János Strausz

Spontaneous Monokine Release by Alveolar Macrophages in Chronic Sarcoidosis

In pulmonary sarcoidosis an activation of alveolar T lymphocytes and alveolar macrophages (AM) has been demonstrated. There is evidence that in contrast to acute disease a heightened T-cell response cannot be observed in the chronic phase of sarcoidosis. The role of AM in the inflammatory process of chronic sarcoidosis is not yet intensively evaluated. To address this question we measured the release of tumor necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1) by AM of 39 patients with chronic sarcoidosis (duration greater than 4 years; 30 active, 9 inactive diseases) without therapy and correlated the monokine release with parameters of T-cell alveolitis and the course of the disease. The T4/T8 ratio was higher in the active than in the inactive group without reaching statistical significance. TNF alpha as well as IL-1 is spontaneously released by AM of the active group 2,099 +/- 518 pg/ml TNF alpha/10(6) cells/24 h and 8/13 (IL-1+/total) respectively. In the inactive group the AM release 375 +/- 246 pg/ml TNF alpha/10(6) cells/24 h which is in the range of the control and 1 out of 5 patients was IL-1-positive. There was no correlation between the monokine release and any parameter of T-cell alveolitis. These data support the hypothesis that the inflammatory process in chronic sarcoidosis is dominated by the activity of AM and that this activity determines the course of the disease.

The EvA study: aims and strategy

The EvA study is a European Union-funded project under the Seventh Framework Programme (FP7), which aims at defining new markers for chronic obstructive pulmonary disease (COPD) and its subtypes. The acronym is derived from emphysema versus airway disease, indicating that the project targets these two main phenotypes of the disease. The EvA study is based on the concept that emphysema and airway disease are governed by different pathophysiological processes, are driven by different genes and have differential gene expression in the lung. To define these genes, patients and non-COPD controls are recruited for clinical examination, lung function analysis and computed tomography (CT) of the lung. CT scans are used to define the phenotypes based on lung density and airway wall thickness. This is followed by bronchoscopy in order to obtain samples from the airways and the alveoli. These tissue samples, along with blood samples, are then subjected to genome-wide expression and association analysis and markers linked to the phenotypes are identified. The population of the EvA study is different from other COPD study populations, since patients with current oral glucocorticoids, antibiotics and exacerbations or current smokers are excluded, such that the signals detected in the molecular analysis are due to the distinct inflammatory process of emphysema and airway disease in COPD.

Emphysema- and airway-dominant COPD phenotypes defined by standardised quantitative computed tomography

EvA (Emphysema versus Airway disease) is a multicentre project to study mechanisms and identify biomarkers of emphysema and airway disease in chronic obstructive pulmonary disease (COPD). The objective of this study was to delineate objectively imaging-based emphysema-dominant and airway disease-dominant phenotypes using quantitative computed tomography (QCT) indices, standardised with a novel phantom-based approach. 441 subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1–3) were assessed in terms of clinical and physiological measurements, laboratory testing and standardised QCT indices of emphysema and airway wall geometry. QCT indices were influenced by scanner non-conformity, but standardisation significantly reduced variability (p<0.001) and led to more robust phenotypes. Four imaging-derived phenotypes were identified, reflecting “emphysema-dominant”, “airway disease-dominant”, “mixed” disease and “mild” disease. The emphysema-dominant group had significantly higher lung volumes, lower gas transfer coefficient, lower oxygen (PO2) and carbon dioxide (PCO2) tensions, higher haemoglobin and higher blood leukocyte numbers than the airway disease-dominant group. The utility of QCT for phenotyping in the setting of an international multicentre study is improved by standardisation. QCT indices of emphysema and airway disease can delineate within a population of patients with COPD, phenotypic groups that have typical clinical features known to be associated with emphysema-dominant and airway-dominant disease. Standardisation of quantitative CT improves delineation of emphysema and airway phenotypes in a multicentre study http://ow.ly/10zjhV

Beryllium-induced disturbances of the murine immune system reflect some phenomena observed in sarcoidosis

Sarcoidosis is a systemic granulomatous disorder of unknown origin. In respect to clinical and immunological characteristics, it is indistinguishable from berylliosis. As an approach to develop a murine model reflecting some aspects of sarcoidosis, we attempted to induce berylliosis in mice by treating inbred F1 mice (C57B16 x DBA/2) with 3 mg beryllium sulfate (BeSO4) per kg body weight intraperitoneally. Either pure BeSO4 or BeSO4 in combination with incomplete Freunds adjuvant was administered. Alternatively, pure BeSO4 was injected 2 days after a single application of cyclophosphamide (150 mg/kg). The spleen index, the spontaneous and phorbolmyristate acetate (PMA)-induced radical oxygen intermediates (ROI) released by peritoneal macrophages, and the proliferative activity of spleen mononuclear cells in response to BeSO4 and concanavalin A (ConA) were evaluated and compared to the corresponding changes observed in sarcoidosis. In all three modes of BeSO4 treatment, the spontaneous ROI release by peritoneal macrophages was significantly elevated. These elevations were very similar to those observed with alveolar macrophages in active sarcoid alveolitis. After BeSO4 treatment, a small proliferative activity of spleen mononuclear cells in response to BeSO4 could be observed. Further, BeSO4-treated spleen mononuclear cells exhibited a markedly reduced response to ConA stimulation (approximately 20% of control) which parallels the reduced proliferative capacity of sarcoid peripheral blood mononuclear cells (approximately 45% of control). This reduction could be abolished by pretreating the mice with cyclophosphamide. BeSO4 treatment in combination with incomplete Freunds adjuvant resulted in a significant increase of spleen mononuclear cell proliferation (1.9-fold) after in vitro stimulation with BeSO4, and prevented the low responsiveness to ConA.(ABSTRACT TRUNCATED AT 250 WORDS)

Phenotypes of organ involvement in sarcoidosis

Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype–Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis. The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol. From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular–cardiac–cutaneous–central nervous system disease involvement, 3) musculoskeletal–cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement. These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies. Five new clinical phenotypes of sarcoidosis have been identified by analysing organ manifestations of 1932 patients http://ow.ly/UYLC30jpUkq

Változások a nem-kissejtes tüdőrák diagnosztikus és terápiás stratégiájában@@@Changes in the diagnostic and therapeutic strategies of non-small cell lung cancer

Major advancements have been made in the clinical management of non-small cell lung cancer (NSCLC) in the past decade. This development involved the introduction of pemetrexed and several targeted therapies (bevacizumab, erlotinib, gefitinib) in the first and second line treatments of NSCLC. Novel maintenance therapeutic strategies for NSCLC (erlotinib) and for non-squamous-NSCLC (pemetrexed, bevacizumab+erlotinib) have also been developed resulting in a significant improvement in patients survival. These changes have modified registrations of various drugs and require continuous update of guidelines and reimbursement schemes as well. These advantages are based on refinement of differential diagnosis of NSCLC and on the development of molecular predictive markers. Our aim is to summarize the changes in the diagnosis and therapy of NSCLC and to present the altered therapeutic scheme.

Változások a nem-kissejtes tüdőrák diagnosztikus és terápiás stratégiájában

Major advancements have been made in the clinical management of non-small cell lung cancer (NSCLC) in the past decade. This development involved the introduction of pemetrexed and several targeted therapies (bevacizumab, erlotinib, gefitinib) in the first and second line treatments of NSCLC. Novel maintenance therapeutic strategies for NSCLC (erlotinib) and for non-squamous-NSCLC (pemetrexed, bevacizumab+erlotinib) have also been developed resulting in a significant improvement in patients survival. These changes have modified registrations of various drugs and require continuous update of guidelines and reimbursement schemes as well. These advantages are based on refinement of differential diagnosis of NSCLC and on the development of molecular predictive markers. Our aim is to summarize the changes in the diagnosis and therapy of NSCLC and to present the altered therapeutic scheme.

Paradigmaváltás a tüdőrákok nem sebészi mintavételében@@@Non-surgical biopsy in lung cancer: a paradigm shift

Histological subgroups of non-small cell lung cancer have different prognosis and they require different therapeutic approaches. Accordingly, there is a clinical need in this field to supplement conventional pathological diagnostics with protein and genetic biomarkers that can help to recognize patients responsive to these therapies. Methods for subgroup classification and target identification were developed using surgical samples (surgical lung tumor specimens are available only in 20% of all lung cancer cases). The majority of lung cancer patients, however, have tumors that are irresectable at the time of diagnosis. Therefore, their diagnosis is usually based on bronchoscopically removed tissue or needle biopsy samples analyzed mainly by cytology. Because of the growing need for immunohistochemistry and molecular pathology in lung cancer diagnosis, emphasis should be given to diagnostic bronchoscopic procedures providing tissue samples. Combination of the different biopsy techniques (histology, cytology, bronchial brush, BAL, TBNA etc.), embedding the cells (preparing cell blocks) and, moreover, the availability of immunohistochemical and molecular pathological facilities are all required to set up the proper diagnosis and therapeutic strategy in human lung cancer. Strausz J, Tímár J. Non-surgical biopsy in lung cancer: a paradigm shift.

Paradigmaváltás a tüdőrákok nem sebészi mintavételében

Histological subgroups of non-small cell lung cancer have different prognosis and they require different therapeutic approaches. Accordingly, there is a clinical need in this field to supplement conventional pathological diagnostics with protein and genetic biomarkers that can help to recognize patients responsive to these therapies. Methods for subgroup classification and target identification were developed using surgical samples (surgical lung tumor specimens are available only in 20% of all lung cancer cases). The majority of lung cancer patients, however, have tumors that are irresectable at the time of diagnosis. Therefore, their diagnosis is usually based on bronchoscopically removed tissue or needle biopsy samples analyzed mainly by cytology. Because of the growing need for immunohistochemistry and molecular pathology in lung cancer diagnosis, emphasis should be given to diagnostic bronchoscopic procedures providing tissue samples. Combination of the different biopsy techniques (histology, cytology, bronchial brush, BAL, TBNA etc.), embedding the cells (preparing cell blocks) and, moreover, the availability of immunohistochemical and molecular pathological facilities are all required to set up the proper diagnosis and therapeutic strategy in human lung cancer. Strausz J, Tímár J. Non-surgical biopsy in lung cancer: a paradigm shift.

[Non-surgical biopsy in lung cancer: a paradigm shift].

Histological subgroups of non-small cell lung cancer have different prognosis and they require different therapeutic approaches. Accordingly, there is a clinical need in this field to supplement conventional pathological diagnostics with protein and genetic biomarkers that can help to recognize patients responsive to these therapies. Methods for subgroup classification and target identification were developed using surgical samples (surgical lung tumor specimens are available only in 20% of all lung cancer cases). The majority of lung cancer patients, however, have tumors that are irresectable at the time of diagnosis. Therefore, their diagnosis is usually based on bronchoscopically removed tissue or needle biopsy samples analyzed mainly by cytology. Because of the growing need for immunohistochemistry and molecular pathology in lung cancer diagnosis, emphasis should be given to diagnostic bronchoscopic procedures providing tissue samples. Combination of the different biopsy techniques (histology, cytology, bronchial brush, BAL, TBNA etc.), embedding the cells (preparing cell blocks) and, moreover, the availability of immunohistochemical and molecular pathological facilities are all required to set up the proper diagnosis and therapeutic strategy in human lung cancer. Strausz J, Tímár J. Non-surgical biopsy in lung cancer: a paradigm shift.