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Suayib Yalcin,1 Sahin Lacin,2 Ahmed Omar Kaseb,3 Bora Peynircioğlu,4 Murat Cantasdemir,5 Barbaros Erhan Çil,6 Pervin Hurmuz,7 Ahmet Bülent Doğrul,8 Murat Fani Bozkurt,9 Hüseyin Abali,10 Okan Akhan,4 Halis Şimşek,11 Berksoy Sahin,12 Faruk N Aykan,13 İdris Yücel,14 Gürkan Tellioğlu,15 Fatih Selçukbiricik,2 Philip A Philip16 1Department of Medical Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey; 2Department of Medical Oncology, Koç University Faculty of Medicine, İstanbul, Turkey; 3Department of Gastrointestinal Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA; 4Department of Radiology, Hacettepe University Faculty of Medicine, Ankara, Turkey; 5Department of Radiology, Memorial Şişli Hospital, İstanbul, Turkey; 6Department of Radiology, Koç University Faculty of Medicine, İstanbul, Turkey; 7Department of Radiation Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey; 8Department of General Surgery, Hacettepe University Faculty of Medicine, Ankara, Turkey; 9Department of Nuclear Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey; 10Department of Medical Oncology, Bahrain Oncology Center, Muharraq, Bahrain; 11Department of Gastroenterology, Hacettepe University Faculty of Medicine, Ankara, Turkey; 12Department of Medical Oncology, Cukurova University Faculty of Medicine, Adana, Türkiye; 13Department of Medical Oncology, Istinye University Faculty of Medicine Bahçeşehir Liv Hospital, İstanbul, Turkey; 14Medicana International Hospital Samsun, Department of Medical Oncology, Samsun, Turkey; 15Department of General Surgery, Koç University Faculty of Medicine, İstanbul, Turkey; 16Department of Medicine, Division of Hematology-Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USACorrespondence: Sahin Lacin, Email sahin.lacin@hotmail.comAbstract: Hepatocellular carcinoma (HCC), the most prevalent liver tumor, is usually linked with chronic liver diseases, particularly cirrhosis. As per the 2020 statistics, this cancer ranks 6th in the list of most common cancers worldwide and is the third primary source of cancer-related deaths. Asia holds the record for the highest occurrence of HCC. HCC is found three times more frequently in men than in women. The primary risk factors for HCC include chronic viral infections, excessive alcohol intake, steatotic liver disease conditions, as well as genetic and family predispositions. Roughly 40– 50% of patients are identified in the late stages of the disease. Recently, there have been significant advancements in the treatment methods for advanced HCC. The selection of treatment for HCC hinges on the stage of the disease and the patient’s medical status. Factors such as pre-existing liver conditions, etiology, portal hypertension, and portal vein thrombosis need critical evaluation, monitoring, and appropriate treatment. Depending on the patient and the characteristics of the disease, liver resection, ablation, or transplantation may be deemed potentially curative. For inoperable lesions, arterially directed therapy might be an option, or systemic treatment might be deemed more suitable. In specific cases, the recommendation might extend to external beam radiation therapy. For all individuals, a comprehensive, multidisciplinary approach should be adopted when considering HCC treatment options. The main treatment strategies for advanced HCC patients are typically combination treatments such as immunotherapy and anti-VEGFR inhibitor, or a combination of immunotherapy and immunotherapy where appropriate, as a first-line treatment. Furthermore, some TKIs and immune checkpoint inhibitors may be used as single agents in cases where patients are not fit for the combination therapies. As second-line treatments, some treatment agents have been reported and can be considered.Keywords: hepatocellular carcinoma, screening, imaging, diagnosis, treatment, immunotherapy, tyrosine kinase inhibitors

Shadi Chamseddine,1,* Michael LaPelusa,2,* Lianchun Xiao,3 Yehia I Mohamed,1 Sunyoung S Lee,1 Zishuo Ian Hu,1 Rikita I Hatia,4 Manal Hassan,4 James C Yao,1 Dan G Duda,5 Saumil Datar,6 Hesham M Amin,7,8 Ahmed O Kaseb1 1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 5Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; 6Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA; 7Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 8MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA*These authors contributed equally to this workCorrespondence: Hesham M Amin, Department of Hematopathology, The University of Texas MD Anderson Cancer Center, MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Houston, TX, 77030, USA, Tel +1 713 794-1769, Fax +1 713 792-7273, Email hamin@mdanderson.org Ahmed O Kaseb, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA, Tel +1-713-792-2828, Fax +1 713-745-1163, Email akaseb@mdanderson.orgIntroduction: In this study, we explored the potential of plasma growth hormone (GH) as a prognostic biomarker in patients with advanced HCC treated with durvalumab plus tremelimumab (D+T).Methods: In this study, we included 16 patients with advanced HCC who received D+T at MD Anderson Cancer Center between 2022 and 2023 and had plasma GH measurements recorded before treatment. Plasma GH levels were measured from prospectively collected blood samples and were correlated with progression-free survival (PFS) and overall survival (OS). The cutoff for normal GH levels in women and men was defined as ≤ 3.7 μg/L and ≤ 0.9 μg/L, respectively. The Kaplan–Meier method was employed to compute the median OS and PFS, while the Log rank test was applied to compare the survival outcomes between the GH-high and GH-low groups.Results: Sixteen patients were included in this analysis, two female and fourteen male, with a median age of 65.5 years. At the time of the analysis, the 6-month OS rate was 100% among GH-low patients (6 patients) and 30% among GH-high patients (10 patients). OS was significantly longer in GH-low patients (not evaluable) compared to GH-high patients (3.94 months) (p = 0.030). PFS was also significantly longer in GH-low patients (not evaluable) compared to the GH-high patients (1.87 months) (p = 0.036).Conclusion: Plasma GH is a prognostic biomarker in patients with advanced HCC treated with D+T. Given the relatively small patient cohort size, this finding should be further validated in larger randomized clinical trials in advanced HCC patients.Keywords: hepatocellular carcinoma, growth hormone, durvalumab, tremelimumab, overall survival, progression-free survival

Ashokkumar Thirunavukkarasu,1 Mohammed Falji A Alanazi,2 Ahmad Homoud Al-Hazmi,1 Bashayer Farhan ALruwaili,1 Aseel Awad Alsaidan,1 Thamer Alshami M Alruwaili,3 Majed Abdulaziz M Algaed,4 Areej Kaseb Alsharari,4 Ragad Humaidi Alenazi,4 Amal Muteb Alshalan,5 Sultan Muteb Alshalan6 1Department of Family and Community Medicine, College of Medicine, Jouf University, Sakaka, Saudi Arabia; 2Department of Public Health, Hafr Al Batin Health Affairs, Hafr Al Batin, Saudi Arabia; 3Department of Pediatrics, College of Medicine, Jouf University, Sakaka, Saudi Arabia; 4College of Medicine, Jouf University, Sakaka, Saudi Arabia; 5Department of Medicine, King Abdulaziz Specialist Hospital, Sakaka, Saudi Arabia; 6Medical Department, North Medical Tower hospital, Arar, Saudi ArabiaCorrespondence: Ashokkumar Thirunavukkarasu, Department of Family and Community Medicine, College of Medicine, Jouf University, Sakaka, 72388, Saudi Arabia, Tel +966-599739619, Email ashokkumar@ju.edu.saBackground: Consumer perception of and satisfaction with vaccination services is a critical and commonly used indicator for evaluating the quality of services provided by concerned authorities. The present survey assessed maternal perceptions, hesitancy, satisfaction, and factors associated with childhood immunization services provided at the primary health centers (PHCs) of eastern Saudi Arabia.Methods: The current analytical cross-sectional study included mothers of childhood vaccine beneficiaries attending PHCs in Hafr Al-Batin. We collected data related to mothers’ perceptions, hesitancy, and satisfaction using a validated Arabic version of the data collection tool. Factors associated with low and high satisfaction with the immunization services were evaluated using logistic regression analysis. We performed Spearman correlation test to identify the correlation between the perception and satisfaction scores.Results: Of the 675 participants, 87.4% were satisfied with the immunization services provided at the PHCs. The participants’ satisfaction was significantly associated with the immunized child’s age group (adjusted odds ratio [AOR] = 1.89, 95% CI = 1.39– 2.89, p = 0.037) and occupation status (AOR = 1.42, 95% CI = 1.17– 1.74, p = 0.024). Vaccine hesitancy was significantly associated with the mother’s age group (AOR = 1.89, 95% CI of AR = 1.35– 3.39, P = 0.003) and number of children (AOR = 1.42, 95% CI of AR = 1.17– 1.74, P = 0.024), Additionally, we found a significant positive correlation (Spearman’s rho = 0.207, p < 0.001) between perception and satisfaction scores.Conclusion: We recommend targeted health education programs for mothers to improve their perceptions and the importance of all recommended childhood vaccines. Additionally, we suggest continuing maternal satisfaction assessments to enhance and maintain the quality of vaccination services.Keywords: childhood vaccines, adverse effect, satisfaction, hesitancy, perception, Saudi Arabia

Ashraf Omar,1 Ahmed Kaseb,2 Tamer Elbaz,1 Mohamed El-Kassas,3 Amr El Fouly,3 Abdel Fatah Hanno,4 Ahmed El Dorry,5 Ahmed Hosni,6 Amr Helmy,7 Amr S Saad,8 Ashwaq Alolayan,9 Basem Elsayed Eysa,10 Emad Hamada,11 Hamdy Azim,11 Hany Khattab,12 Hesham Elghazaly,8 Hesham Tawfik,13 Hisham Ayoub,14 Hussein Khaled,11 Ibtessam Saadeldin,11 Imam Waked,15 Eman MF Barakat,16 Mahmoud El Meteini,17 Mohamed Hamed Shaaban,6 Mohamed EzzElarab,10 Mohamed Fathy,17 Mohamed Shaker,5 Mohamed Sobhi,5 Mohamed Kamal Shaker,16 Mohamed ElGharib,5 Mohammed Abdullah,11 Mohesn Mokhtar,11 Mostafa Elshazli,18 Omar Mohamed Khaleil Heikal,14 Osama Hetta,5 Reda Mahmoud ElWakil,16 Sameh Abdel Wahab,5 Samir Shehata Eid,19 Yousri Rostom20 On behalf of the Egyptian Liver Cancer Committee Study Group1Department of Gastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt; 2Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Endemic Medicine, Faculty of Medicine, Helwan University, Cairo, Egypt; 4Department of Gastroenterology, Faculty of Medicine, Alexandria University, Alexandria, Egypt; 5Department of Interventional Radiology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 6Department of Interventional Radiology, Faculty of Medicine, Cairo University, Cairo, Egypt; 7Department of Surgery, National Liver Institute Menoufia University, Menoufia, Egypt; 8Department of Oncology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 9Department of Oncology, National Guard Hospital, Riyadh, Saudi Arabia; 10Department of Gastroenterology, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt; 11Department of Oncology, Faculty of Medicine, Cairo University, Cairo, Egypt; 12Department of Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt; 13Department of Oncology, Faculty of Medicine, Tanta University, Tanta Egypt; 14Department of Gastroenterology, Military Medical Academy, Cairo, Egypt; 15Department of Gastroenterology, Menoufia Liver Institute, Menoufia, Egypt; 16Department of Gastroenterology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 17Department of Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 18Department of Surgery, Faculty of Medicine, Cairo University, Cairo, Egypt; 19Department of Oncology, Faculty of Medicine, Assiut University, Assiut, Egypt; 20Department of Oncology, Faculty of Medicine, Alexandria University, Alexandria, EgyptCorrespondence: Ashraf Omar, Department of Gastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt, Email abdelazizashraf@hotmail.comAbstract: Globally, hepatocellular carcinoma (HCC) is the fourth most common cause of death from cancer. The prevalence of this pathology, which has been on the rise in the last 30 years, has been predicted to continue increasing. HCC is the most common cause of cancer-related morbidity and mortality in Egypt and is also the most common cancer in males. Chronic liver diseases, including chronic hepatitis C, which is a primary health concern in Egypt, are considered major risk factors for HCC. However, HCC surveillance is recommended for patients with chronic hepatitis B virus (HBV) and liver cirrhosis; those above 40 with HBV but without cirrhosis; individuals with hepatitis D co-infection or a family history of HCC; and Nonalcoholic fatty liver disease (NAFLD) patients exhibiting significant fibrosis or cirrhosis. Several international guidelines aid physicians in the management of HCC. However, the availability and cost of diagnostic modalities and treatment options vary from one country to another. Therefore, the current guidelines aim to standardize the management of HCC in Egypt. The recommendations presented in this report represent the current management strategy at HCC treatment centers in Egypt. Recommendations were developed by an expert panel consisting of hepatologists, oncologists, gastroenterologists, surgeons, pathologists, and radiologists working under the umbrella of the Egyptian Society of Liver Cancer. The recommendations, which are based on the currently available local diagnostic aids and treatments in the country, include recommendations for future prospects.Keywords: hepatocellular carcinoma, clinical recommendations, Egyptian society of liver cancer, hepatitis c virus, Egypt, guidelines

Ahmed O Kaseb,1 Yinghui Guan,2,&ast; Betul Gok Yavuz,1,&ast; Alexander R Abbas,2 Shan Lu,2 Elshad Hasanov,3 Han Chong Toh,4 Wendy Verret,5 Yulei Wang2 1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Oncology Biomarker Development, Genentech Inc, South San Francisco, CA, USA; 3Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore; 5Product Development, Genentech Inc, South San Francisco, CA, USA&ast;These authors contributed equally to this workCorrespondence: Yulei Wang, Department of Oncology Biomarker Development, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA, Tel +1 650 255 9698, Email wang.yulei@gene.com Ahmed O Kaseb, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 426, Houston, TX, 77030, USA, Tel +1 713 792 2828, Email akaseb@mdanderson.orgPurpose: Child-Turcotte-Pugh class A (CTP-A) in unresectable hepatocellular carcinoma (HCC) is the standard criterion for active therapy and clinical trial enrollment. We hypothesized that insulin-like growth factor-1 (IGF-1) derived scores may provide improved survival prediction over CTP classification. This study aimed to evaluate the potential prognostic and predictive effects of IGF-1 derived scores in the phase III IMbrave150 study.Patients and Methods: Baseline and on-treatment serum IGF-1 levels from 371 patients were subjected to central analysis. Patients’ IGF-1 score (1/2/3) and IGF-CTP score (A/B/C) were determined based on pre-specified cutoffs. Outcomes were analyzed by baseline and by on-treatment changes of the IGF-1 and IGF-CTP scores within and between the two treatment arms. The interaction between these scores and outcomes was assessed using univariate and multivariate analyses.Results: Baseline IGF-CTP score (A vs B/C) showed prognostic significance for OS in both the atezolizumab-bevacizumab (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.20– 0.56; P< 0.001) and sorafenib (HR, 0.32; 95% CI, 0.16– 0.65; P=0.002) arms. Baseline IGF-1 score (1 vs 2/3) also showed prognostic significance for OS in both the atezolizumab-bevacizumab (HR, 0.33; 95% CI, 0.20– 0.55; P< 0.001) and sorafenib (HR, 0.48; 95% CI, 0.26– 0.89; P=0.02) arms. HRs for PFS were consistent with those for OS. No significant predictive effects were observed for either score between the two arms. Kinetic analysis revealed that patients with increased IGF-1 score (1-> 2/3) at 3 weeks post treatment had shorter OS than patients with stable IGF-1 score of 1 in both the atezolizumab-bevacizumab (HR, 3.70; 95% CI, 1.56– 8.77; P=0.003) and sorafenib (HR, 5.83; 95% CI, 1.88– 18.12; P=0.0023) arms.Conclusion: Baseline and kinetic change of IGF-CTP and IGF-1 scores are independent prognostic factors for patients with unresectable HCC treated with atezolizumab-bevacizumab or sorafenib. These novel scores may provide improved patient stratification in future HCC clinical trials. IMbrave150 ClincialTrials.gov number, NCT03434379.Keywords: IGF-CTP score, prognostic biomarker, immunotherapy, HCC

Abedul Haque,1 Vishal Sahu,1 Jamie Lynne Lombardo,2 Lianchun Xiao,3 Bhawana George,1 Robert A Wolff,4 Jeffrey S Morris,3 Asif Rashid,2 John J Kopchick,5,6 Ahmed O Kaseb,4 Hesham M Amin1,7 1Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 5Edison Biotechnology Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA; 6Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA; 7MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USACorrespondence: Hesham M Amin, Department of Hematopathology, Unit 072, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA, Tel +1 713 794-1769, Fax +1 713 792-7273, Email hamin@mdanderson.org Ahmed O Kaseb, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA, Tel +1 713 792-2828, Fax +1 713 745-1163, Email akaseb@mdanderson.orgIntroduction: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancers. It is an aggressive neoplasm with dismal outcome because most of the patients present with an advanced-stage disease, which precludes curative surgical options. Therefore, these patients require systemic therapies that typically induce small improvements in overall survival. Hence, it is crucial to identify new and promising therapeutic targets for HCC to improve the current outcome. The liver is a key organ in the signaling cascade triggered by the growth hormone receptor (GHR). Previous studies have shown that GHR signaling stimulates the proliferation and regeneration of liver cells and tissues; however, a definitive role of GHR signaling in HCC pathogenesis has not been identified.Methods: In this study, we used a direct and specific approach to analyze the role of GHR in HCC development. This approach encompasses mice with global (Ghr−/−) or liver-specific (LiGhr−/−) disruption of GHR expression, and the injection of diethylnitrosamine (DEN) to develop HCC in these mice.Results: Our data show that DEN induced HCC in a substantial majority of the Ghr+/+ (93.5%) and Ghr+/- (87.1%) mice but not in the Ghr−/− (5.6%) mice (P < 0.0001). Although 57.7% of LiGhr−/− mice developed HCC after injection of DEN, these mice had significantly fewer tumors than LiGhr+/+ (P < 0.001), which implies that the expression of GHR in the liver cells might increase tumor burden. Notably, the pathologic, histologic, and biochemical characteristics of DEN-induced HCC in mice resembled to a great extent human HCC, despite the fact that etiologically this model does not mimic this cancer in humans. Our data also show that the effects of DEN on mice livers were primarily related to its carcinogenic effects and ability to induce HCC, with minimal effects related to toxic effects.Conclusion: Collectively, our data support an important role of GHR in HCC development, and suggest that exploiting GHR signaling may represent a promising approach to treat HCC.Graphical Abstract: Keywords: hepatocellular carcinoma, growth hormone receptor, Ghr knockout mouse, diethylnitrosamine

Muhammad O Awiwi,1 Khaled M Elsayes,1 Yehia I Mohamed,2 Lina Altameemi,2 Migena Gjoni,3 Omayr Muhammad Irshad,4 Ahmed Sayed Ahmed,5 Ahmad O Kaseb,2 Usama Salem1 1Department of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Internal Medicine, The of Istanbul-Cerrahpasa Hospital, Istanbul, Turkey; 4John Sealy School of Medicine, Galveston, TX, USA; 5Department of Gastroenterology, The University of Texas MD Anderson Cancer Center, Houston, TX, USACorrespondence: Khaled M Elsayes, 1515 Holcombe Blvd, Houston, TX, 77030, USA, Tel +1 877 632-6789, Fax +1 713 794-4535, Email KMElsayes@mdanderson.orgPurpose: To identify prognostic clinical and radiologic features in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab.Patients and Methods: Clinical and imaging records of patients with unresectable HCC were retrospectively reviewed, and baseline features were recorded. Patients’ records and imaging studies were used to determine the patients’ overall survival (OS) and progression-free survival (PFS). Univariate and multivariate analyses were performed to determine prognostic features. Subanalyses of treatment-naïve patients (who never received local or systemic therapy) and previously treated patients were also performed.Results: Fifty-five patients were included in the final analysis, 23 (41.8%) of whom were treatment naïve. The median PFS and OS for the entire cohort were 3.0 months and 7.9 months. The 3-, 6- and 12-month OS rates were 85.5%, 79.8% and 45.7%, respectively. The 3-, 6- and 12-month PFS rates were 50.1%, 41.2% and 20.1%, respectively. On multivariate analysis, independent prognostic features for poor PFS of the entire cohort were pleural effusions (p = 0.047, HR: 6.3; CI: 1.03– 38.90) and hepatic vein tumor thrombus (p = 0.005; HR: 23.37; CI: 2.63– 207.67); independent prognostic features for poor OS were ascites (p = 0.008; HR: 37.37; CI: 2.53– 467.64), pleural effusion (p = 0.003; HR: 110.17; CI: 5.00– 2426.54), and low (< 40HU) pre-contrast attenuation on CT images (p = 0.007; HR: 0.09; CI: 0.02– 0.53). On subanalysis of treatment-naïve patients, the median OS and PFS were 7.4 months and 2.8 months, respectively. The 3-, 6- and 12-month PFS rates were 43.5%, 38.6% and 24.8%, respectively. Pleural effusion was the only independent poor prognostic feature (p = 0.036; HR: 206.34; CI: 1.41– 30,167.58).Conclusion: Independent prognostic features for survival outcomes include the presence of ascites, pleural effusions, hepatic vein tumor thrombus, and HCC with low attenuation (< 40 HU) on unenhanced CT images. Although several biochemical variables were significant on univariate analysis, none were independent predictors of OS or PFS.Keywords: radiographic, radiology, RECIST, survival, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio

Ahmed Omar Kaseb,1 S Cheenu Kappadath,2 Sunyoung S Lee,1 Kanwal Pratap Raghav,1 Yehia I Mohamed,1 Lianchun Xiao,3 Jeffrey S Morris,4 Chimela Ohaji,1 Rony Avritscher,5 Bruno C Odisio,5 Joshua Kuban,5 Mohamed E Abdelsalam,5 Beth Chasen,6 Khaled M Elsayes,7 Mohamed Elbanan,7 Robert A Wolff,1 James C Yao,1 Armeen Mahvash2 1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 5Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 6Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Department of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USACorrespondence: Ahmed Omar Kaseb Email akaseb@mdanderson.orgPurpose: The most common cause of death in advanced/metastatic hepatocellular carcinoma (HCC) is liver failure due to tumor progression. While retrospective studies and meta-analyses of systemic therapy combined with liver-directed therapy have been performed, prospective studies of safety/efficacy of antiangiogenesis followed by intra-arterial therapies are lacking. We tested our hypothesis that sorafenib followed by yttrium 90 glass microspheres (90Y GMs) is safe and that survival outcomes may improve by controlling hepatic tumors.Methods: We enrolled 38 Child–Pugh A patients with advanced/metastatic HCC. In sum, 34 received sorafenib, followed after 4 weeks by 90Y GMs. Analysis of safety and survival outcomes was performed to assess adverse events, median progression-free survival, and overall survival.Results: A total of 34 patients were evaluable: 14 (41.2%) with chronic hepatitis, nine (26.5%) with vascular invasion, and eleven (32.4%) with extrahepatic diseases. Safety analysis revealed that the combination therapy was well tolerated. Grade III–IV adverse events comprised fatigue (n=3), diarrhea (n=2), nausea (n=1), vomiting (n=2), hypertension (n=4), thrombocytopenia (n=1), hyperbilirubinemia (n=1), proteinuria (n=1), hyponatremia (n=1), and elevated alanine or aspartate aminotransferase (n=5). Median progression-free and overall survival were 10.4 months (95% CI 5.8– 14.4) and 13.2 months (95% CI 7.9– 18.9), respectively. Twelve patients (35.3%) achieved partial responses and 16 (47.0%) stable disease. Median duration of sorafenib was 20 (3– 90) weeks, and average dose was 622 (466– 800) mg daily. Dosimetry showed similar mean doses between planned and delivered calculations to normal liver and tumor:normal liver uptake ratio, with no significant correlation with adverse events at 3 and 6 months post-90Y treatment.Conclusion: This is the first prospective study to evaluate sorafenib followed by 90Y in patients with advanced HCC. The study validated our hypothesis of safety with encouraging efficacy signals of the sequencing treatment, and provides proof of concept for future combination modalities for patients with advanced or metastatic HCC.Clinical Trial Registration Number: NCT01900002.Keywords: HCC, sorafenib, yttrium 90, BCLC, hepatocellular carcinoma

Betul Gok Yavuz,1 Elshad Hasanov,2 Sunyoung S Lee,1 Yehia I Mohamed,1 Michael A Curran,3 Eugene J Koay,4 Vittorio Cristini,5,6 Ahmed O Kaseb1 1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Department of Gastrointestinal Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 5Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX, USA; 6Department of Imaging Physics, University of Texas MD Anderson Cancer Center, Houston, TX, USACorrespondence: Ahmed O Kaseb Email akaseb@mdanderson.orgAbstract: Hepatocellular carcinoma (HCC) is the most common liver cancer and one of the leading causes of cancer-related deaths in the world. Multiple immunotherapeutic approaches have been investigated to date, and immunotherapy has become the new standard of care therapy in HCC. However, the current role of immunotherapy in HCC remains non-curative. Given this context, a high priority for oncology is understanding the biomarkers that predict clinical response to immunotherapy, have the potential to improve patient selection to maximize the clinical benefit, and spare unnecessary toxicity. In this review, we summarize the key predictive and prognostic biomarkers investigated in immunotherapy clinical trials in HCC and the emerging biomarkers to serve as a roadmap for future clinical trials. Biomarkers from tumoral tissues including PDL-1 expression, tissue infiltrating lymphocytes, tumor mutational burden (TMB) and specific immune signatures, and from peripheral blood including neutrophil-to-lymphocytes ratio, platelet-to-lymphocytes ratio, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and specific cytokines, along with gut microbiota are among the studied biomarkers to date in the HCC era. More integrative approaches, including mathematical biomarkers to predict immunotherapy outcomes, are yet to be studied in HCC.Keywords: hepatocellular carcinoma, immunotherapy, biomarker

Brian De,1,* Sweet Ping Ng,1,2,* Amy Y Liu,1 Santiago Avila,1 Randa Tao,3 Emma B Holliday,1 Zachary Brownlee,4 Ahmed Kaseb,5 Sunyoung Lee,3 Kanwal Raghav,5 Jean-Nicolas Vauthey,6 Bruce D Minsky,1 Joseph M Herman,1 Prajnan Das,1 Grace L Smith,1 Cullen M Taniguchi,1 Sunil Krishnan,7 Christopher H Crane,8 Clemens Grassberger,9 Theodore S Hong,9 Steven H Lin,1 Albert C Koong,1 Radhe Mohan,1 Eugene J Koay1 1Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Radiation Oncology, Austin Health, Melbourne, Victoria, Australia; 3Department of Radiation Oncology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA; 4Department of Radiation Oncology, Tufts Medical Center, Boston, MA, USA; 5Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 6Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Department of Radiation Oncology, Mayo Clinic Jacksonville, Jacksonville, FL, USA; 8Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 9Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Eugene J KoayMD Anderson Cancer Center, Department of Radiation Oncology, 1400 Pressler St. Unit 1422, Houston, TX, 77030, USATel + 1 713-563-2381Fax +1 713-563-2331Email EKoay@mdanderson.orgBackground: The immune system plays a crucial role in cancer surveillance. Previous studies have shown that lymphopenia associated with radiotherapy (RT) portends a poor prognosis. We sought to differentiate the effects of proton and photon RT on changes in absolute lymphocyte count (ALC) for patients with hepatocellular carcinoma (HCC).Patients and Methods: Patients with HCC treated with definitive RT from 2006 to 2016 were studied. Serial ALCs were graded according to CTCAE v4.0. Overall survival (OS), disease-free survival, and distant metastasis-free survival were analyzed using the Kaplan–Meier method. Univariable and multivariable Cox-proportional hazards analyses were used to identify predictors of OS. A cohort analysis matched for treatment volume was performed to investigate differences in ALC dynamics between photon and proton therapy.Results: Of 143 patients identified, the median age was 66 (range, 19– 90) years. The treatment modality was photon in 103 (72%) and proton in 40 (28%). Median follow-up was 17 months (95% confidence interval, 13– 25 months). The median time to ALC nadir after initiation of RT was 17 days with a median relative decrease of 67%. Those who received proton RT had a higher median ALC nadir (0.41 vs 0.32 k/μL, p=0.002) and longer median OS (33 vs 13 months, p=0.002) than those who received photon RT. Matched cohort analyses revealed a larger low-dose liver volume in the photon group, which correlated with lower ALC. On multivariable Cox analysis, Grade 3 or higher lymphopenia prior to or after RT, portal venous tumor thrombus, larger planning target volumes, Child-Pugh (CP) Class B, and increased CP score after RT were associated with a higher risk of death, whereas the use of proton therapy was associated with lower risk.Conclusion: Grade 3 or higher lymphopenia may be associated with poorer outcomes in patients receiving RT for HCC. Protons may mitigate lymphopenia compared with photons, potentially due to reduced dose exposure of sites of lymphopoiesis.Keywords: lymphocyte count, circulating lymphocytes, splenic dose, liver dose, overall survival

Ajalaya Teyateeti,1,2 Armeen Mahvash,3 James P Long,4 Mohamed E Abdelsalam,3 Rony Avritscher,3 Beth Chasen,1 Ahmed O Kaseb,5 Joshua D Kuban,3 Ravi Murthy,3 Bruno C Odisio,3 Achiraya Teyateeti,6 Homer A Macapinlac,1 S Cheenu Kappadath7 1Department of Nuclear Medicine, Division of Diagnostic Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Division of Nuclear Medicine, Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; 3Department of Interventional Radiology, Division of Diagnostic Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 5Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 6Division of Radiation Oncology, Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; 7Department of Imaging Physics, Division of Diagnostic Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USACorrespondence: S Cheenu KappadathDepartment of Imaging Physics, Division of Diagnostic Imaging, University of Texas MD Anderson Cancer Center, 1155 Pressler Street — Unit 1352, Houston, TX 77030, USATel +1 713 745 2835Email skappadath@mdanderson.orgPurpose: To assess the overall survival (OS) and progression-free survival (PFS) of unresectable hepatocellular carcinoma (HCC) patients undergoing yttrium-90 glass–microsphere transarterial radioembolization (TARE) with and without concurrent sorafenib.Methods: OS and PFS were analyzed in 55 patients with an intrahepatic tumor (IHT) ≤ 50% without advanced or aggressive disease features (ADFs), which was referred to presence of infiltrative/ill-defined HCC, macrovascular invasion, or extrahepatic disease treated with only TARE (TARE_alone) and in 74 patients with IHT ≤ 50% with ADFs or IHT > 50% treated with TARE and sorafenib (TARE_sorafenib). Prognostic factors for OS and PFS were identified using univariate and multivariate analyses.Results: Median OS and PFS of TARE_alone patients were 21.6 (95% CI 6.1– 37.1) and 9.1(95% CI 5.2– 13.0) months, respectively, and for TARE_sorafenib patients 12.4 (95% CI 9.1– 15.6) and 5.1 (95% CI 2.6– 7.5) months, respectively. Better OS was associated with serum AFP < 400 (HR 0.27, p=0.02) in TARE_alone, and IHT ≤ 50% (HR 0.39, p=0.004) and AFP < 400 (HR 0.5, p=0.027) in TARE_sorafenib. Unilobar involvement (HR 0.43, p=0.029) and AFP < 400 ng/mL (HR 0.52, p=0.015) correlated with better PFS in TARE_alone and TARE_sorafenib, respectively. Adverse events (AEs) were more frequent in TARE_sorafenib than TARE_alone (92.4 vs 80.3%), but only 9.3% were grade 3 or higher AEs.Conclusion: TARE_alone provided the most prominent survival benefit in IHT ≤ 50%–without ADF patients who had unilobar HCC and serum AFP < 400 ng/mL. TARE and sorafenib yielded the best outcomes in patients with IHT ≤ 50% and serum AFP < 400 ng/mL, with some additional grade 1– 2 AEs compared to TARE only.Keywords: 90Y, selective internal radiation therapy, TheraSphere, prognostic factors, adverse events

Sahin Lacin,1 Suayib Yalcin,2 Yusuf Karakas,2 Manal M Hassan,3 Hesham Amin,4 Yehia Ibrahim Mohamed,5 Asif Rashid,6 Jeffrey S Morris,7 Lianchun Xiao,8 Aliya Qayyum,9 Ahmed O Kaseb5 1Yeditepe University, Faculty of Medicine, Department of Medical Oncology, İstanbul, Turkey; 2Hacettepe University, Hacettepe Cancer Institute, Department of Medical Oncology, Ankara, Turkey; 3University of Texas, MD Anderson Cancer Center, Department of Epidemiology, Division of Cancer Prevention and Population Sciences, Houston, Texas, USA; 4University of Texas, MD Anderson Cancer Center, Department of Hematopathology, Division of Pathology and Laboratory Medicine, Houston, Texas, USA; 5University of Texas, MD Anderson Cancer Center, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, Houston, Texas, USA; 6University of Texas, MD Anderson Cancer Center, Department of Pathology, Division of Pathology and Laboratory Medicine, Houston, Texas, USA; 7Department of Biostatistics, Epidemiology and Informatics Center for Clinical Epidemiology and Biostatistics University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA; 8University of Texas, MD Anderson Cancer Center, Department of Biostatistics, Division of Basic Sciences, Houston, Texas, USA; 9University of Texas, MD Anderson Cancer Center, Department of Diagnostic Radiology, Division of Diagnostic Imaging, Houston, Texas, USACorrespondence: Suayib YalcinHacettepe University Cancer Institute, Sihhiye 06100, Ankara, TurkeyTel +90 312 309 29 04Fax +90 312 309 29 05Email suayibyalcin@gmail.comBackground: The Child–Turcotte–Pugh score (CTP) is the most commonly used tool to assess hepatic reserve and predict survival in hepatocellular cancer (HCC). The CTP stratification accuracy has been questioned and attempts have been made to improve the objectivity of the system. Serum insulin-like growth factor-1 (IGF-1)-CTP has been proposed to improve CTP prognostic accuracy. We aimed to validate the IGF-CTP score in our patient population.Patients and Methods: A total of 84 diagnosed HCC patients were enrolled prospectively. IGF-CTP scores in addition to CTP scores were calculated. C-index was used to compare the prognostic significance of the two scoring systems and overall survival (OS).Results: Cirrhosis was present in 48 (57.1%) patients, 35 (41.7%) patients were non-cirrhotic, 36 (42.8%) patients were hepatitis B (HBV) positive, and 8 (9.5%) patients were hepatitis C (HCV) positive. Serum IGF-1 levels were significantly lower in cirrhotic compared with non-cirrhotic patients (p=0.04). There was a significant difference in OS rates of patients with serum IGF-1 level < 50 ng/mL and patients with serum IGF-1 levels ≥ 50 ng/mL (p=0.02); the OS rates were 6.5 and 14.8 months, respectively (p=0.02). The median OS of all patients was 7.38 months (95% CI: 5.89– 13.79). The estimated C-index for CTP and IGF-CTP scores was 0.605 (95% CI: 0.538, 0.672) and 0.599 (95% CI: 0.543, 0.655), respectively. The U statistics indicated that the C-indices between two scoring systems are not statistically different (P= 0.91).Conclusion: This study evaluated IGF-1 levels and the IGF-CTP classification in a predominantly HBV (+) cohort of HCC patients with 41.7% non-cirrhotic. Although the prognostic value was similar, among patients with CTP-A, class those reclassified as IGF-CTP B had shorter OS than those with IGF-CTP score A. Thus, further validations of IGF-CTP score in similar populations may add additional value as a stratification tool to predict HCC outcome.Keywords: Child–Turcotte–Pugh, cirrhosis, hepatocellular carcinoma, insulin-like growth factor-1

Ahmed W Moawad,1 Janio Szklaruk,1 Chandana Lall,2 Katherine J Blair,1 Ahmed O Kaseb,3 Amita Kamath,4 Scott A Rohren,5 Khaled M Elsayes1 1Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA; 2Department of Radiology, University of Florida College of Medicine, Jacksonville, FL, USA; 3Department of Gastrointestinal Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA; 4Department of Radiology, Icahn School of Medicine at Mount Sinai West, New York, NY, USA; 5School of Medicine, Baylor College of Medicine, Houston, TX, USACorrespondence: Khaled M ElsayesDepartment of Radiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, TX 77030, USATel +1 713-745-3025Fax +1 713-794-4379Email kmelsayes@mdanderson.orgAbstract: Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide, usually occurring on a background of liver cirrhosis. HCC is a highly vascular tumor in which angiogenesis plays a major role in tumor growth and spread. Tumor-induced angiogenesis is usually related to a complex interplay between multiple factors and pathways, with vascular endothelial growth factor being a major player in angiogenesis. In the past decade, understanding of tumor-induced angiogenesis has led to the emergence of novel anti-angiogenic therapies, which act by reducing neo-angiogenesis, and improving patient survival. Currently, Sorafenib and Lenvatinib are being used as the first-line treatment for advanced unresectable HCC. However, a disadvantage of these agents is the presence of numerous side effects. A major challenge in the management of HCC patients being treated with anti-angiogenic therapy is effective monitoring of treatment response, which decides whether to continue treatment or to seek second-line treatment. Several criteria can be used to assess response to treatment, such as quantitative perfusion on cross-sectional imaging and novel/emerging MRI techniques, including a host of known and emerging biomarkers and radiogenomics. This review addresses the pathophysiology of angiogenesis in HCC, accurate imaging assessment of angiogenesis, monitoring effects of anti-angiogenic therapy to guide future treatment and assessing prognosis.Keywords: angiogenesis, hepatocellular carcinoma, anti-angiogenic therapy, Sorafenib

Mohamed El Kassas,1 Ahmed Tawheed,1 Mohamed Eltabbakh,2 Ahmed Kaseb3 1Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt; 2Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 3Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USACorrespondence: Mohamed El KassasEndemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, EgyptTel +20 111 445 5552Fax +20227239227Email m_elkassas@yahoo.comAbstract: Hepatitis C virus (HCV) infection is known to be one of the leading causes of hepatocellular carcinoma (HCC) all over the world. Previously, multiple studies have confirmed a decreased rate of HCC occurrence or recurrence in the cases of hepatitis C associated cirrhosis after treatment with interferon, in comparison to the untreated cases, even in the absence of clearance of HCV. Treatment programs with direct-acting antivirals (DAAs) as a new method for HCV treatment and cure in 2014, with higher safety and efficacy, were considered as an important step in the treatment of patients with history of HCC, improving their overall prognosis. Recently, reports coming from various European centers claimed that the risk of HCC increased following DAAs therapy, especially in cases with previous HCC. Moreover, other studies revealed that the recurrence of HCC after DAAs treatment was more aggressive. Even though others were not able to conclude the same results, the role of DAA therapy in recurrence of HCC in patients with previous HCC after sustained virological response (SVR) achievement remains questionable. This review explored the existing literature and discussed opinions on the possibility of increasing recurrence of HCC following DAA therapy, possible mechanisms, predictors of HCC recurrence post DAAs, and whether those patients should be treated or not.Keywords: hepatitis C virus, hepatocellular carcinoma, recurrence, direct-acting antiviral agents

Dima Dandachi,1,2 Manal Hassan,3 Ahmed Kaseb,4 Georgios Angelidakis,2 Harrys A Torres2,4 1Department of Infectious Diseases, Baylor College of Medicine, Houston, TX, USA; 2Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Epidemiology, The University of Texas Medical School, Houston, TX, USA; 4Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Introduction: Chronic hepatitis C virus (HCV) infection is one of the leading causes of hepatocellular carcinoma (HCC) worldwide. Antiviral therapy in patients with HCV infection reduces the risk of primary HCC development by 71%–75%. HCV-infected patients with different primary cancers are also at risk for HCC development as a second primary malignancy (HCC-SPM). Limited information is available on the occurrence and characteristics of HCC-SPM. Herein, we determine the prevalence and clinical features of HCV-associated HCC-SPM when compared to primary HCC. Materials and methods: Patients with HCV-associated HCC seen at MD Anderson Cancer Center (2011–2017) were enrolled in a prospective observational study. Patients with multiple cancers diagnosed simultaneously or with hepatitis B virus or HIV coinfections were excluded. At enrollment, patients completed a questionnaire on medical history and HCC risk factors. Information on demographics, comorbidities, HCV treatment, tumor characteristics, treatment modalities, and virologic and oncologic outcomes were extracted from the medical records. Results: Among 171 consecutive patients with HCV-associated HCC enrolled, 26 (15%) had HCC-SPM. Most of the underlying primary cancers were solid tumors (85%). In 12 (46%) of these patients, the diagnosis was made incidentally while undergoing surveillance for primary malignancies, and the majority (81%) had their primary cancer in remission. Most patients (72%) with documented HCV viral load had chronic viremia due to lack of diagnosis, lack of treatment, or prior unsuccessful treatment of HCV infection and only 28% had undetectable viral load following successful antiviral therapy. The overall median survival for both groups was 29 months (95% CI: 23–35) without difference between groups (p=0.2). Conclusion: Cancer patients with any malignancies must be screened for HCV as HCC-SPM can develop in 15% of infected patients. Early HCV diagnosis and treatment should be attempted to prevent the development of HCC-SPM, a condition associated with high mortality in cancer survivors. Keywords: liver cancer, cancer prevention, cancer survivors, DAA, HCV treatment

Ahmed M Khalaf,1 David Fuentes,1 Ali I Morshid,2 Mata R Burke,3 Ahmed O Kaseb,4 Manal Hassan,4 John D Hazle,1 Khaled M Elsayes2 1Department of Imaging Physics, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Diagnostic Radiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, USA; 4Department of Gastrointestinal Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA Abstract: Hepatocellular carcinoma (HCC) is one of the most common primary hepatic malignancies and one of the fastest-growing causes of cancer-related mortality in the United States. The molecular basis of HCC carcinogenesis has not been clearly identified. Among the molecular signaling pathways implicated in the pathogenesis of HCC, the Wnt/β-catenin signaling pathway is one of the most frequently activated. A great effort is under way to clearly understand the role of this pathway in the pathogenesis of HCC and its role in the transition from chronic liver diseases, including viral hepatitis, to hepatocellular adenomas (HCAs) and HCCs and its targetability in novel therapies. In this article, we review the role of the β-catenin pathway in hepatocarcinogenesis and progression from chronic inflammation to HCC, the novel potential treatments targeting the pathway and its prognostic role in HCC patients, as well as the imaging features of HCC and their association with aberrant activation of the pathway. Keywords: hepatocellular carcinoma, Wnt/β-catenin, gadoxetic acid-enhanced magnetic resonance imaging, molecular therapy

Ahmed Omar Kaseb Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, TX, USAJournal of Hepatocellular Carcinoma (JHC) is a peer-reviewed, comprehensive, multidisciplinary, international journal for publication of original, review, editorial, and commentary articles in addition to expert consensus statements and reports in all clinical and research aspects of hepatocellular carcinoma (HCC). JHC is indexed in PubMed and PubMed Central (J Hepatocell Carcinoma), and in the Emerging Sources Citation Index.

Mohamed E Abdelsalam,1 Ravi Murthy,1 Rony Avritscher,1 Armeen Mahvash,1 Michael J Wallace,1 Ahmed O Kaseb,2 Bruno C Odisio,1 1Department of Interventional Radiology, 2Department of Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Abstract: Hepatocellular carcinoma (HCC) is the fifth most frequently occurring cancer globally and predominantly develops in the setting of various grades of underlying chronic liver disease, which affects management decisions. Image-guided percutaneous ablative or transarterial therapies have acquired wide acceptance in HCC management as a single treatment modality or combined with other treatment options in patients who are not amenable for surgery. Recently, such treatment modalities have also been used for bridging or downsizing before definitive treatment (ie, surgical resection or liver transplantation). This review focuses on the use of minimally invasive image-guided locoregional therapies for HCC. Additionally, it highlights recent advancements in imaging and catheter technology, embolic materials, chemotherapeutic agents, and delivery techniques; all lead to improved patient outcomes, thereby increasing the interest in these invasive techniques. Keywords: hepatocelleular carcinoma, locoregional therapy, TACE, ablation, 90Y

Mohamed Magdi El-Sadek Ali Atta,1,2 Hazem Mahmoud Atta,3,4 Magdy Abdel-Mawgoud Gad,2 Laila Ahmad Rashed,4 Ebada M Said,2 Sharaf El-Sayed Ali Hassanien,2 Ahmed O Kaseb5 1Department of Medicine, Rabigh Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 2Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Benha University, Benha, Egypt; 3Department of Clinical Biochemistry, Rabigh Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 4Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt; 5Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Background and aims: Several angiogenic factors are involved in the development and progression of hepatocellular carcinoma (HCC), a hypervascular tumor. Vascular endothelial growth factor (VEGF) is a primary driving force for angiogenesis, and its overexpression has been reported in HCC. However, the significance of plasma and tissue VEGF levels in HCC in Egyptian patients with chronic hepatitis C (CHC) infection is understudied. The aim of this study was to evaluate the role of VEGF (measured in plasma and liver tissue) in patients with hepatitis C virus-related HCC and to assess its significance in the diagnosis and prognosis of HCC. Materials and methods: A total of 90 subjects were studied. Among 90 subjects, 60 with CHC were examined and were subdivided into two groups: 30 patients with CHC-related HCC (HCC group) and 30 patients with CHC without HCC (non-HCC group). Thirty apparently healthy subjects served as the control group. VEGF was estimated in plasma by enzyme-linked immunosorbent assay and its expression in liver tissue was evaluated by real-time polymerase chain reaction. VEGF expression level and its relationship to tumor parameters, patients' liver function profile, and patients' clinical parameters were also investigated. Results: Plasma VEGF levels in the HCC group were significantly higher than those of the non-HCC group, and both groups had significantly higher plasma VEGF levels than did the control group. Liver tissue VEGF expression was significantly higher in the HCC group than in the non-HCC group and positively correlated with plasma VEGF in the HCC group. The plasma VEGF levels were positively correlated with patients' age, aspartate aminotransferase levels, serum alpha-fetoprotein levels, the presence of portal vein thrombosis, and the number of hepatic focal lesions in the HCC group. However, plasma VEGF levels were not significantly correlated with the Child-Pugh score, alanine aminotransferase levels, the size of focal lesions, and Okuda stage. Using both the VEGF and alpha-fetoprotein levels to detect HCC maximizes the sensitivity and specificity. Conclusion: Plasma levels of VEGF may be a useful diagnostic and prognostic marker for HCC in patients who have been diagnosed with CHC. Keywords: VEGF, hepatocellular carcinoma, hepatitis C virus

Armeen Mahvash,1 Ravi Murthy,1 Bruno C Odisio,1 Kanwal Pratap Raghav,2 Lauren Girard,2 Sheree Cheung,1 Van Nguyen,3 Joe Ensor,4 Sameer Gadani,5 Khaled M Elsayes,6 Reham Abdel-Wahab,1,7 Manal Hassan,1 Ahmed S Shalaby,1 James C Yao,1 Michael J Wallace,1 Ahmed O Kaseb2 1Department of Interventional Radiology, 2Department of Gastrointestinal Medical Oncology, 3Department of Pharmacy, 4Department of Statistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 5Department of Radiology, Saint Louis University Hospital, St Louis, MO, 6Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Department of Clinical Oncology, Assiut University Hospital, Assiut, Egypt Purpose: The safety and efficacy of the combined use of sorafenib and yttrium-90 resin microspheres (Y90 RMS) to treat advanced hepatocellular carcinoma (HCC) is not well established. We determined the incidence of adverse events with this combination therapy in patients with advanced HCC at our institution and analyzed the treatment and survival outcomes. Materials and methods: We reviewed the records of 19 patients with Barcelona Clinic Liver Cancer class B or C HCC who underwent treatment with Y90 RMS (for 21 sessions) while receiving full or reduced doses of sorafenib between January 2008 and May 2010. Therapy response was evaluated using Response Evaluation Criteria in Solid Tumors. We evaluated median overall survival (OS) and progression-free survival (PFS) as well as hepatic and extrahepatic disease PFS and incidence of adverse events. Results: The median patient age was 67 years, and portal or hepatic venous invasion was present in eight patients (42%). Ten patients received reduced doses of sorafenib. The median Y90 radiation activity delivered was 41.2 mCi. The partial response of Response Evaluation Criteria in Solid Tumors was observed in four patients (19%). The median hepatic disease PFS was 7.82 months, extrahepatic disease PFS was 8.94 months, OS was 19.52 months, and PFS was 6.63 months. Ninety days after treatment with Y90 RMS, five patients (26%) had grade II adverse events and four patients (21%) had grade III adverse events. Conclusion: OS and PFS outcomes were superior to those observed in prior studies evaluating sorafenib alone in patients with a similar disease status, warranting further study of this treatment combination. Keywords: yttrium-90, sorafenib, hepatocellular carcinoma

Reham Abdel-Wahab,1,2 Samir Shehata,2 Manal M Hassan,1 Mouhammed A Habra,3 Ghazaleh Eskandari,4 Peggy T Tinkey,5 Jennifer Mitchell,5 Ju-Seog Lee,6 Hesham M Amin,4,7 Ahmed O Kaseb11Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Clinical Oncology, Assiut University Hospital, Assiut, Egypt; 3Department of Endocrinology, 4Department of Hematopathology, 5Department of Veterinary Medicine and Surgery, 6Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 7Graduate School of Biomedical Sciences, Houston, TX, USAAbstract: Chronic liver diseases (CLDs) encompass a wide range of illnesses, including nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and viral hepatitis. Deterioration of liver capacity, with subsequent progression into cirrhosis and hepatocellular carcinoma (HCC), ultimately leads to a further decrease in the hepatic reserve. The Child–Turcotte–Pugh scoring system is the standard tool for assessing underlying liver reserve capacity in routine practice and in clinical trials of CLD and HCC. In this review, we highlight the clinical significance of insulin-like growth factor-I (IGF-I) and the growth hormone (GH) signaling pathway in HCC. IGF-I could be a marker for liver reserve capacity in CLDs and HCC in clinical practice. This approach could improve the risk assessment and stratifications of patients on the basis of their underlying liver reserve, either before active treatment in routine practice or before they are enrolled in clinical trials.Keywords: IGF-I, growth hormone, chronic liver disease

Harrys A Torres,1 Ahmed Kaseb,2 Parag Mahale,1 Ethan Miller,3 Catherine Frenette4 1Department of Infectious Diseases, Infection Control and Employee Health, 2Department of Gastrointestinal Medical Oncology, 3Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Department of Liver Transplantation, Weill Cornell Medical College, The Methodist Hospital, Houston, TX, USA Abstract: In patients who undergo liver transplantation (LT), allograft failure secondary to hepatitis C virus (HCV) recurrence after LT accounts for two-thirds of graft failures and deaths. Achievement of sustained virologic response before LT eliminates the risk of HCV recurrence. Only a limited number of studies have evaluated the role of antiviral treatment before LT. No published data are available regarding the use of HCV protease inhibitors before LT. We report our experience using the combination of telaprevir, pegylated interferon alfa-2a (PegIFN alfa-2a), and ribavirin in three patients with HCV-associated hepatocellular carcinoma (HCC) awaiting LT. Two patients had not received, and one had had a partial response to HCV therapy (PegIFN alfa-2a plus ribavirin). All three patients had genotype 1b and were started on telaprevir and full doses of PegIFN alfa-2a and ribavirin. Treatment was planned to be continued until the day of LT or 48 weeks total, whichever came first. One patient still had detectable HCV RNA after 24 weeks of antivirals and was, therefore, excluded from further analysis. The other two patients had undetectable HCV RNA at the end of antiviral therapy. In one of these patients, HCV RNA remained undetectable after LT; the other patient experienced viral relapse. HCV therapy was tolerated by all patients; no patient required permanent discontinuation of therapy because of toxic effects. All three patients experienced hematologic toxic effects. Only one patient required treatment discontinuation, due to progression of HCC. The use of telaprevir-containing regimens appears to be safe in selected patients with HCV-associated HCC awaiting LT, but more studies are warranted to evaluate the safety and efficacy of this treatment combination to prevent post-LT viral recurrence. Keywords: telaprevir, hepatitis C virus, hepatocellular carcinoma, liver transplantation

Ahmed O Kaseb Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Hepatocellular carcinoma (HCC) develops as a consequence of underlying chronic liver disease, most commonly cirrhosis. Therefore, HCC management draws on the expertise of a wide range of medical specialists. Currently, novel therapeutic modalities for HCC are investigated within the framework of a multidisciplinary approach. Therefore, there is a critical need for a dedicated journal for HCC with special emphasis on understanding pathogenesis, emerging diagnosis and treatment approaches, and translational research strategies.The new journal Journal of Hepatocellular Carcinoma strives to be the essential clinical guide for medical and surgical oncologists, hepatologists, interventional radiologists, and all physicians and researchers involved in the care of patients with HCC. Our journal is committed to building an intercontinental community of researchers and clinicians to encourage establishment of collaborations and development of improved strategies to advance the field and help our patients from a global prospective. HCC is a very heterogeneous disease with multiple risk factors and noted differences in natural history and treatment outcomes based on demographics, risk factors, and even geographic locations, as evident by the noted difference in the magnitude of effects and rate of adverse events based on recent clinical trials conducted on different continents using the same systemic or local therapy modality.1 Therefore, one of the ultimate goals of the journal is to advance our understanding of the biology and natural history of HCC given the differential outcome based on these variables.

The epidemic of insulin resistance, obesity, and metabolic syndrome has led to the emergence of nonalcoholic steatohepatitis (NASH) as the most common cause of liver disease in the US. Patients with NASH are at an increased risk for hepatic disease-related morbidity and death, and chronic inflammation in NASH patients can lead to hepatocellular carcinoma (HCC). The prevalence of HCC is higher in males than in females, and genetic studies have identified androgen and androgen receptors (ARs) as partially responsible for the gender disparity in the development of liver disease and HCC. Although many factors are known to play important roles in the progression of inflammation in NASH patients, the role of androgen and AR in the progression of NASH to HCC has been understudied. This review summarizes the evidence for a potential role of androgen and the AR pathway in the development of NASH-related HCC and in the treatment of HCC. It has been proposed that AR plays a role in the progression of HCC: inhibitory roles in early stages of hepatocarcinogenesis and tumor-promoting roles in advanced stages. AR can be activated by several pathways, even in the absence of androgen. While AR has been explored as a potential therapeutic target in HCC, several clinical trials have failed to demonstrate a clinical benefit of antiandrogen drugs in HCC. This review discusses the potential reason for these observations and discuss the potential future trials design in this important setting.