73 results on '"Roberts, Lewis R."'
Search Results
2. Comparison of Surgical Resection and Systemic Treatment for Hepatocellular Carcinoma with Vascular Invasion: National Cancer Database Analysis
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Govalan, Rajalakshmi, Lauzon, Marie, Luu, Michael, Ahn, Joseph C, Kosari, Kambiz, Todo, Tsuyoshi, Kim, Irene K, Noureddin, Mazen, Kuo, Alexander, Walid, Ayoub S, Sundaram, Vinay, Lu, Shelly C, Roberts, Lewis R, Singal, Amit G, Heimbach, Julie K, Agopian, Vatche G, Nissen, Nicholas, and Yang, Ju Dong
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Digestive Diseases ,Patient Safety ,Cancer ,Liver Cancer ,Rare Diseases ,Liver Disease ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,6.4 Surgery ,Hepatocellular carcinoma ,Vascular invasion ,Surgical resection ,Prognosis - Abstract
IntroductionSmall studies from outside of the USA suggest excellent outcomes after surgical resection for hepatocellular carcinoma (HCC) with vascular invasion. The study aims to (1) compare overall survival after surgical resection and systemic therapy among patients with HCC and vascular invasion and (2) determine factors associated with receipt of surgical resection in a US population.MethodsHCC patients with AJCC clinical TNM stage 7th T3BN0M0 diagnosed between 2010 and 2017 from the National Cancer Database were analyzed. Cox and logistic regression analyses identified factors associated with overall survival and receipt of surgical resection.ResultsOf 11,259 patients with T3BN0M0 HCC, 325 (2.9%) and 4,268 (37.9%) received surgical resection and systemic therapy, respectively. In multivariable analysis, surgical resection was associated with improved survival compared to systemic therapy (adjusted hazard ratio: 0.496, 95% confidence interval: 0.426-0.578) with a median survival of 21.4 and 8.1 months, respectively. Superiority of surgical resection was observed in noncirrhotic and cirrhotic subgroups and propensity score matching and inverse probability of treatment weighting adjusted analysis. Asians were more likely to receive surgical resection, whereas Charlson comorbidity ≥3, elevated alpha-fetoprotein, smaller tumor size, care in a community cancer program, and the South or West region were associated with a lower likelihood of surgical resection.ConclusionHCC patients with vascular invasion may benefit from surgical resection compared to systemic therapies. Demographic and clinical features of HCC patients and region and type of treating facility were associated with surgical resection versus systemic treatment.
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- 2021
3. PKCλ/ι Loss Induces Autophagy, Oxidative Phosphorylation, and NRF2 to Promote Liver Cancer Progression
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Kudo, Yotaro, Sugimoto, Masayuki, Arias, Esperanza, Kasashima, Hiroaki, Cordes, Thekla, Linares, Juan F, Duran, Angeles, Nakanishi, Yuki, Nakanishi, Naoko, L'Hermitte, Antoine, Campos, Alex, Senni, Nadia, Rooslid, Tarmo, Roberts, Lewis R, Cuervo, Ana Maria, Metallo, Christian M, Karin, Michael, Diaz-Meco, Maria T, and Moscat, Jorge
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biological Sciences ,Digestive Diseases ,Cancer ,Liver Cancer ,Chronic Liver Disease and Cirrhosis ,Rare Diseases ,Liver Disease ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Autophagy ,Carcinoma ,Hepatocellular ,Cell Line ,Cell Line ,Tumor ,Disease Progression ,HEK293 Cells ,Hep G2 Cells ,Humans ,Isoenzymes ,Liver Neoplasms ,Mice ,Knockout ,NF-E2-Related Factor 2 ,Oxidative Phosphorylation ,Protein Kinase C ,RNA Interference ,NRF2 ,PKCζ ,PKCι ,PKCλ ,atypical PKC ,autophagy ,hepatocellular carcinoma ,metabolic reprogramming ,oxidative phosphorylation ,reactive oxygen species ,Neurosciences ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Oxidative stress plays a critical role in liver tissue damage and in hepatocellular carcinoma (HCC) initiation and progression. However, the mechanisms that regulate autophagy and metabolic reprogramming during reactive oxygen species (ROS) generation, and how ROS promote tumorigenesis, still need to be fully understood. We show that protein kinase C (PKC) λ/ι loss in hepatocytes promotes autophagy and oxidative phosphorylation. This results in ROS generation, which through NRF2 drives HCC through cell-autonomous and non-autonomous mechanisms. Although PKCλ/ι promotes tumorigenesis in oncogene-driven cancer models, emerging evidence demonstrate that it is a tumor suppressor in more complex carcinogenic processes. Consistently, PKCλ/ι levels negatively correlate with HCC histological tumor grade, establishing this kinase as a tumor suppressor in liver cancer.
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- 2020
4. Hepatocellular Carcinoma
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Ehman, Eric C., Torbenson, Michael S., Hallemeier, Christopher L., Heimbach, Julie K., Roberts, Lewis R., Roberts, Lewis R., editor, Yang, Ju Dong, editor, and Venkatesh, Sudhakar K., editor
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- 2020
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5. p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and Liver Cancer
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Duran, Angeles, Hernandez, Eloy D, Reina-Campos, Miguel, Castilla, Elias A, Subramaniam, Shankar, Raghunandan, Sindhu, Roberts, Lewis R, Kisseleva, Tatiana, Karin, Michael, Diaz-Meco, Maria T, and Moscat, Jorge
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Nutrition ,Chronic Liver Disease and Cirrhosis ,Digestive Diseases ,Liver Cancer ,Rare Diseases ,Liver Disease ,Cancer ,Oral and gastrointestinal ,Animals ,HEK293 Cells ,Hepatic Stellate Cells ,Humans ,Liver Cirrhosis ,Liver Neoplasms ,Mice ,Mice ,Knockout ,Receptors ,Calcitriol ,Retinoid X Receptors ,Sequestosome-1 Protein ,Signal Transduction ,fibrosis ,hepatic stellate cells ,hepatocellular carcinoma ,inflammation ,liver cancer ,non-alcoholic steatohepatitis ,nuclear receptors ,p62 ,sequestosome-1 ,vitamin D receptor ,Neurosciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Hepatic stellate cells (HSCs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). Vitamin D receptor (VDR) activation in HSCs inhibits liver inflammation and fibrosis. We found that p62/SQSTM1, a protein upregulated in liver parenchymal cells but downregulated in HCC-associated HSCs, negatively controls HSC activation. Total body or HSC-specific p62 ablation potentiates HSCs and enhances inflammation, fibrosis, and HCC progression. p62 directly interacts with VDR and RXR promoting their heterodimerization, which is critical for VDR:RXR target gene recruitment. Loss of p62 in HSCs impairs the repression of fibrosis and inflammation by VDR agonists. This demonstrates that p62 is a negative regulator of liver inflammation and fibrosis through its ability to promote VDR signaling in HSCs, whose activation supports HCC.
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- 2016
6. DNA methylation of individual repetitive elements in hepatitis C virus infection-induced hepatocellular carcinoma
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Zheng, Yinan, Hlady, Ryan A., Joyce, Brian T., Robertson, Keith D., He, Chunyan, Nannini, Drew R., Kibbe, Warren A., Achenbach, Chad J., Murphy, Robert L., Roberts, Lewis R., and Hou, Lifang
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- 2019
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7. Should AFP (or Any Biomarkers) Be Used for HCC Surveillance?
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Ahmed Mohammed, Hager F. and Roberts, Lewis R.
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- 2017
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8. Loss of LncRNA DUXAP8 synergistically enhanced sorafenib induced ferroptosis in hepatocellular carcinoma via SLC7A11 de‐palmitoylation.
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Shi, Zhehao, Li, Zhiming, Jin, Bin, Ye, Wen, Wang, Luhui, Zhang, Sina, Zheng, Jiuyi, Lin, Zixia, Chen, Bo, Liu, Fangting, Zhang, Baofu, Ding, Xiwei, Yang, Zhen, Shan, Yunfeng, Yu, Zhengping, Wang, Yi, Chen, Jicai, Chen, Qiang, Roberts, Lewis R., and Chen, Gang
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GLUTAMATE transporters ,HEPATOCELLULAR carcinoma ,SORAFENIB ,LINCRNA ,LIVER cancer ,CONTRAST-enhanced ultrasound ,HUMAN facial recognition software - Abstract
Background: Ferroptosis is an important iron‐dependent form of cell death in hepatocellular carcinoma (HCC). Sorafenib, a potent ferroptosis inducer, is used to treat advanced HCC but its efficacy is limited by the development of drug resistance. Methods: The effects of DUXAP8 expression on HCC progression were evaluated by TCGA database, Kaplan‐Meier analysis, and in situ hybridization analysis. Sorafenib resistant HCC cell lines were modeled in vitro to study the regulation of DUXAP8 on ferroptosis in HCC induced by sorafenib. We used RNA pull‐down, immunofluorescence assays, acyl‐biotinyl exchange assay and mass spectrometry analysis to assess the molecular mechanism of ferroptosis regulation by DUXAP8. Syngeneic subcutaneous and orthotopic CDX models were used to assess whether DUXAP8 inhibition improves HCC in vivo. Results: LncRNA DUXAP8, which is highly expressed in liver cancer and associated with poor prognosis, contributes to sorafenib resistance through suppression of ferroptosis. In vitro tests revealed that DUXAP8 reduced the sensitivity of HCC to sorafenib‐induced ferroptosis by acting on SLC7A11, a subunit of the amino acid antiporter system xc‐. DUXAP8 facilitates SLC7A11 palmitoylation and impedes its lysosomal degradation, thereby enhancing SLC7A11 action and suppressing ferroptosis. RNA pull‐down and immunofluorescence assays confirmed that DUXAP8 decreased membrane translocation and promoted sorting of de‐palmitoylated SLC7A11 to lysosomes by binding of DUXAP8 to SLC7A11. In addition, mass spectrometric analysis found that the Cys414 residue of SLC7A11 might be the predominant mutant site responsible for molecular masking of SLC7A11 lysosomal sorting. Further, the antitumor effect of DUXAP8 knockdown was verified in orthotopic and subcutaneous CDX models. Conclusions: Our findings suggest that a novel translational strategy combining sorafenib with DUXAP8 silencing to overcome drug resistance may improve treatment efficacy in patients with advanced HCC. [ABSTRACT FROM AUTHOR]
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- 2023
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9. Evidence for Benefits of Early Treatment Initiation for Chronic Hepatitis B.
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Lim, Young-Suk, Kim, W. Ray, Dieterich, Douglas, Kao, Jia-Horng, Flaherty, John F., Yee, Leland J., Roberts, Lewis R., Razavi, Homie, and Kennedy, Patrick T. F.
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CHRONIC hepatitis B ,HEPATITIS C ,HEPATIC fibrosis ,HEPATOCELLULAR carcinoma - Abstract
Chronic hepatitis B (CHB) is the most common cause of hepatocellular carcinoma (HCC) worldwide. Antiviral treatment reduces the risk of HCC and mortality; nonetheless, globally in 2019, only 2.2% of CHB patients received treatment. Current international CHB guidelines recommend antiviral treatment only in subsets of patients with clear evidence of liver damage. This contrasts with hepatitis C or HIV where early treatment is recommended in all infected patients, regardless of end-organ damage. This narrative review aims to provide an overview of data on the early initiation of antiviral treatment and its related potential economic impact. Literature searches were performed using PubMed and abstracts from international liver congresses (2019–2021). Data on risk of disease progression and HCC and the impact of antiviral treatment in currently ineligible patients were summarized. Cost-effectiveness data on early antiviral treatment initiation were also collated. Accumulating molecular, clinical, and economic data suggest that early initiation of antiviral treatment could save many lives through HCC prevention in a highly cost-effective manner. In light of these data, we consider several alternative expanded treatment strategies that might further a simplified 'treatment as prevention' approach. [ABSTRACT FROM AUTHOR]
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- 2023
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10. TACE versus TARE for patients with hepatocellular carcinoma: Overall and individual patient level meta analysis.
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Brown, Andrew M., Kassab, Ihab, Massani, Marco, Townsend, Whitney, Singal, Amit G., Soydal, Cigdem, Moreno‐Luna, Laura, Roberts, Lewis R., Chen, Vincent L., and Parikh, Neehar D.
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HEPATOCELLULAR carcinoma ,CHEMOEMBOLIZATION ,LIVER cancer ,TUMOR classification ,OVERALL survival - Abstract
Background: Transarterial radioembolization (TARE) is increasingly used as an alternative to transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC). We aimed to perform an overall and individual patient data (IPD) meta‐analysis of studies comparing TACE and TARE. Methods: We performed a systematic literature search using pre‐specified keywords with the aid of an informationist for articles from inception to 3/2020. The primary endpoint was overall survival (OS), and the secondary endpoint was time to progression (TTP). Results: Seventeen studies met inclusion criteria with 2465 unique patients, with one randomized trial, 4 prospective studies and 12 retrospective studies. Barcelona Clinic Liver Cancer (BCLC) stage B (42.8%) was the most common stage followed by BCLC A (30.3%) and BCLC C (29.0%). There was no difference in OS between the two modalities (−0.55 months, 95% CI −1.95 to 3.05). In three studies with available TTP data, TARE resulted in a longer TTP than TACE (mean TTP 17.5 vs. 9.8 months; mean TTP difference 4.8 months, 95% CI 1.3–8.3 months). IPD‐level meta‐analysis of 311 patients from three studies showed no difference in overall OS between the two modalities including among subgroups stratified by tumor stage and liver function. Limitations of the current literature include inconsistent length of follow‐up, inconsistency in response criteria, and safety reporting. Conclusions: Current data suggest TARE provides significantly longer TTP than TACE, although the two treatments do not significantly differ in terms of OS. Given limitations of the current data, there is rationale for prospective studies comparing these modalities. [ABSTRACT FROM AUTHOR]
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- 2023
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11. Role for Putative Hepatocellular Carcinoma Stem Cell Subpopulations in Biological Response to Incomplete Thermal Ablation: In Vitro and In Vivo Pilot Study
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Thompson, Scott M., Callstrom, Matthew R., Butters, Kim A., Sutor, Shari L., Knudsen, Bruce, Grande, Joseph P., Roberts, Lewis R., and Woodrum, David A.
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- 2014
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12. Gaps in hepatocellular carcinoma surveillance in a United States cohort of insured patients with cirrhosis.
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Nguyen, Mindie H., Roberts, Lewis R., Engel-Nitz, Nicole M., Bancroft, Tim, Ozbay, A. Burak, and Singal, Amit G.
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HEPATOCELLULAR carcinoma , *NON-alcoholic fatty liver disease , *MASS surveillance , *CIRRHOSIS of the liver , *MAGNETIC resonance imaging , *VIRAL hepatitis - Abstract
Surveillance for hepatocellular carcinoma (HCC) is known to be underutilized; however, neither the variation of surveillance adherence by cirrhosis etiology nor the patient-side economic burden of surveillance are well understood. To identify potential barriers to HCC surveillance, we assessed utilization patterns and costs among US patients with cirrhosis monitored in routine clinical practice. We conducted a retrospective study of insured adult patients with cirrhosis using national administrative claims data from January 2013 through June 2019. Time up-to-date with recommended surveillance, correlates of surveillance receipt, and surveillance-associated costs were assessed during a ≥ 6-month follow-up. Among 15,543 patients with cirrhosis (mean [SD] age 64.0 [11.1] years, 50.7% male), 45.8% and 58.7% had received any abdominal imaging at 6 and 12 months, respectively. Patients were up-to-date with recommended surveillance for only 31% of a median 1.3-year follow-up. Those with viral hepatitis were more likely to receive surveillance than those with other etiologies (hazard ratio [HR] 1.55, 95% CI 1.11–2.17, p =.010 for patients without a baseline gastroenterologist [GI] visit and 2.69, 95% CI 1.77–4.09, p <.001 for patients with a GI visit, relative to those with nonalcoholic fatty liver disease and no GI visit). For all etiologies except NAFLD, the HR (95% CI) for surveillance receipt was higher among patients with vs without a baseline GI visit (alcohol-related, 1.164 [1.002–1.351] vs 0.880 [0.796–0.972]; viral hepatitis, 2.688 [1.765–4.093] vs 1.553 [1.111–2.171]; Other, 0.612 [0.519–0.722] vs 0.549 [0.470–0.641]). Mean total and patient-paid daily surveillance-related costs ranged from $540 and $113, respectively (ultrasound) to $1580 and $300, respectively (magnetic resonance imaging), and mean estimated patient productivity costs were $730–$2514 annually. HCC surveillance was underutilized and was lowest among patients with nonviral etiologies and those who had not seen a gastroenterologist. Surveillance-related out-of-pocket expenses and lost productivity were substantial. The development of surveillance strategies that reduce patient burden, such as those using blood-based biomarkers, may help improve surveillance adherence and effectiveness. [ABSTRACT FROM AUTHOR]
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- 2022
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13. Gaps in hepatocellular carcinoma surveillance among insured patients with hepatitis B infection without cirrhosis in the United States.
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Nguyen, Mindie H., Roberts, Lewis R., Engel‐Nitz, Nicole M., Bancroft, Tim, Ozbay, A. Burak, and Singal, Amit G.
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HEPATITIS B ,HEPATOCELLULAR carcinoma ,HEPATITIS B virus ,MAGNETIC resonance imaging ,CIRRHOSIS of the liver - Abstract
Suboptimal adherence to guidelines for hepatocellular carcinoma (HCC) surveillance among high‐risk patients is a persistent problem with substantial detriment to patient outcomes. While patients cite cost as a barrier to surveillance receipt, the financial burden they experience due to surveillance has not been examined. We conducted a retrospective administrative claims study to assess HCC surveillance use and associated costs in a US cohort of insured patients without cirrhosis but with hepatitis B virus (HBV) infection, monitored in routine clinical practice. Of 6831 patients (1122 on antiviral treatment, 5709 untreated), only 39.3% and 51.3% had received any abdominal imaging after 6 and 12 months, respectively, and patients were up to date with HCC surveillance guidelines for only 28% of the follow‐up time. Completion of surveillance was substantially higher at 6 and 12 months among treated patients (51.7% and 69.6%, respectively) compared with untreated patients (36.9% and 47.6%, respectively) (p < 0.001). In adjusted models, treated patients were more likely than untreated patients to receive surveillance (hazard ratio [HR] 1.75, 95% confidence interval [CI] 1.53–2.01, p < 0.001), and the proportion of those up to date with surveillance was 9.7% higher (95% CI 6.26–13.07, p < 0.001). Mean total and patient‐paid daily surveillance‐related costs ranged from $99 (ultrasound) to $334 (magnetic resonance imaging), and mean annual patient costs due to lost productivity for surveillance‐related outpatient visits ranged from $93 (using the federal minimum wage) to $321 (using the Bureau of Labor Statistics wage). Conclusion: Use of current HCC surveillance strategies was low across patients with HBV infection, and surveillance was associated with substantial patient financial burden. These data highlight an urgent need for accessible and easy‐to‐implement surveillance strategies with sufficient sensitivity and specificity for early HCC detection. [ABSTRACT FROM AUTHOR]
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- 2022
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14. Mortality burden due to liver cirrhosis and hepatocellular carcinoma in Ghana; prevalence of risk factors and predictors of poor in-hospital survival.
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Nartey, Yvonne A., Antwi, Samuel O., Bockarie, Ansumana S., Hiebert, Lindsey, Njuguna, Henry, Ward, John W., Awuku, Yaw A., Plymoth, Amelie, and Roberts, Lewis R.
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HOSPITAL mortality ,CIRRHOSIS of the liver ,HEPATOCELLULAR carcinoma ,HEPATIC encephalopathy ,HEPATITIS B ,DEATH rate - Abstract
Liver-related diseases, including liver cirrhosis and hepatocellular carcinoma (HCC), are significant causes of mortality globally. Specific causes and predictors of liver-related mortality in low resource settings require assessment to help inform clinical decision making and develop strategies for improved survival. The objectives of this study were to determine the proportion of liver-related deaths associated with liver cirrhosis, HCC, and their known risk factors, and secondly to determine predictors of in-hospital mortality among cirrhosis and HCC patients in Ghana. We first performed a cross-sectional review of death register entries from 11 referral hospitals in Ghana to determine the proportion of liver-related deaths and the proportion of risk factors associated with these deaths. Secondly, we conducted a retrospective cohort review of 172 in-patient liver cirrhosis and HCC cases admitted to a tertiary referral centre and determined predictors of in-hospital mortality using binary logistic regression and Kaplan-Meier survival analysis. In total, 8.8% of deaths in Ghanaian adults were due to liver-related causes. The proportion of liver-related deaths attributed to HBV infection was 48.8% (95% CI: 45.95–51.76), HCV infection was 7.0% (95% CI: 5.58–8.45), HBV-HCV co-infection 0.5% (95% CI: 0.1–0.9) and alcohol was 10.0% (95% CI: 8.30–11.67). Of 172 cases of HCC and liver cirrhosis, the in-patient mortality rate was 54.1%. Predictors of in-patient mortality in cirrhotic patients were increasing WBC (OR = 1.14 95% CI: 1.00–1.30) and the revised model for end-stage liver disease with sodium (MELD-Na) score (OR = 1.24 95% CI: 1.01–1.54). For HCC patients, female sex (OR = 3.74 95% CI: 1.09–12.81) and hepatic encephalopathy (grade 1) were associated with higher mortality (OR = 5.66 95% CI: 1.10–29.2). In conclusion, HBV is linked to a high proportion of HCC-related deaths in Ghana, with high in-hospital mortality rates that require targeted policies to improve survival. [ABSTRACT FROM AUTHOR]
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- 2022
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15. Efficacy and Safety of Transarterial Radioembolization Versus Chemoembolization in Patients With Hepatocellular Carcinoma
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Moreno-Luna, Laura E., Yang, Ju Dong, Sanchez, William, Paz-Fumagalli, Ricardo, Harnois, Denise M., Mettler, Teresa A., Gansen, Denise N., de Groen, Piet C., Lazaridis, Konstantinos N., Narayanan Menon, K. V., LaRusso, Nicholas F., Alberts, Steven R., Gores, Gregory J., Fleming, Chad J., Slettedahl, Seth W., Harmsen, William S., Therneau, Terry M., Wiseman, Gregory A., Andrews, James C., and Roberts, Lewis R.
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- 2013
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16. AS30D Model of Hepatocellular Carcinoma: Tumorigenicity and Preliminary Characterization by Imaging, Histopathology, and Immunohistochemistry
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Thompson, Scott M., Callstrom, Matthew R., Knudsen, Bruce, Anderson, Jill L., Butters, Kim A., Grande, Joseph P., Roberts, Lewis R., and Woodrum, David A.
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- 2013
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17. Association of metabolic health phenotypes, obesity, and hepatocellular carcinoma risk.
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Nasereldin, Duaa S., White, Launia J., Hodge, David O., Roberts, Lewis R., Patel, Tushar, and Antwi, Samuel O.
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The obesity and hepatocellular carcinoma (HCC) risk association may differ by individuals' metabolic health status. To investigate the association between obesity categories and HCC risk among individuals with different metabolic health phenotypes. A case-control study among 518 HCC cases and 1,036 frequency-matched controls was conducted. Body mass index (BMI) was assessed before diagnosis. Pre-diagnosis data on dyslipidemia, hypertension, and diabetes were used to categorize participants as metabolically healthy or metabolically unhealthy. Participants were further categorized into metabolically healthy normal weight (MHNW), metabolically healthy overweight (MHOW), metabolically healthy obese (MHO), metabolically unhealthy normal weight (MUNW), metabolically unhealthy overweight (MUOW), and metabolically unhealthy obese (MHO). We used logistic regression to calculate multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Being overweight (OR=1.68, 95%CI=1.21–2.34) or obese (OR=1.49, 95%CI=1.11–1.89) was associated with higher HCC risk. Among metabolically healthy participants, no association was found between being overweight or obese and HCC risk. However, among the metabolically unhealthy participants, being overweight (OR=1.89, 95%CI=1.31–2.72) or obese (OR=1.50, 95%CI=1.07–2.09) was associated with higher HCC risk. Compared to the MHNW phenotype, no association was found between the MHOW and MHO phenotypes and HCC risk, but the MUNW (OR=1.94, 95%CI=1.09–3.43), MUOW (OR=3.78, 95%CI=2.15–6.65), and MUO (OR=2.93, 95%CI=1.70–5.05) phenotypes were associated with higher HCC risk. The association between BMI and HCC appears to be restricted to individuals with underlying metabolic abnormalities. [ABSTRACT FROM AUTHOR]
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- 2022
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18. RNA Therapeutic Options to Manage Aberrant Signaling Pathways in Hepatocellular Carcinoma: Dream or Reality?
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Sartorius, Kurt, Antwi, Samuel O., Chuturgoon, Anil, Roberts, Lewis R., and Kramvis, Anna
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SMALL interfering RNA ,RNA ,HEPATOCELLULAR carcinoma ,CELLULAR signal transduction ,CATALYTIC RNA - Abstract
Despite the early promise of RNA therapeutics as a magic bullet to modulate aberrant signaling in cancer, this field remains a work-in-progress. Nevertheless, RNA therapeutics is now a reality for the treatment of viral diseases (COVID-19) and offers great promise for cancer. This review paper specifically investigates RNAi as a therapeutic option for HCC and discusses a range of RNAi technology including anti-sense oligonucleotides (ASOs), Aptamers, small interfering RNA (siRNA), ribozymes, riboswitches and CRISPR/Cas9 technology. The use of these RNAi based interventions is specifically outlined in three primary strategies, namely, repressing angiogenesis, the suppression of cell proliferation and the promotion of apoptosis. We also discuss some of the inherent chemical and delivery problems, as well as targeting issues and immunogenic reaction to RNAi interventions. [ABSTRACT FROM AUTHOR]
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- 2022
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19. PSMA as a Theranostic Target in Hepatocellular Carcinoma: Immunohistochemistry and 68Ga‐PSMA‐11 PET Using Cyclotron‐Produced 68Ga.
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Thompson, Scott M., Suman, Garima, Torbenson, Michael S., Chen, Zong‐Ming E., Jondal, Danielle E., Patra, Anurima, Ehman, Eric C., Andrews, James C., Fleming, Chad J., Welch, Brian T., Kurup, Anil N., Roberts, Lewis R., Watt, Kymberly D., Truty, Mark J., Cleary, Sean P., Smoot, Rory L., Heimbach, Julie K., Tran, Nguyen H., Mahipal, Amit, and Yin, Jun
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HEPATOCELLULAR carcinoma ,FIBROBLAST growth factors ,POSITRON emission tomography ,CHRONIC hepatitis B ,HEPATITIS C virus ,HEPATITIS B virus - Abstract
Prostate‐specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with 68Ga‐PSMA‐11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, 68Ga‐PSMA‐11 PET was prospectively performed in patients with treatment‐naïve HCC on a digital PET scanner using cyclotron‐produced 68Ga. Uptake was graded qualitatively and semi‐quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA (P < 0.0001); 91% of HCCs (n = 134) expressed PSMA, which principally localized to tumor‐associated neovasculature. Higher tumor grade was associated with PSMA expression (P = 0.012) but there was no association with tumor size (P = 0.14), fibrosis (P = 0.35), cirrhosis (P = 0.74), hepatitis B virus (P = 0.31), or hepatitis C virus (P = 0.15). Overall survival tended to be longer in patients without versus with PSMA expression (median overall survival: 4.2 vs. 1.9 years; P = 0.273). FGF14 (fibroblast growth factor 14) mRNA expression correlated positively (rho = 0.70; P = 1.70 × 10‐5) and MAD1L1 (Mitotic spindle assembly checkpoint protein MAD1) correlated negatively with PSMA expression (rho = −0.753; P = 1.58 × 10‐6). Of the 190 patients who met the eligibility criteria, 31 patients with 39 HCC lesions completed PET; 64% (n = 25) lesions had pronounced 68Ga‐PSMA‐11 standardized uptake value: SUVmax (median [range] 9.2 [4.9‐28.4]), SUVmean 4.7 (2.4‐12.7), and tumor‐to‐liver background ratio 2 (1.1‐11). Conclusion: Ex vivo expression of PSMA in neovasculature of HCC translates to marked tumor avidity on 68Ga‐PSMA‐11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC. [ABSTRACT FROM AUTHOR]
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- 2022
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20. Mutational spectrum of β-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas
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Taniguchi, Ken, Roberts, Lewis R, Aderca, Ileana N, Dong, Xiangyang, Qian, Chiping, Murphy, Linda M, Nagorney, David M, Burgart, Lawrence J, Roche, Patrick C, Smith, David I, Ross, Julie A, and Liu, Wanguo
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- 2002
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21. Cathepsins as effector proteases in hepatocyte apoptosis
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Roberts, Lewis R., Adjei, Philip N., and Gores, Gregory J.
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- 1999
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22. Therapeutic Underuse and Delay in Hepatocellular Carcinoma: Prevalence, Associated Factors, and Clinical Impact.
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Govalan, Rajalakshmi, Luu, Michael, Lauzon, Marie, Kosari, Kambiz, Ahn, Joseph C., Rich, Nicole E, Nissen, Nicholas, Roberts, Lewis R., Singal, Amit G., and Yang, Ju Dong
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HEPATOCELLULAR carcinoma ,HEALTH facilities ,LOGISTIC regression analysis ,CANCER prognosis ,TREATMENT delay (Medicine) ,PATIENTS' attitudes - Abstract
Prognosis of hepatocellular carcinoma (HCC) could be affected by lack of or delayed therapy. We aimed to characterize the prevalence, correlates, and clinical impact of therapeutic underuse and delay in patients with HCC. Patients with HCC diagnosed between 2010 and 2017 were analyzed from the United States National Cancer Database. Logistic regression analysis identified factors associated with no and delayed (>90 days after diagnosis) HCC treatment. Cox proportional hazards regression with landmark analysis assessed the association between therapeutic delay and overall survival (OS), accounting for immortal time bias. Of 116,299 patients with HCC, 24.2% received no treatment and 18.4% of treated patients had delayed treatment. Older age, Black, Hispanic, lower socioeconomic status, earlier year of diagnosis, treatment at nonacademic centers, Northeast region, increased medical comorbidity, worse liver dysfunction, and higher tumor burden were associated with no treatment. Among treated patients, younger age, Hispanic, Black, treatment at academic centers, West region, earlier tumor stage, and receipt of noncurative treatment were associated with treatment delays. In multivariable Cox regression with a landmark of 150 days, patients with and without treatment delays had similar OS (adjusted hazard ratio [aHR], 1.01; 95% confidence interval [CI], 0.98‐1.04) with a median survival of 33.7 vs. 32.1 months, respectively. However, therapeutic delay was associated with worse OS in patients who had tumor, nodes, and metastases (TNM) stage 1 (aHR, 1.06; 95% CI, 1.01‐1.11) or received curative treatment (aHR, 1.12; 95% CI, 1.05‐1.18). Conclusion: One‐fourth of patients with HCC receive no therapy and one‐fifth of treated patients experience treatment delays. Both were associated with demographic, socioeconomic, and clinical characteristics of patients as well as facility type and region. The association between therapeutic delay and survival was stage and treatment dependent. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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23. Associations of Serum Tumor Biomarkers with Integrated Genomic and Clinical Characteristics of Hepatocellular Carcinoma.
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Ahn, Keun Soo, O'Brien, Daniel R., Kim, Yong Hoon, Kim, Tae-Seok, Yamada, Hiroyuki, Park, Joong-Won, Park, Sang-Jae, Kim, Seoung Hoon, Zhang, Cheng, Li, Hu, Kang, Koo Jeong, and Roberts, Lewis R.
- Subjects
LIVER cancer ,ALPHA fetoproteins ,BIOLOGICAL tags ,P53 protein ,THROMBIN - Abstract
Introduction: Serum α-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-γ-carboxy-pro-thrombin (DCP) are useful biomarkers of hepatocellular carcinoma (HCC). However, associations among molecular characteristics and serum biomarkers are unclear. We analyzed RNA expression and DNA variant data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) to examine their associations with serum biomarker levels and clinical data. Methods: From 371 TCGA-LIHC patients, we selected 91 seen at 3 institutions in Korea and the USA and measured AFP, AFP-L3, and DCP from preoperatively obtained serum. We conducted an integrative clinical and molecular analysis, focusing on biomarkers, and validated the findings with the remaining 280 patients in the TCGA-LIHC cohort. Results: Patients were categorized into 4 subgroups: elevated AFP or AFP-L3 alone (↑AFP&L3), elevated DCP alone (↑DCP), elevation of all 3 biomarkers (elevated levels of all 3 biomarkers [↑All]), and reference range values for all biomarkers (RR). CTNNB1 variants were frequently observed in ↑DCP patients (53.8%) and RR patients (38.5%), but ↑DCP patients with a CTNNB1 variant had worse survival than RR patients. TP53 sequence variants were associated with ↑AFP (30.8%) and ↑DCP (30.8%). The Wnt-β-catenin signaling pathway was activated in the ↑AFP&L3, whereas liver-related Wnt signaling was activated in the RR. TGF-β and VEGF signaling were activated in ↑AFP&L3, whereas dysregulated bile acid and fatty acid metabolism were dominant in ↑DCP. We validated these findings by showing similar results between the test cohort and the remainder of the TCGA-LIHC cohort. Conclusions: Serum AFP, AFP-L3, and DCP levels can help predict variants in the genetic profile of HCC, especially for TP53 and CTNNB1. These findings may facilitate development of an evidence-based approach to treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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24. Exogene: A performant workflow for detecting viral integrations from paired-end next-generation sequencing data.
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Stephens, Zachary, O'Brien, Daniel, Dehankar, Mrunal, Roberts, Lewis R., Iyer, Ravishankar K., and Kocher, Jean-Pierre
- Subjects
HEPATITIS B virus ,WORKFLOW ,HUMAN genome ,WORKFLOW software ,SYSTEM integration ,HEPATOCELLULAR carcinoma ,NUCLEOTIDE sequencing - Abstract
The integration of viruses into the human genome is known to be associated with tumorigenesis in many cancers, but the accurate detection of integration breakpoints from short read sequencing data is made difficult by human-viral homologies, viral genome heterogeneity, coverage limitations, and other factors. To address this, we present Exogene, a sensitive and efficient workflow for detecting viral integrations from paired-end next generation sequencing data. Exogene's read filtering and breakpoint detection strategies yield integration coordinates that are highly concordant with long read validation. We demonstrate this concordance across 6 TCGA Hepatocellular carcinoma (HCC) tumor samples, identifying integrations of hepatitis B virus that are also supported by long reads. Additionally, we applied Exogene to targeted capture data from 426 previously studied HCC samples, achieving 98.9% concordance with existing methods and identifying 238 high-confidence integrations that were not previously reported. Exogene is applicable to multiple types of paired-end sequence data, including genome, exome, RNA-Seq and targeted capture. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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25. Differential characteristics and outcomes of Asian and non‐Asian patients with HBV‐related hepatocellular carcinoma.
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Huang, Daniel Q., Hoang, Joseph K., Leong, Jennifer, Riveiro‐Barciela, Mar, Maeda, Mayumi, Yang, Ju Dong, Accarino, Elena Vargas, Thin, Khin, Trinh, Lindsey, Cheung, Ramsey C., Roberts, Lewis R., Buti, Maria, Schwartz, Myron, and Nguyen, Mindie H.
- Subjects
HEPATOCELLULAR carcinoma ,ASIANS ,SURVIVAL rate ,HEPATITIS B virus ,GENDER - Abstract
Background & Aims: The epidemiology of hepatitis B virus (HBV) infection differs between Asians and non‐Asians, but little is known regarding the effect of ethnicity on outcomes of HBV‐related hepatocellular carcinoma (HCC). We aim to characterize the presentation and survival outcomes in Asian and non‐Asian patients with HBV‐related HCC. Methods: We analyzed the baseline characteristics and long‐term survival of 613 Asian and 410 non‐Asian patients with HBV‐related HCC from three US and one Spanish centre. Results: Overall, non‐Asian patients were more likely to have HIV or hepatitis C co‐infection, cirrhosis, decompensated liver disease and advanced BCLC stage (all P ≤.04). Compared with Asians, non‐Asians were more likely to be listed for transplantation (P <.0001) and undergo HCC treatment with curative intent (P =.003). Propensity‐score matching on HCC diagnosis year, gender and age was performed to balance the two groups for survival analysis and yielded 370 pairs of patients. There was no significant difference in survival overall (P =.43) and among patients with cirrhosis (P =.57). Among patients without cirrhosis, non‐Asians had poorer 5‐year survival compared with Asians (37.6% vs 53.7%, P =.01), and was associated with poorer survival after adjusting for age, gender, diabetes, alcohol, co‐infections, diagnosis date, antiviral therapy, BCLC stage and HCC treatment (adjusted HR 2.01 [95% CI 1.07‐3.74], P =.03). Conclusion: Among HBV‐related HCC patients, non‐Asians presented with more advanced BCLC stage compared to Asians. Non‐Asian ethnicity was independently associated with twice the risk of mortality among patients without cirrhosis, but not among those with cirrhosis. Additional studies are needed to clarify this disparity. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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26. Prognostic Significance of Neutrophil to Lymphocyte Ratio Dynamics in Patients with Hepatocellular Carcinoma Treated with Radioembolization Using Glass Microspheres.
- Author
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Li, Xi, Montazeri, S. Ali, Paz-Fumagalli, Ricardo, Padula, Carlos A., Wang, Weiping, Mody, Kabir, Roberts, Lewis R., Patel, Tushar, Krishnan, Sunil, and Toskich, Beau
- Subjects
LYMPHOCYTE count ,NEUTROPHIL lymphocyte ratio ,HEPATOCELLULAR carcinoma ,RADIOEMBOLIZATION ,WILCOXON signed-rank test ,OVERALL survival - Abstract
Purpose: To study the prognostic significance of neutrophil and lymphocyte dynamics in patients with hepatocellular carcinoma (HCC) treated with radioembolization. Methods: A retrospective, single-center review of clinical records and treatment parameters (liver volume treated, administered activity, and radiation dose) in consecutive patients who received radioembolization for HCC was performed between August 20, 2015, and May 24, 2019. Neutrophil and lymphocyte variables associated with overall survival (OS) were determined by Barcelona Clinic Liver Cancer (BCLC) stage and were correlated with radioembolization treatment parameters. Statistical methods included Wilcoxon signed-rank test, univariate, and multivariate Cox regression analysis; receiver operating characteristic analysis; and the Kaplan-Meier method. Results: One hundred sixty-three patients with a median 67.0 years of age were included for analysis. Eighty-one percent of patients received segmental radioembolization with a median treatment dose of 358 Gray (interquartile range 256–497). The post-treatment lymphocyte count decreased significantly in 94.5 % (p < 0.001) of patients but was not predictive of OS (p = 0.248). The pre-procedure neutrophil to lymphocyte ratio (NLR
pre ) was not predictive of OS (p = 0.891), and the 1-month post-procedure NLR was a borderline independent predictor of OS (p = 0.05). The NLR ratio (NLRR = NLRpost-procedure /NLRpre ) (Hazard ratio [HR], 1.31; 95% Cl, 1.04-1.66) and change in NLR (ΔNLR= NLRpost-procedure - NLRpre ) (HR, 1.09; 95% CI, 1.02–1.15) were associated with worse OS in BCLC C patients. NLRR (> 3.17) and ΔNLR (> 3.74) were independent predictors when adjusted for tumor presentation, treatment parameters, and liver function. Volume of liver treated and administered activity positively correlated with NLRR and ΔNLR (p < 0.001). Conclusion: A decrease in lymphocyte count is common after radioembolization, but of little clinical impact. Neither pre-treatment or post-treatment NLR was a predictor of survival in our study population. NLRR and ΔNLR were independent predictors of survival in BCLC stage C disease and had positive correlations with volume of liver tissue treated and administered activity. [ABSTRACT FROM AUTHOR]- Published
- 2021
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27. One‐carbon metabolism‐related micronutrients intake and risk for hepatocellular carcinoma: A prospective cohort study.
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Antwi, Samuel O., Petrick, Jessica L., Campbell, Peter T., Norez, Daniel A., Stevens, Victoria L., Liao, Linda M., Roberts, Lewis R., Patel, Tushar, and McGlynn, Katherine A.
- Subjects
NICOTINAMIDE ,VITAMIN B6 ,PROPORTIONAL hazards models ,VITAMIN B2 ,DIETARY supplements - Abstract
Deficient intake of micronutrients involved in one‐carbon metabolism (eg, choline, methionine, vitamin B12 and folic acid) leads to hepatocellular carcinoma (HCC) development in rodents, but is under‐investigated in humans. We investigated the association between one‐carbon metabolism‐related micronutrient intake and HCC risk in a prospective cohort of 494 860 participants with 16 years of follow‐up in the NIH‐AARP study. Dietary intakes and supplement use were ascertained at baseline using a food‐frequency questionnaire. Total intake (diet plus supplements) of the following one‐carbon metabolism‐related micronutrients were calculated: folate, methionine and vitamins B2 (riboflavin), B3 (niacin), B6 and B12. These micronutrients were examined both individually and simultaneously, with adjustment for covariates. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over the 16‐year follow‐up period, 647 incident HCC cases were diagnosed. When examined individually, higher total vitamin B3 intake was associated with a lower HCC risk (HRQ5 vs Q1 = 0.60; 95% CI = 0.42‐0.85; Ptrend =.008), and the association remained significant when all six micronutrients were examined simultaneously (HRQ5 vs Q1 = 0.32; 95% CI = 0.18‐0.55; Ptrend <.0001). Among participants with >3 years of follow‐up, higher total vitamin B3 intake was again associated with lower risk (HRQ5 vs Q1 = 0.37; 95% CI = 0.20‐0.68; Ptrend =.001), whereas higher total vitamin B6 intake was associated with higher risk (HRQ5 vs Q1 = 2.04; 95% CI = 1.02‐4.07; Ptrend =.04). Restricted cubic spline analyses showed a dose‐response inverse association between total vitamin B3 intake and HCC risk, and dose‐response positive association between total vitamin B6 intake and HCC risk. The study suggests that higher vitamin B3 intake is associated with lower HCC risk, whereas higher vitamin B6 intake is associated with increased risk. What's new? Dietary micronutrients such as methionine and B vitamins are critical for DNA methylation, owing to methyl groups derived via one‐carbon metabolism. In the liver, deficiency of these methyl donors leads to hypomethylation and altered gene expression, potentially fueling hepatic tumorigenesis. Here, comprehensive investigation of one‐carbon metabolism‐related micronutrient intake and risk of hepatocellular carcinoma (HCC) shows that relatively high vitamin B3 intake is associated with reduced HCC risk. By comparison, elevated vitamin B6 intake was linked to increased HCC risk. The findings suggest that dietary modifications emphasizing healthy vitamin B3 intake while limiting vitamin B6 levels could enhance HCC prevention strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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28. The efficacy, safety, and predictors of outcomes of transarterial radioembolization for hepatocellular carcinoma: a retrospective study.
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Abdallah, Mohamed A., Wongjarupong, Nicha, Hassan, Mohamed A., Taha, Wesam, Abdalla, Abubaker, Bampoh, Sally, Onyirioha, Kristeen, Nelson, Morgan, Glubranson, Lyn A., Wiseman, Gregory A., Fleming, Chad J., Andrews, James C., Mahipal, Amit, and Roberts, Lewis R.
- Subjects
HEPATOCELLULAR carcinoma ,RADIOEMBOLIZATION ,LOGISTIC regression analysis ,RADIATION doses ,RETROSPECTIVE studies - Abstract
Yttrium-90 transarterial radioembolization (TARE) is a safe, effective modality of locoregional therapy for intermediate and advanced-stage hepatocellular carcinoma (HCC). We aim to identify novel predictors of important outcomes of TARE therapy. A single-center retrospective study of 166 patients treated with TARE for HCC at Mayo Clinic Rochester between 2005-2015 and followed until December 2017. Multivariate logistic and stepwise regression analysis models were used to identify variables associated with overall survival (OS) and progression-free survival (PFS). The median OS and the median PFS were12.9 (95% CI: 11.0–17.3), and 8 months (95% CI: 6–11), respectively. Macrovascular invasion (HR: 1.9 [1.3–2.8]), Child-Pugh score (CPS) B or C vs. A (HR: 1.8 [1.2–2.7]), Eastern Cooperative Oncology Group Performance status (ECOG-PS) 2 or 1 vs. 0 (HR: 1.6 [1.1–2.4]) and activity (A) of administered radiation dose (HR: 1.005[1.00–1.010), independently correlated with poorer OS. Infiltrative HCC (HR: 2.4 [1.3–4.5), macrovascular invasion (HR: 1.6 [1.1–2.7]), and high activity of administered radiation dose (HR: 1.005 [1.00–1.010) were associated with worse PFS. In HCC patients treated with TARE; macrovascular invasion, the activity of radiation dose, CPS, ECOG-PS, and infiltrative HCC predict OS and PFS. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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29. Current Status of the GALAD and BALAD Biomarker Models or Hepatocellular Carcinoma.
- Author
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Roberts, Lewis R.
- Subjects
ALPHA fetoproteins ,BILIRUBIN ,HEPATOCELLULAR carcinoma ,CIRRHOSIS of the liver ,MEDICAL research ,RISK assessment ,SERUM albumin ,TUMOR markers ,ROUTINE diagnostic tests ,DISEASE risk factors - Published
- 2019
30. 430 Etiology of Hepatocellular Carcinoma in the 27-County Rochester Epidemiology Project Catchment Area, 2010-2021.
- Author
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VanLith, Caitlin, Uwilingiyimana, Aimee, and Roberts, Lewis R
- Subjects
WATERSHEDS ,HEPATOCELLULAR carcinoma ,ETIOLOGY of diseases ,EPIDEMIOLOGY ,TYPE I interferons - Published
- 2023
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31. Incidence and Risk Factors for Hepatocellular Carcinoma in Cirrhosis: The Multicenter Hepatocellular Carcinoma Early Detection Strategy (HEDS) Study.
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Reddy, K. Rajender, McLerran, Dale, Marsh, Tracey, Parikh, Neehar, Roberts, Lewis R., Schwartz, Myron, Nguyen, Mindie H., Befeler, Alex, Page-Lester, Stephanie, Tang, Runlong, Srivastava, Sudhir, Rinaudo, Jo Ann, Feng, Ziding, and Marrero, Jorge A.
- Abstract
Worldwide, hepatocellular carcinoma (HCC) is a common malignancy. We aimed to prospectively determine the incidence and risk factors of HCC in a U.S. cohort. The multicenter Hepatocellular Carcinoma Early Detection Strategy study of the National Institutes of Health prospectively enrolled patients with cirrhosis who underwent standard surveillance for HCC. Demographics, medical and family history, etiology of liver disease, and clinical features were evaluated for associations with HCC. Between April 10, 2013 and December 31, 2021, 1723 patients were enrolled and confirmed eligible. During median follow-up of 2.2 years (range, 0–8.7 years), there were 109 incident cases of HCC for an incidence rate of 2.4 per 100 person-years: 88 (81%) patients with very early/early Barcelona Clinic Liver Cancer stage (0, A), 20 (18%) intermediate stage (B), and 1 (1%) unknown stage. Risk factor analyses were restricted to 1325 patients, including 95 incident HCC, with at least 6 months of follow-up. The majority were men (53.2%), obese or severely obese (median body mass index, 30.2 kg/m
2 ), and white (86.3%); 42.0% had history of hepatitis C virus infection, 20.7% had alcoholic liver disease, and 24.9% had nonalcoholic fatty liver disease. Fourteen risk factors for HCC were significant (P <.05) in univariate analyses, and a multivariate subset was selected using stepwise logistic regression. The multivariate subset contained gender (P <.001; male; odds ratio [OR], 2.47; 95% confidence interval [CI], 1.54–4.07), years with cirrhosis (P =.004; OR, 1.06; 95% CI, 1.02–1.1), family history of liver cancer (P =.02; yes; OR, 2.69; 95% CI, 1.11–5.86), age (per 5 years; P =.02; OR, 1.17; 95% CI, 1.03–1.33), obesity (P =.02; yes; OR, 1.7; 95% CI, 1.08–2.73), aspartate aminotransferase (log(1+AST); P =.06; OR, 1.54; 95% CI, 0.97–2.42), alpha-fetoprotein (log(1+AFP); P =.07; OR, 1.32; 95% CI, 0.97–1.77), and albumin (P =.10; OR, 0.7; 95% CI, 0.46–1.07). Thus far, this is the largest prospective and geographically diverse study of a U.S. cohort of patients with cirrhosis that validates known risk factors for HCC (gender, age, obesity, years with cirrhosis, family history of liver cancer, baseline AFP, albumin, and AST). The incidence of HCC was 2.4% per 100 person-years. [Display omitted] The multicenter (HEDS) Hepatocellular Carcinoma Early Detection Strategy study uses the largest, multicenter, geographically diverse and prospective U.S. patient cohort to validate several risk factors for hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]- Published
- 2023
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32. Heat stress induced, ligand-independent MET and EGFR signalling in hepatocellular carcinoma.
- Author
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Thompson, Scott M., Jondal, Danielle E., Butters, Kim A., Knudsen, Bruce E., Anderson, Jill L., Callstrom, Matthew R., Woodrum, David A., Stokes, Matthew P., Jia, Xiaoying, Grande, Joseph P., and Roberts, Lewis R.
- Subjects
LIVER cancer ,PHYSIOLOGICAL effects of heat ,EPIDERMAL growth factor receptors ,IMMUNOSTAINING ,CANCER invasiveness ,PROTEIN-tyrosine kinases - Abstract
Purpose: The aims of the present study were 2-fold: first, to test the hypothesis that heat stress induces MET and EGFR signalling in hepatocellular carcinoma (HCC) cells and inhibition of this signalling decreases HCC clonogenic survival; and second, to identify signalling pathways associated with heat stress induced MET signalling. Materials and Methods: MET
+ and EGFR+ HCC cells were pre-treated with inhibitors to MET, EGFR, PI3K/mTOR or vehicle and subjected to heat stress or control ± HGF or EGF growth factors and assessed by colony formation assay, Western blotting and/or quantitative mass spectrometry. IACUC approved partial laser thermal or sham ablation was performed on orthotopic N1S1 and AS30D HCC tumours and liver/tumour assessed for phospho-MET and phospho-EGFR immunostaining. Results: Heat-stress induced rapid MET and EGFR phosphorylation that is distinct from HGF or EGF in HCC cells and thermal ablation induced MET but not EGFR phosphorylation at the HCC tumour ablation margin. Inhibition of the MET and EGFR blocked both heat stress and growth factor induced MET and EGFR phosphorylation and inhibition of MET decreased HCC clonogenic survival following heat stress. Pathway analysis of quantitative phosphoproteomic data identified downstream pathways associated with heat stress induced MET signalling including AKT, ERK, Stat3 and JNK. However, inhibition of heat stress induced MET signalling did not block AKT signalling. Conclusions: Heat-stress induced MET and EGFR signalling is distinct from growth factor mediated signalling in HCC cells and MET inhibition enhances heat stress induced HCC cell killing via a PI3K/AKT/mTOR-independent mechanism. [ABSTRACT FROM AUTHOR]- Published
- 2018
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33. More advanced disease and worse survival in cryptogenic compared to viral hepatocellular carcinoma.
- Author
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Jun, Tomi W., Yeh, Ming‐lun, Yang, Ju Dong, Chen, Vincent L., Nguyen, Pauline, Giama, Nasra H., Huang, Chung‐feng, Hsing, Ann W., Dai, Chia‐yen, Huang, Jee‐fu, Chuang, Wan‐long, Roberts, Lewis R., Yu, Ming‐lung, and Nguyen, Mindie H.
- Subjects
LIVER cancer ,HEPATITIS B virus ,HEPATITIS C virus ,FATTY liver ,COHORT analysis - Abstract
Abstract: Background & Aims: Although hepatitis B virus (HBV) and hepatitis C virus (HCV) infections remain major risk factors for hepatocellular carcinoma (HCC), non‐viral causes of HCC, particularly non‐alcoholic fatty liver disease (NAFLD), are becoming increasingly prevalent. The aim of this study was to compare the clinical characteristics and survival of cryptogenic and viral HCC. Methods: We conducted a retrospective cohort study involving 3878 consecutive HCC patients seen at two tertiary centres in the United States and one in Taiwan from 2004 to 2014. We compared the clinical characteristics, treatment and survival of patients by underlying aetiology: cryptogenic (n = 696), HBV (n = 1304) or HCV (n = 1878). Results: Cirrhosis was present in 66.8% of the cryptogenic HCC patients, compared with 74.7% of HBV‐related HCC (HBV‐HCC) (
P =P <P <- Published
- 2018
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34. Phase I/II Randomized Trial of Sorafenib and Bevacizumab as First-Line Therapy in Patients with Locally Advanced or Metastatic Hepatocellular Carcinoma: North Central Cancer Treatment Group Trial N0745 (Alliance).
- Author
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Hubbard, Joleen, Mahoney, Michelle, Loui, William, Roberts, Lewis, Smyrk, Thomas, Gatalica, Zoran, Borad, Mitesh, Kumar, Shaji, Alberts, Steven, Hubbard, Joleen M, Mahoney, Michelle R, Loui, William S, Roberts, Lewis R, Smyrk, Thomas C, and Alberts, Steven R
- Subjects
ANTINEOPLASTIC agents ,CLINICAL trials ,COMPARATIVE studies ,HEPATOCELLULAR carcinoma ,LIVER tumors ,RESEARCH methodology ,MEDICAL cooperation ,METASTASIS ,RESEARCH ,RESEARCH funding ,UREA ,VITAMIN B complex ,EVALUATION research ,RANDOMIZED controlled trials ,PHARMACODYNAMICS ,VITAMIN therapy ,THERAPEUTICS - Abstract
Background: Angiogenesis has been a major target of novel drug development in hepatocellular carcinoma (HCC). It is hypothesized that the combination of two antiangiogenic agents, sorafenib and bevacizumab, will provide greater blockade of angiogenesis.Objective: To determine the optimal dose, safety, and effectiveness of dual anti-angiogenic therapy with sorafenib and bevacizumab in patients with advanced HCC.Patients and Methods: Patients with locally advanced or metastatic HCC not amenable for surgery or liver transplant were eligible. The phase I starting dose level was bevacizumab 1.25 mg/kg day 1 and 15 plus sorafenib 400 mg twice daily (BID) days 1-28. In the phase II portion, patients were randomized to receive bevacizumab and sorafenib at the maximum tolerated dose (MTD) or sorafenib 400 mg BID.Results: Seventen patients were enrolled in the phase I component. Dose-limiting toxicities included grade 3 hand/foot skin reaction, fatigue, hypertension, alanine/aspartate aminotransferase increase, dehydration, hypophosphatemia, creatinine increase, hypoglycemia, nausea/vomiting, and grade 4 hyponatremia. Seven patients were enrolled in the phase II component at the MTD: sorafenib 200 mg BID days 1-28 and bevacizumab 2.5 mg/kg every other week; 57% (4/7) had grade 3 AEs at least possibly related to treatment. No responses were observed in the phase II portion. Estimated median time to progression and survival were 8.6 months (95% CI: 0.4-16.3) and 13.3 months (95% CI 4.4 - not estimable), respectively.Conclusions: The MTD of the combination is sorafenib 200 mg twice daily on days 1-28 plus bevacizumab 2.5 mg/kg on days 1 and 15 of a 28-day cycle. In the phase II portion of the trial, concerns regarding excessive toxicity, low efficacy, and slow enrollment led to discontinuation of the trial. (Clinical Trials ID: NCT00867321.). [ABSTRACT FROM AUTHOR]- Published
- 2017
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35. Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma.
- Author
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Haber, Philipp K., Castet, Florian, Torres-Martin, Miguel, Andreu-Oller, Carmen, Puigvehí, Marc, Miho, Maeda, Radu, Pompilia, Dufour, Jean-Francois, Verslype, Chris, Zimpel, Carolin, Marquardt, Jens U., Galle, Peter R., Vogel, Arndt, Bathon, Melanie, Meyer, Tim, Labgaa, Ismail, Digklia, Antonia, Roberts, Lewis R., Mohamed Ali, Mohamed A., and Mínguez, Beatriz
- Abstract
Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1. Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response. Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II–related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy. Interferon signaling and major histocompatibility complex–related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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36. Heat Stress-Induced PI3K/mTORC2-Dependent AKT Signaling Is a Central Mediator of Hepatocellular Carcinoma Survival to Thermal Ablation Induced Heat Stress.
- Author
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Thompson, Scott M., Callstrom, Matthew R., Jondal, Danielle E., Butters, Kim A., Knudsen, Bruce E., Anderson, Jill L., Lien, Karen R., Sutor, Shari L., Lee, Ju-Seog, Thorgeirsson, Snorri S., Grande, Joseph P., Roberts, Lewis R., and Woodrum, David A.
- Subjects
LIVER cancer ,LIVER cancer patients ,PHYSIOLOGICAL effects of heat ,PROTEIN kinase B ,CELLULAR signal transduction ,CANCER relapse - Abstract
Thermal ablative therapies are important treatment options in the multidisciplinary care of patients with hepatocellular carcinoma (HCC), but lesions larger than 2–3 cm are plagued with high local recurrence rates and overall survival of these patients remains poor. Currently no adjuvant therapies exist to prevent local HCC recurrence in patients undergoing thermal ablation. The molecular mechanisms mediating HCC resistance to thermal ablation induced heat stress and local recurrence remain unclear. Here we demonstrate that the HCC cells with a poor prognostic hepatic stem cell subtype (Subtype HS) are more resistant to heat stress than HCC cells with a better prognostic hepatocyte subtype (Subtype HC). Moreover, sublethal heat stress rapidly induces phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dependent-protein kinase B (AKT) survival signaling in HCC cells in vitro and at the tumor ablation margin in vivo. Conversely, inhibition of PI3K/mTOR complex 2 (mTORC2)-dependent AKT phosphorylation or direct inhibition of AKT function both enhance HCC cell killing and decrease HCC cell survival to sublethal heat stress in both poor and better prognostic HCC subtypes while mTOR complex 1 (mTORC1)-inhibition has no impact. Finally, we showed that AKT isoforms 1, 2 and 3 are differentially upregulated in primary human HCCs and that overexpression of AKT correlates with worse tumor biology and pathologic features (AKT3) and prognosis (AKT1). Together these findings define a novel molecular mechanism whereby heat stress induces PI3K/mTORC2-dependent AKT survival signaling in HCC cells and provide a mechanistic rationale for adjuvant AKT inhibition in combination with thermal ablation as a strategy to enhance HCC cell killing and prevent local recurrence, particularly at the ablation margin. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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37. Liver Masses: A Clinical, Radiologic, and Pathologic Perspective.
- Author
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Venkatesh, Sudhakar K., Chandan, Vishal, and Roberts, Lewis R.
- Abstract
Liver masses present a relatively common clinical dilemma, particularly with the increasing use of various imaging modalities in the diagnosis of abdominal and other symptoms. The accurate and reliable determination of the nature of the liver mass is critical, not only to reassure individuals with benign lesions but also, and perhaps more importantly, to ensure that malignant lesions are diagnosed correctly. This avoids the devastating consequences of missed diagnosis and the delayed treatment of malignancy or the unnecessary treatment of benign lesions. With appropriate interpretation of the clinical history and physical examination, and the judicious use of laboratory and imaging studies, the majority of liver masses can be characterized noninvasively. Accurate characterization of liver masses by cross-sectional imaging is particularly dependent on an understanding of the unique phasic vascular perfusion of the liver and the characteristic behaviors of different lesions during multiphasic contrast imaging. When noninvasive characterization is indeterminate, a liver biopsy may be necessary for definitive diagnosis. Standard histologic examination usually is complemented by immunohistochemical analysis of protein biomarkers. Accurate diagnosis allows the appropriate selection of optimal management, which is frequently reassurance or intermittent follow-up evaluations for benign masses. For malignant lesions or those at risk of malignant transformation, management depends on the tumor staging, the functional status of the uninvolved liver, and technical surgical considerations. Unresectable metastatic masses require oncologic consultation and therapy. The efficient characterization and management of liver masses therefore requires a multidisciplinary collaboration between the gastroenterologist/hepatologist, radiologist, pathologist, hepatobiliary or transplant surgeon, and medical oncologist. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
38. Heparin-degrading sulfatases in hepatocellular carcinoma: roles in pathogenesis and therapy targets.
- Author
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Lai, Jin-Ping, Thompson, James R, Sandhu, Dalbir S, and Roberts, Lewis R
- Subjects
ANIMALS ,CELLULAR signal transduction ,HEPARIN ,HEPATOCELLULAR carcinoma ,LIVER tumors ,TRANSFERASES - Abstract
Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage at which there are limited treatment options. Two recently identified human heparin-degrading endosulfatases, named sulfatase 1 (SULF1) and sulfatase 2 (SULF2), have been found to be involved in liver carcinogenesis. SULF1 and SULF2 desulfate cell surface and extracellular matrix heparan sulfate proteoglycans and modulate heparin-binding growth factor signaling in multiple cancers, including HCCs. SULF1 inhibits HCC tumor cell growth in vitro and in nude mice in vivo, partially through effects on gene expression mediated through histone H4 acetylation. While SULF1 is downregulated in the majority of HCC cell lines and approximately 30% of primary HCCs, SULF2 is upregulated in almost all HCC cell lines and in 60% of primary HCCs. In contrast to the tumor suppressor effect of SULF1, expression of SULF2 activates MAPK and Akt pathways, promotes HCC cell growth in vitro and in vivo, and is associated with decreased survival of HCC patients. Targeting SULF2 or the interaction between SULF2 and SULF1 may lead to novel therapeutics for the treatment of HCCs. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
39. Heparin-degrading sulfatases in hepatocellular carcinoma: roles in pathogenesis and the therapy targets.
- Author
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Jin-Ping Lai, Thompson, James R., Sandhu, Dalbir S., and Roberts, Lewis R.
- Subjects
LIVER cancer ,DIAGNOSIS ,THERAPEUTICS ,SULFATASES ,CARCINOGENESIS ,HEPARIN - Abstract
Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage at which there are limited treatment options. Two recently identified human heparin-degrading endosulfatases, named sulfatase 1 (SULF1) and sulfatase 2 (SULF2), have been found to be involved in liver carcinogenesis. SULF1 and SULF2 desulfate cell surface and extracellular matrix heparan sulfate proteoglycans and modulate heparin-binding growth factor signaling in multiple cancers, including HCCs. SULF1 inhibits HCC tumor cell growth in vitro and in nude mice in vivo, partially through effects on gene expression mediated through histone H4 acetylation. While SULF1 is downregulated in the majority of HCC cell lines and approximately 30% of primary HCCs, SULF2 is upregulated in almost all HCC cell lines and in 60% of primary HCCs. In contrast to the tumor suppressor effect of SULF1, expression of SULF2 activates MAPK and Akt pathways, promotes HCC cell growth in vitro and in vivo, and is associated with decreased survival of HCC patients. Targeting SULF2 or the interaction between SULF2 and SULF1 may lead to novel therapeutics for the treatment of HCCs. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
40. Sulfatase -2 Regulates Liver Fibrosis through the TGF-β Signaling Pathway.
- Author
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Nakamura, Ikuo, Asumda, Faizal Z., Moser, Catherine D., Kang, Yoo Na N., Lai, Jin-Ping, and Roberts, Lewis R.
- Subjects
TRANSFORMING growth factors-beta ,BIOLOGICAL models ,ANIMAL experimentation ,IMMUNOHISTOCHEMISTRY ,FIBROSIS ,CIRRHOSIS of the liver ,LIVER diseases ,CELLULAR signal transduction ,IMMUNOBLOTTING ,ESTERASES ,MICE ,HEPATOCELLULAR carcinoma - Abstract
Simple Summary: Liver fibrosis and/or cirrhosis is a major risk factor for hepatocellular carcinoma. Hepatic Fibrogenesis is the result of an excessive production and deposition of extracellular matrix by hepatic myofibroblasts, which are primarily formed from hepatic stellate cells. The heparan sulfate editing enzyme sulfatase-2 is known to be elevated in cirrhotic liver and hepatocellular carcinoma. Our aim in this study was to delineate the mechanistic role of sulfatase-2 in fibrotic liver disease using mouse and in vitro cell culture models of liver fibrosis. Our data here demonstrates that mice deficient in sulfatase-2 have reduced liver fibrosis. We also show that sulfatase-2 promotes cell proliferation, cell viability, the production of collagen, migration, and activation of hepatic stellate cells. Our findings highlight sulfatase-2 as a potential target for therapeutic intervention geared at reversing liver fibrosis. Transforming growth factor-β (TGF-β) activates hepatic stellate cells (HSCs), which drive liver fibrosis via the production and deposition of extracellular matrix (ECM). We aimed to elucidate the mechanistic role of sulfatase-2 (SULF2) in liver fibrosis. To this end, we induced liver fibrosis in wild-type (WT) and SULF2 knockout (Sulf2-KO) mice (6–8 weeks-old) via bile duct ligation (BDL), intraperitoneal injection of carbon tetrachloride (CCl
4 ) or thioacetamide (TAA). The levels of fibrosis in the liver sections were assessed via Sirius red and Masson's trichrome staining, immunohistochemistry and immunoblotting for α-smooth muscle actin (α-SMA) and hydroxyproline. To evaluate the interaction between TGF-β and SULF2, we transfected human HSCs with scrambled control shRNA and shRNA constructs targeting SULF2 and measured α-SMA expression following treatment with TGF-β1 ligand. We show here that knockout of SULF2 significantly decreases collagen content, as well as bands of bridging fibrosis, as demonstrated by Sirius red, Masson's trichrome and α-SMA staining after BDL, CCl4 and TAA injection in Sulf2-KO versus WT mice. In all three models of liver fibrosis, we observed significantly lower levels of hydroxyproline in the Sulf2-KO mice compared to the WT mice. HSCs with reduced levels of SULF2 failed to significantly express α-SMA and collagen type I following treatment with TGF-β1. Furthermore, SULF2 co-localizes with TGFBR3 and the in vitro knockdown of SULF2 in HSCs decreases the release of TGF-β1 from TGFBR3. Together, these data suggest that SULF2 regulates liver fibrosis via the TGF-β signaling pathway. Pharmacologic inhibition of SULF2 may represent a novel therapeutic approach to improve liver fibrosis. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
41. Distinct Patterns of HBV Integration and TERT Alterations between in Tumor and Non-Tumor Tissue in Patients with Hepatocellular Carcinoma.
- Author
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Jang, Jeong-Won, Kim, Hye-Seon, Kim, Jin-Seoub, Lee, Soon-Kyu, Han, Ji-Won, Sung, Pil-Soo, Bae, Si-Hyun, Choi, Jong-Young, Yoon, Seung-Kew, Han, Dong-Jin, Kim, Tae-Min, and Roberts, Lewis R.
- Subjects
HEPATITIS B virus ,TELOMERASE reverse transcriptase ,HEPATOCELLULAR carcinoma - Abstract
Although hepatitis B virus (HBV) integration into the cellular genome is well known in HCC (hepatocellular carcinoma) patients, its biological role still remains uncertain. This study investigated the patterns of HBV integration and correlated them with TERT (telomerase reverse transcriptase) alterations in paired tumor and non-tumor tissues. Compared to those in non-tumors, tumoral integrations occurred less frequently but with higher read counts and were more preferentially observed in genic regions with significant enrichment of integration into promoters. In HBV-related tumors, TERT promoter was identified as the most frequent site (38.5% (10/26)) of HBV integration. TERT promoter mutation was observed only in tumors (24.2% (8/33)), but not in non-tumors. Only 3.00% (34/1133) of HBV integration sites were shared between tumors and non-tumors. Within the HBV genome, HBV breakpoints were distributed preferentially in the 3' end of HBx, with more tumoral integrations detected in the preS/S region. The major genes that were recurrently affected by HBV integration included TERT and MLL4 for tumors and FN1 for non-tumors. Functional enrichment analysis of tumoral genes with integrations showed enrichment of cancer-associated genes. The patterns and functions of HBV integration are distinct between tumors and non-tumors. Tumoral integration is often enriched into both human-virus regions with oncogenic regulatory function. The characteristic genomic features of HBV integration together with TERT alteration may dysregulate the affected gene function, thereby contributing to hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
42. Genetic alterations in advanced HBV-related HCC with portal vein tumor thrombosis: Insights from next generation DNA sequencing
- Author
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Chaiteerakij, Roongruedee and Roberts, Lewis R.
- Published
- 2013
- Full Text
- View/download PDF
43. Lymphocyte to Monocyte Ratio Based Nomogram for Predicting Outcomes of Hepatocellular Carcinoma Treated with Sorafenib.
- Author
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Yeonjung Ha, Mohamed Ali, Mohamed A., Petersen, Molly M., Harmsen, William S., Han Chu Lee, Baek-yeol Ryoo, Bampoh, Sally, Valles, Kenneth A., Mady, Mohamad, Missula, Venkata R., Prasai, Kritika, Roberts, Lewis R., and Kang Mo Kim
- Subjects
HEPATOCELLULAR carcinoma ,NOMOGRAPHY (Mathematics) ,SORAFENIB ,PROPORTIONAL hazards models ,HEPATITIS B virus - Abstract
Background/Aims The ability of the pretreatment lymphocyte to monocyte ratio (LMR) to predict outcomes of patients with hepatocellular carcinoma (HCC) receiving sorafenib is not conclusively determined. Methods We retrospectively studied patients treated with sorafenib for HCC in two tertiary referral centers in South Korea (KOR) and United States (US). Primary endpoints were overall survival (OS) and progression-free survival (PFS). Predictive factors for the primary outcomes were determined by Cox proportional hazards models. A risk-assessment tool was developed. Results Compared to the US cohort, the KOR cohort was more heavily pretreated (72.1% vs 35.2%, p<0.001), had higher proportion with hepatitis B virus infection (87.6% vs 5.6%, p<0.001), and more distant metastases (83.2% vs 25.4%, p<0.001). Lower monocyte count in the KOR cohort (median, 462.7 vs 600.0/μL; p=0.023) resulted in a higher LMR (median, 2.6 vs 1.8; p<0.001). High LMR was associated with a significantly higher OS (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.83 to 0.98; p=0.021). This was confirmed in a sensitivity analysis including only Asian patients (HR, 0.90; 95% CI, 0.82 to 0.98; p=0.019). A nomogram for OS was constructed with following variables selected in the multivariate Cox model: LMR, race, previous treatment, log10AFP, lymph node metastasis, and Child-Pugh score. The concordance score was 0.71 (95% CI, 0.67 to 0.75). LMR did not predict PFS. Conclusions Pretreatment LMR predicts OS in HCC patients treated with sorafenib. Our OS nomogram, incorporating LMR, can be offered to clinicians to improve their ability to assess prognosis, strengthen the prognosis-based decision making, and inform patients in the clinic. [ABSTRACT FROM AUTHOR]
- Published
- 2019
44. Liver Lesions in Congestive Hepatopathy
- Author
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Hilscher, Moira B., Wells, Michael L., Kamath, Patrick S., Roberts, Lewis R., editor, Yang, Ju Dong, editor, and Venkatesh, Sudhakar K., editor
- Published
- 2020
- Full Text
- View/download PDF
45. The tumor microenvironment in hepatocellular carcinoma: Current status and therapeutic targets
- Author
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Yang, Ju Dong, Nakamura, Ikuo, and Roberts, Lewis R.
- Subjects
- *
EXTRACELLULAR matrix , *LIVER cancer , *CARCINOGENESIS , *HEPATOCYTE growth factor , *METALLOPROTEINASES , *FIBROBLAST growth factors , *SULFATASES - Abstract
Abstract: A growing body of literature highlights the cross-talk between tumor cells and the surrounding peri-tumoral stroma as a key modulator of the processes of hepatocarcinogenesis, epithelial mesenchymal transition (EMT), tumor invasion and metastasis. The tumor microenvironment can be broadly classified into cellular and non-cellular components. The major cellular components include hepatic stellate cells, fibroblasts, immune, and endothelial cells. These cell types produce the non-cellular components of the tumor stroma, including extracellular matrix (ECM) proteins, proteolytic enzymes, growth factors and inflammatory cytokines. The non-cellular component of the tumor stroma modulates hepatocellular carcinoma (HCC) biology by effects on cancer signaling pathways in tumor cells and on tumor invasion and metastasis. Global gene expression profiling of HCC has revealed that the tumor microenvironment is an important component in the biologic and prognostic classification of HCC. There are substantial efforts underway to develop novel drugs targeting tumor–stromal interactions. In this review, we discuss the current knowledge about the role of the tumor microenvironment in pathogenesis of HCC, the role of the tumor microenvironment in the classification of HCC and efforts to develop treatments targeting the tumor microenvironment. [Copyright &y& Elsevier]
- Published
- 2011
- Full Text
- View/download PDF
46. BALAD and BALAD-2 predict survival of hepatocellular carcinoma patients: a North American cohort study.
- Author
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Wongjarupong, Nicha, Negron-Ocasio, Gabriela M., Mara, Kristin C., Prasai, Kritika, Abdallah, Mohamed A., Ahn, Keun Soo, Yang, Ju Dong, Addissie, Benyam D., Giama, Nasra H., Harmsen, William S., Therneau, Terry M., and Roberts, Lewis R.
- Subjects
- *
HEPATOCELLULAR carcinoma , *SURVIVAL rate , *NEUTROPHIL lymphocyte ratio , *COHORT analysis , *AMERICAN studies , *DIAGNOSIS - Abstract
The BALAD score and BALAD-2 class derived from bilirubin, albumin, AFP, AFP-L3, and des-gamma-carboxyprothrombin (DCP) are effective in predicting mortality in HCC, but have not been validated in North America. 148 HCC patients from 2000 to 2015 who had all five biomarkers tested at diagnosis were included. Hazard ratios (HR) were calculated. 75 patients died during a median follow-up of 21.9 months. 1-and 3-year survival rates were 70.8% and 47.6%. 114 (77%) had cirrhosis. The HR (95%CI) for death were 1.24 (0.42–3.67), 1.79 (0.61–5.26), 2.83 (0.95–8.38), and 7.19 (2.26–22.91) for BALAD scores 1, 2, 3, and 4 vs. BALAD 0. The HR (95%CI) for death were 1.25 (0.65–2.40), 1.75 (0.94–3.23), and 6.20 (3.29–11.68) for BALAD-2 classes 2, 3, and 4 vs. BALAD-2 class 1. A multivariate model incorporating maximal tumor diameter, tumor number, neutrophil-lymphocyte ratio, and BALAD had HR of 1.43 (1.14–1.81) per increase of 1 BALAD score. A similar model with BALAD-2 had HR of 1.50 (1.18–1.90) per increase of 1 BALAD-2 class. BALAD models at diagnosis can predict the survival of HCC patients in North America. AFP, AFP-L3, and DCP reflect tumor progression and metastasis of HCC and distinguish the BALAD model from other predictive models. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
47. Apobec1 complementation factor overexpression promotes hepatic steatosis, fibrosis, and hepatocellular cancer.
- Author
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Blanc, Valerie, Riordan, Jesse D., Soleymanjahi, Saeed, Nadeau, Joseph H., Nalbantoglu, ILKe, Yan Xie, Molitor, Elizabeth A., Madison, Blair B., Brunt, Elizabeth M., Mills, Jason C., Rubin, Deborah C., Ng, Irene O., Yeonjung Ha, Roberts, Lewis R., Davidson, Nicholas O., Xie, Yan, and Ha, Yeonjung
- Subjects
- *
LIVER cancer , *FATTY liver , *FATTY degeneration , *FIBROSIS , *RNA-binding proteins , *PROTEIN metabolism , *PROTEINS , *RESEARCH , *LIVER tumors , *ANIMAL experimentation , *RESEARCH methodology , *CIRRHOSIS of the liver , *MEDICAL cooperation , *EVALUATION research , *COMPARATIVE studies , *HEPATOCELLULAR carcinoma , *MICE - Abstract
The RNA-binding protein Apobec1 complementation factor (A1CF) regulates posttranscriptional ApoB mRNA editing, but the range of RNA targets and the long-term effect of altered A1CF expression on liver function are unknown. Here we studied hepatocyte-specific A1cf-transgenic (A1cf+/Tg), A1cf+/Tg Apobec1-/-, and A1cf-/- mice fed chow or high-fat/high-fructose diets using RNA-Seq, RNA CLIP-Seq, and tissue microarrays from human hepatocellular cancer (HCC). A1cf+/Tg mice exhibited increased hepatic proliferation and steatosis, with increased lipogenic gene expression (Mogat1, Mogat2, Cidea, Cd36) associated with shifts in polysomal RNA distribution. Aged A1cf+/Tg mice developed spontaneous fibrosis, dysplasia, and HCC, and this development was accelerated on a high-fat/high-fructose diet and was independent of Apobec1. RNA-Seq revealed increased expression of mRNAs involved in oxidative stress (Gstm3, Gpx3, Cbr3), inflammatory response (Il19, Cxcl14, Tnfα, Ly6c), extracellular matrix organization (Mmp2, Col1a1, Col4a1), and proliferation (Kif20a, Mcm2, Mcm4, Mcm6), and a subset of mRNAs (including Sox4, Sox9, Cdh1) were identified in RNA CLIP-Seq. Increased A1CF expression in human HCC correlated with advanced fibrosis and with reduced survival in a subset with nonalcoholic fatty liver disease. In conclusion, we show that hepatic A1CF overexpression selectively alters polysomal distribution and mRNA expression, promoting lipogenic, proliferative, and inflammatory pathways leading to HCC. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
48. Rationale and design of the Hepatocellular carcinoma Early Detection Strategy study: A multi-center longitudinal initiative of the National Cancer Institute's Early Detection Research Network.
- Author
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Borges, Kelly A., Dai, Jianliang, Parikh, Neehar D., Schwartz, Myron, Nguyen, Mindie H., Roberts, Lewis R., Befeler, Alex S., Srivastava, Sudhir, Rinaudo, Jo Ann, Feng, Ziding, Marrero, Jorge A., and Reddy, K. Rajender
- Subjects
- *
LIVER cancer , *DISEASE incidence , *CANCER-related mortality , *BIOMARKERS , *BLOOD serum analysis - Abstract
Abstract Background Hepatocellular carcinoma (HCC) is a common malignancy with a steadily rising incidence and associated morbidity and mortality. Cirrhosis of the liver is presently the leading risk factor for developing HCC. Abdominal imaging, with or without alpha-fetoprotein (AFP) testing, every 6 months is the current surveillance strategy for patients at risk. The available biomarkers for detecting this cancer at an early stage have inadequate sensitivity and specificity. Methods The Hepatocellular carcinoma Early Detection Strategy (HEDS) study, a multi-center initiative of the National Cancer Institutes' (NCI) Early Detection Research Network (EDRN), launched an effort to establish what has become the nation's largest comprehensive biorepository and database on patients at high risk of developing HCC. The cohort has been developed in seven clinical centers across the USA. Subjects are enrolled for a five-year period involving data and specimen collection every six months in accordance with standard surveillance for HCC. Extensive clinical data are collected and specimens are stored at a central repository. Results The database and biorepository contain longitudinally collected clinical data and serum and plasma samples from 1482 participants with cirrhosis and without evidence of HCC at baseline. Fifty-six percent are male, 85% Caucasian, 30% have a history of chronic HCV and 71% have compensated cirrhosis. Conclusions The HEDS cohort provides opportunities for the continued study of the incidence and course of HCC in a comprehensively followed population of patients at high risk for this malignancy. Further, the EDRN biorepository provides a distinct opportunity for the development of novel biomarkers. Trial registry URL: https://edrn.nci.nih.gov/protocols/316-hepatocellular-carcinoma-early-detection-strategy. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
49. MR elastography of hepatocellular carcinoma: Correlation of tumor stiffness with histopathology features—Preliminary findings.
- Author
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Thompson, Scott M., Wang, Jin, Chandan, Vishal S., Glaser, Kevin J., Roberts, Lewis R., Ehman, Richard L., and Venkatesh, Sudhakar K.
- Subjects
- *
LIVER cancer , *ELASTOGRAPHY , *HISTOPATHOLOGY , *TUMOR grading , *CANCER invasiveness , *DIAGNOSIS , *MAGNETIC resonance imaging - Abstract
Purpose To determine if tumor stiffness by MR Elastography (MRE) is associated with hepatocellular carcinoma (HCC) pathologic features. Material and methods A retrospective review was undertaken of all patients with pathologically confirmed HCC who underwent MRE prior to loco-regional therapy, surgical resection or transplant between 1/1/2007 to 12/31/2015. An independent observer measured tumor stiffness (kilopascals, kPa) by drawing regions of interest (ROI) covering the HCC and in the case of HCCs with non-enhancing/necrotic components, only the solid portion was included in the ROI. HCC tumor grade (WHO criteria), vascular invasion and tumor encapsulation were assessed from retrievable pathology specimens by an expert hepatobiliary pathologist. Tumor stiffness was compared by tumor grade, size, presence of capsule and vascular invasion using Student's t -test (or Exact Mann-Whitney test). Results 21 patients were identified who had pathologically confirmed HCCs and tumor MRE data. 17 patients (81.0%) had underlying chronic liver disease. The mean ± SD tumor size (cm) was 5.3 ± 3.9 cm. The mean ± SD tumor stiffness was 5.9 ± 1.4 kPa. Tumors were graded as well differentiated (N = 2), moderately differentiated (N = 11) and poorly differentiated (N = 8). There was a trend toward increased tumor stiffness in well/moderately differentiated HCCs (6.5 ± 1.2 kPa; N = 13) compared to poorly differentiated HCCs (4.9 ± 1.2 kPa; N = 8) (p < 0.01). There was no significant correlation between tumor stiffness and liver stiffness or tumor size. There was no significant difference in tumor stiffness by presence or etiology of chronic liver disease, vascular invasion or tumor encapsulation. Conclusion Preliminary data suggest that tumor stiffness by MRE may be able to differentiate HCC tumor grade. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
50. Additive effect of apicidin and doxorubicin in sulfatase 1 expressing hepatocellular carcinoma in vitro and in vivo
- Author
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Lai, Jin-Ping, Sandhu, Dalbir S., Moser, Catherine D., Cazanave, Sophie C., Oseini, Abdul M., Shire, Abdirashid M., Shridhar, Viji, Sanderson, Schuyler O., and Roberts, Lewis R.
- Subjects
- *
ANTIBIOTICS , *LIVER cancer , *CANCER chemotherapy , *XENOGRAFTS , *SULFATASES , *MITOGEN-activated protein kinases , *HISTONE deacetylase , *DOXORUBICIN - Abstract
Background/Aims: There are limited chemotherapy options for hepatocellular carcinoma (HCC). The heparin-degrading endosulfatase SULF1 functions as a liver tumor suppressor. We investigated the effects of the histone deacetylase inhibitor apicidin in combination with doxorubicin in SULF1-expressing HCC cells in vitro and in SULF1-expressing xenografts in nude mice. Methods: We evaluated the effects of apicidin alone or combined with doxorubicin on apoptosis, caspase activity, and phosphorylation of Erk and Akt in SULF1-transfected Huh7 and Hep3B cells in vitro and in vivo. Results: Apicidin induced HCC cell apoptosis and caspase activation in a dose- and time-dependent manner. Apicidin-induced caspase activation was significantly inhibited by the caspase inhibitor Z-Vad-fmk. Apicidin also decreased phosphorylation of both Erk and Akt. Expression of constitutively-active Mek1 and Akt significantly decreased apicidin-induced apoptosis. The combination of doxorubicin with apicidin significantly increased the anti-tumor effect in the SULF1-expressing Huh7 and Hep3B cells as compared to either apicidin or doxorubicin alone, both in vitro and in vivo. Conclusions: The combination of a histone deacetylase inhibitor with doxorubicin may be a novel and promising therapeutic modality for HCCs, particularly for SULF1-expressing HCCs. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
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