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Jain A, Mishra AK, Hurkat P, Shilpi S, Mody N, Jain SK. Navigating liver cancer: Precision targeting for enhanced treatment outcomes. Drug Deliv Transl Res 2025; 15:1935-1961. [PMID: 39847205 DOI: 10.1007/s13346-024-01780-x] [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] [Accepted: 12/18/2024] [Indexed: 01/24/2025]
Abstract
Cancer treatments such as surgery and chemotherapy have several limitations, including ineffectiveness against large or persistent tumors, high relapse rates, drug toxicity, and non-specificity of therapy. Researchers are exploring advanced strategies for treating this life-threatening disease to address these challenges. One promising approach is targeted drug delivery using prodrugs or surface modification with receptor-specific moieties for active or passive targeting. While various drug delivery systems have shown potential for reaching hepatic cells, nano-carriers offer significant size, distribution, and targetability advantages. Engineered nanocarriers can be customized to achieve effective and safe targeting of tumors by manipulating physical characteristics such as particle size or attaching receptor-specific ligands. This method is particularly advantageous in treating liver cancer by targeting specific hepatocyte receptors and enzymatic pathways for both passive and active therapeutic strategies. It highlights the epidemiology of liver cancer and provides an in-depth analysis of the various targeting approaches, including prodrugs, liposomes, magneto-liposomes, micelles, glycol-dendrimers, magnetic nanoparticles, chylomicron-based emulsion, and quantum dots surface modification with receptor-specific moieties. The insights from this review can be immensely significant for preclinical and clinical researchers working towards developing effective treatments for liver cancer. By utilizing these novel strategies, we can overcome the limitations of conventional therapies and offer better outcomes for liver cancer patients.
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Affiliation(s)
- Ankit Jain
- Department of Pharmacy, Birla Institute of Technology and Science (BITS), Pilani Campus, Pilani, Rajasthan, 333031, India.
| | - Ashwini Kumar Mishra
- Department of Pharmaceutics, School of Pharmacy & Technology Management, SVKM'S NMIMS Deemed-to-be University, Shirpur, Maharashtra, 425405, India
- Central Ayurveda Research Institute, Jhansi, Uttar Pradesh, 284003, India
| | - Pooja Hurkat
- Dr. Hari Singh Gour Central University, Sagar, 470003, MP, India
| | - Satish Shilpi
- School of Pharmaceuticals and Population Health Informatics, FOP, DIT University, Dehradun, Uttarakahnad, India
| | - Nishi Mody
- Dr. Hari Singh Gour Central University, Sagar, 470003, MP, India
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Ye-Tran X, Bouattour M, Fresneau B, Turpin A, Perret A, Vitellius C, Coriat R, Blanc JF, Lequoy M, Regnault H, Pietrasz D, Sefrioui D, Lecomte T, Moati E, Caliez O, Nguyen-Khac E, Walter T, Hautefeuille V. Response to systemic treatments and survival of fibrolamellar carcinomas: An AGEO-SFCE French multicenter retrospective cohort. Dig Liver Dis 2025:S1590-8658(25)00328-7. [PMID: 40316454 DOI: 10.1016/j.dld.2025.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 02/13/2025] [Accepted: 04/07/2025] [Indexed: 05/04/2025]
Abstract
INTRODUCTION Fibrolamellar carcinomas (FLC) are rare and predominantly advanced hepatic malignancies, lacking a clear consensus on anti-tumor treatments (ATT). The primary objective of the study was to determine whether any ATT appeared to give favorable outcomes in terms of morphological objective response (ORR) and disease control (DCR) rate according to RECIST 1.1 criteria. PATIENTS AND METHODS This retrospective multicentric French cohort from 14 centers included 44 patients with histologically proven FLC who received at least one ATT (chemotherapy and/or tyrosine kinase inhibitors, TKI) and underwent at least one morphological evaluation. . RESULTS A total of 40 anti-tumor responses were analyzed after a first line treatment. No complete response was observed, with an ORR in 13 % of cases, a DCR in 55 % of cases and 45 % of disease progression. GEMOX regimen (n = 9) showed an ORR of 11 % and a DCR of 33 %; the combination of doxorubicin and platinum-based chemotherapy (n = 6) achieved an ORR of 33 % and a DCR of 83 %. For TKI, sorafenib (n = 10) and sunitinib (n = 3), there was no objective response, with a DCR of 40 % and 33 % respectively. The median and the 5-years overall survival were 3.3 years and 35 % (95 %CI=[0.23-0.54]) respectively. CONCLUSION FLC have a poor prognosis; ATT show mild response rate. Further approaches and personalized medicine seem to be an unmet need for patients with FLC and new treatments should be urgently developed.
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Affiliation(s)
- Xixi Ye-Tran
- Gastroenterology Department, Grand Hôpital de l'Est Francilien (GHEF), Meaux, France
| | - Mohamed Bouattour
- Liver Cancer Unit, Assistance Publique - Hôpitaux de Paris, Beaujon University Hospital, Clichy, France
| | - Brice Fresneau
- Gustave Roussy, Department of Children and Adolescents Oncology, Villejuif, F-94805, France
| | - Anthony Turpin
- Medical Oncology - Lille University Hospital - Lille, France
| | - Audrey Perret
- Medical Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Carole Vitellius
- Hepato-Gastroenterology Department, University Hospital, Angers, France
| | - Romain Coriat
- Department of gastroenterology and endoscopy, Hôpital Cochin, Université Paris Cité, Paris, France
| | - Jean Frederic Blanc
- Department of Digestive Oncology, Hôpital Haut-Lévêque, Bordeaux University Hospital, Pessac, France
| | - Marie Lequoy
- Department of Hepatology, AP-HP, Saint-Antoine Hospital, F-75012, Paris, France
| | - Hélène Regnault
- Department of Hepatology, Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Créteil, France
| | - Daniel Pietrasz
- Department of Digestive, Oncological, and Transplant Surgery, Paul Brousse Hospital, Paris-Saclay University, Villejuif, France
| | - David Sefrioui
- Department of Gastroenterology, Digestive Oncology Unit, Rouen University Hospital, Rouen, France
| | - Thierry Lecomte
- Hepato-gastroenterology and Digestive Oncology, Tours University Hospital, Tours, France
| | - Emilie Moati
- Department of Gastroenterology and Digestive Oncology, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, Institut du Cancer Paris Carpem, Paris, France
| | - Olivier Caliez
- Department of Hepato-gastroenterology, Assistance Publique, Hôpitaux de Paris, Pitié Salpêtrière University Hospital, Paris, France
| | - Eric Nguyen-Khac
- Hepato-gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France
| | - Thomas Walter
- Gastroenterology and Digestive Oncology, Edouard Herriot University Hospital, Hospices Civils de Lyon, Lyon, France
| | - Vincent Hautefeuille
- Hepato-gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France.
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Zhang W, Hong X, Xiao Y, Wang H, Zeng X. Sorafenib resistance and therapeutic strategies in hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer 2025; 1880:189310. [PMID: 40187502 DOI: 10.1016/j.bbcan.2025.189310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 03/30/2025] [Accepted: 03/30/2025] [Indexed: 04/07/2025]
Abstract
Hepatocellular carcinoma (HCC) remains one of the most prevalent and lethal cancers globally. While surgical resection and liver transplantation offer potential cures for early-stage HCC, the majority of patients are diagnosed at advanced stages where such interventions are not viable. Sorafenib, a multi-target kinase inhibitor, has been a cornerstone in the treatment of advanced HCC since its approval in 2007. Despite its significant clinical impact, less than half of the treated patients derive long-term benefits due to the emergence of resistance and associated side effects. This review focuses on the role of sorafenib, an FDA-approved multi-target kinase inhibitor, in treating advanced HCC, discusses the mechanisms underlying its therapeutic effects and associated resistance, and explores additional therapeutic strategies being investigated to improve patient outcomes.
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Affiliation(s)
- Weijing Zhang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China
| | - Xuechuan Hong
- Department of Cardiology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
| | - Yuling Xiao
- Department of Cardiology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China; State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Hongbo Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
| | - Xiaodong Zeng
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
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Majeed A, Alaparthi S, Halegoua-DeMarzio D, Eberle-Singh J, Jiang W, Anne PR, Shah AP, Bowne WB, Lin D. Complete Pathologic Response to Gemcitabine and Oxaliplatin Chemotherapy After Prior Therapies in a Patient With Hepatocellular Carcinoma and Peritoneal Metastases Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy. World J Oncol 2024; 15:511-520. [PMID: 38751709 PMCID: PMC11092419 DOI: 10.14740/wjon1840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 05/01/2024] [Indexed: 05/18/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is often diagnosed at a late stage and frequently recurs despite curative intervention, leading to poor survival outcomes. Frontline systemic therapies include combination immunotherapy regimens and tyrosine kinase inhibitors. We report a case of a 38-year-old woman with chronic hepatitis B and C coinfection-associated non-cirrhotic HCC, which recurred in the peritoneum after initial resection of her primary tumor. Disease progression occurred on both atezolizumab/bevacizumab and lenvatinib, and she was subsequently treated with gemcitabine and oxaliplatin (GEMOX) chemotherapy and exhibited a profound clinical response on imaging with normalization of alpha fetoprotein (AFP) after several months. Following extensive multidisciplinary discussion, she underwent cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) that removed all visible macroscopic tumor. Her pathology demonstrated a complete pathologic response. She received two additional months of postoperative chemotherapy, and then proceeded with close monitoring off therapy. To our knowledge, this is the first reported case of a complete pathologic response to GEMOX chemotherapy in the context of CRS/HIPEC for peritoneal metastases in HCC, after progression on standard immunotherapy and tyrosine kinase inhibitor treatments. In this report, we review the current systemic treatment landscape in HCC. We highlight potential consideration of cytotoxic chemotherapy, which is less frequently utilized in current practice, in selected patients with HCC, and discuss the role of CRS/HIPEC in the management of peritoneal metastases. Further investigation regarding predictors of response to systemic treatments is strongly needed. Multidisciplinary management may ultimately prolong survival in patients with advanced HCC.
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Affiliation(s)
- Amry Majeed
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Sneha Alaparthi
- Department of General Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Dina Halegoua-DeMarzio
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Jaime Eberle-Singh
- Department of Pathology and Genomic Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Wei Jiang
- Department of Pathology and Genomic Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Pramila Rani Anne
- Department of Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Ashesh P. Shah
- Department of General Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Wilbur B. Bowne
- Department of General Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Daniel Lin
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, PA, USA
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Ningarhari M, Bertez M, Ploquin A, Bertrand N, Desauw C, Cattan S, Catala P, Vandamme H, Cheymol C, Truant S, Lassailly G, Louvet A, Mathurin P, Dharancy S, Turpin A. Conventional cytotoxic chemotherapy for gastrointestinal cancer in patients with cirrhosis: A multicentre case-control study. Liver Int 2024; 44:682-690. [PMID: 38031969 DOI: 10.1111/liv.15813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 11/08/2023] [Accepted: 11/23/2023] [Indexed: 12/01/2023]
Abstract
BACKGROUND & AIMS Progresses in management make a higher proportion of cirrhotic patients with gastrointestinal (GI) cancer candidates to chemotherapy. Data are needed on the safety and liver-related events associated with the use of chemotherapy in these patients. METHODS Forty-nine patients with cirrhosis receiving chemotherapy against GI cancer from 2013 to 2018 were identified in the French Health Insurance Database using ICD-10 codes K70-K74, and matched 1:2 to non-cirrhotic controls (n = 98) on age, tumour type and type of treatment. Adverse events (AE), dose tapering, discontinuation rate, liver-related events and survival rate were compared. RESULTS Patients with cirrhosis (Child-Pugh A 91%) more often received lower doses (38.8% vs 7.1%, p < .001), without significant differences in terms of grade 3/4 AE or dose tapering rates (29.6% vs. 36.7%; 22.3% vs 24.4%, respectively). Treatment discontinuation rate was higher in patients with cirrhosis (23.3% vs. 11.3%, p = .005). Child-Pugh (p = .007) and MELD (p = .025) scores increased under chemotherapy. Five patients with cirrhosis (10.2%) had liver decompensation within 12 months, and 17.2% of deaths in the cirrhosis group were liver-related versus 0% in matched controls. WHO-PS stage > 1 (HR 3.74, CI95%: 2.13-6.57, p < .001), TNM-stage M1 (HR 3.61, CI 95%: 1.82-7.16, p < .001), non-colorectal cancer (HR 1.73, CI 95%: 1.05-2.86, p = .032) and bilirubin higher than 5 mg/dL (HR 2.26, CI 95%: 1.39-3.70, p < .001) were independent prognostic factors of 2-year mortality, whereas cirrhosis was not. CONCLUSIONS Chemotherapy should be proposed only in patients with compensated cirrhosis with close monitoring of liver function. Dose management remains challenging. Multidisciplinary management is warranted to improve these patients' outcomes.
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Affiliation(s)
- Massih Ningarhari
- CHU Lille, Hôpital Huriez, Maladies de l'Appareil Digestif, Lille, France
| | - Marlène Bertez
- CHU Lille, Hôpital Huriez, Maladies de l'Appareil Digestif, Lille, France
| | - Anne Ploquin
- Université de Lille, CNRS INSERM UMR9020-U1277, CANTHER Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
- CHU Lille, Hôpital Huriez, Medical Oncology Department, Lille, France
| | - Nicolas Bertrand
- Université de Lille, CNRS INSERM UMR9020-U1277, CANTHER Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
- CHU Lille, Hôpital Huriez, Medical Oncology Department, Lille, France
| | - Christophe Desauw
- Université de Lille, CNRS INSERM UMR9020-U1277, CANTHER Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
- CHU Lille, Hôpital Huriez, Medical Oncology Department, Lille, France
| | - Stéphane Cattan
- CHU Lille, Hôpital Huriez, Maladies de l'Appareil Digestif, Lille, France
| | - Pascale Catala
- Centre Hospitalier de Béthune, Hépato-Gastro-Entérologie, Beuvry, France
| | - Hélène Vandamme
- Centre Hospitalier de Béthune, Hépato-Gastro-Entérologie, Beuvry, France
| | - Claire Cheymol
- GHICL Hôpital Saint-Vincent, Oncologie Médicale, Lille, France
| | - Stéphanie Truant
- CHU Lille, Hôpital Huriez, Chirurgie Digestive et Transplantation, Lille, France
| | | | - Alexandre Louvet
- CHU Lille, Hôpital Huriez, Maladies de l'Appareil Digestif, Lille, France
| | - Philippe Mathurin
- CHU Lille, Hôpital Huriez, Maladies de l'Appareil Digestif, Lille, France
| | - Sébastien Dharancy
- CHU Lille, Hôpital Huriez, Maladies de l'Appareil Digestif, Lille, France
| | - Anthony Turpin
- Université de Lille, CNRS INSERM UMR9020-U1277, CANTHER Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France
- CHU Lille, Hôpital Huriez, Medical Oncology Department, Lille, France
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Ding Y, Wang S, Qiu Z, Zhu C, Wang Y, Zhao S, Qiu W, Wang K, Lv J, Qi W. The worthy role of hepatic arterial infusion chemotherapy in combination with anti-programmed cell death protein 1 monoclonal antibody immunotherapy in advanced hepatocellular carcinoma. Front Immunol 2023; 14:1284937. [PMID: 38022559 PMCID: PMC10644007 DOI: 10.3389/fimmu.2023.1284937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/19/2023] [Indexed: 12/01/2023] Open
Abstract
Systemic therapy remains the primary therapeutic approach for advanced hepatocellular carcinoma (HCC). Nonetheless, its efficacy in achieving control of intrahepatic lesions is constrained. Hepatic arterial infusion chemotherapy (HAIC) is a therapeutic approach that combines localized treatment with systemic antitumor effects, which aim is to effectively manage the progression of cancerous lesions within the liver, particularly in patients with portal vein tumor thrombosis (PVTT). Combining HAIC with anti-programmed cell death protein 1 (anti-PD-1) monoclonal antibody (mAb) immunotherapy is anticipated to emerge as a novel therapeutic approach aimed at augmenting the response inside the localized tumor site and achieving prolonged survival advantages. In order to assess the effectiveness, safety, and applicability of various therapeutic modalities and to address potential molecular mechanisms underlying the efficacy of HAIC-sensitizing immunotherapy, we reviewed the literature about the combination of HAIC with anti-PD-1 mAb therapies.
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Affiliation(s)
- Yixin Ding
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Shasha Wang
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Zhenkang Qiu
- Interventional Medical Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Chunyang Zhu
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Yan Wang
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Shufen Zhao
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Wensheng Qiu
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Kongjia Wang
- Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Jing Lv
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Weiwei Qi
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
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Chen YH, Tsai CH, Chen YY, Wang CC, Wang JH, Hung CH, Kuo YH. Real-world comparison of pembrolizumab and nivolumab in advanced hepatocellular carcinoma. BMC Cancer 2023; 23:810. [PMID: 37644388 PMCID: PMC10463359 DOI: 10.1186/s12885-023-11298-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 08/13/2023] [Indexed: 08/31/2023] Open
Abstract
BACKGROUND Nivolumab and pembrolizumab have not been directly compared in clinical trials, and the aim of this study is to investigate the efficacy and safety of nivolumab versus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) in real-world practice. METHODS We retrospectively reviewed patients with HCC who received intravenous nivolumab or pembrolizumab alone as second-line and later therapy. The objective response was determined according to the Response Evaluation Criteria in Solid Tumors criteria version 1.1. Adverse events (AEs) were graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. The Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS). Prognostic values were estimated using hazard ratios with 95% confidence intervals (CIs). RESULTS In total, 120 patients were enrolled, including 95 who received nivolumab and 25 who received pembrolizumab. All patients were staged as Barcelona Clinic Liver Cancer stage C, and 29 patients were classified as Child-Pugh classification B (7). The response rate of the pembrolizumab and nivolumab groups were 8.0% and 7.4%, respectively. There was no significant difference in the median PFS between the pembrolizumab and nivolumab groups (2.7 months versus 2.9 months). The median OS in the nivolumab group was longer than that in the pembrolizumab group (10.8 months versus 8.1 months); however, the difference was not statistically significant. The effects of pembrolizumab and nivolumab on the median PFS and OS were consistent across the subgroups based on baseline characteristics. The severity of all AEs was grades 1-2 without treatment interruption or dose adjustment; there was no statistically significant difference in the incidence of treatment-related AEs between these two groups. Additionally, the percentage of patients receiving subsequent therapy was consistent between the two groups. CONCLUSION The efficacy and safety of pembrolizumab and nivolumab were comparable in the management of patients with pretreated HCC in real-world practice.
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Affiliation(s)
- Yen-Hao Chen
- Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No.123, Dapi Rd., Niaosong Dist, 833, Kaohsiung, Taiwan.
- School of Medicine, College of Medicine, Chang Gung University, 333, Taoyuan, Taiwan.
- School of Medicine, Chung Shan Medical University, 402, Taichung, Taiwan.
- Department of nursing, School of nursing, Fooyin University, 831, Kaohsiung, Taiwan.
| | - Ching-Hua Tsai
- Division of Trauma Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 833, Kaohsiung, Taiwan
| | - Yen-Yang Chen
- Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No.123, Dapi Rd., Niaosong Dist, 833, Kaohsiung, Taiwan
| | - Chih-Chi Wang
- Division of General Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 833, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 833, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 833, Kaohsiung, Taiwan
| | - Yuan-Hung Kuo
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 833, Kaohsiung, Taiwan
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Integrated Analysis of N1-Methyladenosine Methylation Regulators-Related lncRNAs in Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:cancers15061800. [PMID: 36980686 PMCID: PMC10046959 DOI: 10.3390/cancers15061800] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 03/07/2023] [Accepted: 03/14/2023] [Indexed: 03/19/2023] Open
Abstract
N1-methyladenosine (m1A) and long non-coding RNAs (lncRNAs) play significant roles in tumor progression in hepatocellular carcinoma (HCC). However, their association with HCC is still unclear. In this study, lncRNAs related to m1A were extracted from the mRNA expression matrix in The Cancer Genome Atlas (TCGA) database. Five m1A-related lncRNAs (AL031985.3, NRAV, WAC-AS1, AC026412.3, and AC099850.4) were identified based on lasso Cox regression and they generated a prognostic signature of HCC. The prognostic signature was identified as an independent prognosis factor in HCC patients. Moreover, the prognostic signature achieved better performance than TP53 mutation status or tumor mutational burden (TMB) scores in the stratification of patient survival. The immune landscape indicated that most immune checkpoint genes and immune cells were distributed differently between both risk groups. A higher IC50 of chemotherapeutics (sorafenib, nilotinib, sunitinib, and gefitinib) was observed in the high-risk group, and a lower IC50 of gemcitabine in the low-risk group, suggesting the potential of the prognostic signature in chemosensitivity. In addition, fifty-five potential small molecular drugs were found based on drug sensitivity and NRAV expression. Together, five m1A-related lncRNAs generated a prognostic signature that could be a promising prognostic prediction approach and therapeutic response assessment tool for HCC patients.
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He M, Gu W, Gao Y, Liu Y, Liu J, Li Z. Molecular subtypes and a prognostic model for hepatocellular carcinoma based on immune- and immunogenic cell death-related lncRNAs. Front Immunol 2022; 13:1043827. [PMID: 36479122 PMCID: PMC9720162 DOI: 10.3389/fimmu.2022.1043827] [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: 09/14/2022] [Accepted: 11/04/2022] [Indexed: 11/22/2022] Open
Abstract
Background Accumulating evidence shows that immunogenic cell death (ICD) enhances immunotherapy effectiveness. In this study, we aimed to develop a prognostic model combining ICD, immunity, and long non-coding RNA biomarkers for predicting hepatocellular carcinoma (HCC) outcomes. Methods Immune- and immunogenic cell death-related lncRNAs (IICDLs) were identified from The Cancer Genome Atlas and Ensembl databases. IICDLs were extracted based on the results of differential expression and univariate Cox analyses and used to generate molecular subtypes using ConsensusClusterPlus. We created a prognostic signature based on IICDLs and a nomogram based on risk scores. Clinical characteristics, immune landscapes, immune checkpoint blocking (ICB) responses, stemness, and chemotherapy responses were also analyzed for different molecular subtypes and risk groups. Result A total of 81 IICDLs were identified, 20 of which were significantly associated with overall survival (OS) in patients with HCC. Cluster analysis divided patients with HCC into two distinct molecular subtypes (C1 and C2), with patients in C1 having a shorter survival time than those in C2. Four IICDLs (TMEM220-AS1, LINC02362, LINC01554, and LINC02499) were selected to develop a prognostic model that was an independent prognostic factor of HCC outcomes. C1 and the high-risk group had worse OS (hazard ratio > 1.5, p < 0.01), higher T stage (p < 0.05), higher clinical stage (p < 0.05), higher pathological grade (p < 0.05), low immune cell infiltration (CD4+ T cells, B cells, macrophages, neutrophils, and myeloid dendritic cells), low immune checkpoint gene expression, poor response to ICB therapy, and high stemness. Different molecular subtypes and risk groups showed significantly different responses to several chemotherapy drugs, such as doxorubicin (p < 0.001), 5-fluorouracil (p < 0.001), gemcitabine (p < 0.001), and sorafenib (p < 0.01). Conclusion Our study identified molecular subtypes and a prognostic signature based on IICDLs that could help predict the clinical prognosis and treatment response in patients with HCC.
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Affiliation(s)
- Mingang He
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Wenchao Gu
- Department of Pulmonary and Critical Care Medicine, Shanghai Pudong New Area People’s Hospital, Shanghai, China
| | - Yang Gao
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Ying Liu
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Jie Liu
- Cancer Center, Shandong Public Health Clinical Center, Public Health Clinical Center Affiliated to Shandong University, Jinan, China,*Correspondence: Jie Liu, ; Zengjun Li,
| | - Zengjun Li
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China,*Correspondence: Jie Liu, ; Zengjun Li,
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10
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Huang KW, Lee PC, Chao Y, Su CW, Lee IC, Lan KH, Chu CJ, Hung YP, Chen SC, Hou MC, Huang YH. Durable objective response to sorafenib and role of sequential treatment in unresectable hepatocellular carcinoma. Ther Adv Med Oncol 2022; 14:17588359221099401. [PMID: 35646162 PMCID: PMC9134461 DOI: 10.1177/17588359221099401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 04/21/2022] [Indexed: 11/16/2022] Open
Abstract
Background The response rate to sorafenib is limited for unresectable hepatocellular carcinoma (HCC). Little is known about the long-term outcomes of objective responders. The role of second-line therapies on the survival of sorafenib-responders is unclear. We aimed to delineate the long-term outcomes and the role of subsequent treatment after responding to sorafenib. Methods From September 2012 to December 2019, 922 patients who received sorafenib treatment for unresectable HCC were retrospectively reviewed. Of these, 21 (2.3%) achieved a complete response (CR) and 54 (5.9%) had a partial response (PR) based on mRECIST criteria. Factors associated with survivals were analyzed. Results During the median follow-up of 35.3 months, the median duration of response was 18.3 months (range: 2.3-45.5) for patients achieving CR and 10.0 months (range: 1.9-60.3) for PR. The median overall survival (OS) was 39.5 months [95% confidence interval (CI): 28.4-50.5] including values not yet estimable for CR and 25.8 months for PR. Patients who experienced treatment-related adverse events (TRAEs) had better median OS than those without (44.9 versus 18.1 months, p = 0.003). Eventually, 53 patients developed tumor progression; 30 patients received second-line systemic treatment including nivolumab (n = 8), regorafenib (n = 15), and chemotherapy (n = 7). Sorafenib-nivolumab sequential therapy provided the best median OS versus sorafenib-regorafenib and sorafenib-chemotherapy in these patients (55.8, 39.5, and 25.5 months), respectively. Conclusions The response is durable for advanced HCC patients with CR or PR to sorafenib. Subsequent immunotherapy seems to provide the best survival. This information is important for characterizing outcomes of sorafenib-responders and the choice of sequential treatment.
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Affiliation(s)
- Kuo-Wei Huang
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- Department of Medicine, Taipei City Hospital
Yang-Ming branch, Taipei
| | - Pei-Chang Lee
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- School of Medicine, National Yang Ming Chiao
Tung University, Taipei
| | - Yee Chao
- Department of Oncology, Taipei Veterans General
Hospital, Taipei
| | - Chien-Wei Su
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- School of Medicine, National Yang Ming Chiao
Tung University, Taipei
| | - I-Cheng Lee
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- School of Medicine, National Yang Ming Chiao
Tung University, Taipei
| | - Keng-Hsin Lan
- Division of Gastroenterology and Hepatology,
Department of Medicine Taipei Veterans General Hospital, Taipei
- Institute of Pharmacology, School of Medicine,
National Yang Ming Chiao Tung University, Taipei
| | - Chi-Jen Chu
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- School of Medicine, National Yang Ming Chiao
Tung University, Taipei
| | - Yi-Ping Hung
- Department of Oncology, Taipei Veterans
General Hospital, Taipei
- School of Medicine, National Yang Ming Chiao
Tung University, Taipei
| | - San-Chi Chen
- Institute of Clinical Medicine, School of
Medicine, National Yang Ming Chiao Tung University, Taipei
- Department of Oncology, Taipei Veterans
General Hospital, Taipei
| | - Ming-Chih Hou
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- School of Medicine, National Yang Ming Chiao
Tung University, Taipei
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology,
Department of Medicine, Taipei Veterans General Hospital, Taipei
- Institute of Clinical Medicine, School of
Medicine, National Yang Ming Chiao Tung University, No.201, Sec. 2, Shipai
Road, Beitou District, 11217 Taipei
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11
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Tsvetkova D, Ivanova S. Application of Approved Cisplatin Derivatives in Combination Therapy against Different Cancer Diseases. Molecules 2022; 27:2466. [PMID: 35458666 PMCID: PMC9031877 DOI: 10.3390/molecules27082466] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/07/2022] [Accepted: 04/08/2022] [Indexed: 02/03/2023] Open
Abstract
The problems with anticancer therapy are resistance and toxicity. From 3000 Cisplatin derivatives tested as antitumor agents, most of them have been rejected, due to toxicity. The aim of current study is the comparison of therapeutic combinations of the currently applied in clinical practice: Cisplatin, Carboplatin, Oxaliplatin, Nedaplatin, Lobaplatin, Heptaplatin, and Satraplatin. The literature data show that the strategies for the development of platinum anticancer agents and bypassing of resistance to Cisplatin derivatives and their toxicity are: combination therapy, Pt IV prodrugs, the targeted nanocarriers. The very important strategy for the improvement of the antitumor effect against different cancers is synergistic combination of Cisplatin derivatives with: (1) anticancer agents-Fluorouracil, Gemcitabine, Cytarabine, Fludarabine, Pemetrexed, Ifosfamide, Irinotecan, Topotecan, Etoposide, Amrubicin, Doxorubicin, Epirubicin, Vinorelbine, Docetaxel, Paclitaxel, Nab-Paclitaxel; (2) modulators of resistant mechanisms; (3) signaling protein inhibitors-Erlotinib; Bortezomib; Everolimus; (4) and immunotherapeutic drugs-Atezolizumab, Avelumab, Bevacizumab, Cemiplimab, Cetuximab, Durvalumab, Erlotinib, Imatinib, Necitumumab, Nimotuzumab, Nivolumab, Onartuzumab, Panitumumab, Pembrolizumab, Rilotumumab, Trastuzumab, Tremelimumab, and Sintilimab. An important approach for overcoming the drug resistance and reduction of toxicity of Cisplatin derivatives is the application of nanocarriers (polymers and liposomes), which provide improved targeted delivery, increased intracellular penetration, selective accumulation in tumor tissue, and enhanced therapeutic efficacy. The advantages of combination therapy are maximum removal of tumor cells in different phases; prevention of resistance; inhibition of the adaptation of tumor cells and their mutations; and reduction of toxicity.
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Affiliation(s)
- Dobrina Tsvetkova
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University-Sofia, Dunav Str. 2, 1000 Sofia, Bulgaria
| | - Stefka Ivanova
- Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmacy, Medical University-Pleven, Kliment Ohridski Str. 1, 5800 Pleven, Bulgaria;
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12
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Fan Y, Xue H, Zheng H. Systemic Therapy for Hepatocellular Carcinoma: Current Updates and Outlook. J Hepatocell Carcinoma 2022; 9:233-263. [PMID: 35388357 PMCID: PMC8977221 DOI: 10.2147/jhc.s358082] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/15/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has emerged the culprit of cancer-related mortality worldwide with its dismal prognosis climbing. In recent years, ground-breaking progress has been made in systemic therapy for HCC. Targeted therapy based on specific signaling molecules, including sorafenib, lenvatinib, regorafenib, cabozantinib, and ramucirumab, has been widely used for advanced HCC (aHCC). Immunotherapies such as pembrolizumab and nivolumab greatly improve the survival of aHCC patients. More recently, synergistic combination therapy has boosted first-line (atezolizumab in combination with bevacizumab) and second-line (ipilimumab in combination with nivolumab) therapeutic modalities for aHCC. This review aims to summarize recent updates of systemic therapy relying on the biological mechanisms of HCC, particularly highlighting the approved agents for aHCC. Adjuvant and neoadjuvant therapy, as well as a combination with locoregional therapies (LRTs), are also discussed. Additionally, we describe the promising effect of traditional Chinese medicine (TCM) as systemic therapy on HCC. In this setting, the challenges and future directions of systemic therapy for HCC are also explored.
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Affiliation(s)
- Yinjie Fan
- College of Integrated Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, 110847, People’s Republic of China
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
| | - Hang Xue
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
| | - Huachuan Zheng
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
- Correspondence: Huachuan Zheng, Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China, Tel +86-0314-2279458, Fax +86-0314-2279458, Email
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13
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Marin JJG, Romero MR, Herraez E, Asensio M, Ortiz-Rivero S, Sanchez-Martin A, Fabris L, Briz O. Mechanisms of Pharmacoresistance in Hepatocellular Carcinoma: New Drugs but Old Problems. Semin Liver Dis 2022; 42:87-103. [PMID: 34544160 DOI: 10.1055/s-0041-1735631] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with poor prognosis when diagnosed at advanced stages in which curative treatments are no longer applicable. A small group of these patients may still benefit from transarterial chemoembolization. The only therapeutic option for most patients with advanced HCC is systemic pharmacological treatments based on tyrosine kinase inhibitors (TKIs) and immunotherapy. Available drugs only slightly increase survival, as tumor cells possess additive and synergistic mechanisms of pharmacoresistance (MPRs) prior to or enhanced during treatment. Understanding the molecular basis of MPRs is crucial to elucidate the genetic signature underlying HCC resistome. This will permit the selection of biomarkers to predict drug treatment response and identify tumor weaknesses in a personalized and dynamic way. In this article, we have reviewed the role of MPRs in current first-line drugs and the combinations of immunotherapeutic agents with novel TKIs being tested in the treatment of advanced HCC.
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Affiliation(s)
- Jose J G Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Marta R Romero
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Elisa Herraez
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Maitane Asensio
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Sara Ortiz-Rivero
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Anabel Sanchez-Martin
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Luca Fabris
- Department of Molecular Medicine (DMM), University of Padua, Padua, Italy.,Department of Internal Medicine, Yale Liver Center (YLC), School of Medicine, Yale University New Haven, Connecticut
| | - Oscar Briz
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain.,Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
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14
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Correlation between Immunohistochemical Markers in Hepatocellular Carcinoma Cells and In Vitro High-Throughput Drug Sensitivity Screening. Can J Gastroenterol Hepatol 2022; 2022:5969716. [PMID: 35127582 PMCID: PMC8808116 DOI: 10.1155/2022/5969716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/20/2021] [Accepted: 12/28/2021] [Indexed: 11/17/2022] Open
Abstract
AIM This study analyzed the correlation between immunohistochemical markers in hepatocellular carcinoma cells and the results of in vitro high-throughput drug sensitivity screening, to provide a reference for individualized drug treatment in patients with liver cancer. METHODS Seventy-four patients with hepatocellular carcinoma were included in this study from December 2019 to June 2021, and their liver cancer cells were used for in vitro high-throughput drug sensitivity screening. According to the screening results, the patients were divided into relatively sensitive and insensitive groups, and the correlations between sensitivity and immunohistochemistry results were analyzed statistically. RESULTS Alpha-fetoprotein (AFP)-positive liver cancer cells were significantly more sensitive to gemcitabine than AFP-negative cells (χ 2 = 6.102, P=0.014). AFP was also positively correlated with sensitivity of liver cancer cells to three combined regimens containing oxaliplatin (L-OHP) and epirubicin (EPI) : L-OHP + EPI + irinotecan + 5-fluorouracil (5-FU), L-OHP + irinotecan + EPI, and L-OHP + EPI (χ 2 = 8.168, P=0.004, χ 2 = 5.705, P=0.017, and χ 2 = 8.275, P=0.004, respectively). CONCLUSION Gemcitabine and L-OHP + EPI + irinotecan + 5-FU, L-OHP + EPI, and L-OHP + irinotecan + EPI were more effective against AFP-positive compared with AFP-negative liver cancer cells according to in vitro high-throughput drug sensitivity screening. These results may guide the selection of personalized drug treatments for patients with advanced liver cancer in the future but still need further clinical studies to confirm.
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15
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Xu L, Chen L, Zhang W. Neoadjuvant treatment strategies for hepatocellular carcinoma. World J Gastrointest Surg 2021; 13:1550-1566. [PMID: 35070063 PMCID: PMC8727178 DOI: 10.4240/wjgs.v13.i12.1550] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/27/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) remains high globally. Surgical treatment is the best treatment for improving the prognosis of patients with HCC. Neoadjuvant therapy plays a key role in preventing tumor progression and even downstaging HCC. The liver transplantation rate and resectability rate have increased for neoadjuvant therapy. Neoadjuvant therapy is effective in different stages of HCC. In this review, we summarized the definition, methods, effects, indications and contraindications of neoadjuvant therapy in HCC, which have significance for guiding treatment.
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Affiliation(s)
- Lei Xu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Lin Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Wei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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16
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Gastrointestinal tract involvement in hepatocellular carcinoma: two cases illustrating duodenal and oesophageal invasion. Acta Gastroenterol Belg 2021; 84:660-662. [PMID: 34965048 DOI: 10.51821/84.4.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
We present here two hepatocellular carcinoma (HCC) patients with gastrointestinal tract involvement (GITI). Hemorrhage due to duodenal involvement was the inaugural event of the HCC for the first patient. Dysphagia due to HCC recurrence in the oesophagus four years after left hepatectomy was the call symptom for the second. As incidence of HCC increases, and overall survival improves, incidence of GITI in HCC patients is expected to increase.
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17
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Wang L, Ke J, Wang C, Li Y, Wu G, Ding Q, Luo Q, Cai R, Lv P, Song T, Xiong S. Efficacy and Safety of Banxia XieXin Decoction, a Blended Traditional Chinese Medicine, as Monotherapy for Patients With Advanced Hepatocellular Carcinoma. Integr Cancer Ther 2021; 19:1534735420942587. [PMID: 32787468 PMCID: PMC7427017 DOI: 10.1177/1534735420942587] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Purpose: To explore a new therapeutic option for patients with hepatocellular carcinoma (HCC), the efficacy and safety of a group of traditional Chinese medicines (Banxia XieXin recipe) as monotherapy for patients with advanced HCC was studied. Materials and Methods: The study included 68 patients with advanced HCC from August 16,2016 to August 15,2019 for analysis. These eligible patients received treatment with Banxia XieXin recipe for at least 1 month. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary efficacy endpoints included objective response rate (ORR) and disease control rate (DCR). In addition, safety was also assessed. Results: The median treatment duration of these 68 patients was 10.3 months (range = 1.6-33.5 months), and follow-up is still ongoing. The median PFS was 6.07 months (95% confidence interval [CI] = 3.748-8.392 months), and the median OS was 12.60 months (95% CI = 8.019-17.181 months). The ORR was 10.3% and the DCR was 41.2%. In the subgroup analysis, the median OS in the transcatheter arterial chemoembolization (TACE) group was not reached, and the median OS in the NO TACE group was 11.30 months (95% CI = 3.219-19.381 months). In addition, no drug-related serious adverse events were observed during the study. Conclusion: This is the first clinical analysis of traditional Chinese medicine as a single treatment for advanced HCC. The obtained results are encouraging as they suggest that this panel of Chinese herbs is safe and it may be effective for patients with advanced HCC in a real-world clinical setting.
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Affiliation(s)
- Lijuan Wang
- Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Jianlong Ke
- Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Cui Wang
- Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Yaling Li
- Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Guoyu Wu
- Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Qian Ding
- Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Qiuyue Luo
- Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Rui Cai
- Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Panpan Lv
- Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Tingting Song
- Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Shaoquan Xiong
- Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
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18
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Hewitt DB, Rahnemai-Azar AA, Pawlik TM. Potential experimental immune checkpoint inhibitors for the treatment of cancer of the liver. Expert Opin Investig Drugs 2021; 30:827-835. [PMID: 34102935 DOI: 10.1080/13543784.2021.1940948] [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] [Indexed: 01/14/2023]
Abstract
Introduction: Traditional systemic therapies offer limited benefit for advanced cancers of the liver. Immune checkpoints are inhibitory regulators of the immune system and the success of immune checkpoint inhibitors (ICIs) in the treatment of other cancers has led to clinical trials investigating the use of ICIs alone or in combination with other therapies for liver cancers.Area covered: Clinical trials involving ICIs for the treatment of liver cancer were broadly reviewed. Hepatocellular carcinoma and intrahepatic cholangiocarcinoma were examined. Phase I/II trials were prioritized, and relevant phase III trials were discussed. MEDLINE, PubMed, ASCO meeting library, and Web of Science databases were searched with the keywords 'immune checkpoint inhibitor' or 'targeted therapy' in combination with 'hepatocellular carcinoma,' or 'intrahepatic cholangiocarcinoma'. Major outcomes were safety and efficacy defined by response rate, progression-free survival, or overall survival.Expert opinion: ICIs can improve progression-free and overall survival among patients with advanced disease with an acceptable safety profile. Given the heterogeneity of liver disease, ideal strategies will likely include a combination of ICIs with additional therapies to achieve the most robust and durable response. Additional biomarkers will be needed to guide combination therapy to personalize treatment regimen for patients with primary liver cancers.
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Affiliation(s)
- D Brock Hewitt
- Division of Surgical Oncology, Department of Surgery, The Ohio State Wexner Medical Center, the James Comprehensive Cancer Center, Columbus, OH, USA
| | - Amir A Rahnemai-Azar
- Division of Surgical Oncology, Department of Surgery, Arrowhead Regional Cancer Center, California University of Science and Medicine, Colton, CA, USA
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, The Ohio State Wexner Medical Center, the James Comprehensive Cancer Center, Columbus, OH, USA
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19
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Palmieri LJ, Dermine S, Coriat R. Potential Areas of Interest in a Trial of Sorafenib Plus Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin for Hepatocellular Carcinoma. JAMA Oncol 2021; 5:1805-1806. [PMID: 31600364 DOI: 10.1001/jamaoncol.2019.4052] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- Lola-Jade Palmieri
- Department of Gastroenterology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Solène Dermine
- Department of Gastroenterology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Romain Coriat
- Department of Gastroenterology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
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20
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Qin JM. Conversion therapy for primary liver cancer: Indications and selective strategies. Shijie Huaren Xiaohua Zazhi 2021; 29:501-510. [DOI: 10.11569/wcjd.v29.i10.501] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Primary liver cancer has an insidious onset and no specific symptoms at early stage. Most patients are in the middle or advanced stage when diagnosed, and only 20%-40% of patients meet the criteria for radical resection. At present, surgical resection is still the main radical treatment for primary liver cancer, but factors such as liver function decompensation, too large tumor volume, too small future liver remnant, intrahepatic multiple metastasis, tumor thrombus invading the large vessels or bile duct, and distant metastasis limit the application of surgical resection or liver transplantation. In recent years, with the advances of basic research of primary liver cancer, the development of surgical techniques and equipment, as well as the development of new molecular targeted drugs and immunotherapy drugs, a part of unresectable patients with primary liver cancer can receive conversion therapy to improve liver function, minimize tumor volume, minimize or inactivate tumor thrombus, and increase the residual liver volume. Following conversion therapy, patients with primary liver cancer can undergo surgical resection or liver transplantation, which greatly improve the therapeutic efficacy and patient survival.
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Affiliation(s)
- Jian-Min Qin
- Department of General Surgery, the Third Hospital Affiliated to Naval Military Medical University, Shanghai 201805, China
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21
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Shang XY, Yu XQ, Yao GD, Song SJ. Daphnegiravone D from Daphne giraldii induces cell death by targeting ATR in Hep3B cells. Bioorg Chem 2021; 110:104802. [PMID: 33730672 DOI: 10.1016/j.bioorg.2021.104802] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 03/02/2021] [Indexed: 01/26/2023]
Abstract
Ataxia telangiectasia and Rad3-related protein (ATR) plays a crucial role in cancer and has become a promising target for cancer therapy. Daphnegiravone D (DGD), which could induce apoptosis and oxidative stress in hepatocellular carcinoma (HCC) cells, but the detailed target protein was still unclear. The study provided that the possible target of DGD against HCC cells was determined by isobaric labels for relative and absolute quantification (iTRAQ) assay. In all changed proteins the fold change of ATR was particularly significant. The results from GO, KEGG and PPI analysis showed that DNA damage, cell cycle, apoptosis, DNA repair related pathways changed and ATR was exactly related to them. Moreover, the mRNA and protein of ATR were both decreased in a concentration-dependent manner, and the results of molecular docking also verified the binding. Additionally, cellular thermal shift assay (CETSA) suggested that DGD could directly target at ATR protein. Furthermore, the knockdown of ATR could increase apoptosis and reactive oxygen species (ROS) which induced by DGD. Since ATR inhibitors were generally used in combination with chemotherapy drugs (especially DNA damage drugs) in clinical trials, we investigated the combined application of DGD and oxaliplatin. The results showed that DGD combined with OXA also increased the apoptosis and ROS production of Hep3B cells over either drug alone. Taken together, this study revealed that DGD targeting ATR could be a promising therapeutic strategy for the treatment of liver cancer.
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Affiliation(s)
- Xin-Yue Shang
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Xiao-Qi Yu
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Guo-Dong Yao
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
| | - Shao-Jiang Song
- Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
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Gryziak M, Woźniak K, Kraj L, Stec R. Milestones in the treatment of hepatocellular carcinoma: A systematic review. Crit Rev Oncol Hematol 2021; 157:103179. [DOI: 10.1016/j.critrevonc.2020.103179] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 11/07/2020] [Accepted: 11/11/2020] [Indexed: 12/20/2022] Open
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Abouelezz K, Khanapara D, Batiha GES, Ahmed EA, Hetta HF. Cytotoxic Chemotherapy as an Alternative for Systemic Treatment of Advanced Hepatocellular Carcinoma in Developing Countries. Cancer Manag Res 2020; 12:12239-12248. [PMID: 33273860 PMCID: PMC7707432 DOI: 10.2147/cmar.s280631] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 11/10/2020] [Indexed: 01/10/2023] Open
Abstract
Systemic therapy options nowadays for advanced hepatocellular carcinoma (HCC) are either immunotherapy with immune checkpoint inhibitors or targeted therapy. As the incidence of liver cancer is much higher in developing countries, these new medications are not readily accessible for most of the patients. Cytotoxic chemotherapy agents are more available and affordable in developing countries. We are trying to explore the effectiveness of the newer cytotoxic agents in the systematic treatment for advanced HCC. This is a systematic review of all randomized controlled trials since 1997 that utilized systemic cytotoxic chemotherapy agents in the systemic treatment for advanced HCC using Scopus, PubMed, and Cochrane library up to February 2020. Six randomized trials were found. Different drugs and dosages were used, so it was statistically inappropriate to conduct a meta-analysis. No Phase III trial showed statistically significant overall survival (OS) benefit for cytotoxic chemotherapy, except subgroup analysis of Chinese patients in one study who had leucovorin, fluorouracil, and oxaliplatin (FOLFOX) regimen. There was no significant progression-free survival (PFS) or response rate in the Phase II trials. There are not enough data to infer the actual benefits of systemic cytotoxic chemotherapy in advanced HCC. However, oxaliplatin-based regimens may give feasible results. Health systems with limited access to targeted therapy and immunotherapy agents may use oxaliplatin-based regimens in clinical trials for advanced HCC. These results should be confirmed in multiple future randomized clinical trials.
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Affiliation(s)
- Khaled Abouelezz
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Dipen Khanapara
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicines, Damanhour University, Damanhour 22511, Egypt
| | - Esraa A Ahmed
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt.,Centre of Excellence in Environmental Studies (CEES), King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Helal F Hetta
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.,Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71526, Egypt
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Guo W, Gao J, Zhuang W, Wu Z, Li B, Chen S. Efficacy and safety of hepatic arterial infusion chemotherapy combined with transarterial embolization for unresectable hepatocellular carcinoma: A propensity score-matching cohort study. JGH OPEN 2020; 4:477-483. [PMID: 32514457 PMCID: PMC7273730 DOI: 10.1002/jgh3.12285] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 08/14/2019] [Accepted: 09/04/2019] [Indexed: 12/24/2022]
Abstract
Purpose The aim of this study was to assess the effectiveness and safety of hepatic arterial infusion chemotherapy (HAIC) using the FOLFOX regimen combined with transarterial embolization (TAE + HAIC) in patients with unresectable hepatocellular carcinoma (HCC). Methods Unresectable HCC patients treated with TAE + HAIC and conventional transcatheter arterial chemoembolization (TACE), respectively, between January 2015 and October 2016 in China were retrospectively assessed. The primary outcome was progression-free survival (PFS), while secondary outcomes included the objective response rate (ORR), the disease control rate (DCR), and main complications. Propensity score matching (PSM) was estimated by multiple logistic regression using caliper matching (caliper 0.2). A Cox proportional hazards model was used to identify those factors shown to be associated with PFS. Results A total of 113 patients were analyzed, with 41 and 72 receiving TAE + HAIC and TACE, respectively. After PSM, 35 pairs of patients were assessed. The median PFS was 7.93 months (95% confidence interval [CI], 4.44-11.42) for the TAE + HAIC group, which was higher compared with 2.60 months (95% CI, 0.93-4.27, P = 0.003) for TACE. The subgroup with Barcelona clinic liver cancer (BCLC) stage C obtained more PFS benefit from TAE + HAIC (P = 0.002). ORRs in the TAE + HAIC and TACE groups were 37.14% (13/35) and 20.00% (7/35, P = 0.112), respectively; DCRs were 88.57% (31/35) and 60.00% (21/35, P = 0.006), respectively. Abundant blood supply (hazard ratio [HR] =0.327, 95% CI 0.173-0.615, P < 0.001) and TAE + HAIC (HR = 0.332, 95% CI 0.177-0.621, P < 0.001) were associated with longer PFS in multivariate analysis. Conclusions Compared with conventional TACE, TAE + HAIC provides more PFS benefits to patients with unresectable HCC, especially in those with BCLC stage C.
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Affiliation(s)
- Wenbo Guo
- Department of Interventional RadiologyThe First Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouGuangdong ProvinceChina
| | - Jian Gao
- Department of Interventional RadiologyBaoan District People's Hospital of ShenzhenShenzhenGuangdong ProvinceChina
| | - Wenquan Zhuang
- Department of Interventional RadiologyThe First Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouGuangdong ProvinceChina
| | - Zhiqiang Wu
- Department of Interventional RadiologyThe First Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouGuangdong ProvinceChina
| | - Bin Li
- Clinical Research UnitThe First Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouGuangdong ProvinceChina
| | - Song Chen
- Department of Interventional RadiologyThe First Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouGuangdong ProvinceChina
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25
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Piñero F, Silva M, Iavarone M. Sequencing of systemic treatment for hepatocellular carcinoma: Second line competitors. World J Gastroenterol 2020; 26:1888-1900. [PMID: 32390700 PMCID: PMC7201145 DOI: 10.3748/wjg.v26.i16.1888] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 03/27/2020] [Accepted: 04/04/2020] [Indexed: 02/06/2023] Open
Abstract
During the last decades, further knowledge of hepatocellular carcinoma (HCC) molecular mechanisms has led to development of effective systemic treatments including tyrosine kinase inhibitors (TKIs) and immunotherapy. In this review, we describe first and second line systemic treatment options for advanced HCC. Several trials have evaluated new drugs for the treatment of HCC patients: In first line, lenvatinib resulted non-inferior to sorafenib and it can be used as alternative, even in the lack of evidence for sequential treatment options in second line after lenvatinib. Recently, atezolizumab plus bevacizumab have shown superiority over sorafenib in first-line. Sorafenib-regorafenib sequential administration in selected patients has opened a new paradigm of treatment in advanced HCC with a life expectancy exceeding two years. Other TKIs for second line treatment include cabozantinib and ramucirumab (specifically for patients with Alpha-fetoprotein values ≥ 400 ng/mL). The combination of TKIs with immunotherapy may represent a big step forward for these patients in the near future.
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Affiliation(s)
- Federico Piñero
- Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
- Latin American Liver Research Educational and Awareness Network, Buenos Aires B1629HJ, Argentina
| | - Marcelo Silva
- Hospital Universitario Austral, Facultad de Ciencias Biomédicas, Universidad Austral, Buenos Aires B1629HJ, Argentina
- Latin American Liver Research Educational and Awareness Network, Buenos Aires B1629HJ, Argentina
| | - Massimo Iavarone
- Division of Gastroenterology and Hepatology, CRC “A.M. e A. Migliavacca” Center for the Study of Liver Disease, University of Milan, Fondazione IRCCS Ca’ Granda Maggiore Hospital, Milan 20121, Italy
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26
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Leoni S, Sansone V, De Lorenzo S, Ielasi L, Tovoli F, Renzulli M, Golfieri R, Spinelli D, Piscaglia F. Treatment of Combined Hepatocellular and Cholangiocarcinoma. Cancers (Basel) 2020; 12:794. [PMID: 32224916 PMCID: PMC7226028 DOI: 10.3390/cancers12040794] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/15/2020] [Accepted: 03/23/2020] [Indexed: 02/07/2023] Open
Abstract
Combined hepatocellular and cholangiocarcinoma (HCC-CC) is a rare primary liver cancer. It is constituted by neoplastic cells of both hepatocellular and cholangiocellular derivation. Different histology types of HCC-CC have been reported, hinting at heterogeneous carcinogenic pathways leading to the development of this cancer. Due to its rarity and complexity, mixed HCC-CC is a scantly investigated condition with unmet needs and unsatisfactory outcomes. Surgery remains the preferred treatment in resectable patients. The risk of recurrence, however, is high, especially in comparison with other primary liver cancers such as hepatocellular carcinoma. In unresectable or recurring patients, the therapeutic options are challenging due to the dual nature of the neoplastic cells. Consequently, the odds of survival of patients with HCC-CC remains poor. We analysed the literature systematically about the treatment of mixed HCC-CC, reviewing the main therapeutic options and their outcomes and analysing the most interesting developments in this topic with a focus on new potential therapeutic avenues.
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Affiliation(s)
- Simona Leoni
- Internal Medicine Unit, Department of Digestive Diseases, Bologna Authority Hospital S.Orsola-Malpighi, 40136 Bologna, Italy
| | - Vito Sansone
- Department of Medical and Surgical Sciences, University of Bologna, Via Massarenti 9, 40136 Bologna, Italy; (V.S.); (L.I.); (F.T.); (F.P.)
| | - Stefania De Lorenzo
- Oncology Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40136 Bologna, Italy;
| | - Luca Ielasi
- Department of Medical and Surgical Sciences, University of Bologna, Via Massarenti 9, 40136 Bologna, Italy; (V.S.); (L.I.); (F.T.); (F.P.)
| | - Francesco Tovoli
- Department of Medical and Surgical Sciences, University of Bologna, Via Massarenti 9, 40136 Bologna, Italy; (V.S.); (L.I.); (F.T.); (F.P.)
| | - Matteo Renzulli
- Radiology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Sant’Orsola Hospital, University of Bologna, 40136 Bologna, Italy; (M.R.); (R.G.); (D.S.)
| | - Rita Golfieri
- Radiology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Sant’Orsola Hospital, University of Bologna, 40136 Bologna, Italy; (M.R.); (R.G.); (D.S.)
| | - Daniele Spinelli
- Radiology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Sant’Orsola Hospital, University of Bologna, 40136 Bologna, Italy; (M.R.); (R.G.); (D.S.)
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences, University of Bologna, Via Massarenti 9, 40136 Bologna, Italy; (V.S.); (L.I.); (F.T.); (F.P.)
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27
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Chagas AL, Mattos AAD, Carrilho FJ, Bittencourt PL, Vezozzo DCP, Horvat N, Rocha MDS, Alves VAF, Coral GP, Alvares-DA-Silva MR, Barros FMDR, Menezes MR, Monsignore LM, Coelho FF, Silva RFD, Silva RDCMA, Boin IDFSF, D Albuquerque LAC, Garcia JHP, Felga GEG, Moreira AM, Braghiroli MIFM, Hoff PMG, Mello VBD, Dottori MF, Branco TP, Schiavon LDL, Costa TDFA. BRAZILIAN SOCIETY OF HEPATOLOGY UPDATED RECOMMENDATIONS FOR DIAGNOSIS AND TREATMENT OF HEPATOCELLULAR CARCINOMA. ARQUIVOS DE GASTROENTEROLOGIA 2020; 57:1-20. [PMID: 32294682 DOI: 10.1590/s0004-2803.202000000-20] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 12/19/2019] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The Brazilian Society of Hepatology (SBH) published in 2015 its first recommendations about the management of HCC. Since then, new data have emerged in the literature, prompting the governing board of SBH to sponsor a single-topic meeting in August 2018 in São Paulo. All the invited experts were asked to make a systematic review of the literature reviewing the management of HCC in subjects with cirrhosis. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of updated recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present manuscript is the final version of the reviewed manuscript containing the recommendations of SBH.
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Affiliation(s)
- Aline Lopes Chagas
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil
- Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
| | - Angelo Alves de Mattos
- Universidade Federal de Ciências da Saúde de Porto Alegre e Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, RS, Brasil
| | - Flair José Carrilho
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil
- Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
| | | | | | - Natally Horvat
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil
- Hospital Sírio-Libanês, São Paulo, SP, Brasil
| | - Manoel de Souza Rocha
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil
| | - Venâncio Avancini Ferreira Alves
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil
- Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
| | - Gabriela Perdomo Coral
- Universidade Federal de Ciências da Saúde de Porto Alegre e Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, RS, Brasil
| | | | | | - Marcos Roberto Menezes
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil
- Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
- Hospital Sírio-Libanês, São Paulo, SP, Brasil
| | - Lucas Moretti Monsignore
- Universidade de São Paulo, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, São Paulo, SP, Brasil
| | | | - Renato Ferreira da Silva
- Faculdade de Medicina de São José do Rio Preto (FAMERP) e Hospital de Base de São José do Rio Preto (FUNFARME), São José do Rio Preto, SP, Brasil
| | - Rita de Cássia Martins Alves Silva
- Faculdade de Medicina de São José do Rio Preto (FAMERP) e Hospital de Base de São José do Rio Preto (FUNFARME), São José do Rio Preto, SP, Brasil
| | | | | | | | | | - Airton Mota Moreira
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, São Paulo, SP, Brasil
- Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
| | | | - Paulo Marcelo Gehm Hoff
- Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
| | | | | | - Tiago Pugliese Branco
- Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, SP, Brasil
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Development of Asialoglycoprotein Receptor-Targeted Nanoparticles for Selective Delivery of Gemcitabine to Hepatocellular Carcinoma. Molecules 2019; 24:molecules24244566. [PMID: 31847085 PMCID: PMC6943439 DOI: 10.3390/molecules24244566] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 12/07/2019] [Accepted: 12/11/2019] [Indexed: 02/06/2023] Open
Abstract
Selective targeting of anticancer drugs to the tumor site is beneficial in the pharmacotherapy of hepatocellular carcinoma (HCC). This study evaluated the prospective of galactosylated chitosan nanoparticles as a liver-specific carrier to improve the therapeutic efficacy of gemcitabine in HCC by targeting asialoglycoprotein receptors expressed on hepatocytes. Nanoparticles were formulated (G1–G5) by an ionic gelation method and evaluated for various physicochemical characteristics. Targeting efficacy of formulation G4 was evaluated in rats. Physicochemical characteristics exhibited by nanoparticles were optimal for administering and targeting gemcitabine effectively to the liver. The biphasic release behavior observed with G4 can provide higher drug concentration and extend the pharmacotherapy in the liver target site. Rapid plasma clearance of gemcitabine (70% in 30 min) from G4 was noticed in rats with HCC as compared to pure drug (p < 0.05). Higher uptake of gemcitabine predominantly by HCC (64% of administered dose; p < 0.0001) demonstrated excellent liver targeting by G4, while mitigating systemic toxicity. Morphological, biochemical, and histopathological examination as well as blood levels of the tumor marker, alpha-fetoprotein, in rats confirmed the curative effect of G4. In conclusion, this study demonstrated site-specific delivery and enhanced in vivo anti-HCC efficacy of gemcitabine by G4, which could function as promising carrier in hepatoma.
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Hilmi M, Neuzillet C, Calderaro J, Lafdil F, Pawlotsky JM, Rousseau B. Angiogenesis and immune checkpoint inhibitors as therapies for hepatocellular carcinoma: current knowledge and future research directions. J Immunother Cancer 2019; 7:333. [PMID: 31783782 PMCID: PMC6884868 DOI: 10.1186/s40425-019-0824-5] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 11/13/2019] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second deadliest cancer worldwide, due to its high incidence and poor prognosis. Frequent initial presentation at advanced stages along with impaired liver function limit the use of a broad therapeutic arsenal in patients with HCC. Although main HCC oncogenic drivers have been deciphered in recent years (TERT, TP53, CTNNB1 mutations, miR122 and CDKN2A silencing), therapeutic applications derived from this molecular knowledge are still limited. Given its high vascularization and immunogenicity, antiangiogenics and immune checkpoint inhibitors (ICI), respectively, are two therapeutic approaches that have shown efficacy in HCC. Depending on HCC immune profile, combinations of these therapies aim to modify the protumoral/antitumoral immune balance, and to reactivate and favor the intratumoral trafficking of cytotoxic T cells. Combination therapies involving antiangiogenics and ICI may be synergistic, because vascular endothelial growth factor A inhibition increases intratumoral infiltration and survival of cytotoxic T lymphocytes and decreases regulatory T lymphocyte recruitment, resulting in a more favorable immune microenvironment for ICI antitumoral activity. First results from clinical trials evaluating combinations of these therapies are encouraging with response rates never observed before in patients with HCC. A better understanding of the balance and interactions between protumoral and antitumoral immune cells will help to ensure the success of future therapeutic trials. Here, we present an overview of the current state of clinical development of antitumoral therapies in HCC and the biological rationale for their use. Moreover, translational studies on tumor tissue and blood, prior to and during treatment, will help to identify biomarkers and immune signatures with predictive value for both clinical outcome and response to combination therapies.
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MESH Headings
- Angiogenesis Inhibitors/administration & dosage
- Angiogenesis Inhibitors/adverse effects
- Angiogenesis Inhibitors/therapeutic use
- Animals
- Antineoplastic Agents, Immunological/administration & dosage
- Antineoplastic Agents, Immunological/adverse effects
- Antineoplastic Agents, Immunological/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Biomarkers, Tumor/antagonists & inhibitors
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/pathology
- Clinical Trials as Topic
- Combined Modality Therapy
- Disease Susceptibility
- Humans
- Immunomodulation/drug effects
- Liver Neoplasms/drug therapy
- Liver Neoplasms/etiology
- Liver Neoplasms/pathology
- Molecular Targeted Therapy
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/immunology
- Neovascularization, Pathologic/metabolism
- Treatment Outcome
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/genetics
- Tumor Microenvironment/immunology
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Affiliation(s)
- Marc Hilmi
- Department of Medical Oncology, Curie Institute, University of Versailles Saint-Quentin, Paris, France
| | - Cindy Neuzillet
- Department of Medical Oncology, Curie Institute, University of Versailles Saint-Quentin, Paris, France
| | - Julien Calderaro
- Department of Pathology, Henri Mondor Hospital, Créteil, France
- IMRB-INSERM U955 Team 18, Créteil, France
- Université Paris-Est-Créteil, Créteil, France
| | - Fouad Lafdil
- IMRB-INSERM U955 Team 18, Créteil, France
- Université Paris-Est-Créteil, Créteil, France
- Institut Universitaire de France, Paris, France
| | - Jean-Michel Pawlotsky
- IMRB-INSERM U955 Team 18, Créteil, France
- Université Paris-Est-Créteil, Créteil, France
- National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Henri Mondor Hospital, Créteil, France
| | - Benoit Rousseau
- IMRB-INSERM U955 Team 18, Créteil, France.
- Department of Medicine, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Zhao X, Liu X, Zhang P, Liu Y, Ran W, Cai Y, Wang J, Zhai Y, Wang G, Ding Y, Li Y. Injectable peptide hydrogel as intraperitoneal triptolide depot for the treatment of orthotopic hepatocellular carcinoma. Acta Pharm Sin B 2019; 9:1050-1060. [PMID: 31649853 PMCID: PMC6804453 DOI: 10.1016/j.apsb.2019.06.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 05/10/2019] [Accepted: 05/20/2019] [Indexed: 12/18/2022] Open
Abstract
Chemotherapy is among the limited choices approved for the treatment of hepatocellular carcinoma (HCC) at intermediate and advanced stages. Preferential and prolonged drug exposure in diseased sites is required to maximize the therapeutic index of the drug. Here, we report an injectable supramolecular peptide hydrogel as an intraperitoneal depot for localized and sustained release of triptolide for the treatment of orthotopic HCC. We chose peptide amphiphile C16-GNNQQNYKD-OH-based nanofibers as gelators and carriers for triptolide. Sustained triptolide release from the hydrogel was achieved over 14 days in vitro, with higher accumulation in and cytotoxicity against human HCC Bel-7402 in comparison with L-02 fetal hepatocytes. After intraperitoneal injection, the hydrogel showed prolonged retention over 13 days and preferential accumulation in the liver, realizing HCC growth inhibition by 99.7 ± 0.1% and animal median survival extension from 19 to 43 days, without causing noticeable pathological changes in the major organs. These results demonstrate that injectable peptide hydrogel can be a potential carrier for localized chemotherapy of HCC.
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Key Words
- ANOVA, analysis of variance
- AST, aspartate transaminase
- ATL, alanine transaminase
- AUC0–13, areas under the curve
- AURKA, aurora A kinase
- Akt, protein kinase B
- BUN, blood urea nitrogen
- Bel-7402/Luc, luciferase transfected human HCC cell line Bel-7402
- C16-N, C16-GNNQQNYKD-OH
- C16-N/DiI, DiI-labeled C16-N
- C16-N/DiR, DiR-labeled C16-N hydrogel
- C16-N/T, triptolide-loaded peptide amphiphile-based hydrogel
- CAS, Chinese Academy of Sciences
- CD, circular dichroism
- CKS2, cyclin kinase subunit-2
- CRE, creatinine
- DL, drug loading
- DSPE-PEG, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000]
- DSPE-PEG/DiI, DiI-labeled DSPE-PEG
- DSPE-PEG/DiR, DiR-labeled DSPE-PEG micelle
- DSPE-PEG/T, drug-loaded DSPE-PEG micelles
- EE, encapsulation efficiency
- FBS, fetal bovine serum
- FI range, fluorescence intensity range
- FI, fluorescence intensity
- GEMOX, gemcitabine and oxaliplatin
- H&E, hematoxylin and eosin
- HFIP, 1,1,1,3,3,3-hexafluoro-2-propanol
- HPLC, high-performance liquid chromatography
- Hepatocellular carcinoma
- Hydrogel
- LC–MS, liquid chromatography–mass spectrometry
- OB glue, EPIGLUs
- Peptide amphiphile
- RFI, relative fluorescence intensity
- Self-assembly
- TACE, transarterial chemoembolization
- TEM, transmission electron microscopy
- TIR, tumor inhibition rate
- Tmax, time to reach highest fluorescence intensity
- Triptolide
- d-Luciferin, (S)-4,5-dihydro-2-(6-hydroxy-2-benzothiazolyl)-4-thiazolecarboxylic acid potassium
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Affiliation(s)
- Xiyue Zhao
- Department of Chemistry, Shanghai University, Shanghai 200444, China
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Xiaoyu Liu
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Pengcheng Zhang
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Corresponding authors. Tel./fax: +86 21 20231979.
| | - Yiran Liu
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Nano Science and Technology Institute, University of Science and Technology of China, Suzhou 215123, China
| | - Wei Ran
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ying Cai
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Junyang Wang
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Jilin University, Changchun 130012, China
| | - Yihui Zhai
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Guanru Wang
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yaping Ding
- Department of Chemistry, Shanghai University, Shanghai 200444, China
| | - Yaping Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- School of Pharmacy, Yantai University, Yantai 264005, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Corresponding authors. Tel./fax: +86 21 20231979.
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Guo Y, Li X, Sun X, Wang J, Yang X, Zhou X, Liu X, Liu W, Yuan J, Yao L, Li X, Shen L. Combined Aberrant Expression of NDRG2 and LDHA Predicts Hepatocellular Carcinoma Prognosis and Mediates the Anti-tumor Effect of Gemcitabine. Int J Biol Sci 2019; 15:1771-1786. [PMID: 31523182 PMCID: PMC6743297 DOI: 10.7150/ijbs.35094] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 06/17/2019] [Indexed: 01/13/2023] Open
Abstract
The Warburg effect is one of the important hallmarks of cancer. The activation of oncogene and inactivation of tumor suppressor gene contribute to the enhancement of glycolytic enzymes and the Warburg effect. The N-myc downstream regulated gene 2 (NDRG2) is a tumor suppressor gene and is frequently lost in various types of cancer. However, little is known about glycolytic function and therapeutic value of NDRG2 in hepatocellular carcinoma (HCC). In this study, we found that NDRG2 and lactate dehydrogenase A (LDHA) were aberrantly expressed in HCC and were closely related to the Warburg effect. The correlation between NDRG2 and LDHA expression predicted HCC prognosis and the clinical response to chemotherapy. NDRG2 expression was significantly decreased while LDHA expression was increased in HCC specimens. NDRG2 and LDHA expression was significantly correlated with differentiation status, vascular invasion, and TNM stage of HCC. NDRG2 inhibited LDHA expression, the Warburg effect and the growth of HCC cells. Furthermore, NDRG2 mediated gemcitabine-induced inhibition of LDHA expression and the Warburg effect in HCC cells. Taken together, our data suggest that NDRG2 plays an important role in inhibiting the Warburg effect and the malignant growth of HCC via LDHA. NDRG2 combined with LDHA might be powerful prognostic biomarkers and targets for chemotherapy treatment of HCC.
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Affiliation(s)
- Yan Guo
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Xi'an Li
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Xiang Sun
- Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Jiancai Wang
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Xu Yang
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Xin Zhou
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Xinping Liu
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Wenchao Liu
- Department of Oncology, State Key Discipline of Cell Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Jianlin Yuan
- Department of Urology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Libo Yao
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Xia Li
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Lan Shen
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
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2018 Korean Liver Cancer Association-National Cancer Center Korea Practice Guidelines for the Management of Hepatocellular Carcinoma. Korean J Radiol 2019; 20:1042-1113. [PMID: 31270974 PMCID: PMC6609431 DOI: 10.3348/kjr.2019.0140] [Citation(s) in RCA: 191] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 02/24/2019] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and the fourth most common cancer in men in Korea, where the prevalence of chronic hepatitis B infection is high in middle-aged and elderly patients. These practice guidelines will provide useful and constructive advice for the clinical management of patients with HCC. A total of 44 experts in hepatology, oncology, surgery, radiology, and radiation oncology in the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2014 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions.
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CCN2-MAPK-Id-1 loop feedback amplification is involved in maintaining stemness in oxaliplatin-resistant hepatocellular carcinoma. Hepatol Int 2019; 13:440-453. [PMID: 31250351 PMCID: PMC6661033 DOI: 10.1007/s12072-019-09960-5] [Citation(s) in RCA: 12] [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: 02/21/2019] [Accepted: 06/11/2019] [Indexed: 12/24/2022]
Abstract
Background Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Chemotherapy is an alternative treatment for advanced HCCs, but chemo-resistance prevents cancer therapies from achieving stable and complete responses. Understanding the underlying mechanisms in chemo-resistance is critical to improve the efficacy of HCC. Methods The expression levels of Id-1 and CCN2 were detected in large cohorts of HCCs, and functional analyses of Id-1 and CCN2 were performed both in vitro and in vivo. cDNA microarrays were performed to evaluate the alterations of expression profiling of HCC cells with overexpression of CCN2. Finally, the role of downstream signaling of MAPK/Id-1 signaling pathway in oxaliplatin resistance were also explored. Results The increased expression of Id-1 and CCN2 were closely related to oxaliplatin resistance in HCC. Upregulation of CCN2 and Id-1 was independently associated with shorter survival and increased recurrence in HCC patients, and significantly enhanced oxaliplatin resistance and promoted lung metastasis in vivo, whereas knock-down of their expression significantly reversed the chemo-resistance and inhibited HCC cell stemness. cDNA microarrays and PCR revealed that Id-1 and MAPK pathway were the downstream signaling of CCN2. CCN2 significantly enhanced oxaliplatin resistance by activating the MAPK/Id-1 signaling pathway, and Id-1 could upregulate CCN2 in a positive feedback manner. Conclusions CCN2/MAPK/Id-1 loop feedback amplification is involved in oxaliplatin resistance, and the combination of oxaliplatin with inhibitor of CCN2 or MAPK signaling could provide a promising approach to ameliorating oxaliplatin resistance in HCC. Electronic supplementary material The online version of this article (10.1007/s12072-019-09960-5) contains supplementary material, which is available to authorized users.
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Merle P, Blanc JF, Phelip JM, Pelletier G, Bronowicki JP, Touchefeu Y, Pageaux G, Gerolami R, Habersetzer F, Nguyen-Khac E, Casadei-Gardini A, Borbath I, Tran A, Wege H, Saad AS, Colombo M, Abergel A, Richou C, Waked I, Yee NS, Molé A, Attali P, Le Boulicaut J, Vasseur B. Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial. Lancet Gastroenterol Hepatol 2019; 4:454-465. [PMID: 30954567 DOI: 10.1016/s2468-1253(19)30040-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 01/31/2019] [Accepted: 02/01/2019] [Indexed: 01/24/2023]
Abstract
BACKGROUND Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma. We assessed the intravenous perfusion of doxorubicin-loaded nanoparticles in patients with hepatocellular carcinoma in whom previous sorafenib therapy had failed. METHODS We did a multicentre, open-label, randomised, controlled phase 3 trial at 70 sites in 11 countries. Patients with hepatocellular carcinoma with one or more previous systemic therapies, including sorafenib, were randomly assigned to receive 30 mg/m2 doxorubicin-loaded nanoparticles (30 mg/m2 group), 20 mg/m2 doxorubicin-loaded nanoparticles (20 mg/m2 group), or standard care using a computer-generated randomisation list prepared by the funder and stratified by geographic region. Patients in the experimental groups received perfusion of the drug every 4 weeks and those in the control group received any systemic anticancer therapy (except sorafenib) as per investigator decision. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01655693. FINDINGS Between June 15, 2012, and Jan 27, 2017, 541 patients were screened, of whom 144 were excluded and 397 were randomly assigned to one of the groups (133 to the 30 mg/m2 group; 130 to the 20 mg/m2 group; and 134 to the control group). Median follow-up was 22·7 months (IQR 11·2-34·9). After pooling the doxorubicin groups for the efficacy analysis, median overall survival was 9·1 months (95% CI 8·1-10·4) in the pooled doxorubicin-loaded nanoparticles group and 9·0 months (7·1-11·8) in the control group (HR 1·00 [95% CI 0·78-1·28], two-sided p=0·99). 227 (94%) of 242 patients who received doxorubicin-loaded nanoparticles and 100 (75%) of 134 patients in the control group had at least one treatment-emergent adverse event. The most common drug-related grade 3 or 4 treatment-emergent adverse events were neutropenia (25 [10%] of 242 treated with doxorubicin-loaded nanoparticles and eight [6%] of 134 in the control group), asthenia (six [2%] and four [3%]), and thrombocytopenia (three [1%] and ten [7%]). Six (2%) patients treated with doxorubicin-loaded nanoparticles and one (1%) of those in the control group were deemed by investigators to have had a drug-related death. Serious adverse events occurred in 74 (31%) patients who received doxorubicin-loaded nanoparticles and 48 (36%) in the control group. INTERPRETATION Doxorubicin-loaded nanoparticles did not improve overall survival for patients with hepatocellular carcinoma in whom previous sorafenib treatment had failed. FUNDING Onxeo.
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Affiliation(s)
- Philippe Merle
- Service d'Hépatologie et Gastroentérologie, Hôpital de la Croix-Rousse, Lyon, France.
| | | | - Jean-Marc Phelip
- Centre Hospitalier Universitaire (CHU) de Saint-Étienne, Saint-Étienne, France
| | | | | | | | | | | | - François Habersetzer
- Centre Hospitalier Regional Universitaire de Strasbourg-Hôpital Civil, Strasbourg, France
| | | | - Andrea Casadei-Gardini
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy
| | - Ivan Borbath
- Université Catholique de Louvain Saint-Luc, Brussels, Belgium
| | | | - Henning Wege
- Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | - Amr Shafik Saad
- Department of Oncology, Ain Shams University Hospitals, Cairo, Egypt
| | - Massimo Colombo
- Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda-Ospedale Maggiore Policlinico, Milano, Italy
| | - Armand Abergel
- CHU de Clermont-Ferrand-Hôpital Estaing, Clermont-Ferrand, France
| | | | - Imam Waked
- National Liver Institute, Menoufyia University, Menoufyia, Egypt
| | - Nelson S Yee
- Penn State Cancer Institute Milton S Hershey Medical Center, Hershey, PA, USA
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Jiang JM, Ohri N, Tang J, Moadel R, Cynamon J, Kaubisch A, Kinkhabwala M, Garg MK, Guha C, Kabarriti R. Centers with more therapeutic modalities are associated with improved outcomes for patients with hepatocellular carcinoma. J Gastrointest Oncol 2019; 10:546-553. [PMID: 31183206 DOI: 10.21037/jgo.2019.01.30] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background Higher facility volume is correlated to better overall survival (OS), but there is little knowledge on the effect of facility treatment modality number on OS in hepatocellular carcinoma (HCC). Methods This is a retrospective analysis of data from the National Cancer Database (NCDB) from 2004-2014 on patients with non-metastatic HCC. Treatment modalities assessed were surgical resection, transplantation, ablation, radioembolization, stereotactic body radiation therapy (SBRT), single-agent chemotherapy, and multi-agent chemotherapy. Facilities were dichotomized at the median of the listed treatment modalities. Results There were a total of 112,512 patients with non-metastatic HCC. Of a total of 1,230 sites, 830 (67.5%) used four or fewer modalities. Average survival for patients treated at facilities using fewer modalities was 12.0 and 23.5 months for those treated at facilities with more modalities [hazard ratio (HR) =0.52, 95% confidence interval (CI): 0.51-0.53, P<0.001]. After adjusting for facility volume, liver function, tumor and patient characteristics and other prognostic factors in a multivariable Cox model, treatment at a multi-modality facility still provided a survival advantage (HR =0.60, 95% CI: 0.52-0.70, P<0.001). This benefit also persisted after propensity score matching. Sensitivity analysis varying the cut point from 2 to 6 modalities for dichotomization showed that the benefit persisted. Subgroup stratified analyses based on stage showed that the benefit in OS was highest for patients with stage I and II (P≤0.002) but was not significant for stage III or IVa. Conclusions Institutions that offered more treatment modalities had improved OS for patients with non-metastatic HCC, especially for those with stage I and II.
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Affiliation(s)
- Julie M Jiang
- Departments of Radiation Oncology, Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY, USA
| | - Nitin Ohri
- Departments of Radiation Oncology, Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY, USA
| | - Justin Tang
- Departments of Radiation Oncology, Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY, USA
| | - Renee Moadel
- Departments of Radiology (Nuclear Medicine), Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY, USA
| | - Jacob Cynamon
- Departments of Radiology (Vascular & Interventional Radiology), Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY, USA
| | - Andreas Kaubisch
- Departments of Medicine (Oncology), Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY, USA
| | - Milan Kinkhabwala
- Departments of Surgery, Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY, USA
| | - Madhur K Garg
- Departments of Radiation Oncology, Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY, USA
| | - Chandan Guha
- Departments of Radiation Oncology, Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY, USA
| | - Rafi Kabarriti
- Departments of Radiation Oncology, Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY, USA
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2018 Korean Liver Cancer Association-National Cancer Center Korea Practice Guidelines for the Management of Hepatocellular Carcinoma. Gut Liver 2019; 13:227-299. [PMID: 31060120 PMCID: PMC6529163 DOI: 10.5009/gnl19024] [Citation(s) in RCA: 241] [Impact Index Per Article: 40.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 01/24/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and the fourth most common cancer in men in Korea, where the prevalence of chronic hepatitis B infection is high in middle-aged and elderly patients. These practice guidelines will provide useful and constructive advice for the clinical management of patients with HCC. A total of 44 experts in hepatology, oncology, surgery, radiology and radiation oncology in the Korean Liver Cancer Association-National Cancer Center Korea Practice Guideline Revision Committee revised the 2014 Korean guidelines and developed new recommendations that integrate the most up-to-date research findings and expert opinions.
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Gans JH, Lipman J, Golowa Y, Kinkhabwala M, Kaubisch A. Hepatic Cancers Overview: Surgical and Chemotherapeutic Options, How Do Y-90 Microspheres Fit in? Semin Nucl Med 2019; 49:170-181. [DOI: 10.1053/j.semnuclmed.2019.01.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Sorafenib alone vs. sorafenib plus GEMOX as 1 st-line treatment for advanced HCC: the phase II randomised PRODIGE 10 trial. Br J Cancer 2019; 120:896-902. [PMID: 30944458 PMCID: PMC6734663 DOI: 10.1038/s41416-019-0443-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 03/08/2019] [Accepted: 03/14/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Sorafenib remains one major first-line therapeutic options for advanced hepatocellular carcinoma (aHCC), with modest efficacy. We investigated the addition of gemcitabine and oxaliplatin (GEMOX) to sorafenib in aHCC patients. METHODS Our multicentre phase II trial randomised aHCC first-line patients to sorafenib (400 mg BID) or sorafenib-GEMOX every 2 weeks (1000 mg/m2 gemcitabine; 100 mg/m2 oxaliplatin). Primary endpoint was the 4-month progression-free survival (PFS) rate. RESULTS Ninety-four patients were randomised (sorafenib-GEMOX: n = 48; sorafenib: n = 46). Median age was 64 years, PS 0 (69%) or 1 (31%), 63% patients had cirrhosis, 29% portal vein thrombosis and 70% extra-hepatic disease. Median duration of sorafenib treatment was 4 months (1-51); median number of GEMOX cycles was 7 (1-16). The 4-month PFS rates were 64% and 61% in the sorafenib-GEMOX and sorafenib arms, respectively; median PFS and OS were 6.2 (95% CI: 3.8-6.8) and 13.5 (7.5-16.2) months, and 4.6 (3.9-6.2) months and 14.8 (12.2-22.2), respectively. The ORR/DCR were 9%/70% and 15%/77% in the sorafenib-GEMOX and sorafenib alone arms, respectively. Main toxicities were (sorafenib-GEMOX/sorafenib) neutropenia (23%/0), thrombocytopenia (33%/0), diarrhoea (18%/9), peripheral neuropathy (5%/0) and hand-foot syndrome (5%/18). CONCLUSIONS Addition of GEMOX had an inpact on ORR and was well-tolerated as frontline systemic therapy. The benefit on PFS seems moderate; no subsequent study was planned.
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A novel liver-specific fluorescent anti-cancer drug delivery system using indocyanine green. Sci Rep 2019; 9:3044. [PMID: 30816163 PMCID: PMC6395603 DOI: 10.1038/s41598-019-39269-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 01/21/2019] [Indexed: 12/21/2022] Open
Abstract
Indocyanine green (ICG) accumulates only in hepatocytes and their malignant counterpart, hepatocellular carcinoma (HCC). We have developed ICG-conjugated anti-cancer drugs and noted their significant accumulation in HCC cells both in vitro and in vivo. ICG-conjugated gemcitabine was less toxic to normal cells and it had superior anti-tumor action compared to gemcitabine alone in a subcutaneous tumor xenograft. ICG conjugation can provide a novel fluorescent drug delivery system for treatment of liver cancer and this system can be used to both diagnose and treat HCC.
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Couri T, Pillai A. Goals and targets for personalized therapy for HCC. Hepatol Int 2019; 13:125-137. [PMID: 30600478 DOI: 10.1007/s12072-018-9919-1] [Citation(s) in RCA: 366] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 12/04/2018] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide and its incidence continues to rise. While cirrhosis underlies most cases of HCC, many molecular pathways are implicated in HCC carcinogenesis, including the TERT promoter mutation, Wnt/β-catenin, P53, Akt/mTOR, vascular endothelial growth factor receptor (VEGFR), and endothelial growth factor receptor (EGFR)/RAS/MAPK pathways. While the most widely used staging and treatment algorithm for HCC-the Barcelona Clinic Liver Cancer (BCLC) system-does not recommend systemic molecular therapy for early HCC, a variety of treatment options are available depending upon the stage of HCC at diagnosis. Determining the best treatment options must take into account not only the burden and extent of HCC, but also the patient's performance status, underlying liver function, extra-hepatic disease and co-morbidities. Radiofrequency or microwave ablation, liver resection, or liver transplantation, all potential curative therapies for HCC, should be the first-line treatments when possible. For patients who are not candidates of curative treatments, locoregional therapies such as transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and stereotactic body radiation (SBRT) can improve survival and quality of life. Sorafenib, a multi-kinase VEGF inhibitor, is the most widely used systemic chemotherapy approved as a first-line agent for unresectable or advanced HCC. Clinical trials are underway directed towards molecular therapies that target different aspects of the hepatocellular carcinogenesis cascade. Ideally, the goal of future therapy should be to target multiple pathways in the HCC cascade with combination treatments to achieve personalized care aimed at improving overall survival.
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Affiliation(s)
- Thomas Couri
- Department of Internal Medicine, University of Chicago Medical Center, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA
| | - Anjana Pillai
- Division of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medical Center, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA.
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A Phase I Study of Combination Therapy with Sorafenib and 5-Fluorouracil in Patients with Advanced Hepatocellular Carcinoma. Drugs R D 2018; 17:381-388. [PMID: 28573606 PMCID: PMC5629128 DOI: 10.1007/s40268-017-0187-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background and aims Sorafenib is the first molecular targeted drug approved for the treatment of advanced hepatocellular carcinoma (HCC) and is a potent small molecule inhibitor of multiple kinases. Combination therapy with sorafenib and other cytotoxic agents for HCC may result in additive anticancer activity. The purpose of this phase I study was to investigate the safety and tolerability of combination therapy with sorafenib and 5-fluorouracil (5-FU) and to determine the optimum dose of 5-FU for a phase II trial. Methods This phase I study used a conventional 3 + 3 dose-escalation design. The primary endpoint was to determine the maximum tolerated dose (MTD) of 5-FU in combination with sorafenib and to determine the recommended dosage (RD) for phase II. The secondary endpoints evaluated were toxicity and the tumor response rate. All patients received 800 mg of sorafenib daily and three different dosages of 5-FU (250, 350, and 450 mg/m2/day) for 20 days by intravenous infusion in 1 month as one cycle. Results Twelve patients with advanced HCC were evaluated. The MTD of 5-FU in combination with sorafenib was 450 mg/m2/day, and 350 mg/m2/day was selected as the RD for a phase II study. Thrombocytopenia, stomatitis, and hand-foot skin reaction were observed as grade 3 adverse events. Nine patients achieved stable disease (75%), and three patients (25%) were judged to have progressive disease. The disease control rate was 75%. Conclusions Combination therapy with sorafenib and 5-FU appears to be well tolerated and may have the potential to be an option for advanced HCC.
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Fu XT, Song K, Zhou J, Shi YH, Liu WR, Tian MX, Jin L, Shi GM, Gao Q, Ding ZB, Fan J. Autophagy activation contributes to glutathione transferase Mu 1-mediated chemoresistance in hepatocellular carcinoma. Oncol Lett 2018; 16:346-352. [PMID: 29928420 PMCID: PMC6006440 DOI: 10.3892/ol.2018.8667] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2017] [Accepted: 03/21/2018] [Indexed: 02/07/2023] Open
Abstract
Glutathione transferase Mu 1 (GSTM1) induces cancer drug resistance by hydrolyzing cancer chemotherapeutics or activating the anti-apoptosis pathway. However, the chemoresistance-inducing mechanism of GSTM1 in hepatocellular carcinoma (HCC) remains unknown. In the present study, the expression of GSTM1 was examined in three HCC cell lines. Oxaliplatin and sorafenib were selected as chemotherapeutic agents. Small interfering RNA was used to decrease GSTM1 expression. Cell death was measured using MTT and annexin V/propidium iodide assays. Activation of autophagy was evaluated by green fluorescent protein-light chain 3 redistribution and analysis of autophagy-related 5 expression in MHCC97-H and Huh-7 cells. A stepwise increase in GSTM1 expression with increasing metastatic potential of HCC cell lines was revealed. Cell death induced by oxaliplatin and sorafenib was significantly increased following GSTM1-knockdown in MHCC97-H and Huh-7 cells. Activation of autophagy was significantly inhibited by silencing GSTM1 expression. The results of the present study suggest that GSTM1 may protect HCC cells against the effect of oxaliplatin treatment through activating autophagy. The present study provides a novel perspective on HCC drug-resistance.
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Affiliation(s)
- Xiu-Tao Fu
- Department of Liver Surgery, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai 200032, P.R. China
| | - Kang Song
- Department of Liver Surgery, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai 200032, P.R. China
| | - Jian Zhou
- Department of Liver Surgery, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai 200032, P.R. China.,Department of Molecular Cell Biology, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Ying-Hong Shi
- Department of Liver Surgery, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai 200032, P.R. China
| | - Wei-Ren Liu
- Department of Liver Surgery, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai 200032, P.R. China
| | - Meng-Xin Tian
- Department of Liver Surgery, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai 200032, P.R. China
| | - Lei Jin
- Department of Liver Surgery, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai 200032, P.R. China
| | - Guo-Ming Shi
- Department of Liver Surgery, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai 200032, P.R. China
| | - Qiang Gao
- Department of Liver Surgery, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai 200032, P.R. China
| | - Zhen-Bin Ding
- Department of Liver Surgery, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai 200032, P.R. China
| | - Jia Fan
- Department of Liver Surgery, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai 200032, P.R. China.,Department of Molecular Cell Biology, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China
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Lee DW, Lee KH, Kim HJ, Kim TY, Kim JS, Han SW, Oh DY, Kim JH, Im SA, Kim TY. A phase II trial of S-1 and oxaliplatin in patients with advanced hepatocellular carcinoma. BMC Cancer 2018; 18:252. [PMID: 29506478 PMCID: PMC5838934 DOI: 10.1186/s12885-018-4039-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 01/23/2018] [Indexed: 02/01/2023] Open
Abstract
Background Oxaliplatin is a platinum derivative that has shown efficacy in advanced hepatocellular carcinoma. S-1 is an oral fluoropyrimidine that has substituted for 5-fluorouracil in many cancers. This was a multicenter, open-label, single-arm phase II trial that evaluated the efficacy of S-1 and oxaliplatin (SOX) in advanced hepatocellular carcinoma. All patients included in the present study were systemic treatment-naïve. Prior treatment with sorafenib was allowed, but other treatments were not. Methods Patients received S-1 (40 mg/m2 twice daily from day 1–14) and oxaliplatin (130 mg/m2 on day 1) every 3 weeks. The primary end point was time to progression (TTP). Secondary end points included progression-free survival, overall survival (OS), response rate, and safety profile. Results Thirty six patients with advanced hepatocellular carcinoma were included in this study. The median TTP was 3.0 months (95% confidence interval (CI), 0.75–5.25), and the median OS was 10.3 months (95% CI, 6.4–14.3). Bone metastasis was associated with poorer TTP and OS. The efficacy of SOX was unaffected by prior sorafenib or locoregional therapy. The objective response rate was 13.9%. No grade 4 toxicity or death from adverse events occurred. The most common grade 3 toxicities were neutropenia (13.9%), thrombocytopenia (13.9%), and diarrhea (8.3%). Conclusions Although this trial did not meet its primary end point, the SOX regimen showed comparable efficacy and safety to the 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) regimen. As the SOX regimen is easier for patients, SOX may be a reasonable substitute for FOLFOX in hepatocellular carcinoma. Trial registration Clinicaltrials.gov NCT01429961. Registered 7 September 2011.
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Affiliation(s)
| | - Kyung-Hun Lee
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-ro, Jongno-gu, Seoul, 110-744, South Korea
| | - Hee-Jun Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, South Korea
| | - Tae-Yong Kim
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-ro, Jongno-gu, Seoul, 110-744, South Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Jin-Soo Kim
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, South Korea
| | - Sae-Won Han
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-ro, Jongno-gu, Seoul, 110-744, South Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Do-Youn Oh
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-ro, Jongno-gu, Seoul, 110-744, South Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Jee Hyun Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Seock-Ah Im
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-ro, Jongno-gu, Seoul, 110-744, South Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Tae-You Kim
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-ro, Jongno-gu, Seoul, 110-744, South Korea. .,Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
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Effect of diosmin on apoptotic signaling molecules in N-nitrosodiethylamine-induced hepatocellular carcinoma in experimental rats. Mol Cell Biochem 2018; 449:27-37. [PMID: 29479636 DOI: 10.1007/s11010-018-3339-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 02/22/2018] [Indexed: 12/22/2022]
Abstract
The aim of the present study was to evaluate the antioxidant and chemopreventive efficiency of diosmin against N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis in adult male rats. Rats were classified into four groups as follows: Group I: Control, Group II: NDEA-induced hepatocellular carcinogenic rats, Group III: Cancer-bearing animals treated with diosmin (200 mg/kg/body weight/day) orally for 28 days, Group IV: Control animals treated with diosmin (200 mg/kg/body weight/day) alone for 28 days. The model of NDEA-induced HCC rats elicited significant increases in alpha-fetoprotein (AFP), lipid peroxidation (LPO) and increase in anti-apoptotic proteins (Bcl-2, Bcl-xL and Mcl-1) with a concomitant significant decline in liver antioxidant enzymes, pro-apoptotic (Bax and Bad) and caspase-3 &-9 proteins. The oral administration of diosmin as a protective agent normalized the altered levels of AFP, LPO, antioxidant enzymes, pro- and anti-apoptotic proteins as well as caspase-3 and -9 proteins. Transmission electron microscopical studies also revealed that treatment of diosmin has a perspective anti-cancer activity by rearranging hepatic cell structure and its integrity. Results of this study suggest that diosmin may be one of a pharmacological and therapeutic representative against hepatocellular carcinoma.
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Salimon M, Prieux-Klotz C, Tougeron D, Hautefeuille V, Caulet M, Gournay J, Matysiak-Budnik T, Bennouna J, Tiako Meyo M, Lecomte T, Zaanan A, Touchefeu Y. Gemcitabine plus platinum-based chemotherapy for first-line treatment of hepatocholangiocarcinoma: an AGEO French multicentre retrospective study. Br J Cancer 2018; 118:325-330. [PMID: 29169182 PMCID: PMC5808029 DOI: 10.1038/bjc.2017.413] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 10/17/2017] [Accepted: 10/20/2017] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Hepatocholangiocarcinoma (cHCC-ICC) is a rare liver tumour for which no data on chemosensitivity exist. The aims of this multicentre study were to evaluate overall survival (OS), progression-free survival (PFS), and prognostic factors in cHCC-ICC treated by gemcitabine plus platinum as first-line. METHODS Unresectable cHCC-ICC treated by gemcitabine plus platinum-based chemotherapy between 2008 and 2017 were retrospectively analysed. Diagnosis was based on histology or, in case of ICC or HCC histology, on discordant computerised tomography scan enhancement patterns associated with discordant serum tumour marker elevation suggesting the alternative tumour. OS and PFS were evaluated by Kaplan-Meier method and prognostic factors by Log-rank test and Cox model. RESULTS Among 30 patients included, cHCC-ICC was histologically proven in 22 (73.3%). 18 (60%) received gemcitabine plus oxaliplatin (GEMOX), 9 (30%) GEMOX plus bevacizumab, and 3 (10%) gemcitabine plus cisplatin. RECIST criteria were reported in 28 patients: 8 (28.6%) showed partial response, 14 (50%) stable disease, and 6 (21.4%) tumour progression at first evaluation. Median PFS and OS were 9.0 and 16.2 months, respectively. Serum bilirubin ⩾30 μmol l-1 (P=0.001) and positive serology for HBV and/or HCV (P=0.014) were independent poor prognostic factors for OS. CONCLUSIONS Gemcitabine plus platinum-based chemotherapy is effective as first-line for advanced cHCC-ICC.
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Affiliation(s)
- Maëva Salimon
- Institut des Maladies de l'appareil Digestif, Nantes University Hospital, 1 place Alexis Ricordeau, Nantes 44000, France
| | - Caroline Prieux-Klotz
- Department of Gastroenterology and Oncology, Cochin University Hospital, Paris 75014, France
| | - David Tougeron
- Department of Gastroenterology, Poitiers University Hospital, Poitiers 86600, France
| | - Vincent Hautefeuille
- Amiens University Hospital, Department of Gastroenterology and Oncology, Amiens 80054, France
| | - Morgane Caulet
- Tours University Hospital, Department of Gastroenterology and Oncology, Tours 37000, France
| | - Jérôme Gournay
- Institut des Maladies de l'appareil Digestif, Nantes University Hospital, 1 place Alexis Ricordeau, Nantes 44000, France
| | - Tamara Matysiak-Budnik
- Institut des Maladies de l'appareil Digestif, Nantes University Hospital, 1 place Alexis Ricordeau, Nantes 44000, France
| | - Jaafar Bennouna
- Institut des Maladies de l'appareil Digestif, Nantes University Hospital, 1 place Alexis Ricordeau, Nantes 44000, France
| | - Manuela Tiako Meyo
- Department of Gastroenterology and Digestive Oncology, Sorbonne Paris Cité, Paris Descartes University, Georges Pompidou European Hospital, Paris 75015, France
| | - Thierry Lecomte
- Tours University Hospital, Department of Gastroenterology and Oncology, Tours 37000, France
| | - Aziz Zaanan
- Department of Gastroenterology and Digestive Oncology, Sorbonne Paris Cité, Paris Descartes University, Georges Pompidou European Hospital, Paris 75015, France
| | - Yann Touchefeu
- Institut des Maladies de l'appareil Digestif, Nantes University Hospital, 1 place Alexis Ricordeau, Nantes 44000, France
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He MK, Zou RH, Li QJ, Zhou ZG, Shen JX, Zhang YF, Yu ZS, Xu L, Shi M. Phase II Study of Sorafenib Combined with Concurrent Hepatic Arterial Infusion of Oxaliplatin, 5-Fluorouracil and Leucovorin for Unresectable Hepatocellular Carcinoma with Major Portal Vein Thrombosis. Cardiovasc Intervent Radiol 2018; 41:734-743. [PMID: 29327075 DOI: 10.1007/s00270-017-1874-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 12/29/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Sorafenib is recommended for the first-line treatment of advanced hepatocellular carcinoma (HCC). However, the median progression-free survival (PFS) of patients with HCC and major portal vein tumor thrombosis treated with sorafenib monotherapy is no more than 3 months. A prospective single-arm phase II study was conducted to determine whether adding hepatic arterial infusion chemotherapy of oxaliplatin, 5-fluorouracil and leucovorin to sorafenib could improve on these results. METHODS Thirty five patients were treated with sorafenib 400 mg orally twice a day, oxaliplatin 85 mg/m2 HAI on day 1, leucovorin 400 mg/m2 HAI on days 1, and 5-fluorouracil 2800 mg/m2 on days 1 and 2, repeated every 21 days. The primary end point was the 3-month PFS rate. RESULTS The 3-, 6-, and 12-month PFS rates were 82.9, 51.4, and 22.9%, respectively. The median PFS and overall survival was 6.7 and 13.2 months, respectively. The objective response rate was 40%, and the disease control rate was 77.1% by RECIST criteria. Five (14.3%) patients achieved conversion to complete resection after the study treatment, and one of them experienced a pathological complete response. Treatment-related deaths did not occur. Grade 3-4 toxicities consisted of increases in aspartate aminotransferase (31.4%), hand-foot syndrome (17.1%), thrombocytopenia (14.3%), and neutropenia (8.6%). CONCLUSIONS The combination treatment met the pre-specified end point of a 3-month progression free survival rate exceeding 65% and was clinical tolerable. The merits of this approach need to be established with a phase III trial. Clinical trial number http://ClinicalTrials.gov (No. NCT02981498).
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Affiliation(s)
- Min-Ke He
- Department of Hepatobiliary Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, China
| | - Ru-Hai Zou
- Department of Ultrasonography, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, China
| | - Qi-Jiong Li
- Department of Hepatobiliary Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, China
| | - Zhong-Guo Zhou
- Department of Hepatobiliary Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, China
| | - Jing-Xian Shen
- Department of Radiology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, China
| | - Yong-Fa Zhang
- Department of Liver Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zi-Shan Yu
- Department of Hepatobiliary Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, China
| | - Li Xu
- Department of Hepatobiliary Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, China
| | - Ming Shi
- Department of Hepatobiliary Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, China.
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Liao B, Zhang Y, Sun Q, Jiang P. Vorinostat enhances the anticancer effect of oxaliplatin on hepatocellular carcinoma cells. Cancer Med 2018; 7:196-207. [PMID: 29239146 PMCID: PMC5773972 DOI: 10.1002/cam4.1278] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2017] [Revised: 10/14/2017] [Accepted: 11/08/2017] [Indexed: 12/12/2022] Open
Abstract
Oxaliplatin-based systemic chemotherapy has been proposed to have efficacy in hepatocellular carcinoma (HCC). We investigated the combination of vorinostat and oxaliplatin for possible synergism in HCC cells. SMMC7721, BEL7402, and HepG2 cells were treated with vorinostat and oxaliplatin. Cytotoxicity assay, tumorigenicity assay in vitro, cell cycle analysis, apoptosis analysis, western blot analysis, animal model study, immunohistochemistry, and quantitative PCR were performed. We found that vorinostat and oxaliplatin inhibited the proliferation of SMMC7721, BEL7402, and HepG2 cells. The combination index (CI) values were all <1, and the dose-reduction index values were all greater than 1 in the three cell lines, indicating a synergistic effect of combination of the two agents. Coadministration of vorinostat and oxaliplatin induced G2/M phase arrest, triggered caspase-dependent apoptosis, and decreased tumorigenicity both in vitro and in vivo. Vorinostat suppressed the expression of BRCA1 induced by oxaliplatin. In conclusion, cotreatment with vorinostat and oxaliplatin exhibited synergism in HCC cells. The combination inhibited cell proliferation and tumorigenicity both in vitro and in vivo through induction of cell cycle arrest and apoptosis. Our results predict that a combination of vorinostat and oxaliplatin may be useful in the treatment of advanced HCC.
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Affiliation(s)
- Bo Liao
- Department of Hepatopancreatobiliary SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Yingying Zhang
- Intensive Care UnitZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Quan Sun
- Department of Hepatopancreatobiliary SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Ping Jiang
- Department of Hepatopancreatobiliary SurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
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Ma J, Zeng S, Zhang Y, Deng G, Qu Y, Guo C, Yin L, Han Y, Cai C, Li Y, Wang G, Bonkovsky HL, Shen H. BMP4 promotes oxaliplatin resistance by an induction of epithelial-mesenchymal transition via MEK1/ERK/ELK1 signaling in hepatocellular carcinoma. Cancer Lett 2017; 411:117-129. [PMID: 28987388 DOI: 10.1016/j.canlet.2017.09.041] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 08/30/2017] [Accepted: 09/25/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Bone morphogenetic protein-4 (BMP4) is a key regulator of epithelial-mesenchymal transition (EMT), which is crucial for cancer cells to acquire chemoresistance. The effects of BMP4 on OXA sensitivity in HCC need to be elucidated. METHODS Functional analysis of BMP4 on EMT-regulated OXA sensitivity was performed in human HCC specimens, in the HCC cell lines HepG2 and HCCLM3, and in a subcutaneous tumor model receiving OXA treatment. The downstream signaling targets of BMP4 in HCC were profiled and confirmed. RESULTS BMP4 expression was significantly increased in HCC tissue, and was correlated with tumor de-differentiation and unfavorable prognosis. BMP4 promoted HCC EMT and was correlated with OXA resistance. Blocking of BMP4 reversed EMT and increased OXA chemosensitivity in vitro and in vivo. ELK1, a transcription factor involved in EMT, was an important mediator of BMP4-induced OXA resistance in HCC. Blocking of MEK/ERK/ELK1 attenuated BMP4-induced EMT and enhanced OXA sensitivity. CONCLUSIONS BMP4 induces EMT and OXA chemoresistance via MEK/ERK/ELK1 signaling pathway in HCC. BMP4 may be a valuable therapeutic target for HCC patients receiving OXA-based chemotherapy.
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Affiliation(s)
- Junli Ma
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Shan Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Yan Zhang
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Ganlu Deng
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Yanling Qu
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Cao Guo
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Ling Yin
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Ying Han
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Changjing Cai
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Yiyi Li
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Guqi Wang
- School of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157 USA; Whole Pharm Biotechnology Corp., Matthews, NC 28105, USA
| | - Herbert L Bonkovsky
- School of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157 USA.
| | - Hong Shen
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
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Hypoxia induces universal but differential drug resistance and impairs anticancer mechanisms of 5-fluorouracil in hepatoma cells. Acta Pharmacol Sin 2017; 38:1642-1654. [PMID: 28713155 DOI: 10.1038/aps.2017.79] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 03/23/2017] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most refractory cancers. The mechanisms by which hypoxia further aggravates therapeutic responses of advanced HCC to anticancer drugs remain to be clarified. Here, we report that hypoxia (1% O2) caused 2.55-489.7-fold resistance to 6 anticancer drugs (sorafenib, 5-fluorouracil [5-FU], gemcitabine, cisplatin, adriamycin and 6-thioguanine) in 3 HCC cell lines (BEL-7402, HepG2 and SMMC-7721). Among the 6 drugs, sorafenib, the sole one approved for HCC therapy, inhibited proliferation with little influence from hypoxia and displayed the smallest variation among the 3 HCC cell lines tested. By contrast, the inhibition of proliferation by 5-FU, which has been extensively tested in clinical trials but has not been approved for HCC therapy, was severely affected by hypoxia and showed a large variation among these cell lines. In 5-FU-treated HCC cells, hypoxia reduced the levels of basal thymidylate synthase (TS) and functional TS, leading to decreased dTMP synthesis and DNA replication. Hypoxia also affected the accumulation of FdUTP and its misincorporation into DNA. Consequently, both single-strand breaks and double-strand breaks in DNA were reduced, although hypoxia also inhibited DNA repair. In 5-FU-treated HCC cells, hypoxia further abated S-phase arrest, alleviated the loss of mitochondrial membrane potential, diminished the activation of caspases, and finally resulted in reduced induction of apoptosis. Thus, hypoxia induces universal but differential drug resistance. The extensive impacts of hypoxia on the anticancer mechanisms of 5-FU contributes to its hypoxia-induced resistance in HCC cells. We propose that hypoxia-induced drug resistance and interference of hypoxia with anticancer mechanisms could be used as candidate biomarkers in selecting and/or developing anticancer drugs for improving HCC therapy.
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Abdel-Rahman O, Helbling D, Schöb O, Eltobgy M, Mohamed H, Schmidt J, Giryes A, Mehrabi A, Iype S, John H, Tekbas A, Zidan A, Oweira H. Cigarette smoking as a risk factor for the development of and mortality from hepatocellular carcinoma: An updated systematic review of 81 epidemiological studies. J Evid Based Med 2017; 10:245-254. [PMID: 28891275 DOI: 10.1111/jebm.12270] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Accepted: 08/13/2017] [Indexed: 01/11/2023]
Abstract
BACKGROUND AND AIMS Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and its incidence has increased during the past decade. While hepatitis B and C virus infections and alcohol were established risk factors, the impact of smoking on the incidence and mortality of HCC was needed to be confirmed. METHODS We reviewed cohort and case-control studies evaluating the association between cigarette smoking and incidence and mortality of HCC from MEDLINE and Google Scholar. We also checked reference lists of original studies and review articles manually for cross-references up to February 2016. We extracted the relevant information on participant characteristics and study outcomes, as well as information on the methodology of the studies. We also assessed the quality of the included trials using critical appraisal skills program checklists. Meta-analysis was performed by using RevMan 5.3 software. RESULTS A total of 81 studies were included in the systematic review. Pooled OR for HCC development with current smokers was 1.55 (95% CI: 1.46 to 1.65; P < 0.00001). Pooled OR for HCC development with former smokers was 1.39 (95% CI: 1.26 to 1.52; P < 0.00001) and pooled OR for HCC development with heavy smokers was 1.90 (95% CI: 1.68 to 2.14; P < 0.00001). Pooled OR for the mortality of current smokers with HCC was 1.29 (95% CI: 1.23 to 1.34; P < 0.00001); and for former smokers with HCC, it was 1.20 (95% CI: 1.00 to 1.42; P = 0.04). CONCLUSIONS Cigarette smoking increases the incidence and mortality of HCC. Further studies are needed to evaluate possible impact of quitting smoking on decreasing this risk.
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Affiliation(s)
- Omar Abdel-Rahman
- Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
- Department of Medical Oncology, Gastrointestinal Tumor Center Zurich, Zurich, Switzerland
| | - Daniel Helbling
- Department of Medical Oncology, Gastrointestinal Tumor Center Zurich, Zurich, Switzerland
| | - Othmar Schöb
- Surgical Center Zurich, Hirslanden Hospital Zurich, Zurich, Switzerland
| | - Mostafa Eltobgy
- Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Hadeer Mohamed
- Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Jan Schmidt
- Surgical Center Zurich, Hirslanden Hospital Zurich, Zurich, Switzerland
| | - Anwar Giryes
- Department of Medical Oncology, Gastrointestinal Tumor Center Zurich, Zurich, Switzerland
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
| | - Satheesh Iype
- Department of Surgery, Cambridge University Hospital, Cambridge, United Kingdom
| | - Hannah John
- Department of Surgery, Cambridge University Hospital, Cambridge, United Kingdom
| | - Aysun Tekbas
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
| | - Ahmad Zidan
- Department of HPB and Liver Transplantation, Rajhy Liver Hospital, Assiut University, Assiut, Egypt
| | - Hani Oweira
- Surgical Center Zurich, Hirslanden Hospital Zurich, Zurich, Switzerland
- Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
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