Publications by authors named "Chee Kiat Tan"

59 Publications

Contextual and individual factors associated with knowledge, awareness and attitude on liver diseases: A large-scale Asian study.

J Viral Hepat 2021 Nov 24. Epub 2021 Nov 24.

Kantar Health, Singapore, Singapore.

There are limited data to provide better understanding of the knowledge/awareness of general population towards liver health in Asia. We sought to identify the knowledge gaps and attitudes towards liver health and liver diseases as well as evaluate associated individual-level and macro-level factors based on contextual analysis. An online survey assessing knowledge, awareness and attitudes towards liver health and disease was conducted among 7500 respondents across 11 countries/territories in Asia. A liver index was created to measure the respondents' knowledge level and the degree of awareness and attitudes. Multilevel logistic regression was performed to identify individual factors and contextual effects that were associated with liver index. The overall liver index (0-100-point scale) was 62.4 with 6 countries/territories' liver indices greater than this. In the multilevel model, the inclusion of geographical information could explain for 9.6% of the variation. Residing in a country/territory with higher HBV prevalence (80% IOR: 1.20-2.79) or higher HCV death rate (80% IOR: 1.35-3.13) increased the individual probability of obtaining a high overall liver index. Individual factors like age, gender, education, household income, disease history and health screening behaviour were also associated with liver index (all p-values<0.001). The overall liver index was positively associated with the two macro-level factors viz. HBV prevalence and HCV death rate. There is a need to formulate policies especially in regions of lower HBV prevalence and HCV death rate to further improve the knowledge, awareness and attitudes of the general public towards liver diseases.
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http://dx.doi.org/10.1111/jvh.13636DOI Listing
November 2021

A study of 3013 cases of hepatocellular carcinoma: Etiology and therapy before and during the current decade.

JGH Open 2021 Sep 27;5(9):1015-1018. Epub 2021 Jul 27.

Department of Hepatology and Gastroenterology Singapore General Hospital Singapore.

Background And Aim: Hepatocellular carcinoma (HCC) is a significant global problem. With advances in HCC diagnosis and therapy, our hypothesis is that there are significant differences in the clinical characteristics and treatment of HCC over the years.

Methods: Patients with HCC between 1980 and 2018 from three major tertiary hospitals in Singapore were enrolled into a Research Electronic Data Capture database. Clinical characteristics and treatment of HCC were compared between those diagnosed before 2008 (cohort A) and during the current decade (ie from 2008 onwards) (cohort B).

Results: There were 3013 patients. Mean age of HCC diagnosis was significantly older in cohort B (68.6 61.2 years,  < 0.001). The most common etiology remained as chronic hepatitis B infection but the proportion due to hepatitis B was significantly lower in cohort B (46.6% 57.2%,  < 0.0001). The prevalence of cryptogenic/non-alcoholic steatohepatitis was significantly higher in cohort B than cohort A (27.1% 18.6%,  < 0.0001). More patients received curative therapy in cohort B (43.7% 27.1%,  < 0.0001.

Conclusion: In this largest collection of HCC patients in Singapore, patients are diagnosed with HCC at an older age and cryptogenic/non-alcoholic steatohepatitis is becoming more important as an etiology of HCC in the current decade. More patients also received curative therapy in the current decade.
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http://dx.doi.org/10.1002/jgh3.12624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8454472PMC
September 2021

Improving the Communication and Understanding of the Opt-Out Organ Donation Law Among Young Adults.

Transplant Proc 2021 Sep 23;53(7):2095-2104. Epub 2021 Aug 23.

National Organ Transplant Unit, Ministry of Health, Singapore; Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore; Duke-NUS Medical School, Singapore. Electronic address:

Lack of knowledge adversely affects one's attitude toward organ donation. To increase understanding, Singapore informs each citizen and permanent resident turning 21 years old through information mailers sent to their place of residence. This study measured the current knowledge on organ donation of 106 polytechnic students (aged 16-24 years) and their reception toward 3 versions of the information mailers (current, revised version 1, and version 2). It was found that 69% of respondents were unaware of the Human Organ Transplant Act. The current mailer also lacks appeal, with only 3.8% of respondents preferring the current version, compared with 42% to 44% who preferred revised version 1 and 52% to 55% who preferred revised version 2. Qualitative responses suggest that the assimilation of elements in both new versions (ie, visuals, layout, and font) will likely lead to better appeal. Findings therefore reinforced the need for revision of current information mailers to captivate young adults to find out about organ donation in Singapore and make informed end-of-life decisions. Further research should consider eliciting more detailed qualitative responses in a conducive setting under a wider time frame.
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http://dx.doi.org/10.1016/j.transproceed.2021.07.044DOI Listing
September 2021

Poor Outcomes of Cirrhosis due to Nonalcoholic Steatohepatitis Compared With Hepatitis B After Decompensation With Ascites.

Am J Gastroenterol 2021 07;116(7):1437-1446

Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore.

Introduction: Decompensation with ascites portends a poor prognosis in cirrhosis. The aim of this study was to compare the outcomes of patients with nonalcoholic steatohepatitis (NASH) with hepatitis B virus (HBV) cirrhosis after decompensation with ascites.

Methods: We conducted a retrospective study to evaluate the outcomes of patients with NASH and HBV cirrhosis who were admitted to hospital for first-onset ascites from January 1, 2004, to June 30, 2015. They were followed up until death, liver transplantation, or loss to follow up.

Results: Patients with NASH had lower median (interquartile range) Model for End-Stage Liver Disease score (11 [9-14] vs 14 [11-17], P < 0.001). Over 60 months, patients with NASH cirrhosis had higher cumulative incidence of dilutional hyponatremia (P < 0.001) and refractory ascites (P = 0.028). They also had higher cumulative incidence of cirrhosis-related deaths and liver transplantation compared with HBV cirrhosis (65.7%; [95% confidence interval (CI) 53.6-75.4] vs 42.5% [95% CI 32.4-55.2], P = 0.008). Multivariable competing risk analysis showed that NASH (subdistribution hazard ratio [sHR] 1.88 [95% CI 1.14-3.11], P = 0.014), non-Chinese ethnicity (sHR 1.63 [95% CI 1.06-2.50], P = 0.027), history of hepatocellular carcinoma (sHR 1.76 [95% CI 1.05-2.95], P = 0.033), estimated glomerular filtration rate <60 mL/min/1.73 m2 (sHR 1.70 [95% CI 1.09-2.65], P = 0.020), and Model for End-Stage Liver Disease score ≥15 (sHR 3.26 [95% CI 2.11-5.05], P < 0.001) were independent predictors of poor transplant-free survival.

Discussion: Patients with decompensated cirrhosis due to NASH had much poorer prognosis compared with HBV with more complications and greater healthcare resource utilization. Greater awareness is necessary for early diagnosis of NASH before decompensation.
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http://dx.doi.org/10.14309/ajg.0000000000001176DOI Listing
July 2021

Public awareness and knowledge of liver health and diseases in Singapore.

J Gastroenterol Hepatol 2021 Aug 30;36(8):2292-2302. Epub 2021 Mar 30.

Kantar Health, Singapore.

Background And Aim: Despite efforts in controlling and managing liver diseases, significant health issues remain. This study aims to evaluate the degree of public awareness and knowledge regarding liver health and diseases in Singapore.

Methods: A cross-sectional, self-reported, web-based questionnaire was administered to 500 adult individuals. Questionnaire items pertained to knowledge and awareness of overall liver health, liver diseases and their associated risk factors.

Results: Sixty-four percent of respondents were ≥35 years old and 54.0% were male. While majority agreed that regular screening was important for liver health (91.2%), only 65.4% attended health screening within recent 2 years. Hepatitis B had more awareness than hepatitis C among the respondents. About 70% agreed the consequences of viral hepatitis included liver cirrhosis, failure, and/or cancer. Yet, only 15% knew hepatitis C is not preventable by vaccination and more than half mistaken hepatitis B and C are transmissible via contaminated or raw seafood. Despite 75% being aware of non-alcoholic fatty liver disease, many were not aware of the related risk factors and complications. Awareness of specific screening and diagnostic tests for liver health was poor as one-fifth correctly identified the diagnostic tests for viral hepatitis. Preferences for doctor's consultation, TV, or newspapers (online) as information channels contrasted those currently used in the public health education efforts.

Conclusions: The levels of understanding of liver diseases, risk factors, and potential complications are suboptimal among the Singapore public. More public education efforts aligned with respondents' information-seeking preferences could facilitate addressing misperceptions and increase knowledge about liver diseases.
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http://dx.doi.org/10.1111/jgh.15496DOI Listing
August 2021

High-stakes examinations during the COVID-19 pandemic: to proceed or not to proceed, that is the question.

Postgrad Med J 2021 Jul 15;97(1149):427-431. Epub 2021 Jan 15.

Gastroenterology and Hepatology, Singapore General Hospital, Singapore.

The COVID-19 pandemic has disrupted education-related activities, including the conduct of examinations. We review the literature regarding high-stakes examinations during the pandemic, discuss the decision-making process of whether to proceed with a high-stakes examination and share published experiences in conducting high-stakes examinations during the pandemic. We illustrate our own recent experiences of decision-making and conduct of our high-stakes gastroenterology licencing examinations during the height of the COVID-19 pandemic. It is possible to conduct high-stakes examinations virtually during pandemic situations with fidelity and adherence to the established format and standards.
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http://dx.doi.org/10.1136/postgradmedj-2020-139241DOI Listing
July 2021

Masquerading Hypervascular Exophytic Liver Nodule.

Eur J Case Rep Intern Med 2020 6;7(11):001840. Epub 2020 Aug 6.

Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore.

Patients with liver cirrhosis are at increased risk of developing hepatocellular carcinoma (HCC) and are placed on routine surveillance for HCC. Diagnosis algorithms are in place to guide clinicians in the evaluation of liver lesions detected during surveillance. Radiological assessments are critical with diagnostic criteria based on identification of typical hallmarks of HCCs on multiphasic computed tomography (CT) and dynamic contrast-enhanced magnetic resonance imaging (MRI). We report a patient with a hypervascular exophytic lesion indeterminate for HCC on CT imaging. While the detection of an exophytic arterially-enhancing lesion in an at-risk patient on CT imaging may prompt clinicians to treat the lesion as HCC without further evaluation, the patient underwent contrast-enhanced MRI with the lesion being eventually diagnosed as an exophytic haemangioma. Thus, no further action was necessary and the patient was continued on routine HCC surveillance.

Learning Points: Radiological surveillance for hepatocellular carcinoma (HCC) is routine in patients at risk of HCC.Diagnosis algorithms that are in place for indeterminate lesions detected during HCC surveillance should be adhered to in order to achieve an accurate diagnosis.Sequential imaging with contrast-enhanced (gadoxetate) MRI should be used to obviate the need for an invasive biopsy when an exophytic lesion indeterminate for HCC is identified during CT imaging in a patient with liver cirrhosis, especially when a hepatic haemangioma remains a differential diagnosis.
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http://dx.doi.org/10.12890/2020_001840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654990PMC
August 2020

An Improved qFibrosis Algorithm for Precise Screening and Enrollment into Non-Alcoholic Steatohepatitis (NASH) Clinical Trials.

Diagnostics (Basel) 2020 Aug 28;10(9). Epub 2020 Aug 28.

Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore.

Background: Many clinical trials with potential drug treatment options for non-alcoholic fatty liver disease (NAFLD) are focused on patients with non-alcoholic steatohepatitis (NASH) stages 2 and 3 fibrosis. As the histological features differentiating stage 1 (F1) from stage 2 (F2) NASH fibrosis are subtle, some patients may be wrongly staged by the in-house pathologist and miss the opportunity for enrollment into clinical trials. We hypothesized that our refined artificial intelligence (AI)-based algorithm (qFibrosis) can identify these subtle differences and serve as an assistive tool for in-house pathologists.

Methods: Liver tissue from 160 adult patients with biopsy-proven NASH from Singapore General Hospital (SGH) and Peking University People's Hospital (PKUH) were used. A consensus read by two expert hepatopathologists was organized. The refined qFibrosis algorithm incorporated the creation of a periportal region that allowed for the increased detection of periportal fibrosis. Consequently, an additional 28 periportal parameters were added, and 28 pre-existing perisinusoidal parameters had altered definitions.

Results: Twenty-eight parameters (20 periportal and 8 perisinusoidal) were significantly different between the F1 and F2 cases that prompted a change of stage after a careful consensus read. The discriminatory ability of these parameters was further demonstrated in a comparison between the true F1 and true F2 cases as 26 out of the 28 parameters showed significant differences. These 26 parameters constitute a novel sub-algorithm that could accurately stratify F1 and F2 cases.

Conclusion: The refined qFibrosis algorithm incorporated 26 novel parameters that showed a good discriminatory ability for NASH fibrosis stage 1 and 2 cases, representing an invaluable assistive tool for in-house pathologists when screening patients for NASH clinical trials.
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http://dx.doi.org/10.3390/diagnostics10090643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554942PMC
August 2020

Validation of the Expanded Baveno-VI Criteria for Screening Gastroscopy in Asian Patients with Compensated Advanced Chronic Liver Disease.

Dig Dis Sci 2021 04 21;66(4):1343-1348. Epub 2020 May 21.

Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore, Singapore.

Background: The expanded Baveno-VI criteria may further reduce the need for screening gastroscopy compared to Baveno-VI criteria.

Aim: We sought to validate the performance of these criteria in a cohort of compensated advanced chronic liver disease (cACLD) patients with predominantly hepatitis B infection.

Methods: Consecutive cACLD patients from 2006 to 2012 with paired liver stiffness measurements and screening gastroscopy within 1 year were included. The expanded Baveno-VI criteria were applied to evaluate the sensitivity (SS), specificity (SP), positive predictive value (PPV) and negative predictive value (NPV) for the presence of high-risk varices (HRV).

Results: Among 165 cACLD patients included, 17 (10.3%) had HRV. The commonest etiology of cACLD was chronic hepatitis B (36.4%) followed by NAFLD (20.0%). Application of expanded Baveno-VI criteria avoided more screening gastroscopy (43.6%) as compared to the original Baveno-VI criteria (18.8%) without missing more HRV (1 with both criteria). The overall SS, SP, PPV and NPV of the expanded Baveno-VI criteria in predicting HRV were 94.1%, 48.0%, 17.2% and 98.6%, respectively.

Conclusion: Application of the expanded Baveno-VI criteria can safely avoid screening gastroscopy in 43.6% of cACLD patients with an excellent ability to exclude HRV.
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http://dx.doi.org/10.1007/s10620-020-06334-yDOI Listing
April 2021

Chapter of Gastroenterologists professional guidance for management of patients with liver disease in Singapore during the COVID-19 pandemic.

Singapore Med J 2020 12 29;61(12):619-623. Epub 2020 Apr 29.

Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore.

In this paper, we aim to provide professional guidance to clinicians who are managing patients with chronic liver disease during the current coronavirus disease 2019 (COVID-19) pandemic in Singapore. We reviewed and summarised the available relevant published data on liver disease in COVID-19 and the advisory statements that were issued by major professional bodies, such as the American Association for the Study of Liver Diseases and European Association for the Study of the Liver, contextualising the recommendations to our local situation.
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http://dx.doi.org/10.11622/smedj.2020069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930298PMC
December 2020

Comparisons between non-alcoholic steatohepatitis and alcohol-related hepatocellular carcinoma.

Clin Mol Hepatol 2020 04 9;26(2):196-208. Epub 2020 Jan 9.

Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore.

Background/aims: Non-alcoholic liver disease and alcoholic liver disease begin as simple steatosis that may progress to steatohepatitis and ensuing liver-related complications such as cirrhosis and hepatocellular carcinoma (HCC). We explored differences in characteristics between non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis-related (ASH) HCC.

Methods: NASH and ASH patients were identified from our department's prospective HCC database. A total of 54 and 45 patients met predefined inclusion and exclusion criteria for the NASH-HCC and ASH-HCC groups, respectively. Clinical, biochemical and tumor characteristics were studied.

Results: NASH-HCC patients were older compared to ASH-HCC patients (72±9 vs. 66±9 years, P<0.001) and less male predominant (65% vs. 98%, P<0.001). Prevalence of diabetes mellitus (78% vs. 36%, P<0.001) and hypertension (80% vs. 58%, P<0.001) were significantly higher in the NASH-HCC group. Liver function tests and Child-Pugh scores were similar. There were no differences in alpha-fetoprotein level, lesions found at diagnosis (unifocal/multifocal) or prevalence of portal vein invasion. In both groups, almost half of the patients were in TNM stage 4 at the time of diagnosis and more than 50% of patients were not suitable for any therapy. Median survival in the NASH-HCC and ASH-HCC groups were 13 and 7 months respectively (P=0.113).

Conclusion: Despite significant differences in demography of the NASH-HCC and ASH-HCC groups, liver and tumor characteristics were comparable. Most patients were diagnosed late and were not amenable to curative or locoregional therapies. Better characterization of patients with NASH and ASH at risk of HCC is necessary to optimize screening, surveillance, and management strategies.
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http://dx.doi.org/10.3350/cmh.2019.0012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160352PMC
April 2020

Repeat liver resection versus salvage liver transplant for recurrent hepatocellular carcinoma: A propensity score-adjusted and -matched comparison analysis.

Ann Hepatobiliary Pancreat Surg 2019 Nov 29;23(4):305-312. Epub 2019 Nov 29.

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore.

Backgrounds/aims: Repeat liver resection (RLR) and salvage liver transplantation (SLT) are viable treatment options for recurrent hepatocellular carcinoma (HCC). With possibly superior survival outcomes than RLR, SLT is however, limited by liver graft availability and poses increased perioperative morbidity. In this study, we seek to compare the outcomes of RLR and SLT for patients with recurrent HCC.

Methods: Between 1999 and 2018, 94 and 16 consecutive patients who underwent RLR and SLT respectively were identified. Further retrospective subgroup analysis was conducted, comparing 16 RLR with 16 SLT patients via propensity-score matching.

Results: After propensity-score adjusted analyses, SLT demonstrated inferior short-term perioperative outcomes than RLR, with increased major morbidity (57.8% vs 5.4 %, =0.0001), reoperations (39.1% vs 0, <0.0001), renal insufficiency (30.1% vs 3%, =0.0071), bleeding (19.8% vs 2.2%, =0.0289), prolonged intensive care unit stay (median=4 vs 0 days, <0.0001) and hospital stay (median=19.8 vs 7.1days, <0.001). However, SLT showed significantly lower recurrence rate (15.4% versus 70.3%, =0.0005) and 5-year cumulative incidence of recurrences (19.4% versus 68.4%, =0.005). Propensity-matched subgroup analysis showed concordant findings.

Conclusions: While SLT offers potentially reduced risks of recurrence and trended towards improved long-term survival outcomes relative to RLR, it has poorer short-term perioperative outcomes. Patient selection is prudent amidst organ shortages to maximise allocated resources and optimise patient outcomes.
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http://dx.doi.org/10.14701/ahbps.2019.23.4.305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893044PMC
November 2019

qFIBS: An Automated Technique for Quantitative Evaluation of Fibrosis, Inflammation, Ballooning, and Steatosis in Patients With Nonalcoholic Steatohepatitis.

Hepatology 2020 06 7;71(6):1953-1966. Epub 2020 May 7.

Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Beijing, China.

Background And Aims: Nonalcoholic steatohepatitis (NASH) is a common cause of chronic liver disease. Clinical trials use the NASH Clinical Research Network (CRN) system for semiquantitative histological assessment of disease severity. Interobserver variability may hamper histological assessment, and diagnostic consensus is not always achieved. We evaluate a second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) imaging-based tool to provide an automated quantitative assessment of histological features pertinent to NASH.

Approach And Results: Images were acquired by SHG/TPEF from 219 nonalcoholic fatty liver disease (NAFLD)/NASH liver biopsy samples from seven centers in Asia and Europe. These were used to develop and validate qFIBS, a computational algorithm that quantifies key histological features of NASH. qFIBS was developed based on in silico analysis of selected signature parameters for four cardinal histopathological features, that is, fibrosis (qFibrosis), inflammation (qInflammation), hepatocyte ballooning (qBallooning), and steatosis (qSteatosis), treating each as a continuous rather than categorical variable. Automated qFIBS analysis outputs showed strong correlation with each respective component of the NASH CRN scoring (P < 0.001; qFibrosis [r = 0.776], qInflammation [r = 0.557], qBallooning [r = 0.533], and qSteatosis [r = 0.802]) and high area under the receiver operating characteristic curve values (qFibrosis [0.870-0.951; 95% confidence interval {CI}, 0.787-1.000; P < 0.001], qInflammation [0.820-0.838; 95% CI, 0.726-0.933; P < 0.001), qBallooning [0.813-0.844; 95% CI, 0.708-0.957; P < 0.001], and qSteatosis [0.939-0.986; 95% CI, 0.867-1.000; P < 0.001]) and was able to distinguish differing grades/stages of histological disease. Performance of qFIBS was best when assessing degree of steatosis and fibrosis, but performed less well when distinguishing severe inflammation and higher ballooning grades.

Conclusions: qFIBS is an automated tool that accurately quantifies the critical components of NASH histological assessment. It offers a tool that could potentially aid reproducibility and standardization of liver biopsy assessments required for NASH therapeutic clinical trials.
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http://dx.doi.org/10.1002/hep.30986DOI Listing
June 2020

Circulating microRNAs as Potential Diagnostic and Prognostic Biomarkers in Hepatocellular Carcinoma.

Sci Rep 2019 07 18;9(1):10464. Epub 2019 Jul 18.

Division of Cellular & Molecular Research, National Cancer Centre Singapore, Singapore, Singapore.

Hepatocellular carcinoma (HCC) is the fifth most common cancer with high mortality, due to late diagnosis and limited treatment options. Blood miRNAs, which circulate in a highly stable, cell-free form, show promise as novel potential biomarkers for early detection of HCC. Whole miRNome profiling was performed to identify deregulated miRNAs between HCC and normal healthy (NH) volunteers. These deregulated miRNAs were validated in an independent cohort of HCC, NH and chronic Hepatitis B (CHB) volunteers and finally in a 3 cohort comprising NH, CHB, cirrhotic and HCC volunteers to evaluate miRNA changes during disease progression. The associations between circulating miRNAs and liver-damage markers, clinicopathological characteristics and survival outcomes were analysed to identify prognostic markers. Twelve miRNAs are differentially expressed between HCC and NH individuals in all three cohorts. Five upregulated miRNAs (miR-122-5p, miR-125b-5p, miR-885-5p, miR-100-5p and miR-148a-3p) in CHB, cirrhosis and HCC patients are potential biomarkers for CHB infection, while miR-34a-5p can be a biomarker for cirrhosis. Notably, four miRNAs (miR-1972, miR-193a-5p, miR-214-3p and miR-365a-3p) can distinguish HCC from other non-HCC individuals. Six miRNAs are potential prognostic markers for overall survival.
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http://dx.doi.org/10.1038/s41598-019-46872-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639394PMC
July 2019

Letter: impact of hepatitis B core-related antigen on the incidence of hepatocellular carcinoma in patients treated with nucleos(t)ide analogues-further clarifications needed.

Aliment Pharmacol Ther 2019 07;50(2):232

Department of Gastroenterology & Hepatology, Singapore General Hospital Singapore, Singapore, Singapore.

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http://dx.doi.org/10.1111/apt.15254DOI Listing
July 2019

Outcomes of salvage liver transplant for recurrent hepatocellular carcinoma: A comparison with primary liver transplant.

Ann Hepatobiliary Pancreat Surg 2019 Feb 28;23(1):1-7. Epub 2019 Feb 28.

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore.

Backgrounds/aims: Salvage liver transplantation (SLT) is a therapeutic strategy for recurrent hepatocellular carcinoma (HCC). However, it remains controversial with compromised survival outcomes and increased perioperative morbidity compared to primary liver transplant (PLT). In the present work, we describe our institution's experience on SLT by comparing outcomes of SLT to PLT for HCCs.

Methods: Retrospective analysis was conducted for 49 transplant patients from 2006-2017. A comparative analysis was carried out between 14 SLT patients and 35 PLT patients.

Results: SLT patients demonstrated significantly shorter time to recurrence than PLT patients (median=5.5 versus 23 months, <0.001) with a trend towards increased perioperative major morbidity (42.9% versus 37%, =0.711), inferior 5-year overall survival (61% versus 75%, =0.345) and inferior 5-year recurrence-free survival (57% versus 72%, =0.263). However, overall survival from the point of primary resection over a 10-year period showed no statistical difference between the 2 groups (SLT=60% versus PLT=61%, =0.685).

Conclusions: SLT is a viable treatment strategy for HCCs. However, it exhibited poorer short-term perioperative and oncologic outcomes than PLT. SLT requires better patient selection with liver donor grafts for optimization of resource allocation in this era of organ shortage. Considering the worldwide shortages in liver grafts, it is hypothesized that optimization of a salvage transplant strategy may improve resource allocation and reap optimal patient outcomes.
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http://dx.doi.org/10.14701/ahbps.2019.23.1.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405363PMC
February 2019

Quantification of hepatic steatosis in chronic liver disease using novel automated method of second harmonic generation and two-photon excited fluorescence.

Sci Rep 2019 02 27;9(1):2975. Epub 2019 Feb 27.

Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore, Singapore.

The presence of hepatic steatosis (HS) is an important histological feature in a variety of liver disease. It is critical to assess HS accurately, particularly where it plays an integral part in defining the disease. Conventional methods of quantifying HS remain semi-quantitative, with potential limitations in precision, accuracy and subjectivity. Second Harmonic Generation (SHG) microscopy is a novel technology using multiphoton imaging techniques with applicability in histological tissue assessment. Using an automated algorithm based on signature SHG parameters, we explored the utility and application of SHG for the diagnosis and quantification of HS. SHG microscopy analysis using GENESIS (HistoIndex, Singapore) was applied on 86 archived liver biopsy samples. Reliability was correlated with 3 liver histopathologists. Data analysis was performed using SPSS. There was minimal inter-observer variability between the 3 liver histopathologists, with an intraclass correlation of 0.92 (95% CI 0.89-0.95; p < 0.001). Good correlation was observed between the histopathologists and automated SHG microscopy assessment of HS with Pearson correlation of 0.93: p < 0.001. SHG microscopy provides a valuable tool for objective, more precise measure of HS using an automated approach. Our study reflects proof of concept evidence for potential future refinement to current conventional histological assessment.
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http://dx.doi.org/10.1038/s41598-019-39783-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393558PMC
February 2019

Influence of HIV Infection on the Natural History of Hepatocellular Carcinoma: Results From a Global Multicohort Study.

J Clin Oncol 2019 02 18;37(4):296-304. Epub 2018 Dec 18.

19 James J. Peters Veterans Affairs Medical Center, Bronx, NY.

Purpose: Conflicting evidence indicates that HIV seropositivity may influence the outcome of patients with hepatocellular carcinoma (HCC), a leading cause of mortality in people with HIV. We aimed to verify whether HIV affected the overall survival (OS) of patients with HCC, independent of treatment and geographic origin.

Patients And Methods: We designed an international multicohort study of patients with HCC accrued from four continents who did not receive any anticancer treatment. We estimated the effect of HIV seropositivity on patients' OS while accounting for common prognostic factors and demographic characteristics in uni- and multivariable models.

Results: A total of 1,588 patients were recruited, 132 of whom were HIV positive. Most patients clustered within Barcelona Clinic Liver Cancer (BCLC) C or D criteria (n = 1,168 [74%]) and Child-Turcotte-Pugh (CTP) class B (median score, 7; interquartile range [IQR], 3). At HCC diagnosis, the majority of patients who were HIV-positive (n = 65 [64%]) had been on antiretrovirals for a median duration of 8.3 years (IQR, 8.59 years) and had median CD4 cell counts of 256 (IQR, 284) with undetectable HIV RNA (n = 68 [52%]). OS decreased significantly throughout BCLC stages 0 to D (16, 12, 7.5, 3.1, and 3 months, respectively; P < .001). Median OS of patients who were HIV-positive was one half that of their HIV-uninfected counterparts (2.2 months [bootstrap 95% CI, 1.2 to 3.1 months] v 4.1 months [95% CI, 3.6 to 4.4 months]). In adjusted analyses, HIV seropositivity increased the hazard of death by 24% ( P = .0333) independent of BCLC ( P < .0001), CTP ( P < .0001), α-fetoprotein ( P < .0001), geographical origin ( P < .0001), and male sex ( P = .0016). Predictors of worse OS in patients who were HIV-positive included CTP ( P = .0071) and α-fetoprotein ( P < .0001).

Conclusion: Despite adequate antiretroviral treatment, HIV seropositivity is associated with decreased survival in HCC, independent of stage, anticancer treatment, and geographical origin. Mechanistic studies investigating the immunobiology of HIV-associated HCC are urgently required.
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http://dx.doi.org/10.1200/JCO.18.00885DOI Listing
February 2019

Sofosbuvir-velpatasvir for treatment of chronic hepatitis C virus infection in Asia: a single-arm, open-label, phase 3 trial.

Lancet Gastroenterol Hepatol 2019 02 14;4(2):127-134. Epub 2018 Dec 14.

Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Background: Treatment with combined sofosbuvir and velpatasvir has resulted in high sustained virological response rates in patients chronically infected with hepatitis C virus (HCV) with genotypes 1-6 in clinical trials and real-world settings, but its efficacy and safety has not been assessed in Asia, a region with diverse HCV genotypes.

Methods: In this single-arm, open-label, phase 3 trial, we recruited patients from 38 sites across China, Thailand, Vietnam, Singapore, and Malaysia, who were chronically infected with HCV genotypes 1-6, and were HCV treatment-naive or treatment-experienced, either without cirrhosis or with compensated cirrhosis. Patients self-administered a combined sofosbuvir (400 mg) and velpatasvir (100 mg) tablet once daily for 12 weeks. The primary efficacy endpoint was sustained virological response, defined as HCV RNA less than 15 IU/mL at 12 weeks after completion of treatment (SVR12), assessed in all patients who received at least one dose of study drug. The primary safety endpoint was the proportion of adverse events leading to premature discontinuation of study drug. This trial is registered with ClinicalTrials.gov, number NCT02671500, and is completed.

Findings: Between April 14, 2016, and June 30, 2017, 375 patients were enrolled in the study, of whom 374 completed the full treatment course and one discontinued treatment. Overall, 362 (97% [95% CI 94-98]) of 375 patients achieved SVR12. Among 42 patients with HCV genotype 3b, all of whom had baseline resistance-associated substitutions in NS5A, 25 (89% [95% CI 72-98]) of 28 patients without cirrhosis and seven (50% [23-77]) of 14 patients with cirrhosis achieved SVR12. The most common adverse events were upper respiratory tract infection (36 [10%] patients) and headache (18 [5%] patients). There were no discontinuations due to adverse events. Serious adverse events were reported in three (1%) patients, none of which was judged to be related to sofosbuvir-velpatasvir treatment.

Interpretation: Consistent with data from other phase 3 studies, single-tablet sofosbuvir-velpatasvir for 12 weeks is an efficacious and safe treatment for Asian patients with chronic HCV infection, but might have lower efficacy in those infected with HCV genotype 3b and with cirrhosis.

Funding: Gilead Sciences.
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http://dx.doi.org/10.1016/S2468-1253(18)30343-1DOI Listing
February 2019

Editorial: hepatitis B, fatty liver, and metabolic syndrome-interaction or co-existence?

Aliment Pharmacol Ther 2018 11;48(10):1160-1161

Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore.

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http://dx.doi.org/10.1111/apt.14992DOI Listing
November 2018

Comparison of Hepatocellular Carcinoma in Patients with Cryptogenic Versus Hepatitis B Etiology: A Study of 1079 Cases Over 3 Decades.

Dig Dis Sci 2019 02 16;64(2):585-590. Epub 2018 Oct 16.

Department of Gastroenterology and Hepatology, Singapore General Hospital, Academia, 20 College Road, Singapore, 169856, Singapore.

Background: Traditionally in Asia, hepatitis B (HBV) accounts for the majority of hepatocellular carcinoma (HCC), but increasingly, non-viral or nonalcoholic steatohepatitis (NASH) etiology may play a more prominent role with current socioeconomic changes. There remains a paucity in data comparing NASH-HCC to HBV-related HCC. In this study, we explored the differences in clinical characteristics between HBV- and cryptogenic-related HCC.

Methods: Patients with HCC seen in the Department of Gastroenterology and Hepatology, Singapore General Hospital were enrolled in an ongoing database since 1980. Patients with HCC attributed to HBV or cryptogenic etiology were identified. Comparison of clinical characteristics was performed between the two groups.

Results: There were 916 HBV-HCC patients and 163 cryptogenic HCC patients, accounting for 70.9% and 12.6% of the total HCC cases (1292 patients), respectively. Out of the total cohort enrolled from 1980 to 2005, the ratio of cryptogenic to HBV patients was 1:6.7, while from 2006 to the current year, the ratio of cryptogenic to HBV patients has increased significantly to 1:3.9. Relative to patients with HBV, cryptogenic HCC patients were older (67.6 vs. 59.4 years old; p < 0.001), had lower proportion of male patients (69.9% vs. 83.8%; p < 0.001), and had higher incidence of smoking (32.2% vs. 25.8%; p = 0.008). HBV group had higher alanine transaminase (60.9 ± 85.7 U/L vs. 48.0 ± 52.1 U/L; p = 0.003), hemoglobin (12.7 ± 2.28 g/dL vs. 12.0 ± 2.46 g/dL, p < 0.001), albumin (32.9 ± 6.8 g/L vs. 31.3 ± 7.7 g/L; p = 0.007), and prothrombin time (13.2 ± 2.95 s vs. 12.7 ± 2.01 s, p = 0.023), as compared to the cryptogenic group. Cryptogenic HCC patients presented more frequently with unifocal HCC (55.2% vs. 46.5%; p = 0.002). There was no difference in the proportions of patients receiving surgical resection in both groups (23.5% in HBV group vs. 17.9% in cryptogenic group; p = 0.202). Cox regression analysis revealed no survival difference between cryptogenic-related HCC and HBV-related HCC (p = 0.367).

Conclusion: Temporal trends suggest that HCC attributed to HBV is on the decline, while cryptogenic- or NASH-related HCC is an emerging clinical entity. A paradigm shift in approach to screening, surveillance, and management of HCC may be required in view of the changing landscape of HCC epidemiology into an increasing non-viral etiology.
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http://dx.doi.org/10.1007/s10620-018-5331-xDOI Listing
February 2019

Second harmonic generation microscopy provides accurate automated staging of liver fibrosis in patients with non-alcoholic fatty liver disease.

PLoS One 2018 20;13(6):e0199166. Epub 2018 Jun 20.

Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore.

Background: Assessment of severity of liver fibrosis is essential in the management of non-alcoholic fatty liver disease (NAFLD). Second Harmonic Generation (SHG) microscopy is a novel optical tissue imaging system that provides automated quantification of fibrosis based on unique architectural features of collagen. This study aims to develop and validate a SHG-based index for automated staging of liver fibrosis in patients with NAFLD.

Methods: SHG microscopy was performed on archived liver biopsy specimens from 83 patients with NAFLD. A unique algorithm was developed to identify specific SHG parameters that correlated with fibrosis stage. The accuracy of the algorithm was compared against clinical assessment by experienced liver histopathologists using the Brunt fibrosis staging and further validated using the leave-one-out cross-validation method.

Results: Mean age of the study cohort was 51.8 ± 11.7 years, with 41% males. A fibrosis index (SHG B-index) was developed comprising 14 unique SHG-based collagen parameters that correlated with severity of NAFLD fibrosis in a continuous fashion. The SHG B-index had excellent correlation with Brunt fibrosis stage (Spearman's correlation 0.820, p<0.001). AUROCs for prediction of Brunt fibrosis stages 1, 2, 3 and 4 were 0.853, 0.967, 0.985 and 0.941 respectively. In the cross-validation analysis, the SHG B-index demonstrated high specificity for diagnosis of all grades of fibrosis. A SHG B-index score of >1.76 had an overall diagnostic accuracy of 98.5% for prediction of presence of bridging fibrosis (Brunt stage ≥3) with sensitivity of 87.5%, specificity 98.0%, positive predictive value 96.6% and negative predictive value 92.6%.

Conclusion: The SHG B-index is a unique SHG-based index that provides accurate automated assessment of fibrosis stage in NAFLD patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199166PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010245PMC
December 2018

Deciphering the epidemiology of hepatocellular carcinoma through the passage of time: A study of 1,401 patients across 3 decades.

Hepatol Commun 2017 08 14;1(6):564-571. Epub 2017 Jun 14.

Department of Gastroenterology and Hepatology Singapore General Hospital Singapore.

Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers globally. With advances in therapy for chronic viral hepatitis, changing social circumstances, and increasing practice of HCC surveillance, the epidemiology of HCC is expected to change over time. We explored the temporal trends in HCC in Singapore, a multiethnic Asian country, over the last 3 decades. Patients with HCC were prospectively enrolled and stratified into two cohorts (C1, 1988-2002; C2, 2003-2016). Patient and tumor characteristics, management, and survival were compared between the two cohorts, and a survival census was performed on October 31, 2015. There were 1,401 patients, and the mean age at diagnosis of HCC for C1 and C2 was 60.1 and 63.5 years, respectively. Male patient preponderance decreased significantly, with the male to female ratio falling from 5.2:1 to 3.9:1 between C1 and C2. Hepatitis B, although still the predominant risk factor for HCC, showed a significant decline from C1 to C2 (76.5% to 68.2%), while the nonviral etiology increased significantly over the same period (14.4% versus 25.0%, respectively). Significantly more patients in C2 than C1 were diagnosed through surveillance (39.2% versus 11.3%, respectively) and had better physical performance (Eastern Cooperative Oncology Group 0, 62.1% versus 20.4%, respectively). While Child-Pugh status was comparable, significantly more patients in C2 than C1 had early stage disease (Barcelona Clinic Liver Cancer 0-A, 39.5% versus 7.4%, respectively), which translated into significantly higher median survival (18.6 months versus 3.8 months, respectively). : Over the past 3 decades, hepatitis B-related HCC has been decreasing while HCC due to nonviral etiology has been increasing significantly. Surveillance to diagnose early stage HCC is important in improving the outcome of HCC. ( 2017;1:564-571).
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http://dx.doi.org/10.1002/hep4.1059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678902PMC
August 2017

Low serum albumin predicts early mortality in patients with severe hypoxic hepatitis.

World J Hepatol 2017 Aug;9(22):959-966

Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore 169856, Singapore.

Aim: To evaluate the incidence, etiology, and predictors of mortality of severe hypoxic hepatitis.

Methods: We used computerized patient records to identify consecutive cases of severe hypoxic hepatitis admitted to a tertiary hospital in Singapore over a one-year period. We defined severe hypoxic hepatitis as elevation of serum transaminases more than 100 times upper limit of normal in the clinical setting of cardiac, circulatory or respiratory failure after exclusion of other causes of hepatitis. We used multivariable regression analysis to determine predictors for mortality.

Results: We identified 75 cases of severe hypoxic hepatitis out of 71380 hospital admissions over one year, providing an incidence of 1.05 cases per 1000 admissions. Median age was 65 years (range 19-88); 57.3% males. The most common etiologies of severe hypoxic hepatitis were acute myocardial infarction and sepsis. Fifty-three patients (71%) died during the hospitalization. The sole independent predictive factor for mortality was serum albumin measured at the onset of severe hypoxic hepatitis. Patients with low serum albumin of less than 28 g/L have more than five-fold increase risk of death (OR = 5.39, 95%CI: 1.85-15.71).

Conclusion: Severe hypoxic hepatitis is uncommon but has a high mortality rate. Patients with low serum albumin are at highest risk of death.
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http://dx.doi.org/10.4254/wjh.v9.i22.959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550761PMC
August 2017

Barcelona Clinic Liver Cancer outperforms Hong Kong Liver Cancer staging of hepatocellular carcinoma in multiethnic Asians: Real-world perspective.

World J Gastroenterol 2017 Jun;23(22):4054-4063

James Weiquan Li, Boon-Bee George Goh, Pik-Eu Chang, Chee-Kiat Tan, Department of Gastroenterology and Hepatology, Singapore 169856, Singapore.

Aim: To compare the Barcelona Clinic Liver Cancer (BCLC) and Hong Kong Liver Cancer (HKLC) classification systems when applied to HCC patients from the largest tertiary-level centre in Singapore.

Methods: One thousand two hundred and seventy hepatocellular carcinoma (HCC) patients prospectively enrolled in a tertiary-level centre registry in Singapore since 1988 were studied. Patients were grouped into their respective BCLC and HKLC stages. Data such as demography, aetiology of HCC and type of treatment were collected. Survival data was based on census with the National Registry of Births and Deaths on 31 October 2015. Statistical analyses were done using SPSS version 21 (Chicago, IL, United States). Survival analyses were done by the Kaplan-Meier method. Differences in survival rates were compared using the log-rank test.

Results: The median age at presentation was 63 years (range 13-94); male 82.4%; Chinese 89.4%, Malay 7.1%, Indian, 2.8%. Hepatitis B was the predominant aetiology (75.0%; Hepatitis C 7.2%, Hepatitis B and C co-infection 3.8%, non-viral 14.0%). Both BCLC and HKLC staging systems showed good separation with overall log rank test confirming significant survival differences between stages in our cohort ( < 0.001). 206 out of the 240 patients (85.8%) assigned for curative treatment by the BCLC treatment algorithm received curative therapy for HCC [Stage 0 93.2% (68/73); Stage A 82.6% (138/167)]. In contrast, only 341/558 (61.1%) patients received curative treatment despite being assigned for curative treatment by the HKLC treatment algorithm [Stage I 72.7% (264/363); Stage II 40.2% (66/164); Stage Va 35.5% (11/31)]. Patients who were assigned to curative treatment by HKLC but did not receive curative treatment had significantly poorer ECOG ( < 0.001), higher Child-Pugh status ( < 0.001) and were older (median age 66 61, < 0.001) than those who received curative therapy. Median overall survival in patients assigned to curative treatment groups by BCLC and HKLC were 6.1 and 2.6 years respectively ( < 0.001). When only patients receiving curative treatment were analyzed, BCLC still predicted overall median survival better than HKLC (7.1 years 5.5 years, = 0.037).

Conclusion: BCLC performs better than HKLC in our multiethnic Asian population in allocating patients to curative treatment in a real-life situation as well as in predicting survival.
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http://dx.doi.org/10.3748/wjg.v23.i22.4054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473124PMC
June 2017

Coriolus versicolor (Yunzhi) Use as Therapy in Advanced Hepatocellular Carcinoma Patients with Poor Liver Function or Who Are Unfit for Standard Therapy.

J Altern Complement Med 2017 Aug 4;23(8):648-652. Epub 2017 Apr 4.

1 Department of Medical Oncology, National Cancer Centre Singapore , Singapore, Singapore .

Background: The majority of patients with hepatocellular carcinoma (HCC) are inoperable and results with conventional chemotherapy are dismal. Many end up with no treatment options and resort to alternative medicine. The authors report the use of Coriolus versicolor (CV) in advanced HCC patients with poor liver function or who were unfit to receive standard therapy.

Methods: Fifteen eligible cases were randomized 2:1 to either CV or placebo. The primary endpoint was the median time to progression (TTP) between both arms. Secondary endpoints include evaluating response rates, toxicity, quality of life (QOL), progression-free survival (PFS), and overall survival (OS). Further correlative studies were performed looking at the effect of CV on the immune system.

Results: The median treatment duration was 1.5 cycles and 3 cycles on the placebo and CV arm, respectively. Median TTP was 2.5 (1.4-5.3) months compared to 4.2 (0.4-4.2) months in the CV and placebo arm, respectively, hazard ratio (HR) 0.70 (0.16-3.05 p = 0.634). Median PFS was 2.5 (1.4-5.3) months in the CV and 1.1 (0.4-4.2) months in the placebo arm, HR 0.42 (0.13-1.34, p = 0.144). Median OS was 6.5 (3.3-24.1) and 2.2 (0.8-23.3) months, respectively, HR 0.35 (0.10-1.25, p = 0.105). Social and emotional functioning scores were higher in the CV group compared to placebo group on treatment. CV subjects had less appetite loss and pain symptoms compared to placebo subjects during treatment.

Conclusions: There was no difference in TTP with use of CV compared to placebo. CV subjects generally had better QOL on treatment compared to placebo subjects. The utility of this supplement in patients whose primary treatment goal is palliation should be further explored.
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http://dx.doi.org/10.1089/acm.2016.0136DOI Listing
August 2017

Hepatitis E in Singapore: A Case-Series and Viral Phylodynamics Study.

Am J Trop Med Hyg 2017 Apr 16;96(4):922-928. Epub 2017 Jan 16.

Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore.

AbstractThe incidence of hepatitis E in Singapore appears to be increasing. A retrospective case-series study of patients diagnosed with hepatitis E in a tertiary hospital from 2009 to 2013 was conducted. Of 16 cases, eight (50%) were solid-organ transplant recipients (SOTRs), and 14 (88%) were found infected by genotype 3 hepatitis E virus (HEV-3). Bayesian inferences based on HEV subgenomic sequences from seven cases suggest that HEV-3 strains were introduced to Singapore as two principal lineages. Within limitations of the study, it can be inferred that one lineage, in the 3efg clade, emerged about 83 years ago, probably originating from Japan, whereas the other, in the 3abchij clade, emerged about 40 years ago, from the United States. Establishment and subsequent transmissions of strains from these two lineages likely contribute to the current endemicity of hepatitis E in Singapore.
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http://dx.doi.org/10.4269/ajtmh.16-0482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392643PMC
April 2017

Peretinoin as an adjuvant therapy for hepatocellular carcinoma.

Authors:
Chee-Kiat Tan

Expert Rev Gastroenterol Hepatol 2016 Nov 27;10(11):1201-1210. Epub 2016 Sep 27.

a Department of Gastroenterology and Hepatology , Singapore General Hospital , Singapore , Singapore.

Introduction: The current curative treatment modalities for hepatocellular carcinoma (HCC) are unfortunately fraught with high rates of HCC recurrence. Hence there is a need to prevent or reduce HCC recurrence after initial curative therapy. Peretinoin is a synthetic oral retinoid showing significant reduction in the incidence of recurrent or new HCC in patients who had received curative HCC therapy. Areas covered: Peretinoin is analysed against the background of molecular pathogenesis of the different causes of HCC. Publications related to peretinoin since 1996 are reviewed, covering clinical characteristics, safety and tolerance profile as well as the current status of clinical development. Expert commentary: Early phase studies are promising but we need to await the results of the ongoing phase III study of peretinoin in hepatitis C related HCC. Long term impact of peretinoin may be diminished by the foreseeable near eradication of hepatitis C by the direct acting antivirals.
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http://dx.doi.org/10.1080/17474124.2016.1238303DOI Listing
November 2016
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