Exacerbação aguda da fibrose pulmonar idiopática

AbstractSome patients with Idiopathic Pulmonary Fibrosis (IPF) have disease accelerated deterioration without identifiable cause referred as “acute exacerbation” or “accelerated stage”. It is characterized by severe worsening of dyspnea, hypoxemia and new or progressive opacities on imaging studies. The typical histological findings are diffuse alveolar damage in addition to the features of usual interstitial pneumonia pattern. Mortality in this clinical entity is very high and no efficacious therapeutic have been described.The authors describe the clinical, functional and radiological features, treatment and evolution of five patients with IPF acute exacerbation. A discussion will be carry out concerning the IPF acute exacerbation usual features comparing with the alterations noticed in those patients.Rev Port Pneumol 2009; XV (2): 305-31

Disruption of BASIGIN decreases lactic acid export and sensitizes non-small cell lung cancer to biguanides independently of the LKB1 status

Most cancers rely on aerobic glycolysis to generate energy and metabolic intermediates. To maintain a high glycolytic rate, cells must efficiently export lactic acid through the proton-coupled monocarboxylate transporters (MCT1/4). These transporters require a chaperone, CD147/BASIGIN (BSG) for trafficking to the plasma membrane and function. To validate the key role of these transporters in lung cancer, we first analysed the expression of MCT1/4 and BSG in 50 non-small lung cancer (NSCLC) cases. These proteins were specifically upregulated in tumour tissues. We then disrupted BSG in three NSCLC cell lines (A549, H1975 and H292) via ‘Zinc-Finger Nucleases’. The three homozygous BSG-/- cell lines displayed a low MCT activity (10- to 5-fold reduction, for MCT1 and MCT4, respectively) compared to wild-type cells. Consequently, the rate of glycolysis, compared to the wild-type counterpart, was reduced by 2.0- to 3.5-fold, whereas the rate of respiration was stimulated in BSG-/- cell lines. Both wild-type and BSG-null cells were extremely sensitive to the mitochondria inhibitor metformin/ phenformin in normoxia. However, only BSG-null cells, independently of their LKB1 status, remained sensitive to biguanides in hypoxia in vitro and tumour growth in nude mice. Our results demonstrate that inhibiting glycolysis by targeting lactic acid export sensitizes NSCLC to phenformin.The JP team was funded from Ligue Nationale Contre le Cancer (LNCC Equipe labellisee), Fondation ARC, INCa, ANR, the EU-FP7 "METOXIA", SERVIER-CNRS, and Centre Lacassagne. SG received a fellowship from Fundacao para a Ciencia e Tecnologia (SFRH/BD/33503/2010) and IM was supported by a fellowship from LNCC. We thank Dr Susan Critchlow (AstraZeneca) for providing the iMCT1/2, the cytometry core facility (CYTOMED) for FACS analysis, and Dr. Christiane Brahimi-Horn for editorial correction of the manuscript

Resistance profile of osimertinib in pre-treated patients with EGFR T790M-mutated non-small cell lung cancer

Background: Osimertinib efficacy in pre-treated patients with epidermal growth factor receptor (EGFR) T790M-mutated non-small cell lung cancer (NSCLC) has been demonstrated in clinical trials, but real-world data, particularly regarding resistance profile, remains limited. This study aims to analyze the resistance mechanisms acquired after treatment with Osimertinib. Methods: Clinical outcomes and molecular results from re-biopsies at the time of osimertinib progression of EGFR T790M-mutated NSCLC patient were analyzed. Results: Twenty-one patients with stage IV adenocarcinoma were included [median 69 years; 57.1% female; 85.7% never-smokers; 23.8% ECOG performance status (PS) >= 2]. Median PFS and OS were 13.4 (95% CI: 8.0-18.9) and 26.4 (95% IC: 8.9-43.8) months, respectively. At the time of analysis, 10 patients had tumor progression (47.6%). T790M loss occurred in 50%, being associated with earlier progression (median PFS 8.1 vs. 21.4 months, p = 0.011). Diverse molecular alterations were identified, including C797S mutation (n = 1), PIK3CA mutation (n = 2), MET amplification (n = 1), CTNNB1 mutation (n = 1), and DCTN1-ALK fusion (n = 1). Histological transformation into small cell carcinoma occurred in one patient. Conclusions: This real-world life study highlights the relevance of re-biopsy at the time of disease progression, contributing to understand resistance mechanisms and to guide treatment strategies

Clinical application of next-generation sequencing of plasma cell-free DNA for genotyping untreated advanced non-small cell lung cancer

Simple Summary Plasma ctDNA is a material source for molecular analysis particularly useful when tissue is not available or sufficient. NGS-based plasma genotyping should be integrated into the clinical workup of newly diagnosed advanced NSCLC. Background: Analysis of circulating tumor DNA (ctDNA) has remarkable potential as a non-invasive lung cancer molecular diagnostic method. This prospective study addressed the clinical value of a targeted-gene amplicon-based plasma next-generation sequencing (NGS) assay to detect actionable mutations in ctDNA in patients with newly diagnosed advanced lung adenocarcinoma. Methods: ctDNA test performance and concordance with tissue NGS were determined, and the correlation between ctDNA findings, clinical features, and clinical outcomes was evaluated in 115 patients with paired plasma and tissue samples. Results: Targeted-gene NGS-based ctDNA and NGS-based tissue analysis detected 54 and 63 genomic alterations, respectively; 11 patients presented co-mutations, totalizing 66 hotspot mutations detected, 51 on both tissue and plasma, 12 exclusively on tissue, and 3 exclusively on plasma. NGS-based ctDNA revealed a diagnostic performance with 81.0% sensitivity, 95.3% specificity, 94.4% PPV, 83.6% NPV, test accuracy of 88.2%, and Cohen's Kappa 0.764. PFS and OS assessed by both assays did not significantly differ. Detection of ctDNA alterations was statistically associated with metastatic disease (p = 0.013), extra-thoracic metastasis (p = 0.004) and the number of organs involved (p = 0.010). Conclusions: This study highlights the potential use of ctDNA for mutation detection in newly diagnosed NSCLC patients due to its high accuracy and correlation with clinical outcomes

Exacerbação aguda da fibrose pulmonar idiopática Acute exacerbation of idiopathic pulmonary fibrosis

Alguns doentes com fibrose pulmonar idiopática (FPI) apresentam durante a sua evolução fases deagravamento clínico sem causa conhecida, designadas como “exacerbação aguda” ou “fase acelerada” da doença (EA). Caracterizam -se pelo agravamento marcado da dispneia, hipoxemia e pelo aparecimento de novas opacidades pulmonares ou pelo agravamento das já existentes no estudo imagiológico. Os achados histológicos típicos são o dano alveolar difuso (DAD) sobreposto a alterações de pneumonia intersticial usual (UIP). Esta entidade clínica associa -se a uma mortalidade elevada, não havendo até ao momento nenhuma terapêutica de comprovada eficácia. Os autores descrevem os casos clínicos de cinco doentes que apresentaram alterações clínicas, funcionais e radiológicas sugestivas de EA-FPI, assim como o tratamento efectuado e a evolução observada, enquadrando-os na discussão das características normalmente apresentadas por esta entidade.Some patients with Idiopathic Pulmonary Fibrosis (IPF) have disease accelerated deterioration without identifiable cause referred as “acute exacerbation” or “accelerated stage”. It is characterized by severe worsening of dyspnea, hypoxemia and new or progressive opacities on imaging studies. The typical histological findings are diffuse alveolar damage in addition to the features of usual interstitial pneumonia pattern. Mortality in this clinical entity is very high and no efficacious therapeutic have been described. The authors describe the clinical, functional and radiological features, treatment and evolution of five patients with IPF acute exacerbation. A discussion will be carry out concerning the IPF acute exacerbation usual features comparing with the alterations noticed in those patients

Linfangioma cístico do mediastino

Resumo: O linfangioma mediastínico é uma neoplasia vascular rara, correspondendo a 0,7 a 4,5% de todos os tumores do mediastino. É um tumor benigno, que ocorre geralmente como uma massa mediastínica de crescimento lento. A maioria dos doentes está assintomática, sendo diagnosticado incidentalmente, após a realização de uma radiografia torácica de rotina. O tratamento de eleição consiste na ressecção cirúrgica completa. O prognóstico depende do grau de ressecabilidade e, se a lesão for totalmente removida, não se esperam recidivas.Rev Port Pneumol 2006; XII (6): 731-735 Abstract: Mediastinal lymphangioma is a rare vascular neoplasm, accounting for 0.7 to 4.5% of all the mediastinum tumors. It is a benign tumor, generally occurring as a mediastinal mass of slow growth. Most patients are asymptomatic, being incidentally diagnosed after a routine chest radiograph. The best treatment consists of complete surgical resection. Prognosis depends on the degree of resecability degree, and recurrence is not expected if the lesion is totally removed.Rev Port Pneumol 2006; XII (6): 731-735 Palavras-chave: Tumor mediastínico, linfangioma, cistomediastínico, Key-words: Mediastinal tumor, lymphangioma, mediastinal cys

Mediastinal cystic lymphangioma Linfangioma cístico do mediastino

Mediastinal lymphangioma is a rare vascular neoplasm, accounting for 0.7 to 4.5% of all the mediastinum tumors. It is a benign tumor, generally occurring as a mediastinal mass of slow growth. Most patients are asymptomatic, being incidentally diagnosed after a routine chest radiograph. The best treatment consists of complete surgical resection. Prognosis depends on the degree of resecability degree, and recurrence is not expected if the lesion is totally removed.O linfangioma mediastínico é uma neoplasia vascular rara, correspondendo a 0,7 a 4,5% de todos os tumores do mediastino. É um tumor benigno, que ocorre geralmente como uma massa mediastínica de crescimento lento. A maioria dos doentes está assintomática, sendo diagnosticado incidentalmente, após a realização de uma radiografia torácica de rotina. O tratamento de eleição consiste na ressecção cirúrgica completa. O prognóstico depende do grau de ressecabilidade e, se a lesão for totalmente removida, não se esperam recidivas

Epithelioid hemangioendothelioma - A rare pulmonary tumor Hemangioendotelioma epitelióide - Um tumor pulmonar raro

The authors report a case of a rare pulmonary neoplasm - epithelioid hemangio-endothelioma, in a 39 year-old woman, asymptomatic until December 2003, when she developed pleuritic and right-sided chest pain. The patient presented a previous chest radiograph, performed 13 years before, which showed multiple small bilateral pulmonary nodules attributed to tuberculous sequelae. The definitive histological diagnosis was made by lung biopsy through thoracotomy. The patient developed a clinical and imagiological worsening and then therapy with interferon α-2a was started. Even with imagiological stability of pulmonary lesions the patient remained symptomatic and died nine months after the diagnosis had been established. The authors emphasise the rarity of this type of pulmonary neoplasm and discuss its clinical presentation, histological features, treatment and prognosis.Os autores descrevem um caso de uma neoplasia pulmonar rara - hemangio-endotelioma epitelióide - numa doente do sexo feminino, de 39 anos, assintomática até Dezembro de 2003, altura em que apresentou toracalgia direita de características pleuríticas. A doente era portadora de uma radiografia torácica antiga, efectuada há 13 anos, que revelava múltiplos pequenos nódulos pulmonares bilaterais, atribuídos a sequelas de tuberculose pulmonar. O diagnóstico histológico definitivo foi efectuado através de biópsia pulmonar por toracotomia. Dado a doente ter apresentado agravamento clínico e imagiológico foi iniciada terapêutica com interferão α-2a. Apesar da estabilidade imagiológica das lesões pulmonares, a doente manteve-se sintomática e faleceu nove meses depois do diagnóstico ter sido estabelecido. Os autores realçam a raridade deste tipo de neoplasia pulmonar e discutem a sua apresentação clínica, características histológicas, tratamento e prognóstico

Pneumonite intersticial não específica: entidade clínico-patológica, padrão histológico ou apenas grupo heterogéneo de pneumonites intersticiais não classificadas?

RESUMO: A pneumonite intersticial não específica (NSIP), descrita pela primeira vez em 1994 por Katzenstein e Fiorelli, apresenta-se como uma eventual entidade clínico-patológica individualizável dentro do grupo das pneumonites intersticiais idiopáticas (IIP). Aliada a alterações histológicas distintas, apresentauma evolução clínica mais favorável, com consequente melhor prognóstico do que a fibrose pulmonar idiopática (IPF), grupo onde geralmente estas alterações eram incluídas. Estas diferenças levam a que, apesar das dúvidas que ainda envolvem a NSIP, o seu reconhecimento seja importante, uma vez que as atitudes clínicas e terapêuticas se diferenciam da IPF. A NSIP engloba padrões histológicos diferentes, dividindo-se nomeadamente em casos de predomínio inflamatório (tipo celular) ou de predomínio fibroso (tipo fibrosante), com os últimos a evidenciarem uma maior gravidade e pior prognóstico do que os primeiros. Os autores descrevem dois casos de NSIP, seguidos de uma revisão e discussão do tema.REV PORT PNEUMOL 2004; X (4): 331-345 ABSTRACT: Nonspecific interstitial pneumonitis (NSIP) initially described by Katzenstein and Fiorelli in 1994, seems to be a distinct clinicopathologic entity among idiopathic interstitial pneumonitis (IIP). Besides different histologic features from other IIP, NSIP is characterized by a better long-term outcome, associated with a better steroids responsiveness than idiopathic pulmonar fibrosis (IPF), where usually were included. Thus, differentiating NSIP from other IIP, namely IPF is very significant, since it has important therapeutic and prognostic implications. NSIP encloses different pathologies, namely those with inflammatory predominance (cellular subtype) or fibrous predominance (fibrosing subtype). NSIP is reviewed and discussed by the authors, after two clinical cases description.REV PORT PNEUMOL 2004; X (4): 331-345 Palavras chave: pneumonites intersticiais idiopáticas, pneumonite intersticial não específica: tipo celular, tipo fibrosante, Key words: idiopathic interstitial pneumonitis, non-specific interstitial pneumonitis, cellular subtype, fibrosing subtyp

Enfisema lobar congénito com apresentação neonatal: Revisão de quatro casos clínicos Congenital lobar emphysema of the newborn: Report of four clinical cases

Introdução: O enfisema lobar congénito (ELC) é uma anomalia rara do desenvolvimento pulmonar e a apresentação neonatal ocorre em cerca de 50% dos casos. Os autores apresentam quatro casos clínicos de ELC no recém-nascido. Casos clínicos: Quatro recém-nascidos de termo, 3M/1F, admitidos por dificuldade respiratória com início variável entre as 20 horas e os 18 dias de vida, apresentaram radiografia de tórax na admissão sugestiva de ELC, diagnóstico confirmado por tomografia axial computorizada. O ELC afectou o lobo superior direito em três casos e o lobo Resumo Introdução: O enfisema lobar congénito (ELC) é uma anomalia rara do desenvolvimento pulmonar e a apresentação neonatal ocorre em cerca de 50% os casos. Os autores apresentam quatro casos clínicos de ELC no recém-nascido. Casos clínicos: Quatro recém-nascidos de termo, 3M/1F, admitidos por dificuldade respiratória com início variável entre as 20 horas e os 18 dias de vida, apresentaram radiografia de tórax na admissão sugestiva de ELC, diagnóstico confirmado por tomografia axial computorizada. O ELC afectou o lobo superior direito em três casos e o lobo médio em um caso. Foi efectuada lobectomia nos quatro recém-nascidos. O estudo anatomopatológico das peças operatórias confirmou o diagnóstico nos quatro casos, tendo revelado hipoplasia da cartilagem da árvore brônquica em três. Conclusão: A casuística está de acordo com a literatura no predomínio no sexo masculino, forma de apresentação, tempo variável até ao diagnóstico, envolvimento unilobar e não identificação de causa evidente num dos casos. O tratamento cirúrgico foi universal.Introduction: Congenital lobar emphysema (CLE) is a rare anomaly of lung development that presents in the neonatal period in about 50% of the cases. The authors report four clinical cases of congenital lobar emphysema in the newborn. Clinical cases: Four term newborns, 3M/ 1F, were admitted for respiratory distress starting between 20 hours of life and 18 days. The chest x-ray at admission was suggestive of CLE and the diagnosis was confirmed by computorized tomography. The CLE affected the right upper lobe in three cases and the medium lobe in one case. All patients were treated with lobectomy. The pathological study of the surgical specimens confirmed the diagnosis in the four cases, and revealed hypoplasia of the bronquiolar tree cartilage in three. Conclusions: Our series is according to literature regarding to male gender preponderance, clinical presentation, different time to diagnosis, unilobar involvement and no identification of na evident aetiology in one case. Surgical reatment was universal