الفهرس 
Title pageOnly 14 pages are availabe for public view
 |  | from | 146 |  |  |
| | | from | 146 | | |
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common neoplasm worldwide and
the third most frequent cause of cancer-related death. HCV infection is a major etiological risk factor that predisposes to HCC in Egypt, taking into consideration that Egypt has the highest HCV prevalence in the world with a ratio of about 14.7% among Egyptians aged
15–59 years. The underlying cirrhotic liver disease in HCV infected HCC patients greatly impairs tumor related prognosis, conferring this neoplasm a unique situation, in which accurate prognostic prediction is a relevant and unmet need. A major challenge nowadays in clinical oncology is to develop sensitive and specific diagnostic and prognostic molecular biomarkers for tailored management of cancers including hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) arises most frequently in the setting of chronic liver inflammation and fibrosis, since HCC is usually diagnosed at an advanced stage closely associated with the development of cirrhotic decompensation at which the available treatment options are limited and ineffective. Current methods of HCC management and treatment are more tumor oriented including chemotherapy, radiotherapy, surgical methods such as liver resection and transplantation, transarterial chemoembolization (TACE) and ethanol injection in the tumor cells.
Transarterial chemoembolization is considered the standard treatment for intermediate-stage HCC in patients with preserved liver function. With advances in imaging and periodic surveillance of high-risk patients with chronic hepatitis, more patients are diagnosed with early-stage HCC, hence extending the role of TACE to become an efficient and safe treatment for resectable early-stage HCC with an overall survival rate similar to that of hepatic resection and subsequently could be used as an alternative treatment in selected patients with resectable early-stage HCC.
Identifying emerging genetic factors which are contributing in HCC pathogenesis is considered a revolution in research fields of genetics and oncology. Detection of early promising diagnostic and prognostic bio- and genetic markers and development of molecular targeted therapies for HCV related HCC is the hope of most researchers in the related fields.
Human cancer is associated with changes in micro-RNA (miRNA) expression. It was recently reported that the pattern of miRNA expression varies dramatically across tumor types and that miRNA profiles reflect the tumor behavior. Numerous studies investigated the potential clinical utility of miRNAs as a diagnostic, prognostic and therapeutic target in cancer. In HCC, several miRNAs were studied yet the available data on their predicting power in response to therapy are not that much, so it was noteworthy to study two potential miRNAs (miR-210 and miR-373) in that aspect.
The primary aim of the present study was to assess the circulating forms of miR-210, miR-373 in Egyptian patients with hepatocellular carcinoma whom underwent super selective transarterial chemoembolization (ssTACE). The study also evaluated the potential roles of the studied miRNAs as predictors of response to ssTACE and evaluate their discriminatory power in classification of patients into responders and non responders
to super selective trans arterial chemoembolization.
The current study was conducted on fifty three HCC patients on top of chronic HCV infection referred to the intervention radiology unit at department of radiodiagnosis and Intervention, Alexandria University Hospitals for ssTACE. HCC patients with portal vein thrombosis, biliary invasion or BCLC(C,D), as well as patients with hepatitis B viral infection, renal failure, heart failure, chest diseases, peripheral vascular disease and those with other types of malignancies were excluded from the study. Twenty healthy volunteers of matched age and gender were included in the study as a reference (control) group to calculate the relative quantitation of miR-210 and miR-373. Response to ssTACE in HCC patients was established based on mRECIST criteria.
Peripheral blood samples were obtained from HCC patients and reference group. Laboratory investigations included determination of complete blood picture, prothrombin time and INR calculation, selected biochemical parameters and alpha fetoprotein. Plasma expressions of miR-210 and miR-373 were analyzed by RQ-PCR. Calculations of the inflammatory score and ALBI grade were done for all cases. Patients were followed up for three months after completing ssTACE sessions to judge the response to ssTACE according to mRECIST criteria by CT scanning of the tumor at the end of the follow up period.
Results of the present study identified forty five responders and eight non responders based on mRECIST criteria of response. An up regulation of plasma miR-373 levels in non responders compared to responders was evident in this study, with no statistically significant difference noted in plasma level of miR-210 between both groups of patients. The study of the predictive power of miR-373 in relation to other confounding factors
(pre- ssTACE tumor volume, inflammatory score and ALBI grade) showed that miR-373 itself and inflammatory score were independent predictors of response for ssTACE in HCV infected HCC patients.
Comparative study of both inflammatory score and ALBI grade between responders and non responders showed that inflammatory score was significantly higher in responders compared to non responders, whereas ALBI grade was found to be significantly higher in non responders compared to responders.
Diagnostic test accuracy using ROC curve analysis of the studied pre- ssTACE tumor volume, inflammatory score, miR-373 and ALBI grade revealed diagnostic sensitivities of 100%, 87.5%, 75% and 87.5% respectively and specificities of 66.67%,77.78%, 84.44 and 73.33% respectively. The combined ROC curves
(serial approach) of pre-ssTACE tumor volume and miR-373 achieved an overall sensitivity of 75 % and a specificity and 93.33%.
from the current study the following was concluded:
Both miR-373 and inflammatory score could represent potential prognostic markers of response to ssTACE in HCV infected HCC patients.
Both miR-373, inflammatory score and ALBI grade could be used as molecular and biochemical discriminatory markers of response to ssTACE in HCV infected HCC patients.
MiR-373 can be used as a confirmatory molecular marker to patients that were primiraly diagnosed as non responders by pre -ssTACE tumor volume.
ALBI grade can be used as a simple, cheap and easy method to assess hepatic reserve in HCV infected HCC patients.
Taking all the above mentioned data into consideration, determination of the circulating miR-373 expression level in plasma of HCC patients will help in better selection of HCC patients who are best candidates for ssTACE favoring tailored clinical management of HCC patients.