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Summary: Cancer 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. [ABSTRACT FROM AUTHOR]

Summary: Chronic obstructive pulmonary disease (COPD) exacerbations could represent an opportunity for pro-active COPD management rather than mere treatment if previously unknown disease is discovered; the extent of underdiagnosis and undertreatment of COPD in patients attending an emergency department (ED) with an exacerbation is not known. During 2002, we recalled 131 COPD patients in stable conditions, 4–8 weeks after they had attended the ED or been discharged from our University Hospital (North-West of Italy). Information on diagnosis and management prior to the ED attendance were collected; spirometry and arterial blood gas analyses were performed. One-third of patients had never been diagnosed and treated even though 83% of them had moderate-to-very-severe COPD and about 30% already had respiratory failure. Only 20% had received information on the nature of the disease and none had received a written action plan. Only 60% were receiving long-acting bronchodilators and 41% of patients with respiratory failure were receiving long-term oxygen. A substantial number of undiagnosed and untreated patients with moderate-to-very-severe COPD came to our attention through an exacerbation. This enforces the importance of exacerbations as the starting point of pro-active COPD management and of the ED as a valuable sentinel to identify this subset of patients. [Copyright &y& Elsevier]

Summary: An unusual case of smoking-related centrilobular emphysema with normal spirometry. A 64-year-old man presented with severe dyspnoea and respiratory failure. Pulmonary function and mechanics were normal except for a marked reduction in diffusing capacity of the lung. High-resolution CT scan showed diffuse centrilobular emphysema also involving lower lobes. Pulmonary embolism, cardiac or pulmonary shunt and immunopathologically based vasculitis were excluded. Pulmonary pressure was at the upper limit of normality but within few months he developed a severe pulmonary hypertension. Although spirometry is the only physiologic measure recommended by the updated Global Initiative for Chronic Obstructive Lung Disease guidelines for confirming the diagnosis it should be recognized that diffuse emphysema may occur with only abnormalities in gas exchange without airflow obstruction. The identification of different phenotypes within COPD is important for understanding disease heterogeneity and progression. [Copyright &y& Elsevier]

Abstract: Radiofrequency thermal ablation (RFTA) is a local tumor-destructing technique that can potentially modulate the host immune response through mechanisms that are not clearly defined. We assessed whether RFTA could affect multiple systemic inflammatory and immunological parameters, including CD25+Foxp3+ cells, in patients with primary or metastatic lung tumors. Three days after RFTA, a moderate and temporary systemic inflammatory response developed, as demonstrated by the increase in peripheral neutrophils and monocytes and in plasma levels of proinflammatory chemokines (MIP-1α, MIP-1β, eotaxin, and interleukin[IL]-8) and acute phase reactants (complement C3 and C4, serum amyloid, α1 antichymotrypsin, and C-reactive protein). Moreover, we found a concomitant release of the anti-inflammatory factor IL-10. Thirty days after RFTA, a significant reduction in CD25+Foxp3+ counts with an increase in CD4+ T-cell proliferation and number of interferon-γ-secreting cells was observed. The reduction in CD25+Foxp3+ cells lasted up to 90 days after treatment. The use of RFTA in lung cancer patients has an immunomodulatory activity: it induces a self-limiting systemic inflammation early and later a reduction of circulating CD25+Foxp3+ Tregs. In addition to tumor ablation, downmodulation of this regulatory subset might be an important mechanism involved in the long-term clinical efficacy of RFTA. [Copyright &y& Elsevier]

Background: Bronchiolitis obliterans syndrome (BOS) affects long-term survival of lung transplant (Tx) recipients (LTRs), with no consistently effective treatment strategy. Identifying early markers of BOS is of paramount importance for improving graft survival. Methods: We used 2-dimensional gel electrophoresis and protein identification by mass spectrometry to compare the protein profile of bronchoalveolar lavage fluid (BALf) in two groups of LTRs: one composed of patients with BOS and the other composed of patients with good graft function at >5 years post-surgery (stable LTRs). Based on the hypothesis that only proteins of lung origin could represent reliable BOS markers, we also evaluated paired plasma samples. Proteins of interest were also assessed in the BALf of control subjects and results confirmed by dot- blot analysis. Results: Among 11 differentially expressed proteins, we identified 2 locally produced factors: peroxiredoxin II (PRXII), exclusively expressed in BOS; and surfactant protein A (SP-A), expressed consistently less in BOS patients than in stable LTRs. PRXII expression was never observed in BALf from control subjects, whereas SP-A was present in higher amounts compared with stable LTRs and BOS patients. Finally, the time course of SP-A was studied in 5 LTRs who subsequently developed BOS. A reduction in BALf SP-A content was detectable early after Tx, preceding BOS onset in 4 of 5 patients. Conclusions: Our results suggest that testing SP-A levels in BALf could predict LTR patients who are at higher risk of BOS development. [Copyright &y& Elsevier]

Abstract: The role of T regulatory (Treg) cells in human cancer has not yet been clarified. We assessed the presence and function of CD4+ and CD8+ Treg cell subsets in the peripheral blood of patients with lung cancer (LC) and pleural mesothelioma (PM). We found a low but significant increase in the number of CD4+ T cells with phenotype and functional features of Treg cells in LC patients compared to normal healthy controls (NHC). Furthermore, total CD4+ T cells from LC patients proliferated less than cells from controls, suggesting that the increase in the CD4+ Treg cell pool has functional importance. LC patients also showed an expansion of the CD8+CD28− T cell subset and these cells expressed Foxp3 mRNA, as recently observed in alloantigen-specific CD8+CD28− T suppressor cells. No variation of peripheral Treg cell subsets was found in patients with PM, a disease with a predominantly localized nature. However, the lack of correlation between cancer stage and the number or the function of peripheral Treg cells in LC patients refuted the hypothesis that these cells are involved in tumor spreading. A possible involvement of the peripheral Treg cell pool in cancer development and/or in inducing systemic immunosuppression in LC patients can be hypothesized. [Copyright &y& Elsevier]