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Non-small-cell lung cancer is a heterogeneous disease that is difficult to treat. Through efforts to define the molecular mechanisms involved in lung oncogenesis, molecularly targeted approaches for patients with lung cancer have now reached the clinical arena. Despite elucidation of some molecular mechanisms of lung carcinogenesis, prognosis for patients remains poor. This Review aims to highlight the functional associations between key oncogenes that drive lung tumorigenesis and are distinct targetable molecules. Oncogenes are defined by acquisition of mutations, which results in a dominant gain-of-function of the targeted protein. In this situation, a single mutated allele is sufficient to induce malignant transformation. Importantly, tumours become addicted to particular genetic alterations that cause oncogene activation and the continued expression of the signalling. An increasing amount of evidence sustains the rationale for targeting of oncogenic pathways rather than a single oncogene. A clear priority for both researchers and clinicians is to better understand the complexity of biological networks underlying lung cancer pathogenesis. This paradigmatic shift in tailoring therapies should effectively improve outcomes for patients.

Chronic obstructive pulmonary disease (COPD) is a common, complex disorder, and dissection of its individual components is considered one of the research priorities for this disease. Several lines of evidence suggest that, in spite of the massive role of cigarette smoking, common COPD is not just an environmental phenocopy of COPD associated with alpha1-antitrypsin deficiency: from the racial/ethnic variability in COPD prevalence to the individual susceptibility to cigarette smoke, from the familial aggregation of lung function levels to the familial clustering of COPD symptoms, all lines tend to point to common COPD having a genetic component. The challenge in the last three decades has been to define the borders of this component, its relative weight with respect to the environmental component, and to identify the susceptibility and/or resistance genes. Taking advantage from the knowledge, albeit limited, of the biochemical basis of COPD, a number of genetic polymorphisms have been investigated, mostly in case-control association studies. Although such a strategy is considered more successful than linkage analysis for investigating complex, non-Mendelian disorders and in spite of the considerable amount of data collected, the overall result of the genetic investigations into COPD has so far been largely disappointing. A critical evaluation of the published reports shows that a number of issues could have affected the outcome of the investigations: among such issues, the choice of the appropriate clinical phenotype is fundamental.

Chronic obstructive pulmonary disease (COPD) is a common, complex disorder, and dissection of its individual components is considered one of the research priorities for this disease. Several lines of evidence suggest that, in spite of the massive role of cigarette smoking, common COPD is not just an environmental phenocopy of COPD associated with alpha1-antitrypsin deficiency: from the racial/ethnic variability in COPD prevalence to the individual susceptibility to cigarette smoke, from the familial aggregation of lung function levels to the familial clustering of COPD symptoms, all lines tend to point to common COPD having a genetic component. The challenge in the last three decades has been to define the borders of this component, its relative weight with respect to the environmental component, and to identify the susceptibility and/or resistance genes. Taking advantage from the knowledge, albeit limited, of the biochemical basis of COPD, a number of genetic polymorphisms have been investigated, mostly in case-control association studies. Although such a strategy is considered more successful than linkage analysis for investigating complex, non-Mendelian disorders and in spite of the considerable amount of data collected, the overall result of the genetic investigations into COPD has so far been largely disappointing. A critical evaluation of the published reports shows that a number of issues could have affected the outcome of the investigations: among such issues, the choice of the appropriate clinical phenotype is fundamental.

The subset of CD4CD25 regulatory T cells, recently identified in humans, may play a central role in the regulation of immune tolerance to graft survival.

Mesothelioma cells (MMc) are considered to be weakly immunogenic and the experimental approaches attempting to induce an immune response against these cells have been disappointing. Our aim was to investigate whether MMc possess the surface accessory molecules involved in antigen presentation and whether these cells are capable of presenting recall antigens to autologous blood lymphocytes. Four primary MMc cultures were generated from malignant effusions and examined to assess whether the accessory molecules required for antigen presentation were present on their surfaces. Intercellular adhesion molecule-1 (ICAM-1; CD54); class I and class II major histocompatibility complex-DR (MHCI and MHCII-DR); B7–1 (CD80.3); and B7–2 (CD86) expression by MMc was studied by immunocytochemical and/or FACScan analysis. MMc were pulsed with purified protein derivative (PPD), Tetanus toxoid (TT) and Candida albicans (CA) bodies, and incubated with autologous lymphocytes. Lymphocyte proliferation was estimated by radionucleotide incorporation. Phenotypic analysis showed the presence of MHCII-DR, ICAM-1 and B7–2 on primary MMc cultures, whereas the phenotypic evaluation of 2 established MMc lines did not show the presence of the B7–1 and B7–2 molecules. In addition, MHCII-DR was detectable only after interferon gamma (IFN-γ) stimulation. Primary MMc cultures acquired the capability to induce lymphocyte proliferation after pulse with the recall antigens. To achieve characterization of these lymphocytes, we generated a PPD-specific CD4⁺ T-cell clone. PPD-pulsed MMc were shown to specifically induce T-cell clone proliferation through a MHCII-DR-mediated process. We conclude that primary MMc possess the surface molecules required for antigen presentation and can present recall antigens to CD4⁺ lymphocytes. Int. J. Cancer 78:740–749, 1998. © 1998 Wiley-Liss, Inc.

A multicentre trial was carried out to compare the efficacy and safety of dirithromycin with miocamycin in the treatment of patients with acute bronchitis or acute exacerbations of chronic bronchitis. The study was a single-blind, randomized, parallel-group study. Dirithromycin was administered orally at a dosage of 500 mg once daily and miocamycin was administered orally at a dosage of 600 mg twice daily; the duration of therapy was five to seven days for both drugs. The results, in 161 assessable patients (78 taking dirithromycin; 83 taking miocamycin), show that dirithromycin and miocamycin have comparable efficacy and safety in the treatment of bronchitis caused by susceptible bacterial pathogens.