Stefania Edith Vuljan

Higher Risk of Acute Cellular Rejection in Lung Transplant Recipients with Cystic Fibrosis.

BACKGROUND Acute cellular rejection (ACR) affects up to 40% of recipients within the first year after lung transplant (LTx). The aim of this study was to determine the frequency of ACR and associated major risk factors in cystic fibrosis (CF) recipients. Bronchiolitis obliterans syndrome (BOS) and 1-year/long-term survival were also evaluated. MATERIAL AND METHODS ACR was reviewed in 643 scheduled biopsies from 44 CF (Group 1) versus 89 other recipients (Group 2). We performed univariate/multivariate analyses of risk factors for ACR and BOS, and survival analysis. RESULTS Group 1 showed higher ACR frequency, especially for ACR ≥ A2. Multivariable generalized linear models considering both native lung disease and age showed that higher values of ACR index were significantly related to the pretransplant diagnosis of CF. BOS and long-term survival were not influenced by the increased incidence of ACR. Poorer long-term survival was observed in Group 2. CONCLUSIONS CF recipients have a higher ACR risk, which may be due to enhanced immune activation related to a genetic disorder, and younger age.

Morphological and genetic heterogeneity in multifocal lung adenocarcinoma: The case of a never-smoker woman

Discrimination of multifocal primary lung cancers from lung metastases is crucial to allow for an appropriate clinical management. We report here a case of multifocal lung adenocarcinomas with different morphological and molecular patterns. Radical surgery of one lung nodule was performed at the time of diagnosis, and subsequently on two other lung nodules. At the time of distant relapse, biopsy was repeated for molecular characterization. The patient was treated with EGFR tyrosine kinase inhibitor according to the detection of EGFR exon 21 mutation in metastatic sample and in one of the three lung tumors, characterized by lower mutated allele frequency. The progression free survival was three months according to radiological criteria and the treatment was provided for six months, until clinical progression. Following the assessment of EGFR mutations by pyrosequencing, tumor samples were analyzed by a 30-gene next generation sequencing (NGS) panel, allowing to study intra- and inter-tumor heterogeneity and to confirm the three lung tumors as independent. Different molecular profiles of synchronous tumors and identical EGFR, PIK3CA and TP53 mutations in one of three primary lung tumors and the metachronous metastasis were identified. In conclusion, morphological and molecular characterization of multiple lung nodules by NGS may help to define synchronous and metachronous adenocarcinomas, thus affecting surgical indication and systemic treatment. Intratumor heterogeneity may be associated with differential sensitivity to targeted treatment.

Idiopathic pulmonary fibrosis: Are any of the morphological-molecular markers useful in clinical management?

Idiopathic pulmonary fibrosis (IPF), the most common form of chronic interstitial lung disease, is a severe progressive fibrotic disorder of unknown aetiology. The disease has a heterogeneous clinical course, with frequent poor prognosis, similar to malignant disease. Correctly diagnosing IPF has become particularly important in view of the availability of more precise therapeutic indications, thus avoiding steroid treatment and allowing new approaches with novel drugs. To date we have limited information about biomarkers predictive of progressive disease and associated complications. Efforts should be made in the future to more appropriately study lung tissue and then to extrapolate the most clinically fitting biomarkers. This approach is already used in routine management of many cancers and provides a potential road map for more appropriate clinical care of IPF. This review will mainly focus on histology and etiopathogenesis highlighting some morphological and molecular features that may influence the overall management of IPF.

MDM2 and HIF1alpha expression levels in different histologic subtypes of malignant pleural mesothelioma: correlation with pathological and clinical data.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited treatment options. Sarcomatoid/biphasic mesotheliomas are characterized by more aggressive behaviour and a poorer prognosis compared with the epithelioid subtype. To date prognostic and tailored therapeutic biomarkers are lacking. The present study analyzed the expression levels of MDM2 and HIF1alpha in different histologic subtypes from chemonaive MPM patients. Diagnostic biopsies of MPM patients from four Italian cancer centers were centrally collected and analyzed. MDM2 and HIF1alpha expression levels were investigated through immunohistochemistry and RT-qPCR. Pathological assessment of necrosis, inflammation and proliferation index was also performed. Molecular markers, pathological features and clinical characteristics were correlated to overall survival (OS) and progression free survival (PFS). Sixty MPM patients were included in the study (32 epithelioid and 28 non-epithelioid). Higher levels of MDM2 (p < 0.001), HIF1alpha (p = 0.013), necrosis (p = 0.013) and proliferation index (p < 0.001) were seen mainly in sarcomatoid/biphasic subtypes. Higher levels of inflammation were significantly associated with epithelioid subtype (p = 0.044). MDM2 expression levels were correlated with HIF1alpha levels (p = 0.0001), necrosis (p = 0.008) and proliferation index (p = 0.009). Univariate analysis showed a significant correlation of non-epithelioid histology (p = 0.04), high levels of necrosis (p = 0.037) and proliferation index (p = 0.0002) with shorter PFS. Sarcomatoid/biphasic and epithelioid mesotheliomas showed different MDM2 and HIF1alpha expression levels and were characterized by different levels of necrosis, proliferation and inflammation. Further studies are warranted to confirm a prognostic and predictive role of such markers and features.

Nasopharingeal aspirate value in paediatric chronic lower respiratory tract illness

Respiratory viruses are a common cause of illness in children and are responsible for high morbidity and hospitalisation [1]. The role of infectious agents in chronic/recurrent lower respiratory tract illness (LRTI) is not clearly defined, whereas it is well known in acute forms and in exacerbation of respiratory diseases [2–4]. We have previously demonstrated a high frequency of viruses, particularly human rhinovirus (HRV), in children affected by chronic/recurrent LRTI whose bronchoalveolar lavage (BAL) showed changes in cellularity and inflammatory cytokines [5]. BAL is the gold standard for sensitive detection of infective agents of the lower respiratory tract, even if invasive. Nasopharyngeal aspirate (NPA), nasopharyngeal swab and nasal wash have been investigated to find an easier and more reliable technique for viral diagnosis but never in children affected by different forms of chronic/recurrent LRTI [6–8]. Our study aimed to investigate the presence of viral genomes testing the value of NPA in comparison with BAL in a large paediatric population affected by different forms of chronic/recurrent LRTI. Nasopharyngeal aspirate as a sensitive and specific surrogate tool for the detection of respiratory viruses in different forms of chronic/recurrent lower respiratory tract illness http://ow.ly/cd8S30jcwyu

Idiopathic Pulmonary Fibrosis and Antifibrotic Treatments: Focus on Experimental Studies

CONTEXT - Idiopathic pulmonary fibrosis (IPF) is a progressive fatal disease that up to now has been associated with a poor outcome. Some advances have been made in understanding the multiple interrelated pathogenic pathways underlying IPF. The disease is now believed to result from complex interactions among genetic, epigenetic, transcriptional, posttranscriptional, metabolic, and environmental factors. The discovery and validation of theranostic biomarkers are necessary to enable a more precise and earlier diagnosis of IPF and to improve the prediction of future disease behavior. Two drugs recently approved by the US Food and Drug Administration, pirfenidone and nintedanib, have shown the ability to reduce the progression of the disease, although survival benefits are only minimal and neither drug prevents or reverses the disease. OBJECTIVE - To provide a critical overview of the main experimental studies carried out for testing the principal effects of pirfenidone and nintedanib on IPF. DATA SOURCES - Experimental (animal and in vitro) studies concerning both drugs were used. CONCLUSIONS - Pirfenidone has a longer history of preclinical experimental studies than nintedanib. Many studies have been reported more recently (after 2014) and some of them evaluated the association of both drugs, thus suggesting their combination in future therapeutic approaches. Future investigations focusing on targets at molecular, cellular, and tissue levels are necessary to have a better in-depth knowledge of the properties of these drugs and to explore the potential efficacy of both or other drug combinations.