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Takamoto T, Mihara Y, Nishioka Y, Ichida A, Kawaguchi Y, Akamatsu N, Hasegawa K. Surgical treatment for hepatocellular carcinoma in era of multidisciplinary strategies. Int J Clin Oncol 2025; 30:417-426. [PMID: 39907863 PMCID: PMC11842484 DOI: 10.1007/s10147-025-02703-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 01/07/2025] [Indexed: 02/06/2025]
Abstract
Hepatocellular carcinoma (HCC) remains a significant global health challenge, with over 800,000 new cases diagnosed annually. This comprehensive review examines current surgical approaches and emerging multidisciplinary strategies in HCC treatment. While traditional surgical criteria, such as the Barcelona Clinic Liver Cancer (BCLC) staging system, have been relatively conservative, recent evidence from high-volume Asian centers supports more aggressive surgical approaches in carefully selected patients. The review discusses the evolution of selection criteria, including the new "Borderline Resectable HCC" classification system, which provides more explicit guidance for surgical decision-making. Technical innovations have significantly enhanced surgical precision, including three-dimensional simulation, intraoperative navigation systems, and the advancement of minimally invasive approaches. The review evaluates the ongoing debate between anatomical versus non-anatomical resection and examines the emerging role of robotic surgery. In liver transplantation, expanded criteria beyond the Milan criteria show promising outcomes, while the integration of novel biomarkers and imaging techniques improves patient selection. The role of preoperative and adjuvant therapies is increasingly important, with recent trials demonstrating the potential of immune checkpoint inhibitors combined with anti-VEGF agents in both settings. Despite these advances, postoperative recurrence remains a significant challenge. The review concludes that successful HCC treatment requires a personalized approach, integrating surgical expertise with emerging technologies and systemic therapies while considering individual patient factors and regional variations in practice patterns.
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Affiliation(s)
- Takeshi Takamoto
- Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yuichirou Mihara
- Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yujirou Nishioka
- Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Akihiko Ichida
- Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshikuni Kawaguchi
- Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nobuhisa Akamatsu
- Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
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2
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Sangro B, Argemi J, Ronot M, Paradis V, Meyer T, Mazzaferro V, Jepsen P, Golfieri R, Galle P, Dawson L, Reig M. EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma. J Hepatol 2025; 82:315-374. [PMID: 39690085 DOI: 10.1016/j.jhep.2024.08.028] [Citation(s) in RCA: 39] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 08/29/2024] [Indexed: 12/19/2024]
Abstract
Liver cancer is the third leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) accounting for approximately 90% of primary liver cancers. Advances in diagnostic and therapeutic tools, along with improved understanding of their application, are transforming patient treatment. Integrating these innovations into clinical practice presents challenges and necessitates guidance. These clinical practice guidelines offer updated advice for managing patients with HCC and provide a comprehensive review of pertinent data. Key updates from the 2018 EASL guidelines include personalised surveillance based on individual risk assessment and the use of new tools, standardisation of liver imaging procedures and diagnostic criteria, use of minimally invasive surgery in complex cases together with updates on the integrated role of liver transplantation, transitions between surgical, locoregional, and systemic therapies, the role of radiation therapies, and the use of combination immunotherapies at various stages of disease. Above all, there is an absolute need for a multiparametric assessment of individual risks and benefits, considering the patient's perspective, by a multidisciplinary team encompassing various specialties.
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3
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Junxiao W, Rui L, Zhenyu W, Zejie S, Xiang Y, Mingchao D, Hui X. Adjuvant sorafenib for hepatocellular carcinoma after radiofrequency ablation versus radiofrequency ablation: analysis of its efficacy and safety. Front Oncol 2024; 14:1383312. [PMID: 39697221 PMCID: PMC11652347 DOI: 10.3389/fonc.2024.1383312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 11/18/2024] [Indexed: 12/20/2024] Open
Abstract
Objectives For the treatment of early hepatocellular carcinoma, we compared the efficacy and safety of radiofrequency ablation (RFA) alone and radiofrequency ablation combined with sorafenib (RFA+Sor). Methods A total of 164 patients with early HCC were included in the study. There were 87 patients who underwent RFA alone, and 77 patients who underwent RFA+Sor treatment. Overall survival (OS) was the primary endpoint of the study, and recurrence-free survival (RFS) and safety were the secondary endpoints. Results According to the RFA group, the RFS rates were 74.7%, 29.9%, and 11.5% at 1, 2, and 3 years, whereas in the RFA+Sor group, the RFS rates were 72.7%, 19.5%, and 11.7% at 1, 2, and 3 years (P>0.05). RFA and RFA+Sor groups had median OS of 35.0 and 41.0 months, respectively (P>0.05). For the RFA and RFA+Sor groups, the median RFS was 17.0 and 16.0 months, respectively (P>0.05). Based on the univariate regression analysis, there was no statistically significant difference between the subgroups (P>0.05). Skin rashes only occurred in the RFA+Sor group, and other adverse effects were not significantly different between the two groups (P>0.05). Conclusions Treatment with RFA+Sor treatment did not result in a longer OS than treatment with only RFA, however, the adverse effects of adjuvant Sorafenib were acceptable.
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Affiliation(s)
- Wang Junxiao
- Aerospace Medical Center, Aerospace Center Hospital, Beijing, China
- Senior Department of Oncology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Liu Rui
- Department of Interventional Vascular Surgery, Aerospace Center Hospital, Beijing, China
| | - Wen Zhenyu
- Senior Department of Oncology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Sang Zejie
- Senior Department of Oncology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yang Xiang
- Senior Department of Oncology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ding Mingchao
- Department of Interventional Vascular Surgery, Aerospace Center Hospital, Beijing, China
| | - Xie Hui
- Senior Department of Oncology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
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Kudo M. Challenges in Adjuvant Immunotherapy after Resection or Ablation for Hepatocellular Carcinoma at High-Risk of Recurrence. Liver Cancer 2024; 13:573-578. [PMID: 39687037 PMCID: PMC11649295 DOI: 10.1159/000542221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 10/22/2024] [Indexed: 12/18/2024] Open
Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
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Teng W, Wu TC, Lin SM. Hepatocellular carcinoma systemic treatment update: From early to advanced stage. Biomed J 2024:100815. [PMID: 39561966 DOI: 10.1016/j.bj.2024.100815] [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: 06/16/2024] [Revised: 10/14/2024] [Accepted: 11/13/2024] [Indexed: 11/21/2024] Open
Abstract
Hepatocellular carcinoma (HCC) ranks the sixth most common malignancy but the third leading cause of cancer-related mortality in the world. Significant breakthroughs have been made in systemic treatment for HCC over the past two decades, which have improved treatment outcomes. In addition to multiple tyrosine kinase inhibitors (mTKIs), immune checkpoint inhibitors (ICIs) and antiangiogenic drugs are increasingly being applied. The combination of ICI and antiangiogenic or dual ICIs has become the new standard of care due to remarkable response rates. However, currently available systemic regimens are primarily reserved for certain patients in the intermediate and advanced stages who will not benefit from locoregional treatments. Evidence supporting the use of systemic treatment as neoadjuvant or adjuvant therapies in patients with early-stage HCC, especially the high risk of recurrence after curative treatments, remains limited. This review identified recent developments in systemic therapy, including mTKIs and ICIs, considering results on first- and second-line treatment, role of neoadjuvant and adjuvant settings, and combination with loco-regional therapy. Various ongoing clinical trials regarding the role of systemic therapies and potential novel targets in patients with early-, intermediate-, and advanced-stage HCC were also summarized and revealed that systemic therapy is no longer limited to advanced-stage HCC. Moreover, the introduction of T-cell redirecting strategies, including bispecific antibodies and chimeric antigen receptor T cells, has revolutionized the treatment landscape for HCC. Future research should focus on an in-depth exploration of the mechanisms governing the establishment of tumor barriers.
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Affiliation(s)
- Wei Teng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.
| | - Tai-Chi Wu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.
| | - Shi-Ming Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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Stefanini B, Manfredi GF, D’Alessio A, Fulgenzi CA, Awosika N, Celsa C, Pirisi M, Rigamonti C, Burlone M, Vincenzi F, Minisini R, Gennari A, Yip V, Slater S, El-Shakankery K, Jain A, Tovoli F, Piscaglia F, Spalding D, Pai M, Pinato DJ. Delivering adjuvant and neoadjuvant treatments in the early stages of hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2024; 18:647-660. [PMID: 39435480 PMCID: PMC11601036 DOI: 10.1080/17474124.2024.2419519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 10/11/2024] [Accepted: 10/17/2024] [Indexed: 10/23/2024]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) presents a formidable challenge in oncology, demanding innovative treatment approaches. Both adjuvant and neoadjuvant therapies, thanks to the introduction of immunotherapy, have emerged as promising strategies in the management of HCC, aiming to reduce the risk of relapse and ultimately to improve survival. AREAS COVERED This review considers current evidence, ongoing clinical trials, and future strategies to elucidate the evolving landscape of neoadjuvant and adjuvant treatments in HCC. EXPERT OPINION Both adjuvant and neoadjuvant regimens, notably those incorporating immune checkpoint inhibitors, demonstrated encouraging safety profiles and efficacy outcomes in HCC.While significant challenges persist, including optimizing patient selection and endpoint definition, the evolving landscape of neoadjuvant and adjuvant therapy holds promise for maximizing the therapeutic potential of immunotherapy across all stages of HCC. Further insights into tumor biology and host immunity will shape the role of these approaches which are close to becoming reality in clinical practice.
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Affiliation(s)
- Bernardo Stefanini
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Giulia F. Manfredi
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Antonio D’Alessio
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Claudia A.M. Fulgenzi
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Nichola Awosika
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Ciro Celsa
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
| | - Mario Pirisi
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Cristina Rigamonti
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Michela Burlone
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Federica Vincenzi
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Rosalba Minisini
- Division of Internal Medicine, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Alessandra Gennari
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Vincent Yip
- Barts and the London HPB Centre, Royal London Hospital, Whitechapel, UK
| | - Sarah Slater
- Barts and the London HPB Centre, Royal London Hospital, Whitechapel, UK
| | - Karim El-Shakankery
- Edinburgh Cancer Centre, Western General Hospital, NHS Lothian, Edinburgh, UK
| | - Ananya Jain
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Francesco Tovoli
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Duncan Spalding
- Hepatobiliary Surgery, Imperial College London and Imperial College NHS Trust, Hammersmith Hospital, London, UK
| | - Madhava Pai
- Hepatobiliary Surgery, Imperial College London and Imperial College NHS Trust, Hammersmith Hospital, London, UK
| | - David J. Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
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Ali FEM, Abdel-Reheim MA, Hassanein EHM, Abd El-Aziz MK, Althagafy HS, Badran KSA. Exploring the potential of drug repurposing for liver diseases: A comprehensive study. Life Sci 2024; 347:122642. [PMID: 38641047 DOI: 10.1016/j.lfs.2024.122642] [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: 02/09/2024] [Revised: 03/24/2024] [Accepted: 04/10/2024] [Indexed: 04/21/2024]
Abstract
Drug repurposing involves the investigation of existing drugs for new indications. It offers a great opportunity to quickly identify a new drug candidate at a lower cost than novel discovery and development. Despite the importance and potential role of drug repurposing, there is no specific definition that healthcare providers and the World Health Organization credit. Unfortunately, many similar and interchangeable concepts are being used in the literature, making it difficult to collect and analyze uniform data on repurposed drugs. This research was conducted based on understanding general criteria for drug repurposing, concentrating on liver diseases. Many drugs have been investigated for their effect on liver diseases even though they were originally approved (or on their way to being approved) for other diseases. Some of the hypotheses for drug repurposing were first captured from the literature and then processed further to test the hypothesis. Recently, with the revolution in bioinformatics techniques, scientists have started to use drug libraries and computer systems that can analyze hundreds of drugs to give a short list of candidates to be analyzed pharmacologically. However, this study revealed that drug repurposing is a potential aid that may help deal with liver diseases. It provides available or under-investigated drugs that could help treat hepatitis, liver cirrhosis, Wilson disease, liver cancer, and fatty liver. However, many further studies are needed to ensure the efficacy of these drugs on a large scale.
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Affiliation(s)
- Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt; Michael Sayegh, Faculty of Pharmacy, Aqaba University of Technology, Aqaba 77110, Jordan
| | - Mustafa Ahmed Abdel-Reheim
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62521, Egypt.
| | - Emad H M Hassanein
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt.
| | - Mostafa K Abd El-Aziz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt
| | - Hanan S Althagafy
- Department of Biochemistry, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Khalid S A Badran
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt
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Li L, Li ZZ, Pan LX, Su JY, Huang S, Ma L, Zhong JH. Adjuvant Therapy for Hepatocellular Carcinoma After Curative Treatment: Several Unanswered Questions. J Clin Transl Hepatol 2024; 12:525-533. [PMID: 38779519 PMCID: PMC11106350 DOI: 10.14218/jcth.2024.00030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/31/2024] [Accepted: 04/09/2024] [Indexed: 05/25/2024] Open
Abstract
Most patients with hepatocellular carcinoma (HCC) have a poor prognosis. Hepatectomy and local ablation are the main curative treatments for HCC. Nevertheless, the recurrence rate after hepatectomy or ablation is up to 70%, which seriously affects patient prognosis. Several adjuvant therapies have been explored to reduce postoperative recurrence. However, although a variety of adjuvant therapies have been shown to reduce the recurrence rate and improve overall survival, a standard consensus of national HCC guidelines for adjuvant treatment is lacking. Therefore, there are significant differences in the recommendations for adjuvant therapy for HCC between the Eastern and Western guidelines. A variety of adjuvant treatment methods, such as antiviral therapy, transarterial chemoembolization or traditional Chinese medicine, are recommended by the Chinese HCC guidelines. However, Western guidelines make few recommendations other than antiviral therapy. Adjuvant immune checkpoint inhibitors are recommended only in the recently updated American Association for the Study of Liver Diseases guidelines. This review summarized the existing adjuvant therapy options after curative hepatectomy or ablation and discusses several important dilemmas of adjuvant treatments.
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Affiliation(s)
- Le Li
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
- Guangxi Academy of Medical Sciences, Emergency Department, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Zhen-Zhen Li
- Pathology Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Li-Xin Pan
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Jia-Yong Su
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Shan Huang
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Liang Ma
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Jian-Hong Zhong
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China
- Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, Guangxi, China
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Zhang T, O’Connor C, Sheridan H, Barlow JW. Vitamin K2 in Health and Disease: A Clinical Perspective. Foods 2024; 13:1646. [PMID: 38890875 PMCID: PMC11172246 DOI: 10.3390/foods13111646] [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: 04/30/2024] [Revised: 05/21/2024] [Accepted: 05/23/2024] [Indexed: 06/20/2024] Open
Abstract
Vitamins are essential organic compounds that vary widely in chemical structure and are vital in small quantities for numerous biochemical and biological functions. They are critical for metabolism, growth, development and maintaining overall health. Vitamins are categorised into two groups: hydrophilic and lipophilic. Vitamin K (VK), a lipophilic vitamin, occurs naturally in two primary forms: phylloquinone (VK1), found in green leafy vegetables and algae, and Menaquinones (VK2), present in certain fermented and animal foods and widely formulated in VK supplements. This review explores the possible factors contributing to VK deficiency, including dietary influences, and discusses the pharmacological and therapeutic potential of supplementary VK2, examining recent global clinical studies on its role in treating diseases such as osteoporosis, osteoarthritis, rheumatoid arthritis, cardiovascular disease, chronic kidney disease, diabetes, neurodegenerative disorders and cancers. The analysis includes a review of published articles from multiple databases, including Scopus, PubMed, Google Scholar, ISI Web of Science and CNKI, focusing on human studies. The findings indicate that VK2 is a versatile vitamin essential for human health and that a broadly positive correlation exists between VK2 supplementation and improved health outcomes. However, clinical data are somewhat inconsistent, highlighting the need for further detailed research into VK2's metabolic processes, biomarker validation, dose-response relationships, bioavailability and safety. Establishing a Recommended Daily Intake for VK2 could significantly enhance global health.
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Affiliation(s)
- Tao Zhang
- School of Food Science & Environmental Health, Technological University Dublin, Grangegorman, 7, D07 ADY7 Dublin, Ireland;
- The Trinity Centre for Natural Products Research (NatPro), School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, 2, D02 PN40 Dublin, Ireland;
| | - Christine O’Connor
- School of Food Science & Environmental Health, Technological University Dublin, Grangegorman, 7, D07 ADY7 Dublin, Ireland;
| | - Helen Sheridan
- The Trinity Centre for Natural Products Research (NatPro), School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, 2, D02 PN40 Dublin, Ireland;
- School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, 2, D02 PN40 Dublin, Ireland
| | - James W. Barlow
- Department of Chemistry, RCSI University of Medicine and Health Sciences, 2, D02 YN77 Dublin, Ireland
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Bao Q, Zeng Y, Lou Q, Feng X, Jiang S, Lu J, Ruan B. Clinical significance of RNA methylation in hepatocellular carcinoma. Cell Commun Signal 2024; 22:204. [PMID: 38566136 PMCID: PMC10986096 DOI: 10.1186/s12964-024-01595-w] [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: 03/26/2024] [Indexed: 04/04/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver malignancy with high mortality rates and poor prognosis. Recent advances in high-throughput sequencing and bioinformatic technologies have greatly enhanced the understanding of the genetic and epigenetic changes in liver cancer. Among these changes, RNA methylation, the most prevalent internal RNA modification, has emerged as a significant contributor of the development and progression of HCC. Growing evidence has reported significantly abnormal levels of RNA methylation and dysregulation of RNA-methylation-related enzymes in HCC tissues and cell lines. These alterations in RNA methylation play a crucial role in the regulation of various genes and signaling pathways involved in HCC, thereby promoting tumor progression. Understanding the pathogenesis of RNA methylation in HCC would help in developing prognostic biomarkers and targeted therapies for HCC. Targeting RNA-methylation-related molecules has shown promising potential in the management of HCC, in terms of developing novel prognostic biomarkers and therapies for HCC. Exploring the clinical application of targeted RNA methylation may provide new insights and approaches for the management of HCC. Further research in this field is warranted to fully understand the functional roles and underlying mechanisms of RNA methylation in HCC. In this review, we described the multifaceted functional roles and potential mechanisms of RNA methylation in HCC. Moreover, the prospects of clinical application of targeted RNA methylation for HCC management are discussed, which may provide the basis for subsequent in-depth research on RNA methylation in HCC.
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Affiliation(s)
- Qiongling Bao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China
| | - Yifan Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China
| | - Qizhuo Lou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China
| | - Xuewen Feng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China
| | - Shuwen Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China.
| | - Bing Ruan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, National Medical Center for Infectious Diseases, Zhejiang University School of Medicine, No. 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, China.
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11
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Llovet JM, Pinyol R, Yarchoan M, Singal AG, Marron TU, Schwartz M, Pikarsky E, Kudo M, Finn RS. Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma. Nat Rev Clin Oncol 2024; 21:294-311. [PMID: 38424197 PMCID: PMC11984461 DOI: 10.1038/s41571-024-00868-0] [Citation(s) in RCA: 99] [Impact Index Per Article: 99.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/02/2024] [Indexed: 03/02/2024]
Abstract
Liver cancer, specifically hepatocellular carcinoma (HCC), is the sixth most common cancer and the third leading cause of cancer mortality worldwide. The development of effective systemic therapies, particularly those involving immune-checkpoint inhibitors (ICIs), has substantially improved the outcomes of patients with advanced-stage HCC. Approximately 30% of patients are diagnosed with early stage disease and currently receive potentially curative therapies, such as resection, liver transplantation or local ablation, which result in median overall survival durations beyond 60 months. Nonetheless, up to 70% of these patients will have disease recurrence within 5 years of resection or local ablation. To date, the results of randomized clinical trials testing adjuvant therapy in patients with HCC have been negative. This major unmet need has been addressed with the IMbrave 050 trial, demonstrating a recurrence-free survival benefit in patients with a high risk of relapse after resection or local ablation who received adjuvant atezolizumab plus bevacizumab. In parallel, studies testing neoadjuvant ICIs alone or in combination in patients with early stage disease have also reported efficacy. In this Review, we provide a comprehensive overview of the current approaches to manage patients with early stage HCC. We also describe the tumour immune microenvironment and the mechanisms of action of ICIs and cancer vaccines in this setting. Finally, we summarize the available evidence from phase II/III trials of neoadjuvant and adjuvant approaches and discuss emerging clinical trials, identification of biomarkers and clinical trial design considerations for future studies.
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Affiliation(s)
- Josep M Llovet
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
- Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
| | - Roser Pinyol
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - Mark Yarchoan
- Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Amit G Singal
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Thomas U Marron
- Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Myron Schwartz
- Department of Liver Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Eli Pikarsky
- The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel-Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Richard S Finn
- Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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Jeon D, Cha HR, Chung SW, Choi J, Lee D, Shim JH, Kim KM, Lim YS, Lee HC, Lee SW, Choi WM. Association between statin use and the prognosis of hepatocellular carcinoma after resection: a nationwide cohort study. EClinicalMedicine 2023; 65:102300. [PMID: 37965429 PMCID: PMC10641481 DOI: 10.1016/j.eclinm.2023.102300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/10/2023] [Accepted: 10/13/2023] [Indexed: 11/16/2023] Open
Abstract
BACKGROUND The majority of patients with hepatocellular carcinoma (HCC) following hepatic resection experience tumor recurrence. Statin use is associated with a reduced risk of HCC development; however, the association between statin use and the prognosis of HCC after resection remains unclear. We aimed to investigate the effect of statin use on the prognosis after hepatic resection among patients with HCC. METHODS A nationwide cohort study was performed with data from the National Health Insurance Service Database in Korea. Among 65,101 HCC patients who underwent hepatic resection between January 2002 and December 2017, we included 21,470 patients. For validation, a hospital-based cohort of 3366 patients with very early or early-stage HCC who received curative-intent hepatic resection between January 2010 and December 2018 was analyzed. Recurrence-free survival (RFS) and overall survival (OS) was compared between statin users and non-users. FINDINGS Among the nationwide cohort of 21,470 patients, 2399 (11.2%) used statins and 19,071 (88.8%) did not. Among the hospital cohort of 3366 patients, 363 (10.8%) used statins and 3003 (89.2%) did not. In the propensity score-matched nationwide cohort, statin users had better RFS (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.56-0.64; P < 0.001) and OS (HR, 0.49; 95% CI, 0.45-0.53; P < 0.001), with a duration-response relationship. In the propensity score-matched validation hospital cohort, statin treatment was significantly associated with better RFS (HR, 0.73; 95% CI, 0.59-0.90; P = 0.003) and OS (HR, 0.48; 95% CI, 0.32-0.72; P < 0.001). The beneficial effects of statins were more prominent in non-cirrhotics, tumors sized ≥3 cm, tumors with microscopic vascular invasion, or early HCC recurrence (<2 years after resection). INTERPRETATION Statin use was associated with a better prognosis in a population-based cohort of patients with HCC after hepatic resection, which was further validated in a large hospital-based cohort. FUNDING Asan Institute for Life Sciences and Corporate Relations; Korean Association for the Study of the Liver.
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Affiliation(s)
- Dongsub Jeon
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hye Ryeong Cha
- Department of Computer Science and Engineering, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea
| | - Sung Won Chung
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jonggi Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Danbi Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ju Hyun Shim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Han Chu Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seung Won Lee
- Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, Republic of Korea
| | - Won-Mook Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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13
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Öcal O, Schütte K, Malfertheiner P, Berg T, Loewe C, Klümpen HJ, Zech CJ, van Delden O, Ümütlü MR, Deniz S, Khaled NB, De Toni EN, Hoang TPT, Seidensticker R, Aghdassi A, Pech M, Ricke J, Seidensticker M. Prognostic value of baseline MRI features in patients treated with thermal ablation for hepatocellular carcinoma. Eur J Radiol 2023; 168:111120. [PMID: 37806190 DOI: 10.1016/j.ejrad.2023.111120] [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: 07/17/2023] [Revised: 09/05/2023] [Accepted: 09/27/2023] [Indexed: 10/10/2023]
Abstract
PURPOSE To investigate prognostic value of baseline MRI features for time-to-recurrence (TTR) and local recurrence in patients with early hepatocellular carcinoma (HCC). METHOD Baseline and follow-up images of 88 patients treated with thermal ablation followed by adjuvant sorafenib or matching placebo due to HCC within the phase II prospective randomized trial (SORAMIC) were included. Baseline MRI images were evaluated in terms of atypical enhancement (lack of wash-in or wash-out), lesion diameter, tumor capsule, peritumoral enhancement on arterial phase, intratumoral fat, irregular margin, satellite lesions, and peritumoral hypointensity on hepatobiliary phase. Prognostic value of these features for TTR and local recurrence were assessed with univariable and multivariable Cox proportional hazard models. RESULTS Recurrence at any location was diagnosed during follow-up in 30 patients, and the median TTR was 16.4 (95% CI, 15 - NA) months. The presence of more than one lesion (p = 0.028) and peritumoral hypointensity on hepatobiliary phase images (p = 0.012) at baseline were significantly associated with shorter TTR in univariable analysis. AFP > 15 mg/dL (p = 0.084), and history of cirrhosis (p = 0.099) were marginally non-significant. Peritumoral hypointensity on hepatobiliary phase images was the only significant risk factor for recurrence in multivariable analysis (p = 0.003). Local recurrence (adjacent to thermal scar) was diagnosed in eleven (8.3%) out of 132 lesions that underwent thermal ablation. The only significant risk factor for local recurrence was a lesion diameter larger than 3 cm (22.2% vs. 4.5%, p = 0.007). CONCLUSIONS Peritumoral hypointensity on hepatobiliary phase can serve as imaging biomarker to identify increased recurrence risk in patients undergoing thermal ablation for early-stage HCC.
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Affiliation(s)
- Osman Öcal
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Kerstin Schütte
- Department of Internal Medicine and Gastroenterology, Niels-Stensen-Kliniken Marienhospital, Osnabrück, Germany
| | | | - Thomas Berg
- Klinik und Poliklinik für Gastroenterologie, Sektion Hepatologie, Universitätsklinikum Leipzig, Germany
| | - Christian Loewe
- Section of Cardiovascular and Interventional Radiology, Department of Bioimaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Heinz Josef Klümpen
- Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Christoph Johannes Zech
- Radiology and Nuclear Medicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Otto van Delden
- Department of Radiology and Nuclear Medicine, Academic University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | | | - Sinan Deniz
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | | | | | | | - Ali Aghdassi
- Department of Medicine A, University Medicine Greifswald, 17489 Greifswald, Germany
| | - Maciej Pech
- Departments of Radiology and Nuclear Medicine, University of Magdeburg, Magdeburg, Germany
| | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Max Seidensticker
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany.
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14
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Minami Y, Aoki T, Hagiwara S, Kudo M. Tips for Preparing and Practicing Thermal Ablation Therapy of Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:4763. [PMID: 37835456 PMCID: PMC10571938 DOI: 10.3390/cancers15194763] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/19/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
Thermal ablation therapy, including radiofrequency ablation (RFA) and microwave ablation (MWA), is considered the optimal locoregional treatment for unresectable early-stage hepatocellular carcinomas (HCCs). Percutaneous image-guided ablation is a minimally invasive treatment that is being increasingly performed because it achieves good clinical outcomes with a lower risk of complications. However, the physics and principles of RFA and MWA markedly differ. Although percutaneous thermal ablation under image guidance may be challenging in HCC cases with limited access or a risk of thermal injury, a number of ablative techniques, each of which may be advantageous and disadvantageous for individual cases, are available. Furthermore, even when a HCC is eligible for ablation based on tumor selection and technical factors, additional patient factors may have an impact on whether it is the appropriate treatment choice. Therefore, a basic understanding of the advantages and limitations of each ablation device and imaging guidance technique, respectively, is important. We herein provide an overview of the basic principles of tissue heating in thermal ablation, clinical and laboratory parameters for ablation therapy, preprocedural management, imaging assessments of responses, and early adverse events. We also discuss associated challenges and how they may be overcome using optimized imaging techniques.
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Affiliation(s)
- Yasunori Minami
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi Osaka-Sayama, Osaka 589-8511, Japan (M.K.)
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15
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Choksi EJ, Elsayed M, Kokabi N. Antitumor Activity of Metformin Combined with Locoregional Therapy for Liver Cancer: Evidence and Future Directions. Cancers (Basel) 2023; 15:4538. [PMID: 37760509 PMCID: PMC10526211 DOI: 10.3390/cancers15184538] [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: 08/17/2023] [Revised: 09/06/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
This article aimed to examine the effect of metformin use on improving outcomes after liver-directed therapy in patients with HCC and identify future directions with the adjuvant use of and potential therapeutic agents that operate on similar mechanistic pathways. Databases were queried to identify pertinent articles on metformin's use as an anti-cancer agent in HCC. Eleven studies were included, with five pre-clinical and six clinical studies. The mean overall survival (OS) and progression-free survival were both higher in the locoregional therapy (LRT) + metformin-treated groups. The outcome variables, including local tumor recurrence rate, reduction in HCC tumor growth and size, tumor growth, proliferation, migration and invasion of HCC cells, HCC cell apoptosis, DNA damage, and cell cycle arrest, showed favorable outcomes in the LRT + metformin-treated groups compared with LRT alone. This systemic review provides a strong signal that metformin use can improve the tumor response after locoregional therapy. Well-controlled prospective trials will be needed to elucidate the potential antitumor effects of metformin and other mTOR inhibitors.
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Affiliation(s)
- Eshani J. Choksi
- School of Osteopathic Medicine, Rowan University, Stratford, NJ 08084, USA;
| | - Mohammad Elsayed
- Interventional Radiology Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Nima Kokabi
- Department of Radiology, Division of Interventional Radiology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
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16
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Seidensticker M, Öcal O, Schütte K, Malfertheiner P, Berg T, Loewe C, Klümpen HJ, van Delden O, Ümütlü MR, Ben Khaled N, de Toni EN, Seidensticker R, Aghdassi A, Tran A, Bronowicki JP, Peynircioglu B, Sangro B, Pech M, Ricke J. Impact of adjuvant sorafenib treatment after local ablation for HCC in the phase II SORAMIC trial. JHEP Rep 2023; 5:100699. [PMID: 36968218 PMCID: PMC10031000 DOI: 10.1016/j.jhepr.2023.100699] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 12/22/2022] [Accepted: 01/17/2023] [Indexed: 03/29/2023] Open
Abstract
Background & Aims The aim of the study was to evaluate the efficacy and safety of adjuvant sorafenib treatment compared with placebo in patients with hepatocellular carcinoma who underwent local ablation. Methods The SORAMIC trial is a randomised controlled trial with diagnostic, local ablation, and palliative sub-study arms. After initial imaging within the diagnostic study, patients were assigned to local ablation or palliative arms. In the local ablation cohort, patients were randomised 1:1 to local ablation + sorafenib vs. local ablation + placebo. The primary endpoint was time-to-recurrence (TTR). Secondary endpoints were local control rate and safety in terms of adverse events and quality-of-life. Results The recruitment was terminated prematurely after 104 patients owing to slow recruitment. One patient was excluded because of a technical failure. Fifty-four patients were randomised to local ablation + sorafenib and 49 to local ablation + placebo. Eighty-eight patients who underwent standardised follow-up imaging comprised the per-protocol population. The median TTR was 15.2 months in the sorafenib arm and 16.4 months in the placebo arm (hazard ratio 1.1; 95% CI 0.53-2.2; p = 0.82). Out of 136 lesions ablated within the trial, there was no difference in local recurrence rate between sorafenib (6/69, 8.6%) and placebo groups (5/67, 5.9%; p = 0.792).Overall (92.5% vs. 71.4%, p = 0.008) and drug-related (81.4% vs. 55.1%, p = 0.003) adverse events were more common in the sorafenib arm compared with the placebo arm. Dose reduction because of adverse events were common in the sorafenib arm (79.6% vs. 30.6%, p <0.001). Conclusions Adjuvant sorafenib did not improve in TTR or local control rate after local ablation in patients with hepatocellular carcinoma within the limitations of an early terminated trial. Impact and implications Local ablation is the standard of care treatment in patients with early stages of hepatocellular carcinoma, along with surgical therapies. However, there is a risk of disease recurrence during follow-up. Sorafenib, an oral medication, is a routinely used treatment for patients with advanced hepatocellular carcinoma. This study found that sorafenib treatment after local ablation in people with early hepatocellular carcinoma did not significantly improve the disease-free period compared with placebo. Clinical trial number EudraCT 2009-012576-27, NCT01126645.
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Key Words
- Adjuvant
- BCLC, Barcelona Clinic Liver Cancer
- CONSORT, Consolidated Standards of Reporting Trials
- CT, computed tomography
- ECOG PS, Eastern Cooperative Oncology Group Performance Status
- HCC, hepatocellular carcinoma
- HR, hazard ratio
- Hepatocellular carcinoma
- ITT, intention-to-treat
- Local ablation
- MRI, magnetic resonance imaging
- MWA, microwave ablation
- PP, per protocol
- RFA, radiofrequency ablation
- RFS, relapse-free survival
- SIRT, selective internal radiation therapy
- SORAMIC, SORAfenib in combination with local MICro-therapy guided by gadolinium-EOB-DTPA-enhanced MRI
- Sorafenib
- TTR, time-to-recurrence
- Time-to-recurrence
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Affiliation(s)
- Max Seidensticker
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Osman Öcal
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Kerstin Schütte
- Department of Internal Medicine and Gastroenterology, Niels-Stensen-Kliniken Marienhospital, Osnabrück, Germany
| | | | - Thomas Berg
- Klinik und Poliklinik für Gastroenterologie, Sektion Hepatologie, Universitätsklinikum Leipzig, Germany
| | - Christian Loewe
- Section of Cardiovascular and Interventional Radiology, Department of Bioimaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Heinz Josef Klümpen
- Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Otto van Delden
- Department of Radiology and Nuclear Medicine, Academic University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | | | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | | | | | - Ali Aghdassi
- Department of Medicine A, University Medicine Greifswald, 17489 Greifswald, Germany
| | - Albert Tran
- Pôle Appareil Digestif, Hôpital l'Archet 2, CHU Nice, Route Saint-Antoine de Ginestière - BP 3079, Nice, France
| | - Jean-Pierre Bronowicki
- Department of Hepatology, INSERM U1254, Hôpital de Brabois, CHU de Nancy, University of Lorraine, Nancy, France
| | - Bora Peynircioglu
- Department of Radiology, Hacettepe University Hospital, Ankara, Turkey
| | - Bruno Sangro
- Liver Unit, Clínica Universidad de Navarra and CIBEREHD, Pamplona, Spain
| | - Maciej Pech
- Department of Radiology and Nuclear Medicine, University of Magdeburg, Magdeburg, Germany
| | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
- Corresponding author. Address: Department of Radiology, University Hospital, Ludwig Maximilian University of Munich, Marchioninistrasse 15, 81377 Munich, Germany. Tel: +49-4400-72750..
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17
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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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18
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Kudo M. New treatment paradigm with systemic therapy in intermediate-stage hepatocellular carcinoma. Int J Clin Oncol 2022; 27:1110-1119. [PMID: 35527313 PMCID: PMC9209396 DOI: 10.1007/s10147-022-02166-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 03/24/2022] [Indexed: 12/11/2022]
Abstract
Since the approval of sorafenib for the treatment of unresectable hepatocellular carcinoma in 2007 (in 2009 in Japan), five more regimens have been approved: lenvatinib, and atezolizumab plus bevacizumab for first-line treatment, and regorafenib, cabozantinib, and ramucirumab for second-line treatment, which are currently available for clinical use. The positive results of durvalumab, a programmed cell death ligand 1 antibody, plus tremelimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 antibody, were also presented at the 2022 American Society Clinical Oncology Gastrointestinal Cancers Symposium as superior to sorafenib in prolonging the overall survival; this combination is expected to be approved by the end of 2022. These systemic therapies are changing the treatment paradigm not only for advanced hepatocellular carcinoma but also for intermediate-stage hepatocellular carcinoma. This review focuses on the role of systemic therapy in intermediate-stage hepatocellular carcinoma.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
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19
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Kudo M. Adjuvant Immunotherapy after Curative Treatment for Hepatocellular Carcinoma. Liver Cancer 2021; 10:399-403. [PMID: 34721502 PMCID: PMC8527902 DOI: 10.1159/000518584] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 07/19/2021] [Indexed: 02/04/2023] Open
Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
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20
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Ganbat D, Jugder BE, Ganbat L, Tomoeda M, Dungubat E, Takahashi Y, Mori I, Shiomi T, Tomita Y. The Efficacy of Vitamin K, A Member Of Naphthoquinones in the Treatment of Cancer: A Systematic Review and Meta-Analysis. Curr Cancer Drug Targets 2021; 21:495-513. [PMID: 33475062 DOI: 10.2174/1568009621999210120182834] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 10/29/2020] [Accepted: 10/30/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Redox dysregulation originating from metabolic alterations in cancer cells contributes to their proliferation, invasion, and resistance to therapy. Conversely, these features represent a specific vulnerability of malignant cells that can be selectively targeted by redox chemotherapeutics. Amongst them, Vitamin K (VitK) carries the potential against cancer stem cells, in addition to the rest of tumor mass. OBJECTIVES To assess the possible benefits and safety of VitK for cancer treatment using a systematic review and meta-analysis with a mixed-methods approach. METHODS We performed a systematic search on several electronic databases for studies comparing VitK treatment with and without combination to the control groups. For quantitative studies, fully or partially reported clinical outcomes such as recurrence rates, survival, overall response and adverse reactions were assessed. For qualitative studies, a narrative synthesis was accomplished. RESULTS Our analysis suggested that the clinical outcome of efficacy, the pooled hazard ratio for progression-free survival, and the pooled relative risk for overall survival, and overall response were significantly higher in the VitK therapy group compared to the placebo group (p<0.05). We did not observe any significant difference in the occurrence of adverse events between groups. Among qualitative studies, VitK treatment targeting myelodysplastic syndrome and advanced solid tumors resulted in 24.1% and 10% of clinical response, respectively. CONCLUSION VitK not only exerts antitumor effects against a wide range of tumor types, but it also has excellent synergism with other therapeutic agents.
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Affiliation(s)
- Dariimaa Ganbat
- Department of Pathology, School of Medicine, International University of Health and Welfare, Narita, Japan
| | - Bat-Erdene Jugder
- Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston Children's Hospital, United States
| | - Lkhamaa Ganbat
- Department of Administration, MCS Property, Ulan-Bator, Mongolia
| | - Miki Tomoeda
- Department of Rehabilitation, Kobe International University, Kobe, Japan
| | - Erdenetsogt Dungubat
- Department of Pathology, School of Medicine, International University of Health and Welfare, Narita, Japan
| | - Yoshihisa Takahashi
- Department of Pathology, School of Medicine, International University of Health and Welfare, Narita, Japan
| | - Ichiro Mori
- Department of Pathology, School of Medicine, International University of Health and Welfare, Narita, Japan
| | - Takayuki Shiomi
- Department of Pathology, School of Medicine, International University of Health and Welfare, Narita, Japan
| | - Yasuhiko Tomita
- Department of Pathology, School of Medicine, International University of Health and Welfare, Narita, Japan
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21
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Haber PK, Puigvehí M, Castet F, Lourdusamy V, Montal R, Tabrizian P, Buckstein M, Kim E, Villanueva A, Schwartz M, Llovet JM. Evidence-Based Management of Hepatocellular Carcinoma: Systematic Review and Meta-analysis of Randomized Controlled Trials (2002-2020). Gastroenterology 2021; 161:879-898. [PMID: 34126063 DOI: 10.1053/j.gastro.2021.06.008] [Citation(s) in RCA: 152] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 05/28/2021] [Accepted: 06/03/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with a rapidly changing landscape of treatments. In the past 20 years, numerous randomized controlled trials (RCTs) have aimed at improving outcomes across disease stages. We aimed to analyze the current evidence and identify potential factors influencing response to therapies. METHODS We conducted a systematic review of phase III RCTs (2002-2020) across disease stages. A meta-analysis was designed to examine the relationship between etiology and outcome after systemic therapies with either tyrosine-kinase inhibitor (TKI)/antiangiogenic or immune checkpoint inhibitor (ICI) therapy. RESULTS Out of 10,100 studies identified, 76 were phase III RCTs. Among them, a rigorous screening algorithm identified 49 with high quality including a total of 22,113 patients undergoing adjuvant (n = 7) and primary treatment for early (n = 2), intermediate (n = 7), and advanced (first-line, n = 21; second-line, n = 12) stages of disease. Nine of these trials were positive, 6 treatments have been adopted in guidelines (sorafenib [2 RCTs], lenvatinib, atezolizumab+bevacizumab, regorafenib, cabozantinib and ramucirumab), but 2 were not (adjuvant CIK cells and sorafenib plus hepatic arterial infusion with FOLFOX). Meta-analysis of 8 trials including 3739 patients revealed ICI therapy to be significantly more effective in patients with viral hepatitis compared with nonviral-related HCC, whereas no differences related to etiology were observed in patients treated with TKI/anti-vascular endothelial growth factor. CONCLUSIONS Among 49 high-quality RCTs conducted in HCC during 2002-2020, 9 resulted in positive results. A meta-analysis of systemic therapies suggests that immunotherapies may be more effective in viral etiologies.
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Affiliation(s)
- Philipp K Haber
- Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Marc Puigvehí
- Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hepatology Section, Gastroenterology Department, Parc de Salut Mar, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Florian Castet
- Translational Research in Hepatic Oncology, Liver Unit, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Hospital Clinic, University of Barcelona, Catalonia, Spain
| | - Vennis Lourdusamy
- Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Robert Montal
- Cancer Biomarkers Research Group, Department of Medical Oncology, Hospital Universitari Arnau de Vilanova-IRBLleida, Lleida, Catalonia, Spain
| | - Parissa Tabrizian
- Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Michael Buckstein
- Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Edward Kim
- Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Augusto Villanueva
- Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Myron Schwartz
- Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Josep M Llovet
- Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Translational Research in Hepatic Oncology, Liver Unit, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Hospital Clinic, University of Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain.
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22
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Su YY, Li CC, Lin YJ, Hsu C. Adjuvant versus Neoadjuvant Immunotherapy for Hepatocellular Carcinoma: Clinical and Immunologic Perspectives. Semin Liver Dis 2021; 41:263-276. [PMID: 34130338 DOI: 10.1055/s-0041-1730949] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Advancement in systemic therapy, particularly immune checkpoint inhibitor (ICI)-based combination regimens, has transformed the treatment landscape for patients with advanced hepatocellular carcinoma (HCC). The advancement in systemic therapy also provides new opportunities of reducing recurrence after curative therapy through adjuvant therapy or improving resectability through neoadjuvant therapy. Improved recurrence-free survival by adjuvant or neoadjuvant ICI-based therapy has been reported in other cancer types. In this article, developments of systemic therapy in adjuvant and neoadjuvant settings for HCC were reviewed. The design of adjuvant and neoadjuvant therapy using ICI-based regimens and potential challenges of trial conduct and result analysis was discussed. Results from these trials may extend the therapeutic benefit of ICI-based systemic therapy beyond the advanced-stage disease and lead to a new era of multidisciplinary management for HCC.
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Affiliation(s)
- Yung-Yeh Su
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.,Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Chen Li
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Yih-Jyh Lin
- Division of General and Transplant Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Liver Cancer Collaborative Oncology Group, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chiun Hsu
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.,Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
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23
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Sultana H, Komai M, Shirakawa H. The Role of Vitamin K in Cholestatic Liver Disease. Nutrients 2021; 13:nu13082515. [PMID: 34444675 PMCID: PMC8400302 DOI: 10.3390/nu13082515] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/14/2021] [Accepted: 07/21/2021] [Indexed: 12/13/2022] Open
Abstract
Vitamin K (VK) is a ligand of the pregnane X receptor (PXR), which plays a critical role in the detoxification of xenobiotics and metabolism of bile acids. VK1 may reduce the risk of death in patients with chronic liver failure. VK deficiency is associated with intrahepatic cholestasis, and is already being used as a drug for cholestasis-induced liver fibrosis in China. In Japan, to treat osteoporosis in patients with primary biliary cholangitis, VK2 formulations are prescribed, along with vitamin D3. Animal studies have revealed that after bile duct ligation-induced cholestasis, PXR knockout mice manifested more hepatic damage than wild-type mice. Ligand-mediated activation of PXR improves biochemical parameters. Rifampicin is a well-known human PXR ligand that has been used to treat intractable pruritus in severe cholestasis. In addition to its anti-cholestatic properties, PXR has anti-fibrotic and anti-inflammatory effects. However, because of the scarcity of animal studies, the mechanism of the effect of VK on cholestasis-related liver disease has not yet been revealed. Moreover, the application of VK in cholestasis-related diseases is controversial. Considering this background, the present review focuses on the effect of VK in cholestasis-related diseases, emphasizing its function as a modulator of PXR.
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Affiliation(s)
- Halima Sultana
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan; (H.S.); (M.K.)
| | - Michio Komai
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan; (H.S.); (M.K.)
| | - Hitoshi Shirakawa
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan; (H.S.); (M.K.)
- International Education and Research Center for Food Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan
- Correspondence: ; Tel.: +81-22-757-4402
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24
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Fujii S, Miura T, Oikawa T, Qin XY, Kojima S, Kagechika H. Design, synthesis and antitumor activity of phthalazine-1,4-dione-based menaquinone analogs. Bioorg Med Chem Lett 2021; 43:128065. [PMID: 33915257 DOI: 10.1016/j.bmcl.2021.128065] [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: 03/19/2021] [Revised: 04/18/2021] [Accepted: 04/23/2021] [Indexed: 10/21/2022]
Abstract
New chemotherapeutics are needed to treat hepatocellular carcinoma (HCC), and menaquinones, homologs of vitamin K consisting of a 1,4-naphthoquinone core and a (poly)isoprene chain, are potential candidates. In this study, we designed and synthesized a series of phthalazine-1,4-dione-based menaquinone analogs. Among them, compounds bearing the intact isoprene chain exhibited selective antiproliferative activity towards HCC cell line JHH7, as compared with normal hepatocytes. The geranyl derivative 10 showed submicromolar potency, and might be a promising lead compound for anticancer agents.
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Affiliation(s)
- Shinya Fujii
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
| | - Takahiro Miura
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
| | - Tsuyoshi Oikawa
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
| | - Xian-Yang Qin
- Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan
| | - Soichi Kojima
- Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan
| | - Hiroyuki Kagechika
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
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25
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Zhang W, Zhang B, Chen XP. Adjuvant treatment strategy after curative resection for hepatocellular carcinoma. Front Med 2021; 15:155-169. [PMID: 33754281 DOI: 10.1007/s11684-021-0848-3] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 02/20/2021] [Indexed: 01/27/2023]
Abstract
Hepatic resection represents the first-line treatment for patients with resectable hepatocellular carcinoma (HCC). However, the 5-year recurrence rates of HCC after surgery have been reported to range from 50% to 70%. In this review, we evaluated the available evidence for the efficiency of adjuvant treatments to prevent HCC recurrence after curative liver resection. Antiviral therapy has potential advantages in terms of reducing the recurrence rate and improving the overall survival (OS) and/or disease-free survival of patients with hepatitis-related HCC. Postoperative adjuvant transarterial chemoembolization can significantly reduce the intrahepatic recurrence rate and improve OS, especially for patients with a high risk of recurrence. The efficacy of molecular targeted drugs as an adjuvant therapy deserves further study. Adjuvant adoptive immunotherapy can significantly improve the clinical prognosis in the early stage. Randomized controlled trial (RCT) studies evaluating adjuvant immune checkpoint inhibitors are ongoing, and the results are highly expected. Adjuvant hepatic artery infusion chemotherapy might be beneficial in patients with vascular invasion. Huaier granule, a traditional Chinese medicine, has been proved to be effective in prolonging the recurrence-free survival and reducing extrahepatic recurrence. The efficiency of other adjuvant treatments needs to be further confirmed by large RCT studies.
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Affiliation(s)
- Wei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Xiao-Ping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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26
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Kudo M. Recent Advances in Systemic Therapy for Hepatocellular Carcinoma in an Aging Society: 2020 Update. Liver Cancer 2020; 9:640-662. [PMID: 33442538 PMCID: PMC7768150 DOI: 10.1159/000511001] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 08/17/2020] [Indexed: 02/04/2023] Open
Abstract
Systemic therapy for hepatocellular carcinoma (HCC) has changed markedly since the introduction of the molecular targeted agent sorafenib in 2007. Sorafenib increased the available treatment options for patients with extrahepatic spread and vascular invasion and improved survival in patients with advanced HCC; however, various shortcomings such as low response rates and relatively high toxicity (e.g., hand-foot skin reaction) prompted concerted efforts aimed at developing new molecular targeted agents to provide more treatment options and second-line agents for patients with disease progression or intolerance to sorafenib. Despite many attempts to develop new drugs between 2007 and 2016, all first-line and second-line clinical trials conducted during this period failed. However, between 2017 and 2019, 4 drugs (lenvatinib as a first-line agent and regorafenib, cabozantinib, and ramucirumab as second-line agents) emerged in quick succession from clinical trials and became available for clinical use. In addition, nivolumab and pembrolizumab were approved as second-line agents after sorafenib. A recent phase III trial (IMbrave150) showed that combination immunotherapy with atezolizumab plus bevacizumab increases overall survival compared with sorafenib therapy; Food and Drug Agency already approved this combination therapy, and worldwide approval is expected soon. This review describes the recent advances in systemic therapy and the use of tyrosine kinase inhibitors (sorafenib, lenvatinib, regorafenib, and cabozantinib), monoclonal antibodies (ramucirumab and bevacizumab), and immune checkpoint inhibitors (nivolumab, pembrolizumab, and atezolizumab) in elderly patients and the similarity of their efficacy and safety profiles to those in the general population.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
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27
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Wang K, Wu Q, Li Z, Reger MK, Xiong Y, Zhong G, Li Q, Zhang X, Li H, Foukakis T, Xiang T, Zhang J, Ren G. Vitamin K intake and breast cancer incidence and death: results from a prospective cohort study. Clin Nutr 2020; 40:3370-3378. [PMID: 33277073 DOI: 10.1016/j.clnu.2020.11.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/20/2020] [Accepted: 11/06/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Vitamin K prevents growth and metastasis of certain cancers, but there is little evidence regarding the association between dietary vitamin K and breast cancer incidence and death. We sought to examine whether intakes of total vitamin K, phylloquinone (vitamin K1) and menaquinones (MKs) (vitamin K2) may influence risks of breast cancer incidence and death in the US population. METHODS Herein, 2286 breast cancer cases and 207 breast cancer deaths were identified during 702,748 person-years of follow-up. Cox regression and competing risk regression were used to estimate multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (95% CIs) by dietary vitamin K intake quintile (Q) for risk of breast cancer incidence and mortality. RESULTS After adjustment for confounders, the total MK intake was associated with an increased risk of breast cancer (HR Q5 vs Q1, 1.26; 95% CI, 1.05 to 1.52; Ptrend, 0.01) and death from breast cancer (HR Q5 vs Q1, 1.71; 95% CI, 0.97 to 3.01; Ptrend, 0.04). Non-linear positive dose-response associations with risks of breast cancer incidence and death were found for total MKs intake (Pnon-linearity<0.05). No statistically significant associations were observed between the intake of total vitamin K and phylloquinone and breast cancer. CONCLUSIONS The present study suggests that total MK intake was associated with an altered risk of the occurrence and death of breast cancer in the general US population. If our findings are replicated in other epidemiological studies, reducing dietary intake of menaquinones may offer a novel strategy for breast cancer prevention.
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Affiliation(s)
- Kang Wang
- Department of Endocrine and Breast Surgery, The First Affiliated hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, 400016, China; Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Oncology-Pathology, Karolinska Institutet, 17164, Stockholm, Sweden
| | - Qianxue Wu
- Department of Endocrine and Breast Surgery, The First Affiliated hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, 400016, China
| | - Zhuyue Li
- West China Hospital / West China School of Nursing, Sichuan University, Chengdu, China
| | - Michael K Reger
- College of Health Professions Ferris State University, 200 Ferris Drive, VFS 300B, Big Rapids, MI, 49307, USA
| | - Yongfu Xiong
- The First Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637007, China
| | - Guochao Zhong
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qing Li
- Department of Endocrine and Breast Surgery, The First Affiliated hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, 400016, China
| | - Xiang Zhang
- Department of Endocrine and Breast Surgery, The First Affiliated hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, 400016, China
| | - Hongyuan Li
- Department of Endocrine and Breast Surgery, The First Affiliated hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, 400016, China
| | - Theodoros Foukakis
- Department of Oncology-Pathology, Karolinska Institutet, 17164, Stockholm, Sweden; Breast Center, Theme Cancer, Karolinska University Hospital, 17176, Stockholm, Sweden
| | - Tingxiu Xiang
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Jianjun Zhang
- Department of Epidemiology, Fairbanks School of Public Health Melvin and Bren Simon Comprehensive Cancer Center Indiana University, 1050 Wishard Boulevard, RG5118, Indianapolis, IN, 46202, USA.
| | - Guosheng Ren
- Department of Endocrine and Breast Surgery, The First Affiliated hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, 400016, China; Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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28
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Nishida N. Long-term prognosis and management of hepatocellular carcinoma after curative treatment. Clin Mol Hepatol 2020; 26:480-483. [PMID: 32951413 PMCID: PMC7641545 DOI: 10.3350/cmh.2020.0208] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 08/14/2020] [Indexed: 12/14/2022] Open
Affiliation(s)
- Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
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29
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Fusaro M, Cosmai L, Evenepoel P, Nickolas TL, Cheung AM, Aghi A, Tripepi G, Plebani M, Iervasi G, Vettor R, Zaninotto M, Ravera M, Foramitti M, Giannini S, Sella S, Gallieni M. Vitamin K and Kidney Transplantation. Nutrients 2020; 12:nu12092717. [PMID: 32899501 PMCID: PMC7551925 DOI: 10.3390/nu12092717] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/28/2020] [Accepted: 09/01/2020] [Indexed: 02/06/2023] Open
Abstract
The assessment of the vitamin K status and its effects on clinical outcomes in kidney transplantation (KT) patients has sparked interest, but it is still largely unfulfilled. In part, this is due to difficulties in laboratory measurements of vitamin K, especially K2 vitamers. Vitamin K status is currently best assessed by measuring undercarboxylated vitamin-K-dependent proteins. The relative contribution of vitamin K1 and K2 to the health status of the general population and CKD (chronic kidney disease) patients, including KT patients, is also poorly studied. Through a complete and first review of the existing literature, we summarize the current knowledge of vitamin K pathophysiology and its potential role in preventing KT complications and improving organ survival. A specific focus is placed on cardiovascular complications, bone fractures, and the relationship between vitamin K and cancer. Vitamin K deficiency could determine adverse outcomes, and KT patients should be better studied for vitamin K assessment and modalities of effective therapeutic approaches.
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Affiliation(s)
- Maria Fusaro
- National Research Council (CNR), Institute of Clinical Physiology (IFC), 56124 Pisa, Italy;
- Department of Medicine, University of Padova, 35128 Padova, Italy;
- Correspondence:
| | - Laura Cosmai
- Nephrology Unit, ASST Fatebenefratelli Sacco, 20157 Milano, Italy; (L.C.); (M.G.)
| | - Pieter Evenepoel
- Laboratory of Nephrology, Department of Immunology and Microbiology, B-3000 Leuven, Belgium;
| | - Thomas L. Nickolas
- Division of Nephrology, Department of Medicine, Columbia University, New York City, NY 10032, USA;
| | - Angela M. Cheung
- Department of Medicine, University of Toronto, Toronto, ON M5S, Canada;
| | - Andrea Aghi
- Department of Medicine, Clinica Medica 1, University of Padua, 35128 Padova, PD, Italy; (A.A.); (S.G.); (S.S.)
| | - Giovanni Tripepi
- CNR-IFC, Clinical Epidemiology of Renal Diseases and Hypertension, Ospedali Riuniti, 89124 Reggio Calabria, Italy;
| | - Mario Plebani
- Laboratory Medicine Unit, Department of Medicine, University of Padua, 35128 Padova, Italy; (M.P.); (M.Z.)
| | - Giorgio Iervasi
- National Research Council (CNR), Institute of Clinical Physiology (IFC), 56124 Pisa, Italy;
| | - Roberto Vettor
- Department of Medicine, University of Padova, 35128 Padova, Italy;
| | - Martina Zaninotto
- Laboratory Medicine Unit, Department of Medicine, University of Padua, 35128 Padova, Italy; (M.P.); (M.Z.)
| | | | - Marina Foramitti
- Divisione di Nefrologia e Dialisi, Renal Department, ASST-Cremona, Largo Priori 1, 26100 Cremona, Italy;
| | - Sandro Giannini
- Department of Medicine, Clinica Medica 1, University of Padua, 35128 Padova, PD, Italy; (A.A.); (S.G.); (S.S.)
| | - Stefania Sella
- Department of Medicine, Clinica Medica 1, University of Padua, 35128 Padova, PD, Italy; (A.A.); (S.G.); (S.S.)
| | - Maurizio Gallieni
- Nephrology Unit, ASST Fatebenefratelli Sacco, 20157 Milano, Italy; (L.C.); (M.G.)
- Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università di Milano, 20157 Milano, Italy
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30
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Kudo M. A Paradigm Change in the Treatment Strategy for Hepatocellular Carcinoma. Liver Cancer 2020; 9:367-377. [PMID: 32999864 PMCID: PMC7506281 DOI: 10.1159/000507934] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 04/16/2020] [Indexed: 02/04/2023] Open
Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
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31
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Chen W, Ma T, Zhang J, Zhang X, Chen W, Shen Y, Bai X, Liang T. A systematic review and meta-analysis of adjuvant transarterial chemoembolization after curative resection for patients with hepatocellular carcinoma. HPB (Oxford) 2020; 22:795-808. [PMID: 31980307 DOI: 10.1016/j.hpb.2019.12.013] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 12/15/2019] [Accepted: 12/20/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND The aim of this study was to systematically evaluate and determine those patients with hepatocellular carcinoma (HCC) that would benefit from the administration of postoperative adjuvant transarterial chemoembolization (PA-TACE). METHODS PubMed, Embase and Cochrane Library were searched for randomized controlled trials (RCTs) and observational studies up to July 30, 2019. The outcome of Overall survival (OS) and disease-free survival (DFS) were extracted and converted to hazard ratios (HRs) with 95% confidence intervals (95%CIs). RESULTS A total of 40 studies (10 RCTs and 30 non-RCTs) involving 11,165 patients were included. Overall, PA-TACE was associated with an increased OS [HR, 0.71 (95% CI, 0.65-0.77); P < 0.001] and DFS [HR, 0.73 (95% CI, 0.66-0.80); P < 0.001]. Subgroup analysis in patients with microvascular invasion (MVI), tumor diameter >5 cm or multinodular tumors demonstrated that PA-TACE improved OS and DFS. In patients without MVI, PA-TACE showed no improvement in OS [HR, 1.14 (95% CI, 0.85-1.53); P = 0.370], and resulted in worse DFS than curative resection alone [HR, 1.20 (95% CI, 1.03-1.39); P = 0.002]. CONCLUSION This meta-analysis indicated that PA-TACE was beneficial in patients with HCC who were at high risk of postoperative recurrence including tumor diameter >5 cm, multinodular tumors and MVI-positive. In patients with tumor diameter ≤5 cm, single tumor or MVI-negative. PA-TACE does not appear to improve outcomes and may potentially promote postoperative recurrence in certain patients.
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Affiliation(s)
- Wen Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, China; Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, China
| | - Tao Ma
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, China; Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, China
| | - Jian Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, China; Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, China
| | - Xiaozhen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, China; Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, China
| | - Wei Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, China; Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, China
| | - Yinan Shen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, China; Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, China
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, China; Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, China; Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, China.
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Lu SD, Li L, Liang XM, Chen W, Chen FL, Fan LL, Ahir BK, Zhang WG, Zhong JH. Updates and advancements in the management of hepatocellular carcinoma patients after hepatectomy. Expert Rev Gastroenterol Hepatol 2019; 13:1077-1088. [PMID: 31648568 DOI: 10.1080/17474124.2019.1684898] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 10/21/2019] [Indexed: 02/07/2023]
Abstract
Introduction: The 5-year recurrence rate of hepatocellular carcinoma (HCC) after hepatic resection or local ablation is up to 70%. Adjuvant therapies to prevent HCC recurrence have been reported but are not currently recommended by EASL or AASLD guidelines. This review examined evidence from randomized controlled trials, meta-analyses and systematic reviews on the safety and efficacy of adjuvant therapies and chemotherapies in HCC patients after resection or local ablation.Areas covered: PubMed was searched through 15 June 2019. Available evidence was assessed based on the GRADE system.Expert commentary: Transarterial chemoembolization is the best adjuvant therapy for HCC patients at high risk of recurrence, antiviral therapy with nucleoside analogs is effective for preventing recurrence of HBV-related HCC, and interferon-α is effective for preventing recurrence of HCV-related HCC. Further studies are needed to clarify the efficacy of adjuvant immune checkpoint inhibitors. Adjuvant sorafenib appears to offer negligible clinical benefit and high risk of adverse effects.
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Affiliation(s)
- Shi-Dong Lu
- Department of Hepatobiliary Surgery, the Third Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lin Li
- Department of Hepatobiliary Surgery, the Third Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xin-Min Liang
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Wu Chen
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Fu-Li Chen
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Lang-Lin Fan
- Grade 2016, Basic medical college of Guangxi Medical University, Nanning, China
| | - Bhavesh K Ahir
- Section of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Wan-Guang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian-Hong Zhong
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
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Vitamin K 2 induces non-apoptotic cell death along with autophagosome formation in breast cancer cell lines. Breast Cancer 2019; 27:225-235. [PMID: 31625014 DOI: 10.1007/s12282-019-01012-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 10/03/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND Vitamin K2 (VK2) has been reported to induce apoptosis in many types of cancer cells including leukemia. However, there are no precise reports regarding the breast cancer cells. From the stand point of clinical implications of VK2 including chemoprevention, we investigated the effects of VK2 on breast cancer cell lines. METHODS Breast cancer cell lines were cultured with VK2, and the cytotoxicity and cell death phenotype were examined. The HL-60 leukemia cells were used as a control for VK2-induced apoptosis. RESULTS VK2 exhibited the cytotoxic effect, especially in triple negative breast cancer cell lines, namely, MDA-MB-231 and MDA-MB-468. However, in contrast to HL-60 cells, typical features of the cells undergoing apoptosis, such as chromatin condensation, nuclear fragments, and cleavage of caspase-3 were not detected. Transmission electron microscopy exhibited an increased number of autophagosomes/autolysosomes with plasma membrane integrity. An autophagy inhibitor, 3-methyladenine, apparently attenuated VK2-induced cytotoxicity, which indicated the involvement of autophagy-dependent cell death. Interestingly, both VK2-induced non-apoptotic cell death in MDA-MB-231 cells and VK2-induced apoptosis in HL-60 cells were suppressed in the presence of reactive oxygen species (ROS) scavengers. Therefore, ROS production by VK2 seems to be located up-stream in the molecular machinery for both the types of cell death execution. CONCLUSION The VK2 induced non-apoptotic cell death along with autophagy, in triple negative breast cancer cell lines. Cell death phenotype induced by VK2 appears to differ among the type of cancers. This suggests the possibility of using VK2 for the breast cancer therapy.
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Minami Y, Kudo M. Adjuvant therapy after radical surgery for hepatocellular carcinoma: still an unmet need. Hepatobiliary Surg Nutr 2019; 8:414-416. [PMID: 31489318 DOI: 10.21037/hbsn.2019.04.05] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Yasunori Minami
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
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35
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Kim SK, Takeda H, Takai A, Matsumoto T, Kakiuchi N, Yokoyama A, Yoshida K, Kaido T, Uemoto S, Minamiguchi S, Haga H, Shiraishi Y, Miyano S, Seno H, Ogawa S, Marusawa H. Comprehensive analysis of genetic aberrations linked to tumorigenesis in regenerative nodules of liver cirrhosis. J Gastroenterol 2019; 54:628-640. [PMID: 30756187 DOI: 10.1007/s00535-019-01555-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 01/30/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) recurrently develops in cirrhotic liver containing a number of regenerative nodules (RNs). However, the biological tumorigenic potential of RNs is still unclear. To uncover the molecular bases of tumorigenesis in liver cirrhosis, we investigated the genetic aberrations in RNs of cirrhotic tissues using next-generation sequencing. METHODS We isolated 205 RNs and 7 HCC tissues from the whole explanted livers of 10 randomly selected patients who had undergone living-donor liver transplantation. Whole-exome sequencing and additional targeted deep sequencing on 30 selected HCC-related genes were conducted to reveal the mutational landscape of RNs and HCCs. RESULTS Whole-exome sequencing demonstrated that RNs frequently harbored relatively high-abundance genetic alterations, suggesting a clonal structure of each RN in cirrhotic liver. The mutation signature observed in RNs was similar to those determined in HCC, characterized by a predominance of C>T transitions, followed by T>C and C>A mutations. Targeted deep sequencing analyses of RNs identified nonsynonymous low-abundance mutations in various tumor-related genes, including TP53 and ARID1A. In contrast, TERT promoter mutations were not detected in any of the RNs examined. Consistently, TERT expression levels in RNs were comparable to those in normal livers, whereas every HCC tissue demonstrated an elevated level of TERT expression. CONCLUSION Analyses of RNs constructing cirrhotic liver indicated that a variety of genetic aberrations accumulate in the cirrhotic liver before the development of clinically and histologically overt HCC. These aberrations in RNs could provide the basis of tumorigenesis in patients with liver cirrhosis.
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Affiliation(s)
- Soo Ki Kim
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.,Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Gastroenterology and Hepatology, Kobe Asahi Hospital, Kobe, Japan
| | - Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.,Department of Omics-Based Medicine, Center for Preventive Medicine, Chiba University, Chiba, Japan
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Tomonori Matsumoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Nobuyuki Kakiuchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.,Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Akira Yokoyama
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kenichi Yoshida
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshimi Kaido
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | | | - Hironori Haga
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Yuichi Shiraishi
- Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Satoru Miyano
- Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Seishi Ogawa
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. .,Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan.
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Kudo M. Immuno-Oncology Therapy for Hepatocellular Carcinoma: Current Status and Ongoing Trials. Liver Cancer 2019; 8:221-238. [PMID: 31602367 PMCID: PMC6738201 DOI: 10.1159/000501501] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 06/14/2019] [Indexed: 02/04/2023] Open
Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
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Vera MC, Lorenzetti F, Lucci A, Comanzo CG, Ceballos MP, Pisani GB, Alvarez MDL, Quiroga AD, Carrillo MC. Vitamin K2 supplementation blocks the beneficial effects of IFN-α-2b administered on the early stages of liver cancer development in rats. Nutrition 2019; 59:170-179. [DOI: 10.1016/j.nut.2018.08.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 08/06/2018] [Accepted: 08/22/2018] [Indexed: 12/14/2022]
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Kuzuya T, Ishigami M, Ishizu Y, Honda T, Hayashi K, Ishikawa T, Hirooka Y, Goto H. Complete response by vitamin K2 analog monotherapy in sorafenib-failure advanced hepatocellular carcinoma: A case report. Hepatol Res 2019; 49:360-364. [PMID: 30051950 DOI: 10.1111/hepr.13237] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 07/15/2018] [Accepted: 07/19/2018] [Indexed: 01/27/2023]
Abstract
There have been reports that a vitamin K2 (VK2) analog is beneficial for the prevention of recurrence in hepatocellular carcinoma (HCC) patients after curative therapy. However, the VK2 analogs in current use do not appear to show dramatic antitumor effects when given alone. Here, we report the case of a 67-year-old male patient with sorafenib-failure advanced HCC who achieved complete response (CR) after VK2 analog monotherapy. At the time of sorafenib failure confirmation, the patient had multiple intrahepatic tumors, multiple lung metastases, and Vp3 portal vein tumor thrombosis. He had poor liver function (Child-Pugh score of 9, Child-Pugh class B) and poor performance status (Eastern Cooperative Oncology Group performance status 2). Both serum α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) levels were elevated (558 900 ng/mL and 917 300 mAU/mL, respectively). Treatment with VK2 analog was initiated at 45 mg/day. Five months later, both tumor markers had decreased to normal levels (AFP 8 ng/mL and DCP 10 mAU/mL). Contrast-enhanced computed tomography showed that all intrahepatic tumors had shrunk, there was no enhancement of tumor staining in the arterial phase, and all lung metastases and portal vein tumor thromboses had disappeared. We considered that CR was achieved according to the modified Response Evaluation Criteria in Solid Tumors. Eighteen months after the start of VK2 analog administration, the patient continues to receive treatment and has remained in CR without adverse events. Here, we report a rare case of sorafenib-failure advanced HCC in which sustained CR was achieved by VK2 analog monotherapy.
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Affiliation(s)
- Teiji Kuzuya
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kazuhiko Hayashi
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tetsuya Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshiki Hirooka
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hidemi Goto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Xia J, Ozaki I, Matsuhashi S, Kuwashiro T, Takahashi H, Anzai K, Mizuta T. Mechanisms of PKC-Mediated Enhancement of HIF-1α Activity and its Inhibition by Vitamin K2 in Hepatocellular Carcinoma Cells. Int J Mol Sci 2019; 20:ijms20051022. [PMID: 30813635 PMCID: PMC6429062 DOI: 10.3390/ijms20051022] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 02/20/2019] [Accepted: 02/21/2019] [Indexed: 01/27/2023] Open
Abstract
Hypoxia-inducible factor 1 (HIF-1) plays important roles in cancer cell biology. HIF-1α is reportedly activated by several factors, including protein kinase C (PKC), in addition to hypoxia. We investigated the role of PKC isoforms and the effects of vitamin K2 (VK2) in the activation process of HIF-1α. Human hepatocellular carcinoma (HCC)-derived Huh7 cells were cultured under normoxic and hypoxic (1% O₂) conditions with or without the PKC stimulator TPA. The expression, transcriptional activity and nuclear translocation of HIF-1α were examined under treatment with PKC inhibitors, siRNAs against each PKC isoform and VK2. Hypoxia increased the expression and activity of HIF-1α. TPA increased the HIF-1α activity several times under both normoxic and hypoxic conditions. PKC-δ siRNA-mediated knockdown, PKC-δ inhibitor (rottlerin) and pan-PKC inhibitor (Ro-31-8425) suppressed the expression and transcriptional activity of HIF-1α. VK2 significantly inhibited the TPA-induced HIF-1α transcriptional activity and suppressed the expression and nuclear translocation of HIF-1α induced by TPA without altering the HIF-1α mRNA levels. These data indicate that PKC-δ enhances the HIF-1α transcriptional activity by increasing the nuclear translocation, and that VK2 might suppress the HIF-1α activation through the inhibition of PKC in HCC cells.
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Affiliation(s)
- Jinghe Xia
- Department of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
| | - Iwata Ozaki
- Department of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
- Health Administration Center, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
| | - Sachiko Matsuhashi
- Department of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
| | - Takuya Kuwashiro
- Department of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
| | - Hirokazu Takahashi
- Department of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
| | - Keizo Anzai
- Department of Internal Medicine, Saga Medical School, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.
| | - Toshihiko Mizuta
- Department of Internal Medicine, Fujikawa Hospital, 1-2-6 Matsubara, Saga 840-0831, Japan.
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Kudo M. Targeted and immune therapies for hepatocellular carcinoma: Predictions for 2019 and beyond. World J Gastroenterol 2019; 25:789-807. [PMID: 30809080 PMCID: PMC6385008 DOI: 10.3748/wjg.v25.i7.789] [Citation(s) in RCA: 116] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 01/10/2019] [Accepted: 01/14/2019] [Indexed: 02/06/2023] Open
Abstract
Systemic therapy for hepatocellular carcinoma (HCC) has markedly advanced since the survival benefit of a molecular targeted agent, sorafenib, were demonstrated in the SHARP and Asia Pacific trials in 2007. Treatment options for patients with advanced HCC increased by sorafenib, and long-term survival for patients with advanced stage HCC has become possible to some extent. However, development of a more potent first-line novel molecular targeted agent replacing sorafenib and a potent second-line agent after disease progression on or intolerant to sorafenib has been warranted because sorafenib lacks tumor shrinking/necrotizing effects and induces relatively severe adverse events such as hand foot skin reaction. Many agents in the 1st line and 2nd line setting were attempted to develop between 2007 and 2016, but all of these clinical trials failed. On the other hand, clinical trials of 4 agents (regorafenib, lenvatinib, cabozantinib, and ramucirumab) succeeded in succession in 2017 and 2018, and their use in clinical practice is possible (regorafenib and lenvatinib) or underway (cabozantinib and ramucirumab). Furthermore, all of 5 clinical trials of combination therapy with transcatheter chemoembolization (TACE) plus a molecular targeted agent failed to date, however, the combination of TACE and sorafenib (TACTICS trials) was reported to be successful and presented at ASCO in 2018. Phase 3 clinical trials of immune checkpoint inhibitors and a combination therapy of immune checkpoint inhibitors and molecular targeted agents are also ongoing, which suggests treatment paradigm of HCC in all stages from early, intermediate and advanced stage, is expected to be changed drastically in the very near future.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka 589-8511, Japan
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Kim M, Basharat A, Santosh R, Mehdi SF, Razvi Z, Yoo SK, Lowell B, Kumar A, Brima W, Danoff A, Dankner R, Bergman M, Pavlov VA, Yang H, Roth J. Reuniting overnutrition and undernutrition, macronutrients, and micronutrients. Diabetes Metab Res Rev 2019; 35:e3072. [PMID: 30171821 DOI: 10.1002/dmrr.3072] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 08/20/2018] [Accepted: 08/26/2018] [Indexed: 12/15/2022]
Abstract
Over-nutrition and its late consequences are a dominant theme in medicine today. In addition to the health hazards brought on by over-nutrition, the medical community has recently accumulated a roster of health benefits with obesity, grouped under "obesity paradox." Throughout the world and throughout history until the 20th century, under-nutrition was a dominant evolutionary force. Under-nutrition brings with it a mix of benefits and detriments that are opposite to and continuous with those of over-nutrition. This continuum yields J-shaped or U-shaped curves relating body mass index to mortality. The overweight have an elevated risk of dying in middle age of degenerative diseases while the underweight are at increased risk of premature death from infectious conditions. Micronutrient deficiencies, major concerns of nutritional science in the 20th century, are being neglected. This "hidden hunger" is now surprisingly prevalent in all weight groups, even among the overweight. Because micronutrient replacement is safe, inexpensive, and predictably effective, it is now an exceptionally attractive target for therapy across the spectrum of weight and age. Nutrition-related conditions worthy of special attention from caregivers include excess vitamin A, excess vitamin D, and deficiency of magnesium.
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Affiliation(s)
- Miji Kim
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Anam Basharat
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Ramchandani Santosh
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Syed F Mehdi
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Zanali Razvi
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Sun K Yoo
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Barbara Lowell
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Amrat Kumar
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Wunnie Brima
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
- Department of Medicine, Albert Einstein College of Medicine, New York, USA
| | - Ann Danoff
- Department of Medicine, Cpl. Michael J Crescenz Veterans Administration Medical Center, Philadelphia, PA, USA
| | - Rachel Dankner
- Department of Epidemiology and Preventive Medicine, School of Public Health, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Michael Bergman
- Department of Medicine, Division of Endocrinology, NYU School of Medicine, New York, NY, USA
| | - Valentin A Pavlov
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
- Center for Biomedical Science and Center for Bioelectric Medicine, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Huan Yang
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
- Center for Biomedical Science and Center for Bioelectric Medicine, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
| | - Jesse Roth
- Laboratory of Diabetes and Diabetes-Related Disorders, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
- Department of Medicine, Albert Einstein College of Medicine, New York, USA
- Center for Biomedical Science and Center for Bioelectric Medicine, The Feinstein Institute for Medical Research, Northwell Health, New York, USA
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Liu S, Li H, Guo L, Zhang B, Zhou B, Zhang W, Zhou J, Fan J, Ye Q. Tumor Size Affects Efficacy of Adjuvant Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma and Microvascular Invasion. Oncologist 2018; 24:513-520. [PMID: 30552155 DOI: 10.1634/theoncologist.2018-0305] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 10/16/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Patients with hepatocellular carcinoma (HCC) and microvascular invasion (mVI) have shown dismal postoperative prognosis; however, whether adjuvant transarterial chemoembolization (TACE) can improve their outcomes remains unclear. MATERIALS AND METHODS We retrospectively identified 549 eligible patients to form the crude cohort and adopted propensity score matching method to assemble another cohort of 444 patients with similar baseline characteristics. We assessed the effects of adjuvant TACE by stratified analyses and multivariate Cox analyses in two cohorts. RESULTS There was significant interaction between tumor size and adjuvant TACE with respect to overall survival (OS; p = .006 for interaction). In the matched cohort, patients who received adjuvant TACE showed higher rates of 5-year OS (72.4% vs. 50.9%, p = .005) and 5-year recurrence-free survival (50.5% vs. 36.4%, p = .003) in the tumor ≤5 cm subgroup, but not in the tumor >5 cm subgroup (32.3% vs. 24.9%, p = .350 and 18.8% vs. 19.7%, p = .180). The independent protective role of adjuvant TACE on OS was observed in patients with tumor ≤5 cm (adjusted odds ratio [OR] = 0.59, 95% confidence interval [CI] 0.36-0.97) but not in patients with tumor >5 cm (adjusted OR = 1.17, 95% CI 0.84-1.62). The effects of adjuvant TACE did not change materially while the analysis was performed in the crude cohort. CONCLUSION For patients with HCC and mVI, adjuvant TACE was associated with improved outcomes, but not for those with tumor >5 cm, according to the current protocol. IMPLICATIONS FOR PRACTICE The outcomes of patients with hepatocellular carcinoma and microvascular invasion who received adjuvant transarterial chemoembolization were inconsistent in this study. According to the current protocol, adjuvant transarterial chemoembolization was associated with improved prognosis in patients with microvascular invasion, except for those with tumor >5 cm. Multivariate Cox models confirmed adjuvant transarterial chemoembolization was an independent protective factor in the tumor ≤5 cm subgroup but not in the tumor >5 cm subgroup.
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Affiliation(s)
- Shuang Liu
- Department of Liver Surgery, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, People's Republic of China
| | - Hui Li
- Department of Liver Surgery, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, People's Republic of China
| | - Lei Guo
- Department of Liver Surgery, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, People's Republic of China
| | - Bo Zhang
- Department of Liver Surgery, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, People's Republic of China
| | - Binghai Zhou
- Department of Liver Surgery, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, People's Republic of China
| | - Wentao Zhang
- Department of Liver Surgery, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, People's Republic of China
| | - Jian Zhou
- Department of Liver Surgery, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, People's Republic of China
| | - Jia Fan
- Department of Liver Surgery, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, People's Republic of China
| | - Qinghai Ye
- Department of Liver Surgery, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, People's Republic of China
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Chung YK, Hwang S, Song GW, Lee YJ, Kim KH, Ahn CS, Moon DB, Ha TY, Jung DH, Park GC, Ryoo BY, Lee SG. Absence of antitumor effects of metformin in sorafenib-treated patients with hepatocellular carcinoma recurrence after hepatic resection and liver transplantation. Ann Hepatobiliary Pancreat Surg 2018; 22:297-304. [PMID: 30588519 PMCID: PMC6295365 DOI: 10.14701/ahbps.2018.22.4.297] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 06/10/2018] [Accepted: 06/14/2018] [Indexed: 01/27/2023] Open
Abstract
Backgrounds/Aims Hepatocellular carcinoma (HCC) recurrence following hepatic resection (HR) and liver transplantation (LT) remains a great concern. We assessed the antitumor effects of metformin in patients treated with sorafenib for HCC recurrence after HR or LT. Methods The two clinical retrospective studies involved metformin therapy of 304 HR patients and 74 LT recipients who were treated with sorafenib. Results In the study involving patients who had undergone HR, death occurred in 245 of the 304 patients (80.6%) during a median follow-up of 10.2 months after sorafenib administration. The metformin HR group (group 1; n=40) showed no prognostic difference in progression-free and overall survival rates compared with the all-HR control group (group 3; n=241) and propensity score-matched HR control group (group 4; n=80). In the clinical study of recipients exposed to LT, death occurred in 62 of the 74 patients (83.8%) during a median follow-up of 13.6 months (range: 3–76 months) after sorafenib administration. The metformin LT group (group 5; n=14) showed no prognostic difference in progression-free and overall survival rates compared with the all-LT control group (group 7; n=43) and propensity score-matched LT control group (group 8; n=28). Conclusions Our clinical studies demonstrated absence of synergistic antitumor effects of metformin. Further high-volume studies are necessary to assess the role of metformin in patients treated with sorafenib for advanced HCC.
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Affiliation(s)
- Yong-Kyu Chung
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Shin Hwang
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gi-Won Song
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young-Joo Lee
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ki-Hun Kim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chul-Soo Ahn
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Deok-Bog Moon
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Tae-Yong Ha
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dong-Hwan Jung
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gil-Chun Park
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Baek-Yeol Ryoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung-Gyu Lee
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Kudo M. Systemic Therapy for Hepatocellular Carcinoma: Latest Advances. Cancers (Basel) 2018; 10:cancers10110412. [PMID: 30380773 PMCID: PMC6266463 DOI: 10.3390/cancers10110412] [Citation(s) in RCA: 133] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 10/23/2018] [Accepted: 10/25/2018] [Indexed: 12/13/2022] Open
Abstract
Systemic therapy for hepatocellular carcinoma (HCC) has changed drastically since the introduction of the molecular targeted agent sorafenib in 2007. Although sorafenib expanded the treatment options for extrahepatic spread (EHS) and vascular invasion, making long-term survival of patients with advanced disease achievable to a certain extent, new molecular-targeted agents are being developed as alternatives to sorafenib due to shortcomings such as its low response rate and high toxicity. Every single one of the many drugs developed during the 10-year period from 2007 to 2016 was a failure. However, during the two-year period from 2017 through 2018, four drugs—regorafenib, lenvatinib, cabozantinib, and ramucirumab—emerged successfully from clinical trials in quick succession and became available for clinical use. The efficacy of combination therapy with transcatheter arterial chemoembolization (TACE) plus sorafenib was also first demonstrated in 2018. Recently, immune checkpoint inhibitors have been applied to HCC treatment and many phase III clinical trials are ongoing, not only on monotherapy with nivolumab, pembrolizumab, and tislelizumab, but also on combination therapy with checkpoint inhibitors, programmed death-1 (PD-1) or PD-ligand 1 (PD-L1) antibody plus a molecular targeted agent (bevacizumab) or the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, tremelimumab. These combination therapies have shown higher response rates than PD-1/PD-L1 monotherapy alone, suggesting a synergistic effect by combination therapy in early phases; therefore, further results are eagerly awaited.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 337-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.
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45
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Wen T, Jin C, Facciorusso A, Donadon M, Han HS, Mao Y, Dai C, Cheng S, Zhang B, Peng B, Du S, Jia C, Xu F, Shi J, Sun J, Zhu P, Nara S, Millis JM. Multidisciplinary management of recurrent and metastatic hepatocellular carcinoma after resection: an international expert consensus. Hepatobiliary Surg Nutr 2018; 7:353-371. [PMID: 30498711 DOI: 10.21037/hbsn.2018.08.01] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is the sixth-most common cancer and the third leading cause of cancer-related death in the world. However, 40-70% patients eventually suffer from postoperative recurrence within 5 years. HCC recurrence after surgery severely affects prognosis of the patients. Nevertheless, there is an opportunity to improve patients' prognosis if doctors and researchers can recognize the importance of a standardized perioperative management and study it in clinical and pre-clinical settings. Hence, based on our own experience and published studies from other researchers, we develop this consensus regarding multidisciplinary management of locally recurrent and metastatic hepatocellular carcinoma after resection. This consensus consists of the entire course of recurrent hepatocellular carcinoma (RHCC) management, including prediction of recurrence, prevention, diagnosis, treatment and surveillance of RHCC. Consensus recommendations are presented with grades of evidences (Ia, Ib, IIa, IIb, III and IV), and strength of recommendations (A, B, C, D and E). We also develop a decision-making path for RHCC treatment, which can intuitively demonstrate the management for RHCC. It is hoped that we may make some effort to standardize the management of RHCC and ultimately understand how to improve outcomes.
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Affiliation(s)
- Tianfu Wen
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Chen Jin
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Antonio Facciorusso
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Matteo Donadon
- Department of Hepatobiliary & General Surgery, Humanitas University, Humanitas Clinical and Research Center, Milan, Italy
| | - Ho-Seong Han
- Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Chaoliu Dai
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang 110000, China
| | - Shuqun Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Baogang Peng
- Department of Liver Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Changjun Jia
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang 110000, China
| | - Feng Xu
- Department of Hepatobiliary and Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang 110000, China
| | - Jie Shi
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Juxian Sun
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Peng Zhu
- Hepatic Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Satoshi Nara
- Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan
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Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. There are two major challenges for HCC, the first being that early detection is generally not applicable, and secondly, it is usually fatal within several months after diagnosis. HCC is an inflammation-induced cancer. It is known that chronic inflammation leads to oxidative/nitrosative stress and lipid peroxidation, generating excess oxidative stress, together with aldehydes which can react with DNA bases to form promutagenic DNA adducts. In this review, the evidence between oxidative stress and liver carcinogenesis is summarized. We focused on the potential of using DNA adducts as oxidative stress biomarkers for liver carcinogenesis.
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Affiliation(s)
- Ying Fu
- Laboratory of Molecular Biology, Center for Cancer Research, NCI, Bethesda, MD 20892, USA
| | - Fung-Lung Chung
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, USA
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47
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Setoguchi S, Watase D, Matsunaga K, Yamakawa H, Goto S, Terada K, Ohe K, Enjoji M, Karube Y, Takata J. Antitumor Effects and Delivery Profiles of Menahydroquinone-4 Prodrugs with Ionic or Nonionic Promoiety to Hepatocellular Carcinoma Cells. Molecules 2018; 23:molecules23071738. [PMID: 30013007 PMCID: PMC6100056 DOI: 10.3390/molecules23071738] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 07/14/2018] [Accepted: 07/15/2018] [Indexed: 12/26/2022] Open
Abstract
Hepatocellular carcinoma (HCC) shows poor prognosis owing to its very frequent recurrence even after curative treatment. Thus, an effective and safe long-term chemopreventive agent is strongly in demand. Menahydroquinone-4 (MKH) is an active form of menaquinone-4 (MK-4, vitamin K₂) that is involved in the synthesis of vitamin K-dependent proteins in the liver. We hypothesized that efficient delivery of MKH might be critical to regulate HCC proliferation. The discovery of a suitable prodrug targeting HCC in terms of delivery and activation could reduce the clinical dose of MK-4 and maximize efficacy and safety. We previously showed that MKH dimethylglycinate (MKH-DMG) enables effective delivery of MKH into HCC cells and exhibits strong antitumor effects compared with MK-4. In this study, we prepared anionic MKH hemi-succinate (MKH-SUC) and non-ionic MKH acetate (MKH-ACT), in addition to cationic MKH-DMG, and evaluated MKH delivery profiles and antitumor effects in vitro. MKH-SUC showed the highest uptake and the most efficient release of MKH among the examined compounds and exhibited rapid and strong antitumor effects. These results indicate that MKH-SUC might have a good potential as an MKH delivery system for HCC that overcomes the limitations of MK-4 as a clinical chemopreventive agent.
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Affiliation(s)
- Shuichi Setoguchi
- Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
| | - Daisuke Watase
- Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
| | - Kazuhisa Matsunaga
- Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
| | - Hirofumi Yamakawa
- Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
| | - Shotaro Goto
- Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
| | - Kazuki Terada
- Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
| | - Kenji Ohe
- Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
| | - Munechika Enjoji
- Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
| | - Yoshiharu Karube
- Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
| | - Jiro Takata
- Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
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48
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Eso Y, Marusawa H. Novel approaches for molecular targeted therapy against hepatocellular carcinoma. Hepatol Res 2018; 48:597-607. [PMID: 29689631 DOI: 10.1111/hepr.13181] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 04/06/2018] [Accepted: 04/11/2018] [Indexed: 02/08/2023]
Abstract
Systemic chemotherapy using a multitargeted tyrosine kinase inhibitor is an established treatment for advanced-stage tumors in various organs. Comprehensive genomic analyses using next-generation sequencing technology revealed the intra- and intertumor heterogeneity of human hepatocellular carcinomas (HCCs), and provided evidence for the use of therapeutic agents effective against multiple targets in tumor cells. Recently, the efficacy and safety of a multitargeted tyrosine kinase inhibitor, lenvatinib, was confirmed by a randomized global phase III trial; thus, lenvatinib was approved as first-line therapy for HCC, providing a new therapeutic option for patients at an advanced stage. In this article, we introduce the application of molecular targeted therapy using lenvatinib and discuss future aspects of therapeutic options for advanced HCC.
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Affiliation(s)
- Yuji Eso
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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49
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Jiao J, Watt GP, Stevenson HL, Calderone TL, Fisher-Hoch SP, Ye Y, Wu X, Vierling JM, Beretta L. Telomerase reverse transcriptase mutations in plasma DNA in patients with hepatocellular carcinoma or cirrhosis: Prevalence and risk factors. Hepatol Commun 2018; 2:718-731. [PMID: 29881823 PMCID: PMC5983165 DOI: 10.1002/hep4.1187] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 03/02/2018] [Accepted: 03/28/2018] [Indexed: 02/06/2023] Open
Abstract
Telomerase reverse transcriptase (TERT) mutation is the most frequent genetic alteration in hepatocellular carcinoma (HCC). Our aims were to investigate whether TERT mutations can be detected in circulating cell‐free DNA (cfDNA) of patients with HCC and/or cirrhosis and characterize clinical parameters associated with these mutations. We retrieved data on TERT C228T and C250T promoter mutations in 196 HCCs from The Cancer Genome Atlas. We measured these TERT mutations in plasma cfDNA in 218 patients with HCC and 81 patients with cirrhosis without imaging evidence of HCC. The prevalence of TERT mutations in The Cancer Genome Atlas HCC specimens was 44.4%. TERT mutations were detected with similar prevalence (47.7%) in plasma cfDNAs from 218 patients with HCC. TERT mutations, either within the HCC or in cfDNA, were associated with male sex, hepatitis C virus (HCV), alcoholic cirrhosis, family history of cancer, and poor prognosis. The high prevalence of TERT mutations in HCCs in male patients with cirrhosis caused by HCV and/or alcohol was confirmed in an independent set of HCCs (86.6%). Finally, TERT mutations were detected in cfDNA of 7 out of 81 (8.6%) patients with cirrhosis without imaging evidence of HCC, including 5 male patients with cirrhosis due to HCV and/or alcohol. Genes involved in xenobiotic and alcohol metabolism were enriched in HCCs with TERT mutations, and vitamin K2 was identified as an upstream regulator. Conclusion: TERT mutations are detectable in plasma cfDNA. Long‐term imaging surveillance of patients with cirrhosis with cfDNA TERT mutations without evidence of HCC is required to assess their potential as early biomarkers of HCC. (Hepatology Communications 2018;2:718‐731)
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Affiliation(s)
- Jingjing Jiao
- Department of Molecular and Cellular Oncology University of Texas MD Anderson Cancer Center Houston TX
| | - Gordon P Watt
- Department of Molecular and Cellular Oncology University of Texas MD Anderson Cancer Center Houston TX.,School of Public Health University of Texas Health Science Center at Houston Brownsville Regional Campus Brownsville TX
| | | | - Tiffany L Calderone
- Department of Molecular and Cellular Oncology University of Texas MD Anderson Cancer Center Houston TX
| | - Susan P Fisher-Hoch
- School of Public Health University of Texas Health Science Center at Houston Brownsville Regional Campus Brownsville TX
| | - Yuanqing Ye
- Department of Epidemiology University of Texas MD Anderson Cancer Center Houston TX
| | - Xifeng Wu
- Department of Epidemiology University of Texas MD Anderson Cancer Center Houston TX
| | - John M Vierling
- Departments of Medicine and Surgery Baylor College of Medicine Houston TX
| | - Laura Beretta
- Department of Molecular and Cellular Oncology University of Texas MD Anderson Cancer Center Houston TX
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50
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Xv F, Chen J, Duan L, Li S. Research progress on the anticancer effects of vitamin K2. Oncol Lett 2018; 15:8926-8934. [PMID: 29805627 PMCID: PMC5958717 DOI: 10.3892/ol.2018.8502] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 02/15/2018] [Indexed: 01/27/2023] Open
Abstract
Despite the availability of multiple therapeutic methods for patients with cancer, the long-term prognosis is not satisfactory in a number of different cancer types. Vitamin K2 (VK2), which exerts anticancer effects on a number of cancer cell lines, is considered to be a prospective novel agent for the treatment of cancer. The present review aims to summarize the results of studies in which VK2 was administered either to patients with cancer or animals inoculated with cancerous cells, particularly investigating the inhibitory effects of VK2 on cancerous cells, primarily involving cell-cycle arrest, cell differentiation, apoptosis, autophagy and invasion. The present review summarizes evidence stating that treatment with VK2 could positively inhibit the growth of cancer cells, making it a potentially useful approach for the prevention and clinical treatment of cancer. Additionally, the combination treatment of VK2 and established chemotherapeutics may achieve better results, with fewer side effects. Therefore, more attention should be paid to the effects of micronutrients on tumors.
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Affiliation(s)
- Fan Xv
- Department of Physiology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Jiepeng Chen
- Sungen Bioscience Co., Ltd., Shantou, Guangdong 515071, P.R. China
| | - Lili Duan
- Sungen Bioscience Co., Ltd., Shantou, Guangdong 515071, P.R. China
| | - Shuzhuang Li
- Department of Physiology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
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