Halina Batura-Gabryel

c-MET Inhibitors in the Treatment of Lung Cancer

Opinion statementLung cancer is the most common malignant neoplasm and constitutes the most common neoplastic cause of death globally. The results of therapies employing standard chemotherapy are unsatisfactory. Currently, efforts are being made to personalize the therapy; numerous clinical studies are being conducted around the world to assess the efficacy and safety of agents directed at molecular targets. One of these molecular targets is the c-MET proto-oncogene, whose primary ligand is hepatocyte growth factor (HGF). C-MET hyperactivity has been observed in numerous neoplasms, including non-small-cell lung carcinoma. Prolonged or continuous activity of the receptor leads to excessive cell proliferation and is related to the development or progression of neoplastic disease. C-MET inhibitors can be classified into three groups: small-molecule tyrosine kinase inhibitors of the c-MET receptor (crizotinib, tivantinib, cabozantinib, foretinib), as well as monoclonal antibodies against c-MET (onartuzumab) and against the HGF ligand (ficlatuzumab, rilotumumab). The efficacy and safety of these agents is assessed both in monotherapy and in combination with other molecularly targeted agents. Furthermore, the toxicity profile of c-MET inhibitors is completely different from that of standard chemotherapy. The best understood c-MET inhibitor used in the treatment of non-small-cell lung carcinoma patients is crizotinib. It is registered for patients with the presence of ALK gene rearrangements after the failure of the first line of treatment based on platinum derivatives. The purpose of this present paper is to present clinical studies that assessed the efficacy and safety of c-MET inhibitors for the treatment of non-small-cell lung carcinoma, as well as current indications for the use of these molecules.

Evaluation of the phenotype pattern of macrophages isolated from malignant and non-malignant pleural effusions.

Macrophages are among the infiltrate components of most malignant tumors. Tumor-associated macrophages (TAMs) may secrete a variety of humoral factors, which promote or inhibit tumor growth. In general, depending on their activation pathway, macrophages exhibit two different patterns of phenotype, M1 or M2. It is assumed that TAMs comprise pattern M2. In the malignant pleural effusion, macrophages are a frequent component of cytological evaluation. In this microenvironment, TAMs could be involved in the development of immunity. The phenotype of macrophages represented in malignant and non-malignant pleural effusions is unknown. In this study, macrophages were isolated from 38 pleural effusions (15 malignant and 23 non-malignant) and the expression of a variety of immune mediators and their receptors was assessed to determine the type of activation (M1 vs. M2). The expression of mRNA was analyzed for IL-1β, IL-4, IL-6, IL-10, IL-11, IL-18, TNFα, TGFβ1, IL1R1, IL1RAP, TLR2, TLR4, VLA4, CD62L, MMP2, MMP9, VEGFA, PDGFA, and PDGFB. In immunohistochemical evaluation, the expressions of CD68, mesothelin, MAC387, IL-1β, IL-6, IL-10, IL-12, TNFα, and CD105 were assessed. The cytoplasmic expression of IFNγ, TNFα, IL-6, and IL-10 and the surface expression of CD11a, CD14, CD15, CD16, CD23, CD25, CD45, CD54, CD62L, CD69, VLA2, VLA3, VLA4, VLA6, TLR2, TLR4, and CCR7 were tested using flow cytometry. In supernatants from macrophages cultures, TNFα, IL-1β, IL-6, IL-8, IL-10, IL-12, MCP1, and VEGF were investigated by cytometric beads array method (CBA flex sets) and TGFβ1 by ELISA. Our results indicate that macrophages from malignant and non-malignant pleural effusions differ from each other and suggest that macrophages isolated from non-malignant effusions show a pattern comparable to M1 while those isolated from malignant effusions express similarity to M2 phenotype, but they have not shown a classical M2 pattern.

Interleukin-17 and interleukin-23: importance in the pathogenesis of lung impairment in patients with systemic sclerosis

T cell abnormalities with a focus on Th17 cells have been associated with the pathogenesis of systemic sclerosis (SSc) and interstitial lung disease (ILD). The aim of this study was to evaluate serum levels of interleukin (IL)‐17, IL‐21 and IL‐23 in SSc patients and to assess their relationship with ILD‐SSc.

Susceptibility loci in lung cancer and COPD: association of IREB2 and FAM13A with pulmonary diseases.

Genome-wide association studies have identified loci at 15q25 (IREB2) and 4q22 (FAM13A), associated with lung cancer (LC) and chronic obstructive pulmonary disease (COPD). The aim of our research was to determine the association of IREB2 and FAM13A SNPs with LC and severe/very severe COPD patients. We examined IREB2 variants (rs2568494, rs2656069, rs10851906, rs13180) and FAM13A (rs1903003, rs7671167, rs2869967) among 1.141 participants (468 LC, 149 COPD, 524 smoking controls). The frequency of the minor IREB2 rs2568494 AA genotype, was higher in LC vs controls (P = 0.0081, OR = 1.682). The FAM13A rs2869967 was associated with COPD (minor CC genotype: P = 0.0007, OR = 2.414). The rs1903003, rs7671167 FAM13A variants confer a protective effect on COPD (both P < 0.002, OR < 0.405). Haplotype-based tests identified an association of the IREB2 AAAT haplotype with LC (P = 0.0021, OR = 1.513) and FAM13A TTC with COPD (P = 0.0013, OR = 1.822). Cumulative genetic risk score analyses (CGRS), derived by adding risk alleles, revealed that the risk for COPD increased with the growing number of the FAM13A risk alleles. OR (95% CI) for carriers of ≥5 risk alleles reached 2.998 (1.8 to 4.97) compared to the controls. This study confirms that the IREB2 variants contribute to an increased risk of LC, whereas FAM13A predisposes to increased susceptibility to COPD.

Plasma Selectins in Patients with Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is an independent risk factor in the pathogenesis of -cardiovascular diseases. The aim of the study was to analyze three specific adhesion molecules involved in the development of an atherosclerotic plaque: E-selectin (endothelium), L-selectin (leukocyte surface), and P-selectin (from platelet), circulating in plasma in patients at different OSA severity. Eighty non-smoking male Caucasians aged 30-64 were enrolled into the study after clinical, biochemical, and polysomnographic examinations. The patients were divided into four groups based on the results of apnea/hypopnea index (AHI): OSA-0 with AHI 0-4.9 (n = 20), OSA-1 with AHI 5-15 (n = 21), OSA-2 with AHI 16-30 (n = 18), OSA-3 with AHI ≥ 31 (n = 21). Complete blood count, oral glucose tolerance test, fasting lipid profile, C-reactive protein and insulin, and plasma concentrations of soluble E-selectin, P-selectin and L-selectin were measured. We found a progressive increase in the concentrations of all three selectins with the severity of OSA. In conclusion, the level of plasma adhesion molecules may be indicative of OSA severity and may contribute to cardiovascular sequelae.

Adipocytokines in sleep apnea syndrome

ObjectiveBiomarkers of adipose tissue may affect glucose and lipid metabolism and present pro-inflammatory properties, thus could be involved in the pathobiochemistry of cardiovascular disease (CVD). The coexistence of sleep apnea syndrome (OSA) and metabolic risk factors of CVD is worth explaining. The aim of the study was to compare the serum adipocytokines in subjects with and without OSA, who had all elevated body mass index (BMI).MethodsOverweight (BMI: 25.0-29.9 kg/m2) and obese (BMI: 30.0-39.9 kg/m2) OSA-suspected Caucasian males, aged 30-63, with no acute disease or chronic disorder underwent polysomnographic evaluation to select OSA-positive (AHI ≥ 5) and OSA-negative (AHI < 5) subjects. Four subgroups were created of 18 persons each: Over(weight)-OSA-Neg, Over-OSA-Pos, Obese-OSA-Neg, Obese-OSA-Pos. In all subjects, plasma carbohydrate and lipid metabolism parameters, and serum uric acid, resistin and leptin concentrations were determined.ResultsA decreased resistin level was observed in Over-OSA-Pos vs. Over-OSA-Neg subjects (P = 0.037) as well as in Obese-OSA-Pos vs. Obese-OSA-Neg (P = 0.045). No differences in leptin concentrations were observed. A positive correlation between leptin and BMI was in both overweight subgroups and a negative one between resistin and fasting glucose was in both obese subgroups.ConclusionsOSA may decrease the serum resistin level in subjects with excess body mass and also may contribute to glucose metabolism, but has no influence on the leptin level.

The diagnostic role of plasma circulating precursors of miRNA-944 and miRNA-3662 for non-small cell lung cancer detection

INTRODUCTION microRNA (miRNA) seem to be most attractive cancer markers due their crucial role in tumor development and possibility of their analysis using liquid biopsy. To date there is little known about role of miRNA precursors (pri-miRNA) in carcinogenesis and their utility as tumor markers. MATERIAL AND METHODS miRNA-944 and miRNA-3662 precursors as potential non-small cell lung cancer (NSCLC) markers were analyzed in plasma samples of 56 patients in an early stage of NSCLC and 100 healthy individuals. RESULTS Diagnostic test based on two studied markers for stage I-IIIA of the disease allowed to distinguish NSCLC from healthy individuals with 75.7% sensitivity and 82.3% specificity (AUC=0.898). pri-miRNA-944 distinguished SCC from AC with sensitivity of 78.6% and specificity of 91.7% (AUC=0.771), and pri-miRNA-3662 distinguished AC from SCC with 57.1% sensitivity and 90% specificity (AUC=0.845). CONCLUSION Circulating pri-miRNA-944 and 3662 can improve non-invasive NSCLC detection of operable stages of SCC and AC. miRNA precursors could be considered as novel potential lung cancer biomarkers.

ENDOTHELIUM-DERIVED MARKERS AND ANTIOXIDANT STATUS IN THE BLOOD OF OBSTRUCTIVE SLEEP APNEA MALES

ObjectiveThe relationship between obstructive sleep apnea (OSA) and cardiovascular disease is intensively discussed. Endothelial leukocyte adhesion molecule (E-selectin) is one of factors facilitating leukocyte migration to the subendothelial layer which could be considered proatherogenic. The aim of the study was to determine E-selectin levels and total plasma antioxidant status (TAS) in the blood of different stage OSA patients.MethodsNon-smoking, OSA-suspected males, aged 30-63, were selected for the study. An EMBLA polysomnographic system was used to establish the severity of apneic episodes. The results of apnea/hypopnea index (AHI) allowed dividing patients into the following groups: OSA-0 with AHI 0-4.9 (n = 14), OSA-1 with AHI 5-15 (n = 14), OSA-2 with AHI 16-30 (n = 13), OSA-3 with AHI ≥ 30 (n = 13). Complete blood count (CBC), glycemia during oral glucose tolerance test, fasting plasma lipid profile, uric acid, and high sensitivity C-reactive protein (hsCRP) were estimated among routine parameters. We determined plasma concentrations of E-selectin and total antioxidant status.ResultsWe found progressively decreasing concentrations of TAS (P = 0.03) and increased concentrations of E-selectin (P = 0.0001) from OSA-0 to OSA-3 subjects. No correlation between E-selectin and metabolic parameters was noted.ConclusionIn the studied OSA groups, E-selectin appeared an independent proatherogenic factor.

Impulse oscillometry in the diagnosis of airway resistance in chronic obstructive pulmonary disease.

Spirometry is a standard lung function test for diagnosis and staging of chronic obstructive pulmonary disease (COPD). Impulse oscillometry (IOS) can be complementary to spirometry, especially in patients at advanced age and with physical or mental disorders who cannot be diagnosed through spirometry. The aim of this study was to compare IOS and spirometry in the assessment of airway obstruction in COPD. The study was conducted in 112 stable COPD patients, including 29 females and 83 males of the mean age of 69±11 years. The oscillometric evaluation included total (R5), peripheral (R5-R20), and negative reactance (X5), which were compared with the predicted forced expiratory volume in 1 s (FEV1%pred). The findings show a significantly negative correlation between FEV1%pred and the R5, R5-R20, and X5. COPD patients had increased R5, R5-R20, and X5. The severity of bronchial obstruction found by impulse oscillometry correlated well the spirometric assessment. IOS is a simple to perform test that may be helpful for functional examination of COPD patients.

Serum Clara cell 16-kDa protein levels and lung impairment in systemic sclerosis patients

OBJECTIVE To assess clinical utility of serum Clara cell 16-kDa protein measurements in relation with staging system for systemic sclerosis associated interstitial lung disease. MATERIALS AND METHODS Serum levels of Clara cell 16-kDa protein were determined by ELISA in 28 systemic sclerosis patients and 30 healthy controls, and correlated with staging system for systemic sclerosis associated interstitial lung disease in systemic sclerosis patients. Lung involvement was assessed functionally (body plethysmography, diffusing capacity of the lung for carbon monoxide) and radiologically (an average disease extent on high resolution computed tomography of the lungs) in SSc patients. RESULTS We observed statistically significant differences in serum Clara cell 16-kDa protein levels between systemic sclerosis patients and healthy controls only in non-smokers. However, serum Clara cell 16-kDa protein concentrations were significantly elevated in patients with high resolution computed tomography extent >20% in comparison to patients with high resolution computed tomography extent <20% (p=0.01). They correlated positively with average disease extent on high resolution computed tomography (p=0.04), an extent of a reticular pattern on high resolution computed tomography (p<0.01), and negatively with a total lung capacity (p=0.03) and the results of the 6-min walk test (p<0.01). CONCLUSIONS Clara cell 16-kDa protein levels can be considered as a supplemental serum biomarker for systemic sclerosis associated interstitial lung disease.