Radiosensitization of Hepatocellular Carcinoma through Targeting Radio-Associated MicroRNA

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. For patients who are resistant to monotherapy, multimodal therapy is a basic oncologic principle that incorporates surgery, radiotherapy (RT), and chemotherapy providing survival benefits for patients with most types of cancer. Although liver has low tolerance for radiation, high-precision RT for local HCC minimizes the likelihood of radiation-induced liver disease (RILD) in noncancerous liver tissue. RT have several therapeutic benefits, including the down-staging of tumors to make them resectable and repression of metastasis. The DNA damage response (DDR) is a cellular response to irradiation (IR), including DNA repair of injured cells and induction of programmed cell death, thereby resulting in maintenance of cell homeostasis. Molecules that block the activity of proteins in DDR pathways have been found to enhance radiotherapeutic effects. These molecules include antibodies, kinase inhibitors, siRNAs and miRNAs. MicroRNAs (miRNAs) are short non-coding regulatory RNAs binding to the 3′-untranslated regions (3′-UTR) of the messenger RNAs (mRNAs) of target genes, regulating their translation and expression of proteins. Thus, miRNAs and their target genes constitute complicated interactive networks, which interact with other molecules during carcinogenesis. Due to their promising roles in carcinogenesis, miRNAs were shown to be the potential factors that mediated radiosensitivity and optimized outcomes of the combination of systemic therapy and radiotherapy.

A Reappraisal of Chemotherapy-Induced Liver Injury in Colorectal Liver Metastases before the Era of Antiangiogenics

Background and Aims.Chemotherapy of colorectal liver metastases can induce hepatotoxicity in noncancerous liver. We describe these lesions and assess risk factors and impacts on postresection morbidity and mortality in naive patients to chemotherapy before the era of bevacizumab.Methods.Noncancerous liver tissue lesions were analysed according to tumour, chemotherapy, surgery, and patient characteristics.Results.Fifty patients aged 62 ± 9.3 years were included between 2003 and 2007. Thirty-three (66%) received chemotherapy, with Folfox (58%), Folfiri (21%), LV5FU2 (12%), or Xelox (9%) regimens. Hepatotoxicity consisted of 18 (36%) cases of severe sinusoidal dilatation (SD), 13 (26%) portal fibrosis, 7 (14%) perisinusoidal fibrosis (PSF), 6 (12%) nodular regenerative hyperplasia (NRH), 2 (4%) steatosis >30%, zero steatohepatitis, and 16 (32%) surgical hepatitis. PSF was more frequent after chemotherapy (21% versus 0%, ), especially LV5FU2 (). SD was associated with oxaliplatin (54.5% versus 23.5%, ) and low body mass index (). NRH was associated with oxaliplatin () and extensive resection (). No impact on mortality and morbidity was observed, apart postoperative elevation of bilirubin levels in case of PSF (), longer hospitalization in case of surgical hepatitis (), and greater blood loss in case of portal fibrosis ().Conclusions.Chemotherapy of colorectal liver metastases induces sinusoidal dilatation related to oxaliplatin and perisinusoidal fibrosis related to 5FU, without any impact on postoperative mortality.

Overexpression of Cyclooxygenase-2 in Noncancerous Liver Tissue Increases the Postoperative Recurrence of Hepatocellular Carcinoma in Patients with Hepatitis B Virus-Related Cirrhosis

BACKGROUND: Many previous studies have evaluated the histopathological features of tumours as risk factors for postoperative recurrence in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). However, there have been few large studies investigating the relationship between cyclooxygenase-2 (COX-2) expression in non-cancerous regions of the liver and postoperative recurrence in the remnant liver, especially in HBV-related HCC.OBJECTIVE: To evaluate the significance of COX-2 expression levels in noncancerous liver regions as a prognostic indicator of HCC in patients with HBV-related cirrhosis.METHODS: A total of 124 patients who underwent curative resection for HCC were reviewed retrospectively. Immunohistochemistry was used to evaluate the expression of COX-2 in noncancerous liver tissue. Clinicopathological variables were compared between patients with high COX-2 expression (n=58 [COX-2-positive group]) and patients with low COX-2 expression (n=66; [COX-2-negative group]). Univariate and multivariate analyses were performed to identify factors that affected disease recurrence.RESULTS: There was a significant correlation between COX-2 expression and alanine aminotransferase levels and vascular invasion. The recurrence-free survival rates in the COX-2-positive group were significantly lower than the rates in the COX-2-negative group. On multivariate analysis, the overexpression of COX-2 in noncancerous liver regions was found to be an unfavourable prognostic indicator for the recurrence of HCC.CONCLUSIONS: The results of the current study suggest that over-expression of COX-2 in noncancerous liver regions is an independent and significant indicator predictive of early recurrence of HCC in patients with HBV-related cirrhosis.