The role of Micro-RNAs in Hepatocellular Carcinoma: From Molecular Biology to Treatment

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer deaths. microRNAs (miRNAs) are evolutionary conserved small non-coding RNA that negatively regulate gene expression and protein translation. Recent evidences have shown that they are involved in many biological processes, from development and cell-cycle regulation to apoptosis. miRNAs can behave as tumor suppressor or promoter of oncogenesis depending on the cellular function of their targets. Moreover, they are frequently dysregulated in HCC. In this review we summarize the latest findings of miRNAs regulation in HCC and their role as potentially diagnostic and prognostic biomarkers for HCC. We highlight development of miRNAs as potential therapeutic targets for HCC

Early onset of hypertension and serum electrolyte changes as potential predictive factors of activity in advanced hcc patients treated with sorafenib: Results from a retrospective analysis of the HCC-AVR group

Hypertension (HTN) is frequently associated with the use of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway and appears to be a generalized effect of this class of agent. We investigated the phenomenon in 61 patients with advanced hepatocellular carcinoma (HCC) receiving sorafenib. Blood pressure and plasma electrolytes were measured on days 1 and 15 of the treatment. Patients with sorafenib-induced HTN had a better outcome than those without HTN (disease control rate: 63.4% vs. 17.2% (p=0.001); progression-free survival 6.0 months (95% CI 3.2-10.1) vs. 2.5 months (95% CI 1.9-2.6) (p<0.001) and overall survival 14.6 months (95% CI9.7-19.0) vs. 3.9 months (95% CI 3.1-8.7) (p=0.003). Sodium levels were generally higher on day 15 than at baseline (+2.38, p<0.0001) in the group of responders (+4.95, p <0.0001) compared to patients who progressed (PD) (+0.28, p=0.607). In contrast, potassium was lower on day 14 (-0.30, p=0.0008) in the responder group (-0.58, p=0.003) than in those with progressive disease (-0.06, p=0.500). The early onset of hypertension is associated with improved clinical outcome in HCC patients treated with sorafenib. Our data are suggestive of an activation of the renin-angiotensin system in patients with advanced disease who developed HTN during sorafenib treatment

Tracking the 2015 Gastrointestinal Cancers Symposium: bridging cancer biology to clinical gastrointestinal oncology

The 2015 Gastrointestinal Cancers Symposium (San Francisco, CA, USA; January 15–17) is the world-class conference co-sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, the American Gastroenterological Association Institute, and the Society of Surgical Oncology, in which the most innovative research results in digestive tract oncology are presented and discussed. In its twelfth edition, the meeting has provided new insights focusing on the underpinning biology and clinical management of gastrointestinal malignancies. More than 3,400 health care professionals gathered from all over the world to share their experiences on how to bridge the recent novelties in cancer biology with everyday medical practice. In this article, the authors report on the most significant advances, didactically moving on three different anatomic tracks: gastroesophageal malignancies, pancreatic and biliary cancers, and colorectal adenocarcinomas

Angiogenesis genotyping in the selection of first-line treatment with either sunitinib or pazopanib for advanced renal cell carcinoma

Recent data from the COMPARZ study seem to suggest a noninferiority of pazopanib confronted with sunitinib in PFS and OS. We previously reported how VEGF and VEGFR polymorphisms might have a predictive role in patients treated with first-line sunitinib. Aim of our study was to investigate whether tumour angiogenesis genotyping could influence clinical outcome in RCC patients treated with either sunitinib or pazopanib, in order to help clinicians select the appropriate treatment for each patient. Results: 19 patients were treated with pazopanib while 78 received sunitinib. VEGF A rs833061 resulted significant in PFS in sunitinib vs pazopanib patients (CC+CT > TT in sunitinib, TT > CC+CT in pazopanib; p CC in sunitinib, CC > GG+CG in pazopanib; p CC in sunitinib, CC > AA+AC in pazopanib; p < 0,0001). OS showed no statistically significant difference. Conclusions: In our analysis patients with opposite polymorphisms of rs833061, rs2010963, rs699947 of VEGF A seems to have a better PFS if treated with either sunitinib or pazopanib. Our data seem to suggest that biology could have a role choosing first line treatment for mRCC patients. Methods: A retrospective analysis on 97 histologic samples of mRCC patients was conducted for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs

Interplay Between SIRT-3, Metabolism and Its Tumor Suppressor Role in Hepatocellular Carcinoma

Sirtuins (SIRT), first described as nicotinamide adenine dinucleotide (NAD + )-dependent type III histone deacetylases, are produced by cells to support in the defense against chronic stress conditions such as metabolic syndromes, neurodegeneration, and cancer. SIRT-3 is one of the most studied members of the mitochondrial sirtuins family. In particular, its involvement in metabolic diseases and its dual role in cancer have been described. In the present review, based on the evidence of SIRT-3 involvement in metabolic dysfunctions, we aimed to provide an insight into the multifaceted role of SIRT-3 in many solid and hematological tumors with a particular focus on hepatocellular carcinoma (HCC). SIRT-3 regulatory effect and involvement in metabolism dysfunctions may have strong implications in HCC development and treatment. Research literature widely reports the relationship between metabolic disorders and HCC development. This evidence suggests a putative bridge role of SIRT-3 between metabolic diseases and HCC. However, further studies are necessary to demonstrate such interconnection

Metronomic capecitabine versus best supportive care as second-line treatment in hepatocellular carcinoma: A retrospective study

Preliminary studies suggest that capecitabine may be safe and effective in HCC patients. The aim of this study was to retrospectively evaluate the safety and efficacy of metronomic capecitabine as second-line treatment. This multicentric study retrospectively analyzed data of HCC patients unresponsive or intolerant to sorafenib treatment with metronomic capecitabine or best supportive care (BSC).Median progression free survival was 3.1 months in patients treated with capecitabine (95%CI: 2.7-3.5). Median overall survival was 12.0 months (95% CI: 10.7-15.8) in patients receiving capecitabine, while 9.0 months (95% CI: 6.5-13.9) in patients receiving BSC. The result of univariate unweighted Cox regression model shows a 46% reduction in death risk for patients on capecitabine (95%CI: 0.357-0.829; p=0.005) compared to patients receiving BSC alone. After weighting for potential confounders, death risk remained essentially unaltered (45%; 95%CI: 0.354-0.883; p = 0.013). Metronomic capecitabine seems a safe second-line treatment for HCC patients in terms of management of adverse events, showing a potential anti-tumour activity which needs further evaluation in phase III studies

VEGF and VEGFR polymorphisms affect clinical outcome in advanced renal cell carcinoma patients receiving first-line sunitinib

Background: Currently, sunitinib represents one of the therapeutic strongholds for renal cell carcinoma, but the criteria for treatment selection are lacking. We assessed the role of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) polymorphisms in the prediction of the clinical outcome in metastatic renal cell carcinoma (mRCC) patients.Methods:A total of 84 tumour samples from mRCC patients receiving first-line sunitinib were tested for VEGF and VEGFR single-nucleotide polymorphisms (SNPs). The SNP results were correlated with progression-free survival (PFS) and overall survival (OS).Results:Median PFS was 8.22 months, although whereas median OS was 32.13 months. The VEGF A rs833061 resulted significant in PFS (17 vs 4 months; P<0.0001) and OS (38 vs 10 months; P<0.0001). The VEGF A rs699947 was significant for PFS (18 vs 4 months; P=0.0001) and OS (37 vs 16 months; P<0.0001). The VEGF A rs2010963 was significant in PFS (18 vs 8 vs 2 months; P=0.0001) and OS (31 vs 36 vs 9 months; P=0.0045). The VEGR3 rs6877011 was significant in PFS (12 vs 4 months; P=0.0075) and OS (36 vs 17 months; P=0.0001). At multivariate analysis, rs833061, rs2010963 and rs68877011 were significant in PFS, and rs833061 and rs68877011 were independent factors in OS.Conclusions:In our analysis, patients with TT polymorphism of rs833061, CC polymorphism of rs699947, CC polymorphism of rs2010963 and CG polymorphism of rs6877011 seem to have a worse PFS and OS when receiving first-line sunitini

Phosphorylated AKT and MAPK expression in primary tumours and in corresponding metastases and clinical outcome in colorectal cancer patients receiving irinotecan-cetuximab

Clinical observations suggested that a non negligible proportion of patients, ranging from 40% to 70%, does not seem to benefit from the use of anti-EGFR targeted antibodies even in the absence of a mutation of the K- RAS gene. The EGFR pathway activation via the Ras-Raf-MAP-kinase and the protein-serine/threonine kinase AKT could determine resistance to anti-EGFR treatment.We tested the interaction between phosphorylated AKT and MAPK expression in colorectal tumours and corresponding metastases and global outcome in K-RAS wild type patients receiving irinotecan-cetuximab.Seventy-two patients with histologically proven metastatic colorectal cancer, treated with Irinotecan and Cetuximab based chemotherapy, were eligible for our analysis.In metastases pAKT correlated with RR (9% vs. 58%, p\u2009=\u20090.004), PFS (2.3 months vs. 9.2 months p\u2009&lt;\u20090.0001) and OS (6.1 months vs. 26.7 months p\u2009&lt;\u20090.0001) and pMAPK correlated with RR (10% vs. 47%, p\u2009=\u20090.002), PFS (2.3 months vs. 8.6 months p\u2009&lt;\u20090.0001) and OS (7.8 months vs. 26 months p\u2009=\u20090.0004). At multivariate analysis pAKT and pMAPK in metastases were able to independently predict PFS. pAKT in metastases independently correlated with RR as wellpAKT and pMAPK expression in metastases may modulate the activity of EGFR-targeted antibodies. We could speculate that in patients with pAKT and pMAPK metastases expression targeting these factors may be crucial