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Sökning: WFRF:(Villani S) > Göteborgs universitet

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1.
  • Durno, C., et al. (författare)
  • Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance
  • 2021
  • Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 39:25, s. 2779-
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.
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2.
  • Das, A., et al. (författare)
  • Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
  • 2022
  • Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28:1, s. 125-135
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy. © 2022, The Author(s).
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3.
  • Markevych, I., et al. (författare)
  • Residential greenspace and lung function decline over 20 years in a prospective cohort: The ECRHS study
  • 2023
  • Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 178
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The few studies that have examined associations between greenspace and lung function in adulthood have yielded conflicting results and none have examined whether the rate of lung function decline is affected.Objective: We explored the association between residential greenspace and change in lung function over 20 years in 5559 adults from 22 centers in 11 countries participating in the population-based, international European Community Respiratory Health Survey.Methods: Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were measured by spirometry when participants were approximately 35 (1990-1994), 44 (1999-2003), and 55 (2010-2014) years old. Greenness was assessed as the mean Normalized Difference Vegetation Index (NDVI) in 500 m, 300 m, and 100 m circular buffers around the residential addresses at the time of lung function measurement. Green spaces were defined as the presence of agricultural, natural, or urban green spaces in a circular 300 m buffer. Associations of these greenspace parameters with the rate of lung function change were assessed using adjusted linear mixed effects regression models with random intercepts for subjects nested within centers. Sensitivity analyses considered air pollution exposures.Results: A 0.2-increase (average interquartile range) in NDVI in the 500 m buffer was consistently associated with a faster decline in FVC (-1.25 mL/year [95% confidence interval:-2.18 to-0.33]). These associations were especially pronounced in females and those living in areas with low PM10 levels. We found no consistent asso-ciations with FEV1 and the FEV1/FVC ratio. Residing near forests or urban green spaces was associated with a faster decline in FEV1, while agricultural land and forests were related to a greater decline in FVC. Conclusions: More residential greenspace was not associated with better lung function in middle-aged European adults. Instead, we observed slight but consistent declines in lung function parameters. The potentially detri-mental association requires verification in future studies.
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4.
  • Das, Anirban, et al. (författare)
  • Combined immunotherapy improves outcome for replication repair deficient (RRD) high-grade glioma failing anti-PD1 monotherapy: A report from the International RRD Consortium.
  • 2023
  • Ingår i: Cancer discovery. - 2159-8290.
  • Tidskriftsartikel (refereegranskat)abstract
    • Immune-checkpoint inhibition (ICI) is effective for replication-repair deficient, high-grade gliomas (RRD-HGG). Clinical/biologic impact of immune-directed approaches after failing ICI-monotherapy are unknown. We performed an international study on 75 patients treated with anti-PD1; 20 are progression-free (median follow-up: 3.7-years). After 2nd-progression/recurrence (n=55), continuing ICI-based salvage prolonged survival to 11.6-months (n=38; p<0.001), particularly for those with extreme mutation burden (p=0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and immune-microenvironment. Response to re-irradiation was explained by an absence of deleterious post-radiation indel signatures (ID8). Increased CTLA4-expression over time, and subsequent CTLA4-inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to reinvigoration of peripheral immune and radiological responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/ synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology.
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5.
  • Marcon, A., et al. (författare)
  • Trends in smoking initiation in Europe over 40 years: A retrospective cohort study
  • 2018
  • Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 13:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Tobacco consumption is the largest avoidable health risk. Understanding changes of smoking over time and across populations is crucial to implementing health policies. We evaluated trends in smoking initiation between 1970 and 2009 in random samples of European populations. We pooled data from six multicentre studies involved in the Ageing Lungs in European Cohorts consortium, including overall 119,104 subjects from 17 countries (range of median ages across studies: 33-52 years). We estimated retrospectively trends in the rates of smoking initiation (uptake of regular smoking) by age group, and tested birth cohort effects using Age-Period-Cohort (APC) modelling. We stratified all analyses by sex and region (North, East, South, West Europe). Smoking initiation during late adolescence (16-20 years) declined for both sexes and in all regions (except for South Europe, where decline levelled off after 1990). By the late 2000s, rates of initiation during late adolescence were still high (40-80 per 1000/year) in East, South, and West Europe compared to North Europe (20 per 1000/year). Smoking initiation rates during early adolescence (11-15 years) showed a marked increase after 1990 in all regions (except for North European males) but especially in West Europe, where they reached 40 per 1000/year around 2005. APC models supported birth cohort effects in the youngest cohorts. Smoking initiation is still unacceptably high among European adolescents, and increasing rates among those aged 15 or less deserve attention. Reducing initiation in adolescents is fundamental, since youngsters are particularly vulnerable to nicotine addiction and tobacco adverse effects.
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6.
  • Lytras, T., et al. (författare)
  • Cumulative Occupational Exposures and Lung-Function Decline in Two Large General-Population Cohorts
  • 2021
  • Ingår i: Annals of the American Thoracic Society. - New York : American Thorax Society. - 1546-3222 .- 2329-6933 .- 2325-6621 .- 1943-5665. ; 18:2, s. 238-246
  • Tidskriftsartikel (refereegranskat)abstract
    • Rationale: Few longitudinal studies have assessed the relationship between occupational exposures and lung-function decline in the general population with a sufficiently long follow-up. Objectives: To examine the potential association in two large cohorts: the ECRHS (European Community Respiratory Health Survey) and the SAPALDIA (Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults). Methods: General-population samples of individuals aged 18 to 62 were randomly selected in 1991-1993 and followed up approximately 10 and 20 years later. Spirometry (without bronchodilation) was performed at each visit. Coded complete job histories during follow-up visits were linked to a job-exposure matrix, generating cumulative exposure estimates for 12 occupational exposures. Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were jointly modeled in linear mixed-effects models, fitted in a Bayesian framework, taking into account age and smoking. Results: A total of 40,024 lung-function measurements from 17,833 study participants were analyzed. We found accelerated declines in FEV1 and the FEV1/FVC ratio for exposure to biological dust, mineral dust, and metals (FEV1 = -15.1 ml, -14.4 ml, and -18.7 ml, respectively; and FEV1/FVC ratio = -0.52%, -0.43%, and -0.36%, respectively; per 25 intensity-years of exposure). These declines were comparable in magnitude with those associated with long-term smoking. No effect modification by sex or smoking status was identified. Findings were similar between the ECRHS and the SAPALDIA cohorts. Conclusions: Our results greatly strengthen the evidence base implicating occupation, independent of smoking, as a risk factor for lung-function decline. This highlights the need to prevent or control these exposures in the workplace.
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7.
  • Lytras, T., et al. (författare)
  • Occupational exposures and incidence of chronic bronchitis and related symptoms over two decades: The European Community Respiratory Health Survey
  • 2019
  • Ingår i: Occupational and environmental medicine. - : BMJ. - 1351-0711 .- 1470-7926. ; 76:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: Chronic bronchitis (CB) is an important chronic obstructive pulmonary disease (COPD)-related phenotype, with distinct clinical features and prognostic implications. Occupational exposures have been previously associated with increased risk of CB but few studies have examined this association prospectively using objective exposure assessment. We examined the effect of occupational exposures on CB incidence in the European Community Respiratory Health Survey. Methods: Population samples aged 20-44 were randomly selected in 1991-1993, and followed up twice over 20 years. Participants without chronic cough or phlegm at baseline were analysed. Coded job histories during follow-up were linked to the ALOHA Job Exposure Matrix, generating occupational exposure estimates to 12 categories of chemical agents. Their association with CB incidence over both follow-ups was examined with Poisson models using generalised estimating equations. Results: 8794 participants fulfilled the inclusion criteria, contributing 13 185 observations. Only participants exposed to metals had a higher incidence of CB (relative risk (RR) 1.70, 95% CI 1.16 to 2.50) compared with non-exposed to metals. Mineral dust exposure increased the incidence of chronic phlegm (RR 1.72, 95% CI 1.43 to 2.06). Incidence of chronic phlegm was increased in men exposed to gases/fumes and to solvents and in women exposed to pesticides. Conclusions: Occupational exposures are associated with chronic phlegm and CB, and the evidence is strongest for metals and mineral dust exposure. The observed differences between men and women warrant further investigation. © Author(s) (or their employer(s)) 2019.
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8.
  • Henneberger, P K, et al. (författare)
  • The occupational contribution to severe exacerbation of asthma.
  • 2010
  • Ingår i: The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 36:4, s. 743-50
  • Tidskriftsartikel (refereegranskat)abstract
    • The goal of this study was to identify occupational risk factors for severe exacerbation of asthma and estimate the extent to which occupation contributes to these events. The 966 participants were working adults with current asthma who participated in the follow-up phase of the European Community Respiratory Health Survey. Severe exacerbation of asthma was defined as self-reported unplanned care for asthma in the past 12 months. Occupations held in the same period were combined with a general population job-exposure matrix to assess occupational exposures. 74 participants reported having had at least one severe exacerbation event, for a 1-yr cumulative incidence of 7.7%. From regression models that controlled for confounders, the relative risk (RR) was statistically significant for low (RR 1.7, 95% CI 1.1-2.6) and high (RR 3.6, 95% CI 2.2-5.8) biological dust exposure, high mineral dust exposure (RR 1.8, 95% CI 1.02-3.2), and high gas and fumes exposure (RR 2.5, 95% CI 1.2-5.5). The summary category of high dust, gas, or fumes exposure had RR 3.1 (95% CI 1.9-5.1). Based on this RR, the population attributable risk was 14.7% among workers with current asthma. These results suggest occupation contributes to approximately one in seven cases of severe exacerbation of asthma in a working population, and various agents play a role.
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9.
  • Kim, Jeong-Lim, et al. (författare)
  • Predictors of respiratory sickness absence: An international population-based study
  • 2013
  • Ingår i: American Journal of Industrial Medicine. - : Wiley. - 0271-3586 .- 1097-0274. ; 56:5, s. 541-549
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Respiratory tract-related occupational disability is common among adults of working age. We examined occupational vapors, gas, dust, or fume (VGDF) exposure as a predictor of disability, based on respiratory sickness absence among the actively employed, at an early point at which prevention may be most relevant. Methods: Currently employed European Community Respiratory Health Survey II participants (n=6,988) were classified into three mutually exclusive, condition/symptom-based categories: physician-diagnosed asthma, self-reported rhinitis, and wheeze/breathlessness (n=4,772). Logistic regression analysis estimated the odds of respiratory sickness absence (past 12 months) by VGDF exposure. Results: In the condition/symptom groups, 327 (6.9%) reported respiratory sickness absence. Exposure to VGDF was associated with increased odds of respiratory sickness absence: asthma odds ratio [OR] 2.0 (95% confidence interval [CI] 1.1-3.6), wheeze/breathlessness OR 2.2 (95% CI 1.01-4.8); rhinitis OR 1.9 (95% CI 1.02-3.4). Conclusion: One in 15 currently employed with asthma, breathlessness, or rhinitis reported respiratory sickness absence. VGDF exposure doubled the odds of respiratory sickness absence, suggesting a focus for disability prevention. Am. J. Ind. Med. 56:541-549, 2013. © 2013 Wiley Periodicals, Inc.
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10.
  • Lytras, T., et al. (författare)
  • Occupational exposures and 20-year incidence of COPD: the European Community Respiratory Health Survey
  • 2018
  • Ingår i: Thorax. - : BMJ. - 0040-6376 .- 1468-3296. ; 73:11
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Occupational exposures have been associated with an increased risk of COPD. However, few studies have related objectively assessed occupational exposures to prospectively assessed incidence of COPD, using postbronchodilator lung function tests. Our objective was to examine the effect of occupational exposures on COPD incidence in the European Community Respiratory Health Survey. Methods General population samples aged 20-44 were randomly selected in 1991-1993 and followed up 20 years later (2010-2012). Spirometry was performed at baseline and at follow-up, with incident COPD defined using a lower limit of normal criterion for postbronchodilator FEV1/FVC. Only participants without COPD and without current asthma at baseline were included. Coded job histories during follow-up were linked to a Job-Exposure Matrix, generating occupational exposure estimates to 12 categories of agents. Their association with COPD incidence was examined in log-binomial models fitted in a Bayesian framework. Findings 3343 participants fulfilled the inclusion criteria; 89 of them had COPD at follow-up (1.4 cases/1000 person-years). Participants exposed to biological dust had a higher incidence of COPD compared with those unexposed (relative risk (RR) 1.6, 95% CI 1.1 to 2.3), as did those exposed to gases and fumes (RR 1.5, 95% CI 1.0 to 2.2) and pesticides (RR 2.2, 95% CI 1.1 to 3.8). The combined population attributable fraction for these exposures was 21.0%. Interpretation These results substantially strengthen the evidence base for occupational exposures as an important risk factor for COPD.
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