RESUMO
Introduction: Sarcoidosis is a highly variable disease in terms of organ involvement, type of onset and course. Associations of genetic polymorphisms with sarcoidosis phenotypes have been observed and suggest genetic signatures. Methods: After obtaining a positive vote of the competent ethics committee we genotyped 1909 patients of the deeply phenotyped Genetic-Phenotype Relationship in Sarcoidosis (GenPhenReSa) cohort of 31 European centers in 12 countries with 116 potentially disease-relevant single-nucleotide polymorphisms (SNPs). Using a meta-analysis, we investigated the association of relevant phenotypes (acute vs. sub-acute onset, phenotypes of organ involvement, specific organ involvements, and specific symptoms) with genetic markers. Subgroups were built on the basis of geographical, clinical and hospital provision considerations. Results: In the meta-analysis of the full cohort, there was no significant genetic association with any considered phenotype after correcting for multiple testing. In the largest sub-cohort (Serbia), we confirmed the known association of acute onset with TNF and reported a new association of acute onset an HLA polymorphism. Multi-locus models with sets of three SNPs in different genes showed strong associations with the acute onset phenotype in Serbia and Lublin (Poland) demonstrating potential region-specific genetic links with clinical features, including recently described phenotypes of organ involvement. Discussion: The observed associations between genetic variants and sarcoidosis phenotypes in subgroups suggest that gene-environment-interactions may influence the clinical phenotype. In addition, we show that two different sets of genetic variants are permissive for the same phenotype of acute disease only in two geographic subcohorts pointing to interactions of genetic signatures with different local environmental factors. Our results represent an important step towards understanding the genetic architecture of sarcoidosis.
RESUMO
The 3rd class of BRAF (B-Raf Proto-Oncogene, Serine/Threonine Kinase) variants including G466, D594, and A581 mutations cause kinase death or impaired kinase activity. It is unlikely that RAF (Raf Proto-Oncogene, Serine/Threonine Kinase) inhibitors suppress ERK (Extracellular Signal-Regulated Kinase) signaling in class 3 mutant-driven tumors due to the fact that they preferentially inhibit activated BRAF V600 mutants. However, there are suggestions that class 3 mutations are still associated with enhanced RAS/MAPK (RAS Proto-Oncogene, GTPase/Mitogen-Activated Protein Kinase) activation, potentially due to other mechanisms such as the activation of growth factor signaling or concurrent MAPK pathway mutations, e.g., RAS or NF1 (Neurofibromin 1). A 75-year-old male patient with squamous-cell cancer (SqCC) of the lung and with metastases to the kidney and mediastinal lymph nodes received chemoimmunotherapy (expression of Programmed Cell Death 1 Ligand 1 (PD-L1) on 2% of tumor cells). The chemotherapy was limited due to the accompanying myelodysplastic syndrome (MDS), and pembrolizumab monotherapy was continued for up to seven cycles. At the time of progression, next-generation sequencing was performed and a c.1781A>G (p.Asp594Gly) mutation in the BRAF gene, a c.1381C>T (p.Arg461Ter) mutation in the NF1 gene, and a c.37C>T (p.Gln13Ter) mutation in the FANCC gene were identified. Combined therapy with BRAF (dabrafenib) and MEK (trametinib) inhibitors was used, which resulted in the achievement of partial remission of the primary lesion and lung nodules and the stabilization of metastatic lesions in the kidney and bones. The therapy was discontinued after five months due to myelosuppression associated with MDS. The molecular background was decisive for the patient's fate. NSCLC patients with non-V600 mutations in the BRAF gene rarely respond to anti-BRAF and anti-MEK therapy. The achieved effectiveness of the treatment could be related to a mutation in the NF1 tumor suppressor gene. The loss of NF1 function causes the excessive activation of KRAS and overactivity of the signaling pathway containing BRAF and MEK, which were the targets of the therapy. Moreover, the mutation in the FANCC gene was probably related to MDS development. The NGS technique was crucial for the qualification to treatment and the prediction of the NSCLC course in our patient. The mutations in two genesthe BRAF oncogene and the NF1 tumor suppressor genewere the reason for the use of dabrafenib and trametinib treatment. The patients achieved short-term disease stabilization. This proved that coexisting mutations in these genes affect the disease course and treatment efficacy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Masculino , Humanos , Idoso , Genes da Neurofibromatose 1 , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Piridonas/farmacologia , Pirimidinonas/farmacologia , Proteínas Serina-Treonina Quinases/genética , Carcinoma de Células Escamosas/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Serina/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Introduction: Factors other than PD-L1 (Programmed Death Ligand 1) are being sought as predictors for cancer immuno- or chemoimmunotherapy in ongoing studies and long-term observations. Despite high PD-L1 expression on tumor cells, some patients do not benefit from immunotherapy, while others, without the expression of this molecule, respond to immunotherapy. Attention has been paid to the composition of the gut microbiome as a potential predictive factor for immunotherapy effectiveness. Materials and Methods: Our study enrolled 47 Caucasian patients with stage IIIB or IV non-small cell lung cancer (NSCLC). They were eligible for treatment with first- or second-line immunotherapy or chemoimmunotherapy. We collected stool samples before the administration of immunotherapy. We performed next-generation sequencing (NGS) on DNA isolated from the stool sample and analyzed bacterial V3 and V4 of the 16S rRNA gene. Results: We found that bacteria from the families Barnesiellaceae, Ruminococcaceae, Tannerellaceae, and Clostridiaceae could modulate immunotherapy effectiveness. A high abundance of Bacteroidaaceae, Barnesiellaceae, and Tannerellaceae could extend progression-free survival (PFS). Moreover, the risk of death was significantly higher in patients with a high content of Ruminococcaceae family (HR = 6.3, 95% CI: 2.6 to 15.3, p < 0.0001) and in patients with a low abundance of Clostridia UCG-014 (HR = 3.8, 95% CI: 1.5 to 9.8, p = 0.005) regardless of the immunotherapy line. Conclusions: The Clostridia class in gut microbiota could affect the effectiveness of immunotherapy, as well as the length of survival of NSCLC patients who received this method of treatment.
RESUMO
The significance of Akkermansia bacteria presence in gut micobiome, mainly Akkermansia mucinifila, is currently being investigated in the context of supporting therapy and marker for response to immunotherapy in cancer patients. It is indicated that patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) respond better to treatment if this bacterium is present in the intestine.We performed next-generation sequencing of the gut microbiome from patients treated in the first or second line therapy with anti-PD-1 (anti-programmed death 1) or anti-PD-L1 (anti-programmed death ligand 1) monoclonal antibodies. In our study group of 47 NSCLC patients, the percentage of Akkermansiaceae was higher in patients with disease stabilization and with partial response to immunotherapy compared to patients with disease progression. Moreover, we found that a higher percentage of Akkermansiaceae was present in patients with squamous cell carcinoma compared to adenocarcinoma. Our study showed that Akkermansiaceae could be supporting marker for response to immunotherapies in NSCLC patients, nonetheless further in-depth studies should be conducted in the role of Akkermansiaceae in cancer immunotherapy.
RESUMO
Osimertnib is still widely used in the treatment of NSCLC patients who have previously received erlotinib, gefitinib or afatinib and have developed resistance to these drugs mediated by the T790M mutation in exon 20 of EGFR gene. We assessed the results of T790M mutation testing in liquid biopsy by Entrogen test and real-time PCR technique in routine clinical practice. Analysis was conducted in 73 plasma samples from 41 patients with locally advanced or metastatic lung adenocarcinoma treated with first- or second-generation of EGFR TKIs. We detected T790M mutation in 18 patients (43.9% of patients, 24.6% positive tests in 73 samples). The incidence of T790M mutation in liquid biopsy was significantly higher in patients with T3-T4 tumors compared to patients with T0-T2 tumors (p = 0.0368, χ2 = 4.36). Median PFS at the time of progression according to RECIST was significantly (p = 0.0444) higher in patients with T790M mutation than in patients without this mutation (22.5 vs. 15 months). Our results confirmed that T790M mutation is more often detected in patients with a large tumor spreading in the chest and with the long duration of response to first- or second generation of EGFR TKIs. The low sensitivity of the real-time PCR technique in T790M mutation detection could be partially compensated by repeating the tests.
Assuntos
Adenocarcinoma de Pulmão , Receptores ErbB , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Humanos , Biópsia Líquida/métodos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
In patients with advanced non-small cell lung cancer (NSCLC), comprehensive genetic diagnostics is currently carried out in order to qualify for molecularly targeted therapies and immunotherapy. The aim of the study was to assess the usefulness of the reverse transcriptase (RT-PCR) method in the diagnosis of gene rearrangements, the effectiveness of EGFR, ALK, ROS1, and PD-L1 inhibitors in first-line treatment in NSCLC patients. We enrolled 95 non-squamous NSCLC patients with known status of EGFR, ALK, ROS1, MET and RET genes and PD-L1 protein expression. We used the real time PCR, fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and RT-PCR techniques for determination of predictive factors. In patients with ALK and ROS1 genes alteration, the median overall survival was 34 months in crizotinib treated patients and 6 months in patients who received chemotherapy (HR = 0.266, p = 0.0056). The risk of death was lower in patients treated with molecularly targeted therapies or immunotherapy compared to patients with predictive factors without personalized treatment (HR = 0.265, 95% CI 0.116-0.606) and to patient without predictive factors who received chemotherapy (HR = 0.42, 95% CI 0.162-1.09). Diagnosis of predictive factors and implementation of personalized treatment are key to prolonging the survival in advanced NSCLC patients.
Assuntos
Quinase do Linfoma Anaplásico/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Crizotinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Idoso , Feminino , Humanos , Imuno-Histoquímica/métodos , Imunoterapia/métodos , Hibridização in Situ Fluorescente/métodos , MasculinoRESUMO
INTRODUCTION: Bronchoscopy is the main method in the diagnosis of various lung diseases. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the most modern bronchoscopic technique useful in diagnosis and staging of lung cancer (LC). OBJECTIVE: The aim of the study was to assess the yield of bronchoscopy in patients with suspected various respiratory diseases including LC. In particular, we examined the efficiency of different biopsy techniques in the diagnosis of LC in correlation with its localisation and pathomorphological type. PATIENTS AND METHODS: The results of pathomorphological examinations from 5279 bronchoscopies performed in 2016-2018 were analysed. The material was collected with EBUS-TBNA, endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and endobronchial forceps biopsy. Clinical and demographic factors were analysed using the Fisher χ2 test. RESULTS: 5279 patients were diagnosed due to various respiratory symptoms. LC was confirmed in 36.42% of patients. 40.81% of patients had no definitive pathomorphological diagnosis. Among patients with LC, the most frequent diagnosis was non-small cell LC: squamous cell lung cancer (SCC)-32.07% and adenocarcinoma (AC)-30.61%, then small cell LC-25.83% and not otherwise specified non-small cell lung cancer (NSCLC-NOS)-11.49%. Diagnosis of SCC was obtained significantly more often (χ2=43.143, p<0.000001) by forceps biopsy (41.09%) than by EBUS-TBNA/EUS-FNA (26.62%). On the contrary, diagnosis of AC or NSCLC-NOS was significantly more often (χ2=20.394, p<0.000007, and χ2=3.902, p<0.05, respectively) observed in EBUS-TBNA/EUS-FNA (34.31% and 12.6%) than in endobronchial biopsies (24.52% and 9.64%). CONCLUSIONS: The use of bronchoscopy in the diagnosis of various lung diseases is vital but also has many limitations. Effectiveness of EBUS-TBNA and endobronchial forceps biopsy in the diagnosis of lung cancer is strongly affected by tumour localisation and type of cancer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Broncoscopia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos Transversais , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Mediastino/patologia , Estadiamento de NeoplasiasRESUMO
Anti-programmed death-1 or anti-programmed death-ligand 1 (PD-L1) blockade may be ineffective in some patients with non-small cell lung cancer (NSCLC) with high percentage of tumor cells with PD-L1 expression. In addition, immunotherapy may provide great benefits in patients without PD-L1 expression. The present study assessed PD-L1 protein expression by immunohistochemistry, copy number variation (CNV) of PD-L1 and two single nucleotide polymorphisms (SNPs), rs822335 and rs822336, in the promoter of PD-L1 by quantitative PCR in 673 patients with NSCLC. Overall survival time of patients with NSCLC depending on the assessed predictive factors (PD-L1 CNV or SNP) and the treatment methods (immunotherapy in first/second line of treatment or chemotherapy) was analyzed. The present study revealed significantly higher PD-L1 copies number in patients with ≥10% and ≥50% of tumor cells with PD-L1 expression compared to patients with lower percentage of PD-L1-positive tumor cells (P=0.02 and P=0.0002, respectively). There was a significant positive correlation (R=0.2; P=0.01) between number of PD-L1 copies and percentage of tumor cells with PD-L1 protein expression. Percentage of tumor cells with PD-L1 expression was lower in patients with TT genotype of the rs822335 polymorphism compared to those with CC genotype (P=0.03). The present study observed significantly higher risk of death in patients treated with chemotherapy compared to those treated with immunotherapy (P<0.0001; hazard ratio=2.4768; 95% confidence interval, 2.0120-3.0490). The present study demonstrated a close relationship between PD-L1 copies number, genotype of rs822335 PD-L1 polymorphism and PD-L1 protein expression on tumor cells. However, the impact of CNV and SNPs of PD-L1 on overall survival of patients with NSCLC requires further investigation.
RESUMO
INTRODUCTION: Osimertinib is a third-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has demonstrated efficacy in the treatment of EGFR-mutant non-small-cell lung cancer (NSCLC) in prospective clinical trials. MATERIAL AND METHODS: This retrospective analysis evaluated the outcomes of 32 pretreated patients with EGFR T790M mutation who received osimertinib in clinical practice at seven centers in Poland within the Expanded Drug Access Program. Osimertinib was used in the second line in 59% of patients and in later lines in 41%. RESULTS: Objective response was attained in 16 patients (50%), and 12 subjects (38%) had stable disease. Median progression -free survival was 11.3 months in the overall population, 12.6 months in patients with EGFR exon 19 mutation and 7.5 months in patients with EGFR exon 21 mutation (p = 0.045). Median overall survival (OS) was 18.3 months. Overall, 58.4% and 45.6% of patients remained in follow-up after 12 and 24 months, respectively. Median OS appeared longer for patients without cerebral metastases than for those with cerebral metastases (27.4 vs 9.4 months, respectively; p = 0.078), and for patients with the Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 than those with ECOG PS 2 (27.4 vs 11.8 months, respectively; p = 0.189), although neither result reached statistical significance. Median OS of patients with partial response, stable disease and progressive disease was 27.4, 12.7 and 4.5 months, respectively (p < 0.001). Age, comorbidities, line of treatment with osimertinib, and type of activating EGFR mutation did not impact on OS. Adverse events of any grade or grade 3/4 were reported in 38% and 9% of patients, respectively. One person discontinued due to interstitial pneumonia. CONCLUSION: These results confirm the value of osimertinib in patients with previously treated EGFR T790M-mutant NSCLC. Clinical benefit was evident in patients with cerebral metastases and moderate performance status.
Assuntos
Acrilamidas/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Polônia , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Immunotherapy with immune checkpoint inhibitors (ICI) is a new option of treatment in a growing range of neoplasms. In addition to an antitumor effect, ICI are associated with autoimmune reactions resulting in a wide spectrum of toxicities that have not been seen in patients receiving chemotherapy. In this article, we present a case of a patient with advanced lung adenocarcinoma who developed an EDTA-dependent pseudothrombocytopenia (PTCP) during pembrolizumab therapy. To the best of our knowledge, this is the first reported case of EDTA-dependent PTCP occurring during immunotherapy treatment of nonsmall lung cell cancer with ICI. The phenomenon of EDTA-dependent PTCP may prompt clinical decisions, as unnecessary transfusions or even exclusion from pembrolizumab therapy. Therefore, it is important to be aware of PTCP as a possible side effect of this therapy.
RESUMO
INTRODUCTION: Expression of PD-L1 protein on tumor cells, which is so far the only validated predictive factor for immunotherapy, is regulated by epigenetic and genetic factors. Among the most important ones that regulate gene expression are microRNAs. MATERIALS AND METHODS: The study included 60 patients with NSCLC who underwent first or second line immunotherapy with pembrolizumab or nivolumab. FFPE materials were collected before the start of immunotherapy. We examined relative expression of microRNAs (miR-141, miR-200a, miR-200b, miR-200c, miR-429, miR-508-3p, miR-1184, miR-1255a) and PD-L1 mRNA expression. Copy number variation (CNV) of PD-L1 gene by qPCR and FISH methods were assessed. Two single nucleotide polymorphisms (SNPs) in promoter region of PD-L1 gene (rs822335 and rs822336) were examined. Expression of PD-L1 protein on tumor cells was assessed by immunohistochemistry (IHC). The response rate to immunotherapy and progression free survival (PFS) measured in weeks and overall survival (OS) measured in months from the start of immunotherapy were evaluated. RESULTS: Response to immunotherapy was observed in nine patients (15%, including one complete response), disease stabilization in 22 patients (36.7%), and progression in 29 patients (48.3%). Significantly higher (p=0.015) expression of miR-200b and significantly lower (p=0.043) expression of miR-429 were observed in responders compared to patients who did not respond to immunotherapy. The median PFS in the whole group of patients was 16 weeks, and the median OS was 10.5 month. In univariate analysis, the median PFS was significantly higher in patients with high miR-200b expression (HR=0.4253, 95%CI: 0.1737-1.0417, p=0.05) and high miR-508 expression (HR=0.4401, 95%CI: 0.1903-1.0178, p=0.05) and with low expression of miR-429 (HR=0.1288, 95%CI: 0.01727-0.9606, p=0.0456) compared to patients with low and high expression of these molecules, respectively. The median OS was higher in patients with low expression of miR-429 (HR=0,6288, 95%CI: 0,3053-1,2949, p=0.06) compared with patients with high expression of this microRNA. In multivariate analysis, we found that patients with PD-L1 expression on ≥1% of tumor cells compared to patients without PD-L1 expression on cancer cells had a significantly lower risk of progression (HR=0.3857, 95%CI: 0.1612-0.9226, p=0.0323) and death (HR=0.377, 95%CI: 0.1636-0.8688, p=0.022). CONCLUSION: The miR-200b and miR-429 molecules in tumor cells seem to have greatest impact on the effectiveness of immunotherapy in NSCLC patients.
RESUMO
Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype-Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular-cardiac-cutaneous-central nervous system disease involvement, 3) musculoskeletal-cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement.These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies.
Assuntos
Fenótipo , Sarcoidose/diagnóstico , Sarcoidose/fisiopatologia , Abdome , Doença Aguda , Adulto , Idoso , Europa (Continente) , Olho/fisiopatologia , Oftalmopatias/fisiopatologia , Feminino , Volume Expiratório Forçado , Genótipo , Humanos , Artropatias/fisiopatologia , Pulmão/fisiopatologia , Pneumopatias/fisiopatologia , Linfonodos/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pele/fisiopatologia , Dermatopatias/fisiopatologia , Atenção Terciária à Saúde , População BrancaRESUMO
INTRODUCTION: Sarcoidosis is a multisystem granulomatous disease of unknown etiology. Current theory on the etiology of this disease involves participation of genetic factors and unknown antigens present in the patients' environment. The aim of the study was to evaluate the prevalence of different polymorphic forms of the ACE gene in healthy individuals and sarcoidosis patients, and to estimate the risk of sarcoidosis in carriers of different ACE genotypes living in rural and urban settings. MATERIAL AND METHODS: The study group included 180 patients with pulmonary sarcoidosis. Assessment of the disease was based on clinical features, laboratory and imaging examinations, as well as bronchoscopy with bronchoalveolar lavage (BAL). ACE gene polymorphism was examined in DNA isolated from peripheral blood or BAL fluid (BALF) leukocytes. RESULTS: Incidence of sarcoidosis was not influenced by gender, age or place of residence of the patients. There were no differences in the frequency of particular genotypes in patients with sarcoidosis and in healthy individuals. The risk of disease did not depend on the ACE gene polymorphism. There were no differences in the frequencies of the different genotypes and alleles of the ACE gene in patients with sarcoidosis divided by gender, age and place of residence or by clinical manifestation of sarcoidosis. CONCLUSIONS: Our results do not support the previous concept which suggested a higher incidence of sarcoidosis in individuals living in rural areas and in carriers of selected ACE genotypes. It is possible that this is related to the changing environment of rural areas, increasing urbanization and pollution.
RESUMO
The diagnosis of cutaneous sarcoidosis relies mainly on the patient's history, presence of characteristic skin lesions and histological examination that shows a granulomatous, non-necrotizing dermal infiltration. The aim of the study was to assess the ultrasonographic features of cutaneous lesions of sarcoidosis before and after treatment. A 38-year-old woman with systemic sarcoidosis and specific cutaneous lesions was treated with systemic steroids followed by hydroxychloroquine. Ultrasonographic examination of the cutaneous sarcoidosis lesions was performed with a Philips iU 22 and Siemens Acuson S 2000 device, with the use of linear 15 MHz and 17 MHz transducers. Histological examination of skin lesions showed characteristic, naked, non-necrotizing granulomas in the upper dermis. Ultrasound examination revealed well-demarcated, hypoechogenic changes. Power-Doppler scan revealed increased vascularity within the lesions and the surrounding tissue. Clinical improvement of the skin lesions was confirmed by ultrasound examination, which showed a decrease in their size and normalization of dermal echogenicity and vascularity. Ultrasound examination can show cutaneous sarcoidosis lesions and their regression after appropriate treatment.
RESUMO
Erlotinib is a reversible tyrosine kinase inhibitor of epidermal growth factor receptor (TKI EGFR). In Poland, as of July 2012, it is used in the treatment only of patients with non-small cell lung cancer (NSCLC) and with EGFR mutation gene after standard chemotherapy failure. The effectiveness of erlotinib in second- or third-line treatment of NSCLC patients without EGFR activating mutation gene remains debatable. Clinical trial results indicated that TKI EGFR showed an efficacy of 7080% in patients with EGFR mutations, while the clinical response to treatment among unselected Caucasian patients is only 10%. The present study was conducted in a group of 71 patients with inoperable, locally advanced or metastatic NSCLC treated with erlotinib as the second- or third-line therapy. Molecular tests (examination of EGFR mutation and gene amplification) were carried out retrospectively. Objective response rate, overall survival (OS) and progression-free survival (PFS) were calculated. Effects of clinical and molecular factors including the presence of EGFR mutations, EGFR gene amplification, patient performance status, rash, smoking status, time from diagnosis to start of therapy, weight loss and the serum LDH levels were analyzed. An objective response in the form of partial response occurred in only 5 patients (7%), who carried EGFR gene mutation. Median time to PFS for the entire group of patients was 1.5 months and median OS was 10 months. The strongest factors increasing the risk of progression in patients treated with erlotinib were the absence of activating mutations in the EGFR gene (6fold increased risk) and no treatmentrelated rash (4.5fold increased risk). The most important factors affecting the risk of early mortality were poor performance status (HR 37.344; P>0.0001), no treatment-related rash (HR 14.9348; P=0.0002) and a short response time on the first-line chemotherapy (HR 9.519; P=0.0445).
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Mutação/genética , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Adenoescamoso/tratamento farmacológico , Carcinoma Adenoescamoso/genética , Carcinoma Adenoescamoso/mortalidade , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/mortalidade , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Taxa de SobrevidaRESUMO
INTRODUCTION: Adult-onset thymoma may be responsible for several diseases, such as pure red cell aplasia, myasthenia gravis, and immunodeficiency (Good's syndrome). Thymectomy does not always improve the patient's condition, and may even produce additional symptoms. Its pathogenesis is still not entirely understood, but autoimmunological processes and bone marrow defect are the most frequently suggested. MATERIALS AND METHODS: Eleven patients (mean age: 56.2+/-15.5 years) were analyzed 6 months to 10 years after thymectomy due to thymoma as were 25 healthy persons serving as controls. Enzyme-linked immunosorbent assay (ELISA) and flow cytometry techniques were used to evaluate the immunological status of the subjects. RESULTS: Good's syndrome was diagnosed in one patient, 4 subjects suffered from myasthenia gravis, and recurrent infections of upper and lower respiratory tract appeared in 9 patients. The immunological analyses (ELISA and flow cytometry) revealed a significantly lower IgG level (p<0.05), percentage of peripheral blood B lymphocytes (p<0.0005), and CD4:CD8 ratio (p<0.05) in thymectomized patients compared with the healthy controls. The percentages of CD4+ and CD8+ T lymphocytes expressing CD28 antigen were significantly lower in thymectomized patients than in healthy subjects (p<0.005 and p<0.01, respectively). The percentage of naive T helper lymphocytes was significantly lower in the patients than in the control group (p<0.05). CONCLUSIONS: Immunodeficiency and recurrent infections may be the first symptoms of immunological disturbances after thymectomy in adults. It is suggested that regular medical monitoring of these patients is important in preventing further complications, which may result in irreversible lung tissue destruction.
Assuntos
Suscetibilidade a Doenças/imunologia , Doenças Respiratórias/diagnóstico , Doenças Respiratórias/imunologia , Timectomia/efeitos adversos , Adulto , Idoso , Feminino , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/imunologia , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/diagnóstico , Miastenia Gravis/imunologia , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/imunologiaRESUMO
INTRODUCTION: The release of tumor necrosis factor (TNF-alpha) is increased in sarcoidosis patients. TNF-alpha exerts its effect by binding to specific cell surface receptors. There are only fragmentary data concerning the expression of tumor necrosis factor receptors (TNFRs) on bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) lymphocytes. The aim of the study was to evaluate TNFRI (CD120a) and TNFRII (CD120b) expression on T cells and the level of soluble TNFRs in specimens of patients with different clinical manifestation and clinical outcome of sarcoidosis. MATERIAL AND METHODS: We examined 49 patients with newly diagnosed pulmonary sarcoidosis. TNFRI and TNFRII density on CD4+ and CD8+ BALF and PB cells surface was estimated using monoclonal antibodies and a flow cytometry technique. The level of TNFRs in PB serum and BALF cell culture supernatant (CCS) was measured using ELISA. Immunological analyses were also performed on PB samples collected from 10 healthy volunteers. RESULTS: The level of soluble TNFRI (sTNFRI) in PB serum was similar in sarcoidosis patients and healthy subjects, whereas the concentration of sTNFRII in serum was significantly higher in the sarcoidosis group (P<0.001). Patients without acute symptoms of sarcoidosis, patients with radiological stage II/III as well as patients with further disease progression showed a tendency to higher levels of sTNFRs in PB serum and lower levels of sTNFRs in BALF CCS compared to Löfgren syndrome and radiological stage I subjects, and patients with spontaneous resolution of sarcoidosis. More than 80% of BALF and PB lymphocytes of sarcoidosis patients expressed both CD120a and CD120b antigens. The percentage of double-positive CD4+CD120a+ and CD4+CD120b+ cells in PB was significantly higher (P<0.005) in sarcoidosis patients than in healthy subjects. The highest percentage of CD4+CD120a+ and CD4+CD120b+ lymphocytes in BALF was determined in patients with acute disease, and in PB of patients with further spontaneous improvement. CONCLUSION: The evaluation of sTNFRs and TNFRs expression on T-helper cells may be useful in the estimation of sarcoidosis activity.
Assuntos
Receptores do Fator de Necrose Tumoral/análise , Sarcoidose Pulmonar/imunologia , Linfócitos T/imunologia , Adulto , Artralgia/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Relação CD4-CD8 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Eritema Nodoso/imunologia , Etanercepte , Feminino , Humanos , Imunoglobulina G/análise , Imunoglobulina G/sangue , Masculino , Prognóstico , Receptores do Fator de Necrose Tumoral/sangue , Receptores Tipo I de Fatores de Necrose Tumoral/análise , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Receptores Tipo II do Fator de Necrose Tumoral/análise , Receptores Tipo II do Fator de Necrose Tumoral/sangue , SíndromeRESUMO
INTRODUCTION: Sarcoidosis is a multisystemic disease of unknown etiology characterized by the formation of immune granulomas in involved organs. The cytokine profile in inflamed lesions of sarcoidosis is mainly determined by T helper 1 (Th1) cells. Interleukin 18 (IL-18) is primarily a monocyte/macrophage-derived cytokine. IL-18 has been recently identified as an IFNgamma-inducing factor. The cytokine plays an important role in the induction of Th1 response and it may be responsible for sarcoidosis progression. The aim of the study was to assess the usefulness of IL-18 estimation in the sarcoidosis diagnosis and the disease course prognosis. MATERIAL AND METHODS: The diagnosis of sarcoidosis was established in 88 patients (the mean age of 38.1+/-10.8 years). We measured IL-18 level in plasma and bronchoalveolar lavage fluid (BALF) cell culture supernatant (CCS) using the enzyme-linked immunoassay technique (ELISA). We also performed the flow cytometric analysis of BALF lymphocyte phenotype. Statistica 5.0 and non-parametric tests: the Mann-Whitney U-test and the Spearman correlation test, were used for statistical analysis. RESULTS: The patient group consisted of 55 subjects without acute symptoms of sarcoidosis, 14 patients with acute Löfgren syndrome and 19 subjects with Löfgren syndrome in the past. Lung hilar lymphadenopathy was diagnosed in 49 patients and lung interstitial changes in 39 subjects. After 6-month-observation, 49 patients were in remission, 20 subjects manifested persistent disease and 19 patients had sarcoidosis progression. Plasma IL-18 level was significantly (P<0.0001) higher in sarcoidosis patients (383+/-250pg/ml) than in control subjects (146+/-72pg/ml). Plasma IL-18 level was similar both in subjects with Löfgren syndrome and in other patients. However, IL-18 level in BALF CCS was significantly (P<0.05) lower in Löfgren syndrome patients than in subjects without acute manifestation of the disease. The highest IL-18 level in plasma was found in patients with disease progression, in subjects with lung interstitial changes and in patients with extrapulmonary manifestation of the disease. We observed a positive correlation between plasma IL-18 level and the percentage of BALF lymphocytes (R=0.202, P=0.06) as well as the percentage of activated HLA DR+T cells (R=0.23, P<0.05). There was a negative correlation between the IL-18 level in BALF CCS and the percentage of BALF CD3-positive and CD4-positive lymphocytes (R=-0.27, -0.23, P<0.05). CONCLUSION: IL-18 may play a significant role in the prolongation of sarcoidosis course. Its estimation may become a good prognostic factor, which should be analyzed together with other factors useful in sarcoidosis monitoring.
Assuntos
Interleucina-18/análise , Sarcoidose/metabolismo , Adulto , Biomarcadores/análise , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Células Cultivadas , Progressão da Doença , Feminino , Humanos , Interleucina-18/sangue , Contagem de Linfócitos , Masculino , Testes de Função Respiratória , Sarcoidose/sangue , Sarcoidose/fisiopatologiaRESUMO
BACKGROUND: Sarcoidosis is a multi-organ granulomatous disorder of undetermined aetiology with 90% of patients exhibiting some degree of pulmonary involvement. Transbronchial biopsy and endobronchial biopsy (EBB) with a fiber-optic bronchoscope, which demonstrate giant or epithelial cells of granuloma formation, have been established as standard methods for histological confirmation of sarcoidosis. OBJECTIVES: The analysis of EBB and bronchoalveolar lavage (BAL) specimens was used to assess the frequency of positive EBB findings in patients with pulmonary sarcoidosis. The influence of spirometric abnormalities and BAL findings on EBB-based diagnosis was also evaluated. METHODS: The examined group of patients comprised 60 subjects mean age 39.4 +/- 9.65 years). The results of pulmonary function tests, EBB and BAL were analysed. RESULTS: EBB was performed on 52 patients. Positive histological results were found in 40% of subjects; 12 of them were affected by spirometry impairment. All patients with restriction and almost half of the subjects with obstruction disorders had positive EBB findings. In the BAL fluid, the percentage of CD3+ and CD4+ cells was significantly lower and the percentage of CD19+ and CD8+ lymphocytes was significantly higher in patients with positive biopsies in comparison with the subjects with negative EBB findings. CONCLUSIONS: Positive biopsies are related to the intensity of abnormalities in the pulmonary function tests and BAL, and may reflect an advanced stage of sarcoidosis.