Clinical Outcomes Depending on Sympathetic Innervation in Pancreatic Cancer.

BACKGROUND: The aim of our study was to evaluate sympathetic neuronal remodeling in patients with pancreatic cancer, together with its correlation with clinical outcomes. METHODS: In this descriptive, retrospective study, we analyzed pancreatic cancer specimens and peritumoral pancreatic tissue from 122 patients. We also investigated tyrosine hydroxylase immunoreactivity for the analysis of sympathetic nerve fibers and beta 2 adrenoreceptors immunoreactivity. To investigate the potential interaction between tyrosine hydroxylase (TH), beta 2 adrenoreceptors (B2A) immunoreactivity, and clinicopathological outcomes, we used the median to classify each case as TH+, respectively, B2A+ (if it presented a value higher than the median). RESULTS: Firstly, the overall survival was analyzed according to TH and B2A immunoreactivity, in both intratumoral and peritumoral tissue. Only B2A immunoreactivity in the peritumoral pancreatic tissue influenced overall survival at 5 years of follow-up; thus, B2A+ patients recorded a 5-year survival of only 3% compared to B2A- patients who recorded an overall survival at 5 years of follow-up of 14% (HR = 1.758, 95% CI of ratio 1.297 to 2.938, p = 0.0004). Additionally, the increased immunoreactivity of B2A in the peritumoral tissue was also associated with other factors of poor prognosis, such as moderately or poorly differentiated tumors, the absence of response to first-line chemotherapy, or metastatic disease. CONCLUSIONS: The increased immunoreactivity of beta 2 adrenoreceptors in pancreatic peritumoral tissue represents a poor prognostic factor in pancreatic cancer.

Factors Associated with Stroke in Atrial Fibrillation. A Retrospective Study.

AIM: The aim of our study was to retrospectively evaluate known factors such as CHA2DS2-VASc, but, also, new factors (such as left atrial remodeling), associated with the development of stroke in patients with atrial fibrillation (AFi). MATERIAL AND METHODS: We performed a retrospective study in which 251 patients with AFi were included. 47 patients had an ischemic stroke before the diagnosis of AFi, at the time of diagnosis or after AFi was diagnosed. The CHA2DS2-VASc score was analyzed for all patients together with other left atrial remodeling parameters. RESULTS: We observed that among the patients with ischemic stroke approximately 61.70% were over 72.5 years old compared to those without stroke who presented this age in a proportion of only 44.61% (OR=2.001, P=0.0367). The CHA2DS2-VASc score had the greatest statistical impact for stroke, as expected. Patients with a CHA2DS2-VASc score >4.5 presented stroke in a proportion of 87.23% compared to CHA2DS2-VASc <4.5 who had stroke only in a proportion of 12.77% (OR=11.51, P=<0.0001). Regarding left atrial remodeling parameters, low LA ejection fraction was associated with a high percentage of stroke among patients (61.70%) compared to those with LA EF>34.5% who had stroke only in a percentage of 38.30% (OR= 2.124, P=0.0238). CONCLUSIONS: Although the CHA2DS2-VASc score remains a good factor for predicting the association of AFi with ischemic stroke, echocardiographic parameters for the evaluation of the left atrium can be used as new risk factors for predicting the occurrence of ischemic stroke in patients with AFi.

Classical Therapies Versus Combined Therapies in Diabetic Neuropathy.

The aim of our study was to evaluate the classical therapies represented by adequate glycemic control and lifestyle changes versus classical therapies combined with new antioxidant therapies in patients with diabetic neuropathy. We conducted an observational, prospective study, between October 2017 and December 2019, which included a number of 188 patients suffering from diabetic neuropathy. In order to evaluate the response to the therapeutic protocol, we used the MNSI (Michigan neuropathy screening instrument). Responder group was defined as a decrease in MNSI (<7) from baseline to one year. According to this 34.04% (n=64) of patients were responders to classical therapy while a higher number of patients responded to combined therapy (n=73, representing 38.83%). In the group of responders, the subgroups that predicted the prevention of MNSI increase (decrease in the impact of diabetic neuropathy) in the group treated with combined therapy compared to classical therapy, related to clinicopathological features, after one year included: gender female (p=0.0415), body mass index <30kg/m2 (p=0.0335), absence of cardiovascular disease (p=0.0006) and absence of dyslipidemia (p=0.0288). In conclusion, we demonstrated an increased response to combined therapy after one year of treatment. Thus, combined therapy is an alternative for reducing side effects and for increasing efficiency.

Antiplatelet therapy in secondary ischemic stroke prevention - a short review.

Platelets play an essential role in atherothrombosis and for this reason they are the primary target of antithrombotic therapy in ischemic stroke. We discussed here the evidence for efficacy and safety of current knowledge in antiplatelet therapy for stroke prevention after an acute ischemic stroke or transient ischemic attack. After an acute episode, long-term antithrombotic therapy is essential for the secondary prevention of stroke recurrence and complications. Antiplatelet therapy for acute ischemic stroke (non-cardioembolic) or ischemic stroke consists of three antiplatelet drugs, in accordance with Food and Drug Administration (FDA) from the USA and also with the Guidelines published by the American Heart Association (AHA) and nevertheless with the Guidelines of the American Stroke Association (ASA), in 2014, for preventing vascular events, such as stroke. These are aspirin, clopidogrel and dipyridamole. Moreover, recent randomized clinical trials and the last Guidelines for stroke of AHA∕ASA, in 2018, also mention ticagrelor. All of these antiplatelet therapies, besides inhibiting acute arterial thrombosis, also interfere with physiological hemostasis. In conclusion, we can say that current recommendations focused primarily on the therapy with aspirin for the secondary prevention of stroke in patients that presented vascular events, such as ischemic stroke of non-cardioembolic cause or transient ischemic attack and, as appropriate, aspirin plus dipyridamol or clopidogrel. The new therapy with ticagrelor in secondary stroke prevention seems to be promising, but more randomized clinical trials are needed to accurately assess the safety and efficacy of this new antiplatelet drug.

Assessment of T- and B-lymphocytes and VEGF-A in acute pancreatitis.

AIM: Highlighting certain characteristics of T- and B-lymphocytes, as well as of vascular endothelial growth factor-A (VEGF-A) as a prognosis factors for patients suffering from acute pancreatitis, with the scope of establishing diagnosis and therapy. MATERIALS AND METHODS: Pancreatic tissue samples were analyzed, originating from 21 patients deceased due to acute pancreatitis, between the years 2015 and 2016. The study group was subdivided into two subgroups by pathology duration. As control group, pancreatic tissue fragments were sampled from eight patients, deceased due to non-pancreatic acute surgical abdomen (NPASA). RESULTS: By analyzing the immunohistochemical expression of T-lymphocytes (immunomarked with the anti-CD3 antibody) and of B-lymphocytes (immunomarked with the anti-CD20 antibody), both on the tissue sections originating from the study patients, as well as the control group patients, we established that these were mostly present in the interstitium, following which the acini, less frequently in the islets, in general with B-lymphocytes being less present than T-lymphocytes. VEGF-A also tends to emerge in the acini periphery, at the border with the stromal connective tissue, while the islets are almost negative for VEGF-A. CONCLUSIONS: We can state that the decreased expression of T- and B-lymphocytes in normal pancreatic tissue, surrounding the necrosis areas, can be used as an aggravated prognosis factor for patients diagnosed with acute pancreatitis. Moreover, the increased immunohistochemical expression of VEGF-A can play an important role in tracking the evolution and pathology of acute pancreatitis.

B2 adrenergic receptors and morphological changes of the enteric nervous system in colorectal adenocarcinoma.

AIM: To study the morphology of the enteric nervous system and the expression of beta-2 adrenergic (B2A) receptors in primary colorectal cancer. METHODS: In this study, we included forty-eight patients with primary colorectal cancer and nine patients for control tissue from the excision of a colonic segment for benign conditions. We determined the clinicopathological features and evaluated the immunohistochemical expression pattern of B2A receptors as well as the morphological changes of the enteric nervous system (ENS). In order to assess statistical differences, we used the student t-test for comparing the means of two groups and one-way analysis of variance with Bonferroni's post hoc analysis for comparing the means of more than two groups. Correlations were assessed using the Pearson's correlation coefficient. RESULTS: B2A receptors were significantly associated with tumor grading, tumor size, tumor invasion, lymph node metastasis (P < 0.05), while there were no statistically significant associations with gender, CRC location and gross appearance (P > 0.05). We observed, on one hand, a decrease of the relative area for both Auerbach and Meissner plexuses with the increase of the tumor grading, and on the other hand, an increase of the relative area of other nervous elements not in the Meissner plexus or in the Auerbach plexus with the tumor grading. For G1 tumors we found that epithelial B2A area showed an inverse correlation with the Auerbach plexus areas [r(14) = -0.531, P < 0.05], while for G2 tumors, epithelial B2A areas showed an indirect variation with both the Auerbach plexus areas [r(14) = -0.453, P < 0.05] and the Meissner areas [r(14) = -0.825, P < 0.01]. For G3 tumors, the inverse dependence increased for both Auerbach [r(14) = -0.587, P < 0.05] and Meissner [r(14) = -0.934, P < 0.05] plexuses. CONCLUSION: B2A receptors play an important role in colorectal carcinogenesis and can be utilized as prognostic factors. Furthermore, study of the ENS in colorectal cancer may lead to targeted molecular therapies.

Collagen I and III, MMP-1 and TIMP-1 immunoexpression in dilated cardiomyopathy.

The extracellular matrix (ECM) remodeling represents the pathological substrate of dilated cardiomyopathy (DCM). In this study, we statistically analyzed the immunoexpression of collagen I and III, matrix metalloproteinase-1 (MMP-1) and its tissue inhibitor-1 (TIMP-1) in the myocardial tissue in 18 cases of DCM compared to a control group. We observed a significant increase in the immunoexpression of collagen I and III in patients with DCM and a significant reduction in the immunoexpression of MMP-1 compared with the control group. Also, the collagen I and TIMP-1 expression indicated a positive linear correlation and respectively a negative linear relationship with collagen III and MMP-1. The analyzed markers in this study can be used to quantify the degree of collagen sclerosis from the ECM of DCM.

Synaptophysin expression as prognostic factor for survival in colorectal carcinomas.

The aim of this study is to assess the status of synapses in normal colorectal tissue compared to neoplastic colorectal tissue, and to correlate this status with survival in patients with colorectal neoplasia. Our study included 61 patients diagnosed with colorectal adenocarcinoma, representing the study group, and 53 patients diagnosed with benign conditions, that required a resection of a colorectal segment, representing the control group. We performed the immunohistochemical staining by using anti-synaptophysin antibody, which identifies synaptic vesicles and, so, we managed to analyze the expression of synapses in colorectal adenocarcinoma. Regarding both the signal area and integrated optical density (IOD) of the synaptophysin, the univariate analysis with a log-rank (Mantel-Cox) test indicated that patients with a low level of synaptophysin had a better overall survival rate than those with a high-level synaptophysin. Also, we noticed that tumor size, tumor invasion and lymph node metastasis were significantly associated with the overall survival rate, whereas the other clinicopathological features were not. In conclusion, the status of synaptic vesicles evaluated via synaptophysin expression in patients with colorectal cancer positively correlates with the survival rate and it can play a role in the neoplastic therapy process.

Implications of inflammation and remodeling of the enteric glial cells in colorectal adenocarcinoma.

AIM: The aim of our study was to assess glial fibrillary acidic protein (GFAP) glial cell phenotype in the enteric nervous system (ENS) in colorectal adenocarcinoma of different tumor grading and, also, to establish correlations between these changes and the tumor proliferative activity and the tumor-infiltrating leukocytes. PATIENTS, MATERIALS AND METHODS: We ran an observational, prospective study on a group of 52 patients diagnosed with colorectal adenocarcinoma. They were surgically treated in the 1st Surgery Clinic of the Emergency County Hospital of Craiova, Romania. From the surgically resected pieces, after pathological confirmation and tumor grading, 3-µm thick seriate sections were cut and processed for immunohistochemistry for detecting GFAP, S100, CD45 and Ki-67. RESULTS: Evaluation of GFAP glial cell type in the ENS of colorectal cancer with different stages of differentiation showed that the density of these nervous elements is higher in well-differentiated (G1) colorectal tumors compared to moderately differentiated (G2) and poorly differentiated (G3) colorectal tumors. For well-differentiated colorectal adenocarcinoma, we did not find any correlations between GFAP glial cell type in the ENS and the tumor proliferative activity or with tumor-infiltrating leukocytes. In what the moderately and poorly differentiated adenocarcinoma are concerned, we found a high inverse variation between GFAP glial cell type in the ENS and the proliferative activity, on one hand, and, between GFAP glial cell type in the ENS and the tumor-infiltrating leukocytes, on the other hand. CONCLUSIONS: The decrease in the density of GFAP glial cell type in the ENS with tumor grading of colorectal cancer and the inverse variation with the tumor proliferative activity and with the tumor-infiltrating leukocytes might serve as putative prognostic factors in colorectal cancer.

From molecular mechanism to morphological changes in cardiomyopathy.

The aim of this study is to make a foray in the world of constitutive elements of the architectural and functional organizing of the cardiomyocytes involved in cardiomyopathies and of the genetic molecules that they express. Primary cardiomyopathies represent a group of diseases characterized by primary structural and functional changes of the myocardium, without myocardial ischemic disease, hypertension, valvulopathies or congenital cardiac diseases being involved. In the pathogenesis of the cardiomyopathies proteins, especially from the sarcomere, Z-disc, cellular cytoskeleton, sarcolemma, intercalated discs, nuclear envelope and other constitutive proteins of the cardiomyocytes are involved. Deciphering of these pathophysiological mechanisms is part of the new model of personalized medicine, and it is useful in developing and in the optimization of new strategies for the management of the patients diagnosed with this type of disease.

Neuro-neoplastic interrelationships in colorectal level - immunohistochemical aspect in three cases and review of the literature.

Colorectal cancer represents a severe public health issue. Recent studies have shown the essential role played by nerves and their neurotransmitters in tumor initiation and progression. The aim of this study is to asses the expression of beta 2-adrenergic receptors (ß2A) for adrenaline and noradrenaline, and the expression of M3 muscarinic receptors (M3R) for acetylcholine (neurotransmitters produced and released by sympathetic and parasympathetic afferents of the digestive tract and also by the enteric nervous system) in different tumor gradings of colorectal adenocarcinoma, and also the tropomyosin receptor kinase A (TrkA) for the nerve growth factor produced by the cells of colorectal adenocarcinoma. Beta 2-adrenergic receptors were expressed both in normal colic tissue and in the tumor tissues, from the three patients included in the study. It was observed that both area and integrated optical density (IOD) are more elevated for this type of receptor in tumor tissues than in normal colic tissue. For the M3 muscarinic receptors, similarly to beta 2-adrenergic receptors, it was observed a growth both of the area and of the IOD with the tumor grading. The presence of TrkA receptors was also observed both in the normal colic mucosa and in the tumor tissues examined, but with a significant reduction of the signal in the poorly differentiated tumor tissue. Understanding the neurobiology of cancer in this context becomes necessary for establishing much more complex and targeted molecular targeted therapies.