Dan Ionut Gheonea

Autophagy in colorectal cancer: An important switch from physiology to pathology

Colorectal cancer (CRC) remains a leading cause of cancer death in both men and women worldwide. Among the factors and mechanisms that are involved in the multifactorial etiology of CRC, autophagy is an important transformational switch that occurs when a cell shifts from normal to malignant. In recent years, multiple hypotheses have been considered regarding the autophagy mechanisms that are involved in cancer. The currently accepted hypothesis is that autophagy has dual and contradictory roles in carcinogenesis, but the precise mechanisms leading to autophagy in cancer are not yet fully defined and seem to be context dependent. Autophagy is a surveillance mechanism used by normal cells that protects them from the transformation to malignancy by removing damaged organelles and aggregated proteins and by reducing reactive oxygen species, mitochondrial abnormalities and DNA damage. However, autophagy also supports tumor formation by promoting access to nutrients that are critical to the metabolism and growth of tumor cells and by inhibiting cellular death and increasing drug resistance. Autophagy studies in CRC have focused on several molecules, mainly microtubule-associated protein 1 light chain 3, beclin 1, and autophagy related 5, with conflicting results. Beneficial effects were observed for some agents that modulate autophagy in CRC either alone or, more often, in combination with other agents. More extensive studies are needed in the future to clarify the roles of autophagy-related genes and modulators in colorectal carcinogenesis, and to develop potential beneficial agents for the prognosis and treatment of CRC.

Contrast-enhanced ultrasonography parameters in neural network diagnosis of liver tumors

AIM To study the role of time-intensity curve (TIC) analysis parameters in a complex system of neural networks designed to classify liver tumors. METHODS We prospectively included 112 patients with hepatocellular carcinoma (HCC) (n = 41), hypervascular (n = 20) and hypovascular (n = 12) liver metastases, hepatic hemangiomas (n = 16) or focal fatty changes (n = 23) who underwent contrast-enhanced ultrasonography in the Research Center of Gastroenterology and Hepatology, Craiova, Romania. We recorded full length movies of all contrast uptake phases and post-processed them offline by selecting two areas of interest (one for the tumor and one for the healthy surrounding parenchyma) and consecutive TIC analysis. The difference in maximum intensities, the time to reaching them and the aspect of the late/portal phase, as quantified by the neural network and a ratio between median intensities of the central and peripheral areas were analyzed by a feed forward back propagation multi-layer neural network which was trained to classify data into five distinct classes, corresponding to each type of liver lesion. RESULTS The neural network had 94.45% training accuracy (95% CI: 89.31%-97.21%) and 87.12% testing accuracy (95% CI: 86.83%-93.17%). The automatic classification process registered 93.2% sensitivity, 89.7% specificity, 94.42% positive predictive value and 87.57% negative predictive value. The artificial neural networks (ANN) incorrectly classified as hemangyomas three HCC cases and two hypervascular metastases, while in turn misclassifying four liver hemangyomas as HCC (one case) and hypervascular metastases (three cases). Comparatively, human interpretation of TICs showed 94.1% sensitivity, 90.7% specificity, 95.11% positive predictive value and 88.89% negative predictive value. The accuracy and specificity of the ANN diagnosis system was similar to that of human interpretation of the TICs (P = 0.225 and P = 0.451, respectively). Hepatocellular carcinoma cases showed contrast uptake during the arterial phase followed by wash-out in the portal and first seconds of the late phases. For the hypovascular metastases did not show significant contrast uptake during the arterial phase, which resulted in negative differences between the maximum intensities. We registered wash-out in the late phase for most of the hypervascular metastases. Liver hemangiomas had contrast uptake in the arterial phase without agent wash-out in the portal-late phases. The focal fatty changes did not show any differences from surrounding liver parenchyma, resulting in similar TIC patterns and extracted parameters. CONCLUSION Neural network analysis of contrast-enhanced ultrasonography - obtained TICs seems a promising field of development for future techniques, providing fast and reliable diagnostic aid for the clinician.

Expression of vascular endothelial growth factor and epidermal growth factor receptor in pancreatic ductal adenocarcinomas, neuroendocrine tumours and chronic pancreatitis.

Objective: Angiogenesis is a crucial event for pancreatic carcinogenesis, and it also plays an important role in chronic pancreatitis. The aim of our study was to evaluate the mRNA expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) in chronic inflammatory or malignant pancreatic pathology in order to elucidate the differences in expression patterns and potential clinical implications. Methods: Thirty-five patients who had undergone endoscopic ultrasonography followed by endoscipic ultrasound-guided fine needle aspiration (EUS-FNA) of focal pancreatic masses were included in the study. VEGF and EGFR mRNA expression levels in the samples collected by EUS-FNA were analyzed using quantitative real-time polymerase chain reaction (PCR). Results: VEGF expression was detected in all chronic pancreatitis and adenocarcinoma samples and in only 62.5% of pancreatic neuroendocrine tumors. EGFR expression was detected in only 40% of the chronic pancreatitis cases, 76.9% of adenocarcinomas and in 50% of pancreatic neuroendocrine tumors. Both VEGF and EGFR mRNA levels were significantly higher in pancreatic ductal adenocarcinoma than those in normal tissue. VEGF expression inversely correlated with pancreatic ductal adenocarcinoma size, while EGFR expression was related to local invasiveness of adenocarcinoma. Conclusion: Both VEGF and EGFR mRNA expression in EUS-FNA samples may be used as a diagnostic marker associated with invasiveness in patients with pancreatic adenocarcinoma.

Sa1000 Focal Liver Lesions Classification by Artificial Neural Networks and Support Vector Machines Employing Dynamic Imaging Data

RHH by pooling all available evidence in a systematic review and meta-analysis. Methods We conducted a comprehensive literature search using Ovid on MEDLINE (1946-2013), EMBASE (1988-2013), PubMed (1946-2013), Cochrane Library, and the Web of Science to identify studies on TIPS for RHH. Two reviewers independently screened article titles and abstracts for eligibility. Among information abstracted from each study was number of participants, outcomes of interest (mortality/survival, symptom response, HE and change in hepatic venous pressure gradient (HVPG)). Complete response was defined by resolution of HH without further need for thoracentesis, while a partial response was defined as improvement in symptoms and/or a decrease need for thoracentesis. New onset or worsening of baseline HE within 30 days of TIPS was considered a complication of the procedure. Data were pooled using a fixed-effects meta-analysis. Outcomes are expressed as proportions. Heterogeneity was assessed using the I2 and Cochrane Q test. Results Seven studies, involving 203 patients were included in the analyses. The mean age of the patients was 56.3 years, with 50.7% being male. The majority of patients were Child-Pugh Class C (56.9%), while 40.7% and 0.8% were Child-Pugh Class B and A, respectively. The mean follow up period was 11.9 ± 3.6 months. The mean preand post-TIPS HVPG was 20.14 mmHg (range: 17.4-26) and 7.37 mmHg (range: 5.7-10), respectively. Response to TIPS was complete in 55.8% (95% CI 44.7-66.9) and partial in 17.6% (95% CI 10.9-24.2). There was no response in 21.2% (95% CI 14.2-28.3) of patients. The incidence of post-TIPS HE was 11.7% (95% CI 6.3-17.2). The mortality within 30days of TIPS placement was 16.6% (95% CI 10.222.9), while the overall mortality was 49.1% (95% CI 38.8-59.5). The mean 1-year survival (reported by 2 studies) was 56%. Predictors of mortality included older age, severity of liver disease and non-response to TIPS. Conclusion TIPS is associated with symptomatic relief in approximately 75% of patients with RHH. Although TIPS increases the incidence of HE, response to treatment may be associated with improved survival. TIPS should be used cautiously in older patients with more severe underlying liver disease.