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Zhou H, Wang Y, Wang D, Zhang M, Wang K, Liu C. PRMT1 promotes immune escape in hepatocellular carcinoma by regulating arginine methylation modification of MYC protein. Epigenetics 2025; 20:2509044. [PMID: 40401713 PMCID: PMC12101584 DOI: 10.1080/15592294.2025.2509044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 05/12/2025] [Accepted: 05/15/2025] [Indexed: 05/23/2025] Open
Abstract
Arginine methyltransferase 1 (PRMT1) is widely recognized as an oncogene in various cancers. However, its specific role and underlying mechanisms in hepatocellular carcinoma (HCC) remain insufficiently understood. This study investigated the function of PRMT1 in HCC development and immune evasion. A comprehensive approach combining database analysis (including TCGA, The Human Protein Atlas, Kaplan-Meier Plotter, and TIMER2.0), molecular techniques (such as RT-qPCR, Western blot analysis, and co-immunoprecipitation), cell-based assays (including MTT, colony formation, transwell, and T cell killing assays), and in vivo models was employed to explore PRMT1's role in HCC. The findings revealed a marked upregulation of PRMT1 in both HCC clinical samples and cell lines. Depletion of PRMT1 inhibited cell proliferation and immune evasion while reducing cell migration and invasion. Mechanistically, PRMT1 was shown to interact with MYC, facilitating its arginine methylation and enhancing its protein stability. Moreover, re-expression of MYC significantly reversed the anti-tumour effects associated with PRMT1 depletion. In vivo experiments further corroborated these results. Collectively, PRMT1 promotes HCC progression and immune escape by mediating ADMA methylation of MYC, thereby regulating its stability and expression.
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Affiliation(s)
- Han Zhou
- General Surgery Department, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei, China
| | - Yang Wang
- Gastrointestinal Surgery Department, Tangshan Central Hospital, Tangshan, Hebei, China
| | - Dan Wang
- Anesthesiology Department, Nanjing Chest Hospital, Nanjing, Jiangsu, China
| | - Mei Zhang
- General Surgery Department. II, Tangshan Nanhu Hospital, Tangshan, Hebei, China
| | - Kaidi Wang
- Geriatrics Department, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei, China
| | - Chunhui Liu
- General Surgery Department, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei, China
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Fu XL, Guo SM, Ma JQ, Ma FY, Wang X, Tang YX, Li Y, Zhang WY, Ye LH. HBXIP induces PARP1 via WTAP-mediated m 6A modification and CEBPA-activated transcription in cisplatin resistance to hepatoma. Acta Pharmacol Sin 2024; 45:2405-2419. [PMID: 38871923 PMCID: PMC11489769 DOI: 10.1038/s41401-024-01309-5] [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: 01/26/2024] [Accepted: 05/08/2024] [Indexed: 06/15/2024]
Abstract
Poly (ADP-ribose) polymerase 1 (PARP1) is a DNA-binding protein that is involved in various biological functions, including DNA damage repair and transcription regulation. It plays a crucial role in cisplatin resistance. Nevertheless, the exact regulatory pathways governing PARP1 have not yet been fully elucidated. In this study, we present evidence suggesting that the hepatitis B X-interacting protein (HBXIP) may exert regulatory control over PARP1. HBXIP functions as a transcriptional coactivator and is positively associated with PARP1 expression in tissues obtained from hepatoma patients in clinical settings, and its high expression promotes cisplatin resistance in hepatoma. We discovered that the oncogene HBXIP increases the level of PARP1 m6A modification by upregulating the RNA methyltransferase WTAP, leading to the accumulation of the PARP1 protein. In this process, on the one hand, HBXIP jointly activates the transcription factor ETV5, promoting the activation of the WTAP promoter and further facilitating the promotion of the m6A modification of PARP1 by WTAP methyltransferase, enhancing the RNA stability of PARP1. On the other hand, HBXIP can also jointly activate the transcription factor CEBPA, enhance the activity of the PARP1 promoter, and promote the upregulation of PARP1 expression, ultimately leading to enhanced DNA damage repair capability and promoting cisplatin resistance in hepatoma. Notably, aspirin inhibits HBXIP, thereby reducing the expression of PARP1. Overall, our research revealed a novel mechanism for increasing PARP1 abundance, and aspirin therapy could overcome cisplatin resistance in hepatoma.
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Affiliation(s)
- Xue-Li Fu
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Shi-Man Guo
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Jia-Qi Ma
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Fang-Yuan Ma
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Xue Wang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Yan-Xin Tang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Ye Li
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Wei-Ying Zhang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
| | - Li-Hong Ye
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
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Yee SK, Hernandez BY, Kwee S, Wong LL. Hepatocellular carcinoma in Pacific Islanders: comparison of Pacific Island-born vs. US-born. HEPATOMA RESEARCH 2023; 9:7. [PMID: 37035453 PMCID: PMC10079260 DOI: 10.20517/2394-5079.2022.85] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/18/2023]
Abstract
Aim To describe demographic, clinical, and outcome differences in Pacific Island-born (PI-born) compared to US-born hepatocellular carcinoma (HCC) patients of Pacific Island ancestry within a clinical cohort in Hawaii. Methods A prospectively collected database of 1608 patients diagnosed with HCC over a 30-year period (1993-2022) identified 252 patients of Pacific Islander ethnicity. Data collected: demographics, medical history, laboratory data, tumor characteristics, treatment, and survival. Patients were divided into two groups: PI-born and US-born. Categorical variables were analyzed using ANOVA and chi-square analysis. Odds ratios with 95% confidence intervals were calculated using univariate and multivariate logistic regression. Overall survival was evaluated using Kaplan-Meier analysis. Results PI-born patients were younger (57.3 vs. 61.8 years, P = 0.002) and more likely to have hepatitis B (OR 14.10, 7.50-26.50) and underlying cirrhosis (OR 2.28, 1.17-4.45). In comparison, US-born patients had a significantly higher likelihood of Hepatitis C, nonalcoholic steatohepatitis/nonalcoholic fatty liver disease, history of non-HCC cancer, and positive smoking history compared to PI-born patients. PI-born patients were more likely to forego treatment (OR 3.22, 1.77-5.87) and be lost to follow-up (OR 9.21, 1.97-43.03). Both groups were equally likely to have the opportunity for curative surgical treatment (liver resection or transplant). US-born status was associated with higher mortality risk, while transplantation was associated with lower mortality risk. The PI-born cohort demonstrated higher overall survival at 3 and 5 years compared to US-born. Conclusion HBV remains the primary risk factor for HCC in PI-born patients, whereas HCC in US-born patients is more associated with the adoption of a Westernized lifestyle.
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Affiliation(s)
- Shelby K. Yee
- Department of Surgery, John A. Burns School of Medicine, Honolulu, HI 96813, USA
| | | | - Sandi Kwee
- University of Hawaii Cancer Center, Honolulu, HI 96813, USA
| | - Linda L. Wong
- Department of Surgery, John A. Burns School of Medicine, Honolulu, HI 96813, USA
- University of Hawaii Cancer Center, Honolulu, HI 96813, USA
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Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Cheng AL, Vogel A, Tovoli F, Ueshima K, Aikata H, López CL, Pracht M, Meng Z, Daniele B, Park JW, Palmer D, Tamai T, Saito K, Dutcus CE, Lencioni R. Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study. J Hepatol 2023; 78:133-141. [PMID: 36341767 DOI: 10.1016/j.jhep.2022.09.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 08/26/2022] [Accepted: 09/08/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND & AIMS Validated surrogate endpoints for overall survival (OS) are important for expediting the clinical study and drug-development processes. Herein, we aimed to validate objective response as an independent predictor of OS in individuals with unresectable hepatocellular carcinoma (HCC) receiving systemic anti-angiogenic therapy. METHODS We investigated the association between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study of lenvatinib vs. sorafenib. We conducted landmark analyses (Simon-Makuch) of OS by objective response at 2, 4, and 6 months after randomization. RESULTS Median OS was 21.6 months (95% CI 18.6-24.5) for responders (investigator-assessed mRECIST) vs. 11.9 months (95% CI 10.7-12.8) for non-responders (hazard ratio [HR] 0.61; 95% CI 0.49-0.76; p <0.001). Objective response by IRR per mRECIST and RECIST v1.1 supported the association with OS (HR 0.61; 95% CI 0.51-0.72; p <0.001 and HR 0.50; 95% CI 0.39-0.65; p <0.001, respectively). OS was significantly prolonged for responders vs. non-responders (investigator-assessed mRECIST) at the 2-month (HR 0.61; 95% CI 0.49-0.76; p <0.001), 4-month (HR 0.63; 95% CI 0.51-0.80; p <0.001), and 6-month (HR 0.68; 95% CI 0.54-0.86; p <0.001) landmarks. Results were similar when assessed by IRR, with both mRECIST and RECIST v1.1. An exploratory multivariate Cox regression analysis identified objective response by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44-0.68; p <0.0001) and IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38-0.64; p <0.0001) as independent predictors of OS in individuals with unresectable HCC. CONCLUSIONS Objective response was an independent predictor of OS in individuals with unresectable HCC in REFLECT; additional studies are needed to confirm surrogacy. Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival vs. those with stable/progressive/non-evaluable disease. GOV NUMBER NCT01761266. IMPACT AND IMPLICATIONS This analysis of data taken from a completed clinical trial (REFLECT) looked for any link between objective response and overall survival time in individuals with unresectable HCC receiving anti-angiogenic treatments. Significantly longer median overall survival was found for responders (21.6 months) vs. non-responders (11.9 months). Overall survival was also significantly longer for responders vs. non-responders (based on objective response status at 2, 4, and 6 months) in the landmark analysis. Our results indicate that objective response is an independent predictor of overall survival in this setting, confirming its validity as a rapid marker of efficacy that can be applied in phase II trials; however, further validation is required to determine is validity for other systemic treatments (e.g. immunotherapies), or as a surrogate of overall survival.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
| | - Richard S Finn
- Department of Gastroenterology and Hepatology, Geffen School of Medicine, UCLA Medical Center, Santa Monica, CA, USA
| | - Shukui Qin
- Director of Chinese PLA Cancer Center, Nanjing Bayi Hospital, Nanjing, Jiangsu, China
| | - Kwang-Hyub Han
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kenji Ikeda
- Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan
| | - Ann-Lii Cheng
- Oncology, Internal and General Medicine, National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Francesco Tovoli
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
| | - Kazuomi Ueshima
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Hiroshi Aikata
- Department of Medicine and Molecular Science, Hiroshima University Hospital, Hiroshima, Japan
| | - Carlos López López
- Department of Medical Oncology, Marqués de Valdecilla University Hospital, IDIVAL, Santander, Spain
| | - Marc Pracht
- Department of Medical Oncology, Comprehensive Cancer Center Eugène Marquis, Rennes, France
| | - Zhiqiang Meng
- Department of Integrative Oncology, Fudan University, Shanghai Cancer Center, Shanghai, China
| | - Bruno Daniele
- Department of Oncology, Azienda Ospedaliera G. Rummo, Benevento, Italy and Ospedale del Mare, Naples, Italy
| | - Joong-Won Park
- Department of Internal Medicine, National Cancer Center Korea, Goyang-si, Republic of Korea
| | - Daniel Palmer
- Department of Medical Oncology, The Clatterbridge Cancer Centre, Birkenhead, England, UK
| | | | - Kenichi Saito
- Biostatistics and Clinical Research, Eisai Inc., Nutley, NJ, USA
| | - Corina E Dutcus
- Biostatistics and Clinical Research, Eisai Inc., Nutley, NJ, USA
| | - Riccardo Lencioni
- Department of Radiology, Miami Cancer Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Radiology, University of Pisa School of Medicine, Pisa, Italy
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Kronenfeld JP, Ryon EL, Goldberg D, Lee RM, Yopp A, Wang A, Lee AY, Luu S, Hsu C, Silberfein E, Russell MC, Merchant NB, Goel N. Survival inequity in vulnerable populations with early-stage hepatocellular carcinoma: a United States safety-net collaborative analysis. HPB (Oxford) 2021; 23:868-876. [PMID: 33487553 PMCID: PMC8205960 DOI: 10.1016/j.hpb.2020.11.1150] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/12/2020] [Accepted: 11/24/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Access to health insurance and curative interventions [surgery/liver-directed-therapy (LDT)] affects survival for early-stage hepatocellular carcinoma (HCC). The aim of this multi-institutional study of high-volume safety-net hospitals (SNHs) and their tertiary-academic-centers (AC) was to identify the impact of type/lack of insurance on survival disparities across hospitals, particularly SNHs whose mission is to minimize insurance related access-to-care barriers for vulnerable populations. METHODS Early-stage HCC patients (2012-2014) from the US Safety-Net Collaborative were propensity-score matched by treatment at SNH/AC. Overall survival (OS) was the primary outcome. Multivariable Cox proportional-hazard analysis was performed accounting for sociodemographic/clinical parameters. RESULTS Among 925 patients, those with no insurance (NI) had decreased curative surgery, compared to those with government insurance (GI) and private insurance [PI, (PI-SNH:60.5% vs. GI-SNH:33.1% vs. NI-SNH:13.6%, p < 0.001)], and decreased median OS (PI-SNH:32.1 vs. GI-SNH:22.8 vs. NI-SNH:9.4 months, p = 0.002). On multivariable regression controlling for sociodemographic/clinical parameters, NI-SNH (HR:2.5, 95% CI:1.3-4.9, p = 0.007) was the only insurance type/hospital system combination with significantly worse OS. CONCLUSION NI-SNH patients received less curative treatment than other insurance/hospitals types suggesting that treatment barriers, beyond access-to-care, need to be identified and addressed to achieve survival equity in early-stage HCC for vulnerable populations (NI-SNH).
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Affiliation(s)
- Joshua P Kronenfeld
- Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, 1120 NW 14th Street, Suite 410, Miami, FL 33136, USA
| | - Emily L Ryon
- Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, 1120 NW 14th Street, Suite 410, Miami, FL 33136, USA
| | - David Goldberg
- Division of Digestive Health and Liver Disease, Department of Medicine, University of Miami Miller School of Medicine, 1475 NW 12th Ave, Miami, FL 33136, USA
| | - Rachel M Lee
- Winship Cancer Institute, Division of Surgical Oncology, Department of Surgery, Emory University, 1365-C Clifton Road NE Atlanta, 30322, Georgia
| | - Adam Yopp
- Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical School, 2201 Inwood Rd 3rd Floor Suite 500, Dallas, TX 75390, USA
| | - Annie Wang
- Division of Surgical Oncology, Department of Surgery, NYU Langone Health, 160 East 34th Street, 3rd Floor, New York, NY, 10016, USA
| | - Ann Y Lee
- Division of Surgical Oncology, Department of Surgery, NYU Langone Health, 160 East 34th Street, 3rd Floor, New York, NY, 10016, USA
| | - Sommer Luu
- Division of Surgical Oncology, Department of Surgery, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA
| | - Cary Hsu
- Division of Surgical Oncology, Department of Surgery, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA
| | - Eric Silberfein
- Division of Surgical Oncology, Department of Surgery, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA
| | - Maria C Russell
- Winship Cancer Institute, Division of Surgical Oncology, Department of Surgery, Emory University, 1365-C Clifton Road NE Atlanta, 30322, Georgia
| | - Nipun B Merchant
- Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, 1120 NW 14th Street, Suite 410, Miami, FL 33136, USA
| | - Neha Goel
- Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, 1120 NW 14th Street, Suite 410, Miami, FL 33136, USA.
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Zhou K, Pickering TA, Gainey CS, Cockburn M, Stern MC, Liu L, Unger JB, El-Khoueiry AB, Terrault NA. Presentation, Management, and Outcomes Across the Rural-Urban Continuum for Hepatocellular Carcinoma. JNCI Cancer Spectr 2021; 5:pkaa100. [PMID: 33442663 PMCID: PMC7791625 DOI: 10.1093/jncics/pkaa100] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 09/30/2020] [Indexed: 12/15/2022] Open
Abstract
Background Hepatocellular carcinoma is 1 of few cancers with rising incidence and mortality in the United States. Little is known about disease presentation and outcomes across the rural-urban continuum. Methods Using the population-based Surveillance, Epidemiology, and End Results registry, we identified adults with incident hepatocellular carcinoma between 2000 and 2016. Urban, suburban, and rural residence at time of cancer diagnosis were categorized by the Census Bureau’s percent of the population living in nonurban areas. We examined association between place of residence and overall survival. Secondary outcomes were late tumor stage and receipt of therapy. Results Of 83 368 incident cases of hepatocellular carcinoma, 75.8%, 20.4%, and 3.8% lived in urban, suburban, and rural communities, respectively. Median survival was 7 months (interquartile range = 2-24). All stage and stage-specific survival differed by place of residence, except for distant stage. In adjusted models, rural and suburban residents had a respective 1.09-fold (95% confidence interval [CI] = 1.04 to 1.14; P < .001) and 1.08-fold (95% CI = 1.05 to 1.10; P < .001) increased hazard of overall mortality as compared with urban residents. Furthermore, rural and suburban residents had 18% (odds ratio [OR] = 1.18, 95% CI = 1.10 to 1.27; P < .001) and 5% (OR = 1.05, 95% CI = 1.02 to 1.09; P = .003) higher odds of diagnosis at late stage and were 12% (OR = 0.88, 95% CI = 0.80 to 0.94; P < .001) and 8% (OR = 0.92, 95% CI = 0.88 to 0.95; P < .001) less likely to receive treatment, respectively, compared with urban residents. Conclusions Residence in a suburban and rural community at time of diagnosis was independently associated with worse indicators across the cancer continuum for liver cancer. Further research is needed to elucidate the primary drivers of these rural-urban disparities.
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Affiliation(s)
- Kali Zhou
- Department of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Trevor A Pickering
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
| | - Christina S Gainey
- Department of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Myles Cockburn
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.,Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Mariana C Stern
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.,Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Lihua Liu
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.,Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Jennifer B Unger
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.,Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Anthony B El-Khoueiry
- Department of Medicine, University of Southern California, Los Angeles, CA, USA.,Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Norah A Terrault
- Department of Medicine, University of Southern California, Los Angeles, CA, USA
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Kim N, Cheng J, Huang WY, Kimura T, Zeng ZC, Lee VHF, Kay CS, Seong J. Dose-Response Relationship in Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: A Pooled Analysis of an Asian Liver Radiation Therapy Group Study. Int J Radiat Oncol Biol Phys 2020; 109:464-473. [PMID: 33229165 DOI: 10.1016/j.ijrobp.2020.09.038] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 09/13/2020] [Accepted: 09/16/2020] [Indexed: 02/08/2023]
Abstract
PURPOSE Despite the worldwide implementation of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC), there is a lack of consensus guideline on prescription dose. Herein, this multinational study aimed to investigate the effects of the prescribed radiation dose on oncologic outcomes of SBRT for HCC. METHODS AND MATERIALS The multi-institutional retrospective cohort included 510 patients treated with SBRT between 2010 and 2016. All relevant clinical factors and factors related to SBRT were analyzed to evaluate freedom from local progression (FFLP) and overall survival (OS). Based on a biologically effective dose (BED) cutoff value of 100 Gy, 198 tumors were selected from each group in propensity score matching (PSM). RESULTS Baseline characteristics in the BED <100 Gy group were unfavorable (Child-Pugh class B, 19%; advanced stage, 72%; median tumor size was 4 cm) compared with the BED ≥100 Gy group. With a median follow-up of 22 (interquartile range, 9.8-37.6) months, the 2-year FFLP and OS rates were 77% and 73%, respectively. Patients treated with a BED ≥100 Gy showed better rates of 2-year FFLP and OS than patients treated with a BED <100 Gy (FFLP, 89% vs 69%; OS, 80% vs 67%; P < .001). In the multivariable analysis before and after PSM, BED ≥100 Gy was identified as the main prognostic factor for both FFLP and OS (P < .01). Additionally, a dose-response relationship was observed between FFLP and BED (odds ratio, 0.92 per 5 Gy, P = .048). CONCLUSIONS A BED ≥100 Gy was significantly associated with outcomes, and a dose-response relationship was observed between local tumor progression and BED. Given that SBRT is being increasingly used in HCC, detailed consensus guidelines regarding SBRT dose prescription should be established.
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Affiliation(s)
- Nalee Kim
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jason Cheng
- Department of Radiation Oncology, National Taiwan University Hospital, Taipei City, Taiwan
| | - Wen-Yen Huang
- Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan
| | - Tomoki Kimura
- Department of Radiation Oncology, Hiroshima University Hospital, Hiroshima, Japan
| | - Zhao Chong Zeng
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Victor H F Lee
- Department of Radiation Oncology, University of Hong Kong, Hong Kong, People's Republic of China
| | - Chul Seung Kay
- Department of Radiation Oncology, Incheon St. Mary Hospital, Incheon, Republic of Korea
| | - Jinsil Seong
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
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Aly A, Malangone-Monaco E, Noxon V, Henriques C, Benavente F, Kim A. Treatment patterns and direct medical costs among patients with advanced hepatocellular carcinoma. Curr Med Res Opin 2020; 36:1813-1823. [PMID: 32969741 DOI: 10.1080/03007995.2020.1824899] [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] [Indexed: 10/25/2022]
Abstract
AIMS This study assessed the real-world United States (US) treatment patterns and the associated economic burden in patients diagnosed with advanced hepatocellular carcinoma (HCC). METHODS The MarketScan database was used to identify patients newly diagnosed with HCC who received systemic therapy between 2011 and 2018 and continuously enrolled for ≥6 months (baseline period) prior and ≥1 month following HCC diagnosis. Treatment patterns (systemic and locoregional therapy), healthcare resource utilization, and costs were reported during follow-up. RESULTS The final sample included 1580 patients (median age, 61; 78% male; median follow up, 8.7 months). The most common first line of therapy (LOT) was sorafenib (78%). The median time from HCC diagnosis to start of sorafenib was 43 days, and the median duration of sorafenib therapy was 60 days. Only 17% of patients received second LOT, and non-sorafenib treatment use increased to 66% (mostly chemotherapy combination). Transarterial chemoembolization was the most commonly observed locoregional therapy prior to the first LOT. The multivariable-adjusted average all-cause total cost among sorafenib treated patients was $17,642 (95% CI: $16,711-$18,558) per-patient per-month), of which $11,393 were HCC-specific. CONCLUSIONS In patients who received first-line therapy for HCC, the duration of therapy was short (potentially due to progression or tolerability). Most patients did not continue to second-line therapy. Despite the short duration of therapy, HCC patients still incur a high economic burden, and there is a need for more effective and tolerable treatments.
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Affiliation(s)
| | | | | | | | | | - Amy Kim
- Johns Hopkins, Columbia, MD, USA
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Li Y, Zhang Y, Zhang S, Huang D, Li B, Liang G, Wu Y, Jiang Q, Li L, Lin C, Wei Z, Meng L. circRNA circARNT2 Suppressed the Sensitivity of Hepatocellular Carcinoma Cells to Cisplatin by Targeting the miR-155-5p/PDK1 Axis. MOLECULAR THERAPY-NUCLEIC ACIDS 2020; 23:244-254. [PMID: 33425483 PMCID: PMC7772525 DOI: 10.1016/j.omtn.2020.08.037] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 08/28/2020] [Indexed: 01/27/2023]
Abstract
Circular RNA (circRNA) is a novel subclass of noncoding-RNA molecules that participate in development and progression of a variety of human diseases via sponging microRNAs (miRNAs). Until now, the contributions of circRNAs in chemoresistance of hepatocellular carcinoma (HCC) remain largely unknown. In the present study, we aimed to investigate the role of circRNA in cisplatin resistance of HCC. We investigated the expression of circRNAs in 5 paired cisplatin-sensitive and cisplatin-resistant HCC tissues by microarray analysis. The qRT-PCR analysis was to investigate the expression pattern of circARNT2 in HCC patient tissues and cell lines. Then, the effects of circARNT2 on cisplatin resistance, cell proliferation, and apoptosis were assessed in HCC in vitro and in vivo. circARNT2 was significantly upregulated in HCC tissues and cell lines. Overexpression of circARNT2 in HCC was significantly correlated with aggressive characteristics and served as an independent risk factor for overall survival in patients with HCC. In vitro experiments showed that knockdown of circARNT2 inhibited cell proliferation and enhances the cisplatin sensitivity of HCC cells. Furthermore, circARNT2 facilitates HCC progression in vivo. We demonstrated that circARNT2 acts as a sponge for miR-155-5p and verified that PDK1 is a novel target of miR-155-5p. In summary, our study demonstrated that circARNT2 modulates cisplatin resistance through miR-155-5p/PDK1 pathway. Our findings indicated that circARNT2 may serve as a promising therapeutic target for overcoming cisplatin resistance for HCC.
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Affiliation(s)
- Yueyong Li
- Department of Interventional Medicine, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Yingjun Zhang
- Department of Medical Imageology, Hunan University of Medicine, Huaihua 418000, China
| | - Shuai Zhang
- Department of Interventional Radiology, the Affiliated Hospital of Guizhou Medical University, Guiyang 550000, China.,Department of Interventional Radiology, the Affiliated Cancer Hospital of Guizhou Medical University, Guiyang 550000, China
| | - Deyou Huang
- Department of Radiology, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Baosheng Li
- Department of Radiology, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Gencheng Liang
- Department of Interventional Medicine, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Yingning Wu
- Department of Interventional Medicine, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Qiulan Jiang
- Department of Interventional Medicine, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Longhua Li
- Department of Interventional Medicine, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Cheng Lin
- Department of Interventional Medicine, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Zhonghen Wei
- Department of Interventional Medicine, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Lingzhang Meng
- Center for Systemic Inflammation Research, School of Preclinical Medicine, Youjiang Medical University for Nationalities, Baise City 533000, Guangxi Province, China
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10
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Shimose S, Iwamoto H, Tanaka M, Niizeki T, Shirono T, Nakano M, Okamura S, Noda Y, Kamachi N, Sakai M, Suzuki H, Nomiyama M, Kuromatsu R, Koga H, Torimura T. Increased Arterio-Portal Shunt Formation after Drug-Eluting Beads TACE for Hepatocellular Carcinoma. Oncology 2020; 98:558-565. [PMID: 32422633 DOI: 10.1159/000507262] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 03/14/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND AND AIMS Conventional transcatheter arterial chemoembolization (C-TACE) and drug-eluting bead (DEB)-based TACE are current treatments for hepatocellular carcinoma (HCC). We compared the therapeutic efficacies and adverse events of these methods in a single-center retrospective cohort study. METHODS We enrolled 174 patients treated between January 2010 and October 2016; 98 and 76 underwent C-TACE and DEB-TACE, respectively, with 76 and 22 of the former group and 49 and 27 of the latter group classified as Child-Pugh class A and B, respectively. Therapeutic outcomes, progression-free survival (PFS), and adverse events were evaluated. RESULTS The PFS rates in the C-TACE and DEB-TACE groups were 8.1 and 6.1 months, respectively (p = 0.79). The response and disease control rates were 64 and 71% in C-TACE patients and 69 and 78% in DEB-TACE patients, respectively (p = 0.25). Postprocedural pain, vomiting, and fever were more frequent following C-TACE than DEB-TACE (p < 0.001). In contrast, the incidences of bilomas and arterio-portal shunts were significantly higher following DEB-TACE (p < 0.001); the incident rates of arterio-portal shunt formation were 8.1 and 48.7% in patients undergoing C-TACE and DEB-TACE, respectively. Child-Pugh class A was significantly associated with arterio-portal shunt formation after DEB-TACE on multivariate analysis. CONCLUSIONS There were no significant differences in the therapeutic efficacies of C-TACE and DEB-TACE. However, the frequency of arterio-portal shunt formation was significantly higher in HCC patients with Child-Pugh class A undergoing DEB-TACE. Our findings imply that C-TACE should be selected for HCC patients with Child-Pugh class A and DEB-TACE should be chosen for those with Child-Pugh class B.
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Affiliation(s)
- Shigeo Shimose
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan, .,IWAMOTO Medical Clinic, Kitakyusyu, Japan,
| | | | - Takashi Niizeki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Tomotake Shirono
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Masahito Nakano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Syusuke Okamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Yu Noda
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Naoki Kamachi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Miwa Sakai
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Hiroyuki Suzuki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Mika Nomiyama
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Ryoko Kuromatsu
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
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11
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Insurance status impacts treatment for hepatocellular carcinoma. Ann Hepatol 2020; 18:461-465. [PMID: 31040093 DOI: 10.1016/j.aohep.2018.10.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 08/30/2018] [Accepted: 10/04/2018] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM Previous studies have identified treatment disparities in the treatment of hepatocellular carcinoma (HCC) based on insurance status and provider. Recent studies have shown more Americans have healthcare insurance; therefore we aim to determine if treatment disparities based on insurance providers continue to exist. MATERIALS AND METHODS A retrospective database analysis using the NIS was performed between 2010 and 2013 including adult patients with a primary diagnosis of HCC determined by ICD-9 codes. Multivariable logistic regressions were performed to analyze differences in treatment, mortality, features of decompensation, and metastatic disease based on the patient's primary payer. RESULTS This study included 62,368 patients. Medicare represented 44% of the total patients followed by private insurance (27%), Medicaid (19%), and other payers (10%). Patients with Medicare, Medicaid, and other payer were less likely to undergo liver transplantation [(OR 0.63, 95% CI 0.47-0.84), (OR 0.23, 95% CI 0.15-0.33), (OR 0.26, 95% CI 0.15-0.45)] and surgical resection [(OR 0.74, 95% CI 0.63-0.87), (OR 0.40, 95% CI 0.32-0.51), (OR 0.42, 95% CI 0.32-0.54)] than patients with private insurance. Medicaid patients were less likely to undergo ablation then patients with private insurance (OR 0.52, 95% CI 0.40-0.68). Patients with other forms of insurance were less likely to undergo transarterial chemoembolization (TACE) compared to private insurance (OR 0.64, 95% CI 0.43-0.96). CONCLUSION Insurance status impacts treatment for HCC. Patients with private insurance are more likely to undergo curative therapies of liver transplantation and surgical resection compared to patients with government funded insurance.
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12
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Singh SK, Singh R. Liver cancer incidence and mortality: Disparities based on age, ethnicity, health and nutrition, molecular factors, and geography. CANCER HEALTH DISPARITIES 2020; 4:e1-e10. [PMID: 34164612 PMCID: PMC8218735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Liver cancer (LCa) is the fifth and eighth leading cause of cancer death for men and women, respectively. However, despite improvements in treatment strategies and options, it has limited therapeutic options. Worldwide, the prevalence of LCa varies widely. Various factors are associated with the development of LCa, and its incidence, morbidity, and mortality rates differ due to disparities that are multifactorial and complex, including genetic and geographic factors. The frequency of LCa varies by race/ethnicity, age and sex and relates to viral infections, lifestyle, nutrition, obesity, and health. In addition, various molecular factors, including cytokines, hormones, apoptosis, and mutations, are involved in disparities in the progression and mortality of LCa. Here, we provide an overall perspective on LCa by presenting available information on these associated factors and discussing their importance in its disproportionate incidences and clinical outcomes.
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Affiliation(s)
- Santosh Kumar Singh
- Department of Microbiology, Biochemistry and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA, USA, 30310
| | - Rajesh Singh
- Department of Microbiology, Biochemistry and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA, USA, 30310
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13
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Kudo M, Ueshima K, Chiba Y, Ogasawara S, Obi S, Izumi N, Aikata H, Nagano H, Hatano E, Sasaki Y, Hino K, Kumada T, Yamamoto K, Imai Y, Iwadou S, Ogawa C, Okusaka T, Kanai F, Arai Y. Objective Response by mRECIST Is an Independent Prognostic Factor for Overall Survival in Hepatocellular Carcinoma Treated with Sorafenib in the SILIUS Trial. Liver Cancer 2019; 8:505-519. [PMID: 31799207 PMCID: PMC6883462 DOI: 10.1159/000503032] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 09/01/2019] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVE In SILIUS (NCT01214343), combination of sorafenib and hepatic arterial infusion chemotherapy did not significantly improve overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC) compared with sorafenib alone. In this study, we explored the relationship between objective response by mRECIST and OS in the sorafenib group, in the combination group, and in all patients in the SILIUS trial. METHODS Association between objective response and OS in patients treated with sorafenib (n = 103) or combination (n = 102) and all patients (n = 205) were analyzed. The median OS of responders was compared with that of non-responders. Landmark analyses were performed according to objective response at several fixed time points, as sensitivity analyses, and the effect on OS was evaluated by Cox regression analysis with objective response as a time-dependent covariate, with other prognostic factors. RESULTS In the sorafenib group, OS of responders (n = 18) was significantly better than that of non-responders (n = 78) (p < 0.0001), where median OS was 27.2 (95% CI, 16.0-not reached) months for responders and 8.9 (95% CI, 6.5-12.6) months for non-responders. HRs from landmark analyses at 4, 6, and 8 months were 0.45 (p = 0.0330), 0.37 (p = 0.0053), and 0.36 (p = 0.0083), respectively. Objective response was an independent predictor of OS based on unstratified Cox regression analyses. In the all patients and the combination group, similar results were obtained. CONCLUSIONS In the SILIUS trial, objective response by sorafenib assessed by mRECIST is an independent prognostic factor for OS in patients with HCC.
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Affiliation(s)
- Masatoshi Kudo
- Kindai University Faculty of Medicine, Osaka-Sayama, Japan,*Masatoshi Kudo, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 337-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511 (Japan), E-Mail
| | | | - Yasutaka Chiba
- Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | | | | | - Namiki Izumi
- Japanese Red Cross Musashino Hospital, Musashino, Japan
| | | | - Hiroaki Nagano
- Osaka University Graduate School of Medicine, Osaka, Japan
| | - Etsuro Hatano
- Kyoto University, Graduate School of Medicine, Kyoto, Japan
| | - Yutaka Sasaki
- Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | | | | | | | | | | | | | | | - Fumihiko Kanai
- Chiba University Graduate School of Medicine, Chiba, Japan
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14
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Sellers CM, Uhlig J, Ludwig JM, Taddei T, Stein SM, Lim JK, Kim HS. The impact of socioeconomic status on outcomes in hepatocellular carcinoma: Inferences from primary insurance. Cancer Med 2019; 8:5948-5958. [PMID: 31436905 PMCID: PMC6792508 DOI: 10.1002/cam4.2251] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Accepted: 03/28/2019] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND To investigate the impact of insurance status on outcomes in patients with hepatocellular carcinoma (HCC). METHODS Patients diagnosed with HCC in the cancer registry from 2005 to 2016 were retrospectively stratified by insurance group. Overall survival was assessed via Kaplan-Meier curves and Cox proportional hazard models including potential confounders in multivariable analyses. RESULTS Seven hundred and sixty-nine patients met inclusion criteria (median age 63 years, 78.8% male, 65.9% Caucasian). 44.5% had private insurance (n = 342), 29.1% had Medicare (n = 224), and 26.4% had Medicaid (n = 203). At diagnosis, Medicaid patients had higher rates of Child-Pugh B (32.0%) and C disease (23.6%) vs Medicare (28.6% and 9.8%) and private insurance (26.9% and 6.7%, P < 0.0001) and higher MELD scores (median 11.0) vs Medicare (9.0) and private insurance (9.0, P = 0.0266). Across insurance groups, patients had similar distribution of American Joint Committee on Cancer stage, tumor size, and multifocal tumor burden. Patients with private insurance had the highest survival (median OS 21.9 months) vs Medicare (17.7 months) and Medicaid (13.0 months, overall P = 0.0061). On univariate analysis, Medicaid patients demonstrated decreased survival vs private insurance (HR 1.40, 95% CI: 1.146-1.715, P = 0.0011). After adjustment for liver disease factors, this survival difference lost statistical significance (Medicaid vs private insurance, HR 1.02, 95% CI: 0.819-1.266, P = 0.8596). CONCLUSION Medicaid was associated with advanced liver disease at HCC diagnosis; however, insurance status is not an independent predictor of HCC survival.
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Affiliation(s)
- Cortlandt M. Sellers
- Section of Interventional Radiology, Department of Radiology and Biomedical ImagingYale School of MedicineNew HavenCT
| | - Johannes Uhlig
- Section of Interventional Radiology, Department of Radiology and Biomedical ImagingYale School of MedicineNew HavenCT
- Department for Diagnostic and Interventional RadiologyUniversity Medical Center GoettingenGoettingenGermany
| | - Johannes M. Ludwig
- Section of Interventional Radiology, Department of Radiology and Biomedical ImagingYale School of MedicineNew HavenCT
- Department of Diagnostic and Interventional Radiology and NeuroradiologyUniversity Hospital Essen, University of Duisburg‐EssenEssenGermany
| | - Tamar Taddei
- Section of Digestive Diseases, Department of Internal MedicineYale School of MedicineNew HavenConnecticut
| | - Stacey M. Stein
- Section of Medical Oncology, Department of Internal MedicineYale School of MedicineNew HavenConnecticut
- Yale Cancer Center, Yale School of MedicineNew HavenConnecticut
| | - Joseph K. Lim
- Section of Digestive Diseases, Department of Internal MedicineYale School of MedicineNew HavenConnecticut
| | - Hyun S. Kim
- Section of Interventional Radiology, Department of Radiology and Biomedical ImagingYale School of MedicineNew HavenCT
- Section of Medical Oncology, Department of Internal MedicineYale School of MedicineNew HavenConnecticut
- Yale Cancer Center, Yale School of MedicineNew HavenConnecticut
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15
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Sobotka LA, Hinton A, Conteh LF. African Americans are less likely to receive curative treatment for hepatocellular carcinoma. World J Hepatol 2018; 10:849-855. [PMID: 30533185 PMCID: PMC6280157 DOI: 10.4254/wjh.v10.i11.849] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Revised: 07/23/2018] [Accepted: 08/21/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To determine if racial disparities continue to exist in the treatment of hepatocellular carcinoma (HCC).
METHODS A retrospective database analysis using the Nationwide Inpatient Sample was performed including patients with a primary diagnosis of HCC. Univariate and multivariate analyses were utilized to determine racial disparities in liver decompensation, treatment, inpatient mortality, and metastatic disease.
RESULTS A total of 62604 patients with HCC were included consisting of 32428 Caucasian, 9726 African-American, 8988 Hispanic, and 11462 patients of other races. Caucasian patients were more likely to undergo curative therapies of liver transplant (OR: 2.66, 95%CI: 1.92-3.68), resection (OR: 1.82, 95%CI: 1.48-2.23), and ablation (OR: 1.77, 95%CI: 1.36-2.30) than African-American patients. Hispanic patients were more likely to undergo transplant (OR: 2.18, 95%CI: 1.40-3.39) and ablation (OR: 1.46, 95%CI: 1.05-2.03) than African-American patients. Patients of other races were more likely to receive a liver transplant (OR: 2.41, 95%CI: 1.62-3.61), resection (OR: 1.79 95%CI: 1.39-2.32), and ablation (OR: 2.03, 95%CI: 1.47-2.80) than African-American patients. There are no differences in the rates of transarterial chemoembolization between races.
CONCLUSION Racial disparities in HCC treatment exist despite emphasis to support equality in healthcare. African-American patients are less likely to undergo curative treatments for HCC.
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Affiliation(s)
- Lindsay A Sobotka
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Alice Hinton
- Division of Biostatistics, College of Public Health, The Ohio State University, OH 43210, United States
| | - Lanla F Conteh
- Department of Gastroenterology and Hepatology, The Ohio State Wexner Medical Center, Columbus, OH 43210, United States
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16
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Kamo N, Kaido T, Yagi S, Okajima H, Uemoto S. Liver Transplantation for Intermediate-Stage Hepatocellular Carcinoma. Liver Cancer 2018; 7:179-189. [PMID: 29888207 PMCID: PMC5985555 DOI: 10.1159/000487058] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Accepted: 01/22/2018] [Indexed: 02/04/2023] Open
Abstract
Transarterial chemoembolization is the standard treatment for patients with intermediate-stage hepatocellular carcinoma (HCC) according to the Barcelona Clinic Liver Cancer staging system. However, in Japan, not a few patients with intermediate-stage HCC undergo liver transplantation (LT). The present study investigated characteristics and outcomes of LT for intermediate-stage HCC. Between February 1999 and November 2016, a total of 226 patients underwent LT for HCC at our institute. Among these, 56 patients showed intermediate-stage HCC (24.8%). We examined overall survival and recurrence rate after LT according to our extended criteria (maximum size ≤5 cm, number ≤10, des-gamma-carboxy prothrombin ≤400 mAU/mL) and pretreatment. One-, 3-, and 5-year overall survival and recurrence rates of LT for intermediate-stage HCC were 88/64/58% and 22/34/44%, respectively. One-, 3-, and 5-year overall survival and recurrence rates in patients within (n = 35) the criteria (94/80/80% and 9/15/22%, respectively) were significantly better than those in patients beyond (n = 21) the criteria (81/43/29%, p = 0.002 and 39/41/66%, p = 0.001, respectively). Forty-nine cases (88%) had a history of pretreatment. In patients within our extended criteria, overall survival and recurrence rates did not differ significantly between patients with (n = 31) and without (n = 4) pretreatment. In conclusion, outcomes after LT for intermediate-stage HCC are more favorable if patients meet our extended criteria.
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Affiliation(s)
| | - Toshimi Kaido
- *Toshimi Kaido, MD, PhD, Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan), E-Mail
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17
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Gong Y, Wu X, Wang T, Zhao J, Liu X, Yao Z, Zhang Q, Jian X. Targeting PEPT1: a novel strategy to improve the antitumor efficacy of doxorubicin in human hepatocellular carcinoma therapy. Oncotarget 2018; 8:40454-40468. [PMID: 28465466 PMCID: PMC5522267 DOI: 10.18632/oncotarget.17117] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 04/02/2017] [Indexed: 01/10/2023] Open
Abstract
Proton coupled oligopeptide transporter 1 (PEPT1) is a member of the peptide transporter superfamily and plays important role in the absorption of oligopeptide and peptidomimetic drugs. Our previous research verified that PEPT1 expressed specifically in human Hepatocellular carcinoma (HCC) tissue and cell lines and showed potential transport activity to be a new candidate of the tumor therapeutic target. In this study, we aim to explore the feasibility of a novel tumor target therapeutic strategy: Targeting PEPT1 to improve the antitumor efficacy of Doxorubicin in human HCC therapy. First, Doxorubicin was conjugated with Glycylglycylglycine (Gly-Gly-Gly) − a tripeptide which was known as the substrate of PEPT1 and characterized by HPLC and MS successfully. Doxorubicin-tripeptide conjugate was then observed to clarify the target delivery by PEPT1 and the antitumor effect on human hepatocarcinoma in vivo and in vitro. Furthermore, the improvement of the toxic and side effect of Doxorubicin after conjugation was also evaluated by some biochemical tests. Our results reveal that targeting PEPT1 may contribute to the efficient delivery of Doxorubicin to hepatocarcinoma cells and the reduction of drug toxicity. PEPT1 has the prospect to be a novel target of HCC therapy.
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Affiliation(s)
- Yanxia Gong
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, 300052, China.,Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin, 300100, China
| | - Xiang Wu
- Central Laboratory, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Tao Wang
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Jia Zhao
- Clinical Laboratory, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Xi Liu
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Zhi Yao
- Department of Immunology, School of Basic Medical Science, Tianjin Medical University, Tianjin, 300070, China
| | - Qingyu Zhang
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Xu Jian
- Central Laboratory, Tianjin Medical University General Hospital, Tianjin, 300052, China
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18
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Gong Y, Zhang J, Wu X, Wang T, Zhao J, Yao Z, Zhang Q, Liu X, Jian X. Specific expression of proton-coupled oligopeptide transporter 1 in primary hepatocarcinoma-a novel strategy for tumor-targeted therapy. Oncol Lett 2017; 14:4158-4166. [PMID: 28943923 PMCID: PMC5592876 DOI: 10.3892/ol.2017.6724] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 05/16/2017] [Indexed: 12/13/2022] Open
Abstract
Proton-coupled oligopeptide transporter 1 (PEPT1) is a membrane protein which expressed predominantly in intestine and recognized as the target of dietary nutrients (di/tripeptide) or peptidomimetic drug for delivery. The information on the existence of PEPT1 in carcinomas were limited. Our study aimed to investigate the expression profile and transport activity of PEPT1 both in human hepatocarcinoma tissues and cell lines. Western blotting and an immunofluorescence assay revealed the high level of PEPT1 protein expression in hepatocarcinoma Bel-7402, SMMC-7721, HepG2, HEP3B, SK-HEP-1 cell lines. Quantitative real time PCR showed the mRNA expression of PEPT1 in Bel-7402, SMMC-7721, HepG2, HEP3B, SK-HEP-1 cells. High level PEPT1 expression in hepatocarcinoma patient samples were observed by Immunohistology and showed a significant correlation between protein level and pathological grade. Functional activities were also studied using D-Ala-Lys-AMCA (a substrate of peptide transporter) in above five hepatocarcinoma cell lines. The uptake tests performed by fluorescent microscopy suggested that PEPT1 can transport both D-Ala-Lys-AMCA into the hepatocarcinoma cells and the uptake can be competitively inhibited by three PEPT1 substrates (Gly-sar, Gly-gln and Glyglygly). In conclusion, our findings provided the novel information on the expression and function of PEPT1 in human hepatocarcinoma and expanded the potential values for tumor specific drug delivery.
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Affiliation(s)
- Yanxia Gong
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.,Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin 300100, P.R. China
| | - Jie Zhang
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Xiang Wu
- Central Laboratory, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Tao Wang
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Jia Zhao
- Clinical Laboratory, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Zhi Yao
- Department of Immunology, School of Basic Medical Science, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Qingyu Zhang
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Xi Liu
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Xu Jian
- Central Laboratory, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
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19
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Kollmann D, Selzner N, Selzner M. Bridging to liver transplantation in HCC patients. Langenbecks Arch Surg 2017; 402:863-871. [PMID: 28755240 DOI: 10.1007/s00423-017-1609-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 07/19/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Liver transplantation (LT) is the only cure for patients diagnosed with unresectable hepatocellular carcinoma (HCC), and HCC has become the leading indication for LT in the USA. The shortage of liver grafts results in a significant waiting time for LT with the risk of tumour progression. Treating HCCs during the waiting time prior to transplantation (bridging therapy) is an attractive strategy to reduce the risk of exceeding the tumour criteria for transplantation. Studies on bridging therapy are heterogenous and due to ethical issues, mostly of retrospective design. PURPOSE We summarize the main studies and methods that have been reported on bridging therapies for patients with HCC waiting for a LT. CONCLUSION During the waiting period for LT, patients with HCC at risk for tumour progression and therefore bridging therapy is recommended for patients with an estimated waiting time of ≥6 months. Bridging therapy for patients with HCC prior to LT mainly include locoregional therapies (LRTs), with transarterial chemoembolization (TACE) being the most common, followed by radio frequency ablation (RFA). Because of a continuous enhancement of therapy options, including a more precise adjustment of external radiotherapy, further possibilities for an individualized bridging therapy for patients with HCC have been developed. Patients with compensated liver cirrhosis and small tumour size are preferably treated with RFA, whereas patients with larger tumour size but compensated liver function are treated with TACE/TARE. Patients with uncompensated liver cirrhosis and larger tumour size can nowadays be successfully bridged to LT with external radiotherapy without increasing the risk for further deterioration of liver function.
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Affiliation(s)
- Dagmar Kollmann
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, University Health Network, Toronto, Canada
| | - Nazia Selzner
- Department of Medicine, Toronto General Hospital, University Health Network, Toronto, Canada
| | - Markus Selzner
- Multi Organ Transplant Program, Department of Surgery, Toronto General Hospital, University Health Network, Toronto, Canada. .,General Surgery and Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, 585 University Avenue, 11 PMB 178, Toronto, ON, M5G 2N2, Canada.
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Han X, Wang X, Zhao B, Chen G, Sheng Y, Wang W, Teng M. MicroRNA-187 inhibits tumor growth and metastasis via targeting of IGF-1R in hepatocellular carcinoma. Mol Med Rep 2017. [PMID: 28627639 DOI: 10.3892/mmr.2017.6788] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the primary and most frequently occurring type of malignant liver cancer, accounting for 70-85% of total liver cancer cases worldwide. It has previously been demonstrated that the aberrant expression of microRNAs (miR) contributes to carcinogenesis and progression of various human malignancies, including HCC. However, mechanisms underlying the differential expression and specific roles of miR‑187 in HCC remain to be elucidated, particularly regarding how the modulation of malignant phenotypes in HCC cells occurs. The present study demonstrated that miR‑187 was significantly downregulated in HCC tissues and cell lines. Restoration of miR‑187 expression inhibited cell proliferation, migration and invasion in HCC. Furthermore, insulin‑like growth factor 1 receptor (IGF‑1R) was demonstrated to act as a direct target gene of miR‑187 in HCC. IGF‑1R knockdown mimicked the effects of miR‑187 overexpression in HCC, resulting in a significant inhibition of cell proliferation, migration and invasion. The results of the present study demonstrated that miR‑187 acted as a tumor suppressor in HCC progression via direct targeting of IGF‑1R. miR‑187 may therefore exhibit the potential to act as a novel and therapeutic target for HCC treatment in the future.
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Affiliation(s)
- Xinqiang Han
- Department of Interventional Medicine and Vascular Surgery, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China
| | - Xuemin Wang
- Department of Gastroenterology, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China
| | - Baolei Zhao
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China
| | - Gang Chen
- Department of Interventional Medicine and Vascular Surgery, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China
| | - Yuguo Sheng
- Department of Interventional Medicine and Vascular Surgery, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China
| | - Wenming Wang
- Department of Interventional Medicine and Vascular Surgery, The Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong 256603, P.R. China
| | - Mujian Teng
- Department of Hepatobiliary Surgery, Qianfoshan Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China
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Gou Q, He S, Zhou Z. Protein arginine N-methyltransferase 1 promotes the proliferation and metastasis of hepatocellular carcinoma cells. Tumour Biol 2017; 39:1010428317691419. [PMID: 28231732 DOI: 10.1177/1010428317691419] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma is the most common subtype of liver cancer. Protein arginine N-methyltransferase 1 was shown to be upregulated in various cancers. However, the role of protein arginine N-methyltransferase 1 in hepatocellular carcinoma progression remains incompletely understood. We investigated the clinical and functional significance of protein arginine N-methyltransferase 1 in a series of clinical hepatocellular carcinoma samples and a panel of hepatocellular carcinoma cell lines. We performed suppression analysis of protein arginine N-methyltransferase 1 using small interfering RNA to determine the biological roles of protein arginine N-methyltransferase 1 in hepatocellular carcinoma. In addition, the expression of epithelial-mesenchymal transition indicators was verified by western blotting in hepatocellular carcinoma cell lines after small interfering RNA treatment. Protein arginine N-methyltransferase 1 expression was found to be significantly upregulated in hepatocellular carcinoma cell lines and clinical tissues. Moreover, downregulation of protein arginine N-methyltransferase 1 in hepatocellular carcinoma cells by small interfering RNA could inhibit cell proliferation, migration, and invasion in vitro. These results indicate that protein arginine N-methyltransferase 1 may contribute to hepatocellular carcinoma progression and serves as a promising target for the treatment of hepatocellular carcinoma patients.
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Affiliation(s)
- Qing Gou
- 1 Department of Interventional Radiology, Cancer Center, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, P.R. China
| | - ShuJiao He
- 2 Department of Cancer Center, Southern Medical University, Guangzhou, P.R. China.,3 Department of Cancer Center, Chinese Medicine-Integrated Hospital, Guangzhou, P.R. China
| | - ZeJian Zhou
- 1 Department of Interventional Radiology, Cancer Center, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, P.R. China
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Bridging locoregional therapy: Longitudinal trends and outcomes in patients with hepatocellular carcinoma. Transplant Rev (Orlando) 2017; 31:136-143. [PMID: 28214240 DOI: 10.1016/j.trre.2017.01.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 01/28/2017] [Indexed: 12/19/2022]
Abstract
The purpose of this article is to analyze longitudinal trends in locoregional therapy (LRT) use and review locoregional therapy's role in the management of hepatocellular carcinoma prior to orthotropic liver transplantation Porrett et al. (2006) . LRT has a role in both bridge to transplantation and downstaging of patients not initially meeting Milan or UCSF Criteria. Due to the lack of randomized controlled trials, no specific bridging LRT modality is recommended over another for treating patients on the waiting list, however each modality has unique and patient-specific advantages. Pre-transplant LRT use in the United States has increased dramatically over the last two decades with more than 50% of the currently listed patients receiving LRT Freeman et al. (2008) . Despite these national trends, significant differences in LRT utilization, referral patterns, recurrence rates and survival have been observed among UNOS regions, socioeconomic levels and races. The use of LRT as a biologic selection tool based on response to treatment has shown promising results in its ability to predict successful post-transplant outcomes.
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Stewart SL, Kwong SL, Bowlus CL, Nguyen TT, Maxwell AE, Bastani R, Chak EW, Chen Jr MS. Racial/ethnic disparities in hepatocellular carcinoma treatment and survival in California, 1988-2012. World J Gastroenterol 2016; 22:8584-8595. [PMID: 27784971 PMCID: PMC5064040 DOI: 10.3748/wjg.v22.i38.8584] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 08/16/2016] [Accepted: 09/12/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To describe racial/ethnic differences in treatment and survival among liver cancer patients in a population-based cancer registry.
METHODS Invasive cases of primary hepatocellular carcinoma, n = 33270, diagnosed between January 1, 1988-December 31, 2012 and reported to the California Cancer Registry were analyzed by race/ethnicity, age, gender, geographical region, socio-economic status, time period of diagnosis, stage, surgical treatment, and survival. Patients were classified into 15 racial/ethnic groups: non-Hispanic White (White, n = 12710), Hispanic (n = 8500), Chinese (n = 2723), non-Hispanic Black (Black, n = 2609), Vietnamese (n = 2063), Filipino (n = 1479), Korean (n = 1099), Japanese (n = 658), American Indian/Alaskan Native (AIAN, n = 281), Laotian/Hmong (n = 244), Cambodian (n = 233), South Asian (n = 190), Hawai`ian/Pacific Islander (n = 172), Thai (n = 95), and Other Asian (n = 214). The main outcome measures were receipt of surgical treatment, and cause-specific and all-cause mortality.
RESULTS After adjustment for socio-demographic characteristics, time period, and stage of disease, compared to Whites, Laotian/Hmong [odds ratio (OR) = 0.30, 95%CI: 0.17-0.53], Cambodian (OR = 0.65, 95%CI: 0.45-0.96), AIAN (OR = 0.66, 95%CI: 0.46-0.93), Black (OR = 0.76, 95%CI: 0.67-0.86), and Hispanic (OR = 0.78, 95%CI: 0.72-0.84) patients were less likely, whereas Chinese (OR = 1.58, 95%CI: 1.42-1.77), Koreans (OR = 1.45, 95%CI: 1.24-1.70), Japanese (OR = 1.41, 95%CI: 1.15-1.72), and Vietnamese (OR = 1.26, 95%CI: 1.12-1.42) were more likely to receive surgical treatment. After adjustment for the same covariates and treatment, cause-specific mortality was higher for Laotian/Hmong [(hazard ratio (HR) = 1.50, 95%CI: 1.29-1.73)], Cambodians (HR = 1.35, 95%CI: 1.16-1.58), and Blacks (HR = 1.07, 95%CI: 1.01-1.13), and lower for Chinese (HR = 0.82, 95%CI: 0.77-0.86), Filipinos (HR = 0.84, 95%CI: 0.78-0.90), Vietnamese (HR = 0.85, 95%CI: 0.80-0.90), Koreans (HR = 0.90, 95%CI: 0.83-0.97), and Hispanics (HR = 0.91, 95%CI: 0.88-0.94); results were similar for all-cause mortality.
CONCLUSION Disaggregated data revealed substantial racial/ethnic differences in liver cancer treatment and survival, demonstrating the need for development of targeted interventions to mitigate disparities.
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miR-503 suppresses metastasis of hepatocellular carcinoma cell by targeting PRMT1. Biochem Biophys Res Commun 2015; 464:982-987. [PMID: 26163260 DOI: 10.1016/j.bbrc.2015.06.169] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 06/30/2015] [Indexed: 11/22/2022]
Abstract
Accumulating evidence indicates that microRNAs function as oncogenes or tumor suppressor genes in human cancer. MiR-503 is deregulated in various human cancers and has been associated with hepatocellular carcinoma (HCC) progression. However, the underlying mechanisms of miR-503 involvement in the development and progression of HCC remains poorly understood. In the present study, we report that miR-503 suppresses cell metastasis in HCC through targeting the protein arginine methyl transferase 1 (PRMT1) mRNA. Notably, we identified that miR-503 was able to target 3'-untranslated region (3'-UTR) of PRMT1 mRNA by luciferase reporter gene assays. Then, we revealed that miR-503 was able to reduce the expression of PRMT1 at the levels of mRNA and protein using RT-PCR and Western blotting analysis. The expression levels of miR-503 were negatively related to those of PRMT1 mRNA in clinical HCC tissues. In terms of function, transwell and wound healing assays demonstrated that the miR-503 remarkably inhibited invasion and migration of HCC cells, which was reversed by overexpressed PRMT1. Furthermore, exogenous expression of miR-503 dramatically suppressed epithelial-mesenchymal transition (EMT) via PRMT1 in HCC cells. In conclusion, we denomstrated PRMT1 as a novel target gene of miR-503 and miR-503-mediated PRMT1 could also emerge as a potential important biomarker for HCC.
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