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Zeng ZM, Mo N, Zeng J, Ma FC, Jiang YF, Huang HS, Liao XW, Zhu GZ, Ma J, Peng T. Advances in postoperative adjuvant therapy for primary liver cancer. World J Gastrointest Oncol 2022; 14:1604-1621. [PMID: 36187393 PMCID: PMC9516643 DOI: 10.4251/wjgo.v14.i9.1604] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 05/13/2022] [Accepted: 07/26/2022] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous, invasive, and conventional chemotherapy-insensitive tumor with unique biological characteristics. The main methods for the radical treatment of HCC are surgical resection or liver transplantation. However, recurrence rates are as high as 50% and 70% at 3 and 5 years after liver resection, respectively, and even in Milan-eligible recipients, the recurrence rate is approximately 20% at 5 years after liver transplantation. Therefore, reducing the postoperative recurrence rate is key to improving the overall outcome of liver cancer. This review discusses the risk factors for recurrence in patients with HCC radical surgical resection and adjuvant treatment options that may reduce the risk of recurrence and improve overall survival, including local adjuvant therapy (e.g., transcatheter arterial chemoembolization), adjuvant systemic therapy (e.g., molecular targeted agents and immunotherapy), and other adjuvant therapies (e.g., antiviral and herbal therapy). Finally, potential research directions that may change the paradigm of adjuvant therapy for HCC are analyzed.
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Affiliation(s)
- Zhi-Ming Zeng
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Ning Mo
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jie Zeng
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Fu-Chao Ma
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yan-Feng Jiang
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Hua-Sheng Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xi-Wen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Guang-Zhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jie Ma
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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Álvarez-Mercado AI, Caballeria-Casals A, Rojano-Alfonso C, Chávez-Reyes J, Micó-Carnero M, Sanchez-Gonzalez A, Casillas-Ramírez A, Gracia-Sancho J, Peralta C. Insights into Growth Factors in Liver Carcinogenesis and Regeneration: An Ongoing Debate on Minimizing Cancer Recurrence after Liver Resection. Biomedicines 2021; 9:1158. [PMID: 34572344 PMCID: PMC8470173 DOI: 10.3390/biomedicines9091158] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/29/2021] [Accepted: 09/01/2021] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma has become a leading cause of cancer-associated mortality throughout the world, and is of great concern. Currently used chemotherapeutic drugs in the treatment of hepatocellular carcinoma lead to severe side effects, thus underscoring the need for further research to develop novel and safer therapies. Liver resection in cancer patients is routinely performed. After partial resection, liver regeneration is a perfectly calibrated response apparently sensed by the body's required liver function. This process hinges on the effect of several growth factors, among other molecules. However, dysregulation of growth factor signals also leads to growth signaling autonomy and tumor progression, so control of growth factor expression may prevent tumor progression. This review describes the role of some of the main growth factors whose dysregulation promotes liver tumor progression, and are also key in regenerating the remaining liver following resection. We herein summarize and discuss studies focused on partial hepatectomy and liver carcinogenesis, referring to hepatocyte growth factor, insulin-like growth factor, and epidermal growth factor, as well as their suitability as targets in the treatment of hepatocellular carcinoma. Finally, and given that drugs remain one of the mainstay treatment options in liver carcinogenesis, we have reviewed the current pharmacological approaches approved for clinical use or research targeting these factors.
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Affiliation(s)
- Ana I. Álvarez-Mercado
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
- Institute of Nutrition and Food Technology, Biomedical Research Center, University of Granada, 18016 Armilla, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain
| | - Albert Caballeria-Casals
- Hepatic Ischemia-Reperfusion Injury Department, Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (C.R.-A.); (M.M.-C.)
| | - Carlos Rojano-Alfonso
- Hepatic Ischemia-Reperfusion Injury Department, Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (C.R.-A.); (M.M.-C.)
| | - Jesús Chávez-Reyes
- Facultad de Medicina e Ingeniería en Sistemas Computacionales Matamoros, Universidad Autónoma de Tamaulipas, Matamoros 87300, Mexico; (J.C.-R.); (A.C.-R.)
| | - Marc Micó-Carnero
- Hepatic Ischemia-Reperfusion Injury Department, Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (C.R.-A.); (M.M.-C.)
| | - Alfredo Sanchez-Gonzalez
- Teaching and Research Department, Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, Ciudad Victoria 87087, Mexico;
| | - Araní Casillas-Ramírez
- Facultad de Medicina e Ingeniería en Sistemas Computacionales Matamoros, Universidad Autónoma de Tamaulipas, Matamoros 87300, Mexico; (J.C.-R.); (A.C.-R.)
- Teaching and Research Department, Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, Ciudad Victoria 87087, Mexico;
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, CIBEREHD, 03036 Barcelona, Spain;
- Barcelona Hepatic Hemodynamic Laboratory, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain
| | - Carmen Peralta
- Hepatic Ischemia-Reperfusion Injury Department, Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (C.R.-A.); (M.M.-C.)
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Esagian SM, Kakos CD, Giorgakis E, Burdine L, Barreto JC, Mavros MN. Adjuvant Transarterial Chemoembolization Following Curative-Intent Hepatectomy Versus Hepatectomy Alone for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Cancers (Basel) 2021; 13:2984. [PMID: 34203692 PMCID: PMC8232114 DOI: 10.3390/cancers13122984] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/07/2021] [Accepted: 06/09/2021] [Indexed: 02/07/2023] Open
Abstract
The role of adjuvant transarterial chemoembolization (TACE) for patients with resectable hepatocellular carcinoma (HCC) undergoing hepatectomy is currently unclear. We performed a systematic review of the literature using the MEDLINE, Embase, and Cochrane Library databases. Random-effects meta-analysis was carried out to compare the overall survival (OS) and recurrence-free survival (RFS) of patients with resectable HCC undergoing hepatectomy followed by adjuvant TACE vs. hepatectomy alone in randomized controlled trials (RCTs). The risk of bias was assessed using the Risk of Bias 2.0 tool. Meta-regression analyses were performed to explore the effect of hepatitis B viral status, microvascular invasion, type of resection (anatomic vs. parenchymal-sparing), and tumor size on the outcomes. Ten eligible RCTs, reporting on 1216 patients in total, were identified. The combination of hepatectomy and adjuvant TACE was associated with superior OS (hazard ratio (HR): 0.66, 95% confidence interval (CI): 0.52 to 0.85; p < 0.001) and RFS (HR: 0.70, 95% CI: 0.56 to 0.88; p < 0.001) compared to hepatectomy alone. There were significant concerns regarding the risk of bias in most of the included studies. Overall, adjuvant TACE may be associated with an oncologic benefit in select HCC patients. However, the applicability of these findings may be limited to Eastern Asian populations, due to the geographically restricted sample. High-quality multinational RCTs, as well as predictive tools to optimize patient selection, are necessary before adjuvant TACE can be routinely implemented into standard practice. PROSPERO Registration ID: CRD42021245758.
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Affiliation(s)
- Stepan M. Esagian
- Oncology Working Group, Society of Junior Doctors, 15123 Athens, Greece;
| | - Christos D. Kakos
- Surgery Working Group, Society of Junior Doctors, 15123 Athens, Greece;
| | - Emmanouil Giorgakis
- Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (E.G.); (L.B.); (J.C.B.)
| | - Lyle Burdine
- Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (E.G.); (L.B.); (J.C.B.)
| | - J. Camilo Barreto
- Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (E.G.); (L.B.); (J.C.B.)
| | - Michail N. Mavros
- Surgery Working Group, Society of Junior Doctors, 15123 Athens, Greece;
- Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; (E.G.); (L.B.); (J.C.B.)
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Yu MC, Wu TH, Lee CW, Lee YS, Lian JH, Tsai CL, Hsieh SY, Tsai CN. Percentage genome change and chromosome 7q amplification predict sorafenib response in advanced hepatocellular carcinoma. Biomed J 2020; 44:S73-S83. [PMID: 35747997 PMCID: PMC9038951 DOI: 10.1016/j.bj.2020.07.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Revised: 07/05/2020] [Accepted: 07/13/2020] [Indexed: 12/24/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) may arise from genomic instability and has dismal outcome. Sorafenib is the first-line treatment for advanced stage HCC, but its therapeutic efficacy is less than 50%. Biomarkers for predicting the therapeutic efficacy of sorafenib administration to patients with advanced HCC are required. Here, we evaluated the role of chromosomal copy number aberrations (CNAs) in patients with advanced HCC who were treated with sorafenib along with their drug response. Methods The response to sorafenib treatment of twenty-three HCC patients who developed advanced recurrence after partial hepatectomy was analyzed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Formalin fixed paraffin embedded (FFPE) tissue specimens obtained after tumor resection were analyzed using the Affymetrix OncoScan® FFPE assay. Results From the 23 patients analyzed in this study, 7 (30.4%) had complete/partial response to sorafenib (CR/PR), 7 (30.4%) had stable disease (SD), and 9 (39.1%) had progressive disease (PD). The mean genome-wide percentage of genome change acquisition via the OncoScan platform was 19.8% for patients with CR/PR/SD and 50.02% in the PD group (p = 0.055). Percentage of genome change above 33% was associated with adverse outcomes for sorafenib treatment in the time-to-progression analysis (p = 0.007) and overall survival (p = 0.096). Among these CNAs, amplification of chromosome 7q, containing the multidrug resistance gene ATP Binding Cassette Subfamily B Member 1 (ACBC1), significantly associated with poor overall survival (p = 0.004) and time-to-progression (p < 0.001). Conclusions Higher percentage genome change and amplification of chromosome 7q in advanced HCC is associated with sorafenib resistance.
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Kumar A, Acharya SK, Singh SP, Arora A, Dhiman RK, Aggarwal R, Anand AC, Bhangui P, Chawla YK, Datta Gupta S, Dixit VK, Duseja A, Kalra N, Kar P, Kulkarni SS, Kumar R, Kumar M, Madhavan R, Mohan Prasad V, Mukund A, Nagral A, Panda D, Paul SB, Rao PN, Rela M, Sahu MK, Saraswat VA, Shah SR, Shalimar, Sharma P, Taneja S, Wadhawan M, The INASL Task-Force on Hepatocellular Carcinoma. 2019 Update of Indian National Association for Study of the Liver Consensus on Prevention, Diagnosis, and Management of Hepatocellular Carcinoma in India: The Puri II Recommendations. J Clin Exp Hepatol 2020; 10:43-80. [PMID: 32025166 PMCID: PMC6995891 DOI: 10.1016/j.jceh.2019.09.007] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 09/15/2019] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality, and healthcare expenditure in patients with chronic liver disease in India. The Indian National Association for Study of the Liver (INASL) had published its first guidelines on diagnosis and management of HCC (The Puri Recommendations) in 2014, and these guidelines were very well received by the healthcare community involved in diagnosis and management of HCC in India and neighboring countries. However, since 2014, many new developments have taken place in the field of HCC diagnosis and management, hence INASL endeavored to update its 2014 consensus guidelines. A new Task Force on HCC was constituted that reviewed the previous guidelines as well as the recent developments in various aspects of HCC that needed to be incorporated in the new guidelines. A 2-day round table discussion was held on 5th and 6th May 2018 at Puri, Odisha, to discuss, debate, and finalize the revised consensus statements. Each statement of the guideline was graded according to the Grading of Recommendations Assessment Development and Evaluation system with minor modifications. We present here the 2019 Update of INASL Consensus on Prevention, Diagnosis, and Management of Hepatocellular Carcinoma in India: The Puri-2 Recommendations.
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Key Words
- AFP, alpha-fetoprotein
- AIH, autoimmune hepatitis
- ALT, alanine aminotransferase
- DAA, direct-acting antiviral
- DALY, disability-adjusted life-year
- DNA, deoxyribonucleic acid
- GRADE, Grading of Recommendations Assessment Development and Evaluation
- Gd-BOPTA, gadolinium benzyloxypropionictetraacetate
- Gd-EOB-DTPA, gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid
- HBV, hepatitis B virus
- HBeAg, hepatitis B envelope antigen
- HCC, hepatocellular carcinoma
- HIV, human immunodeficiency virus
- IARC, International Agency for Research on Cancer
- IFN, interferon
- INASL, Indian National Association for Study of the Liver
- MiRNA, micro-RNA
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- PIVKA, protein induced by vitamin K absence
- RFA
- RNA, ribonucleic acid
- SVR, sustained virological response
- TACE
- TACE, trans-arterial chemoembolization
- TARE, transarterial radioembolization
- TNF, tumor necrosis factor
- WHO, World Health Organization
- liver cancer
- targeted therapy
- transplant
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Affiliation(s)
- Ashish Kumar
- Institute of Liver Gastroenterology & Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India
| | - Subrat K. Acharya
- Department of Gastroenterology and Hepatology, KIIT University, Patia, Bhubaneswar, Odisha, 751 024, India
| | - Shivaram P. Singh
- Department of Gastroenterology, SCB Medical College, Cuttack, Dock Road, Manglabag, Cuttack, Odisha, 753 007, India
| | - Anil Arora
- Institute of Liver Gastroenterology & Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India
| | - Radha K. Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Rakesh Aggarwal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh, 226 014, India
| | - Anil C. Anand
- Department of Gastroenterology, Indraprastha Apollo Hospital, Sarita Vihar, New Delhi, 110 076, India
| | - Prashant Bhangui
- Medanta Institute of Liver Transplantation and Regenerative Medicine, Medanta the Medicity, CH Baktawar Singh Road, Sector 38, Gurugram, Haryana, 122 001, India
| | - Yogesh K. Chawla
- Department of Gastroenterology, Kalinga Institute of Medical Sciences (KIMS), Kushabhadra Campus (KIIT Campus-5), Patia, Bhubaneswar, Odisha, 751 024, India
| | - Siddhartha Datta Gupta
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Vinod K. Dixit
- Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, 221 005, India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Naveen Kalra
- Department of Radio Diagnosis and Imaging, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Premashish Kar
- Department of Gastroenterology and Hepatology, Max Super Speciality Hospital, Vaishali, Ghaziabad, Uttar Pradesh, 201 012, India
| | - Suyash S. Kulkarni
- Division of Interventional Radiology, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai, Maharashtra, 400 012, India
| | - Rakesh Kumar
- Department of Nuclear Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver & Biliary Sciences, Sector D-1, Vasant Kunj, New Delhi, 110 070, India
| | - Ram Madhavan
- Department of Radiation Oncology, Amrita Institute of Medical Sciences, Amrita University, Peeliyadu Road, Ponekkara, Edappally, Kochi, Kerala, 682 041, India
| | - V.G. Mohan Prasad
- Department of Gastroenterology, VGM Gastro Centre, 2100, Trichy Road, Rajalakshmi Mills Stop, Singanallur, Coimbatore, Tamil Nadu, 641 005, India
| | - Amar Mukund
- Department of Radiology, Institute of Liver & Biliary Sciences, Sector D-1, Vasant Kunj, New Delhi, 110 070, India
| | - Aabha Nagral
- Department of Gastroenterology, Jaslok Hospital & Research Centre, 15, Dr Deshmukh Marg, Pedder Road, Mumbai, Maharashtra, 400 026, India
| | - Dipanjan Panda
- Department of Oncology, Institutes of Cancer, Indraprastha Apollo Hospital, Sarita Vihar, New Delhi, 110 076, India
| | - Shashi B. Paul
- Department of Radiodiagnosis, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Padaki N. Rao
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, No. 6-3-661, Punjagutta Road, Somajiguda, Hyderabad, Telangana, 500 082, India
| | - Mohamed Rela
- The Institute of Liver Disease & Transplantation, Gleneagles Global Health City, 439, Cheran Nagar, Perumbakkam, Chennai, Tamil Nadu, 600 100, India
| | - Manoj K. Sahu
- Department of Medical Gastroenterology, IMS & SUM Hospital, K8 Kalinga Nagar, Shampur, Bhubaneswar, Odisha 751 003, India
| | - Vivek A. Saraswat
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh, 226 014, India
| | - Samir R. Shah
- Department of Gastroenterology, Jaslok Hospital & Research Centre, 15, Dr Deshmukh Marg, Pedder Road, Mumbai, Maharashtra, 400 026, India
| | - Shalimar
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Praveen Sharma
- Institute of Liver Gastroenterology & Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India
| | - Sunil Taneja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Manav Wadhawan
- Liver & Digestive Diseases Institute, Institute of Liver & Digestive Diseases, BLK Super Specialty Hospital, Delhi, 110 005, India
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Vennarecci G, Ferraro D, Tudisco A, Levi Sandri GB, Guglielmo N, Berardi G, Sperduti I, Ettorre GM. The ALPPS procedure: hepatocellular carcinoma as a main indication. An Italian single-center experience. Updates Surg 2019; 71:67-75. [PMID: 30255436 DOI: 10.1007/s13304-018-0596-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 09/10/2018] [Indexed: 12/15/2022]
Abstract
The ALPPS is a technique that allows achieving hepatic resection by a rapid future liver remnant hypertrophy. The aim of this study was to report the experience of an Italian center with ALPPS in patients with liver tumors. A retrospective analysis of patients undergoing ALPPS between 2012 and 2017 was performed. Patients' characteristics and disease presentation, increase in future liver remnant (FLR) as well as intraoperative and postoperative short- and long-term outcomes were evaluated. A total of 24 patients underwent the ALPPS procedure: 17 procedures for hepatocarcinoma (HCC), 5 for colorectal liver metastases (CRLM), 1 for cholangiocarcinoma (CC) and 1 for Merkel Cell Carcinoma liver metastasis (MCCLM). Macrovascular invasion (MVI) was recorded in 10 (41.6%) patients: 8 (33.3%) patients with HCC had invasion of portal vein (5), middle hepatic vein (2) and inferior vena cava (1). One patient with CRLM had involvement of middle hepatic vein and one patient with CC had involvement of right portal vein and middle hepatic vein. A p-ALPPS in 14 cases (58.3%), 10 t-ALPPS (41.6%) and hanging maneuver in 19 patients (80%) were performed. Median postoperative stay was 26 days (range 16-68 days). 90-day mortality was 8.3% (two patients, one with CC and one with HCC), 90-day mortality for HCC was 5.8%. After stage 1, we counted 15 complications all of grade I; after stage 2 the number of complications was increased to 37:33 were of grade I and 4 were of grade IV. R0 resection was achieved in all patients with 100% oncology feasibility. After a median follow-up of 10 months (range 2-54), disease recurrence has been recorded in 6 patients with HCC and in 2 with CRLM. Eleven patients died, nine affected by HCC, one by CRLM, and one by CC. 2-years OS and disease-free survival (DFS) for the entire group were 47.3% and 47.5%, respectively. Concerning patients operated on for HCC, the 2-years OS and DFS were 38.5% and 60%, respectively. The ALPPS procedure is an interesting approach for large primary or secondary liver tumor with small FLR above all for large HCC associated with MVI, with acceptable OS and DFS.
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Affiliation(s)
- Giovanni Vennarecci
- Division of General Surgery and Liver Transplantation, S. Camillo Hospital, Circ.ne Gianicolense 87, 00151, Rome, Italy.
| | - Daniele Ferraro
- Division of General Surgery and Liver Transplantation, S. Camillo Hospital, Circ.ne Gianicolense 87, 00151, Rome, Italy
| | - Antonella Tudisco
- Division of General Surgery and Liver Transplantation, S. Camillo Hospital, Circ.ne Gianicolense 87, 00151, Rome, Italy
| | - Giovanni Battista Levi Sandri
- Division of General Surgery and Liver Transplantation, S. Camillo Hospital, Circ.ne Gianicolense 87, 00151, Rome, Italy
| | - Nicola Guglielmo
- Division of General Surgery and Liver Transplantation, S. Camillo Hospital, Circ.ne Gianicolense 87, 00151, Rome, Italy
| | - Giammauro Berardi
- Division of General Surgery and Liver Transplantation, S. Camillo Hospital, Circ.ne Gianicolense 87, 00151, Rome, Italy
| | - Isabella Sperduti
- Biostatistical Unit, Regina Elena National Cancer Institute, Rome, Italy
| | - Giuseppe Maria Ettorre
- Division of General Surgery and Liver Transplantation, S. Camillo Hospital, Circ.ne Gianicolense 87, 00151, Rome, Italy
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Dai J, Huang Q, Niu K, Wang B, Li Y, Dai C, Chen Z, Tao K, Dai J. Sestrin 2 confers primary resistance to sorafenib by simultaneously activating AKT and AMPK in hepatocellular carcinoma. Cancer Med 2018; 7:5691-5703. [PMID: 30311444 PMCID: PMC6247041 DOI: 10.1002/cam4.1826] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 09/04/2018] [Accepted: 09/10/2018] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the malignancy derived from normal hepatocytes with increasing incidence and extremely poor prognosis worldwide. The only approved first‐line systematic treatment agent for HCC, sorafenib, is capable to effectively improve advanced HCC patients’ survival. However, it is gradually recognized that the therapeutic response to sorafenib could be drastically diminished after short‐term treatment, defined as primary resistance. The present study is aimed to explore the role of stress‐inducible protein Sestrin2 (SESN2), one of the most important sestrins family members, in sorafenib primary resistance. Herein, we initially found that SESN2 expression was significantly up‐regulated in both HCC cell lines and tissues compared to normal human hepatocytes and corresponding adjacent liver tissues, respectively. In addition, SESN2 expression was highly correlated with sorafenib IC50 of HCC cell lines. Thereafter, we showed that sorafenib treatment resulted in an increase of SESN2 expression and the knockdown of SESN2 exacerbated sorafenib‐induced proliferation inhibition and cell apoptosis. Further mechanistic study uncovered that SESN2 deficiency impaired both AKT and AMPK phosphorylation and activation after sorafenib treatment. Moreover, the correlations between SESN2 expression and both phosphor‐AKT and phosphor‐AMPK expression were illustrated in HCC tissues. Taken together, our study demonstrates that SESN2 activates AKT and AMPK signaling as a novel mechanism to induce sorafenib primary resistance in HCC.
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Affiliation(s)
- Jimin Dai
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Air Force Medical University, Xi'an, China.,The Cadet Team 6 (Regiment 6) of School of Basic Medicine, Air Force Medical University, Xi'an, China
| | - Qichao Huang
- State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Air Force Medical University, Xi'an, China
| | - Kunwei Niu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Bo Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Yijie Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Chen Dai
- Department of Orthopedics, The First Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Zhinan Chen
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, Air Force Medical University, Xi'an, China
| | - Kaishan Tao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Jingyao Dai
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Air Force Medical University, Xi'an, China.,Department of Cell Biology, National Translational Science Center for Molecular Medicine, Air Force Medical University, Xi'an, China
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