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Wolfgang Schuette,1 Claus-Peter Schneider,2,3 Walburga Engel-Riedel,4 Christian Schumann,5,6 Martin Kohlhaeufl,7 Monika Heidi Ursel Serke,8 Gert Hoeffken,9 Cornelius Kortsik,10 Martin Reck11 1Department of Internal Medicine II, Hospital Martha-Maria Halle-Doelau, Halle, 2Department of Pneumonology, Central Hospital, Bad Berka, 3Department of Internal Medicine, DRK Manniske Hospital, Bad Frankenhausen, 4Cologne Clinics, Merheim Lung Hospital, Cologne, 5Pneumonology, Department of Internal Medicine II, University Hospital Ulm, 6Clinic for Pneumology, Thoracic Oncology, Sleep, and Respiratory Critical Care, Kempten-Oberallgäu, 7Center of Pneumonology and Chest Surgery, Hospital Schillerhoehe, Gerlingen, 8Pneumonology, Lung Clinics, Hemer, 9Center of Pneumonology, Chest and Vascular Surgery, Specialty Hospital Coswig, Coswig, 10Department of Pneumonology, Catholic Hospital, Mainz, 11Department of Thoracic Oncology, Lung Clinic, Grosshansdorf, Germany Background: The aim of the study was to investigate in terms of noninferiority the efficacy and safety of a monochemotherapy regimen of pemetrexed plus bevacizumab (BevPem) versus carboplatin/pemetrexed plus bevacizumab (BevCPem) in elderly patients as first-line treatment for advanced metastatic or recurrent nonsquamous non-small-cell lung cancer (NSCLC).Materials and methods: 65Plus was a Phase III, randomized, open-label study. In total, 253 patients received BevPem (n=119) or BevCPem (n=134). The primary outcome measure was progression-free survival. Secondary end points were overall survival, tumor response, and safety outcomes. Evaluations were performed for the whole study population and stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS).Results: Noninferiority of BevPem in comparison to BevCPem could not be demonstrated for the overall population (P=0.7864). Significant superiority of the combined treatment BevCPem was seen in patients of ECOG PS 0–1 (median PFS 5.1 vs 6.9 months, HR 1.353, 95% CI 1.03–1.777), while the opposite tendency was observed in patients with ECOG PS 2 (median PFS 2.9 vs 1.5 months, HR 0.628, 95% CI 0.195–2.025). Overall, better tolerability was found for the BevPem group, irrespective of ECOG PS.Conclusion: Results from the 65plus study give evidence that BevPem and BevCPem treatments may exert differential effects on PFS, depending on the patients ECOG PS. It appears that patients with better ECOG PS (0–1) benefited more from the combined treatment with carboplatin, while the group comprising more severely impaired patients (ECOG PS 2) benefited more from the monochemotherapy. Keywords: bevacizumab, pemetrexed, carboplatin, NSCLC, elderly patients

Novel diagnostic tools are needed to diagnose latent infection and to provide biologically meaningful surrogate markers to define cellular immune responses against Mycobacterium tuberculosis (MTB). Interferon gamma-based assays have recently been developed in addition to the more than 100-year-old tuberculin skin test (TST) for the immune diagnosis of MTB in blood. The advent of soluble MHC/peptide tetramer molecules allows to objectively enumerate antigen-specific T cells. We identified novel MHC class II-restricted MTB epitopes and used HLA-DR4 tetrameric complexes to visualize ex vivo CD4+ T cells directed against the antigens Ag85B and the 19-kDa lipoprotein, shared between MTB and other Mycobacterium species, and CD4+ T cells which recognize the MTB-associated ESAT-6 antigen. MTB-reactive CD4+ T cells reside predominantly in the CD45RA+ CD28+ and CD45− CD28+ T-cell subset and recognize naturally processed and presented MTB epitopes. HLA-DR4-restricted, Ag85B or ESAT-6-specific CD4+ T cells show similar dynamics over time in peripheral blood mononuclear cells (PBMC) when compared with CD8+ T cells directed against the corresponding HLA-A2-presented MTB epitopes in patients with pulmonary MTB infection and subsequent successful therapy. This was not found to be true for T-cell responses directed against the 19-kDa lipoprotein. The dissection of the cellular immune response in M. tuberculosis infection will enable novel strategies for monitoring MTB vaccine candidates and to gauge CD4+ T cells directed against MTB. [ABSTRACT FROM AUTHOR]

Challenged by scattered understanding of protective immunity to Mycobacterium tuberculosis (MTB), we have mapped peptide epitopes to human leukocyte antigen (HLA)-A*0101, A*0201, A*1101, A*2402, B*0702, B*0801 and B*1501 of the secreted mycobacterial antigen Ag85B, a vaccine candidate that may be associated with immune protection. Affinity (ED50) and half-life (t1/2, off-rate) analysis for individual peptide species on HLA-A and HLA-B molecules revealed binding ranges between 10−3 and 10−7 M. After selection of the best matches, major histocompatibility complex class I/peptide tetramer complexes were constructed to measure the CD8+ T-cell responses directly ex vivo in peripheral blood mononuclear cells (PBMC) derived from 57 patients with acute pulmonary tuberculosis. Three patterns of (allele-) specific CD8+ recognition were identified: (a). Focus on one dominant epitope with additional recognition of several subdominant T-cell epitopes (HLA-A*0301, A*2402, B*0801 and B*1501); (b). Co-dominant recognition of two distinct groups of peptides presented by HLA-B*0702; and (c). Diverse and broad recognition of peptides presented by HLA-A*0201. Peptides that bound with slow off-rates to class I alleles, that is HLA-A*0201, were associated with low frequency of CD8+ T cells in PBMCs from patients with tuberculosis. HLA-B alleles showed fast off-rates in peptide binding and restricted high numbers (up to 6%) of antigen-specific CD8+ T cells in patients with pulmonary tuberculosis.Genes and Immunity (2007) 8, 334–343; doi:10.1038/sj.gene.6364392; published online 12 April 2007 [ABSTRACT FROM AUTHOR]

Discusses a case of a biphasic pulmonary blastoma (BPB) with emphasis on expression of the stem cell factor receptor KIT (CD117). Case of a 61-year-old male patient with a BPB of the upper right lobe; Immunohistochemical analysis using a panel of several antibodies including anti-CD117; Strong cytoplasmic expression of CD117 in the epithelium and spindle cells.

SUMMARY In response to antigenic stimulation, naive MHC-class I restricted and antigen-specific CD8+ CD45RA+ CD28+ T cells undergo clonal expansion, differentiate into CD8+ CD45RO+ memory T cells and convert to CD8+ CD45RA+ CD28- T cells displaying potent immune effector functions upon re-encounter with the nominal antigen. We show that the effector CD8+ CD45RA+ CD28- T cell subset is expanded in peripheral blood lymphocytes (PBL) from patients with human papilloma virus (HPV)+ cervical lesions as well as in PBL from patients with pulmonary tuberculosis. Flow-cytometric cell sorted CD8+ CD45RA+ CD28- and CD8+ CD45RA+ CD28- T cells were tested for recognition of HLA-A2 restricted peptides derived either from the human papillomavirus (HPV)16-E7 gene product, or from M. tuberculosis antigens. Mostly CD8+ CD45+ CD28- T cells define antigen/peptide-specific and MHC-restricted responses. These data were confirmed in PBL from patients with tuberculosis using HLA-A2 tetramer-complexes loaded with a peptide from the M. tuberculosis Ag85b antigen by flow cytometry. The sorting of this T cell subset enables to determine the fine specificity of CD8+ effector T cells without the need for in vitro manipulation. [ABSTRACT FROM AUTHOR]

Eosinophil cationic protein (ECP) is a cationic protein secreted by eosinophils with toxic properties for the respiratory epithelium. Sputum-ECP levels have been shown to correlate inversely with airflow obstruction in asthma. In the present study we investigated whether ECP concentrations are different between asthmatic patients and patients with chronic bronchitis Sputum-ECP concentrations from seven patients with bronchial asthma and seven patients with chronic bronchitis matched for FEV1 were corn pared (FEV1 Asthma : 66.1 ± 29.0% of predicted: FEV1 Chronic Bronchitis : 65.2 ± 33.3% of predicted; p = n.s.). Furthermore, sputum-ECP levels in 4 asthmatic patients with severe airflow obstruction and in 1 patient with chronic bronchitis were measured before and after initiation of a 7-day oral therapy with methylprednisolone 20 mg BID. Changes in sputum-ECP values were corn pared with changes in FEV1 in these 5 patients. Sputum-ECP levels and pulmonary function were measured as previously described (Am Rev Respir Dis 1992: 145: 604). Sputum-ECP levels from asthmatics were significantly elevated compared with patients with chronic bronchitis: asthma: 893.4 μ 346.2 μg/l per g sputum: chronic bronchitis: 30.0 μ 8.5 μg/l per g sputum (p = 0.002). The degree of airway obstruction correlated with the sputum-ECP levels in asthmatics (r = -0.76, p = 0.05), but not in the patients with chronic bronchitis (r = 0.24, p = n.s.). In a separate group of 4 patients with asthma, elevated sputum-ECP revels prior to initiation of systemic corticosteroid therapy were associated with a marked improvement in FEV1 after treatment, through this was not observed in one patient with chronic bronchitis and low sputum-ECP levels. We conclude that airflow obstruction in bronchial asthma, but not chronic bronchitis, is associated with elevated sputum-ECP concentrations. Furthermore, preliminary data suggest that elevated sputum-ECP levels predict reversibility of airflow obstruction with systemic corticosteroid therapy. Hence, sputum-ECP levels might be helpful in the differential diagnosis and treatment strategies of bronchial asthma and chronic bronchitis, especially in those patients who lack significant peripheral blood- or sputum-eosinophilia. [ABSTRACT FROM AUTHOR]