Ovarian cancer deaths attributable to asbestos exposure in Lombardy (Italy) in 2000-2018.

OBJECTIVES: We aimed to estimate the fraction of deaths from ovarian cancer attributable to asbestos exposure in Lombardy Region, Italy, using a novel approach that exploits the fact that ovarian cancer asbestos exposure is associated with pleural cancer and other risk factors for breast cancer. METHODS: This ecological study is based on the Italian National Institute of Statistics mortality data. We formulate a trivariate Bayesian joint disease model to estimate the attributable fraction (AF) and the number of ovarian cancer deaths attributable to asbestos exposure from the geographic distribution of ovarian, pleural and breast cancer mortality at the municipality level from 2000 to 2018. Expected deaths and standardised mortality ratios were calculated using regional rates. RESULTS: We found shared dependencies between ovarian and pleural cancer, which capture risk factors common to the two diseases (asbestos exposure), and a spatially structured clustering component shared between ovarian and breast cancer, capturing other risk factors. Based on 10 462 ovarian cancer deaths, we estimated that 574 (95% credibility interval 388-819) were attributable to asbestos (AF 5.5%; 95% credibility interval 3.7-7.8). AF reaches 34%-47% in some municipalities with known heavy asbestos pollution. CONCLUSIONS: The impact of asbestos on ovarian cancer occurrence can be relevant, particularly in areas with high asbestos exposure. Estimating attributable cases was possible only by using advanced Bayesian modelling to consider other risk factors for ovarian cancer. These findings are instrumental in tailoring public health surveillance programmes and implementing compensation and prevention policies.

Mortality and cancer incidence in a population exposed to TCDD after the Seveso, Italy, accident (1976-2013).

OBJECTIVES: The Seveso accident (1976) caused the contamination with 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) in an area north of Milan, Italy. We report the results of the update of mortality and cancer incidence in the exposed population through 2013. METHODS: The study cohort includes subjects living in three contaminated zones with decreasing TCDD soil concentrations (zone A, B and R) and in a surrounding uncontaminated territory (reference). Poisson models stratified/adjusted for gender, age and period were fitted to calculate rate ratios (RRs) and 95% CIs. RESULTS: In zone A in males, we found elevated mortality from circulatory diseases in the first decade after the accident (17 deaths, RR 2.00, 95% CI 1.24 to 3.23). In females, mortality from diabetes mellitus was increased, with a positive trend across zones. Incidence of soft tissue sarcoma was increased in males in zone R in the first decade (6 cases, RR 2.62, 95% CI 1.01 to 6.83). In females in zone B, there was an excess of non-Hodgkin's lymphoma after 30 years (6 cases, RR 2.87, 95% CI 1.14 to 7.23). Multiple myeloma was increased in the second decade in females in zone B (4 cases, RR 5.09, 95% CI 1.82 to 14.2) and in males in zone R (11 cases, RR 2.15, 95% CI 1.08 to 4.26). In males in zone R, there was a leukaemia excess after 30 years (23 cases, RR 2.02, 95% CI 1.04 to 3.93). CONCLUSIONS: Although with different patterns across gender, zone and time, we confirmed previous results of increased cardiovascular diseases, diabetes, soft tissue sarcoma, and lymphatic and haematopoietic cancers.

Red cell distribution width and prognosis in myelofibrosis patients treated with ruxolitinib.

We evaluated RDW in a single-center series of 61 consecutive patients with primary and secondary MF at diagnosis and during treatment with ruxolitinib (RUX) and examined any possible prognostic impact. Elevated RDW values were present in all but 4 patients at diagnosis with a median RDW of 18.9%. RDW was higher in subjects with palpable splenomegaly (p = 0.02), higher ferritin, as well as among those cases who did not receive any cytoreduction before RUX (p = 0.04). Interestingly, higher RDW at diagnosis also correlated with a shorter time from MF diagnosis to RUX start (-4.1 months per one RDW unit; p = 0.03). We observed a modest increase (< 1%) in RDW during the first 6 months of RUX treatment. In a multivariable random-intercept model that considered all time points and contained the covariates time and RUX dose, we also observed a clear decrease in RDW with increasing hemoglobin (Hb) during RUX (slope: -0.4% per g/dL of Hb; p < 0.001). The median RDW at diagnosis of 18.9% was used as a cut-off to identify two subgroups of patients [Group 1: RDW 19.0-25.7%; Group 2: RDW 13.1-18.7%], showing a difference in mortality [Group 1 vs. 2: crude HR 2.88; p = 0.01]. Using continuous RDW at diagnosis, the crude HR was 1.21 per RDW unit (p = 0.002). In a Cox model adjusted for gender, age and Hb at diagnosis, the HR was 1.13 per RDW unit (p = 0.07). RDW may have prognostic significance at MF diagnosis and during RUX, helping in the rapid detection of patients with poor prognosis.

Gender Differences in Sinonasal Cancer Incidence: Data from the Italian Registry.

BACKGROUND: Although rare, sinonasal cancers (SNCs) have a high occupational attributable fraction. METHODS: We applied gender-based approaches to descriptive analyses, incidence, and patterns of exposures using the Italian National Sinonasal Cancer Registry (ReNaTuNS: Registro Nazionale Tumori Naso-Sinusali). RESULTS: The study included 2851 SNC patients. SNC was diagnosed more often in men (73%) than in women (27%). The most frequent morphology in men was intestinal-type adenocarcinoma (33%), whereas in women, it was squamous cell carcinoma (49%). Nasal cavities were predominant in both genders (50%), ethmoidal sinus in men (24%), and maxillary in women (24%). Incidence rates were 0.76 (per 100,000 person-years) in men and 0.24 in women and increased by age, more evidently in men, peaking over 75 years in both. Occupational exposures to wood and leather dusts were the most frequent (41% for men, 33% for women). Few exposures were extra-occupational or domestic. Unlikely exposure was relevant in women (57%). CONCLUSIONS: The surveillance of SNC cases through a registry that allows for the identification of and compensation for this occupational disease is important in Italy, where numerous workers are exposed to carcinogens for SNC, without even being aware. Considering the rarity of the disease, particularly among women, the ReNaTuNS can provide a method to analyze gender differences.

Dominant stricture in paediatric-onset primary sclerosing cholangitis is associated with impaired prognosis in a long-term follow-up.

BACKGROUND AND OBJECTIVES: The impact of dominant stricture (DS) on the outcomes of paediatric-onset primary sclerosing cholangitis (PSC) is unknown. This study was aimed at investigating the impact of DS on the clinical course and prognosis of patients with paediatric-onset PSC. METHODS: Patients with paediatric-onset PSC diagnosed between January 1993 and May 2017 were identified from hospital records or our PSC registry. Data including clinical, laboratory, cholangiography, and cytology at diagnosis and during follow-up (until July 2023) were reviewed. We graphed the Kaplan-Meier failure function and fitted crude and multivariable Cox model to calculate hazard ratios (HR) and 95% confidence intervals (CI) for selected variables. In these analyses, DS was treated as a time-varying variable. RESULTS: We identified 68 patients (42 males) with paediatric-onset PSC (median age at diagnosis 15 years). The median follow-up was 13 years and the median age at the last follow-up was 27 years. In total, 35 (51%) had concomitant autoimmune hepatitis. DS was diagnosed in 33 patients (48%): in eight at the time of PSC diagnosis (12%) and in 25 (37%) by the end of follow-up. In patients with DS, two developed cirrhosis, seven were transplanted and one patient was operated for a biliary mass with low-grade dysplasia. In patients without a DS, two developed cirrhosis, and four were transplanted; one female was excluded from survival analysis because she already had cirrhosis at the time of PSC diagnosis. Cirrhosis or biliary dysplasia or needing liver transplantation for these indications were more frequent after the development of DS (10/33, adjusted HR 4.26, 95%CI: 1.26-14.4). No cholangiocarcinomas or deaths occurred during the follow-up. CONCLUSIONS: DS was present at diagnosis or developed during follow-up in about half of the patients with paediatric-onset PSC and was associated with impaired outcome.

Assessing joint health in haemophilia patients: The combined value of physical examination and ultrasound imaging.

INTRODUCTION: Early diagnosis of joint damage is pivotal in haemophilia to prevent the occurrence and progression of haemophilic arthropathy thus providing optimal personalised management. The haemophilia joint health score version 2.1 (HJHS) is based on a physical examination of the mainly affected joints. Musculoskeletal ultrasound has demonstrated the capability to detect early changes in terms of synovitis and osteochondral damage. The haemophilia early detection with ultrasound (HEAD-US) score has been proposed as a simple and reliable evaluation tool. AIM: This study aims to investigate the correlation between the HJHS and the HEAD-US scores performed by two independent operators (physical therapist and musculoskeletal ultrasound expert) for the evaluation of the joint health status of patients with haemophilia. METHODS: Consecutive adult patients independent of the severity degree were included. Elbows, knees and ankles were evaluated by a physical therapist by HJHS and by a musculoskeletal ultrasound expert following the HEAD-US protocol. RESULTS: We observed a good positive correlation between HJHS and HEAD-US (Spearman's rho 0.72). The main discrepancy in conceptually similar domains was found between the HJHS swelling and the HEAD-US synovitis (rho 0.17), as ultrasound was able to detect even mild synovitis when HJHS swelling was scored 0 in up to 40% of cases. CONCLUSIONS: The HJHS and HEAD-US correlate well even when performed by two independent operators. Musculoskeletal ultrasound is particularly useful for the early detection of synovitis. The routine assessment of both scores helps clinicians define the stage and extension of joint involvement and set up a personalised treatment.

Cancer-Specific Mortality Odds Ratios in the Food, Accommodation, and Beverage Activities in Italy.

OBJECTIVES: This study investigated cancer-specific mortality risks of workers employed in food, accommodation and beverage (FAB) activities. Methods: We performed a case-control study based on countrywide mortality and National Social Insurance data. Adjusted cancer-specific mortality odds ratios (MOR) were calculated. We modeled occupational exposure as "ever/never been employed" in FAB activities, using other sectors as reference. Analysis was performed by gender, length of employment and year of smoke banning. Results: About 20,000 cancer deaths in FAB were analyzed. Working in restaurants was positively associated with cancer of lung (MOR = 1.24), bladder (MOR = 1.24), pharynx, and larynx. Accommodation was associated with cancer of pharynx (MOR = 1.46), while beverage with cancer of liver (MOR = 1.22). Gender, length of employment and smoke banning were found effective in modifying some risks. Conclusions: Workers in FAB sectors were at risk for several cancers.

APOBEC shapes tumor evolution and age at onset of lung cancer in smokers.

APOBEC enzymes are part of the innate immunity and are responsible for restricting viruses and retroelements by deaminating cytosine residues1,2. Most solid tumors harbor different levels of somatic mutations attributed to the off-target activities of APOBEC3A (A3A) and/or APOBEC3B (A3B)3-6. However, how APOBEC3A/B enzymes shape the tumor evolution in the presence of exogenous mutagenic processes is largely unknown. Here, by combining deep whole-genome sequencing with multi-omics profiling of 309 lung cancers from smokers with detailed tobacco smoking information, we identify two subtypes defined by low (LAS) and high (HAS) APOBEC mutagenesis. LAS are enriched for A3B-like mutagenesis and KRAS mutations, whereas HAS for A3A-like mutagenesis and TP53 mutations. Unlike APOBEC3A, APOBEC3B expression is strongly associated with an upregulation of the base excision repair pathway. Hypermutation by unrepaired A3A and tobacco smoking mutagenesis combined with TP53-induced genomic instability can trigger senescence7, apoptosis8, and cell regeneration9, as indicated by high expression of pulmonary healing signaling pathway, stemness markers and distal cell-of-origin in HAS. The expected association of tobacco smoking variables (e.g., time to first cigarette) with genomic/epigenomic changes are not observed in HAS, a plausible consequence of frequent cell senescence or apoptosis. HAS have more neoantigens, slower clonal expansion, and older age at onset compared to LAS, particularly in heavy smokers, consistent with high proportions of newly generated, unmutated cells and frequent immuno-editing. These findings show how heterogeneity in mutational burden across co-occurring mutational processes and cell types contributes to tumor development, with important clinical implications.

Lung fibre burden and risk of malignant mesothelioma in shipyard workers: a necropsy-based case-control study.

OBJECTIVES: In Italy, the highest pleural cancer mortality and incidence have been observed among Italian regions where the 2 largest Italian shipyards were (and are) located. The objective of this study was to assess the exposure-response relationship for mesothelioma among male workers employed in the Monfalcone, Italy, shipyard. METHODS: We conducted a necropsy-based case-control study. Cases (N = 102) were mesothelioma decedents and controls were those with lung cancer (N = 84). Complete job histories were available; the lung fibre content was measured using a scanning electron microscope with X-ray fluorescence, after sample preparation according to the European Respiratory Society guidelines. Odds ratios and 95% confidence intervals of mesothelioma by fibre type and lung fibre burden, as a categorical or continuous variable, were assessed by unconditional logistic regression, adjusted for age and time since exposure cessation. Analyses for the amphibole and chrysotile lung fibre burden were mutually adjusted. We calculated a cumulative exposure index by applying a job-exposure matrix to the job histories of study cases and assessed its correlation with the lung fibre burden. RESULTS: We found an odds ratio of 22.0 (confidence intervals 5.66-85.7) for the highest lung fibre burden category (mean 43.8 million total asbestos fibres per gram of dry tissue) compared with the reference (mean 0.48). Using log10-transformed lung fibre burden, we found that the odds ratio was 3.71 (confidence intervals 2.03-6.79) for a 10-fold lung fibre burden increase. Results for the amphibole lung fibre burden were similar. Odds ratios increased over chrysotile lung fibre burden categories (P-trend = 0.025), and the odds ratio for a 10-fold increase was 4.73 (confidence intervals 0.32-70.4). CONCLUSIONS: The cumulative exposure index was correlated with total and amphibole lung fibre burden, but not with chrysotile lung fibre burden. Mesothelioma risk was proportional to total, amphibole, and chrysotile lung fibre burden in shipyard workers.

The Effectiveness of the Third Dose of COVID-19 Vaccine: When Should It Be Performed?

BACKGROUND: COVID-19 vaccination is the most significant step toward the long-term mitigation of SARS-CoV-2-related complication, avoiding disease and death and decreasing virus spread. This study aimed to evaluate, in a real-world setting, booster dose effectiveness to reduce COVID-19 risk considering the amount of time after the end of the two-dose vaccination cycle. A sub-analysis was conducted to adjust the booster dose effect for occupational and demographic factors. METHODS: About 16,000 COVID-19-vaccinated HCWs of three University Hospital Networks in Milan (HN1/HN2/HN3) were included in the study. Data were collected by Occupational Health Physicians of the HNs within specific computerized databases. RESULTS: In univariable analysis, booster dose administration displayed a slightly higher risk of infection with respect to not receiving it, OR = 1.18, with 95% confidence interval (C.I) [0.99, 1.41]. When the model was adjusted with the modulating effect of time from the completion of the vaccination cycle on booster dose administration, the latter resulted in strong protective effect against infection, OR = 0.43, 95% CI [0.26, 0.74]. However, considering the modifying influence of time from the vaccination cycle's completion, the administration of booster doses appeared to have a protective effect against infection. In HN1, students and resident physicians displayed lower odds of infection with respect to physicians. Lastly, a non-linear effect of age was reported. CONCLUSIONS: Our findings suggest that the correct timing in vaccine scheduling and administration is critical to vaccine effectiveness. These findings, applicable to all vaccinations, should help in setting up more effective vaccination strategies.

Survival of Patients with Sinonasal Cancers in a Population-Based Registry, Lombardy, Italy, 2008-2023.

Sinonasal cancers (SNCs) are rare malignancies associated with occupational exposures. The aim of this study was to analyse the survival of SNC patients using data from the population-based SNC registry of the Lombardy region (10 million people), Italy. We included epithelial SNC cases registered in 2008-2020 and followed-up for vital status until 31 July 2023. Multivariate flexible parametric models with time-dependent covariates were fitted to calculate excess hazard ratios (EHRs) and 95% confidence intervals (CIs) of death. Based on 827 cases (553 males, 274 females) and 514 deaths (345 males, 169 females), the 5-year observed survival was 49% and the net survival was 57%. Age had a substantial impact on survival, particularly within the first year (EHR, 1.35; 95% CI, 1.12-1.51 per 10 years). Compared with the nasal cavity, the EHR for paranasal sinuses was 4.70 (95% CI, 2.96-7.47) soon after diagnosis. Compared with squamous cell carcinomas, the EHR was 0.69 (95% CI, 0.52-0.91) for adenocarcinomas, 1.68 (95% CI, 1.20-2.35) for undifferentiated and unspecified carcinomas, and 1.78 (95% CI, 1.07-2.95) for neuroendocrine carcinomas. Age and cancer site showed time-dependent effects on prognosis, especially within the first month after diagnosis. Prognosis was also markedly affected by cancer morphology. No associations were found for gender and period of diagnosis.

Sinonasal Cancer Cases in a Nationwide Hospital Cancer Registry in Brazil, 2007-2021.

BACKGROUND: Sinonasal cancers (SNC) are rare cancers with a high proportion attributable to occupational carcinogens. This study aims to describe the sociodemographic, clinical, and occupational characteristics of subjects with SNC in Brazil. METHODS: Observational study conducted with secondary data from a network of Hospital Cancer Registries. We selected epithelial/unspecified SNC records with a year of diagnosis from 2007 to 2021. We performed descriptive statistics of SNC cases and calculated crude and age-standardized rates (ASR, standard: world population) by gender and Region of residence. RESULTS: We identified 2,384 cases, 1,553 (65.1%) in men and 831 (34.9%) in women. The mean age at diagnosis was 59 years for both. Most SNC (50.7% in men and 53.2% in women) originated from the maxillary sinus. Most (65.5% in men and 54.5% in women) were squamous cell carcinomas. Information on occupation was missing in the years 2019-2021. Most male SNC patients (44.8%) were employed in group 6 (Agricultural, forestry, and fishing workers), while women had been mainly (34.6%) working in groups 8 (Workers in the production of industrial goods and services, machine operators) and in group 6 (27.6%). Crude SNC incidence rates were 1.0 per million person-years in men and 0.5 in women, while ASR were 1.0 and 0.4, respectively. In both genders, the highest ASR was in Minas Gerais (men: 1.9; women: 0.7). CONCLUSIONS: Establishing the profile of Brazilians with sinonasal cancer can stimulate epidemiologic research for monitoring this group of cancers with a high association with occupational exposures.

Outcome of atypical hemolytic uremic syndrome: role of triggers and complement abnormalities in the response to C5 inhibition.

BACKGROUND: Atypical-hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy often due to uncontrolled complement activation, characterized by high risk of end-stage kidney disease (ESKD). Eculizumab has improved the outcome, however, its efficacy varies among patients and its discontinuation is debated. METHODS: To identify characteristics associated with treatment response, we analyzed 244 aHUS patients referred to our center. Patients were classified according to the presence/absence of complement abnormalities and/or triggers at onset in 4 categories: (1) primary (complement abnormality without trigger), (2) secondary (trigger without complement abnormality), (3) combined (trigger and complement abnormality), (4) idiopathic (no trigger, no complement abnormality). Response to treatment was evaluated by comparing the response to eculizumab with that of conventional therapy. Short- and long-term outcomes were evaluated with the relapse rate after discontinuation of C5-inhibition. RESULTS: Patients had a better outcome with eculizumab compared to conventional treatment, with a response rate of 81.9% vs 56.9%, p < 0.001 and a long-term cumulative incidence of ESKD of 5.8% vs 22.5% (hazard ratio 0.25, 95% confidence interval: 0.10-0.80). The excellent global response was driven by the primary and combined groups (89.8% vs 54.0% and 89.3% vs 54.2%, respectively). The relapse rate following discontinuation of the C5-inhibitor was as high as 66.7% in the primary group, 18.7% in the combined, and 0% in the secondary and idiopathic groups. CONCLUSIONS: Our data show a better outcome in aHUS patients treated with C5-inhibition, particularly in the primary and combined forms, which have a high risk of relapse after discontinuation that is not observed in the secondary and idiopathic forms.

Prevalent occupational exposures and risk of lung cancer among women: Results from the application of the Canadian Job-Exposure Matrix (CANJEM) to a combined set of ten case-control studies.

BACKGROUND: Worldwide, lung cancer is the second leading cause of cancer death in women. The present study explored associations between occupational exposures that are prevalent among women, and lung cancer. METHODS: Data from 10 case-control studies of lung cancer from Europe, Canada, and New Zealand conducted between 1988 and 2008 were combined. Lifetime occupational history and information on nonoccupational factors including smoking were available for 3040 incident lung cancer cases and 4187 controls. We linked each reported job to the Canadian Job-Exposure Matrix (CANJEM), which provided estimates of probability, intensity, and frequency of exposure to each selected agent in each job. For this analysis, we selected 15 agents (cleaning agents, biocides, cotton dust, synthetic fibers, formaldehyde, cooking fumes, organic solvents, cellulose, polycyclic aromatic hydrocarbons from petroleum, ammonia, metallic dust, alkanes C18+, iron compounds, isopropanol, and calcium carbonate) that had lifetime exposure prevalence of at least 5% in the combined study population. For each agent, we estimated lung cancer risk in each study center for ever-exposure, by duration of exposure, and by cumulative exposure, using separate logistic regression models adjusted for smoking and other covariates. We then estimated the meta-odds ratios using random-effects meta-analysis. RESULTS AND CONCLUSIONS: None of the agents assessed showed consistent and compelling associations with lung cancer among women. The following agents showed elevated odds ratio in some analyses: metallic dust, iron compounds, isopropanol, and organic solvents. Future research into occupational lung cancer risk factors among women should prioritize these agents.

Lung Cancer Risks Associated with Occupational Exposure to Pairs of Five Lung Carcinogens: Results from a Pooled Analysis of Case-Control Studies (SYNERGY).

BACKGROUND: While much research has been done to identify individual workplace lung carcinogens, little is known about joint effects on risk when workers are exposed to multiple agents. OBJECTIVES: We investigated the pairwise joint effects of occupational exposures to asbestos, respirable crystalline silica, metals (i.e., nickel, chromium-VI), and polycyclic aromatic hydrocarbons (PAH) on lung cancer risk, overall and by major histologic subtype, while accounting for cigarette smoking. METHODS: In the international 14-center SYNERGY project, occupational exposures were assigned to 16,901 lung cancer cases and 20,965 control subjects using a quantitative job-exposure matrix (SYN-JEM). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for ever vs. never exposure using logistic regression models stratified by sex and adjusted for study center, age, and smoking habits. Joint effects among pairs of agents were assessed on multiplicative and additive scales, the latter by calculating the relative excess risk due to interaction (RERI). RESULTS: All pairwise joint effects of lung carcinogens in men were associated with an increased risk of lung cancer. However, asbestos/metals and metals/PAH resulted in less than additive effects; while the chromium-VI/silica pair showed marginally synergistic effect in relation to adenocarcinoma (RERI: 0.24; CI: 0.02, 0.46; p = 0.05). In women, several pairwise joint effects were observed for small cell lung cancer including exposure to PAH/silica (OR = 5.12; CI: 1.77, 8.48), and to asbestos/silica (OR = 4.32; CI: 1.35, 7.29), where exposure to PAH/silica resulted in a synergistic effect (RERI: 3.45; CI: 0.10, 6.8). DISCUSSION: Small or no deviation from additive or multiplicative effects was observed, but co-exposure to the selected lung carcinogens resulted generally in higher risk than exposure to individual agents, highlighting the importance to reduce and control exposure to carcinogens in workplaces and the general environment. https://doi.org/10.1289/EHP13380.

Respirable crystalline silica and lung cancer in community-based studies: impact of job-exposure matrix specifications on exposure-response relationships.

OBJECTIVES: The quantitative job-exposure matrix SYN-JEM consists of various dimensions: job-specific estimates, region-specific estimates, and prior expert ratings of jobs by the semi-quantitative DOM-JEM. We analyzed the effect of different JEM dimensions on the exposure-response relationships between occupational silica exposure and lung cancer risk to investigate how these variations influence estimates of exposure by a quantitative JEM and associated health endpoints. METHODS: Using SYN-JEM, and alternative SYN-JEM specifications with varying dimensions included, cumulative silica exposure estimates were assigned to 16 901 lung cancer cases and 20 965 controls pooled from 14 international community-based case-control studies. Exposure-response relationships based on SYN-JEM and alternative SYN-JEM specifications were analyzed using regression analyses (by quartiles and log-transformed continuous silica exposure) and generalized additive models (GAM), adjusted for age, sex, study, cigarette pack-years, time since quitting smoking, and ever employment in occupations with established lung cancer risk. RESULTS: SYN-JEM and alternative specifications generated overall elevated and similar lung cancer odds ratios ranging from 1.13 (1st quartile) to 1.50 (4th quartile). In the categorical and log-linear analyses SYN-JEM with all dimensions included yielded the best model fit, and exclusion of job-specific estimates from SYN-JEM yielded the poorest model fit. Additionally, GAM showed the poorest model fit when excluding job-specific estimates. CONCLUSION: The established exposure-response relationship between occupational silica exposure and lung cancer was marginally influenced by varying the dimensions of SYN-JEM. Optimized modelling of exposure-response relationships will be obtained when incorporating all relevant dimensions, namely prior rating, job, time, and region. Quantitative job-specific estimates appeared to be the most prominent dimension for this general population JEM.

Increased Risk of Thyroid Eye Disease Following Covid-19 Vaccination.

CONTEXT: SARS-CoV-2 infection and Covid-19 vaccines have been associated with thyroid disorders. OBJECTIVE: We analyzed the risk of thyroid eye disease (TED) following Covid-19 vaccination. This was a self-controlled case series study at a tertiary referral center for TED. A total of 98 consecutive patients with newly developed (n = 92) or reactivated (n = 6) TED occurring between January 1, 2021, and August 31, 2022, were included. TED was assessed in patients undergoing Covid-19 vaccination. Person-days were defined as exposed if TED occurred 1 to 28 days after vaccination, and unexposed if occurring outside this time window. Conditional Poisson regression models were fitted to calculate incidence rate ratio (IRR) and 95% CI of exposed vs unexposed. Sensitivity analyses were conducted considering different exposed periods, and effect modification by potential TED risk factors. RESULTS: Covid-19 vaccines were administered in 81 people, 25 (31%) of whom developed TED in exposed and 56 (69%) in unexposed periods. The IRR for TED was 3.24 (95% CI 2.01-5.20) and 4.70 (95% CI 2.39-9.23) in patients below 50 years of age. Sex, smoking, and radioiodine treatment did not modify the association between TED and vaccination. TED risk was unrelated to the number of vaccine doses, and progressively decreased over time following vaccination (P trend = .03). CONCLUSION: The risk of TED was significantly increased after Covid-19 vaccination, especially in people below 50 years of age. Possible mechanisms include spike protein interaction with the angiotensin-converting enzyme II receptor, cross-reactivity with thyroid self-proteins, and immune reactions induced by adjuvants. We suggest monitoring of individuals undergoing Covid-19 vaccination, especially if young and at risk for autoimmunity.

Occupational Benzene Exposure and Lung Cancer Risk: A Pooled Analysis of 14 Case-Control Studies.

Rationale: Benzene has been classified as carcinogenic to humans, but there is limited evidence linking benzene exposure to lung cancer. Objectives: We aimed to examine the relationship between occupational benzene exposure and lung cancer. Methods: Subjects from 14 case-control studies across Europe and Canada were pooled. We used a quantitative job-exposure matrix to estimate benzene exposure. Logistic regression models assessed lung cancer risk across different exposure indices. We adjusted for smoking and five main occupational lung carcinogens and stratified analyses by smoking status and lung cancer subtypes. Measurements and Main Results: Analyses included 28,048 subjects (12,329 cases, 15,719 control subjects). Lung cancer odds ratios ranged from 1.12 (95% confidence interval, 1.03-1.22) to 1.32 (95% confidence interval, 1.18-1.48) (Ptrend = 0.002) for groups with the lowest and highest cumulative occupational exposures, respectively, compared with unexposed subjects. We observed an increasing trend of lung cancer with longer duration of exposure (Ptrend < 0.001) and a decreasing trend with longer time since last exposure (Ptrend = 0.02). These effects were seen for all lung cancer subtypes, regardless of smoking status, and were not influenced by specific occupational groups, exposures, or studies. Conclusions: We found consistent and robust associations between different dimensions of occupational benzene exposure and lung cancer after adjusting for smoking and main occupational lung carcinogens. These associations were observed across different subgroups, including nonsmokers. Our findings support the hypothesis that occupational benzene exposure increases the risk of developing lung cancer. Consequently, there is a need to revisit published epidemiological and molecular data on the pulmonary carcinogenicity of benzene.