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Sökning: WFRF:(Frumento Paolo)

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1.
  • Acevedo, Nathalie, et al. (författare)
  • DNA Methylation Levels in Mononuclear Leukocytes from the Mother and Her Child Are Associated with IgE Sensitization to Allergens in Early Life
  • 2021
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:2
  • Tidskriftsartikel (refereegranskat)abstract
    • DNA methylation changes may predispose becoming IgE-sensitized to allergens. We analyzed whether DNA methylation in peripheral blood mononuclear cells (PBMC) is associated with IgE sensitization at 5 years of age (5Y). DNA methylation was measured in 288 PBMC samples from 74 mother/child pairs from the birth cohort ALADDIN (Assessment of Lifestyle and Allergic Disease During INfancy) using the HumanMethylation450BeadChip (Illumina). PBMCs were obtained from the mothers during pregnancy and from their children in cord blood, at 2 years and 5Y. DNA methylation levels at each time point were compared between children with and without IgE sensitization to allergens at 5Y. For replication, CpG sites associated with IgE sensitization in ALADDIN were evaluated in whole blood DNA of 256 children, 4 years old, from the BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology) cohort. We found 34 differentially methylated regions (DMRs) associated with IgE sensitization to airborne allergens and 38 DMRs associated with sensitization to food allergens in children at 5Y (Sidak p <= 0.05). Genes associated with airborne sensitization were enriched in the pathway of endocytosis, while genes associated with food sensitization were enriched in focal adhesion, the bacterial invasion of epithelial cells, and leukocyte migration. Furthermore, 25 DMRs in maternal PBMCs were associated with IgE sensitization to airborne allergens in their children at 5Y, which were functionally annotated to the mTOR (mammalian Target of Rapamycin) signaling pathway. This study supports that DNA methylation is associated with IgE sensitization early in life and revealed new candidate genes for atopy. Moreover, our study provides evidence that maternal DNA methylation levels are associated with IgE sensitization in the child supporting early in utero effects on atopy predisposition.
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  • Carrasquilla, Germán D, et al. (författare)
  • Postmenopausal hormone therapy and risk of stroke : A pooled analysis of data from population-based cohort studies.
  • 2017
  • Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 14:11
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Recent research indicates a favourable influence of postmenopausal hormone therapy (HT) if initiated early, but not late, on subclinical atherosclerosis. However, the clinical relevance of timing of HT initiation for hard end points such as stroke remains to be determined. Further, no previous research has considered the timing of initiation of HT in relation to haemorrhagic stroke risk. The importance of the route of administration, type, active ingredient, and duration of HT for stroke risk is also unclear. We aimed to assess the association between HT and risk of stroke, considering the timing of initiation, route of administration, type, active ingredient, and duration of HT.METHODS AND FINDINGS: Data on HT use reported by the participants in 5 population-based Swedish cohort studies, with baseline investigations performed during the period 1987-2002, were combined in this observational study. In total, 88,914 postmenopausal women who reported data on HT use and had no previous cardiovascular disease diagnosis were included. Incident events of stroke (ischaemic, haemorrhagic, or unspecified) and haemorrhagic stroke were identified from national population registers. Laplace regression was employed to assess crude and multivariable-adjusted associations between HT and stroke risk by estimating percentile differences (PDs) with 95% confidence intervals (CIs). The fifth and first PDs were calculated for stroke and haemorrhagic stroke, respectively. Crude models were adjusted for age at baseline only. The final adjusted models included age at baseline, level of education, smoking status, body mass index, level of physical activity, and age at menopause onset. Additional variables evaluated for potential confounding were type of menopause, parity, use of oral contraceptives, alcohol consumption, hypertension, dyslipidaemia, diabetes, family history of cardiovascular disease, and cohort. During a median follow-up of 14.3 years, 6,371 first-time stroke events were recorded; of these, 1,080 were haemorrhagic. Following multivariable adjustment, early initiation (<5 years since menopause onset) of HT was associated with a longer stroke-free period than never use (fifth PD, 1.00 years; 95% CI 0.42 to 1.57), but there was no significant extension to the time period free of haemorrhagic stroke (first PD, 1.52 years; 95% CI -0.32 to 3.37). When considering timing as a continuous variable, the stroke-free and the haemorrhagic stroke-free periods were maximal if HT was initiated approximately 0-5 years from the onset of menopause. If single conjugated equine oestrogen HT was used, late initiation of HT was associated with a shorter stroke-free (fifth PD, -4.41 years; 95% CI -7.14 to -1.68) and haemorrhagic stroke-free (first PD, -9.51 years; 95% CI -12.77 to -6.24) period than never use. Combined HT when initiated late was significantly associated with a shorter haemorrhagic stroke-free period (first PD, -1.97 years; 95% CI -3.81 to -0.13), but not with a shorter stroke-free period (fifth PD, -1.21 years; 95% CI -3.11 to 0.68) than never use. Given the observational nature of this study, the possibility of uncontrolled confounding cannot be excluded. Further, immortal time bias, also related to the observational design, cannot be ruled out.CONCLUSIONS: When initiated early in relation to menopause onset, HT was not associated with increased risk of incident stroke, regardless of the route of administration, type of HT, active ingredient, and duration. Generally, these findings held also for haemorrhagic stroke. Our results suggest that the initiation of HT 0-5 years after menopause onset, as compared to never use, is associated with a decreased risk of stroke and haemorrhagic stroke. Late initiation was associated with elevated risks of stroke and haemorrhagic stroke when conjugated equine oestrogen was used as single therapy. Late initiation of combined HT was associated with haemorrhagic stroke risk.
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3.
  • Gordon, Max, et al. (författare)
  • Age- and health-related quality of life after total hip replacement.
  • 2014
  • Ingår i: Acta orthopaedica. - : Medical Journals Sweden AB. - 1745-3682 .- 1745-3674. ; 85:3, s. 244-249
  • Tidskriftsartikel (refereegranskat)abstract
    • Background - While age is a common confounder, its impact on health-related quality of life (HRQoL) after total hip replacement is uncertain. This could be due to improper statistical modeling of age in previous studies, such as treating age as a linear variable or by using age categories. We hypothesized that there is a non-linear association between age and HRQoL. Methods - We selected a nationwide cohort from the Swedish Hip Arthroplasty Register of patients operated with total hip replacements due to primary osteoarthritis between 2008 and 2010. For estimating HRQoL, we used the generic health outcome questionnaire EQ-5D of the EuroQol group that consits or 2 parts: the EQ-5D index and the EQ VAS estimates. Using linear regression, we modeled the EQ-5D index and the EQ VAS against age 1 year after surgery. Instead of using a straight line for age, we applied a method called restricted cubic splines that allows the line to bend in a controlled manner. Confounding was controlled by adjusting for preoperative HRQoL, sex, previous contralateral hip surgery, pain, and Charnley classification. Results - Complete data on 27,245 patients were available for analysis. Both the EQ-5D index and EQ VAS showed a non-linear relationship with age. They were fairly unaffected by age until the patients were in their late sixties, after which age had a negative effect. Interpretation - There is a non-linear relationship between age and HRQoL, with improvement decreasing in the elderly.
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4.
  • Gordon, Max, et al. (författare)
  • Women in Charnley class C fail to improve in mobility to a higher degree after total hip replacement.
  • 2014
  • Ingår i: Acta orthopaedica. - : Medical Journals Sweden AB. - 1745-3682 .- 1745-3674. ; 85:4, s. 335-41
  • Tidskriftsartikel (refereegranskat)abstract
    • The Charnley comorbidity classification organizes patients into 3 classes: (A) 1 hip involved, (B) 2 hips involved, and (C) other severe comorbidities. Although this simple classification is a known predictor of health-related quality of life (HRQoL) after total hip replacement (THR), interactions between Charnley class, sex, and age have not been investigated and there is uncertainty regarding whether A and B should be grouped together.
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  • Lo Martire, Riccardo, et al. (författare)
  • Predictors of Sickness Absence in a Clinical Population With Chronic Pain
  • 2021
  • Ingår i: Journal of Pain. - Philadelphia, PA, United States : Churchill Livingstone. - 1526-5900 .- 1528-8447. ; 22:10, s. 1180-1194
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic pain-related sickness absence is an enormous socioeconomic burden globally. Optimized interventions are reliant on a lucid understanding of the distribution of social insurance benefits and their predictors. This register-based observational study analyzed data for a 7-year period from a population-based sample of 44,241 chronic pain patients eligible for interdisciplinary treatment (IDT) at specialist clinics. Sequence analysis was used to describe the sickness absence over the complete period and to separate the patients into subgroups based on their social insurance benefits over the final 2 years. The predictive performance of features from various domains was then explored with machine learning-based modeling in a nested cross-validation procedure. Our results showed that patients on sickness absence increased from 17% 5 years before to 48% at the time of the IDT assessment, and then decreased to 38% at the end of follow-up. Patients were divided into 3 classes characterized by low sickness absence, sick leave, and disability pension, with eight predictors of class membership being identified. Sickness absence history was the strongest predictor of future sickness absence, while other predictors included a 2008 policy, age, confidence in recovery, and geographical location. Information on these features could guide personalized intervention in the specialized healthcare. PERSPECTIVE: This study describes sickness absence in patients who visited a Swedish pain specialist interdisciplinary treatment clinic during the period 2005 to 2016. Predictors of future sickness absence are also identified that should be considered when adapting IDT programs to the patient's needs.
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8.
  • Lo Martire, Riccardo, et al. (författare)
  • Sickness Absence and Disability Pension Among Patients With Chronic Pain in Interdisciplinary Treatment or Unspecified Interventions
  • 2023
  • Ingår i: Journal of Pain. - : Elsevier. - 1526-5900 .- 1528-8447. ; 24:11, s. 2003-2013
  • Tidskriftsartikel (refereegranskat)abstract
    • Interdisciplinary treatment is a widely implemented strategy for the rehabilitation of patients with chronic pain. A primary treatment objective is to decrease the load on the social insurance system; however, it is questionable whether interdisciplinary treatment reduces sickness absence and disability pension (SA/DP). This register-based observational study compared SA and DP between patients in interdisciplinary treatment and unspecified interventions. With data from 7,752 Swedish specialist health care patients in their prime working age, we analyzed total net SA/DP days over 3 years from the first visit to a pain rehabilitation center. A zero-one-inflated beta model, adjusted for theoretically substantiated confounders, was used to estimate the mean differences in total days and the proportions of patients with both zero and maximum days. Compared with unspecified interventions, interdisciplinary treatment resulted in a mean (95% confidence interval) absolute increase of 50 (37, 62) total days, a 13.0% (11.3%, 14.6%) decrease in patients with zero days, and a 1.5% (.2%, 2.8%) decrease in patients with the maximum days. These findings support that interdisciplinary treatment increases SA/DP compared to less intensive interventions but reduces the risk of maximum days, implying that it is advantageous for patients with the highest absence. This highlights the need for improved patient selection procedures and the adaptation of interdisciplinary treatment programs to more adequately target SA/DP reduction.
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9.
  • LoMartire, Riccardo, et al. (författare)
  • The value of interdisciplinary treatment for sickness absence in chronic pain : A nationwide register-based cohort study
  • 2021
  • Ingår i: European Journal of Pain. - : Wiley. - 1090-3801 .- 1532-2149. ; 25:10, s. 2190-2201
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Interdisciplinary treatment (IDT) is an internationally recommended intervention for chronic pain, despite inconclusive evidence of its effects on sickness absence. Methods With data from 25,613 patients in Swedish specialist healthcare, we compared sickness absence, in the form of both sick leave and disability pensions, over a 5-year period between patients either allocated to an IDT programme or to other/no interventions (controls). To obtain population-average estimates, a Markov multistate model with theory-based inverse probability weights was used to compute both the proportion of patients on sickness absence and the total sickness absence duration. Results IDT patients were more likely than controls to receive sickness absence benefits at any given time (baseline: 49% vs. 46%; 5-year follow-up: 36% vs. 35%), and thereby also had a higher total duration, with a mean (95% CI) of 67 (87, 48) more days than controls over the 5-year period. Intriguingly, sick leave was higher in IDT patients (563 [552, 573] vs. 478 [466, 490] days), whereas disability pension was higher in controls (152 [144, 160] vs. 169 [161, 178] days). Conclusion Although sickness absence decreased over the study period in both IDT patients and controls, we found no support for IDT decreasing sickness absence more than other/no interventions in chronic pain patients. Significance In this large study of chronic pain patients in specialist healthcare, sickness absence is compared over a 5-year period between patients in an interdisciplinary treatment programme and other/no interventions. Sickness absence decreased over the study period in bothgroups; however, there was no support forthat it decreased more with interdisciplinary treatment than alternative interventions.
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11.
  • Msellem, Mwinyi, et al. (författare)
  • Increased Sensitivity of Plasmodium falciparum to Artesunate/Amodiaquine Despite 14 Years as First-Line Malaria Treatment, Zanzibar
  • 2020
  • Ingår i: Emerging Infectious Diseases. - : Centers for Disease Control and Prevention (CDC). - 1080-6040 .- 1080-6059. ; 26:8, s. 1767-1777
  • Tidskriftsartikel (refereegranskat)abstract
    • Artemisinin-based combination therapies (ACTs) are first-line treatments for uncomplicated Plasmodium falciparum malaria. ACT resistance is spreading in Asia but not yet in Africa. Reduced effects of ACT partner drugs have been reported but with little information regarding widely used artesunate/amodiaquine (ASAQ). We studied its efficacy in Zanzibar after 14 years as first-line treatment directly by an in vivo, single-armed trial and indirectly by prevalences of different genotypes in the P. falciparum chloroquine-resistance transporter, multidrug-resistance 1, and Kelch 13 propeller domain genes. In vivo efficacy was higher during 2017 (100%; 95% CI 97.4%-100%) than during 2002-2005 (94.7%; 95% CI 91.9%-96.7%) (p = 0.003). Molecular findings showed no artemisinin resistance-associated genotypes and major increases in genotypes associated with high sensitivity/efficacy for amodiaquine than before ASAQ was introduced. Thus, the efficacy of ASAQ is maintained and appears to be increased after long-term use in contrast to what is observed for other ACTs used in Africa.
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12.
  • Olén, Ola, et al. (författare)
  • Childhood onset inflammatory bowel disease and risk of cancer : a Swedish nationwide cohort study 1964-2014
  • 2017
  • Ingår i: BMJ-BRITISH MEDICAL JOURNAL. - : B M J Group. - 1756-1833. ; 11:Suppl. 1, s. S14-S15
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: To assess risk of cancer in patients with childhood onset inflammatory bowel disease in childhood and adulthood.Design: Cohort study with matched general population reference individuals using multivariable Cox regression to estimate hazard ratios.Setting: Swedish national patient register (both inpatient and non-primary outpatient care) 1964-2014.Participants: Incident cases of childhood onset (<18 years) inflammatory bowel disease (n=9405: ulcerative colitis, n=4648; Crohn's disease, n=3768; unclassified, n=989) compared with 92 870 comparators from the general population matched for sex, age, birth year, and county.Main outcome measures: Any cancer and cancer types according to the Swedish Cancer Register.Results: During follow-up through adulthood (median age at end of follow-up 27 years), 497 (3.3 per 1000 person years) people with childhood onset inflammatory bowel disease had first cancers, compared with 2256 (1.5 per 1000 person years) in the general population comparators (hazard ratio 2.2, 95% confidence interval 2.0 to 2.5). Hazard ratios for any cancer were 2.6 in ulcerative colitis (2.3 to 3.0) and 1.7 in Crohn's disease (1.5 to 2.1). Patients also had an increased risk of cancer before their 18th birthday (2.7, 1.6 to 4.4; 20 cancers in 9405 patients, 0.6 per1000 person years). Gastrointestinal cancers had the highest relative risks, with a hazard ratio of 18.0 (14.4 to 22.7) corresponding to 202 cancers in patients with inflammatory bowel disease. The increased risk of cancer (before 25th birthday) was similar over time (1964-1989: 1.6, 1.0 to 2.4; 1990-2001: 2.3, 1.5 to 3.3); 2002-06: 2.9, 1.9 to 4.2; 2007-14: 2.2, 1.1 to 4.2).Conclusion: Childhood onset inflammatory bowel disease is associated with an increased risk of any cancer, especially gastrointestinal cancers, both in childhood and later in life. The higher risk of cancer has not fallen over time.
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13.
  • Olén, Ola, et al. (författare)
  • Increased Mortality of Patients With Childhood- Onset Inflammatory Bowel Diseases, Compared With the General Population
  • 2019
  • Ingår i: Gastroenterology. - : Saunders Elsevier. - 0016-5085 .- 1528-0012. ; 156:3, s. 614-622
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND & AIMS: Childhood-onset inflammatory bowel disease (IBD) is believed to be a more severe disease than adultonset IBD, but there is little information on all-cause and causespecific mortality in patients with childhood-onset IBD. We performed a population-based cohort study, with 50 years of follow-up, to estimate absolute and relative risks for overall and cause-specific mortality in patients with childhood-onset IBD, during childhood and adulthood.METHODS: We identified children with a diagnosis of IBD (younger than 18 years) in the Swedish nationwide health registers (1964-2014; n = 9442) and individuals from the general population matched for sex, age, calendar year, and place of residence (reference group; n = 93,180). Hazard ratios (HR) for death were estimated using Cox regression separately in patients with ulcerative colitis (n = 4671), Crohn's disease (n = 3780), and IBD unclassified (n = 991). HRs were compared among calendar periods.RESULTS: During 138,690 person-years of follow-up, 294 deaths (2.1/1000 person-years) occurred among the patients with IBD compared with 940 deaths in the reference group (0.7/1000 person-years; adjusted HR, 3.2; 95% confidence interval [CI] 2.8-3.7). Mean age at end of follow-up was 30 years. HRs were increased for patients with ulcerative colitis 4.0, 95% CI 3.4-4.7; Crohn's disease 2.3, 95% CI 1.8-3.0; and IBD unclassified 2.0, 95% CI 1.2-3.4. Among patients younger than 18 years, there were 27 deaths from IBD 4.9, 95% CI 3.0-7.7. Among young adults with IBD, we found no evidence that HRs for death decreased from 1964 through 2014 (P = .90).CONCLUSIONS: Children with IBD have a 3-fold increase in risk of death when followed through adulthood. The relative risk for death has not decreased with development of new drugs for treatment of IBD.
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14.
  • Orellana, Cecilia, et al. (författare)
  • Organisational factors and under-reporting of occupational injuries in Sweden : a population-based study using capture-recapture methodology
  • 2021
  • Ingår i: Occupational and Environmental Medicine. - : BMJ. - 1351-0711 .- 1470-7926. ; 78:10, s. 745-752
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective To estimate the magnitude of under-reporting of non-fatal occupational injuries (OIs) by different organisational factors in Sweden for the year 2013.Methods Capture–recapture methods were applied using two data sources: (1) the national OI register and (2) records from a labour market insurance company. To assure comparability of data sources, the analysis was restricted to the public sector and private companies with at least 50 employees. OIs were matched using personal identification number and reported injury dates (±7 days). Organisational factors were obtained from the national labour market register and injury severity (no healthcare/only outpatient/hospitalised) from the National Patient Register. Total number of OIs and ascertainment by data sources were estimated assuming data source independence.Results There were an estimated 98 493 OIs in 2013. Completeness of reporting OIs to the national register and to the insurance company was estimated at 73% and 43%, respectively. No report to either source was estimated at 15 000 OIs (~15%). Under-reporting to the national register differed by selected organisational factors, being higher among organisations in the public sector, those with more females, with a younger workforce and with a higher proportion of immigrants. Overall under-reporting was more common in agriculture (19.7%), other services (19.3%), commerce and hospitality (19.1%), health (18.4%) and education (18.4%). Under-reporting decreased as injury severity increased, with little variations across sectors of economic activity.Conclusions Results suggest considerable under-reporting of OIs in Sweden and differential under-reporting by organisational factors. Results are relevant for official estimates of burden and for setting priorities for workplace safety and prevention.
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15.
  • Rimes-Stigare, Claire, et al. (författare)
  • Evolution of chronic renal impairment and long-term mortality after de novo acute kidney injury in the critically ill; a Swedish multi-centre cohort study
  • 2015
  • Ingår i: Critical Care. - : BioMed Central. - 1364-8535 .- 1466-609X. ; 19:221
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Acute Kidney Injury (AKI) is common in critical ill populations and its association with high short-term mortality is well established. However, long-term risks of death and renal dysfunction are poorly understood and few studies exclude patients with pre-existing renal disease, meaning outcome for de novo AKI has been difficult to elicit. We aimed to compare the long-term risk of Chronic Kidney Disease (CKD), End Stage Renal Disease (ESRD) and mortality in critically ill patients with and without severe de novo AKI. Method: This cohort study was conducted between 2005 and 2011 in Swedish intensive care units (ICU). Data from 130134 adult patients listed on the Swedish intensive care register-database was linked with other national registries. Patients with pre-existing CKD (4192) and ESRD (1389) were excluded, as were cases (26771) with incomplete data. Patients were classified according to AKI exposure during ICU admission. Outcome in the de novo AKI group was compared to the non-exposed (no-AKI) intensive care control group. Primary outcome was all-cause mortality. Follow-up ranged from one to seven years (median 2.1 years). Secondary outcomes were incidence of CKD and ESRD and median follow-up was 1.3 years. Results: Of 97 782 patients, 5273 (5.4%) had de novo AKI. These patients had significantly higher crude mortality at one (48.4% vs. 24.6%) and five years (61.8% vs. 39.1%) compared to the control group. The first 30% of deaths in AKI patients occurred within 11 days of ICU admission whilst the 30-centile in the no-AKI group died by 748 days. CKD was significantly more common in AKI survivors at one year (6.0% vs. 0.44%) than in no-AKI group (adjusted incidence rate ratio (IRR) 7.6). AKI patients also had significantly higher rates of ESRD at one (2.0% vs. 0.08%) and at five years (3.9% vs. 0.3%) than those in the comparison group (adjusted IRR 22.5). Conclusion: This large cohort study demonstrated that de novo AKI is associated with increased short and long-term risk of death. AKI is independently associated with increased risk of CKD and ESRD as compared to an ICU control population. Severe de novo AKI survivors should be routinely followed-up and their renal function monitored.
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16.
  • Sottile, Rosa, et al. (författare)
  • NK- and T-cell subsets in malignant mesothelioma patients : Baseline pattern and changes in the context of anti-CTLA-4 therapy
  • 2019
  • Ingår i: International Journal of Cancer. - : WILEY. - 0020-7136 .- 1097-0215. ; 145:8, s. 2238-2248
  • Tidskriftsartikel (refereegranskat)abstract
    • Malignant mesothelioma (MM) is a highly aggressive form of cancer with limited treatment options. Although the role of NK cells has been studied in many solid tumors, the pattern of NK-cell subsets and their recognition of mesothelioma cells remain to be explored. We used RNA expression data of MM biopsies derived from the cancer genome atlas to evaluate the immune cell infiltrates. We characterized the phenotype of circulating NK and T cells of 27 MM patients before and after treatment with an anti-CTLA-4 antibody (tremelimumab). These immune cell profiles were compared to healthy controls. The RNA expression data of the MM biopsies indicated the presence of NK cells in a subgroup of patients. We demonstrated that NK cells recognize MM cell lines and that IL-15 stimulation improved NK cell-mediated lysis in vitro. Using multivariate projection models, we found that MM patients had a perturbed ratio of CD56(bright) and CD56(dim) NK subsets and increased serum concentrations of the cytokines IL-10, IL-8 and TNF-alpha. After tremelimumab treatment, the ratio between the CD56(bright) and CD56(dim) subsets shifted back towards physiological levels. Furthermore, the improved overall survival was correlated with low TIM-3(+)CD8(+) T-cell frequency, high DNAM-1(+)CD56(dim) NK-cell frequency and high expression levels of NKp46 on the CD56(dim) NK cells before and after immune checkpoint blockade. Together, our observations suggest that NK cells infiltrate MM and that they can recognize and kill mesothelioma cells. The disease is associated with distinct lymphocytes patterns, some of which correlate with prognosis or are affected by treatment with tremelimumab.
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