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Wang X, Liang X, Zhang N, Wang Y, Hu M, Shi Y, Yao M, Hou L, Jiang L. Gamma-tocotrienol Inhibits Proliferation and Growth of HSD17B4 Overexpressing HepG2 Liver Cancer Cells. Curr Cancer Drug Targets 2025; 25:170-182. [PMID: 38934283 DOI: 10.2174/0115680096319171240623091614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 05/24/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024]
Abstract
INTRODUCTION Hydroxysteroid 17-beta dehydrogenase 4 (HSD17B4) is involved in the progression of hepatocellular carcinoma (HCC). AIMS This study aimed to investigate the inhibitory effect of gamma-tocotrienol (γ-T3) on the proliferation and growth of HSD17B4-overexpressing HepG2 cells. METHODS HepG2 cells were transfected with empty or HSD17B4-overexpressing plasmids, followed by vitamin E (VE) or γ-T3 treatment. MTS assay, Western blotting, qRT-PCR, and flow cytometry were employed to assess cell proliferation, protein expression, mRNA levels, and apoptosis. HSD17B4 interaction with γ-T3 was assessed by quantifying γ-T3 in the collected precipitate of HSD17B4 using anti-flag magnetic beads. Tumor xenografts were established in NSG mice, and tumor growth was monitored. RESULTS HSD17B4 overexpression significantly promoted HepG2 cell proliferation, which was effectively counteracted by VE or γ-T3 treatment in a dose-dependent manner. VE and γ-T3 did not exert their effects through direct regulation of HSD17B4 expression. Instead, γ-T3 was found to interact with HSD17B4, inhibiting its activity in catalyzing the conversion of estradiol (E2) into estrone. Moreover, γ-T3 treatment led to a reduction in cyclin D1 expression and suppressed key proliferation signaling pathways, such as ERK, MEK, AKT, and STAT3. Additionally, γ-T3 promoted apoptosis in HSD17B4-overexpressing HepG2 cells. In an in vivo model, γ-T3 effectively reduced the growth of HepG2 xenograft tumors. CONCLUSION In conclusion, our study demonstrates that γ-T3 exhibits potent anti-proliferative and anti-tumor effects against HepG2 cells overexpressing HSD17B4. These findings highlight the therapeutic potential of γ-T3 in HCC treatment and suggest its role in targeting HSD17B4-associated pathways to inhibit tumor growth and enhance apoptosis.
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Affiliation(s)
- Xiaoming Wang
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, 050000, Hebei, China
- Department of Clinical Laboratory, First Hospital of Tsinghua University (Beijing Huaxin Hospital), Beijing, 100016, China
| | - Xijia Liang
- Department of Clinical Laboratory, The 980th Hospital of PLA Joint Logistical Support Force (Bethune International Peace Hospital), Shijiazhuang, 050000, Hebei, China
| | - Nan Zhang
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, 050000, Hebei, China
- College of Integrative Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050000, Hebei, China
| | - Yaqi Wang
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, 050000, Hebei, China
- Department of Clinical Laboratory, Hebei Province Hospital of Chinese Medicine, Shijiazhuang, 050000, Hebei, China
| | - Meng Hu
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, 050000, Hebei, China
- Department of Complex Preparation, Shijiazhuang No.4 Pharmaceutical, Shijiazhuang, 050000, Hebei, China
| | - Yun Shi
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, 050000, Hebei, China
| | - Min Yao
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, 050000, Hebei, China
| | - Lianguo Hou
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, 050000, Hebei, China
| | - Lingling Jiang
- Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education of China, Hebei Medical University, Shijiazhuang, 050000, Hebei, China
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Seydi H, Nouri K, Shokouhian B, Piryaei A, Hassan M, Cordani M, Zarrabi A, Shekari F, Vosough M. MiR-29a-laden extracellular vesicles efficiently induced apoptosis through autophagy blockage in HCC cells. Eur J Pharm Biopharm 2024; 203:114470. [PMID: 39197541 DOI: 10.1016/j.ejpb.2024.114470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 08/06/2024] [Accepted: 08/21/2024] [Indexed: 09/01/2024]
Abstract
BACKGROUND In spite of significant advancements in theraputic modalities for hepatocellular carcinoma (HCC), there is still a high annual mortality rate with a rising incidence. Major challenges in the HCC clinical managment are related to the development of therapy resistance, and evasion of tumor cells apoptosis which leading unsatisfactory outcomes in HCC patients. Previous investigations have shown that autophagy plays crucial role in contributing to drug resistance development in HCC. Although, miR-29a is known to counteract authophagy, increasing evidence revealed a down-regulation of miR-29a in HCC patients which correlates with poor prognosis. Beside, evidences showed that miR-29a serves as a negative regulator of autophagy in other cancers. In the current study, we aim to investigate the impact of miR-29a on the autophagy and apoptosis in HCC cells using extracellular vesicles (EVs) as a natural delivery system given their potential in the miRNA delivery both in vitro and in vivo. METHOD Human Wharton's Jelly mesenchymal stromal cell-derived extracellular vesicles were lately isolated through 20,000 or 110,000 × g centrifugation (EV20K or EV110K, respectively), characterized by western blot (WB), scanning electron microscopy (SEM), and dynamic light scattering (DLS). miR-29a was subsequently loaded into these EVs and its loading efficiency was evaluated via RT-qPCR. Comprehensive in vitro and in vivo assessments were then performed on Huh-7 and HepG2 cell lines. RESULTS EV20K-miR-29a treatment significantly induces cell apoptosis and reduces both cell proliferation and colony formation in Huh-7 and HepG2 cell lines. In addition, LC3-II/LC3-I ratio was increased while the expression of key autophagy regulators TFEB and ATG9A were downregulated by this treatment. These findings suggest an effective blockade of autophagy by EV20K-miR-29a leading to apoptosis in the HCC cell lines through concomitant targeting of critical mediators within each pathway.
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Affiliation(s)
- Homeyra Seydi
- Department of Developmental Biology, University of Science and Culture, ACECR, Tehran 14155-4364, Iran; Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 14155-4364, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 14155-4364, Iran
| | - Kosar Nouri
- Department of Developmental Biology, University of Science and Culture, ACECR, Tehran 14155-4364, Iran; Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 14155-4364, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 14155-4364, Iran
| | - Bahare Shokouhian
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 14155-4364, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 14155-4364, Iran; Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Piryaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biology, Complutense University of Madrid, Madrid 28040, Spain; Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid 28040, Spain
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Turkey; Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan 320315, Taiwan; Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600 077, India.
| | - Faezeh Shekari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 14155-4364, Iran; Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 14155-4364, Iran; Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
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Romero-Gutiérrez M, Pascual S, Márquez L, Gómez-Rubio M, Miquel M, Alarcón C, Ferrer T, Aracil C, Horta D, Latorre R, González Santiago J, Bernal V, Fernández C, Piqueras B, Gutiérrez ML, Martín A, Morillas J, Morales D, Blanco S, Rendón P, Chico I, Testillano M, Delgado C, Matilla A, Gómez Rodríguez R. Spontaneously ruptured hepatocellular carcinoma on non-cirrhotic liver: A prospective case series. GASTROENTEROLOGIA Y HEPATOLOGIA 2024; 47:683-690. [PMID: 37633519 DOI: 10.1016/j.gastrohep.2023.08.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/15/2023] [Accepted: 08/21/2023] [Indexed: 08/28/2023]
Abstract
BACKGROUND AND AIMS Spontaneous ruptured hepatocellular carcinoma is an uncommon complication, and there are scarce data about non-cirrhotic patients. Tumor treatment is not standardized and the risk of peritoneal dissemination is unclear. AIM we analyzed the treatment and survival in patients with rHCC on non-cirrhotic liver. METHODS One hundred and forty-one non-cirrhotic patients with hepatocellular carcinoma diagnosed by histology were included in a multicenter prospective registry (2018-2022). Seven of them (5%) presented with hemoperitoneum due to spontaneous rupture. RESULTS Liver disease was associated in three patients (42.9%). A single nodule was detected in three cases (42.9%). One patient had vascular invasion and none extrahepatic spread. Initial hemostatic therapy and sequential treatment was individualized. Patients with single nodule were treated: resection (one case) with recurrence at 4 months treated with TACE and sorafenib. TACE/TAE followed by surgery (two cases) one in remission 43 months later, the other had liver recurrence at 18 months and was transplanted. Patients with multiple lesions were treated: TAE/emergency surgery and subsequent systemic therapy (two cases), one received lenvatinib (1-year survival) and the other sorafenib (5-month survival). TAE and surgery with subsequent systemic therapy (one case). Initial hemostatic surgery, dying on admission (one case). No patient developed intraperitoneal metastasis. All patients with multiple lesions died by tumor. The 3-year survival rate was 42.9%. CONCLUSIONS Initial hemostasis was achieved in all patients by TAE/TACE or surgery. Subsequent treatment was individualized, based on tumor characteristics, regardless of rupture. Long-time remission could be achieved in single nodule patients.
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Affiliation(s)
| | - Sonia Pascual
- Hospital General Universitario Dr. Balmis, Alicante, Spain
| | - Laura Márquez
- Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | | | | | | | - Teresa Ferrer
- Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | - Carles Aracil
- Hospital Universitario Arnau de Vilanova, Lleida, Spain
| | - Diana Horta
- Hospital Universitario Mútua de Terrassa, Barcelona, Spain
| | - Raquel Latorre
- Hospital Universitario Son Llàtzer, Palma de Mallorca, Spain
| | | | - Vanesa Bernal
- Hospital Universitario Miguel Servet, Zaragoza, Spain
| | | | | | | | - Ana Martín
- Hospital Universitario Doce de Octubre, Madrid, Spain
| | | | | | - Sonia Blanco
- Hospital Universitario de Basurto, Bilbao, Spain
| | | | | | | | | | - Ana Matilla
- Hospital General Universitario Gregorio Marañón, Madrid, Spain
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Franchi E, Dondossola DE, Marini GMF, Iavarone M, Del Prete L, Di Benedetto C, Donato MF, Antonelli B, Lampertico P, Caccamo L. Impact of Pre-Liver Transplant Treatments on the Imaging Accuracy of HCC Staging and Their Influence on Outcomes. Cancers (Basel) 2024; 16:1043. [PMID: 38473400 DOI: 10.3390/cancers16051043] [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: 12/04/2023] [Revised: 01/30/2024] [Accepted: 01/31/2024] [Indexed: 03/14/2024] Open
Abstract
The outcome of liver transplantation (LT) for hepatocarcinoma (HCC) is strongly influenced by HCC staging, which is based on radiological examinations in a pre-LT setting; concordance between pre-LT radiological and definitive pathological staging remains controversial. To address this issue, we retrospectively analyzed our LT series to assess concordance between radiology and pathology and to explore the factors associated with poor concordance and outcomes. We included all LTs with an HCC diagnosis performed between 2013 and 2018. Concordance (Co group) was defined as a comparable tumor burden in preoperative imaging and post-transplant pathology; otherwise, non-concordance was diagnosed (nCo group). Concordance between radiology and pathology was observed in 32/134 patients (Co group, 24%). The number and diameter of the nodules were higher when nCo was diagnosed, as was the number of pre-LT treatments. Although concordance did not affect survival, more than three pre-LT treatments led to a lower disease-free survival. Patients who met the Milan Criteria (Milan-in patients) were more likely to receive ≥three prior treatments, leading to a lower survival in multi-treated Milan-in patients than in other Milan-in patients. In conclusion, the concordance rate between the pre-LT imaging and histopathological results was low in patients with a high number of nodules. Multiple bridging therapies reduce the accuracy of pre-LT imaging in predicting HCC stages and negatively affect outcomes after LT.
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Affiliation(s)
- Eloisa Franchi
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Daniele Eliseo Dondossola
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi, 20122 Milan, Italy
| | - Giulia Maria Francesca Marini
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi, 20122 Milan, Italy
| | - Massimo Iavarone
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Luca Del Prete
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Clara Di Benedetto
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Maria Francesca Donato
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Barbara Antonelli
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Pietro Lampertico
- Department of Pathophysiology and Transplantation, Università degli Studi, 20122 Milan, Italy
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Lucio Caccamo
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
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Jin J, Ren M. The biological function of miR-128-2 in hepatocellular carcinoma and its molecular mechanism functioning. Pathol Res Pract 2024; 254:155178. [PMID: 38309020 DOI: 10.1016/j.prp.2024.155178] [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: 04/22/2023] [Revised: 01/24/2024] [Accepted: 01/27/2024] [Indexed: 02/05/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) represents the major type of primary liver cancers, which is a most prevalent malignancy, as well as seriously threatens people's life and health. MiR-128-2 was reported to be associated with several human cancers, and is participated in the pathogenesis and development of cancers. Our research was performed to explore the expression profile and diagnostic significance of miR-128-2 in HCC. METHODS The serum miR-128-2 expression was measured in 130 HCC subjects and 118 healthy people using quantitative real-time polymerase chain reaction (qRT-PCR) assay. Chi-square (ÿ2) test was utilized to estimate the relationship of miR-128-2 level with clinicopathological characteristic. In addition, the diagnostic accuracy of miR-128-2 in HCC was estimated via receiver operating characteristic (ROC) curve analysis. RESULTS Compared with healthy individuals, the level of miR-128-2 was obviously up-regulated in HCC cases (P < 0.01). And its level was closely related to AFP level (P = 0.013), TNM stage (P = 0.009) and differentiation (P = 0.036). Nevertheless, there was no obvious relationship with age, gender, tumor size, HBV status, ALT or metastasis (all P > 0.05). According to the ROC curve, serum miR-128-2 had a high value in discriminating HCC cases from control individuals, with a AUC value of 0.880 combing with the sensitivity of 79.2% and the specificity of 83.9%. CONCLUSION The serum level of miR-128-2 in cases with HCC was obviously increased, which was related to the malignant progression of HCC. Due to the reasonable sensitivity and specificity, miR-128-2 might be as a new and effective marker for the diagnosis of HCC.
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Affiliation(s)
- Jingzhe Jin
- Department of Oncology, Dandong First Hospital, Dandong 118000, Liaoning, China.
| | - Mingcheng Ren
- Department of Oncology, Dandong Cancer Hospital, Dandong 118000, Liaoning, China
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Long H, Peng C, Ding H, Zheng Y, Zhou J, Chen W, Zhong X, Shi Y, Duan Y, Xie X, Kuang M, Xie X, Lin M. Predicting symptomatic post-hepatectomy liver failure in patients with hepatocellular carcinoma: development and validation of a preoperative nomogram. Eur Radiol 2023; 33:7665-7674. [PMID: 37314474 DOI: 10.1007/s00330-023-09803-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 03/12/2023] [Accepted: 03/26/2023] [Indexed: 06/15/2023]
Abstract
OBJECTIVE To develop and validate a nomogram based on liver stiffness (LS) for predicting symptomatic post-hepatectomy (PHLF) in patients with hepatocellular carcinoma (HCC). METHODS A total of 266 patients with HCC were enrolled prospectively from three tertiary referral hospitals from August 2018 to April 2021. All patients underwent preoperative laboratory examination to obtain parameters of liver function. Two-dimensional shear wave elastography (2D-SWE) was performed to measure LS. Three-dimensional virtual resection obtained the different volumes including future liver remnant (FLR). A nomogram was developed by using logistic regression and determined by receiver operating characteristic (ROC) curve analysis and calibration curve analysis, which was validated internally and externally. RESULTS A nomogram was constructed with the following variables: FLR ratio (FLR of total liver volume), LS greater than 9.5 kPa, Child-Pugh grade, and the presence of clinically significant portal hypertension (CSPH). This nomogram enabled differentiation of symptomatic PHLF in the derivation cohort (area under curve [AUC], 0.915), internal fivefold cross-validation (mean AUC, 0.918), internal validation cohort (AUC, 0.876) and external validation cohort (AUC, 0.845). The nomogram also showed good calibration in the derivation, internal validation, and external validation cohorts (Hosmer-Lemeshow goodness-of-fit test, p = 0.641, p = 0.06, and p = 0.127, respectively). Accordingly, the safe limit of the FLR ratio was stratified using the nomogram. CONCLUSION An elevated level of LS was associated with the occurrence of symptomatic PHLF in HCC. A preoperative nomogram integrating LS, clinical and volumetric features was useful in predicting postoperative outcomes in patients with HCC, which might help surgeons in the management of HCC resection. CLINICAL RELEVANCE STATEMENT A serial of the safe limit of the future liver remnant was proposed by a preoperative nomogram for hepatocellular carcinoma, which might help surgeons in 'how much remnant is enough in liver resection'. KEY POINTS • An elevated liver stiffness with the best cutoff value of 9.5 kPa was associated with the occurrence of symptomatic post-hepatectomy liver failure in hepatocellular carcinoma. • A nomogram based on both quality (Child-Pugh grade, liver stiffness, and portal hypertension) and quantity of future liver remnant was developed to predict symptomatic post-hepatectomy liver failure for HCC, which enabled good discrimination and calibration in both derivation and validation cohorts. • The safe limit of future liver remnant volume was stratified using the proposed nomogram, which might help surgeons in the management of HCC resection.
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Affiliation(s)
- Haiyi Long
- Division of Interventional Ultrasound, Department of Medical Ultrasonics, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhong Shan Road 2, Guangzhou, 510080, China
| | - Chuan Peng
- Department of Ultrasonography, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Hong Ding
- Department of Ultrasound, Huashan Hospital, Fudan University. No. 12 Middle Urumqi Road, Shanghai, 200040, China
| | - Yun Zheng
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Jianhua Zhou
- Department of Ultrasonography, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Wei Chen
- Department of Pancreaticobiliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhong Shan Road 2, Guangzhou, 510080, China
| | - Xian Zhong
- Division of Interventional Ultrasound, Department of Medical Ultrasonics, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhong Shan Road 2, Guangzhou, 510080, China
| | - Yifan Shi
- Division of Interventional Ultrasound, Department of Medical Ultrasonics, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhong Shan Road 2, Guangzhou, 510080, China
| | - Yu Duan
- Division of Interventional Ultrasound, Department of Medical Ultrasonics, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhong Shan Road 2, Guangzhou, 510080, China
| | - Xiaohua Xie
- Division of Interventional Ultrasound, Department of Medical Ultrasonics, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhong Shan Road 2, Guangzhou, 510080, China
| | - Ming Kuang
- Division of Interventional Ultrasound, Department of Medical Ultrasonics, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhong Shan Road 2, Guangzhou, 510080, China
- Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhong Shan Road 2, Guangzhou, 510080, China
| | - Xiaoyan Xie
- Division of Interventional Ultrasound, Department of Medical Ultrasonics, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhong Shan Road 2, Guangzhou, 510080, China.
| | - Manxia Lin
- Division of Interventional Ultrasound, Department of Medical Ultrasonics, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhong Shan Road 2, Guangzhou, 510080, China.
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Daif A, Al-Azzawi MA, Sakr MA, Ismail HA, Gadallah M. Noninvasive identification of molecular biomarkers of hepatocellular carcinoma in HCV-Egyptian patients. J Egypt Natl Canc Inst 2023; 35:11. [PMID: 37121922 DOI: 10.1186/s43046-023-00170-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 04/06/2023] [Indexed: 05/02/2023] Open
Abstract
BACKGROUND This study was performed to investigate the expression of different biomarkers in patients with hepatocellular carcinoma and its connection with detective biomarkers. To achieve this objective, seventy subjects were examined in this study, sub-grouped to forty HCC patients and thirty HCV-affected patients with matched thirty healthy individuals. The study involved several groups of participants who were matched based on their age and gender. METHODS The expression pattern of biomarkers was monitored by quantitative polymerase chain reaction (qRT-PCR). Finally, we utilized a ROC curve to investigate the predictive accurateness of those distinct biomarkers as well as a traditional tumor marker, AFP, in detecting HCC cases. RESULTS The baseline biomarker expression levels were markedly greater in HCC patients than in those affected by HCV or healthy subjects. We stated that the sensitivity and the specificity of the different biomarkers alone did not improve than that of AFP alone. When comparing AFP with different biomarkers, the diagnostic validity improves only when combining with CK-1. CONCLUSIONS Overall, our results indicate that CK-1 mRNA expression could help as a noninvasive tumor biomarker for HCC prognosis and diagnosis when combining with AFP.
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Affiliation(s)
- Ahmed Daif
- Molecular Diagnostics and Therapeutics Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat City, Egypt
| | - Mahmood A Al-Azzawi
- Department of Forensic Science, College of Science, AlKarkh University of Science, Baghdad, Iraq
| | - Moustafa A Sakr
- Molecular Diagnostics and Therapeutics Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat City, Egypt.
| | - Hisham A Ismail
- Molecular Diagnostics and Therapeutics Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat City, Egypt
| | - Mahmoud Gadallah
- Molecular Diagnostics and Therapeutics Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat City, Egypt
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Cabral LKD, Giraudi PJ, Giannelli G, Dituri F, Negro R, Tiribelli C, Sukowati CHC. Network Analysis for the Discovery of Common Oncogenic Biomarkers in Liver Cancer Experimental Models. Biomedicines 2023; 11:342. [PMID: 36830879 PMCID: PMC9953082 DOI: 10.3390/biomedicines11020342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/12/2023] [Accepted: 01/20/2023] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy marked by heterogeneity. This study aimed to discover target molecules for potential therapeutic efficacy that may encompass HCC heterogeneity. In silico analysis using published datasets identified 16 proto-oncogenes as potential pharmacological targets. We used an immortalized hepatocyte (IHH) and five HCC cell lines under two subtypes: S1/TGFβ-Wnt-activated (HLE, HLF, and JHH6) and the S2/progenitor subtype (HepG2 and Huh7). Three treatment modalities, 5 µM 5-Azacytidine, 50 µM Sorafenib, and 20 nM PD-L1 gene silencing, were evaluated in vitro. The effect of treatments on the proto-oncogene targets was assessed by gene expression and Western blot analysis. Our results showed that 10/16 targets were upregulated in HCC cells, where cells belonging to the S2/progenitor subtype had more upregulated targets compared to the S1/TGFβ-Wnt-activated subtype (81% vs. 62%, respectively). Among the targets, FGR was consistently down-regulated in the cell lines following the three different treatments. Sorafenib was effective to down-regulate targets in S2/progenitor subtype while PD-L1 silencing was able to decrease targets in all HCC subtypes, suggesting that this treatment strategy may comprise cellular heterogeneity. This study strengthens the relevance of liver cancer cellular heterogeneity in response to cancer therapies.
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Affiliation(s)
- Loraine Kay D. Cabral
- Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, Italy; (L.K.D.C.); (P.J.G.); (C.T.)
- Doctoral School in Molecular Biomedicine, University of Trieste, 34127 Trieste, Italy
| | - Pablo J. Giraudi
- Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, Italy; (L.K.D.C.); (P.J.G.); (C.T.)
| | - Gianluigi Giannelli
- National Institute of Gastroenterology IRCCS “S. De Bellis” Research Hospital, 70013 Bari, Italy; (G.G.); (F.D.); (R.N.)
| | - Francesco Dituri
- National Institute of Gastroenterology IRCCS “S. De Bellis” Research Hospital, 70013 Bari, Italy; (G.G.); (F.D.); (R.N.)
| | - Roberto Negro
- National Institute of Gastroenterology IRCCS “S. De Bellis” Research Hospital, 70013 Bari, Italy; (G.G.); (F.D.); (R.N.)
| | - Claudio Tiribelli
- Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, Italy; (L.K.D.C.); (P.J.G.); (C.T.)
| | - Caecilia H. C. Sukowati
- Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, Italy; (L.K.D.C.); (P.J.G.); (C.T.)
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
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9
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Jung J, Park S, Jang Y, Lee SH, Jeong YS, Yim SY, Lee JS. Clinical Significance of Glycolytic Metabolic Activity in Hepatocellular Carcinoma. Cancers (Basel) 2022; 15:186. [PMID: 36612182 PMCID: PMC9818850 DOI: 10.3390/cancers15010186] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/17/2022] [Accepted: 12/23/2022] [Indexed: 12/31/2022] Open
Abstract
High metabolic activity is a hallmark of cancers, including hepatocellular carcinoma (HCC). However, the molecular features of HCC with high metabolic activity contributing to clinical outcomes and the therapeutic implications of these characteristics are poorly understood. We aimed to define the features of HCC with high metabolic activity and uncover its association with response to current therapies. By integrating gene expression data from mouse liver tissues and tumor tissues from HCC patients (n = 1038), we uncovered three metabolically distinct HCC subtypes that differ in clinical outcomes and underlying molecular biology. The high metabolic subtype is characterized by poor survival, the strongest stem cell signature, high genomic instability, activation of EPCAM and SALL4, and low potential for benefitting from immunotherapy. Interestingly, immune cell analysis showed that regulatory T cells (Tregs) are highly enriched in high metabolic HCC tumors, suggesting that high metabolic activity of cancer cells may trigger activation or infiltration of Tregs, leading to cancer cells' evasion of anti-cancer immune cells. In summary, we identified clinically and metabolically distinct subtypes of HCC, potential biomarkers associated with these subtypes, and a potential mechanism of metabolism-mediated immune evasion by HCC cells.
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Affiliation(s)
- Joann Jung
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Sowon Park
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yeonwoo Jang
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Sung-Hwan Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Yonsei 03722, Republic of Korea
- Division of Hepatobiliary and Pancreas, Department of Surgery, CHA Bundang Medical Center, CHA University, Seongnam 46371, Republic of Korea
| | - Yun Seong Jeong
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Sun Young Yim
- Division of Hepatobiliary and Pancreas, Department of Surgery, CHA Bundang Medical Center, CHA University, Seongnam 46371, Republic of Korea
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Ju-Seog Lee
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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10
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Mahmoud K, Swidan S, El-Nabarawi M, Teaima M. Lipid based nanoparticles as a novel treatment modality for hepatocellular carcinoma: a comprehensive review on targeting and recent advances. J Nanobiotechnology 2022; 20:109. [PMID: 35248080 PMCID: PMC8898455 DOI: 10.1186/s12951-022-01309-9] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 02/12/2022] [Indexed: 12/12/2022] Open
Abstract
Liver cancer is considered one of the deadliest diseases with one of the highest disease burdens worldwide. Among the different types of liver cancer, hepatocellular carcinoma is considered to be the most common type. Multiple conventional approaches are being used in treating hepatocellular carcinoma. Focusing on drug treatment, regular agents in conventional forms fail to achieve the intended clinical outcomes. In order to improve the treatment outcomes, utilizing nanoparticles-specifically lipid based nanoparticles-are considered to be one of the most promising approaches being set in motion. Multiple forms of lipid based nanoparticles exist including liposomes, solid lipid nanoparticles, nanostructured lipid carriers, microemulsion, nanoemulsion, phytosomes, lipid coated nanoparticles, and nanoassemblies. Multiple approaches are used to enhance the tumor uptake as well tumor specificity such as intratumoral injection, passive targeting, active targeting, and stimuli responsive nanoparticles. In this review, the effect of utilizing lipidic nanoparticles is being discussed as well as the different tumor uptake enhancement techniques used.
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Affiliation(s)
- Khaled Mahmoud
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, 11837, Egypt
- The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, 11837, Egypt
| | - Shady Swidan
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, 11837, Egypt.
- The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, 11837, Egypt.
| | - Mohamed El-Nabarawi
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
| | - Mahmoud Teaima
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt
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11
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Beumer BR, Buettner S, Galjart B, van Vugt JLA, de Man RA, IJzermans JNM, Koerkamp BG. Systematic review and meta-analysis of validated prognostic models for resected hepatocellular carcinoma patients. Eur J Surg Oncol 2021; 48:492-499. [PMID: 34602315 DOI: 10.1016/j.ejso.2021.09.012] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 09/13/2021] [Accepted: 09/15/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Many prognostic models for Hepatocellular Carcinoma (HCC) have been developed to inform patients and doctors about individual prognosis. Previous reviews of these models were qualitative and did not assess performance at external validation. We assessed the performance of prognostic models for HCC and set a benchmark for biomarker studies. METHODS All externally validated models predicting survival for patients with resected HCC were systematically reviewed. After selection, we extracted descriptive statistics and aggregated c-indices using meta-analysis. RESULTS Thirty-eight validated prognostic models were included. Models used on average 7 (IQR:4-9) prognostic factors. Tumor size, tumor number, and vascular invasion were almost always included. Alpha-fetoprotein (AFP) was commonly incorporated since 2007. Recently, the more subjective items ascites and encephalopathy have been dropped. Eight established models performed poor to moderate at external validation, with a pooled C-index below 0.7; including the Barcelona Clinic Liver Cancer (BCLC) system, the American Joint Committee on Cancer (AJCC) 7th edition, the Cancer of the Liver Italian (CLIP) Program, and the Japan Integrated Staging (JIS) score. Out of 24 prognostic models predicting OS, only 6 (25%) had good performance at external validation with pooled C-indices above 0.7; the Li-post (0.77), Li-OS (0.74), Yang-pre (0.74), Yang-post (0.76), Shanghai-score (0.70), and Wang-nomogram (0.71). Models improved over time, but overall performance and study quality remained low. CONCLUSIONS Six validated prognostic models demonstrated good performance for predicting survival after resection of HCC. These models can guide patients and doctors and are a benchmark for future models incorporating novel biomarkers.
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Affiliation(s)
- Berend R Beumer
- Erasmus MC Transplant Institute, Department of Surgery Division of HPB & Transplant Surgery, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands
| | - Stefan Buettner
- Erasmus MC Transplant Institute, Department of Surgery Division of HPB & Transplant Surgery, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands
| | - Boris Galjart
- Erasmus MC Transplant Institute, Department of Surgery Division of HPB & Transplant Surgery, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands
| | - Jeroen L A van Vugt
- Erasmus MC Transplant Institute, Department of Surgery Division of HPB & Transplant Surgery, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands
| | - Robert A de Man
- Erasmus MC Transplant Institute, Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands
| | - Jan N M IJzermans
- Erasmus MC Transplant Institute, Department of Surgery Division of HPB & Transplant Surgery, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands
| | - Bas Groot Koerkamp
- Erasmus MC Transplant Institute, Department of Surgery Division of HPB & Transplant Surgery, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
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12
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Atwa SM, Odenthal M, El Tayebi HM. Genetic Heterogeneity, Therapeutic Hurdle Confronting Sorafenib and Immune Checkpoint Inhibitors in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:4343. [PMID: 34503153 PMCID: PMC8430643 DOI: 10.3390/cancers13174343] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/03/2021] [Accepted: 08/05/2021] [Indexed: 12/24/2022] Open
Abstract
Despite the latest advances in hepatocellular carcinoma (HCC) screening and treatment modalities, HCC is still representing a global burden. Most HCC patients present at later stages to an extent that conventional curative options are ineffective. Hence, systemic therapy represented by the tyrosine kinase inhibitor, sorafenib, in the first-line setting is the main treatment modality for advanced-stage HCC. However, in the two groundbreaking phase III clinical trials, the SHARP and Asia-Pacific trials, sorafenib has demonstrated a modest prolongation of overall survival in almost 30% of HCC patients. As HCC develops in an immune-rich milieu, particular attention has been placed on immune checkpoint inhibitors (ICIs) as a novel therapeutic modality for HCC. Yet, HCC therapy is hampered by the resistance to chemotherapeutic drugs and the subsequent tumor recurrence. HCC is characterized by substantial genomic heterogeneity that has an impact on cellular response to the applied therapy. And hence, this review aims at giving an insight into the therapeutic impact and the different mechanisms of resistance to sorafenib and ICIs as well as, discussing the genomic heterogeneity associated with such mechanisms.
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Affiliation(s)
- Sara M. Atwa
- Pharmaceutical Biology Department, German University in Cairo, Cairo 11865, Egypt;
- Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Margarete Odenthal
- Institute for Pathology, University Hospital Cologne, 50924 Cologne, Germany;
| | - Hend M. El Tayebi
- Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
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13
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Beumer BR, de Wilde RF, Metselaar HJ, de Man RA, Polak WG, Ijzermans JNM. The Treatment Effect of Liver Transplantation versus Liver Resection for HCC: A Review and Future Perspectives. Cancers (Basel) 2021; 13:cancers13153730. [PMID: 34359629 PMCID: PMC8345205 DOI: 10.3390/cancers13153730] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/19/2021] [Accepted: 07/22/2021] [Indexed: 12/17/2022] Open
Abstract
For patients presenting with hepatocellular carcinoma within the Milan criteria, either liver resection or liver transplantation can be performed. However, to what extent either of these treatment options is superior in terms of long-term survival is unknown. Obviously, the comparison of these treatments is complicated by several selection processes. In this article, we comprehensively review the current literature with a focus on factors accounting for selection bias. Thus far, studies that did not perform an intention-to-treat analysis conclude that liver transplantation is superior to liver resection for early-stage hepatocellular carcinoma. In contrast, studies performing an intention-to-treat analysis state that survival is comparable between both modalities. Furthermore, all studies demonstrate that disease-free survival is longer after liver transplantation compared to liver resection. With respect to the latter, implications of recurrences for survival are rarely discussed. Heterogeneous treatment effects and logical inconsistencies indicate that studies with a higher level of evidence are needed to determine if liver transplantation offers a survival benefit over liver resection. However, randomised controlled trials, as the golden standard, are believed to be infeasible. Therefore, we suggest an alternative research design from the causal inference literature. The rationale for a regression discontinuity design that exploits the natural experiment created by the widely adopted Milan criteria will be discussed. In this type of study, the analysis is focused on liver transplantation patients just within the Milan criteria and liver resection patients just outside, hereby ensuring equal distribution of confounders.
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Affiliation(s)
- Berend R. Beumer
- Department of Surgery Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, Erasmus MC, University Medical Centre Rotterdam, 3015AA Rotterdam, The Netherlands; (B.R.B.); (R.F.d.W.); (W.G.P.)
| | - Roeland F. de Wilde
- Department of Surgery Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, Erasmus MC, University Medical Centre Rotterdam, 3015AA Rotterdam, The Netherlands; (B.R.B.); (R.F.d.W.); (W.G.P.)
| | - Herold J. Metselaar
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, Erasmus MC, University Medical Centre Rotterdam, 3015AA Rotterdam, The Netherlands; (H.J.M.); (R.A.d.M.)
| | - Robert A. de Man
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, Erasmus MC, University Medical Centre Rotterdam, 3015AA Rotterdam, The Netherlands; (H.J.M.); (R.A.d.M.)
| | - Wojciech G. Polak
- Department of Surgery Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, Erasmus MC, University Medical Centre Rotterdam, 3015AA Rotterdam, The Netherlands; (B.R.B.); (R.F.d.W.); (W.G.P.)
| | - Jan N. M. Ijzermans
- Department of Surgery Division of HPB & Transplant Surgery, Erasmus MC Transplant Institute, Erasmus MC, University Medical Centre Rotterdam, 3015AA Rotterdam, The Netherlands; (B.R.B.); (R.F.d.W.); (W.G.P.)
- Correspondence: ; Tel.: +31-010-7032396
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14
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Wang X, Lei Y, Huan H, Chen S, Ma K, Feng K, Lau WY, Xia F. Bisegmentectomy 7-8 for Small-for-Size Remanant Liver for Cirrhotic Patients Under Right Hemi-hepatectomy With Hepatocellular Carcinoma: A Case-Matched Comparative Study. Front Surg 2021; 8:675666. [PMID: 34336916 PMCID: PMC8319602 DOI: 10.3389/fsurg.2021.675666] [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: 03/03/2021] [Accepted: 04/15/2021] [Indexed: 12/24/2022] Open
Abstract
Aim: To compare the short- and long-term treatment outcomes of bisegmentectomy 7-8 vs. right hepatectomy for patients with hepatocellular carcinoma and cirrhosis. Methods: Thirty six cirrhotic HCC patients with infiltration of right hepatic vein in segments 7-8 underwent bisegmentectomy 7-8 for small-for-size remanant liver under right hemi-hepatectomy. Its outcome was compared with a case-matched control group of cirrhotic HCC patients who underwent right hemi-hepatectomy during the study period. Results: The study group consisted of 36 patients and the control group 36 patients selected from 1,526 patients matched with age, tumor size, tumor location, and Pugh-Child staging. There were no significant differences between the two groups in operative parameters and in perioperative main complications which included hemorrhage, bile leakage, ascites, pleural effusion, and liver failure. The overall morbidity rate and morbidity rate classified according to Clavien's classification were similar. There was no in-hospital mortality or 90 day post-operative mortality. The mean follow-up was 30 and 32 months for the study group and control group, respectively. The disease free survival rate (DFS) for the study group was just significantly better than the control group. The median DFS was 24 months for the study group and 8 months for the control group (P = 0.049). Meanwhile, the median cumulative overall survival was 35 months for the study group and 27 months for the control group (P = 0.494). Conclusion: Bisegmentectomy 7-8 was safe and feasible for selected cirrhosis patients, and did not increase the perioperative risk and inferior long-term overall survival outcomes. It extended the indications for liver resection in patients with borderline volumes of future liver remnant for HCC cirrhotic liver.
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Affiliation(s)
- Xishu Wang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Army Military Medical University, Chongqing, China
| | - Yongrong Lei
- Institute of Hepatobiliary Surgery, Southwest Hospital, Army Military Medical University, Chongqing, China
| | - Hongbo Huan
- Institute of Hepatobiliary Surgery, Southwest Hospital, Army Military Medical University, Chongqing, China
| | - Shu Chen
- Institute of Hepatobiliary Surgery, Southwest Hospital, Army Military Medical University, Chongqing, China
| | - Kuansheng Ma
- Institute of Hepatobiliary Surgery, Southwest Hospital, Army Military Medical University, Chongqing, China
| | - Kai Feng
- Institute of Hepatobiliary Surgery, Southwest Hospital, Army Military Medical University, Chongqing, China
| | - Wan Yee Lau
- Institute of Hepatobiliary Surgery, Southwest Hospital, Army Military Medical University, Chongqing, China.,Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, China
| | - Feng Xia
- Institute of Hepatobiliary Surgery, Southwest Hospital, Army Military Medical University, Chongqing, China
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15
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Wang TC, An TZ, Li JX, Pang PF. Systemic Inflammation Response Index is a Prognostic Risk Factor in Patients with Hepatocellular Carcinoma Undergoing TACE. Risk Manag Healthc Policy 2021; 14:2589-2600. [PMID: 34188570 PMCID: PMC8232961 DOI: 10.2147/rmhp.s316740] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 06/02/2021] [Indexed: 12/12/2022] Open
Abstract
Background Mounting evidence has shown that systemic inflammation response index (SIRI), a novel prognostic biomarker based on peripheral lymphocyte, neutrophil and monocyte counts, is associated with poor prognosis for several tumors. However, the prognostic value of SIRI in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) is elusive. Herein, we aimed to evaluate the correlation between SIRI and clinical outcomes in these patients. Methods A total of 194 consecutive patients who underwent TACE were included in this study. Patients were stratified into high and low SIRI groups based on the cut-off value using receiver operating characteristic (ROC) analysis. Independent risk factors for tumor response were analyzed using forward stepwise logistic regression. A one-to-one propensity score matching (PSM) was conducted to compare progression-free survival (PFS) and overall survival (OS) between low and high SIRI patients. The discriminatory power of the combination of number of tumors and SIRI in predicting initial TACE response was evaluated by ROC analysis. Results Patients were divided into high SIRI (> 0.88) and low SIRI (≤ 0.88) groups. High SIRI (p = 0.003) and more than three tumors (p = 0.002) were significantly related to poorer tumor response. Moreover, the low SIRI group had longer PFS and OS than the high SIRI group (both P < 0.05) before and after PSM. Combination of SIRI and number of tumors can improve the predictive ability to predict initial TACE response with an area under the curve (AUC) of 0.678. Conclusion Pretreatment peripheral blood SIRI was found to be an independent predictor of tumor response and clinical outcomes in patients with HCC undergoing TACE. Patients with high SIRI may have a poor prognosis.
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Affiliation(s)
- Tian-Cheng Wang
- Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, People's Republic of China.,Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China
| | - Tian-Zhi An
- Department of Interventional Radiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People's Republic of China
| | - Jun-Xiang Li
- Department of Interventional Radiology, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, Guizhou, People's Republic of China
| | - Peng-Fei Pang
- Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, People's Republic of China
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16
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Wei Y, Lin Y, Chen W, Liu S, Jin L, Huang D. Computational and In Vitro Analysis of Plumbagin's Molecular Mechanism for the Treatment of Hepatocellular Carcinoma. Front Pharmacol 2021; 12:594833. [PMID: 33912033 PMCID: PMC8072012 DOI: 10.3389/fphar.2021.594833] [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: 08/14/2020] [Accepted: 02/18/2021] [Indexed: 11/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor and the second leading cause of cancer-related death in the world. Plumbagin (PL) is a small molecule naphthoquinone compound isolated from Plumbago zeylanica L. that has important anticancer properties, but its mechanism requires further investigation. In this study, we used a comprehensive network pharmacology approach to study the mechanism of action of PL for the treatment of HCC. The method includes the construction of multiple networks; moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to identify biological processes and signaling pathways. Subsequently, in vitro experiments were performed to verify the predicted molecular mechanisms obtained from the network pharmacology-based analysis. Network pharmacological analysis showed that PL may exert anti-HCC effects by enhancing reactive oxygen species (ROS) production to generate oxidative stress and by regulating the PI3K/Akt and MAPK signaling pathways. In vitro experiments confirmed that PL mainly mediates the production of ROS, regulates the PI3K/Akt and MAPK signaling pathways to promote apoptosis and autophagy, and shows significant therapeutic effects on HCC. In conclusion, our work proposes a comprehensive systems pharmacology approach to explore the potential mechanism of PL for the treatment of HCC.
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Affiliation(s)
- Yanfei Wei
- Department of Physiology, Guangxi University of Chinese Medicine, Nanning, China
| | - Yuning Lin
- Department of Physiology, Guangxi University of Chinese Medicine, Nanning, China
| | - Wanjun Chen
- Department of Physiology, Guangxi University of Chinese Medicine, Nanning, China
| | - Shasha Liu
- Department of Physiology, Guangxi University of Chinese Medicine, Nanning, China
| | - Lijie Jin
- Department of Physiology, Guangxi University of Chinese Medicine, Nanning, China
| | - Delun Huang
- Department of Physiology, Guangxi University of Chinese Medicine, Nanning, China
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17
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Xiang Z, Wang R, Lu Y, Li Y, Wang H, Xiong Q, Dai X, Guo H, Deng Y, Le Y, Zhang M, Zhao Y. Study Protocol: Design and Implementation of the Pediatric Liver Transplantation Biobank. Biopreserv Biobank 2021; 19:111-118. [PMID: 33847526 DOI: 10.1089/bio.2020.0128] [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] [Indexed: 11/12/2022] Open
Abstract
Background: Early treatment of neonatal biliary atresia (BA) and other end-stage liver diseases can delay or prevent the necessity of liver transplantation (LT). The establishment of a standardized clinical pediatric liver transplantation (PLT) biobank is the prerequisite for scientific research, which helps to provide a qualified sample resource platform for research. Methods: Following standardized procedures to establish biobanks, the operational processes and quality control system were formulated. Liver tissue, blood, and stool samples undergoing LT were regularly collected, managed, and stored. Systematic management was conducted in collected specimens and corresponding clinical information. Results: Since implementation in August 2018, we have enrolled 49 unique subjects (0-18 years of age); the biobank contains nearly 3000 biospecimen aliquots. The most common LT diagnosis is BA (61.23%). Conclusion: The establishment of this biobank is a valuable resource that incorporates detailed clinical and biological information. It will help accelerate the pace of PLT discovery research. ClinicalTrials.gov ID: NCT04477967.
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Affiliation(s)
- Zheng Xiang
- Biobank Center of Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, China
- Department of Pediatric Research Institute, Chongqing, China
| | - Ruijue Wang
- Department of Hepatobiliary Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yue Lu
- Biobank Center of Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, China
- Department of Pediatric Research Institute, Chongqing, China
| | - Yingcun Li
- Department of Hepatobiliary Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Haoming Wang
- Department of Hepatobiliary Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Qiang Xiong
- Department of Hepatobiliary Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoke Dai
- Department of Hepatobiliary Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Hongling Guo
- Department of Hepatobiliary Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yuhua Deng
- Department of Hepatobiliary Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Ying Le
- Department of Hepatobiliary Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Mingman Zhang
- Department of Hepatobiliary Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yao Zhao
- Biobank Center of Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, China
- Department of Pediatric Research Institute, Chongqing, China
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18
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Liu Z, Sun J, Wang X, Cao Z. MicroRNA-129-5p promotes proliferation and metastasis of hepatocellular carcinoma by regulating the BMP2 gene. Exp Ther Med 2021; 21:257. [PMID: 33603864 DOI: 10.3892/etm.2021.9688] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 11/26/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumor that poses a serious threat to human health. Due to its occult onset and rapid development, HCC is a challenge to diagnose early and effectively treat, and thus patients with HCC often have an unfavorable prognosis. MicroRNA (miR)-129 and its target gene play an important role in the regulation of various diseases. Therefore, the aim of the present study was to investigate the role and mechanism of action for miR-129-5p in the development of HCC. Quantitative results of clinical samples analyzed using reverse transcription-quantitative PCR suggested that miR-129-5p had a significantly lower expression level in tumoral tissues compared with corresponding peritumoral tissues. Overexpression of miR-129-5p in HCC cells was performed using a transfection technique, followed by MTT, Transwell, invasion and wound healing assays to detect the effect of miR-129-5p on the cell cytotoxicity and metastasis of liver cancer in vitro. The downstream target gene of miR-129-5p, bone morphogenetic protein 2 (BMP2), was determined using a luciferase reporter assay. Overexpression of miR-129-5p played a vital role in decreasing cytotoxicity and promoting metastasis of HCC, which may be attributed to its inhibitory effect on the expression of its target gene, BMP2. In clinical samples, miR-129-5p expression levels were found to be negatively correlated with BMP2 and closely associated with HCC metastasis and infiltration. Collectively, the results suggested that miR-129-5p may contribute to proliferation and metastasis of HCC through its target gene, BMP2, and thus may be a potential novel therapeutic target for the treatment of HCC.
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Affiliation(s)
- Zengyao Liu
- Department of Intervention, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Jiefei Sun
- Interventional Catheter Therapy Section Office, Zhaodong Renmin Hospital, Zhaodong, Heilongjiang 151100, P.R. China
| | - Xiaochun Wang
- Department of Nursing, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Zhenyuan Cao
- Department of Intervention, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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19
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Zhang E, Song B, Shi Y, Zhu H, Han X, Du H, Yang C, Cao Z. Fouling-resistant zwitterionic polymers for complete prevention of postoperative adhesion. Proc Natl Acad Sci U S A 2020; 117:32046-32055. [PMID: 33257542 PMCID: PMC7749340 DOI: 10.1073/pnas.2012491117] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Postoperative adhesions are most common issues for almost any types of abdominal and pelvic surgery, leading to adverse consequences. Pharmacological treatments and physical barrier devices are two main approaches to address postoperative adhesions but can only alleviate or reduce adhesions to some extent. There is an urgent need for a reliable approach to completely prevent postoperative adhesions and to significantly improve the clinical outcomes, which, however, is unmet with current technologies. Here we report that by applying a viscous, cream-like yet injectable zwitterionic polymer solution to the traumatized surface, postoperative adhesion was completely and reliably prevented in three clinically relevant but increasingly challenging models in rats. The success rate of full prevention is over 93% among 42 animals tested, which is a major leap in antiadhesion performance. Clinically used Interceed film can hardly prevent the adhesion in any of these models. Unlike current antiadhesion materials serving solely as physical barriers, the "nonfouling" zwitterionic polymer functioned as a protective layer for antiadhesion applications with the inherent benefit of resisting protein/cell adhesions. The nonfouling nature of the polymer prevented the absorption of fibronectins and fibroblasts, which contribute to the initial and late-stage development of the adhesion, respectively. This is the key working mechanism that differentiated our "complete prevention" approach from current underperforming antiadhesion materials. This work implies a safe, effective, and convenient way to fully prevent postoperative adhesions suffered by current surgical patients.
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Affiliation(s)
- Ershuai Zhang
- Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI 48202
| | - Boyi Song
- Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI 48202
| | - Yuanjie Shi
- Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI 48202
| | - Hui Zhu
- Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI 48202
| | - Xiangfei Han
- Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI 48202
| | - Hong Du
- Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI 48202
| | - Chengbiao Yang
- Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI 48202
| | - Zhiqiang Cao
- Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI 48202
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20
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Chiang MF, Tseng TK, Shih CW, Yang TH, Wu SY. Clinical and contrast-enhanced image features in the prediction model for the detection of small hepatocellular carcinomas. J Cancer 2020; 11:7166-7175. [PMID: 33193879 PMCID: PMC7646160 DOI: 10.7150/jca.47245] [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: 04/21/2020] [Accepted: 10/04/2020] [Indexed: 12/15/2022] Open
Abstract
Purpose: To identify novel radiological features and clinical characteristics to improve diagnostic criteria for early detection of small hepatocellular carcinoma (HCC). Patients and Methods: We retrospectively recruited asymptomatic patients with no history of HCC but a high risk of HCC in whom a new, solitary, well-defined, solid nodule between 10 and 20 mm was detected through a screening ultrasound. We retrospectively collected all clinical data, and patients were examined using dynamic contrast-enhanced computed tomography or magnetic resonance imaging; subsequently, fine-needle biopsy was performed. A multivariate analysis of the predictors of small HCCs was performed by fitting a multiple logistic regression model with the stepwise variable selection method. Results: In total, 392 and 347 patients with a small liver nodule received a final pathologic confirmation of HCC and non-HCC, respectively. The estimated odds ratios and 95% confidence intervals of tumor size > 12.45 mm, age > 56.61 years, liver cirrhosis, hepatitis C virus (HCV) carrier status, ln alpha-fetoprotein (AFP) > 1.954, arterial phase enhancement, and portal or venous phase washout appearance without arterial phase enhancement were 2.0735 (1.4746-2.9155), 1.8878 (1.2949-2.7521), 1.6927 (1.1294-2.5369), 1.6186 (1.0347-2.5321), 2.0297 (1.3342-3.0876), 3.7451 (2.3845-5.8821), and 2.0327 (1.3500-3.0608), respectively. The area under the receiver operating characteristic curves for the diagnosis of small HCCs was 0.79 for arterial phase enhancement and 0.75 for portal or venous phase washout appearance without arterial phase enhancement. Conclusion: Clinical and contrast-enhanced image features are valuable in the prediction model for the detection and early diagnosis of small HCCs in patients with a high risk of HCC. In addition to negative portal or venous washout and negative arterial enhancement in images, age > 56.61 years, tumor size > 12.45 mm, HCV carrier status, and ln(AFP) > 1.954, are useful indicators for the early detection of small HCCs.
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Affiliation(s)
- Ming-Feng Chiang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan
| | - Tse-Kai Tseng
- Department of Radiology, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Lotung, Taiwan
| | - Chia-Wen Shih
- Department of Pathology, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Lotung, Taiwan
| | - Tzeng-Huey Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan
| | - Szu-Yuan Wu
- Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan.,Division of Radiation Oncology, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan.,Big Data Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan.,Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan.,Cancer Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan.,Graduate Institute of Business Administration, Fu Jen Catholic University, Taipei, Taiwan
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21
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Cabral LKD, Tiribelli C, Sukowati CHC. Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity. Cancers (Basel) 2020; 12:1576. [PMID: 32549224 PMCID: PMC7352671 DOI: 10.3390/cancers12061576] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/08/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
Despite advances in biomedicine, the incidence and the mortality of hepatocellular carcinoma (HCC) remain high. The majority of HCC cases are diagnosed in later stages leading to the less than optimal outcome of the treatments. Molecular targeted therapy with sorafenib, a dual-target inhibitor targeting the serine-threonine kinase Raf and the tyrosine kinases VEGFR/PDGFR, is at present the main treatment for advanced-stage HCC, either in a single or combinatory regimen. However, it was observed in a large number of patients that its effectiveness is hampered by drug resistance. HCC is highly heterogeneous, within the tumor and among individuals, and this influences disease progression, classification, prognosis, and naturally cellular susceptibility to drug resistance. This review aims to provide an insight on how HCC heterogeneity influences the different primary mechanisms of chemoresistance against sorafenib including reduced drug intake, enhanced drug efflux, intracellular drug metabolism, alteration of molecular targets, activation/inactivation of signaling pathways, changes in the DNA repair machinery, and negative balance between apoptosis and survival of the cancer cells. The diverse variants, mutations, and polymorphisms in molecules and their association with drug response can be a helpful tool in treatment decision making. Accordingly, the existence of heterogeneous biomarkers in the tumor must be considered to strengthen multi-target strategies in patient-tailored treatment.
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Affiliation(s)
| | | | - Caecilia H. C. Sukowati
- Fondazione Italiana Fegato (Italian Liver Foundation), AREA Science Park, Basovizza, 34149 Trieste, Italy; (L.K.D.C.); (C.T.)
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22
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Sueangoen N, Tantiwetrueangdet A, Panvichian R. HCC-derived EGFR mutants are functioning, EGF-dependent, and erlotinib-resistant. Cell Biosci 2020; 10:41. [PMID: 32190291 PMCID: PMC7076995 DOI: 10.1186/s13578-020-00407-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 03/10/2020] [Indexed: 02/07/2023] Open
Abstract
Background Epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target. Overexpression of EGFR is frequently observed in hepatocellular carcinoma (HCC) and EGFR activation has been proven to be a potential determinant of primary resistance of HCC cells to sorafenib. In our previous study, we found 13 missense mutations in EGFR exon 19-23 from hepatocellular carcinoma (HCC) tissues, but the functions of these mutations have not been determined. This study aims to determine the kinase activity and sensitivity to erlotinib, a 1st-generation EGFR-tyrosine kinase inhibitor (TKI), of seven HCC-derived mutants (K757E, N808S, R831C, V897A, P937L, T940A, and M947T). Results Using transduction of pBabe-puro retroviral vector with or without EGFR, we constructed and determined the function of EGFRs in NIH-3T3 cells stably harboring each of the seven mutants, as well as the erlotinib-sensitive L858R-mutant, the erlotinib-resistant T790M-mutant, and EGFR wild type (WT). Our results indicate that the seven mutants are functioning, EGF-dependent, EGFRs. Cells harboring six of the seven mutants could generate some level of EGFR phosphorylation in the absence of EGF, indicating some constitutive kinase activity, but all of the seven mutants remain primarily EGF-dependent. Our results demonstrate that erlotinib induces differential degree of apoptosis and autophagy among cells harboring different EGFRs: complete apoptosis and autophagy (cleavage of both caspase-3 and PARP, and marked LC3-II increment) in L858R-mutant; partial apoptosis and autophagy (only cleavage of caspase-3, and moderate LC3-II increment) in WT and HCC-derived mutants; and no apoptosis and minimal autophagy (no cleavage of caspase-3 and PARP, and minimal LC3-II increment) in T790M-mutant. The seven HCC-derived mutants are erlotinib-resistant, as treatment with erlotinib up to high concentration could only induce partial inhibition of EGFR phosphorylation, partial or no inhibition of AKT and ERK phosphorylation, and partial apoptosis and autophagy. Conclusion The seven HCC-derived EGFR mutants in this study are functioning, EGF-dependent, and erlotinib-resistant. Erlotinib induces differential degree of apoptosis and autophagy among cells harboring different EGFRs. The degree of inhibition of EGFR phosphorylation by erlotinib is the determining factor for the degree of apoptosis and autophagy amongst cells harboring EGFR mutants. This study paves the way for further investigation into the sensitivity of these HCC-derived mutants to the 3rd-generation irreversible EGFR-TKI, osimertinib.
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Affiliation(s)
- Natthaporn Sueangoen
- Research Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | | | - Ravat Panvichian
- Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Rama 6 Road, Ratchathewi, Bangkok, 10400 Thailand
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23
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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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Shimose S, Kawaguchi T, Iwamoto H, Niizeki T, Shirono T, Tanaka M, Koga H, Torimura T. Indication of suitable transarterial chemoembolization and multikinase inhibitors for intermediate stage hepatocellular carcinoma. Oncol Lett 2020; 19:2667-2676. [PMID: 32218817 PMCID: PMC7068224 DOI: 10.3892/ol.2020.11399] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 11/06/2019] [Indexed: 02/06/2023] Open
Abstract
Prognosis of patients with intermediate stage hepatocellular carcinoma (HCC) treated with transcatheter arterial chemoembolization (TACE) is unsatisfactory. The present study analyzed the indications for suitable TACE in patients with intermediate stage HCC. Additionally, it was investigated whether further TACE or switching to multi-kinase inhibitors (MKIs) was more beneficial for patients with HCC recurrence following initial TACE. The present retrospective study included 238 patients with intermediate stage HCC who were initially treated with TACE (median age, 74 years). A decision-tree analysis was employed to investigate the therapeutic effect profiles and overall survival (OS) rates. In the decision-tree analysis for OS, complete response (CR) by initial TACE was selected as the most important variable. In the decision-tree analysis for CR, <3 liver segments with nodule, simple nodular type and within the up-to-seven criteria were selected as the first, second and third variables associated with a high CR rate (35–64%), respectively. In patients with HCC recurrence having ≥3 liver segments with nodule, out of the up-to-seven criteria, and Child-Pugh class A, the median survival time was significantly longer in those who were treated by switching to MKIs compared with further TACE (44.9 vs. 21.9 months; P=0.003). In intermediate stage HCC, the indications for suitable TACE criteria may be ‘<3 liver segments with nodule’, ‘simple nodular type’, and ‘within the up-to-seven criteria’. Additionally, in patients who were ineligible for TACE criteria, the switch to MKIs may improve the prognosis compared with further TACE in cases of HCC recurrence following first TACE.
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Affiliation(s)
- Shigeo Shimose
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.,Division of Liver Cancer Research, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Takashi Niizeki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Tomotake Shirono
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Masatoshi Tanaka
- Department of Gastroenterology and Hepatology, Yokokura Hospital, Miyama 839-0295, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.,Division of Liver Cancer Research, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.,Division of Liver Cancer Research, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume 830-0011, Japan
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25
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Blüthner E, Jara M, Shrestha R, Faber W, Pratschke J, Stockmann M, Malinowski M. Future liver remnant function as a predictor of postoperative morbidity following liver resection for hepatocellular carcinoma - A risk factor analysis. Surg Oncol 2020; 33:257-265. [PMID: 32561090 DOI: 10.1016/j.suronc.2020.02.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 01/05/2020] [Accepted: 02/07/2020] [Indexed: 01/27/2023]
Abstract
BACKGROUND Advances in anaesthesia and surgical technique have considerably reduced mortality in hepatocellular carcinoma (HCC) patients undergoing liver resection. However, extended resections in patients with liver cirrhosis still represent a challenge. The aim of this study was to investigate the predictive value of volume/function analysis for the prediction of morbidity in HCC patients following liver resection. METHODS Between 2001 and 2014, a total of 261 patients who underwent open hepatectomy for HCC were enrolled in this study. Future liver remnant volume (FLRV) and future liver remnant function (FLRF) based on LiMAx testing were obtained retrospectively. Uni- and multivariable analyses were performed to identify predictors for postoperative ascites, post-hepatectomy haemorrhage (PHH), and wound healing disorders (WHD) within the total cohort and in a subgroup of cirrhotic patients. RESULTS The most commonly observed complication was ascites (57.1%), followed by liver failure (25.3%), PHH (19.5%), and WHD (19.2%). FLRF was a major predictor of postoperative ascites (AUC 0.776; OR 0.987, p = 0.001), PHH (AUC 0.717; OR 0.984, p = 0.001), and WHD (AUC 0.660; OR 0.994, p = 0.032) in total cohort. Multivariable analysis of the cirrhosis subgroup showed FLRF to be an independent predictor of ascites (AUC 0.814; OR 0.989, p = 0.021), PHH (AUC 0.677; OR 0.991, p = 0.040), and WHD (AUC 0.615; OR 0.989, p = 0.033). CONCLUSIONS FLRF is a major predictor of postoperative ascites, haemorrhage, and wound healing disorders in cirrhotic and non-cirrhotic patients whereas FLRV failed to show significant correlations. Preoperative calculation of FLRF may augment surgical decision-making in high-risk patients and thereby improve perioperative outcome.
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Affiliation(s)
- Elisabeth Blüthner
- Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Department of Gastroenterology and Hepatology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Maximilian Jara
- Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Ritesh Shrestha
- Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Wladimir Faber
- Department of General, Visceral, Vascular Surgery, Martin-Luther-Krankenhaus, Caspar-Theyß-Straße 27-31, 14193 Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Martin Stockmann
- Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Department of General, Visceral and Vascular Surgery, Evangelisches Krankenhaus Paul Gerhardt Stift, Paul-Gerhardt-Str. 42-45, 06886 Lutherstadt Wittenberg, Germany
| | - Maciej Malinowski
- Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Department of General, Visceral, Vascular and Pediatric Surgery, Universitätsklinikum des Saarlandes, Kirrberger Straße, 66421 Homburg, Germany.
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26
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Zhang Q, Wang L, Gan C, Yu Y, Li Y, Deng Y, Liu H, You J, Yin W. Cryptotanshinone Induces Apoptosis and Inhibits Migration and Invasion in Human Hepatocellular Carcinoma Cells In Vitro. Nat Prod Commun 2020. [DOI: 10.1177/1934578x19899570] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Cryptotanshinone (CPT), an active quinoid diterpene isolated from Salvia miltiorrhiza Bunge, was previously reported to have potential anticancer effects. However, the mechanisms of CPT on hepatocellular carcinoma (HCC) cells are not well understood. In this study, we investigated the anticancer effects of CPT on HCC cells. Thiazolyl blue tetrazolium bromide assay showed dose-dependent and time-dependent cytotoxicity of CPT on human HCC cells, especially in HCCLM3 and Huh-7 cells. Hoechst 33258 stain, flow cytometry assay, and Western blot assay all indicated that CPT could distinctly induce the apoptosis of human HCC cells and break intracellular homeostasis by triggering the imbalance of mitochondrial transmembrane potential ( Δψm) and reactive oxygen species. In addition, CPT could significantly inhibit HCCLM3 and Huh-7 cells’ migration and invasion via the signal transducers and activators of transcription 3/matrix metalloproteinases mediated signaling pathway. Our findings demonstrated that the antitumor effects of CPT on human HCC cells were by suppressing cell proliferation, inducing cell apoptosis and impairing cell migration and invasion.
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Affiliation(s)
- Qianyu Zhang
- West China School of Public Health and Heathy Food Evaluation Research Center and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Liqun Wang
- West China School of Public Health and Heathy Food Evaluation Research Center and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Cailing Gan
- Laboratory of Liver Surgery and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Yu
- Laboratory of Liver Surgery and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yali Li
- West China School of Public Health and Heathy Food Evaluation Research Center and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Yuanle Deng
- West China School of Public Health and Heathy Food Evaluation Research Center and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Hongyao Liu
- Laboratory of Liver Surgery and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jia You
- West China School of Public Health and Heathy Food Evaluation Research Center and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Wenya Yin
- West China School of Public Health and Heathy Food Evaluation Research Center and West China Fourth Hospital, Sichuan University, Chengdu, China
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Wang Y, Gao B, Tan PY, Handoko YA, Sekar K, Deivasigamani A, Seshachalam VP, OuYang HY, Shi M, Xie C, Goh BKP, Ooi LL, Man Hui K. Genome-wide CRISPR knockout screens identify NCAPG as an essential oncogene for hepatocellular carcinoma tumor growth. FASEB J 2019; 33:8759-8770. [PMID: 31022357 PMCID: PMC6662966 DOI: 10.1096/fj.201802213rr] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 04/02/2019] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is a common and deadly cancer with limited treatment options. Through genome-wide growth depletion screens using clustered regularly interspaced short palindromic repeats and expression profiling of primary HCC tumors, we identified 13 clinically relevant target genes with therapeutic potential. Subsequent functional annotation analysis revealed significant enrichment of these 13 genes in the cell cycle, cell death, and survival pathways. Non-structural maintenance of chromosomes condensin I complex subunit G (NCAPG) was ranked the highest among the depletion screens and multiple HCC expression datasets. Transient inhibition of NCAPG using specific small interfering RNAs resulted in a significant reduction in cell growth, migration, and the down-regulation of mitochondrial gene expression in vitro. Small homologous RNA-mediated knockdown of NCAPG significantly impaired cell viability, caused aberrant mitotic division, fragmented the mitochondrial network, and increased cell death in vitro. HCC cells with a reduced expression of NCAPG formed significantly smaller xenograft tumors in vivo. Importantly, high NCAPG expression was significantly associated with poorer overall and disease-free survival in HCC patients. High NCAPG expression is a novel prognostic biomarker to predict HCC early recurrence after surgical resection. In conclusion, NCAPG is an essential gene for HCC tumor cell survival. It represents a promising novel target for treating HCC and a prognostic biomarker for clinical management of HCC.-Wang, Y., Gao, B., Tan, P. Y., Handoko, Y. A., Sekar, K., Deivasigamani, A., Seshachalam, V. P., OuYang, H.-Y., Shi, M., Xie, C., Goh, B. K. P., Ooi, L. L., Hui, K. M. Genome-wide CRISPR knockout screens identify NCAPG as an essential oncogene for hepatocellular carcinoma tumor growth.
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Affiliation(s)
- Yu Wang
- Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore
| | - Bin Gao
- Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore
| | - Peng Yang Tan
- Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore
| | | | - Karthik Sekar
- Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore
| | - Amudha Deivasigamani
- Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore
| | | | - Han-Yue OuYang
- Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Ming Shi
- Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Chan Xie
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Brian Kim Poh Goh
- Department of Hepato-Pancreato-Biliary and Transplant Surgery, Singapore General Hospital, Singapore
| | - London Lucien Ooi
- Department of Hepato-Pancreato-Biliary and Transplant Surgery, Singapore General Hospital, Singapore
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore
| | - Kam Man Hui
- Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore
- Duke-NUS Medical School, Singapore
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Chou YC, Lao IH, Hsieh PL, Su YY, Mak CW, Sun DP, Sheu MJ, Kuo HT, Chen TJ, Ho CH, Kuo YT. Gadoxetic acid-enhanced magnetic resonance imaging can predict the pathologic stage of solitary hepatocellular carcinoma. World J Gastroenterol 2019; 25:2636-2649. [PMID: 31210715 PMCID: PMC6558433 DOI: 10.3748/wjg.v25.i21.2636] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 04/30/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Although important for determining long-term outcome, pathologic stage of hepatocellular carcinoma (HCC) is difficult to predict before surgery. Current state-of-the-art magnetic resonance imaging (MRI) using gadoxetic acid provides many imaging features that could potentially be used to classify single HCC as pT1 or pT2.
AIM To determine which gadoxetic acid-enhanced MRI (EOB-MRI) findings predict pathologic stage T2 in patients with solitary HCC (cT1).
METHODS Pre-operative EOB-MRI findings were reviewed in a retrospective cohort of patients with solitary HCC. The following imaging features were examined: Hyperintensity in unenhanced T2-weighted images, hypointensity in unenhanced T1-weighted images, arterial enhancement, corona enhancement, washout appearance, capsular appearance, hypointensity in the tumor tissue during the hepatobiliary (HB) phase, peritumoral hypointensity in the HB phase, hypointense rim in the HB phase, intratumoral fat, hyperintensity on diffusion-weighted imaging, hypointensity on apparent diffusion coefficient map, mosaic appearance, nodule-in-nodule appearance, and the margin (smooth or irregular). Surgical pathology was used as the reference method for tumor staging. Univariate and multivariate analyses were performed to identify predictors of microvascular invasion or satellite nodules.
RESULTS There were 39 (34.2%; 39 of 114) and 75 (65.8%; 75 of 114) pathological stage T2 and T1 HCCs, respectively. Large tumor size (≥ 2.3 cm) and two MRI findings, i.e., corona enhancement [odds ratio = 2.67; 95% confidence interval: 1.101-6.480] and peritumoral hypointensity in HB phase images (odds ratio = 2.203; 95% confidence interval: 0.961-5.049) were associated with high risk of pT2 HCC. The positive likelihood ratio was 6.25 (95% confidence interval: 1.788-21.845), and sensitivity of EOB-MRI for detecting pT2 HCC was 86.2% when two or three of these MRI features were present. Small tumor size and hypointense rim in the HB phase were regarded as benign features. Small HCCs with hypointense rim but not associated with aggressive features were mostly pT1 lesions (specificity, 100%).
CONCLUSION Imaging features on EOB-MRI could potentially be used to predict the pathologic stage of solitary HCC (cT1) as pT1 or pT2.
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Affiliation(s)
- Yi-Chen Chou
- Department of Medical Imaging, Chi Mei Medical Center, Tainan 710, Taiwan
| | - I-Ha Lao
- Department of Medical Imaging, Chi Mei Medical Center, Tainan 710, Taiwan
- Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Pei-Ling Hsieh
- Department of Medical Imaging, Chi Mei Medical Center, Tainan 710, Taiwan
| | - Ying-Ying Su
- Department of Medical Imaging, Chi Mei Medical Center, Tainan 710, Taiwan
| | - Chee-Wai Mak
- Department of Medical Imaging, Chi Mei Medical Center, Tainan 710, Taiwan
| | - Ding-Ping Sun
- Department of Surgery, Chi Mei Medical Center, Tainan 710, Taiwan
- Department of Food Science and Technology, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan
| | - Ming-Jen Sheu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Tainan 710, Taiwan
- Department of Medicinal Chemistry, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan
| | - Hsing-Tao Kuo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Tainan 710, Taiwan
- Department of Senior Citizen Service Management, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan
| | - Tzu-Ju Chen
- Department of Pathology, Chi-Mei Medical Center, Tainan 710, Taiwan
- Department of Optometry, Chung Hwa University of Medical Technology, Tainan 717, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan
| | - Chung-Han Ho
- Department of Medical Research, Chi-Mei Medical Center, Tainan 710, Taiwan
- Department of Hospital and Health Care Administration, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan
| | - Yu-Ting Kuo
- Department of Medical Imaging, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Department of Radiology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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Robbins JR, Schmid RK, Hammad AY, Gamblin TC, Erickson BA. Stereotactic body radiation therapy for hepatocellular carcinoma: Practice patterns, dose selection and factors impacting survival. Cancer Med 2019; 8:928-938. [PMID: 30701703 PMCID: PMC6434217 DOI: 10.1002/cam4.1948] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 12/07/2018] [Accepted: 12/10/2018] [Indexed: 12/24/2022] Open
Abstract
Background Stereotactic body radiation therapy (SBRT) is an emerging option for unresectable hepatocellular carcinoma (HCC) without consensus regarding optimal dose schemas. This analysis identifies practice patterns and factors that influence dose selection and overall survival, with particular emphasis on dose and tumor size. Materials/Methods Query of the National Cancer Database (NCDB) identified patients with unresectable, nonmetastatic HCC who received SBRT from 2004 to 2013. Biological Effective Dose (BED) was calculated for each patient in order to uniformly analyze different fractionation regimens. Results A total of 456 patients met the inclusion criteria. The median BED was 100 Gy (22.5‐208.0), which corresponded to the most common dose fractionation (50 Gy in five fractions). Various factors influenced dose selection including tumor size (P < 0.001), tumor stage (P = 0.002), and facility case volume (<0.001). On multivariate analysis, low BED (<75 Gy, HR 2.537, P < 0.001; 75‐100 Gy, HR 1.986, P = 0.007), increasing tumor size (HR 1.067, P = 0.032), elevated AFP (HR 1.585, P = 0.019), stage 3 (HR 1.962, P < 0.001), low‐volume facilities (1‐5 cases HR 1.687, P = 0.006), and a longer time interval from diagnosis to SBRT (>2 to ≤4 months, HR 1.456, P = 0.048; >4 months, HR 2.192, P < 0.001) were associated with worse survival. Conclusion SBRT use is increasing for HCC, and multiple regimens are clinically employed. Although high BED was associated with improved outcomes, multiple factors contributed to the dose selection with favorable patients receiving higher doses. Continued efforts to enhance radiation planning and delivery may help improve utilization, safety, and efficacy.
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Affiliation(s)
- Jared R. Robbins
- Department of Radiation OncologyUniversity of Arizona College of MedicineTucsonArizona
- Department of Radiation OncologyMedical College of WisconsinMilwaukeeWisconsin
| | - Ryan K. Schmid
- Department of Radiation OncologyMedical College of WisconsinMilwaukeeWisconsin
| | - Abdulrahman Y. Hammad
- Division of Surgical OncologyDepartment of SurgeryMedical College of WisconsinMilwaukeeWisconsin
| | - Thomas Clark Gamblin
- Division of Surgical OncologyDepartment of SurgeryMedical College of WisconsinMilwaukeeWisconsin
| | - Beth A. Erickson
- Department of Radiation OncologyMedical College of WisconsinMilwaukeeWisconsin
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Liu S, Huang Y, Liu Y, Wu R, Yang Z, Sun Y, Xiao H, Cheng X, Wu Z. Aggregation-induced emission based PET probe for liver function imaging. NEW J CHEM 2019. [DOI: 10.1039/c9nj04537f] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
A novel aggregation-induced emission based PET probe for liver function imaging was developed.
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Affiliation(s)
- Song Liu
- Brain Institute of Brain Disorders
- Capital Medical University
- Beijing 100069
- China
| | - Yong Huang
- Brain Institute of Brain Disorders
- Capital Medical University
- Beijing 100069
- China
| | - Yajing Liu
- School of Pharmaceutical Science
- Capital Medical University
- Beijing 100069
- China
| | - Renbo Wu
- Brain Institute of Brain Disorders
- Capital Medical University
- Beijing 100069
- China
| | - Zequn Yang
- Brain Institute of Brain Disorders
- Capital Medical University
- Beijing 100069
- China
| | - Yuli Sun
- Brain Institute of Brain Disorders
- Capital Medical University
- Beijing 100069
- China
| | - Hao Xiao
- Brain Institute of Brain Disorders
- Capital Medical University
- Beijing 100069
- China
| | - Xuebo Cheng
- Brain Institute of Brain Disorders
- Capital Medical University
- Beijing 100069
- China
| | - Zehui Wu
- Brain Institute of Brain Disorders
- Capital Medical University
- Beijing 100069
- China
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31
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Sun JP, Ge QX, Ren Z, Sun XF, Xie SP. Down-regulation of HOXB5 inhibits TGF-β-induced migration and invasion in hepatocellular carcinoma cells via inactivation of the PI3K/Akt pathway. RSC Adv 2018; 8:41415-41421. [PMID: 35559288 PMCID: PMC9091567 DOI: 10.1039/c8ra06860g] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 11/22/2018] [Indexed: 11/30/2022] Open
Abstract
HOXB5, a member of the HOX gene family, is a developmental gene which encodes homeoproteins and is known to be a crucial player in development of enteric nervous systems. Recently, HOXB5 was reported to be associated with cancer progression. However, the specific effect of HOXB5 in hepatocellular carcinoma (HCC) remains unclear. In this study, we demonstrated the important role of HOXB5 in HCC. We showed that HOXB5 was up-regulated in HCC tissues and cell lines. Furthermore, down-regulation of HOXB5 inhibited TGF-β-induced HCC cell migration and invasion in vitro and suppressed tumor metastasis in vivo. We also found that the PI3K/Akt pathway partly accounted for the mechanisms underlying the inhibitory effect of HOXB5 down-regulation on TGF-β-induced HCC progression. Taken together, these findings demonstrated that down-regulation of HOXB5 inhibits TGF-β-induced migration and invasion in HCC cells via inactivation of the PI3K/Akt pathway. Thus, HOXB5 may be a novel therapeutic target for HCC treatment.
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Affiliation(s)
- Jin-Ping Sun
- Department of Gastroenterology, Huaihe Hospital of Henan University No. 115 Ximen Street, Longting District Kaifeng 475000 China +86-371-23906892 +86-371-23906892
| | - Quan-Xing Ge
- Department of Gastroenterology, Huaihe Hospital of Henan University No. 115 Ximen Street, Longting District Kaifeng 475000 China +86-371-23906892 +86-371-23906892
| | - Zheng Ren
- Department of Gastroenterology, Huaihe Hospital of Henan University No. 115 Ximen Street, Longting District Kaifeng 475000 China +86-371-23906892 +86-371-23906892
| | - Xin-Fang Sun
- Department of Gastroenterology, Huaihe Hospital of Henan University No. 115 Ximen Street, Longting District Kaifeng 475000 China +86-371-23906892 +86-371-23906892
| | - Shu-Ping Xie
- Department of Gastroenterology, Huaihe Hospital of Henan University No. 115 Ximen Street, Longting District Kaifeng 475000 China +86-371-23906892 +86-371-23906892
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32
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Liver Resection for Solitary Transplantable Hepatocellular Carcinoma: The Role of AFP-Score. World J Surg 2018; 43:221-229. [DOI: 10.1007/s00268-018-4769-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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33
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Amicone L, Marchetti A. Microenvironment and tumor cells: two targets for new molecular therapies of hepatocellular carcinoma. Transl Gastroenterol Hepatol 2018; 3:24. [PMID: 29971255 DOI: 10.21037/tgh.2018.04.05] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 04/11/2018] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC), is one of the most frequent human cancer and is characterized by a high mortality rate. The aggressiveness appears strictly related to the liver pathological background on which cancer develops. Inflammation and the consequent fibro/cirrhosis, derived from chronic injuries of several origins (viral, toxic and metabolic) and observable in almost all oncological patients, represents the most powerful risk factor for HCC and, at the same time, an important obstacle to the efficacy of systemic therapy. Multiple microenvironmental cues, indeed, play a pivotal role in the pathogenesis, evolution and recurrence of HCC as well as in the resistance to standard therapies observed in most of patients. The identification of altered pathways in cancer cells and of microenvironmental changes, strictly connected in pathogenic feedback loop, may permit to plan new therapeutic approaches targeting tumor cells and their permissive microenvironment, simultaneously.
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Affiliation(s)
- Laura Amicone
- Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy
| | - Alessandra Marchetti
- Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy
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34
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Shen JD, Cai XF, Wei J, Gu CY, Ju LL, Wang YF, Dai F, Fu SZ, Bian ZL, Qi LJ. Low expression of trafficking protein particle complex 4 predicts poor prognosis in hepatocellular carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:2691-2698. [PMID: 31938384 PMCID: PMC6958281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Accepted: 02/22/2018] [Indexed: 06/10/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Tumor recurrence and metastasis are major factors that contribute to the poor outcome of patients with HCC. However, it is difficult to predict the prognosis of hepatocellular carcinoma. Trafficking Protein Particle Complex 4 (Trappc4), is associated with tumorigenesis. The present study aimed to detect Trappc4 expression in HCC and its association with clinicopathological patient data. More importantly, this study reveals the relationship between Trappc4 and the prognosis of hepatocellular carcinoma. A total of 148 HCC tissues were assessed for expression of Trappc4 mRNA and protein with (reverse transcription polymerase chain reaction) RT-PCR (n=36), Western blotting (n=4) and immunohistochemistry (n=148), respectively. The data show that Trappc4 mRNA and protein are expressed at low levels in HCC tissues compared to adjacent tissues. Immunohistochemical analysis revealed that 148 cases of HCC showed different degrees of positive expression. Statistical analysis showed that expression of Trappc4 was associated with histological differentiation, TNM stage, and vascular invasion (P < 0.05), but did not correlate with the patient's age, gender, tumor size (P > 0.05). Most importantly, HCC patients with low expression of Trappc4 had shorter survival time compared to patients with high expression. Trappc4 might be involved in the pathogenesis of HCC and could be an important prognostic marker in HCC patients.
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Affiliation(s)
- Jian-Dong Shen
- Department of Invasive Technology, Nantong Third People’s Hospital, Nantong UniversityNantong, Jiangsu Province, China
| | - Xin-Feng Cai
- Department of Liver and Gallbladder Surgery, Nantong Third People’s Hospital, Nantong UniversityNantong, Jiangsu Province, China
| | - Jue Wei
- Department of Gastroenterology, Tongren Hospital, Shanghai Jiaotong University School of MedicineShanghai, China
| | - Chun-Yan Gu
- Department of Pathology, Nantong Third People’s Hospital, Nantong UniversityNantong, Jiangsu Province, China
| | - Lin-Ling Ju
- Nantong Institute of Liver Diseases, Nantong Third People’s Hospital, Nantong UniversityNantong, Jiangsu Province, China
| | - Yi-Fang Wang
- Nantong Institute of Liver Diseases, Nantong Third People’s Hospital, Nantong UniversityNantong, Jiangsu Province, China
| | - Feng Dai
- Department of Invasive Technology, Nantong Third People’s Hospital, Nantong UniversityNantong, Jiangsu Province, China
| | - Shou-Zhong Fu
- Department of Invasive Technology, Nantong Third People’s Hospital, Nantong UniversityNantong, Jiangsu Province, China
| | - Zhao-Lian Bian
- Nantong Institute of Liver Diseases, Nantong Third People’s Hospital, Nantong UniversityNantong, Jiangsu Province, China
| | - Long-Ju Qi
- Department of Invasive Technology, Nantong Third People’s Hospital, Nantong UniversityNantong, Jiangsu Province, China
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35
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Vavra P, Karnik L, Skrobankova M, Jurcikova J, Ihnat P, Zonca P, Peteja M, El-Gendi A, Czudek S. Advancement in liver laparoscopic resection - development of a new surgical device. ACTA ACUST UNITED AC 2018. [PMID: 29513788 PMCID: PMC5856430 DOI: 10.1590/1414-431x20176062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Liver resection is the standard treatment for any liver lesion. Laparoscopic liver
resection is associated with lower intra-operative blood loss and fewer complications
than open resection. Access to the posterior part of the right liver lobe is very
uncomfortable and difficult for surgeons due the anatomic position, especially when
employing laparoscopic surgery. Based on these experiences, a new laparoscopic device
was developed that is capable of bending its long axis and allowing the application
of radiofrequency energy in areas that were not technically accessible. The device is
equipped with four telescopic needle electrodes that cause tissue coagulation after
the delivery of radiofrequency energy. Ex vivo testing was performed
in 2012 and 2014 at the University Hospital, Ostrava, on a porcine liver tissue. The
main goal of this testing was to verify if the newly proposed electrode layout was
suitable for sufficient tissue coagulation and creating a safety zone around lesions.
During the ex vivo testing, the material of needle electrodes was
improved to achieve the lowest possibility of adhesion. The power supply was adjusted
from 20 to 120 W and the ablation time, which varied from 10 to 110 s, was monitored.
Subsequently, optimal power delivery and time for coagulation was determined. This
experimental study demonstrated the feasibility and safety of the newly developed
device. Based on the ex vivo testing, LARA-K1 can create a safety
zone of coagulation. For further assessment of the new device, an in
vivo study should be performed.
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Affiliation(s)
- P Vavra
- Department of Surgical Studies, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.,Department of Surgery, University Hospital Ostrava, Ostrava, Czech Republic.,Department of Cybernetics and Biomedical Engineering, Faculty of Electrical Engineering and Computer Science, VSB-Technical University of Ostrava, Ostrava, Czech Republic
| | - L Karnik
- Department of Robotic, Faculty of Mechanical Engineering, VSB-Technical University of Ostrava, Ostrava, Czech Republic
| | - M Skrobankova
- Department of Surgical Studies, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.,Department of Internal Medicine, University Hospital of Ostrava, Ostrava, Czech Republic
| | - J Jurcikova
- Department of Vice-President for Science and Research, University Hospital Ostrava, Ostrava, Czech Republic
| | - P Ihnat
- Department of Surgical Studies, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.,Department of Surgery, University Hospital Ostrava, Ostrava, Czech Republic
| | - P Zonca
- Department of Surgical Studies, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.,Department of Surgery, University Hospital Ostrava, Ostrava, Czech Republic
| | - M Peteja
- Department of Surgical Studies, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.,Department of Surgery, University Hospital Ostrava, Ostrava, Czech Republic
| | - A El-Gendi
- Department of Surgery, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - S Czudek
- Department of Surgical Studies, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.,Department of Surgery, University Hospital Ostrava, Ostrava, Czech Republic
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The dual-inhibitory effect of miR-338-5p on the multidrug resistance and cell growth of hepatocellular carcinoma. Signal Transduct Target Ther 2018. [PMID: 29527329 PMCID: PMC5837112 DOI: 10.1038/s41392-017-0003-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Chemotherapeutic treatments against hepatocellular carcinoma (HCC) are necessary for both inoperable patients to improve prospects for survival and surgery patients to improve the outcome after surgical resection. However, multidrug resistance (MDR) is a major obstacle to obtaining desirable results. Currently, increasing the chemotherapy sensitivity of tumor cells or discovering novel tumor inhibitors is an effective therapeutic strategy to solve this issue. In the present study, we uncovered the dual-inhibitory effect of miR-338-5p: on the one hand, it could downregulate ABCB1 expression and sensitize HCC cells to doxorubicin and vinblastine by directly targeting the 3′-untranslated region (3′-UTR) of ABCB1, while, on the other hand, it could suppress the proliferation of HCC cells by directly targeting the 3′-UTR of EGFR and reducing EGFR expression. Since EGFR regulates ABCB1 levels, the indirect action of miR-338-5p in ABCB1 modulation was revealed, in which miR-338-5p inhibits ABCB1 expression by targeting the EGFR/ERK1/2 signaling pathway. These data indicate that the miR-338-5p/EGFR/ABCB1 regulatory loop plays a critical role in HCC, and a negative correlation between miR-338-5p and EGFR or ABCB1 was also detected in HCC clinical samples. In conclusion, these findings reveal a critical role for miR-338-5p in the regulation of MDR and proliferation of HCC, suggesting the potential therapeutic implications of miR-338-5p in HCC treatment. A small RNA molecule inhibits the growth of liver cancer cells while also making the cells sensitive to the anti-cancer drugs. These twin effects of the natural microRNA miR-338-5p were discovered by researchers in China, led by Chunzhu Li and Jin Ren at the Center for Drug Safety Evaluation and Research in Shanghai. MicroRNAs control gene activity by interacting with the messenger RNA copies of genes that guide synthesis of the proteins the genes encode. The research identified a gene whose expression miR-338-5p inhibits to restrict the growth of hepatocellular carcinoma – the most common form of liver cancer. This is also one of the most drug-resistant forms of liver cancer. A different gene whose activity miR-338-5p controls to sensitize cells to chemotherapeutic drugs was also identified. Using miR-338-5p to treat liver cancer warrants further investigation.
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Bufalin suppresses hepatocellular carcinoma invasion and metastasis by targeting HIF-1α via the PI3K/AKT/mTOR pathway. Oncotarget 2018; 7:20193-208. [PMID: 26958938 PMCID: PMC4991447 DOI: 10.18632/oncotarget.7935] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Accepted: 01/06/2016] [Indexed: 01/21/2023] Open
Abstract
It has been reported that there are multiple mechanisms by which bufalin could exert its antimetastatic effect. HIF-1α has been reported to be involved in tumor migration and invasion by regulating EMT. However, it is not known whether bufalin could exert the antimetastatic effect by modulating HIF-1α expression in hepatocellular carcinoma. In the present study, we aimed to evaluate the antimetastatic potential of bufalin in vivo and in vitro. Our results demonstrated that the liver/lung metastases were significantly reduced in bufalin-treated mice, as tested in the orthotopic transplanted and tail vein injection tumor models. Furthermore, the epithelial-to-mesenchymal transition (EMT) was inhibited in bufalin-treated tumors, as reflected the upregulation of E-cadherin, and downregulation of N-cadherin, vimentin, Snail. Similar results were observed in SMMC7721 cells treated with bufalin. Moreover, the transforming growth factor-β1 (TGF-β1)-induced EMT was also abrogated by bufalin. Mechanistically, our study demonstrated that hypoxia-inducible factor-1α (HIF-1α) played an important role in the antimetastatic effect of bufalin in hepatocellular carcinoma. Importantly, HIF-1α expression may be regulated through the inhibition of the PI3K/AKT/mTOR pathway. Taken together, our results suggest that bufalin suppresses hepatic tumor invasion and metastasis and that this process may be related to the PI3K/AKT/mTOR/ HIF-1α axis.
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38
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Uchiyama H, Itoh S, Yoshizumi T, Ikegami T, Harimoto N, Soejima Y, Harada N, Morita K, Toshima T, Motomura T, Maehara Y. Living donor liver transplantation for hepatocellular carcinoma: results of prospective patient selection by Kyushu University Criteria in 7 years. HPB (Oxford) 2017; 19:1082-1090. [PMID: 28888776 DOI: 10.1016/j.hpb.2017.08.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 08/02/2017] [Accepted: 08/12/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Expanding patient selection beyond the Milan criteria in living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC) has long been a matter for debate. We have used the Kyushu University Criteria - maximum tumor diameter <5 cm or des-γ-carboxy prothrombin <300 mAU/ml - in LDLT for HCC since June 2007. The aim of the present study was to present the results of our prospective patient selection by Kyushu University Criteria and to confirm whether or not our criteria were justified. METHODS The entire study period was divided into the pre-Kyushu era (July 1999-May 2007) and the Kyushu era (June 2007-November 2014). Eighty-nine and 90 patients underwent LDLT for HCC in the pre-Kyushu era and the Kyushu era, respectively. RESULTS In the pre-Kyushu era, there were significant differences in recurrence-free and disease-specific survival between the beyond-Milan and the within-Milan patients. In the Kyushu era, however, the differences in recurrence-free and disease-specific survival between the beyond-Milan and the within-Milan patients disappeared. The 5-year overall patient survival in the Kyushu era was 89.4%. CONCLUSION Our selection criteria enabled a considerable number of beyond-Milan patients to undergo LDLT without jeopardizing the recurrence-free, and disease-specific, and overall patient survival.
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Affiliation(s)
- Hideaki Uchiyama
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Japan.
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Toru Ikegami
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Norifumi Harimoto
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Yuji Soejima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Noboru Harada
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Kazutoyo Morita
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Takeo Toshima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Takashi Motomura
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Japan
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39
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Wang J, Lian Y, Gu Y, Wang H, Gu L, Huang Y, Zhou L, Huang Y. Synergistic effect of farnesyl transferase inhibitor lonafarnib combined with chemotherapeutic agents against the growth of hepatocellular carcinoma cells. Oncotarget 2017; 8:105047-105060. [PMID: 29285232 PMCID: PMC5739619 DOI: 10.18632/oncotarget.22086] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 10/12/2017] [Indexed: 12/29/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common and deadly cancer worldwide and is often refractory to chemotherapy due to the development of multidrug resistance. Lonafarnib is an orally active and potent non-peptidomimetic inhibitor of farnesyl transferase. Here, using in vitro HCC cell models, we demonstrated that lonafarnib inhibited tumor proliferation and reduced the activity of mitogen-activated protein kinases pathways. In addition, lonafarnib caused G1 to S phase arrest through the downregulation of Cyclin D1, CDK6 and SKP2, while it induced cellular apoptosis by promoting the cleavage and activation of Caspase-3 and PARP. When combined with doxorubicin and sorafenib, lonafarnib was able to increase the sensitivity of HCC cells to chemotherapy. Furthermore, we also constructed ABCB1-overexpressing HCC cells and found that lonafarnib decreased chemoresistance by inhibiting ABCB1-mediated drug efflux activity. These results suggest that lonafarnib may be a promising synergistic agent for improving the treatment of drug-resistant HCC.
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Affiliation(s)
- Jialiang Wang
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yifan Lian
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yurong Gu
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hongbo Wang
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Lin Gu
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanlin Huang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Liang Zhou
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yuehua Huang
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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40
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Involvement of PI3K/Akt pathway in the inhibition of hepatocarcinoma cell invasion and metastasis induced by SASH1 through downregulating Shh-Gli1 signaling. Int J Biochem Cell Biol 2017; 89:95-100. [DOI: 10.1016/j.biocel.2017.06.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 05/18/2017] [Accepted: 06/05/2017] [Indexed: 12/12/2022]
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41
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Wang X, Sun D, Tai J, Wang L. Ganoderic acid A inhibits proliferation and invasion, and promotes apoptosis in human hepatocellular carcinoma cells. Mol Med Rep 2017; 16:3894-3900. [PMID: 28731159 PMCID: PMC5646967 DOI: 10.3892/mmr.2017.7048] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 02/14/2017] [Indexed: 12/23/2022] Open
Abstract
Ganoderic acid A (GA-A), a triterpenoid, has been demonstrated to suppress cell proliferation in various cancers, including breast cancer and osteosarcoma. However, its effect on human hepatocellular carcinoma (HCC) remains to be elucidated. The present study aimed to investigate the effect of GA-A on HCC cells in vitro. The HepG2 and SMMC7721 human HCC cell lines were treated with differing concentrations of GA-A for 24, 48 and 72 h. The cell growth rate, cell cycle and apoptosis, migration and invasion were determined using a Cell Counting Kit-8, flow cytometry and transwell assays, respectively. The expression of apoptosis-associated proteins was detected via western blot analysis. GA-A significantly inhibited the proliferation of human HCC HepG2 and SMMC7721 cells in a dose-dependent manner. Furthermore, GA-A induced cell cycle arrest at the G0/G1 phase and apoptosis, and suppressed the migration and invasion of HCC cells. Furthermore, GA-A decreased the expression of cyclin D1 and increased the expression of p21 and cleaved caspase-3. In conclusion, GA-A suppressed the proliferation of human HCC cells in vitro and may act as a promising natural therapeutic reagent in the treatment of HCC.
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Affiliation(s)
- Xu Wang
- Department of Colorectal and Anal Surgery, The First Hospital, Jilin University, Changchun, Jilin 130000, P.R. China
| | - Di Sun
- Department of Colorectal and Anal Surgery, The First Hospital, Jilin University, Changchun, Jilin 130000, P.R. China
| | - Jiandong Tai
- Department of Colorectal and Anal Surgery, The First Hospital, Jilin University, Changchun, Jilin 130000, P.R. China
| | - Lei Wang
- Department of Colorectal and Anal Surgery, The First Hospital, Jilin University, Changchun, Jilin 130000, P.R. China
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42
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Li J, Li S, Wang X, Wang H. Esculetin induces apoptosis of SMMC-7721 cells through IGF-1/PI3K/Akt-mediated mitochondrial pathways. Can J Physiol Pharmacol 2017; 95:787-794. [PMID: 28177662 DOI: 10.1139/cjpp-2016-0548] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Esculetin (6,7-dihydroxycoumarin) is a coumarin derivative extracted from natural plants and has been reported to have anticancer activity. However, the mechanism by which esculetin prevents human hepatic cancer cell growth is still largely unknown. In this study, we investigated the effect of esculetin on human hepatocellular carcinoma (HCC) SMMC-7721 cells and explored the cell signal mechanism. Our data indicated that esculetin induced apoptosis in SMMC-7721 cells, which were supported by DAPI staining and Annexin V/PI staining. Meanwhile, esculetin increased the activities of caspase-3 and caspase-9, promoted bax expression, decreased bcl-2 expression, and triggered collapse of mitochondrial membrane potential, and increased cytochrome c release from mitochondria. In addition, the inactivation of IGF-1, PI3K, and Akt was observed after esculetin administration. Furthermore, pretreatment with IGF-1 before esculetin administration abrogated the pro-apoptotic effects of esculetin, while PI3K inhibitor increased the pro-apoptotic effects of esculetin. These results indicated that esculetin induced the apoptosis of SMMC-7721 cells through IGF-1/PI3K/Akt-regulated mitochondrial dysfunction.
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Affiliation(s)
- Juan Li
- Department of Infectious Disease, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China
| | - Shuang Li
- Department of Anesthesiology, Taihe District Hospital of Jinzhou City, Jinzhou 121001, China
| | - Xiuli Wang
- Department of Infectious Disease, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China
| | - Hongxin Wang
- Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University, Jinzhou 121001, China
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43
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Gong J, Shen S, Yang Y, Qin S, Huang L, Zhang H, Chen L, Chen Y, Li S, She S, Yang M, Ren H, Hu H. Inhibition of FASN suppresses migration, invasion and growth in hepatoma carcinoma cells by deregulating the HIF-1α/IGFBP1 pathway. Int J Oncol 2017; 50:883-892. [DOI: 10.3892/ijo.2017.3867] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2016] [Accepted: 01/23/2017] [Indexed: 11/06/2022] Open
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44
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Zou CD, Zhao WM, Wang XN, Li Q, Huang H, Cheng WP, Jin JF, Zhang H, Wu MJ, Tai S, Zou CX, Gao X. MicroRNA-107: a novel promoter of tumor progression that targets the CPEB3/EGFR axis in human hepatocellular carcinoma. Oncotarget 2016; 7:266-78. [PMID: 26497556 PMCID: PMC4807997 DOI: 10.18632/oncotarget.5689] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 10/06/2015] [Indexed: 01/05/2023] Open
Abstract
MicroRNAs (miRNAs) are dysregulated in many types of malignancies, including human hepatocellular carcinoma (HCC). MiR-107 has been implicated in several types of cancer regulation; however, relatively little is known about miR-107 in human HCC. In the present study, we showed that the overexpression of miR-107 accelerates the tumor progression of HCC in vitro and in vivo through its new target gene, CPEB3. Furthermore, our results demonstrated that CPEB3 is a newly discovered tumor suppressor that acts via the EGFR pathway. Therefore, our study demonstrates that the newly discovered miR-107/CPEB3/EGFR axis plays an important role in HCC progression and might represent a new potential therapeutic target for HCC treatment.
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Affiliation(s)
- Chen-Dan Zou
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Wei-Ming Zhao
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Xiao-Na Wang
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Qiang Li
- Department of General Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hui Huang
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Wan-Peng Cheng
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Jian-Feng Jin
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - He Zhang
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Ming-Juan Wu
- Academy of Traditional Chinese Medicines, Harbin, China
| | - Sheng Tai
- Department of General Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chao-Xia Zou
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
| | - Xu Gao
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.,Heilongjiang Academy of Medical Science, Harbin, China
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45
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Vavra P, Karnik L, Skrobankova M, Jurcikova J, Prochazka V, Ihnat P, Zonca P, Peteja M, Czudek S. Adjustable Laparoscopic Surgical Device—LARA-K1. Surg Innov 2016; 23:644-645. [DOI: 10.1177/1553350616664073] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Petr Vavra
- University of Ostrava, Ostrava, Czech Republic
- Technical University of Ostrava, Ostrava, Czech Republic
- University Hospital Ostrava, Ostrava, Czech Republic
| | | | | | | | | | - Peter Ihnat
- University of Ostrava, Ostrava, Czech Republic
- University Hospital Ostrava, Ostrava, Czech Republic
| | - Pavel Zonca
- University of Ostrava, Ostrava, Czech Republic
- University Hospital Ostrava, Ostrava, Czech Republic
| | - Matus Peteja
- University of Ostrava, Ostrava, Czech Republic
- University Hospital Ostrava, Ostrava, Czech Republic
| | - Stanislav Czudek
- University of Ostrava, Ostrava, Czech Republic
- University Hospital Ostrava, Ostrava, Czech Republic
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46
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Carrilho FJ, Mattos AAD, Vianey AF, Vezozzo DCP, Marinho F, Souto FJ, Cotrim HP, Coelho HSM, Silva I, Garcia JHP, Kikuchi L, Lofego P, Andraus W, Strauss E, Silva G, Altikes I, Medeiros JE, Bittencourt PL, Parise ER. Brazilian society of hepatology recommendations for the diagnosis and treatment of hepatocellular carcinoma. ARQUIVOS DE GASTROENTEROLOGIA 2016; 52 Suppl 1:2-14. [PMID: 26959803 DOI: 10.1590/s0004-28032015000500001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma is a malignancy of global importance and is associated with a high rate of mortality. Recent advances in the diagnosis and treatment of this disease make it imperative to update the recommendations on the management of the disease. In order to draw evidence-based recommendations concering the diagnosis and management of hepatocellular carcinoma, the Brazilian Society of Hepatology has sponsored a single-topic meeting in João Pessoa (PB). All the invited pannelists were asked to make a systematic review of the literature and to present topics related to the risk factors for its development, methods of screening, radiological diagnosis, staging systems, curative and palliative treatments and hepatocellular carcinoma in noncirrhotic liver. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of those recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present paper is the final version of the reviewed manuscript containing the recommendations of the Brazilian Society of Hepatology.
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Affiliation(s)
| | | | | | | | - Fábio Marinho
- Hospital Português de Beneficiência, Recife, PE, Brazil
| | | | | | | | - Ivonete Silva
- Faculdade de Medicina, Universidade Federal de São Paulo, SP, Brazil
| | | | - Luciana Kikuchi
- Faculdade de Medicina, Universidade de São Paulo, SP, Brazil
| | - Patricia Lofego
- Faculdade de Medicina, Universidade Federal do Espírito Santo, ES, Brazil
| | | | - Edna Strauss
- Faculdade de Medicina, Universidade de São Paulo, SP, Brazil
| | | | | | | | | | - Edison R Parise
- Faculdade de Medicina, Universidade Federal de São Paulo, SP, Brazil
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Moriguchi M, Umemura A, Itoh Y. Current status and future prospects of chemotherapy for advanced hepatocellular carcinoma. Clin J Gastroenterol 2016; 9:184-90. [PMID: 27401471 DOI: 10.1007/s12328-016-0670-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 06/09/2016] [Indexed: 02/06/2023]
Abstract
Sorafenib is the only drug that demonstrates a survival benefit for advanced hepatocellular carcinoma (HCC). However, the therapeutic effect of sorafenib is limited, so development of a more effective treatment method and second-line treatments is needed. Since the advent of sorafenib, clinical studies have been conducted with a variety of drugs and treatment methods, mainly with molecular targeted therapy, but almost all trials have ended in failure. The reasons for the difficulty in the development of a novel drug or treatment method include the diversity of mechanisms in the carcinogenesis and development of HCC, as well as the presence of background liver diseases such as chronic hepatitis and cirrhosis. Trials with immune-checkpoint inhibitors, which have an entirely different anti-tumor mechanism from that of molecular targeted drugs or cytotoxic drugs, have recently begun. Based on the results to date, clinical trials are now being conducted with enriched target subjects. In the future, providing more individualized treatment approaches for patients with advanced HCC will be essential.
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Affiliation(s)
- Michihisa Moriguchi
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, 465 Kajii-cho, Kawaramachi-Hirokouji, Kamigyo-ku, Kyoto, 602-8566, Japan.
| | - Atsushi Umemura
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, 465 Kajii-cho, Kawaramachi-Hirokouji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, 465 Kajii-cho, Kawaramachi-Hirokouji, Kamigyo-ku, Kyoto, 602-8566, Japan
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48
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Kitai S, Kudo M, Nishida N, Izumi N, Sakamoto M, Matsuyama Y, Ichida T, Nakashima O, Matsui O, Ku Y, Kokudo N, Makuuchi M. Survival Benefit of Locoregional Treatment for Hepatocellular Carcinoma with Advanced Liver Cirrhosis. Liver Cancer 2016; 5:175-89. [PMID: 27493893 PMCID: PMC4960362 DOI: 10.1159/000367765] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) with decompensated liver cirrhosis (LC) is a life-threatening condition, which is amenable to liver transplantation (LT) as the standard first-line treatment. However, the application of LT can be limited due to a shortage of donor livers. This study aimed to clarify the effect of non-surgical therapy on the survival of patients with HCC and decompensated LC. METHODS Of the 58,886 patients with HCC registered in the nationwide survey of the Liver Cancer Study Group of Japan (January 2000-December 2005), we included 1,344 patients with primary HCC and Child-Pugh (C-P) grade C for analysis in this retrospective study. Among the patients analyzed, 108 underwent LT, 273 were treated by local ablation therapy (LAT), 370 were treated by transarterial chemoembolization (TACE), and 593 received best supportive care (BSC). The effect of LT, LAT, and TACE on overall survival (OS) was analyzed using multivariate and propensity score analyses. RESULTS Patient characteristics did not differ significantly between each treatment group and the BSC group, after propensity score matching. LAT (hazard ratio [HR]) =0.568; 95% confidence interval [CI], 0.40-0.80) and TACE (HR=0.691; 95% CI, 0.50-0.96) were identified as significant contributors to OS if the C-P score was less than 11 and tumor conditions met the Milan criteria. CONCLUSIONS For patients with HCC within the Milan criteria and with a C-P score of 10 or 11, locoregional treatment can be used as a salvage treatment if LT is not feasible.
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Affiliation(s)
- Satoshi Kitai
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Japan
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Yutaka Matsuyama
- Department of Biostatistics, School of Public Health, University of Tokyo, Tokyo, Japan
| | | | - Osamu Nakashima
- Department of Clinical Laboratory Medicine, Kurume University Hospital, Kurume, Japan
| | - Osamu Matsui
- Department of Radiology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Yonson Ku
- hDepartment of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Norihiro Kokudo
- Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Masatoshi Makuuchi
- Department of Surgery, Japanese Red Cross Medical Center, Tokyo, Japan,*Masatoshi Kudo, MD, PhD, Department of Gastroenterology and Hepatology, Kinki University School of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka 589-8511 (Japan), Tel. +81 723 66 0221 (ext: 3149), E-Mail
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Liu Y, Wang ZX, Cao Y, Zhang G, Chen WB, Jiang CP. Preoperative inflammation-based markers predict early and late recurrence of hepatocellular carcinoma after curative hepatectomy. Hepatobiliary Pancreat Dis Int 2016; 15:266-74. [PMID: 27298102 DOI: 10.1016/s1499-3872(16)60094-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Recurrence of hepatocellular carcinoma (HCC) after curative resection remains a major cause of treatment failure and tumor-related death. Patterns of HCC recurrence can be categorized into early recurrence and late recurrence which have different underlying mechanisms. In this study, we investigated if simple inflammation-based clinical markers can distinguish patterns of recurrence after curative resection of HCC. METHODS A retrospective analysis of 223 patients who underwent curative hepatectomy for HCC was performed. Preoperative inflammation-based factors including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio, gamma-glutamyl transferase/alanine aminotransferase ratio, aspartate aminotransferase/platelet ratio index (APRI) and prognostic nutritional index together with other clinicopathologic parameters were evaluated by univariate analysis and multivariate analysis to identify independent prognostic factors. By combining risk factors, predictive models were established to distinguish populations at high risk of early or late recurrence. RESULTS Age ≤50 years, resection margin ≤1 cm, TNM stage III-IV, NLR>2.75, APRI>0.23 and positive alpha-fetoprotein were independent adverse prognostic factors for early recurrence. Patients with three or more risk factors were at significant higher risk of early recurrence. APRI>0.23 and positive hepatitis B e antigen (HBeAg) were independent risk factors of late recurrence, the coexistence of high APRI and positive HBeAg increased the risk of late recurrence. CONCLUSIONS Preoperative inflammation-based prognostic factors predict early and late recurrence of HCC after curative resection. Different prognostic factor combinations distinguish high-risk populations of early or late HCC recurrence.
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Affiliation(s)
- Yue Liu
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China.
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50
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Yoon HI, Seong J. Optimal Selection of Radiotherapy as Part of a Multimodal Approach for Hepatocellular Carcinoma. Liver Cancer 2016; 5:139-51. [PMID: 27386432 PMCID: PMC4906424 DOI: 10.1159/000367762] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
A multimodal approach to treatment is a basic oncologic principle with proven survival benefits for most cancer types. However, existing guidelines recommend single modalities for treating each stage of hepatocellular carcinoma (HCC). Nonetheless, multimodal approaches can be considered for HCC, depending on the characteristics of the disease in individual cases. Radiotherapy (RT), an effective local modality, is a critical element of most multimodal approaches. Improved RTtechnology and increased understanding of the tolerance of the liver to radiation have contributed to the popularity of RT for treating liver tumors in clinical practice. Consequently, numerous reports have described the effects of RT on liver cancer, despite a lack of stringent evidence for its benefits. RT can be delivered using various technologies and approaches, which may be the source of some confusion. For example, high-dose ablative RT can be curative on its own, or high-dose ablative or conventional RT can complement other treatments such as radiofrequency ablation and transarterial chemoembolization. Combinations of systemic agents and RT can also be applied. This review discusses the optimal selection of RT as part of a multimodal approach for HCC.
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Affiliation(s)
| | - Jinsil Seong
- *Jinsil Seong, MD, PhD, Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University, Health System, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752 (Republic of Korea), Tel. +82 2 2228 8111, E-mail
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