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Ye-Tran X, Bouattour M, Fresneau B, Turpin A, Perret A, Vitellius C, Coriat R, Blanc JF, Lequoy M, Regnault H, Pietrasz D, Sefrioui D, Lecomte T, Moati E, Caliez O, Nguyen-Khac E, Walter T, Hautefeuille V. Response to systemic treatments and survival of fibrolamellar carcinomas: An AGEO-SFCE French multicenter retrospective cohort. Dig Liver Dis 2025:S1590-8658(25)00328-7. [PMID: 40316454 DOI: 10.1016/j.dld.2025.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 02/13/2025] [Accepted: 04/07/2025] [Indexed: 05/04/2025]
Abstract
INTRODUCTION Fibrolamellar carcinomas (FLC) are rare and predominantly advanced hepatic malignancies, lacking a clear consensus on anti-tumor treatments (ATT). The primary objective of the study was to determine whether any ATT appeared to give favorable outcomes in terms of morphological objective response (ORR) and disease control (DCR) rate according to RECIST 1.1 criteria. PATIENTS AND METHODS This retrospective multicentric French cohort from 14 centers included 44 patients with histologically proven FLC who received at least one ATT (chemotherapy and/or tyrosine kinase inhibitors, TKI) and underwent at least one morphological evaluation. . RESULTS A total of 40 anti-tumor responses were analyzed after a first line treatment. No complete response was observed, with an ORR in 13 % of cases, a DCR in 55 % of cases and 45 % of disease progression. GEMOX regimen (n = 9) showed an ORR of 11 % and a DCR of 33 %; the combination of doxorubicin and platinum-based chemotherapy (n = 6) achieved an ORR of 33 % and a DCR of 83 %. For TKI, sorafenib (n = 10) and sunitinib (n = 3), there was no objective response, with a DCR of 40 % and 33 % respectively. The median and the 5-years overall survival were 3.3 years and 35 % (95 %CI=[0.23-0.54]) respectively. CONCLUSION FLC have a poor prognosis; ATT show mild response rate. Further approaches and personalized medicine seem to be an unmet need for patients with FLC and new treatments should be urgently developed.
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Affiliation(s)
- Xixi Ye-Tran
- Gastroenterology Department, Grand Hôpital de l'Est Francilien (GHEF), Meaux, France
| | - Mohamed Bouattour
- Liver Cancer Unit, Assistance Publique - Hôpitaux de Paris, Beaujon University Hospital, Clichy, France
| | - Brice Fresneau
- Gustave Roussy, Department of Children and Adolescents Oncology, Villejuif, F-94805, France
| | - Anthony Turpin
- Medical Oncology - Lille University Hospital - Lille, France
| | - Audrey Perret
- Medical Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Carole Vitellius
- Hepato-Gastroenterology Department, University Hospital, Angers, France
| | - Romain Coriat
- Department of gastroenterology and endoscopy, Hôpital Cochin, Université Paris Cité, Paris, France
| | - Jean Frederic Blanc
- Department of Digestive Oncology, Hôpital Haut-Lévêque, Bordeaux University Hospital, Pessac, France
| | - Marie Lequoy
- Department of Hepatology, AP-HP, Saint-Antoine Hospital, F-75012, Paris, France
| | - Hélène Regnault
- Department of Hepatology, Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Créteil, France
| | - Daniel Pietrasz
- Department of Digestive, Oncological, and Transplant Surgery, Paul Brousse Hospital, Paris-Saclay University, Villejuif, France
| | - David Sefrioui
- Department of Gastroenterology, Digestive Oncology Unit, Rouen University Hospital, Rouen, France
| | - Thierry Lecomte
- Hepato-gastroenterology and Digestive Oncology, Tours University Hospital, Tours, France
| | - Emilie Moati
- Department of Gastroenterology and Digestive Oncology, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, Institut du Cancer Paris Carpem, Paris, France
| | - Olivier Caliez
- Department of Hepato-gastroenterology, Assistance Publique, Hôpitaux de Paris, Pitié Salpêtrière University Hospital, Paris, France
| | - Eric Nguyen-Khac
- Hepato-gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France
| | - Thomas Walter
- Gastroenterology and Digestive Oncology, Edouard Herriot University Hospital, Hospices Civils de Lyon, Lyon, France
| | - Vincent Hautefeuille
- Hepato-gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France.
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Zhang W, Hong X, Xiao Y, Wang H, Zeng X. Sorafenib resistance and therapeutic strategies in hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer 2025; 1880:189310. [PMID: 40187502 DOI: 10.1016/j.bbcan.2025.189310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 03/30/2025] [Accepted: 03/30/2025] [Indexed: 04/07/2025]
Abstract
Hepatocellular carcinoma (HCC) remains one of the most prevalent and lethal cancers globally. While surgical resection and liver transplantation offer potential cures for early-stage HCC, the majority of patients are diagnosed at advanced stages where such interventions are not viable. Sorafenib, a multi-target kinase inhibitor, has been a cornerstone in the treatment of advanced HCC since its approval in 2007. Despite its significant clinical impact, less than half of the treated patients derive long-term benefits due to the emergence of resistance and associated side effects. This review focuses on the role of sorafenib, an FDA-approved multi-target kinase inhibitor, in treating advanced HCC, discusses the mechanisms underlying its therapeutic effects and associated resistance, and explores additional therapeutic strategies being investigated to improve patient outcomes.
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Affiliation(s)
- Weijing Zhang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China
| | - Xuechuan Hong
- Department of Cardiology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
| | - Yuling Xiao
- Department of Cardiology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China; State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Hongbo Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
| | - Xiaodong Zeng
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
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Zeng RW, Ong CEY, Ong EYH, Chung CH, Lim WH, Xiao J, Danpanichkul P, Law JH, Syn N, Chee D, Kow AWC, Lee SW, Takahashi H, Kawaguchi T, Tamaki N, Dan YY, Nakajima A, Wijarnpreecha K, Muthiah MD, Noureddin M, Loomba R, Ioannou GN, Tan DJH, Ng CH, Huang DQ. Global Prevalence, Clinical Characteristics, Surveillance, Treatment Allocation, and Outcomes of Alcohol-Associated Hepatocellular Carcinoma. Clin Gastroenterol Hepatol 2024; 22:2394-2402.e15. [PMID: 38987014 DOI: 10.1016/j.cgh.2024.06.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/25/2024] [Accepted: 06/02/2024] [Indexed: 07/12/2024]
Abstract
BACKGROUND Although the burden of alcohol-associated hepatocellular carcinoma (HCC) is increasing with rising alcohol consumption, clinical presentation and outcomes of alcohol-associated HCC have not been systematically assessed. We aimed to determine the prevalence, clinical characteristics, surveillance rates, treatment allocation, and outcomes of alcohol-associated HCC. METHODS Medline and Embase were searched from inception to January 2023. Proportional data were analyzed using a generalized linear mixed model. The odds ratio (OR) or mean difference comparing alcohol-associated HCC and other causes was obtained with pairwise meta-analysis. Survival outcomes were evaluated using a pooled analysis of hazard ratios. RESULTS Of 4824 records identified, 55 articles (86,345 patients) were included. Overall, 30.4% (95% confidence interval [CI], 24.0%-37.7%) of HCC was alcohol associated, with the highest proportion in Europe and the lowest in the Americas. People with alcohol-associated HCC were more likely male but were similar in age and comorbidities compared with other causes. A total of 20.8% (95% CI, 11.4%-34.9%) of people with alcohol-associated HCC underwent surveillance compared with 35.0%, 31.6%, and 21.4% in hepatitis B virus, hepatitis C virus, and metabolic dysfunction-associated HCC, respectively (all P < .05). Alcohol-associated HCC had a lower likelihood of Barcelona Clínic Liver Cancer C stage (0/A) (OR, 0.7; 95% CI, 0.6-0.9; P = .018) and curative therapy (24.5% vs 33.9%; OR, 0.7; 95% CI, 0.5-0.9; P = .003), and higher mortality (HR, 1.3; 95% CI, 1.1-1.5; P = .012) when compared with other causes. CONCLUSIONS Alcohol-associated HCC is associated with lower surveillance rates, more advanced BCLC stage, lower likelihood of receiving curative therapy, and poorer survival. These data call for measures to reduce heavy alcohol consumption and improve strategies for effective HCC surveillance in high-risk individuals.
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Affiliation(s)
| | - Christen En Ya Ong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Elden Yen Hng Ong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Charlotte Hui Chung
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Wen Hui Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jieling Xiao
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | - Jia Hao Law
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, National University Hospital, Singapore
| | - Nicholas Syn
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Biostatistics & Modelling Domain, Saw Swee Hock School of Public Health, National University of Singapore, Singapore
| | - Douglas Chee
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore
| | - Alfred Wei Chieh Kow
- Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, National University Hospital, Singapore; Division of Surgical Oncology, National University Cancer Institute, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore
| | - Sung Won Lee
- Division of Hepatology, Department of Internal Medicine, Catholic University of Korea, Seoul, Republic of Korea
| | | | - Takumi Kawaguchi
- Department of Digestive Disease Information & Research, School of Medicine, Kurume University, Fukuoka, Japan
| | - Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Yock Young Dan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore
| | - Atsushi Nakajima
- Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Karn Wijarnpreecha
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Arizona College of Medicine, Phoenix, Arizona; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Banner University Medical Center, Phoenix, Arizona
| | - Mark D Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore
| | | | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, California
| | - George N Ioannou
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System, Seattle, Washington; Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington
| | - Darren Jun Hao Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Cheng Han Ng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Digestive Disease Information & Research, School of Medicine, Kurume University, Fukuoka, Japan
| | - Daniel Q Huang
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore.
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Zhang Y, Tu J, Wang J, Dai T, Zheng L, Sun S, Tu C, Li H, Qian L. NFKBIE is a predictive factor of survival and is correlated with immune infiltration and antigen processing and presentation in hepatocellular carcinoma. Oncol Lett 2024; 28:480. [PMID: 39161335 PMCID: PMC11332585 DOI: 10.3892/ol.2024.14613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 02/21/2024] [Indexed: 08/21/2024] Open
Abstract
The important role of the nuclear factor κB (NFκB) pathway in tumour development has long been recognized; however, the role of the NFκB inhibitor family in liver cancer has not been elucidated. Hepatocellular carcinoma (HCC) is a serious public health burden with a high incidence, poor prognosis, and early detection, especially in Asia, where hepatitis is prevalent. In the present study, the mRNA expression level of the NFκB inhibitor family was assessed in HCC and normal tissues using the Metabolic Gene Rapid Visualizer, University of Alabama at Birmingham Cancer Data Analysis Portal, and the Tumor Immune Estimation Resource database (TIMER). Survival curves of nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor (NFKBI)E were obtained using the Kaplan-Meier method. Genes co-expressed with NFKBIE in HCC samples were studied using data from the LinkedOmics and the Hepatocellular Carcinoma Databases. Protein-protein interaction networks, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment pathway analyses were used to assess the NFKBIE mechanism in HCC. Using the TIMER database, the association between immune infiltration and NFKBIE was determined. RNA-sequencing (RNA-seq) was used to evaluate the function of NFKBIE in HCC and its impact on proliferation and migration. Western blotting was used to confirm the expression of NFKBIE in HCC cell lines. In addition, NFKBIE overexpression in HCC was demonstrated using tissue microarrays encompassing 80 pairs of HCC and normal liver tissues. NFKBIE was the only NFκB inhibitor with high expression and an improved prognosis in HCC compared with other NFκB inhibitors. NFKBIE was correlated with clinical characteristics, such as tumour grade, tumour protein P53 mutation status and tumour stage. Data obtained from Gene Set Cancer Analysis suggested that NFKBIE may inhibit the PI3K/AKT, RAS/MAPK, RTK and TSC/mTOR pathways. In addition, NFKBIE was significantly associated with B-cell immune infiltration and the RNA-seq data demonstrated that knockdown of NFKBIE significantly affected 'Antigen processing and presentation' and 'hepatocellular carcinoma' pathways. Immunohistochemistry of microarrays of tissue samples revealed that NFKBIE was overexpressed in several stages of HCC. Finally, inhibition of NFKBIE decreased the proliferation and migration of HCC cells. In conclusion, due to its prognostic value and overexpression in HCC, NFKBIE distinguished itself from other NFκB inhibitors. As such, it may provide a novel prognostic indicator and immunotherapeutic target for HCC.
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Affiliation(s)
- Yang Zhang
- Department of Comprehensive Surgery, The First Affiliated Hospital of University of Science and Technology of China West District, Hefei, Anhui 230031, P.R. China
| | - Jinqi Tu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui 241001, P.R. China
| | - Jian Wang
- Department of Comprehensive Surgery, The First Affiliated Hospital of University of Science and Technology of China West District, Hefei, Anhui 230031, P.R. China
| | - Tiancheng Dai
- Department of Medical Laboratory Technology, The First Clinical College of Anhui Medical University, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Lin Zheng
- Department of Comprehensive Surgery, The First Affiliated Hospital of University of Science and Technology of China West District, Hefei, Anhui 230031, P.R. China
| | - Sinan Sun
- Department of Radiation Oncology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230031, P.R. China
| | - Conyin Tu
- Department of Comprehensive Surgery, The First Affiliated Hospital of University of Science and Technology of China West District, Hefei, Anhui 230031, P.R. China
| | - Heng Li
- Department of Comprehensive Surgery, The First Affiliated Hospital of University of Science and Technology of China West District, Hefei, Anhui 230031, P.R. China
| | - Liting Qian
- Department of Radiation Oncology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230031, P.R. China
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Majeed A, Alaparthi S, Halegoua-DeMarzio D, Eberle-Singh J, Jiang W, Anne PR, Shah AP, Bowne WB, Lin D. Complete Pathologic Response to Gemcitabine and Oxaliplatin Chemotherapy After Prior Therapies in a Patient With Hepatocellular Carcinoma and Peritoneal Metastases Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy. World J Oncol 2024; 15:511-520. [PMID: 38751709 PMCID: PMC11092419 DOI: 10.14740/wjon1840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 05/01/2024] [Indexed: 05/18/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is often diagnosed at a late stage and frequently recurs despite curative intervention, leading to poor survival outcomes. Frontline systemic therapies include combination immunotherapy regimens and tyrosine kinase inhibitors. We report a case of a 38-year-old woman with chronic hepatitis B and C coinfection-associated non-cirrhotic HCC, which recurred in the peritoneum after initial resection of her primary tumor. Disease progression occurred on both atezolizumab/bevacizumab and lenvatinib, and she was subsequently treated with gemcitabine and oxaliplatin (GEMOX) chemotherapy and exhibited a profound clinical response on imaging with normalization of alpha fetoprotein (AFP) after several months. Following extensive multidisciplinary discussion, she underwent cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) that removed all visible macroscopic tumor. Her pathology demonstrated a complete pathologic response. She received two additional months of postoperative chemotherapy, and then proceeded with close monitoring off therapy. To our knowledge, this is the first reported case of a complete pathologic response to GEMOX chemotherapy in the context of CRS/HIPEC for peritoneal metastases in HCC, after progression on standard immunotherapy and tyrosine kinase inhibitor treatments. In this report, we review the current systemic treatment landscape in HCC. We highlight potential consideration of cytotoxic chemotherapy, which is less frequently utilized in current practice, in selected patients with HCC, and discuss the role of CRS/HIPEC in the management of peritoneal metastases. Further investigation regarding predictors of response to systemic treatments is strongly needed. Multidisciplinary management may ultimately prolong survival in patients with advanced HCC.
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Affiliation(s)
- Amry Majeed
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Sneha Alaparthi
- Department of General Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Dina Halegoua-DeMarzio
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Jaime Eberle-Singh
- Department of Pathology and Genomic Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Wei Jiang
- Department of Pathology and Genomic Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Pramila Rani Anne
- Department of Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Ashesh P. Shah
- Department of General Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Wilbur B. Bowne
- Department of General Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Daniel Lin
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, PA, USA
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Zhu S, Yu Y, Yang M, Liu X, Lai M, Zhong J, Zhao X, Lu L, Liu Y. Hepatic artery infusion chemotherapy combined with the FOLFOX regimen for the treatment of hepatocellular carcinoma: recent advances and literature review. Expert Rev Anticancer Ther 2024; 24:423-434. [PMID: 38651280 DOI: 10.1080/14737140.2024.2346624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Accepted: 04/19/2024] [Indexed: 04/25/2024]
Abstract
INTRODUCTION The incidence of primary liver cancer (PLC) has experienced a significant global increase, primarily attributed to the rise in hepatocellular carcinoma (HCC). Unfortunately, HCC is often diagnosed in advanced stages, leaving patients with limited treatment options. Therefore, transformation therapy is a crucial approach for long-term survival and radical resection in patients with advanced HCC. Conversion therapy has demonstrated promise in the treatment of advanced HCC. When integrated with the FOLFOX regimen, hepatic artery infusion chemotherapy (HAIC) can significantly improve tumor response efficiency, leading to high conversion and resection rates. AREAS COVERED We reviewed landmark trials of HAIC in combination with different drugs or means for the treatment of HCC to determine the clinical value of HAIC-centric translational therapies in HCC treatment. Furthermore, we specifically emphasize the advantages associated with employing FOLFOX-HAIC in the treatment of advanced HCC. EXPERT OPINION The combination of HAIC with the FOLFOX regimen can help prevent the low intratumoral accumulation and high adverse reaction rate caused by the FOLFOX alone, holding significant potential in the comprehensive treatment of future HCC patients.
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Affiliation(s)
- Suqi Zhu
- Zhuhai Interventional Medical Center, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China
| | - Yahan Yu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China
| | - Mingqi Yang
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China
| | - Xin Liu
- Zhuhai Precision Medical Center, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China
| | - Mingkai Lai
- Zhuhai Interventional Medical Center, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China
| | - Jieren Zhong
- Zhuhai Interventional Medical Center, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China
| | - Xiaoguang Zhao
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China
| | - Ligong Lu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China
| | - Yanyan Liu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong, China
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Ding Y, Wang S, Qiu Z, Zhu C, Wang Y, Zhao S, Qiu W, Wang K, Lv J, Qi W. The worthy role of hepatic arterial infusion chemotherapy in combination with anti-programmed cell death protein 1 monoclonal antibody immunotherapy in advanced hepatocellular carcinoma. Front Immunol 2023; 14:1284937. [PMID: 38022559 PMCID: PMC10644007 DOI: 10.3389/fimmu.2023.1284937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/19/2023] [Indexed: 12/01/2023] Open
Abstract
Systemic therapy remains the primary therapeutic approach for advanced hepatocellular carcinoma (HCC). Nonetheless, its efficacy in achieving control of intrahepatic lesions is constrained. Hepatic arterial infusion chemotherapy (HAIC) is a therapeutic approach that combines localized treatment with systemic antitumor effects, which aim is to effectively manage the progression of cancerous lesions within the liver, particularly in patients with portal vein tumor thrombosis (PVTT). Combining HAIC with anti-programmed cell death protein 1 (anti-PD-1) monoclonal antibody (mAb) immunotherapy is anticipated to emerge as a novel therapeutic approach aimed at augmenting the response inside the localized tumor site and achieving prolonged survival advantages. In order to assess the effectiveness, safety, and applicability of various therapeutic modalities and to address potential molecular mechanisms underlying the efficacy of HAIC-sensitizing immunotherapy, we reviewed the literature about the combination of HAIC with anti-PD-1 mAb therapies.
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Affiliation(s)
- Yixin Ding
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Shasha Wang
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Zhenkang Qiu
- Interventional Medical Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Chunyang Zhu
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Yan Wang
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Shufen Zhao
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Wensheng Qiu
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Kongjia Wang
- Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Jing Lv
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Weiwei Qi
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
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Hou Z, Liu J, Jin Z, Qiu G, Xie Q, Mi S, Huang J. Use of chemotherapy to treat hepatocellular carcinoma. Biosci Trends 2022; 16:31-45. [PMID: 35173139 DOI: 10.5582/bst.2022.01044] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Hepatic malignancies remain a global challenge. Hepatocellular carcinoma (HCC) accounts for around 90% of patients with liver cancer and is the sixth most common neoplasm worldwide and the fourth leading cause of cancer-related death. However, the long-term prognosis for HCC remains far from satisfactory, with a late diagnosis and limited treatment. DOX has served as conventional chemotherapy with the longest history of use. Although conventional chemotherapy is being challenged by molecular therapy and immune therapy, there is renewed optimism and interest in both systematic and locoregional therapy. Combined chemotherapy is widely used in clinical practice. In specific terms, FOLFOX can serve as a first-line (category 2B) option as recommended by the 2021 NCCN guidelines, while the efficacy of LTLD plus RFA has been confirmed in the phase III HEAT study. These approaches have challenged the dominant status of molecular therapy in terms of health economics and they have potential benefits in Asia, where HBV-related hepatocellular carcinoma is prevalent. Moreover, locoregional chemotherapy can be achieved with TACE and HAIC (possibly involving FOLFOX, DOX, mitomycin C, cisplatin, epirubicin, etc.). TACE was officially recommended by the 2021 NCCN guidelines for patients with Child-Pugh class B liver disease. In addition, HAIC has demonstrated a potential advantage in preliminary clinical practice, although it hasn't been included in any guidelines. Hence, this review summarizes large-scale trials and studies examining the development and innovative use of chemotherapeutic agents. Mounting clinical evidence warrants an exploration of the efficacy of chemotherapy.
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Affiliation(s)
- Ziqi Hou
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jie Liu
- Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhaoxing Jin
- Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Guoteng Qiu
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qingyun Xie
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Shizheng Mi
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jiwei Huang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
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9
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Zhang W, Liu Z, Xia S, Yao L, Li L, Gan Z, Tang H, Guo Q, Yan X, Sun Z. GDI2 is a novel diagnostic and prognostic biomarker in hepatocellular carcinoma. Aging (Albany NY) 2021; 13:25304-25324. [PMID: 34894398 PMCID: PMC8714169 DOI: 10.18632/aging.203748] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 11/22/2021] [Indexed: 12/24/2022]
Abstract
Background: GDP Dissociation inhibitor 2 (GDI2) gene has been correlated with some important biological processes in a variety of cancers, whereas the role of GDI2 in hepatocellular carcinoma (HCC) is ill-defined. We aimed to demonstrate the relationship between GDI2 and HCC based on The Cancer Genome Atlas (TCGA) data mining. Methods: The expression of GDI2 was compared between cancer and normal tissues of 371 HCC patients collected from TCGA-LIHC, and verified in HCC cell lines. Gene set enrichment analysis (GSEA) was applied to annotate biological function of GDI2. Furthermore, Wilcoxon rank sum test, Logistics regression, as well as Cox regression and Kaplan-Meier survival analysis, were employed to evaluate the association of GDI2 expression with clinicopathological characteristics, and survival status of HCC patients, respectively. Results: It showed that the expression of GDI2 was much higher in tumor tissues than in normal tissues (P < 0.001) of HCC patients. And the elevated expression of GDI2 was correlated with more aggressive HCC tumor status, including severe primary tumor extent, advanced pathological stage, serious histologic grade, and mutated TP53 status (P < 0.05). Moreover, high GDI2 expression was strongly associated with a poor survival rate (P < 0.001). Both enrichment and immune infiltration analyses implied that GDI2-associated signaling mainly involve lipid metabolism and extracellular matrix (ECM) constructing pathways related to tumor microenvironment (TME) (P < 0.05). Conclusions: The elevated expression of GDI2 predicts poor prognosis in HCC patients, indicating that GDI2 could be applied as a predictive biomarker for diagnosis and prognosis of HCC.
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Affiliation(s)
- Wen Zhang
- School of Medicine, Kunming University of Science and Technology, Affiliated by The First People's Hospital of Yunnan Province, Kunming 650504, Yunnan, China.,Yunnan Digestive Endoscopy Clinical Medical Center, Gastroenterology Department, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan, China
| | - Zhongjian Liu
- Yunnan Digestive Endoscopy Clinical Medical Center, Gastroenterology Department, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan, China
| | - Shilin Xia
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning, China
| | - Lei Yao
- General Surgery Department, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang, China
| | - Lan Li
- Ophthalmology Department, Jiangxi Provincial People's Hospital, Nanchang 330006, Jiangxi, China
| | - Ziying Gan
- Yunnan Digestive Endoscopy Clinical Medical Center, Gastroenterology Department, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan, China
| | - Hui Tang
- Yunnan Digestive Endoscopy Clinical Medical Center, Gastroenterology Department, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan, China
| | - Qiang Guo
- Yunnan Digestive Endoscopy Clinical Medical Center, Gastroenterology Department, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan, China
| | - Xinmin Yan
- Yunnan Digestive Endoscopy Clinical Medical Center, Gastroenterology Department, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan, China
| | - Zhiwei Sun
- School of Medicine, Kunming University of Science and Technology, Affiliated by The First People's Hospital of Yunnan Province, Kunming 650504, Yunnan, China.,Yunnan Digestive Endoscopy Clinical Medical Center, Gastroenterology Department, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan, China
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10
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Li Q, Xiong DL, Wang H, Jin WL, Ma YY, Fan XM. High Expression of SLC41A3 Correlates with Poor Prognosis in Hepatocellular Carcinoma. Onco Targets Ther 2021; 14:2975-2988. [PMID: 33981147 PMCID: PMC8107057 DOI: 10.2147/ott.s296187] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 03/16/2021] [Indexed: 12/16/2022] Open
Abstract
Purpose SLC41A3 is a member of the solute carrier family 41 (SLC41) and is involved in many cellular processes as a magnesium ion transporter. Although it plays an important role in cancer formation and development, the correlation between the expression of SLC41A3 and the occurrence and prognosis of hepatocellular carcinoma (HCC) remains unclear. Therefore, this study was focused on the evaluation of the relationship between SLC41A3 and the development and prognosis of HCC. Patients and Methods Firstly, we collected the mRNA expression of SLC41A3 in HCC through the platform of Oncomine. Then, the subgroups of HCC were performed by the UALCAN website and the prognosis of HCC was analyzed by Kaplan-Meier Plotter database. Subsequently, immunohistochemistry (IHC) method was used to detect SLC41A3 expression in 323 clinically confirmed HCC samples and 184 non-cancerous liver tissues. Finally, function enrichment analysis was done using the LinkInterpreter module in LinkedOmics, and gene set enrichment analysis (GSEA) was performed using TCGA data set. Results The Oncomine database and immunohistochemical (IHC) showed higher SLC41A3 expression in HCC tissue compared to normal tissue. The expression of SLC41A3 was significantly correlated with tumor metastasis, Edmondson grade, microvascular invasion, and AFP level. Kaplan-Meier and Cox regression analyses verified that high SLC41A3 expression is a significant prognostic factor for reduced overall survival in HCC patients. Conclusion Our results demonstrated that high expression of SLC41A3 was the predictor of poor prognosis in HCC patients, suggesting that this protein may be a potential target for HCC therapy.
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Affiliation(s)
- Qian Li
- Graduate Department, Bengbu Medical College, Bengbu, Anhui, 233000, People's Republic of China.,Department of Ultrasound, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People's Republic of China
| | - Dan-Lei Xiong
- School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, 310018, People's Republic of China
| | - Heng Wang
- Graduate Department, Bengbu Medical College, Bengbu, Anhui, 233000, People's Republic of China
| | - Wei-Li Jin
- Department of Gastroenterology, Nanxun People's Hospital (Zhejiang Provincial People's Hospital Nanxun Branch), Huzhou, 313009, Zhejiang Province, People's Republic of China
| | - Ying-Yu Ma
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People's Republic of China
| | - Xiao-Ming Fan
- Graduate Department, Bengbu Medical College, Bengbu, Anhui, 233000, People's Republic of China.,Department of Ultrasound, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People's Republic of China
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11
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Li L, Song S, Fang X, Cao D. Role of ATF3 as a prognostic biomarker and correlation of ATF3 expression with macrophage infiltration in hepatocellular carcinoma. BMC Med Genomics 2021; 14:8. [PMID: 33407456 PMCID: PMC7789720 DOI: 10.1186/s12920-020-00852-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 12/08/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The abnormal expression of activating transcription factor 3 (ATF3), a member of the basic leucine zipper (bZIP) family of transcription factors, is associated with carcinogenesis. However, the expression pattern and exact role of ATF3 in the development and progression of hepatocellular carcinoma (HCC) remain unclear. METHODS We used UALCAN, ONCOMINE, Kaplan-Meier plotter, and cBioPortal databases to investigate the prognostic value of ATF3 expression in HCC. RESULTS ATF3 was found to be expressed at low levels in multiple HCC tumor tissues. Moreover, low ATF3 expression was significantly associated with clinical cancer stage and pathological tumor grade in patients with HCC. Therefore, low expression of ATF3 was significantly associated with poor overall survival in patients with HCC. Functional network analysis showed that ATF3 regulates cytokine receptors and signaling pathways via various cancer-related kinases, miRNAs, and transcription factors. ATF3 expression was found to be correlated with macrophage infiltration levels and with macrophage immune marker sets in HCC patients. CONCLUSIONS Using data mining methods, we clarified the role of ATF3 expression and related regulatory networks in HCC, laying a foundation for further functional research. Future research will validate our findings and establish clinical applications of ATF3 in the diagnosis and treatment of HCC.
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Affiliation(s)
- Lijuan Li
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, No. 466 Xingang Middle Road, Haizhu District, Guangzhou, 510317, Guangdong Province, China
| | - Shaohua Song
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, No. 466 Xingang Middle Road, Haizhu District, Guangzhou, 510317, Guangdong Province, China
| | - Xiaoling Fang
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, No. 466 Xingang Middle Road, Haizhu District, Guangzhou, 510317, Guangdong Province, China
| | - Donglin Cao
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, No. 466 Xingang Middle Road, Haizhu District, Guangzhou, 510317, Guangdong Province, China.
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12
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Abouelezz K, Khanapara D, Batiha GES, Ahmed EA, Hetta HF. Cytotoxic Chemotherapy as an Alternative for Systemic Treatment of Advanced Hepatocellular Carcinoma in Developing Countries. Cancer Manag Res 2020; 12:12239-12248. [PMID: 33273860 PMCID: PMC7707432 DOI: 10.2147/cmar.s280631] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 11/10/2020] [Indexed: 01/10/2023] Open
Abstract
Systemic therapy options nowadays for advanced hepatocellular carcinoma (HCC) are either immunotherapy with immune checkpoint inhibitors or targeted therapy. As the incidence of liver cancer is much higher in developing countries, these new medications are not readily accessible for most of the patients. Cytotoxic chemotherapy agents are more available and affordable in developing countries. We are trying to explore the effectiveness of the newer cytotoxic agents in the systematic treatment for advanced HCC. This is a systematic review of all randomized controlled trials since 1997 that utilized systemic cytotoxic chemotherapy agents in the systemic treatment for advanced HCC using Scopus, PubMed, and Cochrane library up to February 2020. Six randomized trials were found. Different drugs and dosages were used, so it was statistically inappropriate to conduct a meta-analysis. No Phase III trial showed statistically significant overall survival (OS) benefit for cytotoxic chemotherapy, except subgroup analysis of Chinese patients in one study who had leucovorin, fluorouracil, and oxaliplatin (FOLFOX) regimen. There was no significant progression-free survival (PFS) or response rate in the Phase II trials. There are not enough data to infer the actual benefits of systemic cytotoxic chemotherapy in advanced HCC. However, oxaliplatin-based regimens may give feasible results. Health systems with limited access to targeted therapy and immunotherapy agents may use oxaliplatin-based regimens in clinical trials for advanced HCC. These results should be confirmed in multiple future randomized clinical trials.
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Affiliation(s)
- Khaled Abouelezz
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Dipen Khanapara
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicines, Damanhour University, Damanhour 22511, Egypt
| | - Esraa A Ahmed
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt.,Centre of Excellence in Environmental Studies (CEES), King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Helal F Hetta
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.,Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71526, Egypt
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13
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Polidoro MA, Mikulak J, Cazzetta V, Lleo A, Mavilio D, Torzilli G, Donadon M. Tumor microenvironment in primary liver tumors: A challenging role of natural killer cells. World J Gastroenterol 2020; 26:4900-4918. [PMID: 32952338 PMCID: PMC7476172 DOI: 10.3748/wjg.v26.i33.4900] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/24/2020] [Accepted: 08/20/2020] [Indexed: 02/06/2023] Open
Abstract
In the last years, several studies have been focused on elucidate the role of tumor microenvironment (TME) in cancer development and progression. Within TME, cells from adaptive and innate immune system are one of the main abundant components. The dynamic interactions between immune and cancer cells lead to the activation of complex molecular mechanisms that sustain tumor growth. This important cross-talk has been elucidate for several kind of tumors and occurs also in patients with liver cancer, such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Liver is well-known to be an important immunological organ with unique microenvironment. Here, in normal conditions, the rich immune-infiltrating cells cooperate with non-parenchymal cells, such as liver sinusoidal endothelial cells and Kupffer cells, favoring self-tolerance against gut antigens. The presence of underling liver immunosuppressive microenvironment highlights the importance to dissect the interaction between HCC and iCCA cells with immune infiltrating cells, in order to understand how this cross-talk promotes tumor growth. Deeper attention is, in fact, focused on immune-based therapy for these tumors, as promising approach to counteract the intrinsic anti-tumor activity of this microenvironment. In this review, we will examine the key pathways underlying TME cell-cell communications, with deeper focus on the role of natural killer cells in primary liver tumors, such as HCC and iCCA, as new opportunities for immune-based therapeutic strategies.
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Affiliation(s)
- Michela Anna Polidoro
- Hepatobiliary Immunopathology Laboratory, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
| | - Joanna Mikulak
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
- Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Rozzano 20089, Milan, Italy
| | - Valentina Cazzetta
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
| | - Ana Lleo
- Hepatobiliary Immunopathology Laboratory, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
- Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Internal Medicine, Humanitas Clinical and Research Center – IRCCS, Rozzano 20089, Milan, Italy
| | - Domenico Mavilio
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
- Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Rozzano 20089, Milan, Italy
| | - Guido Torzilli
- Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
| | - Matteo Donadon
- Department of Biomedical Science, Humanitas University, Pieve Emanuele 20090, Milan, Italy
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center - IRCCS, Rozzano 20089, Milan, Italy
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14
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Abstract
Primary liver cancer (PLC) is a fatal disease that affects millions of lives worldwide. PLC is the leading cause of cancer-related deaths and the incidence rate is predicted to rise in the coming decades. PLC can be categorized into three major histological subtypes: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined HCC-ICC. These subtypes are distinct with respect to epidemiology, clinicopathological features, genetic alterations, and clinical managements, which are thoroughly summarized in this review. The state of treatment strategies for each subtype, including the currently approved drugs and the potential novel therapies, are also discussed.
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Affiliation(s)
- Mei Feng
- Translational Cancer Research Center, Peking University First Hospital, Beijing 100034, China
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Yisheng Pan
- Department of General Surgery, Peking University First Hospital, Beijing 100034, China
| | - Ruirui Kong
- Translational Cancer Research Center, Peking University First Hospital, Beijing 100034, China
| | - Shaokun Shu
- Translational Cancer Research Center, Peking University First Hospital, Beijing 100034, China
- Department of Biomedical Engineering, Peking University, Beijing 100871, China
- Peking University Cancer Hospital, Beijing 100142, China
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15
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Luo Y, Ye J, Wei J, Zhang J, Li Y. Long non‑coding RNA‑based risk scoring system predicts prognosis of alcohol‑related hepatocellular carcinoma. Mol Med Rep 2020; 22:997-1007. [PMID: 32468063 PMCID: PMC7339747 DOI: 10.3892/mmr.2020.11179] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 04/22/2020] [Indexed: 12/16/2022] Open
Abstract
Increasing evidence suggests that long non-coding RNAs (lncRNAs) serve a crucial role in predicting prognosis for hepatocellular carcinoma (HCC). However, prognostic performance may not be the same for alcohol‑related HCC. The aim of the present study was to screen prognosis‑associated lncRNAs and construct a risk scoring system for alcohol‑related HCC. The expression profiles of lncRNAs in 113 patients with alcohol‑related HCC and 224 with non‑alcohol‑related HCC were obtained from The Cancer Genome Atlas (TCGA) database and screened for differentially expressed lncRNAs. Cox regression analysis was performed to identify prognosis‑associated lncRNAs and select the optimal lncRNA model. A risk scoring system was established to calculate the risk score for each patient. The prognostic ability of this system was tested. Functional enrichment analysis was performed for genes that were highly associated with lncRNA expression. A total of 102 differentially expressed lncRNAs were identified between alcohol‑related and non‑alcohol‑related HCC. Four lncRNAs (AC012640.1, AC013451.2, AC062004.1 and LINC02334) were used to construct the risk assessment model to predict overall survival (OS), and five lncRNAs (ERVH48‑1, LINC02043, LINC01605, AC062004.1 and AL139385) were used to predict recurrence‑free survival (RFS). Patients were assigned to high‑ or low‑risk groups according to the risk score. OS in the high‑risk group was significantly shorter than that of the low‑risk group. The area under the receiver operating characteristic (ROC) curve of risk scoring systems was >0.7. The risk score was an independent prognostic factor for alcohol‑related HCC. Functional enrichment analysis demonstrated that lncRNA‑related genes found in this system were mainly involved in chemical carcinogenesis, drug metabolism, and the cell cycle. In conclusion, this study developed and validated a prognostic scoring system for alcohol‑related HCC based on lncRNAs.
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Affiliation(s)
- Yue Luo
- Department of Medical Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Jiaxiang Ye
- Department of Medical Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Jiazhang Wei
- Department of Otolaryngology and Head and Neck, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi 530021, P.R. China
| | - Jinyan Zhang
- Department of Medical Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Yongqiang Li
- Department of Medical Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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16
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Piñero F, Silva M, Iavarone M. Sequencing of systemic treatment for hepatocellular carcinoma: Second line competitors. World J Gastroenterol 2020; 26:1888-1900. [PMID: 32390700 PMCID: PMC7201145 DOI: 10.3748/wjg.v26.i16.1888] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 03/27/2020] [Accepted: 04/04/2020] [Indexed: 02/06/2023] Open
Abstract
During the last decades, further knowledge of hepatocellular carcinoma (HCC) molecular mechanisms has led to development of effective systemic treatments including tyrosine kinase inhibitors (TKIs) and immunotherapy. In this review, we describe first and second line systemic treatment options for advanced HCC. Several trials have evaluated new drugs for the treatment of HCC patients: In first line, lenvatinib resulted non-inferior to sorafenib and it can be used as alternative, even in the lack of evidence for sequential treatment options in second line after lenvatinib. Recently, atezolizumab plus bevacizumab have shown superiority over sorafenib in first-line. Sorafenib-regorafenib sequential administration in selected patients has opened a new paradigm of treatment in advanced HCC with a life expectancy exceeding two years. Other TKIs for second line treatment include cabozantinib and ramucirumab (specifically for patients with Alpha-fetoprotein values ≥ 400 ng/mL). The combination of TKIs with immunotherapy may represent a big step forward for these patients in the near future.
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Affiliation(s)
- Federico Piñero
- Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
- Latin American Liver Research Educational and Awareness Network, Buenos Aires B1629HJ, Argentina
| | - Marcelo Silva
- Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
- Latin American Liver Research Educational and Awareness Network, Buenos Aires B1629HJ, Argentina
| | - Massimo Iavarone
- Division of Gastroenterology and Hepatology, CRC “A.M. e A. Migliavacca” Center for the Study of Liver Disease, University of Milan, Fondazione IRCCS Ca’ Granda Maggiore Hospital, Milan 20121, Italy
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17
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Lin Y, Liang R, Qiu Y, Lv Y, Zhang J, Qin G, Yuan C, Liu Z, Li Y, Zou D, Mao Y. Expression and gene regulation network of RBM8A in hepatocellular carcinoma based on data mining. Aging (Albany NY) 2020; 11:423-447. [PMID: 30670676 PMCID: PMC6366983 DOI: 10.18632/aging.101749] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 12/25/2018] [Indexed: 12/11/2022]
Abstract
RNA binding motif protein 8A (RBM8A) is an RNA binding protein in a core component of the exon junction complex. Abnormal RBM8A expression is associated with carcinogenesis. We used sequencing data from the Cancer Genome Atlas database and Gene Expression Omnibus, analyzed RBM8A expression and gene regulation networks in hepatocellular carcinoma (HCC). Expression was analyzed using OncomineTM and Gene Expression Profiling Interactive Analysis tools, while RBM8A alterations and related functional networks were identified using cBioPortal. LinkedOmics was used to identify differential gene expression with RBM8A and to analyze Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. Gene enrichment analysis examined target networks of kinases, miRNAs and transcription factors. We found that RBM8A is overexpressed and the RBM8A gene often amplified in HCC. Expression of this gene is linked to functional networks involving the ribosome and RNA metabolic signaling pathways. Functional network analysis suggested that RBM8A regulates the spliceosome, ribosome, DNA replication and cell cycle signaling via pathways involving several cancer-related kinases, miRNAs and E2F Transcription Factor 1. Our results demonstrate that data mining efficiently reveals information about RBM8A expression and potential regulatory networks in HCC, laying a foundation for further study of the role of RBM8A in carcinogenesis.
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Affiliation(s)
- Yan Lin
- Department of Medical Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China
| | - Rong Liang
- Department of Medical Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China
| | - Yufen Qiu
- Maternal and Child Health Hospital and Obstetrics and Gynecology Hospital of Guangxi Zhuang Autonomous Region, Guangxi 530021, People's Republic of China
| | - Yufeng Lv
- Department of Medical Oncology, Affiliated Langdong Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China
| | - Jinyan Zhang
- Department of Medical Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China
| | - Gang Qin
- The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China
| | - Chunling Yuan
- Department of Medical Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China
| | - Zhihui Liu
- Department of Medical Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China
| | - Yongqiang Li
- Department of Medical Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China
| | - Donghua Zou
- The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China
| | - Yingwei Mao
- Department of Biology, Pennsylvania State University, University Park, PA 16802, USA
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18
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Chagas AL, Mattos AAD, Carrilho FJ, Bittencourt PL, Vezozzo DCP, Horvat N, Rocha MDS, Alves VAF, Coral GP, Alvares-DA-Silva MR, Barros FMDR, Menezes MR, Monsignore LM, Coelho FF, Silva RFD, Silva RDCMA, Boin IDFSF, D Albuquerque LAC, Garcia JHP, Felga GEG, Moreira AM, Braghiroli MIFM, Hoff PMG, Mello VBD, Dottori MF, Branco TP, Schiavon LDL, Costa TDFA. BRAZILIAN SOCIETY OF HEPATOLOGY UPDATED RECOMMENDATIONS FOR DIAGNOSIS AND TREATMENT OF HEPATOCELLULAR CARCINOMA. ARQUIVOS DE GASTROENTEROLOGIA 2020; 57:1-20. [PMID: 32294682 DOI: 10.1590/s0004-2803.202000000-20] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 12/19/2019] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The Brazilian Society of Hepatology (SBH) published in 2015 its first recommendations about the management of HCC. Since then, new data have emerged in the literature, prompting the governing board of SBH to sponsor a single-topic meeting in August 2018 in São Paulo. All the invited experts were asked to make a systematic review of the literature reviewing the management of HCC in subjects with cirrhosis. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of updated recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present manuscript is the final version of the reviewed manuscript containing the recommendations of SBH.
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Affiliation(s)
- Aline Lopes Chagas
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil
- Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
| | - Angelo Alves de Mattos
- Universidade Federal de Ciências da Saúde de Porto Alegre e Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, RS, Brasil
| | - Flair José Carrilho
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil
- Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
| | | | | | - Natally Horvat
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil
- Hospital Sírio-Libanês, São Paulo, SP, Brasil
| | - Manoel de Souza Rocha
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil
| | - Venâncio Avancini Ferreira Alves
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil
- Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
| | - Gabriela Perdomo Coral
- Universidade Federal de Ciências da Saúde de Porto Alegre e Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, RS, Brasil
| | | | | | - Marcos Roberto Menezes
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil
- Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
- Hospital Sírio-Libanês, São Paulo, SP, Brasil
| | - Lucas Moretti Monsignore
- Universidade de São Paulo, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, São Paulo, SP, Brasil
| | | | - Renato Ferreira da Silva
- Faculdade de Medicina de São José do Rio Preto (FAMERP) e Hospital de Base de São José do Rio Preto (FUNFARME), São José do Rio Preto, SP, Brasil
| | - Rita de Cássia Martins Alves Silva
- Faculdade de Medicina de São José do Rio Preto (FAMERP) e Hospital de Base de São José do Rio Preto (FUNFARME), São José do Rio Preto, SP, Brasil
| | | | | | | | | | - Airton Mota Moreira
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil
- Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
| | | | - Paulo Marcelo Gehm Hoff
- Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
| | | | | | - Tiago Pugliese Branco
- Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
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Huang D, Fan Q, Liu Z, Zhang S, Huang W, Li H, Liang C, Sun F. An Epitope on EGFR Loading Catastrophic Internalization Serve as a Novel Oncotarget for Hepatocellular Carcinoma Therapy. Cancers (Basel) 2020; 12:E456. [PMID: 32079107 PMCID: PMC7072198 DOI: 10.3390/cancers12020456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 02/12/2020] [Accepted: 02/14/2020] [Indexed: 11/28/2022] Open
Abstract
The precise role of Epidermal Growth Factor Receptor (EGFR) in Hepatocellular carcinoma (HCC) cells is unknown and EGFR inhibitors have not achieved positive clinical results. The rapid and drastic internalization of EGFR has been proved to successfully treat EGFR inhibitor-resistant patients in recent clinical trials. Here, the anti-tumor efficacy of a protein (rLZ-8) from Ganoderma lucidum was evaluated, it was demonstrated that rLZ-8 could bind to EGFR specifically, drastically enter into Hepatoma cells, abrogate endosomal recycling and induce HCC cell death. Surprisingly, we screened a monoclonal antibody which possesses competitive binding site with rLZ-8, it also trigger catastrophic EGFR internalization. This result suggests that it is necessary to investigate the interface of EGFR and rLZ-8 complex. An internalization related epitope (S222/K269) was identified on the dimerization arm of EGFR extracellular domain (ECD). These results suggest vulnerability of HCC cells to catastrophic EGFR internalization that can be targeted by a novel epitope and point to the possible exploitation in the design of anti-EGFR therapeutic biologics for HCC therapy.
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Affiliation(s)
- Dianshuai Huang
- Institute of Frontier Medical Science, Jilin University, Changchun 130021, Jilin, China; (D.H.); (Z.L.); (S.Z.); (W.H.); (H.L.); (C.L.)
| | - Qingjie Fan
- Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, Changchun 130021, Jilin, China;
| | - Zhiyi Liu
- Institute of Frontier Medical Science, Jilin University, Changchun 130021, Jilin, China; (D.H.); (Z.L.); (S.Z.); (W.H.); (H.L.); (C.L.)
| | - Shuqin Zhang
- Institute of Frontier Medical Science, Jilin University, Changchun 130021, Jilin, China; (D.H.); (Z.L.); (S.Z.); (W.H.); (H.L.); (C.L.)
| | - Wei Huang
- Institute of Frontier Medical Science, Jilin University, Changchun 130021, Jilin, China; (D.H.); (Z.L.); (S.Z.); (W.H.); (H.L.); (C.L.)
| | - Hongrui Li
- Institute of Frontier Medical Science, Jilin University, Changchun 130021, Jilin, China; (D.H.); (Z.L.); (S.Z.); (W.H.); (H.L.); (C.L.)
| | - Chongyang Liang
- Institute of Frontier Medical Science, Jilin University, Changchun 130021, Jilin, China; (D.H.); (Z.L.); (S.Z.); (W.H.); (H.L.); (C.L.)
| | - Fei Sun
- Institute of Frontier Medical Science, Jilin University, Changchun 130021, Jilin, China; (D.H.); (Z.L.); (S.Z.); (W.H.); (H.L.); (C.L.)
- Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, Changchun 130021, Jilin, China;
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20
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Han SS, Feng ZQ, Liu R, Ye J, Cheng WW, Bao JB. Bioinformatics Analysis and RNA-Sequencing of SCAMP3 Expression and Correlated Gene Regulation in Hepatocellular Carcinoma. Onco Targets Ther 2020; 13:1047-1057. [PMID: 32099407 PMCID: PMC7007781 DOI: 10.2147/ott.s221785] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 12/17/2019] [Indexed: 12/13/2022] Open
Abstract
Background Secretory Carrier Membrane Proteins 3 (SCAMP3) is a transmembrane protein that affects intracellular trafficking, protein sorting and vesicle formation. Overexpression of SCAMP3 correlates with poorly differentiated hepatocellular carcinoma (HCC). However, the expression and corresponding gene regulation of SCAMP3 in HCC remain unclear. Methods Bioinformatics analyses of clinical parameters and survival data were conducted to predict the prognostic value of SCAMP3 in HCC. RNA sequencing and real-time PCR were conducted to confirm the SCAMP3 expression in HCC tissue. Expression was analyzed using OncomineTM and UALCAN, while SCAMP3 alterations and survival analysis were identified by cBioPortal. Differential gene expression with SCAMP3 was analyzed by LinkedOmics and GEPIA. The target networks of enzymes and co-transcriptional factors were identified using Gene enrichment analysis. Expression of SCAMP3 in HCC tissue was detected by RNA-sequencing and Western-blotting. Results Based on bioinformatics analysis and detection of mRNA expression, SCAMP3 was over-expressed in numerous tumors, especially in HCC. SCAMP3 level was positively correlated with disease stages and tumor grades and negatively correlated with patient survival. Furthermore, functional network analysis indicated that SCAMP3 regulated metabolic process and DNA replication through oxidative phosphorylation and chromatin remodeling or Ribosome. SCAMP3 regulated a number of gene expressions including PPAP2B, SNRK, ARID4A, PRCC, VPS72 via protein binding and proteasome, which may affect cell adhesion, proliferation, transcription, cell cycle and metabolism. Further, Real-time PCR and Western-blotting showed that the SCAMP3 level was increased in HCC tissue. Conclusion The present data analysis efficiently reveals information about SCAMP3 expression and correlated function in HCC, laying a foundation for further study of SCAMP3 in the tumor.
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Affiliation(s)
- Shan-Shan Han
- Beijing Chaoyang Emergency Medical Center, Department of General Surgery, Chaoyang, Beijing 100020, People's Republic of China
| | - Zhi-Qiang Feng
- Beijing Chaoyang Emergency Medical Center, Department of General Surgery, Chaoyang, Beijing 100020, People's Republic of China
| | - Rui Liu
- Medical University of Anhui Air Force Clinical School, Department of Hepatobiliary Surgery, Beijing 100142, People's Republic of China
| | - Jun Ye
- Medical University of Anhui Air Force Clinical School, Department of Hepatobiliary Surgery, Beijing 100142, People's Republic of China
| | - Wei-Wei Cheng
- Medical University of Anhui Air Force Clinical School, Department of Hepatobiliary Surgery, Beijing 100142, People's Republic of China
| | - Jun-Bo Bao
- First People's Hospital of Suqian, Department of Medicine, Suqian, Jiangsu 223800, People's Republic of China
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21
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Liu Y, Zhang J, Chen Y, Sohel H, Ke X, Chen J, Li YX. The correlation and role analysis of COL4A1 and COL4A2 in hepatocarcinogenesis. Aging (Albany NY) 2020; 12:204-223. [PMID: 31905170 PMCID: PMC6977693 DOI: 10.18632/aging.102610] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 12/05/2019] [Indexed: 12/13/2022]
Abstract
Liver fibrosis biomarker, Type IV collagen, may function as hepatocarcinogenesis niche. However, among the six isoforms, the isoforms providing tumor microenvironment and their regulatory network are still unclarified. Based on bioinformatics analysis of hundreds of HCC transcriptome datasets from public databases, we found that COL4A1/2 expressions were significantly correlated with hepatocarcinogenesis, progression, and prognosis. The expressions of COL4A1/2 were significantly upregulated in the preneoplastic and HCC tissues compared with normal tissues. Moreover, the overexpression of COL4A2 was highly correlated with shorter progression-free survival in HCC patients. Bioinformatics analysis also generates an interactive regulatory network in which COL4A1/2 directly binding to integrin alpha-2/beta-1 initiates a sequentially and complicated signaling transduction, to accelerate cell cycle and promote tumorigenesis. Among those pathways, the PI3K-Akt pathway is significantly enriched in cooperative mutations and correlation analysis. This suggests that the key activated signaling is PI3K-Akt pathway which severing as the centerline linked with other pathways (Wnt and MAPK signaling) and cell behaviors signaling (cell cycle control and cytoskeleton change). Switching extracellular matrix collagen isoform may establish pro-tumorigenic and metastatic niches. The findings of COL4A1/2 and related signaling networks are valuable to be further investigated that may provide druggable targets for HCC intervention.
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Affiliation(s)
- Yanli Liu
- Stem Cell Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.,Stem Cell Translational Medicine Center, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jiaye Zhang
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Yan Chen
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Hasan Sohel
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Xinrong Ke
- Stem Cell Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.,Stem Cell Translational Medicine Center, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jingqi Chen
- Stem Cell Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.,Stem Cell Translational Medicine Center, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.,Department of Medical Oncology, Guangzhou Medical University, Guangzhou, China
| | - Yin-Xiong Li
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, China.,University of Chinese Academy of Sciences, Beijing, China
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22
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Abou-Alfa GK, Jarnagin W, El Dika I, D'Angelica M, Lowery M, Brown K, Ludwig E, Kemeny N, Covey A, Crane CH, Harding J, Shia J, O'Reilly EM. Liver and Bile Duct Cancer. ABELOFF'S CLINICAL ONCOLOGY 2020:1314-1341.e11. [DOI: 10.1016/b978-0-323-47674-4.00077-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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23
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Poorebrahim M, Sadeghi S, Ghanbarian M, Kalhor H, Mehrtash A, Teimoori-Toolabi L. Identification of candidate genes and miRNAs for sensitizing resistant colorectal cancer cells to oxaliplatin and irinotecan. Cancer Chemother Pharmacol 2020; 85:153-171. [PMID: 31781855 DOI: 10.1007/s00280-019-03975-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 10/05/2019] [Indexed: 12/16/2022]
Abstract
Drug resistance to irinotecan and oxaliplatin, two widely used chemotherapeutic, has become a common problem in cancerous patients. Despite numerous valuable studies, distinct molecular mechanisms involved in the acquisition of resistance to these anti-cancer drugs have remained a challenge. In this study, we studied the possible resistance mechanisms to irinotecan and oxaliplatin in three CRC cell lines (HCT116, HT29, and LoVo) via integration of microarray data with gene regulatory networks. After determination of hub genes, corresponding miRNAs were predicted using several databases and used in construction and subsequent analysis of miRNA-gene networks. Following to preparation of chemo-resistance CRC cells, a standard real-time PCR was conducted for validation of in silico findings. Topological and functional enrichment analyses of the resulted networks introduced several previously reported drug-resistance genes as well as novel biomarkers as hub genes which seem to be crucial in resistance of colon cancer cells to irinotecan and oxaliplatin. Furthermore, results of the functional annotation revealed the essential role of different signaling pathways like metabolic pathways in drug resistance of CRC cell lines to these drugs. A part of in silico findings was also validated in vitro using oxaliplatin-resistant cell lines. While FOXC1 and NFIC were upregulated in cell lines which were resistant to oxaliplatin, silencing FOXC1 decreased the resistance of SW480 cell line to oxaliplatin. In conclusion, our comparative in silico and in vitro study introduces several novel genes and miRNAs as the resistance-mediators which can be used for sensitizing resistant CRC cells to oxaliplatin and irinotecan.
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Affiliation(s)
- Mansour Poorebrahim
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Solmaz Sadeghi
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Marzieh Ghanbarian
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Hourieh Kalhor
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Amirhosein Mehrtash
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Ladan Teimoori-Toolabi
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
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24
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Merle P, Blanc JF, Phelip JM, Pelletier G, Bronowicki JP, Touchefeu Y, Pageaux G, Gerolami R, Habersetzer F, Nguyen-Khac E, Casadei-Gardini A, Borbath I, Tran A, Wege H, Saad AS, Colombo M, Abergel A, Richou C, Waked I, Yee NS, Molé A, Attali P, Le Boulicaut J, Vasseur B. Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial. Lancet Gastroenterol Hepatol 2019; 4:454-465. [PMID: 30954567 DOI: 10.1016/s2468-1253(19)30040-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 01/31/2019] [Accepted: 02/01/2019] [Indexed: 01/24/2023]
Abstract
BACKGROUND Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma. We assessed the intravenous perfusion of doxorubicin-loaded nanoparticles in patients with hepatocellular carcinoma in whom previous sorafenib therapy had failed. METHODS We did a multicentre, open-label, randomised, controlled phase 3 trial at 70 sites in 11 countries. Patients with hepatocellular carcinoma with one or more previous systemic therapies, including sorafenib, were randomly assigned to receive 30 mg/m2 doxorubicin-loaded nanoparticles (30 mg/m2 group), 20 mg/m2 doxorubicin-loaded nanoparticles (20 mg/m2 group), or standard care using a computer-generated randomisation list prepared by the funder and stratified by geographic region. Patients in the experimental groups received perfusion of the drug every 4 weeks and those in the control group received any systemic anticancer therapy (except sorafenib) as per investigator decision. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01655693. FINDINGS Between June 15, 2012, and Jan 27, 2017, 541 patients were screened, of whom 144 were excluded and 397 were randomly assigned to one of the groups (133 to the 30 mg/m2 group; 130 to the 20 mg/m2 group; and 134 to the control group). Median follow-up was 22·7 months (IQR 11·2-34·9). After pooling the doxorubicin groups for the efficacy analysis, median overall survival was 9·1 months (95% CI 8·1-10·4) in the pooled doxorubicin-loaded nanoparticles group and 9·0 months (7·1-11·8) in the control group (HR 1·00 [95% CI 0·78-1·28], two-sided p=0·99). 227 (94%) of 242 patients who received doxorubicin-loaded nanoparticles and 100 (75%) of 134 patients in the control group had at least one treatment-emergent adverse event. The most common drug-related grade 3 or 4 treatment-emergent adverse events were neutropenia (25 [10%] of 242 treated with doxorubicin-loaded nanoparticles and eight [6%] of 134 in the control group), asthenia (six [2%] and four [3%]), and thrombocytopenia (three [1%] and ten [7%]). Six (2%) patients treated with doxorubicin-loaded nanoparticles and one (1%) of those in the control group were deemed by investigators to have had a drug-related death. Serious adverse events occurred in 74 (31%) patients who received doxorubicin-loaded nanoparticles and 48 (36%) in the control group. INTERPRETATION Doxorubicin-loaded nanoparticles did not improve overall survival for patients with hepatocellular carcinoma in whom previous sorafenib treatment had failed. FUNDING Onxeo.
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Affiliation(s)
- Philippe Merle
- Service d'Hépatologie et Gastroentérologie, Hôpital de la Croix-Rousse, Lyon, France.
| | | | - Jean-Marc Phelip
- Centre Hospitalier Universitaire (CHU) de Saint-Étienne, Saint-Étienne, France
| | | | | | | | | | | | - François Habersetzer
- Centre Hospitalier Regional Universitaire de Strasbourg-Hôpital Civil, Strasbourg, France
| | | | - Andrea Casadei-Gardini
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy
| | - Ivan Borbath
- Université Catholique de Louvain Saint-Luc, Brussels, Belgium
| | | | - Henning Wege
- Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | - Amr Shafik Saad
- Department of Oncology, Ain Shams University Hospitals, Cairo, Egypt
| | - Massimo Colombo
- Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda-Ospedale Maggiore Policlinico, Milano, Italy
| | - Armand Abergel
- CHU de Clermont-Ferrand-Hôpital Estaing, Clermont-Ferrand, France
| | | | - Imam Waked
- National Liver Institute, Menoufyia University, Menoufyia, Egypt
| | - Nelson S Yee
- Penn State Cancer Institute Milton S Hershey Medical Center, Hershey, PA, USA
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Gans JH, Lipman J, Golowa Y, Kinkhabwala M, Kaubisch A. Hepatic Cancers Overview: Surgical and Chemotherapeutic Options, How Do Y-90 Microspheres Fit in? Semin Nucl Med 2019; 49:170-181. [DOI: 10.1053/j.semnuclmed.2019.01.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Sorafenib alone vs. sorafenib plus GEMOX as 1 st-line treatment for advanced HCC: the phase II randomised PRODIGE 10 trial. Br J Cancer 2019; 120:896-902. [PMID: 30944458 PMCID: PMC6734663 DOI: 10.1038/s41416-019-0443-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 03/08/2019] [Accepted: 03/14/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Sorafenib remains one major first-line therapeutic options for advanced hepatocellular carcinoma (aHCC), with modest efficacy. We investigated the addition of gemcitabine and oxaliplatin (GEMOX) to sorafenib in aHCC patients. METHODS Our multicentre phase II trial randomised aHCC first-line patients to sorafenib (400 mg BID) or sorafenib-GEMOX every 2 weeks (1000 mg/m2 gemcitabine; 100 mg/m2 oxaliplatin). Primary endpoint was the 4-month progression-free survival (PFS) rate. RESULTS Ninety-four patients were randomised (sorafenib-GEMOX: n = 48; sorafenib: n = 46). Median age was 64 years, PS 0 (69%) or 1 (31%), 63% patients had cirrhosis, 29% portal vein thrombosis and 70% extra-hepatic disease. Median duration of sorafenib treatment was 4 months (1-51); median number of GEMOX cycles was 7 (1-16). The 4-month PFS rates were 64% and 61% in the sorafenib-GEMOX and sorafenib arms, respectively; median PFS and OS were 6.2 (95% CI: 3.8-6.8) and 13.5 (7.5-16.2) months, and 4.6 (3.9-6.2) months and 14.8 (12.2-22.2), respectively. The ORR/DCR were 9%/70% and 15%/77% in the sorafenib-GEMOX and sorafenib alone arms, respectively. Main toxicities were (sorafenib-GEMOX/sorafenib) neutropenia (23%/0), thrombocytopenia (33%/0), diarrhoea (18%/9), peripheral neuropathy (5%/0) and hand-foot syndrome (5%/18). CONCLUSIONS Addition of GEMOX had an inpact on ORR and was well-tolerated as frontline systemic therapy. The benefit on PFS seems moderate; no subsequent study was planned.
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27
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Nenu I, Breaban I, Pascalau S, Bora CN, Stefanescu H. The future is now: beyond first line systemic therapy in hepatocellular carcinoma. Transl Cancer Res 2019; 8:S261-S274. [PMID: 35117106 PMCID: PMC8797356 DOI: 10.21037/tcr.2018.11.23] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 11/20/2018] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is becoming a worldwide concern due to its rising incidence. Although for the incipient stages there are curative therapies, the advanced disease represents a major provocation for the clinicians. 2008 marked as an important year for the hepatology community with the administration of sorafenib for late stages of HCC. Six years after this major discovery, the multikinase inhibitor still represents an important pillar, the first line treatment for the advanced liver cancer. Lenvatinib may represent a new promising first line strategy, but it is still unavailable in many countries. The last years represented an explosion in the research of HCC. Beyond the first line treatments there are a plethora of new emerging therapies. By far immunotherapy represents the major revolution in oncology. While adoptive immunotherapy is still at the beginning, immune check-point inhibitors bursted in many clinical trials with very encouraging results. This review summarises the major discoveries in the field of HCC with an emphasis on immunotherapy. It also briefly describes the important aspects of primary liver cancer immunology and the major ongoing clinical trials.
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Affiliation(s)
- Iuliana Nenu
- Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, Cluj-Napoca, Romania
- Liver Research Club, Cluj-Napoca, Romania
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Iulia Breaban
- Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, Cluj-Napoca, Romania
- Liver Research Club, Cluj-Napoca, Romania
| | - Sorana Pascalau
- Liver Research Club, Cluj-Napoca, Romania
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Cristina-Nelida Bora
- Liver Research Club, Cluj-Napoca, Romania
- “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Horia Stefanescu
- Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, Cluj-Napoca, Romania
- Liver Research Club, Cluj-Napoca, Romania
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Systemic Management for Advanced Hepatocellular Carcinoma: A Review of the Molecular Pathways of Carcinogenesis, Current and Emerging Therapies, and Novel Treatment Strategies. Dig Dis Sci 2019; 64:1016-1029. [PMID: 30887150 DOI: 10.1007/s10620-019-05582-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) arises from a number of cirrhosis-related and non-cirrhosis-related exposures and is one of the leading causes of cancer-related deaths worldwide. Achieving a durable cure currently relies on either resection or transplantation, but since most patients will be diagnosed with inoperable disease, there is great interest in achieving more effective systemic therapies. At a molecular level, HCC is heterogeneous, but initial treatment strategies, including the use of multi-targeted tyrosine kinase inhibitors and checkpoint inhibitors, have been fairly homogenous, depending on general host factors and overall tumor burden rather than specific molecular signatures. Over the past 2 decades, however, there has been significant success in identifying key molecular targets, including driver mutations involving the telomerase reverse transcriptase, p53, and beta-catenin genes, and significant work is now being devoted to translating these discoveries into the development of robust and well-tolerated targeted therapies. Furthermore, multi-modal therapies have also begun to emerge, harnessing possible synergism amongst a variety of different treatment classes. As the findings of these landmark trials become available over the next several years, the landscape of the systemic management of advanced HCC will change significantly.
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Tumor-associated macrophages modulate resistance to oxaliplatin via inducing autophagy in hepatocellular carcinoma. Cancer Cell Int 2019; 19:71. [PMID: 30962765 PMCID: PMC6434873 DOI: 10.1186/s12935-019-0771-8] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Accepted: 03/02/2019] [Indexed: 12/15/2022] Open
Abstract
Background Oxaliplatin-based chemotherapy is widely used to treat hepatocellular carcinoma (HCC). Recent studies suggested that therapeutic resistance of tumors was affected by tumor microenvironment (TME). As a major component of TME, the role of tumor-associated macrophages (TAMs) on drug resistance in HCC is largely unknown. Methods 26 HCC samples were obtained from patients who had underwent transarterial chemoembolization (TACE) within 3 months before receiving curative resections. Immunohistochemistry was applied to detect the density of TAMs in these tissues. SMMC-7721 and Huh-7 cell lines were used to co-culture with THP-1 derived macrophages. Under oxaliplatin treatment, cell death was measured using MTT and annexin V/propidium iodide assays. Autophagy activation was evaluated by GFP-LC3 redistribution and LC3 conversion in SMMC-7721 and Huh-7. Short-interfering RNA against ATG5 gene was applied to inhibit autophagy. In vivo validation was conducted in Huh-7 with or without macrophages using an HCC xenograft model in nude mice after oxaliplatin administration. Results We found that the density of TAMs in HCC samples was associated with the efficacy of TACE. Macrophages inhibited cell death induced by oxaliplatin in HCC cells. Autophagy was functionally activated in HCC cells after co-culturing with macrophages. Suppression of autophagy using RNA interference of ATG5 in HCC cells promoted the oxaliplatin cytotoxicity in the co-culture system. Critically, co-implantation with macrophages in HCC xenografts weakens cytotoxic effect of oxaliplatin through inducing autophagy to avoid apoptosis. Conclusions Our results suggest that TAMs induce autophagy in HCC cells which might contribute to oxaliplatin resistance. Targeting TAMs is a promising therapeutic strategy to enhance the effects of chemotherapy oxaliplatin in HCC patients.
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da Fonseca LG, Marta GN, Braghiroli MIFM, Chagas AL, Carrilho FJ, Hoff PM, Sabbaga J. Safety and efficacy of cytotoxic chemotherapy in hepatocellular carcinoma after first-line treatment with sorafenib. BMC Cancer 2018; 18:1250. [PMID: 30545331 PMCID: PMC6293528 DOI: 10.1186/s12885-018-5173-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 12/03/2018] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Before the targeted therapies era, cytotoxic chemotherapy (CCT) was an option for advanced hepatocellular carcinoma (HCC), even with the lack of supporting evidence. Since the last decade, sorafenib has been established as the first-line therapy. Although new agents are being incorporated, CCT is still considered in regions where new drugs are not available or for patients who progressed through the approved therapies and remain in good clinical condition. We aimed to describe our experience regarding the use of CCT as second-line treatment after sorafenib. METHODS A database of 273 patients was evaluated. Patients that received CCT after sorafenib progression were selected for the analysis. Descriptive statistics was used for categorical and continue variables. Median survival was estimated with Kaplan-Meier curves. Variables were found to be significant if the two-sided p value was ≤ 0.05 on multivariate testing using the Cox regression model. RESULTS Forty-five patients received CCT; 33 (73.3%) had Child-Pugh classification A, and 34 (75.6%) had stage C according to the Barcelona Clinic Liver Cancer (BCLC) staging system. The most used regimen was doxorubicin in 25 patients (55.6%). Median overall survival (OS) was 8.05 months (95% confidence interval [CI] 2.73 - 9.88 months). The 6-month and 1-year survival probability was 52.4% and 27.36%, respectively. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and disease control with sorafenib was independently associated with better OS in patients treated with CCT. Any-grade toxicities were observed in 82.2% and grade 3-4 in 44.4% of the patients. CONCLUSION In accordance with previous studies, CCT had a notable rate of adverse events. The poor prognosis of this cohort suggests that CCT may not alter the natural history of HCC after sorafenib progression.
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Affiliation(s)
- Leonardo Gomes da Fonseca
- Instituto do Cancer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av Dr Arnaldo, 251, São Paulo, ZIP code: 01246-000, Brazil.
| | - Guilherme Nader Marta
- Instituto do Cancer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av Dr Arnaldo, 251, São Paulo, ZIP code: 01246-000, Brazil
| | - Maria Ignez Freitas Melro Braghiroli
- Instituto do Cancer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av Dr Arnaldo, 251, São Paulo, ZIP code: 01246-000, Brazil
| | - Aline Lopes Chagas
- São Paulo Clínicas Liver Cancer Group, Instituto do Câncer do Estado de São Paulo - Hospital das Clínicas Complex, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Flair Jose Carrilho
- São Paulo Clínicas Liver Cancer Group, Instituto do Câncer do Estado de São Paulo - Hospital das Clínicas Complex, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Paulo Marcelo Hoff
- Instituto do Cancer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av Dr Arnaldo, 251, São Paulo, ZIP code: 01246-000, Brazil
| | - Jorge Sabbaga
- Instituto do Cancer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av Dr Arnaldo, 251, São Paulo, ZIP code: 01246-000, Brazil
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31
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Emerging therapies in advanced hepatocellular carcinoma. Exp Hematol Oncol 2018; 7:17. [PMID: 30087805 PMCID: PMC6076403 DOI: 10.1186/s40164-018-0109-6] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 07/30/2018] [Indexed: 12/14/2022] Open
Abstract
Background Prognosis is very poor for advanced HCC patients partially due to lack of effective systemic treatment. Sorafenib was the only approved agent for advanced HCC since 2007 until recent breakthroughs. In this article, we will review the newer approved and promising agents in the treatment of advanced HCC in the first line setting and beyond progression. Main body The Food and Drug Administration approved sorafenib as it demonstrated 3 months overall survival benefit compared to placebo in the first line setting over 10 years ago. Multiple single agent and combination therapies have been studied but failed to show benefit. Chemotherapy has limited role in patients with advanced HCC given poor hepatic reserve due to underlying cirrhosis. A new era of treatment for advanced HCC arrived recently with exciting data presented for lenvatinib, regorafenib, cabozantinib, nivolumab, ramucirumab and several other promising clinical trials. Conclusion Advanced HCC patients are difficult to treat with poor outcomes. After initial approval of sorafenib in 2007, we recently have multiple new agents that showed benefit and promising activity, and are set to change the landscape of HCC treatment.
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32
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Eatrides J, Wang E, Kothari N, Kim R. Role of Systemic Therapy and Future Directions for Hepatocellular Carcinoma. Cancer Control 2018; 24:1073274817729243. [PMID: 28975834 PMCID: PMC5937243 DOI: 10.1177/1073274817729243] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive tumor that often arises in the setting of liver cirrhosis. Although early-stage disease is often amenable for surgical resection, transplant, or locoregional therapies, many patients are diagnosed at an advanced stage or have poor liver reserve. Systemic therapy is the mainstay of treatment for these patients. At present, the only approved therapy for the treatment of advanced disease is the tyrosine multikinase inhibitor sorafenib. Candidacy for treatment is based on liver reserve. Novel agents for the treatment of this disease are urgently needed. In this article, we review systemic therapy trials and upcoming data for the treatment of HCC.
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Affiliation(s)
- Jennifer Eatrides
- 1 Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Emilie Wang
- 1 Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Nishi Kothari
- 1 Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Richard Kim
- 1 Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
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Lohitesh K, Chowdhury R, Mukherjee S. Resistance a major hindrance to chemotherapy in hepatocellular carcinoma: an insight. Cancer Cell Int 2018; 18:44. [PMID: 29568237 PMCID: PMC5859782 DOI: 10.1186/s12935-018-0538-7] [Citation(s) in RCA: 184] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 03/12/2018] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality, accounting for almost 90% of total liver cancer burden. Surgical resection followed by adjuvant and systemic chemotherapy are the most meticulously followed treatment procedures but the complex etiology and high metastatic potential of the disease renders surgical treatment futile in majority of the cases. Another hindrance to the scenario is the acquired resistance to drugs resulting in relapse of the disease. Hence, to provide insights into development of novel therapeutic targets and diagnostic biomarkers, this review focuses on the various molecular mechanisms underlying chemoresistance in HCC. We have provided a comprehensive summary of the various strategies adopted by HCC cells, extending from apoptosis evasion, autophagy activation, drug expulsion to epigenetic transformation as modes of therapy resistance. The role of stem cells in imparting chemoresistance is also discussed. Furthermore, the review also focuses on how this knowledge might be exploited for the development of an effective, prospective therapy against HCC.
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Affiliation(s)
- K Lohitesh
- Department of Biological-Sciences, Birla Institute of Technology and Sciences (BITS), Campus, VidyaVihar, Pilani, Rajasthan 333031 India
| | - Rajdeep Chowdhury
- Department of Biological-Sciences, Birla Institute of Technology and Sciences (BITS), Campus, VidyaVihar, Pilani, Rajasthan 333031 India
| | - Sudeshna Mukherjee
- Department of Biological-Sciences, Birla Institute of Technology and Sciences (BITS), Campus, VidyaVihar, Pilani, Rajasthan 333031 India
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Ray EM, Sanoff HK. Optimal therapy for patients with hepatocellular carcinoma and resistance or intolerance to sorafenib: challenges and solutions. J Hepatocell Carcinoma 2017; 4:131-138. [PMID: 29184856 PMCID: PMC5687453 DOI: 10.2147/jhc.s124366] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The only US Food and Drug Administration (FDA)-approved first-line systemic therapy for hepatocellular carcinoma (HCC) is sorafenib; however, resistance or intolerance to sorafenib is unfortunately common. In this review, we briefly describe systemic therapies that can be considered for patients with HCC who show resistance or intolerance to sorafenib. For all patients with HCC who need systemic therapy, we strongly advocate for participation in clinical trials. Cytotoxic chemotherapy plays a minor role in the treatment of advanced HCC, with some data supporting the use of FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) and GEMOX (gemcitabine-oxaliplatin). Multi-target kinase inhibitors such as lenvantinib and regorafenib have recently met their primary endpoints as first- and second-line therapy, respectively, with regorafenib now representing the only FDA-approved drug for second-line treatment of HCC. Other targeted therapies remain under investigation, but results so far have not significantly changed clinical practice. Immunotherapy is an interesting area of research in the treatment of HCC with preclinical and early clinical data demonstrating exciting results; thus numerous investigational studies are currently focusing on immunotherapy in the treatment of HCC. While systemic treatment options in HCC remain a challenge for providers, in this review, we summarize the current literature and highlight areas of progress with respect to the treatment of patients with HCC and resistance or intolerance to sorafenib.
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Affiliation(s)
- Emily M Ray
- Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC, USA
| | - Hanna K Sanoff
- Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC, USA
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35
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Patt YZ, Murad W, Fekrazad MH, Baron AD, Bansal P, Boumber Y, Steinberg K, Lee S, Bedrick E, Du R, Lee FC. INST OX-05-024: first line gemcitabine, oxaliplatin, and erlotinib for primary hepatocellular carcinoma and bile duct cancers: a multicenter Phase II trial. Cancer Med 2017; 6:2042-2051. [PMID: 28801995 PMCID: PMC5603839 DOI: 10.1002/cam4.1138] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 04/02/2017] [Accepted: 06/02/2017] [Indexed: 01/07/2023] Open
Abstract
Hepatocellular Carcinoma (HCC) incidence is increasing in the USA. Gemcitabine (G) and oxaliplatin (O) are active in HCC and biliary duct cancer (BDC). Erlotinib (E) is an EGFR tyrosine kinase inhibitor (TKI) with known activity against both. We sought to evaluate the efficacy of the combination G+O+E. Patients with either of the two diagnosis were treated in a phase II trial. Simons 2 stage design was used. A disease-control rate (DCR), complete response (CR) + partial response (PR)+ stable disease (SD) at 24 weeks of ≤20% and >40% (P0 and P1 of 0.2 and 0.4, respectively) were set as undesirable (null) and desirable results. 26 HCC and 7 BDC patients were accrued. In HCC, 1 PR, 10 SD, and 9 PDs were seen. DCR in HCC was 42%. Among seven (7) patients with BDC, one patient was not evaluable; one achieved a long lasting PR, and five patients had SD and DCR was 86%. Median overall survival (OS) times and progression-free survivals (PFS) were 196 and 149 days in HCC and 238 days and not reached in BDC. PFS at 26 weeks in HCC was 41% and at 21 weeks in BDC was 60%. Grade 3 toxicities in >5% of patients were fatigue (12.9%), neutropenia (9.6%), thrombocytopenia (9.6%), and diarrhea (6.4%). G+O+E exceeded both preset P0a and P1 of the primary objective with a PFS of 41% at 26 weeks for HCC and preliminary BDC data may warrant further investigations.
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Affiliation(s)
- Yehuda Z. Patt
- Division of hematology/oncology, Department of medicineUniversity of New Mexico Comprehensive Cancer CenterAlbuquerqueNew Mexico
| | - Waheed Murad
- Division of hematology/oncology, Department of medicineUniversity of New Mexico Comprehensive Cancer CenterAlbuquerqueNew Mexico
- University of California Riverside and Kaiser Permanente RiversideMoreno valleyCalifornia
| | - Mohammed H. Fekrazad
- Division of hematology/oncology, Department of medicineUniversity of New Mexico Comprehensive Cancer CenterAlbuquerqueNew Mexico
- City of Hope National Medical CenterDurateCalifornia
| | - Ari D. Baron
- Pacific Hematology Oncology AssociatesSan FranciscoCalifornia
| | - Pranshu Bansal
- Division of hematology/oncology, Department of medicineUniversity of New Mexico Comprehensive Cancer CenterAlbuquerqueNew Mexico
| | - Yanis Boumber
- Division of hematology/oncology, Department of medicineUniversity of New Mexico Comprehensive Cancer CenterAlbuquerqueNew Mexico
- Fox chase cancer centerPhiladelphiaPennsylvania
| | - Kim Steinberg
- Division of hematology/oncology, Department of medicineUniversity of New Mexico Comprehensive Cancer CenterAlbuquerqueNew Mexico
| | - Sang‐Joon Lee
- Division of hematology/oncology, Department of medicineUniversity of New Mexico Comprehensive Cancer CenterAlbuquerqueNew Mexico
- Division of Epidemiology and BiostatisticsDepartment of MedicineUniversity of New MexicoAlbuquerqueNew Mexico
- Cellitron IncProduct analysis divisionIncheonKorea
| | - Ed Bedrick
- Division of hematology/oncology, Department of medicineUniversity of New Mexico Comprehensive Cancer CenterAlbuquerqueNew Mexico
- Division of Epidemiology and BiostatisticsDepartment of MedicineUniversity of New MexicoAlbuquerqueNew Mexico
| | - Ruofei Du
- Division of hematology/oncology, Department of medicineUniversity of New Mexico Comprehensive Cancer CenterAlbuquerqueNew Mexico
- Division of Epidemiology and BiostatisticsDepartment of MedicineUniversity of New MexicoAlbuquerqueNew Mexico
| | - Fa Chyi Lee
- Division of hematology/oncology, Department of medicineUniversity of New Mexico Comprehensive Cancer CenterAlbuquerqueNew Mexico
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Neuzillet C, de Mestier L, Rousseau B, Mir O, Hebbar M, Kocher HM, Ruszniewski P, Tournigand C. Unravelling the pharmacologic opportunities and future directions for targeted therapies in gastro-intestinal cancers part 2: Neuroendocrine tumours, hepatocellular carcinoma, and gastro-intestinal stromal tumours. Pharmacol Ther 2017; 181:49-75. [PMID: 28723416 DOI: 10.1016/j.pharmthera.2017.07.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the cancer cell molecular biology has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies or small molecule inhibitors directed against proteins that are specifically overexpressed or mutated in cancer cells. These agents, being more specific to cancer cells, were expected to be less toxic than conventional cytotoxic agents. However, their effects have sometimes been disappointing, due to intrinsic or acquired resistance mechanisms, or to an activity restricted to some tumour settings, illustrating the importance of patient selection and early identification of predictive biomarkers of response to these therapies. Targeted agents have provided clinical benefit in many GI cancer types. Particularly, some GI tumours are considered chemoresistant and targeted therapies have offered a new therapeutic base for their management. Hence, somatostatin receptor-directed strategies, sorafenib, and imatinib have revolutioned the management of neuroendocrine tumours (NET), hepatocellular carcinoma (HCC), and gastrointestinal stromal tumours (GIST), respectively, and are now used as first-line treatment in many patients affected by these tumours. However, these agents face problems of resistances and identification of predictive biomarkers from imaging and/or biology. We propose a comprehensive two-part review providing a panoramic approach of the successes and failures of targeted agents in GI cancers to unravel the pharmacologic opportunities and future directions for these agents in GI oncology. In this second part, we will focus on NET, HCC, and GIST, whose treatment relies primarily on targeted therapies.
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Affiliation(s)
- Cindy Neuzillet
- INSERM UMR1149, Beaujon University Hospital (Assistance Publique-Hôpitaux de Paris, AP-HP), Paris 7 Diderot University, 100 Boulevard du Général Leclerc, 92110 Clichy, France; Department of Medical Oncology, Henri Mondor University Hospital (AP-HP), Paris Est Créteil University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; Tumour Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; Barts and The London HPB Centre, The Royal London Hospital, Whitechapel, London E1 1BB, United Kingdom.
| | - Louis de Mestier
- INSERM UMR1149, Beaujon University Hospital (Assistance Publique-Hôpitaux de Paris, AP-HP), Paris 7 Diderot University, 100 Boulevard du Général Leclerc, 92110 Clichy, France; Department of Gastroenterology and Pancreatology, Beaujon University Hospital (AP-HP), Paris 7 Diderot University, 100 Boulevard du Général Leclerc, 92110 Clichy, France
| | - Benoît Rousseau
- Department of Medical Oncology, Henri Mondor University Hospital (AP-HP), Paris Est Créteil University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; Institut Mondor de Recherche Biomédicale, INSERM UMR955 Team 18, Paris Est Créteil University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France
| | - Olivier Mir
- Department of Cancer Medicine - Sarcoma Group, Department of Early Drug Development (DITEP) - Phase 1 Unit, Gustave Roussy Cancer Campus, University of Paris Sud, 114, Rue Edouard Vaillant, 94800 Villejuif, France
| | - Mohamed Hebbar
- Department of Medical Oncology, Lille University Hospital, 1, Rue Polonovski, 59037 Lille, France
| | - Hemant M Kocher
- Tumour Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; Barts and The London HPB Centre, The Royal London Hospital, Whitechapel, London E1 1BB, United Kingdom
| | - Philippe Ruszniewski
- INSERM UMR1149, Beaujon University Hospital (Assistance Publique-Hôpitaux de Paris, AP-HP), Paris 7 Diderot University, 100 Boulevard du Général Leclerc, 92110 Clichy, France
| | - Christophe Tournigand
- Department of Medical Oncology, Henri Mondor University Hospital (AP-HP), Paris Est Créteil University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France
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Cidon EU. Systemic treatment of hepatocellular carcinoma: Past, present and future. World J Hepatol 2017; 9:797-807. [PMID: 28706578 PMCID: PMC5491402 DOI: 10.4254/wjh.v9.i18.797] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Revised: 05/07/2017] [Accepted: 05/12/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common neoplasia which represents the second leading cause of cancer related death. Most cases occur in developing countries, but its incidence is rising in Western countries due to hepatitis C. Although hepatitis therapies have evolved and the HCC screening has increased in several areas, 40% present with advanced disease which is only amenable for palliative systemic treatment. HCC continues posing a challenge, in part due to the inherent chemoresistance of this neoplasia, the pharmacologic challenges due to an ill liver, difficulty in assessing radiological responses accurately, etc. Traditional chemotherapy have shown some responses without clear survival benefit, however, sorafenib demonstrated advantages in survival in advanced HCC when liver function is kept and recently immunotherapy seems to be a promising approach for some patients. This article will briefly expose the most relevant systemic treatment modalities to offer a general view from the past to the future.
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Affiliation(s)
- Esther Una Cidon
- Esther Una Cidon, Department of Medical Oncology, Royal Bournemouth Hospital, Bournemouth BH7 7DW, United Kingdom
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38
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Liu K, Zhang X, Xu W, Chen J, Yu J, Gamble JR, McCaughan GW. Targeting the vasculature in hepatocellular carcinoma treatment: Starving versus normalizing blood supply. Clin Transl Gastroenterol 2017; 8:e98. [PMID: 28617447 PMCID: PMC5518951 DOI: 10.1038/ctg.2017.28] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 04/19/2017] [Indexed: 12/13/2022] Open
Abstract
Traditional treatments for intermediate or advanced stage hepatocellular carcinoma (HCC) such as transarterial chemoembolization (TACE) and anti-angiogenesis therapies were developed to starve tumor blood supply. A new approach of normalizing structurally and functionally abnormal tumor vasculature is emerging. While TACE improves survival in selected patients, the resulting tumor hypoxia stimulates proliferation, angiogenesis, treatment resistance and metastasis, which limits its overall efficacy. Vessel normalization decreases hypoxia and improves anti-tumor immune infiltrate and drug delivery. Several pre-clinical agents aimed at normalizing tumor vasculature in HCC appear promising. Although anti-angiogenic agents with vessel normalizing potential have been trialed in advanced HCC with modest results, to date their primary intention had been to starve the tumor. Judicious use of anti-angiogenic therapies is required to achieve vessel normalization yet avoid excessive pruning of vessels. This balance, termed the normalization window, is yet uncharacterized in HCC. However, the optimal class, dose and schedule of vascular normalization agents, alone or in combination with other therapies needs to be explored further.
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Affiliation(s)
- Ken Liu
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.,Centenary Institute and AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales, Australia
| | - Xiang Zhang
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Weiqi Xu
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Jinbiao Chen
- Centenary Institute and AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales, Australia
| | - Jun Yu
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Jennifer R Gamble
- Centre for the Endothelium, Vascular Biology Program, Centenary Institute, and University of Sydney, Sydney, New South Wales, Australia
| | - Geoffrey W McCaughan
- Centenary Institute and AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales, Australia
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Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with poor prognosis. The incidence of HCC and HCC-related deaths have increased over the last several decades. However, the treatment options for advanced HCC are very limited. Sorafenib remains the only drug approved for systemic treatment for advanced HCC. However, prior to sorafenib era conventional cytotoxic chemotherapies have been studied in advanced HCC. In this review, clinical studies of systemic chemotherapy for advanced HCC will be summarized and discussed.
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Affiliation(s)
- Dae Won Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Chetasi Talati
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Richard Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
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40
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Wu J, Guo J, Cao Q, Wang Y, Chen J, Wang Z, Yuan Z. Autophagy impacts on oxaliplatin-induced hepatocarcinoma apoptosis via the IL-17/IL-17R-JAK2/STAT3 signaling pathway. Oncol Lett 2017; 13:770-776. [PMID: 28356957 PMCID: PMC5351189 DOI: 10.3892/ol.2016.5476] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Accepted: 10/27/2016] [Indexed: 12/22/2022] Open
Abstract
The interleukin (IL)-17/IL-17 receptor (IL-17R) complex has been shown to be important for the regulation of inflammation; however, its role in the regulation of tumor processes has recently emerged as a research focus. The present study demonstrated that oxaliplatin was able to increase the levels of IL-17/IL-17R in hepatocellular carcinoma (HCC) patients and cells lines, and that it had important roles in reducing the susceptibility of the cells to oxaliplatin-induced apoptosis. Furthermore, the expression of autophagy-related proteins was induced by IL-17/IL-17R and autophagy was shown to induce resistance to oxaliplatin in HCC. In addition, the janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway was shown to be an important pathway in the induction of autophagy in response to oxaliplatin. Autopjhagy was inhibited by 3-methyladenine and JAK2/STAT3 signaling was blocked by AG490, which induced apoptosis in SMMC7721 cells treated with oxaliplatin. The results of the present study may help to elucidate the mechanism underlying the role of IL-17/IL-17R-induced autophagy in the chemoresistance of HCC, as well as help to establish and develop measures to overcome chemoresistance in HCC.
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Affiliation(s)
- Jinghua Wu
- Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300000, P.R. China
- Clinical Laboratory, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China
| | - Jiapei Guo
- Clinical Laboratory, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China
| | - Qing Cao
- Clinical Laboratory, Hebei Medical University Second Hospital, Shijiazhuang, Hebei 050000, P.R. China
| | - Yi Wang
- Clinical Laboratory, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China
| | - Junmao Chen
- Clinical Laboratory, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China
| | - Zhigang Wang
- Clinical Laboratory, Tangshan Fengrun Region Second People's Hospital, Tangshan, Hebei 063000, P.R. China
| | - Zhiyong Yuan
- Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300000, P.R. China
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Lin GN, Jiang XM, Peng JW, Xiao JJ, Liu DY, Xia ZJ. Prognostic significance of the peripheral blood absolute monocyte count in patients with locally advanced or metastatic hepatocellular carcinoma receiving systemic chemotherapy. Asian Pac J Cancer Prev 2017; 15:6387-90. [PMID: 25124630 DOI: 10.7314/apjcp.2014.15.15.6387] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The prognostic significance of the circulating absolute monocyte count (AMC) in patients with locally advanced hepatocellular carcinoma (HCC) is uncertain. This study was designed to assess the association of circulating AMC with survival outcomes in patients diagnosed with locally advanced or metastatic HCC receiving systemic chemotherapy. MATERIALS AND METHODS Between January 1, 2005 and December 30, 2012, locally advanced or metastatic HCC patients who had Child-Pugh stage A or B disease and received systemic chemotherapy were retrospectively enrolled. Patient features including gender, age, extrahepatic metastasis, Child-Pugh stage, serum alpha-fetoprotein(AFP) level and AMC were collected to investigate their prognostic impact on overall survival(OS). RESULTS A total of 216 patients were eligible for the study. The optimal cut-off value of AMC for OS analysis was 0.38×10⁹/L. Median OS was 5.84 months in low-AMC group (95% confidence interval [CI], 5.23 to 6.45), and 5.21 months in high-AMC group (95% CI, 4.37 to 6.04; p=0.003). In COX multivariate analysis, elevated AMC remained as an independent prognostic factor for worse OS (HR, 1.578; 95% CI, 1.120 to 2.223, p=0.009). CONCLUSIONS Our results indiicate that circulating AMC is confirmed to be an independent prognostic factor for OS in patients with locally advanced or metastatic HCC receiving systemic chemotherapy.
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Affiliation(s)
- Gui-Nan Lin
- Department of Medical Oncology, Zhongshan Hospital of Sun Yat-sen University, Zhongshan City People's Hospital, Zhongshan, People's Republic of China E-mail :
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Tang SL, Bai MY, Wang JY, Hong PD. Development and application of micro-polysaccharide drug carriers incorporating doxorubicin and superparamagnetic iron oxide for bimodality treatment of hepatocellular carcinoma. Colloids Surf B Biointerfaces 2016; 151:304-313. [PMID: 28040662 DOI: 10.1016/j.colsurfb.2016.12.036] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 11/19/2016] [Accepted: 12/22/2016] [Indexed: 02/07/2023]
Abstract
In this study, we demonstrated a novel polyelectrolyte microparticle, doxorubicin(DOX)-superparamagnetic iron oxide (SPIO)-chondroitin sulfate (CS)/chitosan (CHI)microparticles (MPs), as a drug delivery system for hepatic cancer treatment. We also investigated the properties of these microparticles through composition determination, formulation tests, in vitro study, and in vivo study. The results showed that our DOX-SPIO-CS/CHI MPs had an average diameter of 1.43±0.54μm and exhibited a spherical shape. The encapsulation efficiency of this drug carrier was approximately 31±8.07%, according to our spectroscopic determination. The results of release profile test revealed the sustained-release behavior of DOX-SPIO-CS/CHI MPs, which released 51.5% of DOX within 48h of the testing period. According to the results of a cell viability assay and an animal study, the DOX-SPIO-CS/CHI MPs exhibited stronger cytotoxicity than did free DOX when it was administered to Hep G2 and Huh-6 human liver cancer cell lines in vitro and to nude mice of Hep G2/Huh-6-bearing mice model in vivo.
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Affiliation(s)
- Sung-Ling Tang
- Biomedical Engineering Program, Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei, Taiwan, ROC
| | - Meng-Yi Bai
- Biomedical Engineering Program, Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei, Taiwan, ROC; Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, Taiwan, ROC; Adjunct Appointment to the Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan, ROC.
| | - Jyun-Yi Wang
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, Taiwan, ROC
| | - Po-Da Hong
- Biomedical Engineering Program, Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei, Taiwan, ROC
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Cui X, Lin Z, Chen Y, Mao X, Ni W, Liu J, Zhou H, Shan X, Chen L, Lv J, Shen Z, Duan C, Hu B, Ni R. Upregulated TRIM32 correlates with enhanced cell proliferation and poor prognosis in hepatocellular carcinoma. Mol Cell Biochem 2016; 421:127-137. [PMID: 27573002 DOI: 10.1007/s11010-016-2793-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 08/06/2016] [Indexed: 12/25/2022]
Abstract
Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and the sixth most prevalent human malignancies worldwide. However, the molecular mechanisms underlying hepatocarcinogenesis remain unclear. For HCC patients, there is not only a lack of effective therapeutic targets but also a lack of predictive or prognostic biomarkers. In this article, we reported that TRIM32 was obviously upregulated in HCC tumor tissues and HCC cell lines. Its expression patterns were positively correlated with histological grade, tumor sizes, and HBsAg of HCC patients. TRIM32 expression was a significant predictor for the overall survival time of HCC patients. Moreover, the overexpression of TRIM32 in cells accelerated the G1-S phase transition, promoted cell proliferation rates, and induced the resistance of HCC patients to oxaliplatin. All these findings suggest that TRIM32 might play important roles in the hepatocarcinogenesis. TRIM32 could be a novel direction to explore the mechanism underlying HCC pathogenesis.
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Affiliation(s)
- Xiaopeng Cui
- Department of General Surgery, Affiliated Hospital of Nantong University, Medical College of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Zhipeng Lin
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Yuyan Chen
- Class 5 Grade 13, Clinical Medicine, Medical College, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Xiaofei Mao
- Department of Stomatology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, Liaoning, People's Republic of China
| | - Wenkai Ni
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Jinxia Liu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Huiling Zhou
- Key Laboratory of Neuroregeneration, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Xiaohang Shan
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Lingling Chen
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Jiale Lv
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Zhongyi Shen
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Chengwei Duan
- The Second Peoples' Hospital of Nantong, Nantong, 226001, Jiangsu, People's Republic of China
| | - Baoying Hu
- Basic Medical Research Centre, Medical College, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
| | - Runzhou Ni
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
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Liu L, Zheng YH, Han L, Qin SK. Efficacy and safety of the oxaliplatin-based chemotherapy in the treatment of advanced primary hepatocellular carcinoma: A meta-analysis of prospective studies. Medicine (Baltimore) 2016; 95:e4993. [PMID: 27749557 PMCID: PMC5059059 DOI: 10.1097/md.0000000000004993] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Many clinical studies have demonstrated the survival benefits of oxaliplatin-based chemotherapy for advanced hepatocellular carcinoma patients. Therefore, we aim to evaluate the efficacy and safety of oxaliplatin-based chemotherapy in patients with advanced hepatocellular carcinoma by conducting a meta-analysis of prospective studies. METHODS A comprehensive literature search was performed using the PubMed, Cochrane Library, EMBASE, and Web of Science databases from their inception to June 2016. Only prospective studies evaluating oxaliplatin-based chemotherapy in patients with advanced hepatocellular carcinoma were selected. The main outcomes included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and main adverse events. RESULTS Ten prospective studies involving 525 patients were included. The pooled ORR, 1-year PFS, and OS were 14.4% (95% confidence interval [CI] 9.2-19.6%), 9.3% (95%CI 10-28%), and 35.7% (95%CI 27-44%), respectively, for oxaliplatin-based chemotherapy. The median PFS and OS were 4.7 and 9.4 months, respectively. The incidences of grade 3/4 toxicities of neutropenia, thrombopenia, anemia, neurotoxicity, diarrhea, and nausea/vomiting were 17.2%, 9.2%, 6.0%, 4.8%, 3.1%, and 1.8%, respectively. Subgroup analysis revealed that the pooled ORR was 13.9% (95%CI 6.8-21%) in Asian patients and 12.8% (95%CI 6.8-18.7%) in Western patients. For Asian patients, the median PFS and OS were 4.2 and 9.2 months, and the 1-year PFS and OS were 12.5% and 30.5%, respectively. For Western patients, the median PFS and OS were 4.7 and 9.5 months, and the 1-year PFS and OS were 19.6% and 42.4%, respectively. There were no significant differences in the ORR, 1-year PFS, and OS (P > 0.05) between Asian and Western patients. CONCLUSIONS Oxaliplatin-based chemotherapy appears to be effective and safe for the treatment of advanced hepatocellular carcinoma.
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Affiliation(s)
- Lin Liu
- Department of Oncology, Zhong-Da Hospital, School of Medicine, Southeast University
- Department of Oncology, 81st Hospital of the Chinese People's Liberation Army, Nanjing, Jiangsu, China
- Correspondence: Lin Liu, Department of Oncology, Zhong-Da Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China (e-mail: ); Shu-Kui Qin, Department of Oncology, the 81 Hospital of the Chinese People's Liberation Army, Nanjing, Jiangsu, China (e-mail: )
| | - Ying-hui Zheng
- Department of Oncology, Zhong-Da Hospital, School of Medicine, Southeast University
| | - Li Han
- Department of Oncology, Zhong-Da Hospital, School of Medicine, Southeast University
| | - Shu-Kui Qin
- Department of Oncology, 81st Hospital of the Chinese People's Liberation Army, Nanjing, Jiangsu, China
- Correspondence: Lin Liu, Department of Oncology, Zhong-Da Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China (e-mail: ); Shu-Kui Qin, Department of Oncology, the 81 Hospital of the Chinese People's Liberation Army, Nanjing, Jiangsu, China (e-mail: )
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Shrum B, Costello P, McDonald W, Howlett C, Donnelly M, McAlister VC. In vitro three dimensional culture of hepatocellular carcinoma to measure prognosis and responsiveness to chemotherapeutic agents. Hepatobiliary Surg Nutr 2016; 5:204-8. [PMID: 27275461 DOI: 10.21037/hbsn.2016.01.01] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Understanding the prognosis of hepatocellular carcinoma (HCC) informs plans for care. Tumor morphology and molecular markers have been correlated with outcomes. Three-dimensional tissue culture (3DTC) allows for direct in vitro measurement of a tumor's ability to grow and metastasize. The impact of chemotherapeutic agents, alone or in combinations, may also be measured. METHODS All patients with a presumed diagnosis of HCC were eligible for this study including those undergoing resection, chemoembolization and transplantation. Concomitant diseases and outcomes were recorded. One mm(3) HCC specimens were grown in multiwell plates containing gel media, without and with chemotherapeutic agents. RESULTS Tumors were sampled from 17 patients. Only 13 had HCC, all of whom had liver transplantation. Of the confirmed HCC patients, 6 (46%) are alive and disease free 82 months following transplantation, 1 (7%) is alive with recurrence of disease and 6 (46%) died, with a mean survival of 12 months post liver transplant. Ten of thirteen 3DTC samples grew, having an average migration distance of 108.3µm in the first 24 hours. Two of three patients who had prior chemoembolization had successful 3DTC. Migration distances (µm) were 188.8±104.3, 104.5±111.7 and 39.6±32.4 for tumors categorized as high, intermediate and low grade, respectively. Tumor migration was inhibited by irinotecan, paclitaxel and docetaxel (-68%±7%, -61%±19% and -60%±21%, respectively) whereas the effect was variable with 5 fluorouracil (5FU) and doxorubicin (-12%±51% and 9%±76%, respectively). CONCLUSIONS It is feasible to grow tissue from HCC in 3DTC to study the tumor's capacity to grow and migrate and its responsiveness to commonly used chemotherapeutic protocols.
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Affiliation(s)
- Brad Shrum
- 1 General Surgery Experimental Laboratory, University Hospital, London, ON, Canada ; 2 Department of Pathology, London Health Sciences Centre, London, ON, Canada
| | - Penny Costello
- 1 General Surgery Experimental Laboratory, University Hospital, London, ON, Canada ; 2 Department of Pathology, London Health Sciences Centre, London, ON, Canada
| | - Warren McDonald
- 1 General Surgery Experimental Laboratory, University Hospital, London, ON, Canada ; 2 Department of Pathology, London Health Sciences Centre, London, ON, Canada
| | - Christopher Howlett
- 1 General Surgery Experimental Laboratory, University Hospital, London, ON, Canada ; 2 Department of Pathology, London Health Sciences Centre, London, ON, Canada
| | - Marisa Donnelly
- 1 General Surgery Experimental Laboratory, University Hospital, London, ON, Canada ; 2 Department of Pathology, London Health Sciences Centre, London, ON, Canada
| | - Vivian C McAlister
- 1 General Surgery Experimental Laboratory, University Hospital, London, ON, Canada ; 2 Department of Pathology, London Health Sciences Centre, London, ON, Canada
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Nguyen K, Jack K, Sun W. Hepatocellular Carcinoma: Past and Future of Molecular Target Therapy. Diseases 2015; 4:E1. [PMID: 28933381 PMCID: PMC5456309 DOI: 10.3390/diseases4010001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 12/03/2015] [Accepted: 12/16/2015] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer related mortality worldwide. The incidence of HCC has been increasing annually. Viral infection, alcohol usage, and other causes of cirrhosis have been identified as major risk factors for HCC development. The underlying pathogenesis has not been as well defined. There have been multiple hypotheses to the specific mechanisms of hepatocarcinogenesis and they share the common theme of chronic inflammation, increase oxidative stress, and genomic alteration. Therapeutic options of HCC have been primarily local and/or regional including transplantation, resection, and radial frequency ablation, chemoembolization or radio-embolization. For unresectable or metastatic disease, the options are limited. Conventional chemotherapeutic options have been noted to have limited benefit. Sorafenib has been the one and only systemic therapy which has demonstrated modest overall survival benefit. This has led to more extensive research with focus on targeted therapy. Numerous pre-clinical and early phase clinical studies have been noted but failed to show efficacy in later phase clinical trials. In an effort to identify new potential therapeutic options, new understanding of underlying pathways to hepatocarcinogenesis should be one of the main focuses. This leads to development of more molecularly targeted agents to specific pathways, and immunotherapy. This article provides a review of major studies of molecular targeted agents which attempts to target these specific pathways in HCC.
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Affiliation(s)
- Khanh Nguyen
- University of Pittsburgh Medical Center, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5150 Center Ave. 5th floor, Pittsburgh, PA 15232, USA.
| | - Kerri Jack
- University of Pittsburgh Medical Center, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5150 Center Ave. 5th floor, Pittsburgh, PA 15232, USA.
| | - Weijing Sun
- University of Pittsburgh Medical Center, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5150 Center Ave. 5th floor, Pittsburgh, PA 15232, USA.
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Qin S, Gong X. Progression of systemic chemotherapy with oxaliplatin-containing regimens for advanced hepatocellular carcinoma in China. Hepat Oncol 2015; 3:71-81. [PMID: 30191027 DOI: 10.2217/hep.15.42] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 07/29/2015] [Indexed: 12/29/2022] Open
Abstract
Hepatocellular carcinoma (HCC) characterized by insidious onset is a highly invasive malignance and has a rapid progress. The majority of patients, especially in Asian countries, present with locally advanced or distant metastatic disease at diagnosis and are not eligible for local treatment. Before the publication of the EACH study results showing the survival benefits of the FOLFOX 4 regimen in Chinese patients with advanced HCC, no chemotherapeutical drug or regimen was considered as systemic chemotherapy standard for this group of patients due to the lack of evidence-based recommendations. Oxaliplatin-containing regimens have shown clinical activity against advanced HCC with an acceptable safety profile. The aim of this article is to present a review of the scientific evidence mainly originating from China that supports the recommendation of oxaliplatin-based regimens for the treatment of Chinese patients with advanced HCC.
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Affiliation(s)
- Shukui Qin
- Chinese People's Liberation Army Cancer Center, Bayi Hospital, Nanjing, 210002, China
| | - Xinlei Gong
- Chinese People's Liberation Army Cancer Center, Bayi Hospital, Nanjing, 210002, China
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Becq A, Mateescu C, Khayat D, Bouattour M. Atypical Presentation of Hepatocellular Carcinoma Mimicking a Gastric Hepatoid Adenocarcinoma: A Case Report. Medicine (Baltimore) 2015; 94:e1101. [PMID: 26166099 PMCID: PMC4504550 DOI: 10.1097/md.0000000000001101] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Revised: 06/09/2015] [Accepted: 06/09/2015] [Indexed: 01/29/2023] Open
Abstract
The diagnosis of hepatocellular carcinoma (HCC) relies on imaging tools and biopsy. It usually does not present to be a challenge.Here we report the case of a 69-year-old patient with HCC, initially mistaken for a gastric hepatoid adenocarcinoma (HAC), with a favorable outcome after neoadjuvant chemotherapy.The initial presentation (clinical signs, morphological features, and histological findings) led to the diagnosis of a gastric hepatoid adenocarcinoma. Neoadjuvant chemotherapy by epirubicin, oxaliplatin, and capecitabine protocol was administered. Biological (alpha-fetoprotein [AFP] decreased by a factor of 10), radiological (-35% RECIST), and histological (20% of necrosis) responses were observed. Complete surgical resection was then performed. The final pathological diagnosis was a well-differentiated HCC, staged pT4 N0 (0/24) R0.There are no guidelines as to how such tumors should be managed. Nonetheless, neoadjuvant chemotherapy yielded a good outcome. This observation stresses the importance of the final pathological findings and addresses the issue of neoadjuvant therapy in some cases of HCC.
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Affiliation(s)
- Aymeric Becq
- From the Department of Medical Oncology (AB, CM, MB), Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), Clichy; Department of Medical Oncology (CM, DK), La Pitié Salpêtrière University Hospital (AP-HP - PRES Paris 6 Pierre et Marie Curie), Paris; and Department of Hepatology (MB), Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), Clichy, France
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Kuang Y, El-Khoueiry A, Taverna P, Ljungman M, Neamati N. Guadecitabine (SGI-110) priming sensitizes hepatocellular carcinoma cells to oxaliplatin. Mol Oncol 2015; 9:1799-814. [PMID: 26160429 DOI: 10.1016/j.molonc.2015.06.002] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2014] [Revised: 05/10/2015] [Accepted: 06/05/2015] [Indexed: 12/14/2022] Open
Abstract
Promoter DNA hypermethylation is an important biomarker of hepatocellular carcinoma (HCC), supporting the potential utility of demethylating agents in this disease. Guadecitabine (SGI-110) is a second-generation hypomethylating agent formulated as a dinucleotide of decitabine and deoxyguanosine that yields longer half-life and more extended decitabine exposure than decitabine IV infusion. Here we performed preclinical evaluation of SGI-110 in HCC models to guide the design of a phase I/II clinical trial. HCC cell lines and xenograft models were used to determine the antitumor activity of SGI-110 as a single agent and in combination with oxaliplatin. Pretreatment with low doses of SGI-110 significantly synergized with oxaliplatin yielding enhanced cytotoxicity. The combination of SGI-110 and oxaliplatin was well tolerated and significantly delayed tumor growth in mice compared to oxaliplatin alone. Bromouridine-labeled RNA sequencing (Bru-seq) was employed to elucidate the effects of SGI-110 and/or oxaliplatin on genome-wide transcription. SGI-110 and the combination treatment inhibited the expression of genes involved in WNT/EGF/IGF signaling. DNMT1 and survivin were identified as novel PD markers to monitor the efficacy of the combination treatment. In conclusion, SGI-110 priming sensitizes HCC cells to oxaliplatin by inhibiting distinct signaling pathways. We expect that this combination treatment will show low toxicity and high efficacy in patients. Our study supports the use of the combination of low doses of SGI-110 and oxaliplatin in HCC patients.
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Affiliation(s)
- Yuting Kuang
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA; Department of Medicinal Chemistry, College of Pharmacy, Translational Oncology Program, University of Michigan, Ann Arbor, MI, USA
| | - Anthony El-Khoueiry
- Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | | | - Mats Ljungman
- Department of Radiation Oncology, Translational Oncology Program, University of Michigan, Ann Arbor, MI, USA
| | - Nouri Neamati
- Department of Medicinal Chemistry, College of Pharmacy, Translational Oncology Program, University of Michigan, Ann Arbor, MI, USA.
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2014 KLCSG-NCC Korea Practice Guideline for the Management of Hepatocellular Carcinoma. Gut Liver 2015; 9:267-317. [PMID: 25918260 PMCID: PMC4413964 DOI: 10.5009/gnl14460] [Citation(s) in RCA: 101] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 03/09/2015] [Indexed: 12/23/2022] Open
Abstract
The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group and the National Cancer Center, Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. The primary targets of this guideline are patients with suspicious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC.
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