Scientific Program

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Scientific Program Day 1

Day 13 :

  • Hepatic Pathology

Session Introduction

Ripal T. Gandhi

University of South Florida College of Medicine, USA

Title: Targeted Intra-arterial Gemcitabine: Impact on Survival in Patients with Locally Advanced Pancreatic Cancer—A New Treatment Paradigm
Biography:

Dr. Gandhi graduated with honors from Northwestern University and Harvard University for undergraduate studies and received his medical degree from Northwestern Medical School.  He completed a surgical internship at Cornell University, and residency/fellowship at UCLA Medical Center. He is attending physician at Miami Cardiac & Vascular Institute and Miami Cancer Institute.  He is associate clinical professor at the USF School of Medicine and FIU Medical School. Dr. Gandhi was a research fellow at the NIH and also dedicated an year to research at Memorial Sloan-Kettering Cancer Center.  He is the co-author of the textbook Interventional Oncology.  He is a program director for the International Symposium on Endovascular Therapy (ISET) and Symposium on Clinical Interventional Oncology (CIO).

Abstract:

Introduction: Treatment of patients with locally advanced pancreatic cancer (LAPC) remain a clinical challenge. As intra-arterial (IA) chemotherapy has become a first-line treatment option for patients with hepatic tumors, targeting a similar approach to patients with LAPC is of interest. We have conducted two studies—a safety study (RR1) followed up by a registry study (RR2)—using a strategy of IA gemcitabine with local IA delivery catheter, RC-120, in this patient cohort. Here we update the clinical outcome of our patients with continuing follow up.
 
Methods: The initial RR1 study was a safety study of 20 patients that received dose escalated gemcitabine (Gemzar) ranging from 250-1000mg/m2 twice monthly. RR2 was a registry with 25 patients enrolled (2 patients rolled over from RR1) where patients received up to twice monthly gemcitabine at 1000mg/m2. In both studies, patients were to receive 4 monthly cycles with 2 IA therapies per cycle. Patients in both studies could be enrolled as long as they had locally advanced disease—with or without prior chemotherapy or chemoradiation. If they showed evidence of conversion to resectability, they went on to surgery.  As a routine, time to progression was not measured once they left the IA therapy, but the data for survival was collected on all patients.
 
Results:  43 patients have been treated with IA gemcitabine using RC-120 catheter between the 2 studies from May 2015 to Dec 2018.  The average age of patient enrolled was 69.9 years. Twenty-four of 43 patients had prior treatment before IA therapy: chemotherapy (n=11), chemoradiation (n=12), or prior surgery (n=1). The median gemcitabine dose was 1000mg/m2 and was administered to 33 of the 43-patient cohort. On average each patient received 4 IA therapy, ranging from 1-14. Thirteen of 43 patients completed the planned 4 cycles of IA therapy. For the patients that did not complete the 4 cycles of treatment the reason for early discontinuation was tumor progression (n=13), patient/physician preference (n=9), or severe adverse events (n=6). There is one patient still scheduled for ongoing IA treatments, and one patient had a reduction in tumor size, which led to resection of the pancreatic tumor. 
In the overall cohort 6 of 43 patients are still alive; the median overall survival for the overall cohort was 12.4 months. Of note patients with prior chemoradiation showed the best clinical response in terms of tumor response (CT and tumor markers) and survival across both studies - achieving median survival of 27.8 months with 4 of 12 patients still alive.
 
Conclusion: Localized intra-arterial delivery of gemcitabine using RC-120 catheter demonstrates encouraging results in stabilizing local disease. This benefit is especially pronounced in patients with prior induction therapy with chemoradiation. These early results have led to the initiation of a 300-patient randomized study, TIGeR-PaC (clinicaltrial.gov #NCT03257033), comparing IA 

Khaled Abou el ella

Menoufiya University, Egypt

Title: Liver biopsy is still needed in liver transplantation recipients; single center experience
Biography:

Professor Khaled Abou-El-Ella Professor of Hepatopancreatobilliary surgery (HPB), gastro-intestinal surgery and Liver transplantation Head of the surgical department at the National Liver Institute, Menoufiya University, Egypt Director of the Liver Transplantation Program in New Alex Medical Center, Alexandria, Egypt Consultant of gastrointestinal and liver specialized hospital, Alexandria, Egypt. Graduated from Faculty of Medicine Alexandria University in 1984 PHD Ain Shams University, Egypt 1997 Surgical and Research Fellowship in the University of Tennessee, Memphis Tennessee, 1994-1996

Abstract:

Background: 
Liver transplantation is a final treatment for decompensated liver disease. 
Aim: 
description of post-liver transplant histopathology. 
Methods: 
We enrolled 89 patients divided into two groups according to if underwent on demand liver biopsy (n =34; 38.2%) or not (n =55; 61.8%). Albumin-bilirubin (ALBI) score and Model for End-Stage Liver Disease (MELD) assessed the degree of liver dysfunction.
Results:
Patient underwent liver biopsy (LB) were 44.65±8.46 years old, mainly males (88.2%) with average MELD of 8.74±4.71. 
Most patients were positive pretransplant for HCV (91.2%) and 29.4% had hepatocellular carcinoma on top of hepatitis C. 
Patients underwent LB had worse liver dysfunction by ALBI score (-2.62±0.6 vs. -2.96±0.5; p =0.014) but comparable MELD.
The time till first biopsy was 19.88±11.22 (4-44) months. It was not different statistically with various histopathology (p >0.05). Histopathology of first biopsy was viral chronic hepatitis (50%), acute rejection (20.6%), steatohepatitis (11.8%), chronic rejection (5.9%), chronic hepatitis (5.9%), biliary obstruction (2.9%) and cytomegalovirus hepatitis (2.9%). 
 
 
Most patients were F1 (38.2%) and A1 (35.3%). The immunosuppressive drug regimen had no impact on the histopathology (p >0.05). 
Patients with hepatitis C pretransplant had in a descending manner the following histological diagnosis (p =0.001): viral chronic hepatitis 16(51.6%), acute rejection 7(22.6%), steatohepatitis 4(12.9%), chronic rejection 2 (6.5%), biliary obstruction 1(3.2%) and CMV hepatitis 1(3.2%). 
Some patients required on demand second (n=9) and third biopsied (n=5) that were the same as the first biopsy or completely different. 
Conclusion: 
liver biopsy is a useful tool for diagnosis of liver transplantation complications.
 

Weihua Gong

Zhejiang University, China

Title: Suppression of YAP/TAZ-Notch1-NICD axis by Bromodomain and Extraterminal Proteins inhibition impairs liver regeneration
Biography:

Weihua Gong is affiliated from Zhejiang University, China

Abstract:

Background: Biological mechanisms that control liver regeneration remain poorly defined. However, these mechanisms are remarkable issues in the clinic that affect management of hepatic loss caused by liver surgery, traumatic injury, chronic infection, or liver poisoning. Increasing evidence has shown that various growth factors, cytokines, and metabolic signaling pathways affect the liver regenerative process. Our aim is to study the effect of bromodomain and extraterminal (BET) protein inhibition on liver regeneration and its mechanism.
 
Methods: We studied the role of BET protein inhibitor, JQ1, in liver regeneration in a mouse model after 70% partial hepatectomy (PH). We evaluated yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) and Notch signaling pathways, which were affected by BET protein inhibitor in mouse hepatic tissues in vivo and AML12 cell lines in vitro. We evaluated the role of YAP/TAZ signaling pathway inhibition in liver regeneration in a mouse model after 70% PH. Moreover, we analyzed the relationship of YAP/TAZ and Notch signaling pathways via overexpression or RNA silencing of YAP in AML12 cells. Moreover, we used YAP overexpression mouse model to examine whether it can rescue liver regeneration damage caused by inhibition of BET proteins.
 
Results: In this study, we report that BET protein inhibitor JQ1 molecule impairs the early phase of liver regeneration in a mouse model after 70% PH. Mechanistically, YAP/TAZ and Notch1–NICD pathways were suppressed by BET protein inhibitor in mouse hepatic tissues in vivo and mouse AML12 cell lines in vitro. By using YAP inhibitor, we confirmed that liver regeneration was impaired by the inhibition of YAP/TAZ pathway in vivo. Furthermore, the study showed that YAP knockdown by shRNA in normal mouse hepatic cell line downregulated Notch1 signal transduction, whereas YAP overexpression promoted Notch1–NICD signals. Specific overexpression of YAP in mouse liver could rescue the effect of BET protein inhibition on liver regeneration injury.
 
Conclusion: These results revealed the crucial role of the YAP/TAZ–Notch1–NICD axis in liver regeneration. Therefore, BET protein inhibitors must be used in caution in the treatment of hepatic diseases because of its suppressive roles in liver regeneration.
 

Nafiseh Bahadori birgani

Shahid Beheshti University of Medical Sciences, Iran

Title: Nutritional recommendations for patients with non-alcoholic fatty liver diseases
Biography:

Nafiseh Bahadori birgani is affiliated from Shahid Beheshti University of Medical Sciences, Iran

Abstract:

Fatty liver is the most common liver disease worldwide. Hyperglycemia and hyperinsulinemia induce lipogenesis, thereby increasing the hepatic pool of fatty acids[1]. Nutritional consultations and lifestyle modification are important in the treatment of non-alcoholic fatty liver disease (NAFLD) [2]. The usual management of NAFLD includes lifestyle counseling to achieve a gradual weight reduction and an increase in physical activity. An intensive lifestyle intervention focused on diet, exercise and behavior modification with a goal of 7–10% weight reduction that leads to significant improvement in liver histology in patients with NASH [19]. Indeed, weight loss improves steatosis [20], reduces hepatic inflammation and hepatocellular injury [21], [22] and improves cardiovascular risk profile. [23]. Several changes in dietary intake have occurred in the past few years, including increased energy intake (24%), and increases in added sugars, flour and cereal products, fruit, added fats and total fat intake[42]. Fatty liver disease in humans is an insulin-resistant condition and the liver over-produces glucose and triglycerides due to impaired insulin action[45]. Fatty liver is an independent predictor of diabetes and cardiovascular disease[46]. There are three major sources for increased liver fat accumulation: excessive delivery of free fatty acids from lipolysis of superficial and visceral fat depots (60%), increased de novo hepatic lipogenesis (30%), and increased nutritional intake (10%)[47].