Synchronous Lung Cancers: When Same Histological Types Feature Different Molecular Profiles and Response Phenotypes

We discuss the case of synchronous bilateral lung cancers which feature the same histological phenotype and a different EGFR mutational profile. Both histological and molecular characterizations were performed on specimens derived thorough CT-guided fine needle aspiration. A first-line chemotherapy was unsuccessful. Subsequent objective response to the EGFR inhibitor Erlotinib was clearly coherent with the sequencing data and the mutated nodule was effectively reduced (> 50%) after therapy, while the lesion assessed as EGFR wild type featured a slight response. This report has two relevant implications. It points out that in case of multiple malignant lesions at time of diagnosis, molecular profiling should be as extensive as possible and it might contribute to clarify the association between the lesions found. Besides the molecular analysis on cytology specimens could identify an accurate and safe diagnostic approach for clinical use

Factors Influencing Oxidative Imbalance in Pulmonary Fibrosis: An Immunohistochemical Study

Background. Idiopathic Pulmonary Fibrosis (IPF) is a fatal lung disease of unknown etiology characterized by interstitial fibrosis determining irreversible distortion of pulmonary architecture. Reactive oxygen species (ROS) and markers of oxidative stress play a pivotal role in human IPF pathology, possibly through induction of epithelial-mesenchymal transition (EMT). Methods. We investigated by immunohistochemistry, in UIP and COP tissue samples, the expression of most relevant markers of the molecular interplay involving RAGE, oxidant/antioxidant balance regulation, tissue nitrosylation, and mediators of EMT. Results. In both UIP and COP, the degree of RAGE expression was similarly high, while SODs and i-NOS, diffusely present in COP endoalveolar plugs, were almost absent in UIP fibroblast foci. A lower degree of tissue nitrosilation was observed in UIP than in COP. Conclusions. Fibroblast lesions of UIP and of COP share a similar degree of activation of RAGE, while antioxidant enzyme expression markedly reduced in UIP

Targeting EGFR in non-small-cell lung cancer: Lessons, experiences, strategies

SummaryCancer is a genetic disease and this concept is now widely exploited by both scientists and clinicians to design new targeted molecules. Indeed many data have already allowed us to ameliorate not only our knowledge about cancer onset, but also about patients treatment. Correlation between mutations in cancer alleles and drug response is a key point to identify drugs that match the genetic profile of each individual tumors. On the other hand, experience derived from inhibition of tyrosine kinase receptors has pointed out that targeted treatment is really successful only in a small subset of tumors. The latter are eventually addicted to those genetic alterations which are responsible for receptors activation and for the continued expression of their signalling. Overall these observations provide a strong rationale for a molecular-based diagnosis and patients selection for targeted therapies.This review analyses the current state of the art of molecularly-tailored pharmacological approach to lung cancer, one of the biggest killers among human solid tumors. Main relevance is addressed to genetic lesions activating the EGFR pathway transducers, focusing on their role as markers of targeted drug response

Alpha1-antitrypsin deficiency - diagnostic testing and disease awareness in Germany and Italy.

Summary Background Alpha 1 -antitrypsin (AAT) deficiency, although largely under-diagnosed, is the underlying cause of approximately 1% of COPD cases. Lack of awareness leads to long delays in diagnostic testing. Subsequently, lifestyle and treatment choices with potentially positive effects on prognosis may be postponed. Methods Data on the testing and diagnostic practices for AAT deficiency were derived from the University of Pavia, Italy, and the University of Marburg, Germany. In addition, a survey of physicians was undertaken to explore their awareness and attitudes toward AAT deficiency. Results In Pavia and Marburg, 125 and 729 patients, respectively, were identified with severe AAT deficiency between July 2006 and June 2011. The median time interval between the onset of symptoms and diagnosis was 6 years (interquartile range [IQR], 11; range, 0–40) and 7 years (IQR, 13; range, 0–73), respectively. Augmentation therapy was initiated almost immediately in Germany while treatment was delayed by 3 months in Italy (IQR, 5.25; range, 1–118). Survey data (Italy, n = 181; Germany, n = 180) revealed that pulmonologists had greater knowledge of AAT deficiency than internists and general practitioners, however, overall, only 18–25% of physicians tested all COPD patients. One-third of the respondents stated that they "sometimes" offered augmentation therapy to patients diagnosed with AAT deficiency. Conclusions Major obstacles to AAT deficiency testing are physicians' attitudes and lack of understanding of the condition. A greater adherence to the guidelines that recommend diagnostic testing of all COPD patients, coupled with simpler testing protocols, may decrease delays and positively impact patient outcomes

Successful whole lung lavage in pulmonary alveolar proteinosis secondary to lysinuric protein intolerance: a case report

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare disease characterised by accumulation of lipoproteinaceous material within alveoli, occurring in three clinically distinct forms: congenital, acquired and secondary. Among the latter, lysinuric protein intolerance (LPI) is a rare genetic disorder caused by defective transport of cationic amino acids. Whole Lung Lavage (WLL) is currently the gold standard therapy for severe cases of PAP. CASE PRESENTATION: We describe the case of an Italian boy affected by LPI who, by the age of 10, developed digital clubbing and, by the age of 16, a mild restrictive functional impairment associated with a high-resolution computed tomography (HRCT) pattern consistent with pulmonary alveolar proteinosis. After careful assessment, he underwent WLL. CONCLUSION: Two years after WLL, the patient has no clinical, radiological or functional evidence of pulmonary disease recurrence, thus suggesting that WLL may be helpful in the treatment of PAP secondary to LPI

The rapid FEV(1) decline in chronic obstructive pulmonary disease is associated with predominant emphysema: a longitudinal study.

Early identification of patients with COPD and prone to more rapid decline in lung function is of particular interest from both a prognostic and therapeutic point of view. The aim of this study was to identify the clinical, functional and imaging characteristics associated with the rapid FEV(1) decline in COPD.Between 2001 and 2005, 131 outpatients with moderate COPD in stable condition under maximum inhaled therapy underwent clinical interview, pulmonary function tests and HRCT imaging of the chest and were followed for at least 3 years.Twenty-six percent of patients had emphysema detected visually using HRCT. The FEV(1) decline was 42 ± 66 mL/y in the total sample, 88 ± 76 mL/y among rapid decliners and 6 ± 54 mL/y among the other patients. In the univariable analysis, the decline of FEV(1) was positively associated with pack-years (p0.05), emphysema at HRCT (p0.001), RV (p0.05), FRC (p0.05), FEV(1) (p0.01) at baseline and with number of hospitalizations per year (p0.05) during the follow-up. Using multivariable analysis, the presence of emphysema proved to be an independent prognostic factor of rapid decline (p = 0.001). When emphysema was replaced by RV, the model still remained significant.The rapid decline in lung function may be identified by the presence of emphysema at HRCT or increased RV in patients with a long smoking history

In Lysinuric Protein Intolerance system y+L activity is defective in monocytes and in GM-CSF-differentiated macrophages

<p>Abstract</p> <p>Background</p> <p>In the recessive aminoaciduria Lysinuric Protein Intolerance (LPI), mutations of <it>SLC7A7</it>/y+LAT1 impair system y⁺L transport activity for cationic amino acids. A severe complication of LPI is a form of Pulmonary Alveolar Proteinosis (PAP), in which alveolar spaces are filled with lipoproteinaceous material because of the impaired surfactant clearance by resident macrophages. The pathogenesis of LPI-associated PAP remains still obscure. The present study investigates for the first time the expression and function of y+LAT1 in monocytes and macrophages isolated from a patient affected by LPI-associated PAP. A comparison with mesenchymal cells from the same subject has been also performed.</p> <p>Methods</p> <p>Monocytes from peripheral blood were isolated from a 21-year-old patient with LPI. Alveolar macrophages and fibroblastic-like mesenchymal cells were obtained from a whole lung lavage (WLL) performed on the same patient. System y⁺L activity was determined measuring the 1-min uptake of [³H]-arginine under discriminating conditions. Gene expression was evaluated through qRT-PCR.</p> <p>Results</p> <p>We have found that: 1) system y⁺L activity is markedly lowered in monocytes and alveolar macrophages from the LPI patient, because of the prevailing expression of <it>SLC7A7</it>/y+LAT1 in these cells; 2) on the contrary, fibroblasts isolated from the same patient do not display the transport defect due to compensation by the <it>SLC7A6</it>/y+LAT2 isoform; 3) in both normal and LPI monocytes, GM-CSF induces the expression of <it>SLC7A7</it>, suggesting that the gene is a target of the cytokine; 4) GM-CSF-induced differentiation of LPI monocytes is comparable to that of normal cells, demonstrating that GM-CSF signalling is unaltered; 5) general and respiratory conditions of the patient, along with PAP-associated parameters, markedly improved after GM-CSF therapy through aerosolization.</p> <p>Conclusions</p> <p>Monocytes and macrophages, but not fibroblasts, derived from a LPI patient clearly display the defect in system y⁺L-mediated arginine transport. The different transport phenotypes are referable to the relative levels of expression of <it>SLC7A7 </it>and <it>SLC7A6</it>. Moreover, the expression of <it>SLC7A7 </it>is regulated by GM-CSF in monocytes, pointing to a role of y+LAT1 in the pathogenesis of LPI associated PAP.</p

Screening for Alpha 1 antitrypsin deficiency in Tunisian subjects with obstructive lung disease: a feasibility report

<p>Abstract</p> <p>Background</p> <p>AATD is one of the most common inherited disorders in the World. However, it is generally accepted that AATD in North African populations is not a risk factor for lung and/or liver disease, based on a number of small studies. We therefore planned a screening study for detection of AATD in patients with OLD in a cohort of patients from Kairouan in central Tunisia. Methods: One hundred twenty patients with OLD (asthma, emphysema, COPD) were enrolled in the screening programme. Laboratory diagnosis for AATD was performed according to current diagnostic standards.</p> <p>Results</p> <p>We found that 6/120 OLD patients carried an AAT deficient allele, 1 PI*MZ, 1 PI*MPlowel, 3 PI*MMmalton, 1 PI*MMwurzburg.</p> <p>Conclusion</p> <p>this pilot study demonstrated that alleles related to deficiency of AAT are not absent in the Tunisian population, and that rare AATD variants prevailed over commonest PI*Z variant. These results would support a larger scale screening for AATD in Tunisia.</p

A large kindred of pulmonary fibrosis associated with a novel ABCA3 gene variant

Background: Interstitial lung disease occurring in children is a condition characterized by high frequency of cases due to genetic aberrations of pulmonary surfactant homeostasis, that are also believed to be responsible of a fraction of familial pulmonary fibrosis. To our knowledge, ABCA3 gene was not previously reported as causative agent of fibrosis affecting both children and adults in the same kindred. Methods: We investigated a large kindred in which two members, a girl whose interstitial lung disease was first recognized at age of 13, and an adult, showed a diffuse pulmonary fibrosis with marked differences in terms of morphology and imaging. An additional, asymptomatic family member was detected by genetic analysis. Surfactant abnormalities were investigated at biochemical, and genetic level, as well as by cell transfection experiments. Results: Bronchoalveolar lavage fluid analysis of the patients revealed absence of surfactant protein C, whereas the gene sequence was normal. By contrast, sequence of the ABCA3 gene showed a novel homozygous G &gt; A transition at nucleotide 2891, localized within exon 21, resulting in a glycine to aspartic acid change at codon 964. Interestingly, the lung specimens from the girl displayed a morphologic usual interstitial pneumonitis-like pattern, whereas the specimens from one of the two adult patients showed rather a non specific interstitial pneumonitis-like pattern. Conclusions: We have detected a large kindred with a novel ABCA3 mutation likely causing interstitial lung fibrosis affecting either young and adult family members. We suggest that ABCA3 gene should be considered in genetic testing in the occurrence of familial pulmonary fibrosis

Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) is a severe autoimmune disease caused by autoantibodies that neutralize GM-CSF resulting in impaired function of alveolar macrophages. In this study, we characterize 21 GM-CSF autoantibodies from PAP patients and find that somatic mutations critically determine their specificity for the self-antigen. Individual antibodies only partially neutralize GM-CSF activity using an in vitro bioassay, depending on the experimental conditions, while, when injected in mice together with human GM- CSF, they lead to the accumulation of a large pool of circulating GM-CSF that remains partially bioavailable. In contrast, a combination of three non-cross-competing antibodies completely neutralizes GM-CSF activity in vitro by sequestering the cytokine in high-molecular-weight complexes, and in vivo promotes the rapid degradation of GM-CSF-containing immune complexes in an Fc-dependent manner. Taken together, these findings provide a plausible explanation for the severe phenotype of PAP patients and for the safety of treatments based on single anti-GM-CSF monoclonal antibodies