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Article ; Online: Upregulation of USP22 and ABCC1 during Sorafenib Treatment of Hepatocellular Carcinoma Contribute to Development of Resistance

Yung-Sheng Chang / Chien-Wei Su / San-Chi Chen / Yen-Ying Chen / Yuh-Jin Liang / Jaw-Ching Wu

Cells, Vol 11, Iss 634, p

2022 Volume 634

Abstract: Sorafenib is a small molecule that blocks tumor proliferation by targeting the activity of multi-kinases for the treatment of advanced hepatocellular carcinoma (HCC). Increasing sorafenib resistance following long-term treatment is frequently encountered. ...

Abstract	Sorafenib is a small molecule that blocks tumor proliferation by targeting the activity of multi-kinases for the treatment of advanced hepatocellular carcinoma (HCC). Increasing sorafenib resistance following long-term treatment is frequently encountered. Mechanisms underlying sorafenib resistance remain not completely clear. To further understand the mechanism of sorafenib resistance in HCC, we established sorafenib-resistant cell lines by slowly increasing sorafenib concentration in cell culture medium. Upregulation of USP22 and ABCC1 were found in Sorafenib-resistant cells. Sorafenib-resistant cells treated with USP22 siRNA showed significant reduction in endogenous mRNA and protein levels of ABCC1. During sorafenib treatment, upregulation of USP22 increases ABCC1 expression and subsequently contributes to sorafenib resistance in HCC cells. Immunohistochemical analysis revealed a positive correlation between USP22 and ABCC1 expression in tissue samples from sorafenib-resistant patients (Pearson’s correlation = 0.59, p = 0.03). Our findings indicate that upregulation of USP22 and ABCC1 expression during treatment contribute to sorafenib resistance in HCC cells and that USP22 has strong potential as a therapeutic target for overcoming sorafenib resistance in HCC patients.
Keywords	sorafenib resistance ; USP22 ; ABCC1 ; hepatocellular carcinoma ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The outcomes and prognostic factors of patients with hepatocellular carcinoma and normal serum alpha fetoprotein levels

Chia-Chu Fu / Cheng-Yi Wei / Chi-Jen Chu / Pei-Chang Lee / Teh-Ia Huo / Yi-Hsiang Huang / Yee Chao / Ming-Chih Hou / Jaw-Ching Wu / Chien-Wei Su

Journal of the Formosan Medical Association, Vol 122, Iss 7, Pp 593-

2023 Volume 602

Abstract: Background: Alpha fetoprotein (AFP) is the most widely used tumor marker for hepatocellular carcinoma (HCC). Nevertheless, few studies have investigated the prognostic factors of HCC patients with normal serum AFP levels. Methods: We retrospectively ... ...

Abstract	Background: Alpha fetoprotein (AFP) is the most widely used tumor marker for hepatocellular carcinoma (HCC). Nevertheless, few studies have investigated the prognostic factors of HCC patients with normal serum AFP levels. Methods: We retrospectively enrolled 2198 patients with HCC and normal serum AFP levels (<20 ng/mL) from 2007 to 2020. Overall survival (OS) rates were calculated by the Kaplan–Meier method, and analyses of the prognostic factors were performed using a Cox proportional hazard model. Results: Among the enrolled patients, 1385 (63%) patients were in the low-normal AFP group (serum AFP levels ≤7 ng/mL), and 813 (37%) patients were in the high-normal AFP group (serum AFP levels between 7 and 20 ng/mL). The high-normal AFP group had poorer liver functional reserve, more multiple tumors, and smaller tumor size compared to those in the low-normal AFP group. After a median follow-up of 32.4 months, 942 patients died, and the 5-year OS rate was 54.4%. The 5-year OS rates were 57.4% and 49.8% in the low-normal AFP group and high-normal AFP group, respectively (p = 0.001). A multivariate analysis showed the independent prognostic factors of poor OS were no anti-viral therapy, advanced albumin-bilirubin grades, the presence of vascular invasion, tumor size ≥5 cm, and non-curative treatment modalities. Serum AFP levels were not associated with OS according to the multivariate analysis. Conclusion: Liver functional reserve, anti-viral therapy, tumor size, vascular invasion, and treatment modalities, determined the outcomes of HCC patients with normal serum AFP levels, but serum AFP levels did not.
Keywords	Albumin-bilirubin ; Normal alpha fetoprotein ; Liver cancer ; Outcomes ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2023-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Albumin-Based Liver Reserve Models vs. MELD 3.0 in Prognostic Prediction for Hepatocellular Carcinoma Patients with Renal Insufficiency

Shu-Yein Ho / Po-Hong Liu / Chia-Yang Hsu / Hung-Ting Tseng / Yi-Hsiang Huang / Chien-Wei Su / Ming-Chih Hou / Teh-Ia Huo

International Journal of Molecular Sciences, Vol 24, Iss 23, p

2023 Volume 16987

Abstract: The severity of liver functional reserve is an important prognostic predictor in hepatocellular carcinoma (HCC). The albumin–bilirubin (ALBI), easy (EZ)-ALBI, platelet-albumin–bilirubin (PALBI), platelet–albumin (PAL) score, and MELD 3.0 score are used ... ...

Abstract	The severity of liver functional reserve is an important prognostic predictor in hepatocellular carcinoma (HCC). The albumin–bilirubin (ALBI), easy (EZ)-ALBI, platelet-albumin–bilirubin (PALBI), platelet–albumin (PAL) score, and MELD 3.0 score are used to evaluate the severity of liver dysfunction. However, their prognostic role in HCC patients, specifically with renal insufficiency (RI), is unclear. We aimed to investigate the predictive accuracy of the five models in these patients. A total of 1120 newly diagnosed HCC patients with RI were enrolled. A multivariate Cox proportional analysis was used to identify independent predictors associated with survival. In the Cox model, older age, an α-fetoprotein ≥20 ng/mL, vascular invasion, a medium and high tumor burden score, poor performance status, a higher ALBI grade, an EZ-ALBI grade, a PALBI grade, a PAL grade, and MELD 3.0 score were all independently associated with decreased overall survival (all p < 0.001). Among the five liver reserve models, the ALBI grade is the best surrogate marker to represent liver functional reserve in terms of outcome prediction. The albumin-based liver reserve models (ALBI, EZ-ALBI, PALBI, and PAL) and MELD 3.0 are all feasible prognostic markers to indicate liver injury, specifically in HCC patients with RI. Among them, the ALBI grade is the most robust tool for survival prediction in these patients.
Keywords	hepatocellular carcinoma ; ALBI ; PALBI ; EZ-ALBI ; PAL ; MELD ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2023-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Surgical resection could provide better outcomes for patients with hepatocellular carcinoma and tumor rupture

Chun-Yang Lee / Gar-Yang Chau / Cheng-Yi Wei / Yee Chao / Yi-Hsiang Huang / Teh-Ia Huo / Ming-Chih Hou / Yu-Hui Su / Jaw-Ching Wu / Chien-Wei Su

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 9

Abstract: Abstract We investigated the outcomes of patients with ruptured hepatocellular carcinoma (HCC) and identified the optimal treatment modality for such patients. We retrospectively enrolled 91 patients with treatment-naive HCC and tumor rupture at ... ...

Abstract	Abstract We investigated the outcomes of patients with ruptured hepatocellular carcinoma (HCC) and identified the optimal treatment modality for such patients. We retrospectively enrolled 91 patients with treatment-naive HCC and tumor rupture at diagnosis, including 38 patients who underwent surgical resection (SR) alone, 28 patients who were treated with transarterial chemoembolization (TACE) only, 20 patients who had a sequential combination therapy of TACE and SR, and 5 patients who received best supportive care. After a median follow-up of 13.1 months, 54 patients died. The cumulative 5 years overall survival (OS) rates were 55.1% and 0% in the SR group and non-SR group, respectively (p < 0.001). Non-SR therapy was associated with poorer OS according to a multivariate analysis with a hazard ratio of 6.649 (95% confidence interval 3.581–12.344, p < 0.001). Moreover, whether patients received TACE or not did not impact the OS in both the SR group and the non-SR group. In conclusion, for patients with HCC and tumor rupture at the time of diagnosis, SR could lead to better prognoses than non-surgery treatment modalities. Moreover, a sequential combination of TACE and SR had similar clinical outcomes when compared to SR alone.
Keywords	Medicine ; R ; Science ; Q
Subject code	610 ; 616
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Virological and immunological predictors of long term outcomes of peginterferon alfa-2a therapy for HBeAg-negative chronic hepatitis B

I-Cheng Lee / Chien-Wei Su / Keng-Hsin Lan / Yuan-Jen Wang / Kuei-Chuan Lee / Han-Chieh Lin / Ming-Chih Hou / Yi-Hsiang Huang

Journal of the Formosan Medical Association, Vol 120, Iss 9, Pp 1676-

2021 Volume 1685

Abstract: Background/Purpose: Predictors of long-term outcomes of peginterferon (PegIFN) therapy for patients with chronic hepatitis B (CHB) remain to be explored. This study aimed to evaluate the predictive value of virological and immunological biomarkers and ... ...

Abstract	Background/Purpose: Predictors of long-term outcomes of peginterferon (PegIFN) therapy for patients with chronic hepatitis B (CHB) remain to be explored. This study aimed to evaluate the predictive value of virological and immunological biomarkers and outcomes of PegIFN for CHB. Methods: 57 HBeAg-negative CHB patients receiving 48 weeks of PegIFN therapy were prospectively followed for a median period of 5.3 years after the end of treatment (EOT). Serum CXCL9 and IP-10 levels were measured. Flow cytometry analysis for T cell subsets was performed in 23 patients. Factors associated with long-term outcomes were analyzed. Results: The cumulative incidences of virological relapse, clinical relapse and HBsAg loss at year 7 were 18.1%, 0%, 31.6%, respectively, in patients with sustained off-treatment virological response (SVR), and 100%, 67.4%, 6.7%, respectively, in patients without SVR. By multivariate analysis, baseline CXCL9 > 80 pg/mL (hazard ratio (HR) = 0.418, p = 0.018) and on-treatment HBsAg declines were associated with a lower risk of virological relapse. Non-SVR was the only predictor of clinical relapse. CXCL9 >200 pg/mL (HR = 8.154, p = 0.038) and HBsAg <750 IU/mL (HR = 10.507, p = 0.036) were baseline predictors of HBsAg loss, while HBsAg decline >1 log at EOT (HR = 23.296, p = 0.005) was the on-treatment predictor of HBsAg loss. In subgroup patients with available PBMC, populations of T cell subsets correlated with virological and clinical relapses in univariate analysis. Conclusion: Baseline serum CXCL9 and HBsAg levels could predict HBsAg loss after PegIFN therapy for HBeAg-negative CHB. Combining virological and immunological biomarkers could predict long-term outcomes of PegIFN therapy for HBeAg-negative CHB.
Keywords	Chronic hepatitis B ; CXCL9 ; Peginterferon alfa-2a ; HBsAg loss ; Medicine (General) ; R5-920
Subject code	610 ; 616
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Early and late recurrence of surgically resected hepatitis B virus-related hepatocellular carcinoma on nucleos(t)ide analogues therapy

Chi-Jung Wu / Gar-Yang Chau / I-Cheng Lee / Teh-Ia Huo / Chien-Wei Su / Ming-Chih Hou / Yi-Hsiang Huang

Journal of the Formosan Medical Association, Vol 120, Iss 8, Pp 1563-

2021 Volume 1571

Abstract: Background/Purpose: Hepatocellular carcinoma (HCC) is a highly recurrent tumor. Antiviral therapy with nucleos(t)ide analogues (NUCs) may reduce the risk of recurrence in hepatitis B virus (HBV)-related HCC. The risk factors associated with recurrence in ...

Abstract	Background/Purpose: Hepatocellular carcinoma (HCC) is a highly recurrent tumor. Antiviral therapy with nucleos(t)ide analogues (NUCs) may reduce the risk of recurrence in hepatitis B virus (HBV)-related HCC. The risk factors associated with recurrence in HCC patients after surgical resection and with NUCs treatment should be delineated. Methods: Consecutive 339 HBV-related HCC patients receiving surgical resection of HCC with NUCs therapy (including 256 entecavir, 36 tenofovir, and 18 lamivudine) after the surgery were retrospectively reviewed. Factors related to the recurrence-free survival (RFS) and overall survival (OS) were evaluated. Results: After a median of 48.5 months of follow-up, 183 (54%) patients developed HCC recurrence, with the 5-year RFS of 42.8% and OS of 79%. Male gender (HR = 1.736, p = 0.037), baseline HBsAg level >200 IU/ml (HR = 1.748, p = 0.008), platelet count ≦100 (109/L) (HR = 1.592, p = 0.023), presence of microscopic vascular invasion (MVI) (HR = 1.499, p = 0.026), safety cut margin of ≦0.5 cm (HR = 1.507, p = 0.013), and Ishak fibrosis score 5–6 (HR = 1.579, p = 0.009) were independent factors associated with RFS in multivariate analysis. While tumor burden, platelet count, MVI, and safety cut margin were factors associated with early recurrence; baseline HBsAg level, and platelet count were independent factors associated with late recurrence. Ishak fibrosis score 5–6, poor differentiation, MVI, diabetes mellitus were factors associated with OS in multivariate analysis. Conclusion: For HBV-HCC patients on NUCs treatment, tumor factors are associated with early recurrence, while HBsAg level and thrombocytopenia determines late recurrence. For patient with a high baseline HBsAg level, warning of higher risk of recurrence is required even under NUCs treatment.
Keywords	Early recurrence ; Hepatitis B surface antigen ; Hepatocellular carcinoma ; Late recurrence ; Nucleos(t)ide analogues ; Medicine (General) ; R5-920
Subject code	610 ; 616
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The correlation between fatty liver disease and chronic kidney disease

Po-Chun Chen / Wei-Yu Kao / Yuan-Lung Cheng / Yuan-Jen Wang / Ming-Chih Hou / Jaw-Ching Wu / Chien-Wei Su

Journal of the Formosan Medical Association, Vol 119, Iss 1, Pp 42-

2020 Volume 50

Abstract: Background/purpose: The impact of non-alcoholic fatty liver disease (NAFLD) on the prevalence of chronic kidney disease (CKD) is not fully elucidated. We aimed to assess the correlation between NAFLD and CKD in a large population study. Methods: We ... ...

Abstract	Background/purpose: The impact of non-alcoholic fatty liver disease (NAFLD) on the prevalence of chronic kidney disease (CKD) is not fully elucidated. We aimed to assess the correlation between NAFLD and CKD in a large population study. Methods: We included consecutive subjects who had received health check-up service at Taipei Veterans General Hospital from 2002 to 2009. NAFLD was diagnosed with abdominal ultrasound, and advanced liver fibrosis was determined with NAFLD fibrosis score (NAFLD-FS). CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. Results: Among the 29,797 subjects enrolled in this study, NAFLD and CKD were diagnosed in 44.5% and 20.2% of the population, respectively. Subjects with NAFLD had a higher proportion of CKD compared to those without NAFLD (24.1% vs. 17.1%, p < 0.001). However, NAFLD was not related to CKD with an odds ratio (OR) of 1.015 (95% confidence interval [CI] 0.954–1.081, p = 0.630) after multivariate analyses. Nevertheless, further analyses revealed that among patients with NAFLD, those with advanced fibrosis were more likely to have CKD after adjusting for confounding factors (OR 2.284, 95% CI 1.513–3.448, p < 0.001). Conclusion: NAFLD per se was not a risk factor for CKD, but NAFLD patients with advanced fibrosis faced a higher possibility of CKD. Hence, patients with NAFLD and advanced fibrosis should be screened for CKD and prompted to receive treatment if the diagnosis was made. Keywords: Non-alcoholic fatty liver disease, Kidney diseases, Liver fibrosis
Keywords	Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Evolution of etiology, presentation, management and prognostic tool in hepatocellular carcinoma

Shu-Yein Ho / Po-Hong Liu / Chia-Yang Hsu / Cheng-Yuan Hsia / Yi-Hsiang Huang / Hao-Jan Lei / Chien-Wei Su / Rheun-Chuan Lee / Ming-Chih Hou / Teh-Ia Huo

Scientific Reports, Vol 10, Iss 1, Pp 1-

2020 Volume 8

Abstract: Abstract Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, but its current status is unclear. We aimed to investigate the evolution of etiology, presentation, management and prognostic tool in HCC over the past ...

Abstract	Abstract Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, but its current status is unclear. We aimed to investigate the evolution of etiology, presentation, management and prognostic tool in HCC over the past 12 years. A total of 3349 newly diagnosed HCC patients were enrolled and retrospectively analyzed. The comparison of survival was performed by the Kaplan-Meier method with the log-rank test. Hepatitis B and C virus infection in HCC were continuously declining over the three time periods (2004–2007, 2008–2011, 2012–2015; p < 0.001). At diagnosis, single tumor detection rate increased to 73% (p < 0.001), whereas vascular invasion gradually decreased to 20% in 2012–2015 (p < 0.001). Early stage HCC gradually increased from 2004–2007 to 2012–2015 (p < 0.001). The probability of patients receiving curative treatment and long-term survival increased from 2004–2007 to 2012–2015 (p < 0.001). The Cancer of Liver Italian Program (CLIP) and Taipei Integrated Scoring (TIS) system were two more accurate staging systems among all. In conclusion, the clinical presentations of HCC have significantly changed over the past 12 years. Hepatitis B and C virus-associated HCC became less common, and more patients were diagnosed at early cancer stage. Patient survival increased due to early cancer detection that results in increased probability to undergo curative therapies.
Keywords	Medicine ; R ; Science ; Q
Subject code	610 ; 616
Language	English
Publishing date	2020-03-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Author Correction

Shu-Yein Ho / Po-Hong Liu / Chia-Yang Hsu / Cheng-Yuan Hsia / Yi-Hsiang Huang / Hao-Jan Lei / Chien-Wei Su / Rheun-Chuan Lee / Ming-Chih Hou / Teh-Ia Huo

Scientific Reports, Vol 10, Iss 1, Pp 1-

Evolution of etiology, presentation, management and prognostic tool in hepatocellular carcinoma

2020 Volume 2

Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...

Abstract	An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2020-10-01T00:00:00Z
Publisher	Nature Publishing Group
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Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Aspirin is associated with low recurrent risk in hepatitis B virus-related hepatocellular carcinoma patients after curative resection

Shih-Hao Young / Gar-Yang Chau / I-Cheng Lee / Yi-Chen Yeh / Yee Chao / Teh-Ia Huo / Chien-Wei Su / Han-Chieh Lin / Ming-Chih Hou / Mei-Hsuan Lee / Yi-Hsiang Huang

Journal of the Formosan Medical Association, Vol 119, Iss 1, Pp 218-

2020 Volume 229

Abstract: Background/Purpose: The risk of recurrence after resection of hepatocellular carcinoma (HCC) is high. Apart from nucleos(t)ide analogues therapy, population-based studies suggest statin, nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin have ... ...

Abstract	Background/Purpose: The risk of recurrence after resection of hepatocellular carcinoma (HCC) is high. Apart from nucleos(t)ide analogues therapy, population-based studies suggest statin, nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin have chemopreventive effect on recurrence. The role of those drugs on HCC recurrence should be delineated. Methods: Consecutive 430 hepatitis B surface antigen (HBsAg)-positive patients undergoing curative resection of HCC were enrolled. The detailed medical records including the use of statin, NSAID and aspirin were reviewed. All the patients had regular image study surveillance after the surgery. Predictors associated with recurrence were analyzed by Cox's proportional hazards models. Results: There were 58.8% patients in Barcelona Clinic Liver Cancer (BCLC) stage A, and 37.6% had severe liver fibrosis or cirrhosis. Of them, 47 (10.9%) patients had received potential chemoprophylactic agents either at the time of HCC diagnosis or before their HCC recurrence. During a median 50.3 months of follow-up, 54.7% patients experienced recurrence. The median time to recurrence was 15.4 months. In the univariate analysis, aspirin and statins use were significantly associated a low risk of recurrence (hazard ratio [HR]: 0.18; p = 0.016, and HR: 0.50; p = 0.031, respectively). After adjusting competing factors, large tumor size, severe liver fibrosis, and high alpha-fetoprotein (AFP) level were significantly associated with recurrence. Importantly, aspirin use was found to significantly decrease the risk for HCC recurrence with the adjusted HRs of 0.22–0.24 based on the models. Conclusion: Aspirin use may have chemo-preventive effect on recurrence of hepatitis B virus-related HCC after curative resection. Keywords: Aspirin, HBV, HCC, Recurrence, Resection
Keywords	Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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