Paolo A. Boffetta

Objectives: To provide an evidence-based, comprehensive assessment of the current burden of infection-related cancers in Italy. Methods: We calculated the proportion of cancers attributable to infectious agents (Helicobacter pylori [Hp]; hepatitis B virus [HBV] and hepatitis C virus [HCV]; human papillomavirus [HPV]; human herpesvirus-8 [HHV8]; Epstein–Barr virus [EBV]; and human immunodeficiency virus [HIV]) to estimate the burden of infection-related cancer incidence (2020) and mortality (2017). Data on the prevalence of infections were derived from cross-sectional surveys of the Italian population, and relative risks from meta-analyses and large-scale studies. Attributable fractions were calculated based on the counterfactual scenario of a lack of infection. Results: We estimated that 7.6% of total cancer deaths in 2017 were attributable to infections, with a higher proportion in men (8.1%) than in women (6.9%). The corresponding figures for incident cases were 6.5%, 6.9% and 6.1%. Hp was the first cause of infection-related cancer deaths (3.3% of the total), followed by HCV (1.8%), HIV (1.1%), HBV (0.9%), HPV, EBV and HHV8 (each ≤0.7%). Regarding incidence, 2.4% of the new cancer cases were due to Hp, 1.3% due to HCV, 1.2% due to HIV, 1.0% due to HPV, 0.6% due to HBV and <0.5% due to EBV and HHV8. Conclusions: Our estimate of 7.6% of cancer deaths and 6.9% of incident cases that were attributable to infections in Italy is higher than those estimated in other developed countries. Hp is the major cause of infection-related cancer in Italy. Prevention, screening and treatment policies are needed to control these cancers, which are largely avoidable.

Background: We predicted cancer mortality figures for 2023 for the European Union (EU-27), its five most populous countries, and the UK. We also focused on mortality from lung cancer. Materials and methods: Using cancer death certification and population data from the World Health Organization and Eurostat databases for 1970-2018, we predicted numbers of deaths and age-standardized rates (ASRs) for 2023 for all cancers combined and the 10 most common cancer sites. We investigated the changes in trends over the observed period. The number of avoided deaths over the period 1989-2023 were estimated for all cancers as well as lung cancer. Results: We predicted 1 261 990 cancer deaths for 2023 in the EU-27, corresponding to ASRs of 123.8/100 000 men (−6.5% versus 2018) and 79.3 for women (−3.7%). Over 1989-2023, ∼5 862 600 cancer deaths were avoided in the EU-27 compared with peak rates in 1988. Most cancers displayed favorable predicted rates, with the exceptions of pancreatic cancer, which was stable in EU men (8.2/100 000) and rose by 3.4% in EU women (5.9/100 000), and female lung cancer, which, however, tends to level off (13.6/100 000). Steady declines are predicted for colorectal, breast, prostate, leukemia, stomach in both sexes, and male bladder cancers. The focus on lung cancer showed falls in mortality for all age groups in men. Female lung cancer mortality declined in the young (−35.8%, ASR: 0.8/100 000) and middle-aged (−7%, ASR: 31.2/100 000) but still increased by 10% in the elderly (age 65+ years). Conclusions: The advancements in tobacco control are reflected in favorable lung cancer trends, and should be pushed further. Greater efforts on the control of overweight and obesity, alcohol consumption, infection and related neoplasms, together with improvements in screening, early diagnosis, and treatments may achieve a further 35% reduction in cancer mortality in the EU by 2035.

Gallbladder cancer (GBC) is one of the deadliest malignancy and treatment options are deplorably limited. Better strategies of prevention are urgently needed but knowledge on risk factors remains scarce. Recent data suggested that arsenic (As) may be involved in GBC carcinogenesis but the question remains debated. To date, there are no data on As measurement in GBC samples. This pilot study aimed to measure As concentrations in tissue samples from patients with GBC compared to non-cancerous gallbladder (NCGB). Included patients underwent cholecystectomy at Hospital Clinico Universidad de Chile, Santiago in Chile, a country with high As exposure, between 2001 and 2020. Tissue samples were preserved in formalin-fixed, paraffin-embedded blocks. Selected samples were retrieved, processed and submitted to inductively coupled plasma mass spectrometry (ICP-MS) to determine As concentrations. A total of 77 patients were included, including 35 GBC and 42 NCGB. The two groups were comparable, except for age (68 vs. 49 years, p < 0.001). Measured in 11 GBC and 38 NCGB, total As was detected in 5 GBC (14%) compared to 0 NCGB samples (p < 0.001). GBC group also showed higher median values of As compared to NCGB (p < 0.001). This pilot study provided a proof-of-concept to measure As concentrations in gallbladder samples and showed higher level of As in GBC samples compared to NCGB, paving the way for future studies aiming to investigate the impact of As on GBC, which may contribute to the prevention of this deadly disease.

Introduction: Hazardous exposures from the World Trade Center (WTC) terrorist attacks have been linked to increased incidence of adverse health conditions, often associated with increased mortality. We assessed mortality in a pooled cohort of WTC rescue/recovery workers over 15 years of follow-up. Materials and methods: We analyzed mortality through 2016 in a pooled and deduplicated cohort of WTC rescue/recovery workers from three WTC-exposed cohorts (N = 60,631): the Fire Department of the City of New York (FDNY); the WTC Health Registry (WTCHR); and the General Responder Cohort (GRC). Standardized mortality ratios (SMRs) were estimated to assess mortality vs. the US and NY state populations. Multivariable Cox proportional hazards models were used to examine associations of WTC exposures (date of first arrival, working on the WTC debris pile) with mortality risk. Results: There were 1912 deaths over 697,943.33 person-years of follow-up. The SMR for all-cause mortality was significantly lower-than-expected, both when using US (SMR 0.43, 95% confidence interval [CI] 0.42–0.45) and NYS (SMR 0.51, 95% CI 0.49–0.53) as reference populations. SMRs were not elevated for any of the 28 major causes of death. Arriving at the WTC site on 9/11-9/17/2001 vs. 9/18/2001-6/30/2002 was associated with 30–50% higher risk of all-cause, heart disease and smoking-related mortality in non-FDNY/non-GRC members. Conversely, arriving on 9/11/2001 vs. 9/18/2001-6/30/2002 was associated with 40% lower all-cause and smoking-related mortality risk in FDNY members. Working on vs. off the WTC pile was associated with an increased risk of all-cause mortality in non-FDNY/non-GRC members (adjusted hazard ratio [aHR] 1.25, 95% CI 1.04–1.50), and cancer-specific mortality in GRC members (aHR 1.39, 95% CI 1.05–1.84), but lower mortality risks were found in FDNY members. Conclusions: We did not observe excess mortality among WTC rescue/recovery workers compared with general populations. However, significantly increased mortality risks among some sub-groups with high WTC exposure warrant further investigation.

We review research regarding the epidemiology, risk factors, genetic susceptibility, molecular pathology, and early detection of SCLC, a deadly tumor that accounts for 14% of lung cancers. We first summarize the changing incidences of SCLC globally and in the United States among males and females. We then review the established risk factor (i.e., tobacco smoking) and suspected nonsmoking-related risk factors for SCLC, and emphasize the importance of continued effort in tobacco control worldwide. Review of genetic susceptibility and molecular pathology suggests different molecular pathways in SCLC development compared with other types of lung cancer. Last, we comment on the limited utility of low-dose computed tomography screening in SCLC and on several promising blood-based molecular biomarkers as potential tools in SCLC early detection.

Background: Few studies focused on minor adverse events which may develop after colonoscopy. Aims: To investigate the incidence and factors associated to post-colonoscopy symptoms. Methods: This is a prospective study conducted in 10 Italian hospitals. The main outcome was a cumulative score combining 10 gastrointestinal (GI) symptoms occurring the week following colonoscopy. The analyses were conducted via multivariate logistic regression. Results: Of 793 subjects included in the analysis, 361 (45.5%) complained the new onset of at least one GI symptom after the exam; one symptom was reported by 202 (25.5%), two or more symptoms by 159 (20.1%). Newly developed symptoms more frequently reported were epigastric/abdominal bloating (32.2%), pain (17.3%), and dyspeptic symptoms (17.9%). Symptoms were associated with female sex (odds ratio [OR]=2.54), increasing number of symptoms developed during bowel preparation intake (OR=1.35) and somatic symptoms (OR=1.27). An inverse association was observed with better mood (OR=0.74). A high-risk profile was identified, represented by women with bad mood and somatic symptoms (OR=8.81). Conclusion: About half of the patients develop de novo GI symptoms following colonoscopy. Improving bowel preparation tolerability may reduce the incidence of post-colonoscopy symptoms, especially in more vulnerable patients.

Background: Symptoms developing during bowel preparation are major concerns among subjects who refuse the procedure. Aims: We aimed to explore the determinants of symptoms occurring during preparation among patients undergoing elective colonoscopy. Methods: This is a prospective multicenter study conducted in 10 Italian hospitals. A multidimensional approach collecting socio-demographic, clinical, psychological and occupational information before colonoscopy through validated instruments was used. Outcome was a four-category cumulative score based on symptoms occurring during preparation, according to the Mayo Clinic Bowel Prep Tolerability Questionnaire, weighted by intensity. Missing values were addressed through multiple imputation. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through multivariate logistic regression models. Results: 1137 subjects were enrolled. Severe symptoms were associated with female sex (OR=3.64, 95%CI 1.94-6.83), heavier working hours (OR=1.13, 95% CI=1.01-1.25), previous gastrointestinal symptoms (OR=7.81, 95% CI 2.36-25.8 for high score), somatic symptoms (OR=2.19, 95% CI=1.06-4.49 for multiple symptoms), day-before regimen (OR=2.71, 95%CI 1.28-5.73). On the other hand, age ≥60 years (OR=0.10, 95% CI 0.02-0.44) and good mood (p=0.042) were protective factors. A high-risk profile was identified, including women with low mood and somatic symptoms (OR=15.5, 95%CI 4.56-52.7). Conclusions: We identified previously unreported determinants of symptoms burdening bowel preparation and identified a particularly vulnerable phenotype. Symptoms during preparation especially impact heavier working activity.

Alcohol dehydrogenase 1B (ADH1B) and acetaldehyde dehydrogenase 2 (ALDH2) are the two essential enzymes for alcohol metabolism. Polymorphic variants in these genes have been linked with an elevated risk of some alcohol-related cancers, including oesophageal squamous cell carcinoma (ESCC). In the current study, we aimed to evaluate the distribution of ADH1B (p.His48Arg; rs1229984) and ALDH2 (p.Glu504Lys; rs671) genotypes and investigate the association of these variants with the ESCC risk in Kashmir, India, a region where ESCC is comparatively more prevalent. We analyzed ADH1B and ALDH2 genotypes in 340 histopathologically verified ESCC cases and 800 controls by polymerase chain reaction with confronting two-pair primer (PCR-CTPP) and direct sequencing. To assess the association of the genotypes with ESCC risk, we used conditional logistic regression models. The frequency of mutant ADH1B 48His (ADH1B*) and ALDH2 504Lys (ALDH2*2) alleles was 29.0% and 1.9% respectively in controls. The odds ratio (OR) for the association between the genotypes ALDH2*1/*2, compared to *1/*1, and ESCC risk was above the unity, whereas it was below unity for ALDH2 *2/*2. However, due to a modest number of individuals with variant genotypes in the ALDH2 gene, 95% confidence intervals (Cis) for their associations with ESCC risk could not be calculated in the adjusted models. The corresponding OR (95% CI) was 0.87 (0.45 – 1.69) for ADH1B*2/*2 and 4.61 (0.20 –105.86) for ADH1B*1/*2. The lack of association between studied ADH1B and ALDH2 polymorphic variants and ESCC risk in Kashmir may be supported by the low prevalence of the mutant alleles, which is much lower than the reported prevalence in Chinese and Japanese populations, and low alcohol drinking in the Kashmiri population.

Background: Recent reports of lead poisoning suggest that people who use opium may be exposed to high amounts of lead. Here, we investigate the association between opium use and blood lead levels (BLL) in a population-based cohort study. Methods: In 2017, we studied a random sample of 410 people who currently (both within the past year and the past month) used opium and 104 who did not from participants of the Golestan Cohort Study in northeast Iran. Participants were stratified by sex and tobacco use history, completed a comprehensive opiate and tobacco use questionnaire and provided blood. BLL was measured by Lead Care® II Blood Lead Test Kit, validated by inductively coupled plasma triple quadrupole mass spectrometry. BLL was categorized as “<5 µg/dL”, “elevated” (5-10 µg/dL), “high” (10-50 µg/dL), and “very high” (above 50 µg/dL). To assess the association between BLL categories and opiate use, route of consumption and weekly use, we used ordered logistic regression models, and report OR (odds ratio) and 95% CI (confidence interval) adjusted for age, sex, place of residence, education, occupation, household fuel type, and tobacco use. Results: In the cohort, participants used only raw (teriak) or refined (shireh) opium, which were smoked (45%, n = 184), taken orally (46%, n = 189), or both (9%, n = 37), for a mean duration of 24.2 (standard deviation: 11.6) years. The median BLL was significantly higher in people who currently used opium (11.4 µg/dL; IQR: 5.2-23.4) compared with those who did not (2.3 µg/dL; IQR: 2.3-4.2), and the highest median BLL was seen in oral use (21.7 µg/dL; IQR: 12.1-34.1). The BLL was <5 µg/dL among 79.8% of people with no opiate use, compared with only 22.7% in those using opium. BLL was elevated in 21.7%, high in 50.5% and very high in 5.1% of people using opium. About 95% of those with oral (180/189) or dual use (35/37) and 55% (102/184) of those who smoked opium had levels of blood lead above 5 µg/dL. The OR for the association between any opium use and each unit of increase in BLL category was 10.5 (95%CI: 5.8-19.1), and oral use of opium was a very strong predictor of increasing BLL category (OR=74.1; 95%CI: 35.1-156.3). This odds ratio was 38.8 (95%CI: 15.9-95.1) for dual use and 4.9 (95%CI: 2.6-9.1) for opium smoking. There was an independent dose-response association between average weekly dose and BLL among people using opium, overall and when stratified by route of use. Conclusion: Our results indicate that regular use of lead-adulterated opium can expose individuals to high levels of lead, which may contribute to mortality and cancer risks associated with long-term opium use.

Background: Ovarian cysts represent a common condition among women. Epidemiologic studies are inconsistent in determining if women with cysts are more likely to develop endometrial cancer (EC) regardless of overweight/obesity. We investigated the combined role of cysts and body mass index (BMI) on EC risk. Methods: We pooled data from three case-control studies conducted in Italy and Switzerland on 920 women with EC and 1700 controls. The prevalence of cysts was 5% among both cases and controls, with 63% of cases being overweight/obese. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression models, adjusting for potential confounders. We conducted stratified analyses according to BMI, and estimated the interaction between cysts and BMI; we carried out additional analyses according to age at diagnosis of cysts. Results: Overall, history of cysts was not associated to EC (OR=1.27, 95% CI=0.82–1.97, P = 0.29). Normal weight women reporting cysts had an increased risk of EC (OR=2.49, 95% CI=1.31–4.74), while no such effect was found among overweight/obese women (OR=0.65, 95% CI=0.36–1.18; P for interaction=0.004). The association was limited to women below 65 years of age and was stronger in those who reported cysts at age 48 or older. Conclusions: Cysts appeared to be a risk factor for EC in lean women but not in overweight/obese ones; these results are consistent with an effect of cysts and obesity on EC along common pathways.

Background and Aims: Patients undergoing colonoscopy are often in the workforce. Therefore, colonoscopy may affect patients’ work productivity in terms of missed working days and/or reduced working efficiency. We aimed to investigate the impact of colonoscopy on work productivity and factors influencing this impact. Methods: We conducted a prospective, observational, multicenter study in 10 Italian hospitals between 2016 and 2017. We collected information on individual characteristics, work productivity, symptoms, and conditions before, during, and after the procedure from patients undergoing colonoscopy for several indications using validated tools. Outcomes were interference of preparation with work, absenteeism, and impaired work performance after the procedure. We fitted multivariate logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for potential predictors of the outcomes. Results: Among 1137 subjects in the study, 30.5% reported at least 1 outcome. Impaired work performance was associated with bowel preparation regimen (full dose on the day of colonoscopy vs split dose: OR, 4.04; 95% CI, 1.43-11.5), symptoms during bowel preparation (high symptom score: OR, 3.21; 95% CI, 1.15-8.95), and pain during the procedure (OR, 2.47; 95% CI, 1.40-4.35). Increasing number of working hours and less comfortable jobs were associated with absenteeism (P for trend =.06) and impairment of working performance (P for trend =.01) and GI symptoms both before and after colonoscopy. Conclusions: Occupational and individual characteristics of patients should be considered when scheduling colonoscopy because this procedure may impair work productivity in up to one-third of patients. Split-dose bowel preparation, performing a painless colonoscopy, and preventing the occurrence of GI symptoms may minimize the impact of colonoscopy on work productivity.

Background: Cancer mortality rates, though not absolute numbers of deaths, have been decreasing over the last three decades in Europe. Materials and methods: We estimated projections and the number of avoided deaths for total cancer mortality and 10 major cancer sites, between 1989 and 2022, for the European Union (EU), the UK, France, Germany, Italy, Poland and Spain using cancer death certification and population data since 1970 from the World Health Organization and Eurostat. Results: In the EU, we predict 1 269 200 cancer deaths in 2022; corresponding age-standardized rates (world) fall 6% to 126.9 deaths/100 000 in men and 4% to 80.2/100 000 women since 2017. Male lung cancer is expected to fall 10% reaching 30.9/100 000. The rise in female lung cancer mortality slowed (+2% to 13.8/100 000). We estimated 369 000 (23%) avoided deaths in 2022 alone and a total of 5 394 000 (12%) deaths since the peak rate in 1988. Stomach, colorectal, breast and prostate cancers showed substantial declines, between 5% and 16% over the past 5 years. Pancreatic cancer remained stable in men (8.1/100 000) and rose 3% in women (5.9/100 000), becoming the third cause of cancer mortality in the EU (87 300 deaths), overtaking breast cancer (86 300 deaths). The fall in uterine cancers slowed down (−4%) to 4.7/100 000. Bladder cancer fell 9% in men, but was stable in women. Leukaemias fell more than 10%. Ovarian cancer mortality declined over the past decade in all considered countries. EU predicted rates were 4.3/100 000 (−13%) all ages, 1.2/100 000 (−26%) at 20-49, 15.3/100 000 (−11%) at 50-69 and 32.3/100 000 (−11%) at 70-79 years. Conclusions: We predicted additional declines in cancer mortality rates for 2022. The slowdown in female lung cancer mortality reflects some levelling of smoking in women. Favourable ovarian cancer trends are likely to continue and are largely attributable to the spreading oral contraceptive use and some impact of improved diagnosis and management.

Objective: To update the analysis of mortality of a cohort of talc miners and millers in Northern Italy. Methods: We analyzed overall mortality and mortality from specific causes of death during 1946–2020 of 1749 male workers in a talc mine where asbestos was not detected (1184 miners and 565 millers) employed during 1946–1995. Results: The overall standardized mortality ratio (SMR) was 1.21 (95 % confidence interval [CI] 1.14–1.28); no deaths were observed from pleural cancer. Mortality from lung cancer was not increased (SMR = 1.02 95 % CI 0.82–1.27), while mortality from pneumoconiosis was (SMR 9.55; 95 % CI 7.43–12.08), especially among miners (SMR 12.74; 95 % CI 9.79–16.31). There was a trend in risk of pneumoconiosis with increasing duration of employment in the overall cohort, and the SMR for 25+ years of employment was 15.12 (95 % CI 10.89–20.43). Conclusions: This uniquely long-term follow up confirms the results of previous analyses, namely the lack of association between exposure to talc with no detectable level of asbestos and lung cancer and mesothelioma. Increased mortality from pneumoconiosis among miners is related to past exposure to silica.

Rescue/recovery workers who responded to the World Trade Center (WTC) attacks were exposed to known/suspected carcinogens. Studies have identified a trend toward an elevated risk of cutaneous melanoma in this population; however, few found significant increases. Furthermore, temporal aspects of the association have not been investigated. A total of 44,540 non-Hispanic White workers from the WTC Combined Rescue/Recovery Cohort were studied between March 12, 2002 and December 31, 2015. Cancer data were obtained through linkages with 13 state registries. Poisson regression was used to estimate hazard ratios and 95% confidence intervals using the New York State population as the reference; change points in hazard ratios were estimated using profile likelihood. We observed 247 incident cases of melanoma. No increase in incidence was detected during 2002–2004. From 2005 to 2015, the hazard ratio was 1.34 (95% confidence interval = 1.18–1.52). A dose‒response relationship was observed by arrival time at the WTC site. Risk was elevated just over 3 years after the attacks. Whereas WTC-related exposures to UVR or other agents might have contributed to this result, exposures other than those at the WTC site, enhanced medical surveillance, and lack of a control group with a similar proportion of rescue/recovery workers cannot be discounted. Our results support continued study of this population for melanoma.

This review aimed to describe the potential role of occupational physician in the implementation of a screening program for Helicobacter pylori (Hp) infection for gastric cancer prevention. We reviewed the epidemiological background of gastric cancer and its association with Hp, exploring the hypothesis of a “test-and-treat” protocol among working population. Clinical trials and model-based studies were collected to provided empirical evidence of the feasibility of eradication on large scale. In particular, previous studies conducted in occupational settings were discussed. Hp prevalence ranges between about 20 and 90%, with higher rates in Asia and Latin America and lower rates in Europe and North America. Large-scale trials on screening and treatment of infection have been conducted especially in East Asia, lacking elsewhere. Only few studies investigated Hp prevalence among workers. The benefit of eradication at occupational level has not yet been adequately studied. The design of a workplace-based Hp screening program appears to be innovative and could contribute to controlling gastric cancer. The benefit would involve not only high-risk subjects, but also their families, since the route of transmission is principally within the household. An occupational setting for a Hp screening would have positive consequences in terms of individual and public health.

It has come to our attention that the excel files of the following supplementary tables were not included during the online publication of our article: Table S3, Table S4, Table S8, Table S9, Table S13, and Table S14. These have now been made available online. We apologize for any inconvenience caused.

Background: The aim of this study was to investigate the relationship between high-risk genotypes of Human Papilloma Virus (HPV) and cancer of different subsites of the oral cavity. Material and methods: A pooled analysis of five studies included on the International Head and Neck Cancer Epidemiology (INHANCE) Consortium was conducted. HPV 16 and HPV 18 were considered. Adjusted odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) for HPV and each oral cavity subsites were simultaneously estimated using multinomial logistic regression models. Results: The analysis included 1157 cases and 3272 controls. This study showed a slightly higher prevalence of HPV infection among oral cancer cases than controls. In particular, an increased risk of other and not otherwise specified (NOS) sites within the oral cavity, oral tongue, palate and floor of mouth cancer was observed for overall HPV16 positivity (OR = 1.66, 95 % CI: 1.01−2.72; OR = 1.97, 95 % CI: 1.36−2.85; OR = 2.48, 95 % CI: 1.50−4.11; OR = 2.71, 95 % CI: 1.06−6.95, respectively). In particular, HPV16E7 was related to cancer of floor of mouth, oral cavity NOS and palate (OR = 2.71, 95 % CI: 1.06−6.95; OR = 3.32, 95 % CI:1.53−7.19; OR = 3.34, 95 % CI:1.38−8.06). Results were inconsistent for HPV18 due to low prevalence of infection. Conclusion: Our study suggests that HPV16 infection may increase the risk of developing floor of mouth, gum, tongue, and palate cancers. Clinical relevance: Subjects with HPV infection have a higher risk of cancer from all sites of the oral cavity.

Background and Aims: Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies. Methods: We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays. Results: Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p <0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs. 2% in viral/alcohol-HCC, p = 0.03). Tumour mutational burden was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 vs. 0.94 mutations/megabase; p <0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/TGF-β proliferation subclass tumours (42% vs. 26%, p = 0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of an immunosuppressive cancer field. In 3 murine models of NASH-HCC, key features of human NASH-HCC were preserved. Conclusions: NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature. Lay summary: The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterised. In this study, we uncovered higher rates of ACVR2A mutations (10%) – a potential tumour suppressor – and the presence of a novel mutational signature that characterises NASH-related HCC.

Objective: In the medical and epidemiological literature there is a growing tendency to report an excessive number of decimal digits (often three, sometimes four), especially when measures of relative occurrence are small; this can be misleading. Study Design and Setting: We combined mathematical and statistical reasoning about the precision of relative risks with the meaning of the decimal part of the same measures from biological and public health perspectives. Results: We identified a general rule for minimizing the mathematical error due to rounding of relative risks, depending on the background absolute rate, which justifies the use of one or more decimal digits for estimates close to 1. Conclusions: We suggest that both relative and absolute risk measures (expressed as a rates) should be reported, and two decimal digits should be used for relative risk close to 1 only if the background rate is at least 1/1,000 py. The use of more than two decimal digits is justified only when the background rate is high (ie, 1/10 py).

Background: Several aspects of the association between exposure to air pollution and risk of lung cancer remain unclear. Objective: We aimed at performing a meta-analysis of high-quality cohort studies on exposure to particulate matter (PM) 10 and PM2.5 and risk of lung cancer. Methods: We identified cohort studies published since 2004, that reported risk estimates of lung cancer for exposure to PM2.5 and PM10 adjusted for tobacco smoking and socioeconomic status, and conducted a meta-analysis based on random-effects models, including stratification by outcome, sex, country, tobacco smoking, and age. Results: Results on PM2.5 exposure were available from 15 studies; the summary relative risk (RR) for an increase of 10 μg/m³ was 1.16 (95% confidence interval [CI] 1.09, 1.23). The corresponding RR for PM10 exposure was 1.23 (95 CI 1.05, 1.40; seven studies). A higher risk was suggested in studies based on lung cancer mortality and in studies conducted in East Asia, while no difference was shown according to sex, smoking status or age. There was no suggestion of publication bias. Conclusions: Our meta-analysis supported the hypothesis of an association between exposure to PM2.5 or PM10 and risk of lung cancer, and provided evidence that the magnitude of the risk might be higher than previously estimated, and might be modified by outcome and geographic region.

Background: We predicted cancer mortality statistics for 2021 for the European Union (EU) and its five most populous countries plus the UK. We also focused on pancreatic cancer and female lung cancer. Materials and methods: We obtained cancer death certifications and population data from the World Health Organization and Eurostat databases for 1970-2015. We predicted numbers of deaths and age-standardised (world population) rates for 2021 for total cancers and 10 major cancer sites, using a joinpoint regression model. We calculated the number of avoided deaths over the period 1989-2021. Results: We predicted 1 267 000 cancer deaths for 2021 in the EU, corresponding to age-standardised rates of 130.4/100 000 men (−6.6% since 2015) and 81.0/100 000 for women (−4.5%). We estimated further falls in male lung cancer rates, but still trending upward in women by +6.5%, reaching 14.5/100 000 in 2021. The breast cancer predicted rate in the EU was 13.3/100 000 (−7.8%). The rates for stomach and leukaemias in both sexes and for bladder in males are predicted to fall by >10%; trends for other cancer sites were also favourable, except for the pancreas, which showed stable patterns in both sexes, with predicted rates of 8.1/100 000 in men and 5.6/100 000 in women. Rates for pancreatic cancer in EU men aged 25-49 and 50-64 years declined, respectively, by 10% and 1.8%, while for those aged 65+ years increased by 1.3%. Rates fell for young women only (−3.4%). Over 1989-2021, about 5 million cancer deaths were avoided in the EU27 compared with peak rates in 1988. Conclusion: Overall cancer mortality continues to fall in both sexes. However, specific focus is needed on pancreatic cancer, which shows a sizeable decline for young men only. Tobacco control remains a priority for the prevention of pancreatic and other tobacco-related cancers, which account for one-third of the total EU cancer deaths, especially in women, who showed less favourable trends.