Inhibitory punktów kontrolnych w niedrobnokomórkowym raku płuca — ku praktyce codziennej

Immunoterapia z zastosowaniem leków blokujących punkty kontrolne zdaje się rewolucjonizować leczenie nowotworów litych, w tym raka płuca. Blokery szlaku PD-1, PD-L1 wykazały skuteczność w zakresie długotrwałego przeżycia w zaawansowanym raku płuca z przerzutami. U indywidualnych chorych osiąga się kilkuletnie przeżycia. W leczeniu raka płuca zarejestrowano nivolumab, pembrolizumab i atezolizumab. Obserwacje z praktyki klinicznej wskazują na podobną skuteczność tych leków, jak w próbach klinicznych. Efekty leczenia zależą od stanu sprawności. Wiek, płeć, typ histologiczny, obecność przerzutów do mózgu nie wpływały na wyniki leczenia. Leczenie antagonistami punktów kontrolnych jest bezpieczne i dobrze tolerowane, działania niepożądane wiążą się z zapaleniami o podłożu autoimmunizacyjnym. Poważnym i niekiedy śmiertelnym powikłaniem może być zapalenie pęcherzyków płucnych (pneumonitis), choć zazwyczaj poddaje się leczeniu glikokortykosteroidami. W celu odpowiedniej kwalifikacji chorych do leczenia ocenia się ekspresję PD-L1 na komórkach raka. Tak zwane guzy „gorące”, ze znaczną ekspresją PD-L1 i bogatym naciekiem z limfocytów cytotoksycznych zdają się lepiej odpowiadać na immunoterapię niż guzy „zimne”.Immunoterapia z zastosowaniem leków blokujących punkty kontrolne zdaje się rewolucjonizować leczenie nowotworów litych, w tym raka płuca. Blokery szlaku PD-1, PD-L1 wykazały skuteczność w zakresie długotrwałego przeżycia w zaawansowanym raku płuca z przerzutami. U indywidualnych chorych osiąga się kilkuletnie przeżycia. W leczeniu raka płuca zarejestrowano nivolumab, pembrolizumab i atezolizumab. Obserwacje z praktyki klinicznej wskazują na podobną skuteczność tych leków, jak w próbach klinicznych. Efekty leczenia zależą od stanu sprawności. Wiek, płeć, typ histologiczny, obecność przerzutów do mózgu nie wpływały na wyniki leczenia. Leczenie antagonistami punktów kontrolnych jest bezpieczne i dobrze tolerowane, działania niepożądane wiążą się z zapaleniami o podłożu autoimmunizacyjnym. Poważnym i niekiedy śmiertelnym powikłaniem może być zapalenie pęcherzyków płucnych (pneumonitis), choć zazwyczaj poddaje się leczeniu glikokortykosteroidami. W celu odpowiedniej kwalifikacji chorych do leczenia ocenia się ekspresję PD-L1 na komórkach raka. Tak zwane guzy „gorące”, ze znaczną ekspresją PD-L1 i bogatym naciekiem z limfocytów cytotoksycznych zdają się lepiej odpowiadać na immunoterapię niż guzy „zimne”

Endotoxin markers in bronchoalveolar lavage fluid of patients with interstitial lung diseases

Background: Exposure to inhaled endotoxins (lipopolysaccharides, LPS) of Gram-negative bacteria commonly found in indoor environments and assessed in secondary tobacco smoke, has been associated with airway inflammation and asthma exacerbation. The bronchoalveolar lavage fluid (BALf) from patients with interstitial lung diseases (sarcoidosis, lung fibrosis, smoking-related ILD, eosinophilic disorders) was analyzed for the markers of lipopolysaccharide (LPS, endotoxin). Methods: BALf was obtained from patients with diffuse lung diseases: idiopathic pulmonary fibrosis (n = 42), sarcoidosis (n = 22), smoking-related-ILD (n = 11) and eosinophilic disorders (n = 8). Total cell count and differential cell count were performed. In addition, samples were analyzed for 3-hydroxy fatty acids (3-OHFAs) of 10-18 carbon chain lengths, as markers of LPS, by gas chromatography-tandem mass spectrometry. Results: The highest LPS concentration was found in patients with eosinophilic disorders and the lowest in patients with sarcoidosis (p 25%) and those with lower proportion was also significant (p = 0.014). A significant correlation was found between LPS and eosinophils, but not between LPS and lymphocytes, neutrophils, or macrophages count. Conclusions: A positive relationship of LPS and eosinophilic pulmonary disorders may be linked to a persistent eosinophil activation mediated by Th2 pathway: chronic endotoxin exposure would intensify Th2 pathway resulting in fibrosis and, at the same time, eosinophil stimulation, and hence in eosinophilic pulmonary disorders

Achieving Thoracic Oncology data collection in Europe: a precursor study in 35 Countries

Background: A minority of European countries have participated in international comparisons with high level data on lung cancer. However, the nature and extent of data collection across the continent is simply unknown, and without accurate data collection it is not possible to compare practice and set benchmarks to which lung cancer services can aspire.Methods: Using an established network of lung cancer specialists in 37 European countries, a survey was distributed in December 2014. The results relate to current practice in each country at the time, early 2015. The results were compiled and then verified with co-authors over the following months.Results: Thirty-five completed surveys were received which describe a range of current practice for lung cancer data collection. Thirty countries have data collection at the national level, but this is not so in Albania, Bosnia-Herzegovina, Italy, Spain and Switzerland. Data collection varied from paper records with no survival analysis, to well-established electronic databases with links to census data and survival analyses.Conclusion: Using a network of committed clinicians, we have gathered validated comparative data reporting an observed difference in data collection mechanisms across Europe. We have identified the need to develop a well-designed dataset, whilst acknowledging what is feasible within each country, and aspiring to collect high quality data for clinical research

How to evaluate the immune status of lung cancer patients before immunotherapy

Nowadays, cancer immunotherapy is a promising strategy in solid tumour treatment. It has become a breakthrough in achieving long-term survival in many advanced cases. The essence of modern immunotherapy is to improve the host antitumour immune defence. Currently, it is critically important to determine the biomarkers that could be helpful in planning this type of individual therapy. It has turned out that an important prognostic factor is the evaluation of inflammatory infiltration of the tumour mass, including the characteristics of populations of lymphocytes and macrophages, and the expression of suppressive and regulatory molecules. For lung cancer, <30% of the tumours are resectable and available for a complete microscopic examination. In other cases, the material for the study of inflammatory infiltration may be a tumour biopsy, but this is of limited importance. A valuable way to evaluate the microenvironment of tumour growth is a bronchoalveolar lavage (BAL) fluid examination. In the BAL fluid, the cellular and noncellular components determine the specific type of inflammatory response in an environment of developing cancer. BAL fluid analysis may be a valuable addition to peripheral blood analysis during qualification for modern immunomodulatory therapy. Moreover, it is important material to seek biomarkers of clinical significance

Immunophenotype of T Cells Expressing Programmed Death-1 and Cytotoxic T Cell Antigen-4 in Early Lung Cancer: Local vs. Systemic Immune Response

The overexpression of programmed death-1 (PD-1) and cytotoxic T cell antigen 4 (CTLA-4) receptors on T cells are among the major mechanisms of tumor immunoevasion. However, the expression pattern of these receptors on T cell subpopulations of a different activation status and at different sites is poorly characterized. Thus, we analyzed the expression of PD-1 and CTLA-4 on the na&#239;ve, activated, memory, and activated memory T cells. Bronchoalveolar lavage fluid (BALF) from the lung affected by lung cancer (clBALF), the opposite &#8216;healthy&#8217; lung (hlBALF), and peripheral blood (PB) samples were collected from 32 patients. The cells were analyzed by multiparameter flow cytometry. The proportion of memory, activated, and activated memory CD8+ cells with the expression of PD-1 and CTLA-4 were elevated in the clBALF when compared to the hlBALF (insignificantly), but these proportions were significantly higher in the BALF when compared with the PB. The proportions of PD-1+ and CTLA-4+ T cells were elevated in the squamous cell carcinoma when compared to the adenocarcinoma patients. Also, the expression of PD-1 and CTLA-4 on T cells from the BALF was significantly higher than from PB. We report for the first time the differential expression of checkpoint molecules on CD4+ and CD8+ lymphocytes at a different stage of activation in the local environment of lung cancer. Moreover, the circulating T cells have a distinct expression of these receptors, which suggests their poor utility as biomarkers for immunotherapy

Elevated Foxp3/CD8 Ratio in Lung Adenocarcinoma Metastatic Lymph Nodes Resected by Transcervical Extended Mediastinal Lymphadenectomy

A balance between tumor invasion and immune defence system is widely investigated. Objective. The aim of this study was to evaluate lymphocyte phenotype in lymph nodes (LNs) of patients with lung cancer in relation to the presence of metastases. Methods. We investigated 364 LNs resected by transcervical extended mediastinal lymphadenectomy (TEMLA) of 49 patients with squamous cell carcinoma (SCC) or adenocarcinoma (AD) with (A) and without metastases (B). Expression of CD4, CD8, CD25, CTLA-4, and Foxp3 was assessed by immunohistochemical staining. Results. We observed a strong nuclear staining for Foxp3 in lymphocytes and cancer cells and strong membranous/cytoplasmatic reaction for CD4 and CD8, but low for CD25 and CTLA-4. There were significantly higher proportions of CD8+ cells in AD (B) versus AD (A) LNs (80% versus 52.5%, p<0.05). The Foxp3/CD8 ratio was higher in AD (A) versus AD (B) LNs (0.4 versus 0.25, p<0.05). No significant differences in the cell markers expression in SCC LNs were found. Conclusion. Significant differences in lymphocyte phenotype in AD may indicate an exceptional biology of this type of lung cancer. TEMLA resected LNs may serve as valuable samples for evaluation of immune status in lung cancer patients