) completed the questionnaire, with representation from all regions. 42.1% of DP carried out or are still running programs for the prevention of doping, a percentage that decreases to 27% considering the programs for the prevention of misuse and abuse of drugs and food supplements in sports and in physical activities; in less than half of the DP, 37.5% and 41.7%, respectively, dedicated funds have been allocated. The professionals most involved in prevention of doping are the Specialists in Sport Medicine (81.3%) followed by Specialists in Hygiene (43.8%) and Psychologists (37.5%), while Health Care Assistants (50%) are the professionals most involved in the prevention of the improper use of drugs and food supplements, followed by Specialists in Hygiene and Specialists in Sport Medicine (40%). Most of the DP (71.9%) believe that the introduction of programs to prevent and counteract doping in the LEA will have repercussions on their approach against doping. Conclusions. The survey, although conducted on a limited sample, has provided an important framework relating to programs for the prevention of doping and the misuse and abuse of drugs and food supplements in sports and in the physical activities carried out by DP. A remarkable heterogeneity has been highlighted, both at national and regional level. It is urgent to provide DP with homogeneous and effective organizational models and adequate operational tools, paying particular attention to the training of all the professionals involved. It is also essential to implement permanent monitoring tools.

The gut microbiota is implicated in digestive, metabolic and immune processes of the host. The physiological and pathophysiological functions of the intestinal microbiota depend of its composition, and several individual or external factors may be associated with the presence of some categories, phyla or species of microorganisms in the gut. In particular, two bacterial phyla - Firmicutes and Bacteroidetes - are predominant in the human gut and their relative concentrations seem to be related with age, gender, diet habits and weight status. In the last decade, several studies have tried to characterize the possible role of physical activity in determining qualitative and quantitative composition of the intestinal microbiota. This review is aimed at exploring the current evidences regarding the association between physical activity and gut microbiota composition in animal models and in the humans. Further studies are needed to clarify the mutual relationships among exercise, diet, nutritional supplements/doping agents and gut microbiota.

Currently, physical activity is an important tool that may be useful to improve people health and quality of life through sustainable and effective interventions. In order to obtain durable improvements of individuals' behaviors, however, consistent changes in services organization and the creation of new opportunities in life settings are needed. This requires necessarily the involvement of complementary figures with specific competences. Considering their peculiar training curriculum, Movement Sciences graduates represent key figures in this context and they can operate fully in interventions of health education and promotion, within multidisciplinary teams collaborating with the National Health System (NHS), in order to obtain the global undertaking of citizens.

The WHO Global Action Plan on physical activity underlines the binomial "diet and physical activity" for the maintenance of well-being state. The adequate nutritional intake is required for sport and can be achieved by a well-adjusted diet without adding artificial food supplements, whose abuse can even represent a risk and appear as an antechamber of doping. Within a national doping prevention project, a peer education tool was realized in the form of a book and e-book, based on the principle of the Mediterranean Diet as an effective nutritional support in sport and physical activity. This health-literacy book contains recipes from all Italian regions revised for their capability to satisfy sport nutritional needs.