Role of type IV collagen and matrix metalloproteinase-9 in remodeling of the left ventricular in coronary artery disease

Currently, the analysis of the fibrosis severity during the restructuring of the surrounding extracellular matrix (ECM) is studied in most of the research works devoted to “cardiac remodeling”. At the same time, the role of the basal membrane of cardiomyocytes in heart diseases was not studied. The basal membrane of cardiomyocytes is a highly organized layer of the ECM which is located on the outer side of the sarcolemma. Degradation of ECM components is carried out by different types of matrix metalloproteinases (MMP), which have proteolytic activity and are actively involved in the process of ECM remodeling, destroying its components such as collagen, elastin, fibronectin, glycosaminoglycans and other structural components.Aim. To evaluate the ECM status in patients with coronary artery disease and its effect on left ventricular myocardial remodeling.Material and methods. Morphological and immunohistochemical (IHC) examination of left ventricular myocardial biopsies was performed in 16 patients undergoing left ventricular reconstruction in combination with coronary artery bypass grafting.Results. The IHC study revealed the accumulation of matrix metalloproteinase-9 in the cytoplasm of cardiomyocytes. This accumulation was combined with partial or complete destruction of the basal membranes (BM) of cardiomyocytes formed by type IV collagen.Conclusion. Type IV collagen destruction in basal membranes of left ventricular cardiomyocyteswasrevealed. It iscausedbytheactionofmatrixmetalloproteinase-9, which accumulates in the cell cytoplasm

THE PROGNOSTIC AND DIFFERENTIAL DIAGNOSTIC VALUE OF CYTOKERATIN 7 AND 19, AND THYROID TRANSCRIPTION FACTOR-1 EXPRESSION IN LUNG NEUROENDOCRINE TUMORS OF VARIOUS GRADES

Background: Neuroendocrine tumors of the lung (NETL) are a wide range of tumors with various malignancy grades and prognosis. Despite their prevalence being 20 to 25% of all lung cancers, many aspects that impact their clinical course and prognosis are not well understood. Aim  – to identify morphological and immunophenotypic characteristics of various NETL types would that more accurately reflect their biological potential and allow for prediction of their unfavorable clinical outcomes. Materials and methods: We performed immunohistochemical assessment of the diagnostic biopsies and surgical specimens from 152 patients with NETL aged 53 ± 13 years and identified 49  typical carcinoids, 32 atypical carcinoids, 60  small cell neuroendocrine carcinomas and 11  large cell neuroendocrine carcinomas, which accounted for 32.2, 21.1, 39.5 and 7.2%, respectively. Markers of neuroendocrine differentiation, such as synaptophysin, chromogranin A  and CD56, as well as cytokeratins 7 and 19, thyroid transcription factor-1 (TTF-1), and Ki67 were used. The results were analyzed with analysis of variance (ANOVA), chi-square test (χ²), and post-hoc comparisons with the Bonferroni correction. Results: Most often, the expression of cytokeratins 7 and 19 was found in large cell neuroendocrine carcinoma (72.7 and 90.9%, respectively), less frequently, in atypical carcinoids and small cell neuroendocrine carcinomas (50 and 53.3%; 41.7 and 64.6% of cases, respectively), whereas in typical carcinoids it was rare (5.9 and 15.9%, respectively). The rates of cytokeratin 7 and 19 expression were significantly lower in the typical carcinoids, compared to the atypical carcinoids, small cell neuroendocrine carcinomas and large cell neuroendocrine carcinomas (р < 0.05, χ²). The expression of cytokeratin 19 was significantly more common for large cell neuroendocrine carcinomas, than for small cell neuroendocrine carcinomas and atypical carcinoids (р < 0.01, χ²). The expression of TTF-1 was very rare in the typical carcinoid cells (6.5% of cases) and significantly more often in atypical carcinoids (61.5%) and in small cell neuroendocrine carcinomas and large cell neuroendocrine carcinomas (82.7 and 77.8% of cases, respectively). TTF-1 expression was significantly less frequent in typical than in atypical carcinoids, small cell neuroendocrine carcinomas and large cell neuroendocrine carcinomas (р < 0.01, χ²). The mean index of tumor cell proliferation (Ki67) was the lowest in typical carcinoids (2.6%), amounted to 12% in atypical carcinoids, to 44% in large cell neuroendocrine carcinomas and reached the maximum of 61% in small cell neuroendocrine carcinomas. There were significant differences in the mean Ki67 index in the NETL 4 groups (р < 0.001, ANOVA). Conclusion: Expression of TTF-1, cytokeratin 7 and 19 in the neuroendocrine tumors of the lung is characteristic for a  less differentiated cell immunophenotype and allows for identification of the risk group with unfavorable clinical outcome among low-grade typical and atypical carcinoids

IMMUNOHISTOCHEMICAL DETERMINATION OF EXPRESSION OF SOMATOSTATIN RECEPTORS TYPES 1, 2A, 3 AND 5 IN NEUROENDOCRINE TUMORS OF VARIOUS LOCALIZATION AND GRADE

Background: Prediction of clinical benefits of somatostatin analogues in patients with neuroendocrine tumors (NET) is very important prior to their administration. Data on immunohistochemical assessment of the expression of somatostatin receptors (SSR) of various types, obtained from large samples of NET with various localization, functional activity and degree of malignancy, are scarce; therefore, the study was aimed at assessment of the latter.Materials and methods: We performed an immunohistochemical study with antibodies to SSR1, 2A, 3 and 5  types on tissue samples obtained during diagnostic and intra-operative biopsies from 399 NETs: 168 from pancreas, 120 from gastrointestinal tract (stomach, 48, from small intestine, 39, 14 of which being from duodenum; appendix, 6, colon and the rectum, 15 and 12, respectively), 84 from lung, 6 from thymus/mediastinum, and 21 from NET metastases of unknown primary localization.Results: Very high levels expression of receptors SSR2A preferentially binding to somatostatin analogues, which are currently used in clinical practice, were detected in the small intestine NETs (22/25, 88%), appendix (5/6, 83.3%), colon (10/15, 66.7%), thymus (4/6, 66.7%), atypical carcinoids of the lung (10/15, 66.7%), stomach (27/41, 65.8%) and pancreas (105/165, 63.6%). The lowest expression was found in rectal NETs (5/12, 41.7%) and small and large cell neuroendocrine lung carcinomas (20, 11.1%). Among functioning NETs, the highest level of SSR2A was found in gastrinomas (18/19, 94.7%), glucagonomas (15/16, 93.8%), small intestine carcinoids (31/35, 88.6%), and somatostatinomas (2/3, 66.7%). The lowest expression was detected in ACTH secreting tumors with Cushing's syndrome (11/12, 50%), and in insulinomas (34/69, 49.3%). SSR2A expression in functionally inactive pancreatic NETs was significantly higher than in insulinomas (57/82, 34/69 vs 69.5 and 49.3%, respectively). SSR2A expression was associated with the degree of malignancy and is higher in pancreatic NET Grade 2A (Ki67 to 10%), Grade 2B (Ki67 10–19%) and in neuroendocrine carcinomas Grade  3, compared to Grade  1 (16/50 (32%), 37/61 (60.6%), 8/12 (66.7%) and 20/24 (83.3%), respectively). Overexpression of SSR5, which is the second clinically significant receptor, was observed in NETs of the duodenum (7/10, 70%) and appendix (2/5, 60%), and among functionally active NETs in glucagonomas and gastrinomas (12/15, 80%). SSR3 are less common, than SSR2A and 5, and are found most often in the gastric NETs (6/11, 54.5%), insulinomas (16/37, 43.2%), neuroendocrine carcinomas of pancreas Grade  3 (4/9, 44.7%), and typical lung carcinoids (7/16, 41.2%). SSR1 in all tumors are rare, the maximum level of expression was observed in small intestine carcinoids (9/21, 42.9%).Conclusion: Depending on their localization and grade  of malignancy, neuroendocrine tumors differ in expression of various SSR types. Therefore, determination of the receptor profile of each tumor is necessary before administration of somatostatin analogues