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OBJECTIVES: We studied the short- and long-term effects of imatinib in hospitalized COVID-19 patients. METHODS: Participants were randomized to receive standard of care (SoC) or SoC with imatinib. Imatinib dosage was 400 mg daily until discharge (max 14 days). Primary outcomes were mortality at 30 days and 1 year. Secondary outcomes included recovery, quality of life and long COVID symptoms at 1 year. We also performed a systematic review and meta-analysis of randomized trials studying imatinib for 30-day mortality in hospitalized COVID-19 patients. RESULTS: We randomized 156 patients (73 in SoC and 83 in imatinib). Among patients on imatinib, 7.2% had died at 30 days and 13.3% at 1 year, and in SoC, 4.1% and 8.2% (adjusted HR 1.35, 95% CI 0.47-3.90). At 1 year, self-reported recovery occurred in 79.0% in imatinib and in 88.5% in SoC (RR 0.91, 0.78-1.06). We found no convincing difference in quality of life or symptoms. Fatigue (24%) and sleep issues (20%) frequently bothered patients at one year. In the meta-analysis, imatinib was associated with a mortality risk ratio of 0.73 (0.32-1.63; low certainty evidence). CONCLUSIONS: The evidence raises doubts regarding benefit of imatinib in reducing mortality, improving recovery and preventing long COVID symptoms in hospitalized COVID-19 patients.
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Tratamento Farmacológico da COVID-19 , COVID-19 , Hospitalização , Mesilato de Imatinib , Qualidade de Vida , SARS-CoV-2 , Humanos , Mesilato de Imatinib/uso terapêutico , Feminino , Masculino , Pessoa de Meia-Idade , COVID-19/mortalidade , Hospitalização/estatística & dados numéricos , Idoso , Resultado do Tratamento , AdultoRESUMO
BACKGROUND: Currently, two disease-modifying antifibrotic drugs are indicated for the treatment of idiopathic pulmonary fibrosis. The objective of this study was to analyse antifibrotic and overall prescription medication use of IPF patients in the real world. METHODS: Data was collected from the FinnishIPF registry and the Registry of the Social Insurance Institution of Finland (SII). Purchases of all prescription medicines were assessed. The frequency, the initiation interval, the duration, and the breaks of the antifibrotic treatments were defined. The association between the prescription of antifibrotic therapy and different patient-related clinical parameters was studied. Accordingly, the relationships between the delay in starting therapy and patient-related variables were analysed. RESULTS: Of the 263 IPF patients, 132 (50.2%) had started antifibrotic treatment during the study period 2011-2018. The mean interval from the diagnosis to the first purchase was 367 (SD 429) days. The antifibrotic drug was switched in 14% of patients. Discontinuation of therapy occurred most commonly during the first year of the treatment. The one-year persistence was 77.1% for pirfenidone and 78.9% for nintedanib. A tendency of treating patients under 75 years was noticed. Low forced vital capacity predicted earlier initiation of medication. CONCLUSIONS: The initiation of antifibrotics after diagnosis was slow, probably due to reimbursement limitations. Younger age at diagnosis affected treatment initiation although it is unknown which patients benefit most from these medications. The reasons for discontinuation of the antifibrotic therapy during the first year should be a focus in clinical work and further studies.
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Fibrose Pulmonar Idiopática , Humanos , Finlândia , Fibrose Pulmonar Idiopática/diagnóstico , Capacidade Vital , Piridonas/efeitos adversos , Sistema de Registros , Resultado do Tratamento , Estudos RetrospectivosRESUMO
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) has an unknown aetiology and limited treatment options. A recent meta-analysis identified three novel causal variants in the TERT, SPDL1, and KIF15 genes. This observational study aimed to investigate whether the aforementioned variants cause clinical phenotypes in a well-characterised IPF cohort. METHODS: The study consisted of 138 patients with IPF who were diagnosed and treated at the Helsinki University Hospital and genotyped in the FinnGen FinnIPF study. Data on > 25 clinical parameters were collected by two pulmonologists who were blinded to the genetic data for patients with TERT loss of function and missense variants, SPDL1 and KIF15 missense variants, and a MUC5B variant commonly present in patients with IPF, or no variants were separately analysed. RESULTS: The KIF15 missense variant is associated with the early onset of the disease, leading to progression to early-age transplantation or death. In patients with the KIF15 variant, the median age at diagnosis was 54.0 years (36.5-69.5 years) compared with 72.0 years (65.8-75.3 years) in the other patients (P = 0.023). The proportion of KIF15 variant carriers was 9- or 3.6-fold higher in patients aged < 55 or 65 years, respectively. The variants for TERT and MUC5B had similar effects on the patient's clinical course, as previously described. No distinct phenotypes were observed in patients with the SPDL1 variant. CONCLUSIONS: Our study indicated the potential of KIF15 to be used in the genetic diagnostics of IPF. Further studies are needed to elucidate the biological mechanisms of KIF15 in IPF.
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Fibrose Pulmonar Idiopática , Humanos , Pessoa de Meia-Idade , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/genética , Genótipo , Fenótipo , Mucina-5B/genética , Cinesinas/genéticaRESUMO
Background: Research on health-related quality of life (HRQoL) is crucial for developing comprehensive palliative care in idiopathic pulmonary fibrosis (IPF). Objectives: To study IPF patients' HRQoL compared with general population and its association with dyspnea in a longitudinal follow-up. Design: Assessment of IPF patients' HRQoL by a generic tool. Comparison of baseline data with the general population and a 30-month follow-up with 6 months intervals. Setting/Subjects: In total, 246 IPF patients were recruited from the Finnish nationwide real-life study, FinnishIPF. Measurements: Modified Medical Research Council (MMRC) dyspnea scale for dyspnea and the generic HRQoL tool 15D for the total and dimensional HRQoL were used. Results: At baseline, the mean 15D total score was lower (0.786, standard deviation [SD] 0.116) in IPF patients than in the general population (0.871, SD 0.043) (p < 0.001) and among the IPF patients with MMRC ≥2 compared with those with MMRC <2 (p < 0.001). In patients with MMRC ≥2, significant impairment compared with general population existed in 11 dimensions of HRQoL, such as breathing, usual activities, and sexual activity, whereas this was true in only 4 dimensions in MMRC <2 category. Mental function was not impaired in either group. During the follow-up, 15D total score decreased in both MMRC categories (p < 0.001) but stayed constantly worse in the MMRC ≥2 group. Seven and two dimensions of HRQoL significantly declined in the categories of MMRC <2 and MMRC ≥2, respectively. Conclusions: Patients with IPF, especially if dyspnea limits everyday life, suffer from widely impaired HRQoL, although self-assessed mental capability is preserved. Integrated palliative care is supported to face the multiple needs of IPF patients.
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Fibrose Pulmonar Idiopática , Qualidade de Vida , Humanos , Estudos Longitudinais , Fibrose Pulmonar Idiopática/complicações , Dispneia , Coleta de DadosRESUMO
Background: Pleural mesothelioma (MPM) is an aggressive malignancy with an average patient survival of only 10 months. Interestingly, about 5%-10% of the patients survive remarkably longer. Prior studies have suggested that the tumor immune microenvironment (TIME) has potential prognostic value in MPM. We hypothesized that high-resolution single-cell spatial profiling of the TIME would make it possible to identify subpopulations of patients with long survival and identify immunophenotypes for the development of novel treatment strategies. Methods: We used multiplexed fluorescence immunohistochemistry (mfIHC) and cell-based image analysis to define spatial TIME immunophenotypes in 69 patients with epithelioid MPM (20 patients surviving ≥ 36 months). Five mfIHC panels (altogether 21 antibodies) were used to classify tumor-associated stromal cells and different immune cell populations. Prognostic associations were evaluated using univariate and multivariable Cox regression, as well as combination risk models with area under receiver operating characteristic curve (AUROC) analyses. Results: We observed that type M2 pro-tumorigenic macrophages (CD163+pSTAT1-HLA-DRA1-) were independently associated with shorter survival, whereas granzyme B+ cells and CD11c+ cells were independently associated with longer survival. CD11c+ cells were the only immunophenotype increasing the AUROC (from 0.67 to 0.84) when added to clinical factors (age, gender, clinical stage, and grade). Conclusion: High-resolution, deep profiling of TIME in MPM defined subgroups associated with both poor (M2 macrophages) and favorable (granzyme B/CD11c positivity) patient survival. CD11c positivity stood out as the most potential prognostic cell subtype adding prediction power to the clinical factors. These findings help to understand the critical determinants of TIME for risk and therapeutic stratification purposes in MPM.
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INTRODUCTION: Malignant pleural mesothelioma (MPM) is associated with poor prognosis and is strongly associated with occupational asbestos exposure. Given the importance of asbestos exposure in MPM pathogenesis, we retrospectively analyzed the types and concentrations of asbestos fibers within the lung tissues of patients with MPM and investigated their effects on all-cause mortality. METHODS: We formed a national data set of patients with MPM identified from the Finnish Cancer Registry and Statistics Finland. These data were merged with pulmonary asbestos fiber analysis results received from the Finnish Institute of Occupational Health. RESULTS: We identified 590 patients with MPM who underwent pulmonary asbestos fiber analysis. The median asbestos concentration within dry lung tissue was 3.20 million fibers/gram (range: 0 - 1700 million fibers/gram). Crocidolite and anthophyllite were the most prevalent asbestos fiber types detected in lung tissue. The multivariable risk of death analyses, where changes over time were accounted for, revealed that total asbestos fiber concentration was associated with increased mortality. Nevertheless, no difference in mortality was noted between different fiber types. CONCLUSIONS: Our study revealed that pulmonary fiber concentrations correlated with the manner of asbestos usage. Anthophyllite was identified as the sole fiber in a sizable proportion of cases, supporting its independent role in the pathogenesis of MPM. Our findings suggest that asbestos fiber burden, but not fiber type, may have an impact on the prognosis of MPM.
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Amianto , Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Exposição Ocupacional , Neoplasias Pleurais , Amianto/efeitos adversos , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Mesotelioma/complicações , Exposição Ocupacional/efeitos adversos , Neoplasias Pleurais/patologia , Estudos RetrospectivosRESUMO
OBJECTIVES: Although asbestos exposure is the most common cause of malignant mesothelioma (MM), an aggressive cancer of the pleura or peritoneum, up to 7% of patients harbor a genetic predisposition to MM. Pathogenic germline variants in the BRCA1-associated protein 1 (BAP1) gene cause a dominantly inherited tumor predisposition syndrome, BAP1-TPDS, in which MM is the second most common associated cancer. Other frequent cancers in BAP1-TPDS are uveal melanoma (UM), cutaneous melanoma and renal cell carcinoma. Additionally patients can exhibit benign skin lesions, BAP1-inactivated nevi (BIN). Most BINs arise sporadically, but patients with BAP1-TPDS may harbor multiple BINs before other tumors or as the only indication of the syndrome. Our objective was to establish the frequency of pathogenic germline BAP1 variants in Finnish patients with MM. MATERIALS AND METHODS: 56 DNA samples archived in the Helsinki Biobank from Finnish patients with MM were sequenced for germline BAP1 variations. Formalin fixed paraffin embedded nevi from a pathogenic variant carrier were subjected to immunohistochemistry and exome sequencing. RESULTS: Sanger sequencing identified one patient with Finnish founder mutation c.1780_1781insT, p.(G549Vfs*49) in BAP1. The carrier was diagnosed with MM over fifteen years before the cohorts mean onset age (mean 68, range 27 to 82) although the patient had no asbestos exposure or family history of BAP1-TPDS. However, the patient had three BINs removed prior to the MM. The c.1780_1781insT is now found from five Finnish BAP1-TPDS families with unknown common ancestor. CONCLUSION: The frequency of pathogenic germline BAP1 variants in Finnish patients with MM is 1.8 % (95 % CI, 0.04 to 9.2), comparable to the frequency in Finnish patients with UM (1.9 %). The frequency of recurring BINs in patients with BAP1-TPDS should be studied further and genetic testing for BAP1 variants considered if the patient has ≥ 2 BAP1-TPDS core tumors, including BINs.
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The research of rare and devastating orphan diseases, such as idiopathic pulmonary fibrosis (IPF) has been limited by the rarity of the disease itself. The prognosis is poor-the prevalence of IPF is only approximately four times the incidence, limiting the recruitment of patients to trials and studies of the underlying biology. Global biobanking efforts can dramatically alter the future of IPF research. We describe a large-scale meta-analysis of IPF, with 8,492 patients and 1,355,819 population controls from 13 biobanks around the globe. Finally, we combine this meta-analysis with the largest available meta-analysis of IPF, reaching 11,160 patients and 1,364,410 population controls. We identify seven novel genome-wide significant loci, only one of which would have been identified if the analysis had been limited to European ancestry individuals. We observe notable pleiotropy across IPF susceptibility and severe COVID-19 infection and note an unexplained sex-heterogeneity effect at the strongest IPF locus MUC5B.
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BACKGROUND: Substantial variation in health care costs for malignant pleural mesothelioma (MPM) has previously been identified. MATERIALS AND METHODS: We analyzed the changes in health care costs in MPM in Finland during 2002-2012. Finland has low-threshold public health care and a mandatory Workers' Compensation scheme that covers all occupational-related disease expenses. The costs include treatment costs for inpatients, hospice care, medication costs, rehabilitation costs, and travel costs. All costs are expressed in 2012 prices, adjusted using the consumer price index. RESULTS: A total of 907 MPM patients were included in the study. Mean duration of inpatient episodes increased 7% per year from 2002 to 2012, correlating with total costs (R2 = 0.861, p < 0.05). The annual total costs for treatment increased from 1.7 to 4.3 m during the study period and the cost per patient from 27 000 to 43 000 . The overall costs increased progressively by the number of procedures performed. In patients who had been compensated for occupational cause by Workers' Compensation Center, only 36% of the overall care costs were billed from the insurance company. Billing of inpatient costs was 86% in these patients. CONCLUSION: During the study period, we found that the costs of MPM increased more than the average health care costs. This may be because of advanced diagnostic workup or more costly treatment (e.g., pemetrexed). Moreover, only one-third of all health care costs are charged to Workers' Compensation Insurance.
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Custos de Cuidados de Saúde/estatística & dados numéricos , Seguro Saúde/estatística & dados numéricos , Mesotelioma Maligno/economia , Mesotelioma Maligno/terapia , Finlândia , Humanos , Estudos RetrospectivosRESUMO
BACKGROUND AND OBJECTIVE: Antifibrotic therapy with nintedanib or pirfenidone slows disease progression and reduces mortality in patients with idiopathic pulmonary fibrosis (IPF). However, patients with advanced IPF, as defined by forced vital capacity (FVC) < 50% and/or diffusion capacity for carbon monoxide (DLCO) < 30% of predicted, have not been included in randomized trials, and the outcomes of such patients who initiate treatment are not well understood. We determined lung function, disease progression and mortality outcomes following initiation of antifibrotic therapy in patients with advanced IPF at the time of treatment initiation compared to those with mild-moderate IPF. METHODS: We included 502 patients enrolled in IPF registries from four Nordic countries. Linear mixed models were used to assess change in FVC and DLCO over time. Cox proportional hazards models were used to assess transplant-free survival and progression- and transplant-free survival. RESULTS: Of 502 patients, 66 (13%) had advanced IPF. Annual change in FVC was -125 ml (95% CI -163, -87) among patients with mild-moderate IPF, and +28 ml (95% CI -96, +152) among those with advanced IPF. Advanced IPF at treatment initiation was associated with poorer transplant-free survival (hazard ratio [HR] 2.39 [95% CI 1.66, 3.43]) and progression- and transplant-free survival (HR 1.60 [95% CI 1.15, 2.23]). CONCLUSION: In a broadly representative IPF population, patients with advanced IPF at the initiation of antifibrotic therapy did not have greater lung function decline over time compared with those with mild-moderate IPF, but had substantially higher mortality. Prospective studies are needed to determine the effect of antifibrotic therapy in patients with advanced IPF.
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Fibrose Pulmonar Idiopática , Piridonas , Progressão da Doença , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/uso terapêutico , Piridonas/uso terapêutico , Resultado do Tratamento , Capacidade VitalRESUMO
Malignant pleural mesothelioma (MPM) has a rich stromal component containing mesenchymal fibroblasts. However, the properties and interplay of MPM tumor cells and their surrounding stromal fibroblasts are poorly characterized. Our objective was to spatially profile known mesenchymal markers in both tumor cells and associated fibroblasts and correlate their expression with patient survival. The primary study cohort consisted of 74 MPM patients, including 16 patients who survived at least 60 months. We analyzed location-specific tissue expression of seven fibroblast markers in clinical samples using multiplexed fluorescence immunohistochemistry (mfIHC) and digital image analysis. Effect on survival was assessed using Cox regression analyses. The outcome measurement was all-cause mortality. Univariate analysis revealed that high expression of secreted protein acidic and cysteine rich (SPARC) and fibroblast activation protein in stromal cells was associated with shorter survival. Importantly, high expression of platelet-derived growth factor receptor beta (PDGFRB) in tumor cells, but not in stromal cells, was associated with shorter survival (hazard ratio [HR] = 1.02, p < 0.001). A multivariable survival analysis adjusted for clinical parameters and stromal mfIHC markers revealed that tumor cell PDGFRB and stromal SPARC remained independently associated with survival (HR = 1.01, 95% confidence interval [CI] = 1.00-1.03 and HR = 1.05, 95% CI = 1.00-1.11, respectively). The prognostic effect of PDGFRB was validated with an artificial intelligence-based analysis method and further externally validated in another cohort of 117 MPM patients. In external validation, high tumor cell PDGFRB expression associated with shorter survival, especially in the epithelioid subtype. Our findings suggest PDGFRB and SPARC as potential markers for risk stratification and as targets for therapy.
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Biomarcadores Tumorais/metabolismo , Mesotelioma Maligno/diagnóstico , Osteonectina/metabolismo , Neoplasias Pleurais/diagnóstico , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Idoso , Inteligência Artificial , Estudos de Coortes , Feminino , Fibroblastos/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica/métodos , Masculino , Mesotelioma Maligno/metabolismo , Mesotelioma Maligno/mortalidade , Mesotelioma Maligno/patologia , Neoplasias Pleurais/metabolismo , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/patologia , Prognóstico , Análise de Sobrevida , Estudos de Validação como AssuntoRESUMO
A large number of fibroblast foci (FF) predict mortality in idiopathic pulmonary fibrosis (IPF). Other prognostic histological markers have not been identified. Artificial intelligence (AI) offers a possibility to quantitate possible prognostic histological features in IPF. We aimed to test the use of AI in IPF lung tissue samples by quantitating FF, interstitial mononuclear inflammation, and intra-alveolar macrophages with a deep convolutional neural network (CNN). Lung tissue samples of 71 patients with IPF from the FinnishIPF registry were analyzed by an AI model developed in the Aiforia® platform. The model was trained to detect tissue, air spaces, FF, interstitial mononuclear inflammation, and intra-alveolar macrophages with 20 samples. For survival analysis, cut-point values for high and low values of histological parameters were determined with maximally selected rank statistics. Survival was analyzed using the Kaplan-Meier method. A large area of FF predicted poor prognosis in IPF (p = 0.01). High numbers of interstitial mononuclear inflammatory cells and intra-alveolar macrophages were associated with prolonged survival (p = 0.01 and p = 0.01, respectively). Of lung function values, low diffusing capacity for carbon monoxide was connected to a high density of FF (p = 0.03) and a high forced vital capacity of predicted was associated with a high intra-alveolar macrophage density (p = 0.03). The deep CNN detected histological features that are difficult to quantitate manually. Interstitial mononuclear inflammation and intra-alveolar macrophages were novel prognostic histological biomarkers in IPF. Evaluating histological features with AI provides novel information on the prognostic estimation of IPF.
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Inteligência Artificial , Aprendizado Profundo , Fibroblastos/patologia , Fibrose Pulmonar Idiopática/patologia , Inflamação/patologia , Idoso , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Idiopathic pulmonary fibrosis (IPF) is a severe and progressive lung disease with a poor prognosis. Patients with IPF suffer from a high symptom burden, which impairs their health-related quality of life (HRQoL). Lack of research on IPF symptoms and their clustering, however, makes symptom-centred care challenging. METHODS: We sent two questionnaires, RAND 36-Item Health Survey and Edmonton Symptom Assessment System, to 300 patients from the FinnishIPF registry. Of the 300 patients, 245 (82%) responded. We performed an exploratory factor analysis on the results to search for potential clustering of symptoms into factors. RESULTS: We found three distinct symptom factors: the emotional factor (including depression, anxiety, insomnia, loss of appetite and nausea), the pain factor (pain at rest or in movement) and the respiratory symptoms factor (shortness of breath, cough, tiredness and loss of wellbeing). Correlation was strong within the factors (ρτ 0.78-0.85) and also evident between them. The factors correlated with the different dimensions of HRQoL: the emotional factor with mental health (correlation coefficient=-0.69) and vitality (-0.63), the pain factor with bodily pain (-0.72) and the respiratory symptoms factor with vitality (-0.69), general health (-0.64) and physical functioning (-0.62). CONCLUSION: We found three distinct symptom factors in IPF, of which respiratory and emotional factors showed the strongest association with decreasing HRQoL. Routine assessment of IPF patients' respiratory symptoms, mental health and pain are important as these may be linked with other symptoms and significantly impair the patient's HRQoL.
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Malignant peritoneal mesothelioma (MPeM) is a rare cancer of the mesothelial cells of the peritoneum. Computed tomography (CT) is considered the standard for first-line imaging of MPeM, diagnosis and risk stratification remains challenging. Peritoneal cancer index (PCI), as assessed by CT, is utilized in the prognostic assessment of other malignant intra-abdominal conditions; however, there is limited data concerning the utility of PCI in the diagnosis and workup of MPeM. We studied a retrospective cohort of all patients diagnosed with MPeM from 2000 to 2012 in Finland. CT and magnetic resonance imaging (MRI) were reviewed and scored by an experienced and blinded, board-certified abdominal radiologist. Additional clinical data and outcomes were obtained from Finnish Cancer Registry (FCR), the Workers' Compensations Center (WCC), and Statistics Finland (SF). Abdominal CT or MRI was available for 53 of 90 patients. The median radiographic PCI was 25. PCI score was correlated with overall survival (p = 0.004, Exp(B) = 1.064, 95% CI 1.020-1.110). PCI score ≥ 30 was associated with worse survival (p = 0.002), while PCI ≤ 19 was associated with improved overall survival (p = 0.001). Our study indicates that radiological PCI is prognostic in MPeM and should be assessed during radiographic workup and integrated into clinical decision-making.
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Neoplasias Peritoneais/diagnóstico por imagem , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Idoso , Tomada de Decisão Clínica , Estudos de Coortes , Feminino , Finlândia , Humanos , Imageamento por Ressonância Magnética , Masculino , Neoplasias Peritoneais/mortalidade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Tomografia Computadorizada por Raios XRESUMO
INTRODUCTION: Malignant pleural mesothelioma (MPM) is a fatal malignancy strongly associated with previous asbestos exposure. Overall survival remains dismal, partly owing to poor response to available treatment. The aims of this study were to evaluate diagnostic accuracy in a group of patients with MPM with an unusually long survival time and to assess the factors related to this prolonged survival. MATERIALS AND METHODS: Forty-three patients with overall survival exceeding 5 years were accepted to the long-term survivor (LTS) group, and these patients were compared with 84 patients with epithelial MPM. Data were collected from various national registries and electronic medical records. In addition, all available histopathologic diagnostic samples and computed tomography studies were re-evaluated by experienced specialists. RESULTS: Our study showed a good diagnostic accuracy, with only 1 (0.5%) patient having an incorrect MPM diagnosis. Two (0.9%) localized malignant mesotheliomas and 2 (0.9%) well-differentiated papillary mesotheliomas were also found. LTS patients were younger, more frequently female, had a better performance status at time of diagnosis, and had less evidence of prior asbestos exposure. In multivariate analysis, we showed tumor size, Eastern Cooperative Oncology Group performance status, and first-line treatment (both surgery and chemotherapy) to be associated with survival time. CONCLUSION: We confirmed the diagnosis of MPM in an overwhelming majority of patients in the LTS group. An epithelial subtype of MPM behaving clinically more indolently seems to exist, but further tumor and genetic characterization is needed. The prolonged survival time is most likely explained by a combination of tumor-, patient-, and treatment-related factors.
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Mesotelioma Maligno/mortalidade , Neoplasias Pleurais/mortalidade , Sistema de Registros/estatística & dados numéricos , Idoso , Estudos de Casos e Controles , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Mesotelioma Maligno/patologia , Mesotelioma Maligno/terapia , Pessoa de Meia-Idade , Neoplasias Pleurais/patologia , Neoplasias Pleurais/terapia , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Idiopathic pulmonary fibrosis (IPF) is a lung parenchymal disease of unknown cause usually occurring in older adults. It is a chronic and progressive condition with poor prognosis and diagnosis is largely clinical. Currently, there exist few biomarkers that can predict patient outcome or response to therapies. Together with lack of markers, the need for novel markers for the detection and monitoring of IPF, is paramount. We have performed label-free plasma proteomics of thirty six individuals, 17 of which had confirmed IPF. Proteomics data was analyzed by volcano plot, hierarchical clustering, Partial-least square discriminant analysis (PLS-DA) and Ingenuity pathway analysis. Univariate and multivariate statistical analysis overlap identified haptoglobin-related protein as a possible marker of IPF when compared to control samples (Area under the curve 0.851, ROC-analysis). LXR/RXR activation and complement activation pathways were enriched in t-test significant proteins and oxidative regulators, complement proteins and protease inhibitors were enriched in PLS-DA significant proteins. Our pilot study points towards aberrations in complement activation and oxidative damage in IPF patients and provides haptoglobin-related protein as a new candidate biomarker of IPF.
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Proteínas Sanguíneas , Proteínas do Sistema Complemento/imunologia , Haptoglobinas/metabolismo , Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/metabolismo , Estresse Oxidativo , Proteômica , Transdução de Sinais , Idoso , Biomarcadores , Estudos de Casos e Controles , Proteínas do Sistema Complemento/metabolismo , Biologia Computacional/métodos , Feminino , Humanos , Fibrose Pulmonar Idiopática/patologia , Masculino , Proteoma , Proteômica/métodos , Curva ROCRESUMO
Diffuse malignant mesothelioma (DMM) of the pleura is a rare and aggressive disease, wherein the long-term survival (LTS) rate is low. The epithelioid subtype is the most prevalent form of DMM with the best prognosis. To study prognostic histopathologic factors associated with extended survival in epithelioid DMM, we examined 43 tumors from patients with survival more than five years (LTSs) and compared the findings with 84 tumors from a reference group (RG) with average survival. We analyzed the tumors considering previously published histopathological prognostic features and attempted to identify additional morphological features predictive of extended survival. Most of the LTS tumors presented with nuclear grade I (n = 34, 90%) and a tubulopapillary growth pattern (n = 30, 70%). One LTS tumor had necrosis. In contrast, nuclear grade II (n = 49, 61%) and solid growth pattern (n = 59, 70%) were more frequent in the RG, and necrosis was present in 16 (19%) tumors. We also evaluated the association of asbestos lung tissue fiber burden quantified from autopsy samples with histopathological features and found that elevated asbestos fiber was associated with higher nuclear grade (P < 0.001) and the presence of necrosis (P = 0.021). In univariate survival analysis, we identified the following three novel morphological features associated with survival: exophytic polypoid growth pattern, tumor density, and single mesothelium layered tubular structures. After adjustments, low nuclear grade (P < 0.001) and presence of exophytic polypoid growth (P = 0.024) were associated with prolonged survival. These results may aid in estimating DMM prognosis.
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Células Epitelioides/patologia , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Neoplasias Pleurais/patologia , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/cirurgia , Masculino , Mesotelioma/mortalidade , Mesotelioma/cirurgia , Mesotelioma Maligno , Necrose , Gradação de Tumores , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/cirurgia , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Previous preclinical studies have shown that activin A is overexpressed in malignant pleural mesothelioma (MPM), associates with cancer cachexia, and is observed in in vitro resistance to platinum-based chemotherapy. We evaluated circulating activin levels and their endogenous antagonists' follistatin/follistatin-like 3 in intrathoracic tumors. MATERIALS AND METHODS: Patients suspected of thoracic malignancy were recruited prior to surgery. Serum samples were collected from 21 patients with MPM, 59 patients with non-small-cell lung cancer (NSCLC), and 22 patients with benign lung lesions. Circulating activin/follistatin levels were measured using enzyme-linked immunosorbent assay and compared with clinicopathologic parameters. RESULTS: Circulating activin A levels were elevated in patients with MPM when compared with patients with NSCLC or benign lung lesion samples (P < .0001). Also, follistatin and follistatin-like 3 levels were the highest in MPM, although with less difference compared with activin A. Receiver operating characteristic analysis for activin A for separating NSCLC from benign lung lesion showed an area under the curve of 0.856 (95% confidence interval, 0.77-0.94). Activin A levels were higher in patients with cachexia (P < .001). In patients with MPM, activin A levels correlated positively with computed tomography-based baseline tumor size (R = 0.549; P = .010) and the change in tumor size after chemotherapy (R = 0.743; P = .0006). Patients with partial response or stable disease had lower circulating activin A levels than the ones with progressive disease (P = .028). CONCLUSION: Activin A serum level could be used as a biomarker in differentiating malignant and benign lung tumors. Circulating activin A levels were elevated in MPM and associates with cancer cachexia and reduced chemotherapy response.
Assuntos
Ativinas/sangue , Biomarcadores Tumorais/sangue , Caquexia/diagnóstico , Mesotelioma Maligno/tratamento farmacológico , Platina/efeitos adversos , Neoplasias Pleurais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Caquexia/sangue , Caquexia/induzido quimicamente , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma Maligno/patologia , Pessoa de Meia-Idade , Neoplasias Pleurais/patologia , Prognóstico , Estudos Prospectivos , Curva ROC , Estudos RetrospectivosRESUMO
Idiopathic pulmonary fibrosis (IPF) is characterised by unpredictable disease course and poor survival. After the introduction of novel antifibrotic drugs, the prognosis of patients with IPF is probably changing. FinnishIPF, a nationwide registry of carefully characterised patients, was initiated in Finland in 2011. For the data analysis, we included 453 incident IPF patients diagnosed during 2011-2015. In this study, we describe the demographics and prognosis of these real-life patients. The median overall survival time of registered IPF patients was 4.5â years. The transplant-free survival at 1, 2, 3, 4 and 5â years was 95%, 83%, 70%, 58% and 45%, respectively. Smoking did not have any effect on survival. 117 (26%) patients received pirfenidone or nintedanib. Patients who received ≥6â months of treatment had better survival compared with those who did not receive treatment but this difference disappeared after age adjustment. The transplantation rate was 3%. Although IPF is diagnosed in Finland at a older age, the prognosis is better than expected due to a relatively well preserved lung function at diagnosis. Age and pulmonary function were identified as independent predictors of survival in the entire IPF patient population as well as in patients who had received antifibrotic treatment.
RESUMO
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with a dismal prognosis and an unknown etiology. Inorganic dust is a known risk factor, and air pollution seems to affect disease progression. We aimed to investigate inorganic particulate matter in IPF lung tissue samples. Using polarizing light microscopy, we examined coal dust pigment and inorganic particulate matter in 73 lung tissue samples from the FinnishIPF registry. We scored the amount of coal dust pigment and particulate matter from 0 to 5. Using energy dispersive spectrometry with a scanning electron microscope, we conducted an elemental analysis of six IPF lung tissue samples. We compared the results to the registry data, and to the population density and air quality data. To compare categorical data, we used Fisher's exact test; we estimated the survival of the patients with Kaplan-Meier curves. We found inorganic particulate matter in all samples in varying amounts. Samples from the southern regions of Finland, where population density and fine particle levels are high, more often had particulate matter scores from 3 to 5 than samples from the northern regions (31/50, 62.0% vs. 7/23, 30.4%, pâ¯=â¯0.02). The highest particulate matter scores of 4 and 5 (nâ¯=â¯15) associated with a known exposure to inorganic dust (pâ¯=â¯0.004). An association between particulate matter in the lung tissue of IPF patients and exposure to air pollution may exist.