Publications by authors named "Mei-Hsuan Lee"

112 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

Association between immunologic markers and cirrhosis in individuals with chronic hepatitis B.

Sci Rep 2021 Nov 15;11(1):21194. Epub 2021 Nov 15.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Host immune response and chronic inflammation associated with chronic hepatitis B virus (HBV) infection play a key role in the pathogenesis of liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). We sampled 175 HCC, 117 cirrhotic and 165 non-cirrhotic controls from a prospective cohort study of chronically HBV-infected individuals. Multivariable polytomous logistic regression and canonical discriminant analysis (CDA) were used to compare baseline plasma levels for 102 markers in individuals who developed cirrhosis vs. controls and those who developed HCC vs. cirrhosis. Leave-one-out cross validation was used to generate receiver operating characteristic curves to compare the predictive ability of marker groups. After multivariable adjustment, HGF (Q4v1OR: 3.74; p-trend = 0.0001), SLAMF1 (Q4v1OR: 4.07; p-trend = 0.0001), CSF1 (Q4v1OR: 3.00; p-trend = 0.002), uPA (Q4v1OR: 3.36; p-trend = 0.002), IL-8 (Q4v1OR: 2.83; p-trend = 0.004), and OPG (Q4v1OR: 2.44; p-trend = 0.005) were all found to be associated with cirrhosis development compared to controls; these markers predicted cirrhosis with 69% accuracy. CDA analysis identified a nine marker model capable of predicting cirrhosis development with 79% accuracy. No markers were significantly different between HCC and cirrhotic participants. In this study, we assessed immunologic markers in relation to liver disease in chronically-HBV infected individuals. While validation in required, these findings highlight the importance of immunologic processes in HBV-related cirrhosis.
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http://dx.doi.org/10.1038/s41598-021-00455-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593047PMC
November 2021

Intracellular Accumulation of IFN-λ4 Induces ER Stress and Results in Anti-Cirrhotic but Pro-HCV Effects.

Front Immunol 2021 23;12:692263. Epub 2021 Aug 23.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States.

polymorphisms are inversely associated with the risk of chronic hepatitis C virus (HCV) infection and cirrhosis, two major risk factors for developing hepatocellular carcinoma (HCC). To further explore these inverse associations and their molecular underpinnings, we analyzed polymorphisms represented by the genotype (presence of rs368234815-dG or rs12979860-T alleles) in HCV patients: 2969 from Japan and 2931 from Taiwan. genotype was associated with an increased risk of HCV-related HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058) in the general population of Japanese patients, but not in Taiwanese patients who achieved treatment-induced viral clearance. genotype was also associated with a decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwanese patients). We then engineered HepG2 cells to inducibly express IFN-λ4 in the presence or absence of interferon lambda receptor 1 (IFNLR1). Induction of IFN-λ4 resulted in its intracellular accumulation, mainly in lysosomes and late endosomes, and increased ER stress, leading to apoptosis and reduced proliferation. We identified the very-low-density lipoprotein receptor (), which facilitates HCV entry into hepatocytes, as a transcript induced by IFN-λ4 but not IFN-λ3. Our results suggest that the molecular mechanisms underlying the anti-cirrhotic but pro-HCV associations observed for polymorphisms are, at least in part, contributed by intracellular accumulation of IFN-λ4 causing ER stress in hepatic cells.
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http://dx.doi.org/10.3389/fimmu.2021.692263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419317PMC
August 2021

Resistance profiles of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced non-small-cell lung cancer: a multicenter study using targeted next-generation sequencing.

Eur J Cancer 2021 10 13;156:1-11. Epub 2021 Aug 13.

Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address:

Introduction: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non-small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear.

Methods: This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients' clinicopathologic characteristics and treatment outcomes were analyzed.

Results: Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. Five (16%) ALK mutations (L1196M ×2, I1171T, D1203N, G1269A/F1174L) and 3 possible bypass mutations (NRAS G12V, EGFR R108K, PIK3CA E545K) were found in 32 crizotinib-resistant cancers. Four (22%) ALK mutations (G1128A, G1202R, G1269A, I1171T/E1210K) and 3 possible bypass mutations (KIT D820E, MET E1012∗, EGFR P265_C291del) were found in 18 ceritinib-resistant cancers. Four (17%) ALK mutations (G1202R ×2, W1295C, G1202R/L1196M) and 1 possible bypass mutation (EGFR P753S) were found in 24 alectinib-resistant cancers. Two (11%) ALK mutations (G1202R/G1269A ×2) and 2 possible bypass mutations (BRAF V600E, MET D1246N) were found in 18 lorlatinib-resistant cancers. In patients with simultaneous paired tissue and cfDNA samples (n = 20), mutations were identified in 9 (45%) and 6 (30%) cases, respectively; the concordance rate was 45%.

Conclusions: The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers.
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http://dx.doi.org/10.1016/j.ejca.2021.06.043DOI Listing
October 2021

Impact of Sofosbuvir-Based Direct-Acting Antivirals on Renal Function in Chronic Hepatitis C Patients With Impaired Renal Function: A Large Cohort Study From the Nationwide HCV Registry Program (TACR).

Clin Gastroenterol Hepatol 2021 Jul 30. Epub 2021 Jul 30.

Yang Ming Hospital, Taiwan.

Background & Aims: Sofosbuvir is approved for chronic hepatitis C (CHC) patients with severe chronic kidney disease (CKD). The impact of sofosbuvir-based therapy on renal function augmentation on a real-world nationwide basis is elusive.

Methods: The 12,995 CHC patients treated with sofosbuvir-based (n = 6802) or non-sofosbuvir-based (n = 6193) regimens were retrieved from the Taiwan nationwide real-world HCV Registry Program. Serial estimated glomerular filtration rate (eGFR) levels were measured at baseline, end of treatment (EOT), and end of follow-up (EOF) (3 months after EOT).

Results: The eGFR decreased from baseline (91.4 mL/min/1.73 m) to EOT (88.4 mL/min/1.73 m; P < .001) and substantially recovered at EOF (88.8 mL/min/1.73 m) but did not return to pretreatment levels (P < .001). Notably, a significant decrease in eGFR was observed only in patients with baseline eGFR ≥90 mL/min/1.73 m (from 112.9 to 106.4 mL/min/1.73 m; P < .001). In contrast, eGFR increased progressively in patients whose baseline eGFR was <90 mL/min/1.73 m (from 70.0 to 71.5 mL/min/1.73 m; P < .001), and this increase was generalized across different stages of CKD. The trend of eGFR amelioration was consistent irrespective of sofosbuvir usage. Multivariate adjusted analysis demonstrated that baseline eGFR >90 mL/min/1.73 m was the only factor independently associated with significant slope coefficient differences of eGFR (-1.98 mL/min/1.73 m; 95% confidence interval, -2.24 to -1.72; P < .001). The use of sofosbuvir was not an independent factor associated with eGFR change.

Conclusions: Both sofosbuvir and non-sofosbuvir-based regimens restored renal function in CHC patients with CKD, especially in those with significant renal function impairment.
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http://dx.doi.org/10.1016/j.cgh.2021.07.037DOI Listing
July 2021

Immunologic markers and risk of hepatocellular carcinoma in hepatitis B virus- and hepatitis C virus-infected individuals.

Aliment Pharmacol Ther 2021 09 19;54(6):833-842. Epub 2021 Jul 19.

Genomics Research Center, Academia Sinica, Taipei, Taiwan.

Background: Clinical and experimental studies suggest immunologic proteins contribute to hepatocellular carcinoma (HCC) development.

Aim: To evaluate circulating immunologic markers and HCC risk.

Methods: From a Taiwanese cohort of chronically hepatitis B virus (HBV)-infected individuals followed over time (REVEAL-HBV), we sampled 175 who developed HCC, 117 cirrhosis only, and 165 non-cirrhotic controls. From a similar Taiwanese cohort of chronically hepatitis C virus (HCV)-infected individuals (REVEAL-HCV), we included 94 individuals who developed HCC, 68 cirrhosis only and 100 non-cirrhotic controls. We compared pre-diagnostic plasma levels of 102 markers in HCC cases to non-cirrhotic and cirrhotic controls using polytomous logistic regression. A priori markers included insulin-like growth factor binding protein-3 (IGFBP-3), intercellular adhesion molecule 1 (ICAM-1) and interleukin 6 (IL-6). P-values for other markers were corrected for multiple testing (false discovery rate = 10%).

Results: In both REVEAL-HBV and REVEAL-HCV, increasing levels of ICAM-1 were associated with increased risk of HCC compared to non-cirrhotic controls (P-trend 0.02 and 0.001, respectively). In both REVEAL-HBV and REVEAL-HCV, two novel markers [C-X-C motif chemokine 11 (CXCL11) and hepatocyte growth factor (HGF)] were positively associated [strongest odds ratio (OR) 4.55 for HGF in HCV], while two [complement factor H related 5 (CFHR5) and stem cell factor (SCF)] were negatively associated (strongest OR 0.14 for SCF in HCV) with development of HCC compared to non-cirrhotic controls.

Conclusions: We confirmed the association for ICAM-1 and identified 4 additional proteins associated with HBV- and HCV-related HCC. These findings highlight the importance of immunologic processes in HBV- and HCV-related HCC.
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http://dx.doi.org/10.1111/apt.16524DOI Listing
September 2021

REPLY.

Hepatology 2021 Nov 15;74(5):2925-2926. Epub 2021 Sep 15.

Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD.

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http://dx.doi.org/10.1002/hep.32051DOI Listing
November 2021

The relative importance of predictive factors for single first-generation EGFR-TKI use for more than 5 years in patients with advanced non-small cell lung cancer: Taiwan multicenter TIPS-5 study.

Ther Adv Med Oncol 2021 22;13:17588359211018022. Epub 2021 May 22.

Division of Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, No.110, Sec. 1, Jianguo N. Road, Taichung, 402.

Background: The relative importance of predictive factors for advanced non-small cell lung cancer (NSCLC) patients on epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment remains unclear.

Materials And Methods: We retrospectively enrolled advanced NSCLC patients with single first-generation EGFR-TKI treatment for ⩾5 years (Y) in Taiwan. Clinical data was collected and compared with those of another cohort with single first-line EGFR-TKI treatment for <5 Y. Plasma cell-free DNA (cfDNA) samples were collected from patient subsets, pre- and post-TKI, in the >5 Y group.

Results: Overall, 128 and 278 patients were enrolled in the ⩾5 Y and <5 Y groups, respectively. Significant factors in the multivariate analysis of patients' characteristics including Eastern Cooperative Oncology Group performance status 0-1, postoperative recurrence, without brain metastasis, oligometastasis (each score of 2), female sex, erlotinib use, and without bone metastasis (each score of 1), were incorporated into a risk scoring system. The area under the receiver operating characteristic curve was 0.82 [95% confidence interval (CI): 0.78-0.86]. Of the plasma cfDNA samples from 33 patients in the ⩾5 Y group, only 1 had a T790M in 25 patients without progressive disease. In 27 patients with single agent use for ⩾96 months, 22 (81.5%) received local treatment (surgery or radiotherapy) for the primary lung tumor before and during TKI treatment.

Conclusion: For NSCLC patients with single first-generation EGFR-TKI use for ⩾5 Y, factors with different relative importance exist and the risk-scoring model is feasible with modest accuracy. The role of local treatment for primary tumors in patients with long-term TKI use requires further investigation.
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http://dx.doi.org/10.1177/17588359211018022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142001PMC
May 2021

Genetic variants associated with serum alanine aminotransferase levels among patients with hepatitis C virus infection: A genome-wide association study.

J Viral Hepat 2021 09 3;28(9):1265-1273. Epub 2021 Jun 3.

Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.

Information on genetic variants associated with elevated serum alanine aminotransferase (ALT) levels remains limited. A genome-wide association study was performed to identify single-nucleotide polymorphisms (SNPs) associated with ALT levels. The ALT-associated SNP was further evaluated for hepatocellular carcinoma (HCC) risk. A cohort of 892 anti-HCV seropositive patients was used for genome-wide SNP array to examine the associations with baseline ALT levels. SNPs <10 were further tested for associations with serial ALT levels then validated in 486 anti-HCV seropositives. Multinomial logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals of SNPs associated with ALT. The SNP was evaluated for HCC risk by using Cox's proportional hazards models. After quality control, 803 participants with 564,464 SNPs were included in the analysis. Of these, 12 SNPs were associated with ALT (p < 10 ). Among the participants, 158 (19.7%) had ALT persistently ≤15 U/L, 327 (40.7%) ever >15 U/L but never >45 U/L, and 318 (39.6%) ever >45 U/L during follow-up. The rs568800 was associated with serial ALT levels, and this was replicated in the external population significantly (p < .05). The A allele (vs C) of rs568800 was associated with ALT >15 U/L but ≤45 U/L and ALT >45 U/L, with the adjusted ORs of 1.41 (1.11-1.78) and 1.86 (1.34-2.60), respectively. The adjusted HRs for HCC were 2.09 (0.90-4.89) for AC and 2.64 (1.13-6.17) for AA (CC as a reference). In conclusion, the rs568800 was associated with serum ALT levels and HCC risk. Clinical utility should be evaluated among patients who have received antivirals.
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http://dx.doi.org/10.1111/jvh.13550DOI Listing
September 2021

Postdiagnosis Aspirin Use Associated With Decreased Biliary Tract Cancer-Specific Mortality in a Large Nationwide Cohort.

Hepatology 2021 Oct 20;74(4):1994-2006. Epub 2021 Jul 20.

Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.

Background And Aims: Biliary tract cancer (BTC) is rare and has limited treatment options. We aimed to examine aspirin use on cancer-specific survival in various BTC subtypes, including gallbladder cancer, ampulla of Vater cancer, and cholangiocarcinoma.

Approach And Results: Nationwide prospective cohort of newly diagnosed BTC between 2007 and 2015 were included and followed until December 31, 2017. Three nationwide databases, namely the Cancer Registration, National Health Insurance, and Death Certification System, were used for computerized data linkage. Aspirin use was defined as one or more prescriptions, and the maximum defined daily dose was used to evaluate the dose-response relationship. Cox's proportional hazards models were applied for estimating HRs and 95% CIs. Analyses accounted for competing risk of cardiovascular deaths, and landmark analyses to avoid immortal time bias were performed. In total, 2,519 of patients with BTC were exposed to aspirin after their diagnosis (15.7%). After a mean follow-up of 1.59 years, the 5-year survival rate was 27.4%. The multivariate-adjusted HR for postdiagnosis aspirin users, as compared with nonusers, was 0.55 (95% CI: 0.51 to 0.58) for BTC-specific death. Adjusted HRs for BTC-specific death were 0.53 (95% CI: 0.48 to 0.59) and 0.42 (95% CI: 0.31 to 0.58) for ≤ 1 and > 1 maximum defined daily dose, respectively, and showed a dose-response trend (P < 0.001; nonusers as a reference). Cancer-specific mortality was lower with postdiagnosis aspirin use in patients with all major BTC subtypes.

Conclusions: The nationwide study revealed that postdiagnosis aspirin use was associated with improved BTC-specific mortality of various subtypes. The findings suggest that additional randomized trials are required to investigate aspirin's efficacy in BTC.
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http://dx.doi.org/10.1002/hep.31879DOI Listing
October 2021

Lower starting dose of afatinib for the treatment of metastatic lung adenocarcinoma harboring exon 21 and exon 19 mutations.

BMC Cancer 2021 May 3;21(1):495. Epub 2021 May 3.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background: Afatinib has shown favorable response rates (RRs) and longer progression free survival (PFS) in lung cancer patients harboring EGFR mutations compared with standard platinum-based chemotherapy. However, serious adverse drug reactions (ADRs) limit the clinical application of afatinib.

Methods: We designed a retrospective study, enrolling all patients with metastatic lung adenocarcinoma who were diagnosed and treated with 30 or 40 mg daily afatinib as their initial treatment in three Kaohsiung Medical University-affiliated hospitals in Taiwan.

Results: A total of 179 patients were enrolled in the study, of which 102 (57%) and 77 (43%) received 30 mg and 40 mg afatinib daily as their initial treatment, respectively. The patients initially using 30 mg afatinib daily had a similar RR (75% vs. 83%, p = 0.1672), median PFS (14.5 vs. 14.8 months, log-rank p = 0.4649), and median OS (34.0 vs. 25.2 months, log-rank p = 0.5982) compared with those initially using 40 mg afatinib daily. Patients initially receiving 30 mg afatinib daily had fewer ADRs compared with those using 40 mg daily. The overall incidence of moderate and severe ADRs was significantly lower in patients receiving 30 mg afatinib daily compared with those using 40 mg daily (49% vs. 77%, p = 0.002); similar findings was observed in terms of severe ADRs (7% vs. 24%, p < 0.0001).

Conclusion: Patients receiving 30 mg afatinib daily as their initial treatment had similar RR, PFS, OS, but significantly fewer serious ADRs, as compared with those using 40 mg as their starting dose.
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http://dx.doi.org/10.1186/s12885-021-08235-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091516PMC
May 2021

HLA zygosity increases risk of hepatitis B virus-associated hepatocellular carcinoma.

J Infect Dis 2021 Apr 14. Epub 2021 Apr 14.

Genomics Research Center, Academia Sinica, Taipei, Taiwan.

Background: Diversity in the human leukocyte antigen (HLA) genes might be associated with disease outcomes - the heterozygote advantage hypothesis. We tested this hypothesis in relation to hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC).

Methods: We utilized DNA from >10,000 Taiwanese individuals with current or past HBV infection to examine the association between HLA diversity and critical natural history steps in the progression from HBV infection to HCC. Individuals were classified as homozygotes at a given locus when imputed to carry the same 4-digit allele for the two HLA alleles at that locus.

Results: Increase in number of homozygous HLA class II loci was associated with an increased risk of chronic HBV infection (Ptrend=1.18×10 -7). Among chronic HBV carriers, increase in number of homozygous HLA class II loci was also associated with an increased risk of HBV-associated HCC (Ptrend=0.031). For individual HLA loci, HLA-DQB1 homozygosity was significantly associated with HCC risk (adjusted hazard ratio=1.40, 95% confidence interval=1.06-1.84). We also found that zygosity affects risk of HCC through its ability to affect viral control.

Conclusions: Homozygosity at HLA class II loci, particularly HLA-DQB1, is associated with a higher risk of HBV-associated HCC.
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http://dx.doi.org/10.1093/infdis/jiab207DOI Listing
April 2021

Factors associated with treatment failure of direct-acting antivirals for chronic hepatitis C: A real-world nationwide hepatitis C virus registry programme in Taiwan.

Liver Int 2021 06 12;41(6):1265-1277. Epub 2021 Mar 12.

Division of Gastroenterology, Department of Internal Medicine, Yuan's General Hospital, Kaohsiung, Taiwan.

Background/aims: Direct-acting antivirals (DAAs) are highly effective in treating chronic hepatitis C virus (HCV)-infected patients. The real-world treatment outcome in Taiwanese patients on a nationwide basis is elusive.

Methods: The Taiwan HCV Registry (TACR) programme is a nationwide registry platform including 48 study sites, which is organized and supervised by the Taiwan Association for the Study of the Liver. The primary endpoint was sustained virological response (SVR12, undetectable HCV RNA 12 weeks after end-of-treatment).

Results: A total of 13 951 registered patients with SVR12 data available were analysed (mean age, 63.0 years; female, 55.9%; HCV genotype-1 [GT1], 57.9%; cirrhosis, 38.4%; preexisting hepatocellular carcinoma [HCC], 10.6%; and hepatitis B virus coinfection, 7.7%). The overall SVR12 rate was 98.3%, with 98.7%, 98.0%, 98.4% and 97.4% in treatment-naïve noncirrhotic, treatment-naïve cirrhotic, treatment-experienced noncirrhotic and treatment-experienced cirrhotic patients, respectively. The SVR12 rate was > 95% across all subgroups except treatment-experienced cirrhotic patients who received sofosbuvir/ribavirin (88.7%), treatment-naïve noncirrhotic patients (94.8%) and treatment-experienced cirrhotic (94.8%) patients who received daclatasvir/asunaprevir. The most important factor associated with treatment failure was DAA adherence < 60% ( adjusted odds ratio [aOR]/95% confidence interval [CI]: 117.1/52.4-261.3, P < .001), followed by GT3/GT2 (aOR/CI: 5.78/2.25-14.9, P = .0003 and aOR/CI: 1.55/1.05-2.29, P = .03, compared with GT1), active hepatocellular carcinoma (aOR/CI: 4.29/2.57-7.16, P < .001), the use of sofosbuvir/ribavirin (aOR/CI: 2.51/1.67-3.77, P < .001) and daclatasvir/asunaprevir (aOR/CI: 3.29/1.94-5.58, P < .001), decompensated liver cirrhosis (aOR/CI: 2.50/1.20-5.22, P = .02) and high HCV viral loads (aOR/CI: 2.16/1.57-2.97, P < .001).

Conclusions: DAAs are highly effective in treating Taiwanese HCV patients in the real-world setting. Maintaining DAA adherence and selecting highly efficacious regimens are keys to ensure treatment success.
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http://dx.doi.org/10.1111/liv.14849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252422PMC
June 2021

Systematic Review and Network Meta-Analysis of Immune Checkpoint Inhibitors in Combination with Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Carcinoma.

Cancers (Basel) 2020 Dec 3;12(12). Epub 2020 Dec 3.

Department of General Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 88708, Taiwan.

Patients with extensive-stage small cell lung cancer (ED-SCLC) have a very short survival time even if they receive standard cytotoxic chemotherapy with etoposide and platinum (EP). Several randomized controlled trials have shown that patients with ED-SCLC who received a combination of EP plus immune checkpoint inhibitors (ICIs) had superior survival compared with those who received EP alone. We conducted a systematic review and network meta-analysis to provide a ranking of ICIs for our primary endpoints in terms of overall survival (OS), progression free survival (PFS), and objective response rate (ORR), as well as our secondary endpoint in terms of adverse events. The fractional polynomial model was used to evaluate the adjusted hazard ratios for the survival indicators (OS and PFS). Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being best (Prbest) reference. EP plus nivolumab, atezolizumab or durvalumab had significant benefits compared with EP alone in terms of OS (Hazard Ratio HR = 0.67, 95% Confidence Interval CI = 0.46-0.98 for nivolumab, HR = 0.70, 95% CI = 0.54-0.91 for atezolizumab, HR = 0.73, 95% CI = 0.59-0.90 for durvalumab) but no significant differences were observed for pembrolizumab or ipilimumab. The probability of nivolumab being ranked first among all treatment arms was highest (SCURA = 78.7%, Prbest = 46.7%). All EP plus ICI combinations had a longer PFS compared with EP alone (HR = 0.65, 95% CI = 0.46-0.92 for nivolumab, HR = 0.77, 95% CI = 0.61-0.96 for atezolizumab, HR = 0.78, 95% CI = 0.65-0.94 for durvalumab, HR = 0.75, 95% CI = 0.61-0.92 for pembrolizumab), and nivolumab was ranked first in terms of PFS (SCURA = 85.0%, Prbest = 66.8%). In addition, nivolumab had the highest probability of grade 3-4 adverse events (SUCRA = 84.8%) in our study. We found that nivolumab had the best PFS and OS in all combinations of ICIs and EP, but nivolumab also had the highest probability of grade 3-4 adverse events in our network meta-analysis. Further head-to head large-scale phase III randomized controlled studies are needed to verify our conclusions.
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http://dx.doi.org/10.3390/cancers12123629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761843PMC
December 2020

Patterns of Human Leukocyte Antigen Class I and Class II Associations and Cancer.

Cancer Res 2021 02 3;81(4):1148-1152. Epub 2020 Dec 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Human leukocyte antigen (HLA) gene variation is associated with risk of cancers, particularly those with infectious etiology or hematopoietic origin, given its role in immune presentation. Previous studies focused primarily on HLA allele/haplotype-specific associations. To answer whether associations are driven by HLA class I (essential for T-cell cytotoxicity) or class II (important for T-cell helper responses) genes, we analyzed GWAS from 24 case-control studies and consortia comprising 27 cancers (totaling >71,000 individuals). Associations for most cancers with infectious etiology or of hematopoietic origin were driven by multiple HLA regions, suggesting that both cytotoxic and helper T-cell responses are important. Notable exceptions were observed for nasopharyngeal carcinoma, an EBV-associated cancer, and CLL/SLL forms of non-Hodgkin lymphomas; these cancers were associated with HLA class I region only and HLA class II region only, implying the importance of cytotoxic T-cell responses for the former and CD4 T-cell helper responses for the latter. Our findings suggest that increased understanding of the pattern of HLA associations for individual cancers could lead to better insights into specific mechanisms involved in cancer pathogenesis. SIGNIFICANCE: GWAS of >71,000 individuals across 27 cancer types suggest that patterns of HLA Class I and Class II associations may provide etiologic insights for cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2292DOI Listing
February 2021

Epidemiology of Virus Infection and Human Cancer.

Recent Results Cancer Res 2021 ;217:13-45

Genomics Research Center, Academia Sinica, 128 Academia Road, Sect. 2, Taipei, 115, Taiwan.

Seven viruses including the Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), Kaposi's sarcoma herpes virus (KSHV), human immunodeficiency virus, type-1 (HIV-1), human T cell lymphotrophic virus, type-1 (HTLV-1), and human papillomavirus (HPV) have been classified as Group 1 human carcinogens by the International Agency for Research on Cancer (IARC). The conclusions are based on the findings of epidemiological and mechanistic studies. EBV, HPV, HTLV-1, and KSHV are direct carcinogens; HBV and HCV are indirect carcinogens through chronic inflammation; and HIV-1 is an indirect carcinogen through immune suppression. Some viruses may cause more than one cancer, while some cancers may be caused by more than one virus. However, only a proportion of persons infected by these oncogenic viruses will develop specific cancers. A series of studies have been carried out to assess the viral, host, and environmental cofactors of EBV-associated nasopharyngeal carcinoma, HBV/HCV-associated hepatocellular carcinoma, and HPV-associated cervical carcinoma. Persistent infection, high viral load, and viral genotype are important risk predictors of these virus-caused cancers. Risk calculators incorporating host and viral risk predictors have been developed for the prediction of long-term risk of hepatocellular carcinoma, nasopharyngeal carcinoma and cervical cancer. These risk calculators are useful for the triage and clinical management of infected patients. Both clinical trials and national programs of immunization, antiviral therapy and screening have demonstrated a significant reduction in the incidence of cancers caused by HBV, HCV, and HPV. Future research on gene-gene and gene-environment interactions of oncogenic viruses and the human host using large-scale longitudinal studies with serial measurements of biosignatures are in urgent need.
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http://dx.doi.org/10.1007/978-3-030-57362-1_2DOI Listing
January 2021

Detecting Genetic Ancestry and Adaptation in the Taiwanese Han People.

Mol Biol Evol 2021 Sep;38(10):4149-4165

Faculty of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.

The Taiwanese people are composed of diverse indigenous populations and the Taiwanese Han. About 95% of the Taiwanese identify themselves as Taiwanese Han, but this may not be a homogeneous population because they migrated to the island from various regions of continental East Asia over a period of 400 years. Little is known about the underlying patterns of genetic ancestry, population admixture, and evolutionary adaptation in the Taiwanese Han people. Here, we analyzed the whole-genome single-nucleotide polymorphism genotyping data from 14,401 individuals of Taiwanese Han collected by the Taiwan Biobank and the whole-genome sequencing data for a subset of 772 people. We detected four major genetic ancestries with distinct geographic distributions (i.e., Northern, Southeastern, Japonic, and Island Southeast Asian ancestries) and signatures of population mixture contributing to the genomes of Taiwanese Han. We further scanned for signatures of positive natural selection that caused unusually long-range haplotypes and elevations of hitchhiked variants. As a result, we identified 16 candidate loci in which selection signals can be unambiguously localized at five single genes: CTNNA2, LRP1B, CSNK1G3, ASTN2, and NEO1. Statistical associations were examined in 16 metabolic-related traits to further elucidate the functional effects of each candidate gene. All five genes appear to have pleiotropic connections to various types of disease susceptibility and significant associations with at least one metabolic-related trait. Together, our results provide critical insights for understanding the evolutionary history and adaption of the Taiwanese Han population.
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http://dx.doi.org/10.1093/molbev/msaa276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476137PMC
September 2021

Editorial: genome-wide association for developing chronic hepatitis B-authors' reply.

Aliment Pharmacol Ther 2020 09;52(6):1085-1086

Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.

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http://dx.doi.org/10.1111/apt.15994DOI Listing
September 2020

Development and Validation of a Nomogram for Patients with Nonmetastatic BCLC Stage C Hepatocellular Carcinoma after Stereotactic Body Radiotherapy.

Liver Cancer 2020 Jun 10;9(3):326-337. Epub 2020 Mar 10.

Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

Background: Stereotactic body radiotherapy (SBRT) is an emerging treatment modality for hepatocellular carcinoma (HCC) with promising outcome. However, appropriate survival prediction models are scarce. This study aimed to develop a simple and clinically useful prognostic nomogram for patients with nondistant metastatic Barcelona Clinic Liver Cancer (BCLC) stage C HCC undergoing SBRT.

Methods: The data were based on a prospective multi-institutional registry enrolling 246 patients with nondistant metastatic BCLC stage C HCC treated with SBRT between January 1, 2008 and December 31, 2016. They were randomly divided into two subsets: 164 into the development cohort and 82 into the validation cohort. We identified and included prognostic factors for survival to derive a nomogram in the development cohort. The predictability of the nomogram was evaluated in the validation cohort. The area under the receiver operating characteristic curve (AUROC) and the calibration plot were used to evaluate the performance of the nomogram.

Results: The median survival was 13.5 months, with 1- and 2-year overall survival (OS) rates of 55.0 and 32.9%, respectively. Number of tumors, largest tumor size, macrovascular invasion, Child-Turcotte-Pugh class, and biologically effective dose were significantly associated with OS ( < 0.05). These predictors were included to develop a nomogram with an AUROC of 0.77 (0.73-0.87). The prediction model was well calibrated in the validation cohort. The OS for patients who were divided by their risk scores differed significantly ( < 0.001).

Conclusions: The nomogram we generated had discriminatory and satisfactory predictability for OS among nonmetastatic BCLC stage C HCC patients treated with SBRT. It demands further validations with cross-country data to confirm its worldwide usefulness.
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http://dx.doi.org/10.1159/000505693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325119PMC
June 2020

Epstein-Barr Virus-Based Nasopharyngeal Carcinoma (NPC) Risk Prediction Scores Are Elevated in NPC Multiplex Family Members in Taiwan.

J Infect Dis 2021 02;223(3):441-444

Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

Nasopharyngeal carcinoma (NPC) is caused by Epstein-Barr virus (EBV) and is more likely to occur in susceptible families. Whether genetic susceptibility operates through altered EBV control is incompletely understood. We used a NPC risk prediction model based on 14 EBV markers to compare risk score distribution in unaffected members from multiplex families with that in population-based controls. Despite the absence of NPC at the time of antibody measurement, we observed an upward shift in risk score among multiplex family members compared to the general population, consistent with the possibility that genetic factors affect NPC risk through alterations in EBV control.
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http://dx.doi.org/10.1093/infdis/jiaa385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982447PMC
February 2021

Large-scale genome-wide association study identifies HLA class II variants associated with chronic HBV infection: a study from Taiwan Biobank.

Aliment Pharmacol Ther 2020 08 23;52(4):682-691. Epub 2020 Jun 23.

Taipei, Taiwan.

Background: Chronic hepatitis B virus (HBV) infection is a great health burden with geographical variations.

Aims: To explore genetic variants associated with chronic HBV infection.

Methods: The study included 15 352 participants seropositive for HBV core antibodies in Taiwan Biobank. Among them, 2591 (16.9%) seropositive for HBV surface antigen (HBsAg) were defined as having chronic HBV infection. All participants were examined for whole-genome genotyping by Axiom-Taiwan Biobank Array. The human leucocyte antigen (HLA) imputation was performed after identification of the variants within the region. Logistic regressions were used to estimate odds ratios (ORs) with 95% confidence intervals. Correlations of different HLA allele frequencies with HBsAg seroprevalence were evaluated across worldwide populations by Pearson correlation coefficients. Epitope prediction was performed for HLA alleles using NetMHCIIpan method.

Results: Located within a cluster of 450 single nucleotide polymorphisms in HLA class II, rs7770370 (P = 2.73 × 10 ) was significantly associated with HBV chronicity (P  < 8.6 × 10 ). Imputation analyses showed that HLA-DPA1*02:02 and HLA-DPB1*05:01 were associated with chronic HBV, with adjusted ORs of 1.43 (1.09-1.89) and 1.61 (1.29-2.01). These allele frequencies were positively correlated with global HBsAg seroprevalence, with R of 0.75 and 0.62 respectively (P < 0.05). HLA-DRB1*13:02, HLA-DQA1* 01:02 and HLA-DQB1*06:09 associated with HBV chronicity negatively, with adjusted ORs of 0.31 (0.17-0.58), 0.70 (0.56-0.87) and 0.33 (0.18-0.63). These HLA alleles had various binding affinities to the predicted epitopes derived from HBV nucleocapsid protein.

Conclusions: HLA class II variants are relevant for chronicity after HBV acquisition.
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http://dx.doi.org/10.1111/apt.15887DOI Listing
August 2020

Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project.

J Hepatol 2020 10 11;73(4):863-872. Epub 2020 May 11.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.

Background & Aims: Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear.

Methods: We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study.

Results: During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25-2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06-1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04-1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09-1.31) and EHBDC (HR 1.11; 95% CI 1.01-1.22) in Asian women only.

Conclusion: We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography.

Lay Summary: Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.
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http://dx.doi.org/10.1016/j.jhep.2020.04.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901003PMC
October 2020

Prediagnostic concentrations of circulating bile acids and hepatocellular carcinoma risk: REVEAL-HBV and HCV studies.

Int J Cancer 2020 11 8;147(10):2743-2753. Epub 2020 Jun 8.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

Hepatocellular carcinoma (HCC) is the dominant histologic type of liver cancer, accounting for 75% of cases. Growing evidence suggests that the cross-talk between the gut microbiome and metabolome (ie, gut-liver axis) are related to the development of hepatic inflammation, and ultimately, HCC. Bile acids are metabolites, derived from cholesterol and synthesized in the liver, which may have a critical role in regulation of the gut-liver axis. We investigated whether prediagnostic circulating bile acids were associated with HCC risk, using the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (REVEAL)-Hepatitis B Virus (HBV) and REVEAL-Hepatitis C Virus (HCV) cohorts from Taiwan. Fifteen bile acids were quantitated using liquid chromatography, from 185 cases and 161 matched controls in REVEAL-HBV and 96 cases and 96 matched controls in REVEAL-HCV. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between bile acid levels and HCC were calculated using multivariable-adjusted logistic regression. Higher levels of glycine and taurine conjugated primary bile acids were associated with a 2- to 8-fold increased risk of HBV- (eg, glycocholic acid OR = 3.38, 95% CI: 1.48-7.71, P < .003) and HCV-related HCC (eg, OR = 8.16, 95% CI: 2.21-30.18, P < .001). However, higher levels of the secondary bile acid deoxycholic acid were inversely associated with HBV-related HCC risk (OR = 0.41, 95% CI: 0.19-0.88, P = .02). Our study provides evidence that higher concentrations of bile acids-specifically, conjugated primary bile acids-are associated with increased HCC risk. However, our study does not support the hypothesis that higher levels of secondary bile acids increase liver cancer risk; indeed, deoxycholic acid may be associated with a decreased HCC risk.
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http://dx.doi.org/10.1002/ijc.33051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529994PMC
November 2020

On-Treatment Changes in FIB-4 and 1-Year FIB-4 Values Help Identify Patients with Chronic Hepatitis B Receiving Entecavir Therapy Who Have the Lowest Risk of Hepatocellular Carcinoma.

Cancers (Basel) 2020 May 7;12(5). Epub 2020 May 7.

Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan.

Noninvasive fibrosis indices can help stratify the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving nucleos(t)ide analogue (NA) therapy. We investigated the predictive performance of on-treatment changes in FIB-4 (△FIB-4) and 1-year FIB-4 values (FIB-4 12M) for HCC risk in patients with CHB receiving entecavir therapy. We included 1325 NA-naïve patients with CHB treated with entecavir, retrospectively, from January 2007 to August 2012. A combination of △FIB-4 and FIB-4 12M was used to stratify the cumulative risk of HCC into three subgroups each in the noncirrhotic and cirrhotic subgroups with < 0.0001 by using the log-rank test (noncirrhotic: the highest risk ( = 88): FIB-4 12M ≥ 1.58/△FIB-4 ≥ 0 (hazard ratio (HR): 40.35; 95% confidence interval (CI): 5.107-318.7; <0.0001) and cirrhotic: the highest risk ( = 89): FIB-4 12M ≥2.88/△FIB-4 ≥0 (HR: 9.576; 95% CI: 5.033-18.22; < 0.0001)). Patients with noncirrhotic CHB treated with entecavir who had a FIB-4 12M < 1.58 or FIB-4 12M ≥ 1.58/△FIB-4 < 0 exhibited the lowest 5-year HCC risk (0.6%). A combination of on-treatment changes in FIB-4 and 1-year FIB-4 values may help identify patients with CHB receiving entecavir therapy with the lowest risk of HCC.
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http://dx.doi.org/10.3390/cancers12051177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281667PMC
May 2020

Landscape of Mitochondria Genome and Clinical Outcomes in Stage 1 Lung Adenocarcinoma.

Cancers (Basel) 2020 Mar 23;12(3). Epub 2020 Mar 23.

Institute of Statistical Science, Academia Sinica, Taipei 11529, Taiwan.

Risk factors including genetic effects are still being investigated in lung adenocarcinoma (LUAD). Mitochondria play an important role in controlling imperative cellular parameters, and anomalies in mitochondrial function might be crucial for cancer development. The mitochondrial genomic aberrations found in lung adenocarcinoma and their associations with cancer development and progression are not yet clearly characterized. Here, we identified a spectrum of mitochondrial genome mutations in early-stage lung adenocarcinoma and explored their association with prognosis and clinical outcomes. Next-generation sequencing was used to reveal the mitochondrial genomes of tumor and conditionally normal adjacent tissues from 61 Stage 1 LUADs. Mitochondrial somatic mutations and clinical outcomes including relapse-free survival (RFS) were analyzed. Patients with somatic mutations in the D-loop region had longer RFS (adjusted hazard ratio, adjHR = 0.18, = 0.027), whereas somatic mutations in mitochondrial Complex IV and Complex V genes were associated with shorter RFS (adjHR = 3.69, = 0.012, and adjHR = 6.63, = 0.002, respectively). The risk scores derived from mitochondrial somatic mutations were predictive of RFS (adjHR = 9.10, 95%CI: 2.93-28.32, < 0.001). Our findings demonstrated the vulnerability of the mitochondrial genome to mutations and the potential prediction ability of somatic mutations. This research may contribute to improving molecular guidance for patient treatment in precision medicine.
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http://dx.doi.org/10.3390/cancers12030755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140061PMC
March 2020

Anal human papillomavirus and its associations with abnormal anal cytology among men who have sex with men.

Sci Rep 2020 02 21;10(1):3165. Epub 2020 Feb 21.

Institute of Clinical Medicine, National Yang-Ming University, Taipei, 112, Taiwan.

Human papillomavirus (HPV) infection contributes to most anal cancers and premalignant intraepithelial lesions. This study investigated anal HPV infections and cytological abnormalities among men who have sex with men (MSM). Sociodemographic characteristics and sexual behaviors were collected by using a structured questionnaire. Anal cytological results were examined, and HPV genotyping was performed by the Linear Array HPV Genotyping test. Logistic regression was used to estimate risk factors and their associations with high-risk HPV infection and cytological abnormalities. Among 163 MSM, 101 were seropositive for human immunodeficiency virus (HIV) and 62 were seronegative for HIV. The overall prevalence of HPV was 66.2%. A total of 61.9% and 48.2% of participants had never acquired any of either the quadrivalent or nonavalent vaccine HPV types, respectively. Cytological findings showed 15.3% atypical squamous cells of undetermined significance, 16.6% low-grade squamous intraepithelial lesion, 4.9% atypical squamous cells that cannot exclude high-grade squamous intraepithelial lesion and 17% high-grade squamous intraepithelial lesion. The number of high-risk HPV types was the predominant risk factor for abnormal anal cytology (OR 2.02, 95% CI 1.27-3.24). Infection with high-risk HPV was a significant predictor for cytological abnormality. MSM should be encouraged to obtain the HPV vaccine.
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http://dx.doi.org/10.1038/s41598-020-59967-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035349PMC
February 2020

A high-resolution HLA imputation system for the Taiwanese population: a study of the Taiwan Biobank.

Pharmacogenomics J 2020 10 11;20(5):695-704. Epub 2020 Feb 11.

Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.

An imputation algorithm for human leukocyte antigen (HLA) is helpful for exploring novel disease associations. However, population-specific HLA imputation references are essential for achieving high imputation accuracy. In this study, a subset of 1012 individuals from the Taiwan Biobank (TWB) who underwent both whole-genome SNP array and NGS-based HLA typing were used to establish Taiwanese HLA imputation references. The HIBAG package was used to generate the imputation references for eight HLA loci at a two- and three-field resolution. Internal validation was carried out to evaluate the call threshold and accuracy for each HLA gene. HLA class II genes found to be associated with rheumatoid arthritis (RA) were validated in this study by the imputed HLA alleles. Our Taiwanese population-specific references achieved average HLA imputation accuracies of 98.11% for two-field and 98.08% for three-field resolution. The frequency distribution of imputed HLA alleles among 23,972 TWB subjects were comparable with PCR-based HLA alleles in general Taiwanese reported in the allele frequency net database. We replicated four common HLA alleles (HLA-DRB1*03:01, DRB1*04:05, DQA1*03:03, and DQB1*04:01) significantly associated with RA. The population-specific references provide an informative tool to investigate the associations of HLA variants and human diseases in large-scale population-based studies.
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http://dx.doi.org/10.1038/s41397-020-0156-3DOI Listing
October 2020

class I alleles are associated with clinic-based migraine and increased risks of chronic migraine and medication overuse.

Cephalalgia 2020 04 23;40(5):493-502. Epub 2020 Jan 23.

Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei.

Objective: We aimed to evaluate associations of human leukocyte antigen variants with migraine or headache in hospital and population-based settings.

Methods: The case-control study population, aged 30-70, included 605 clinic-based migraine patients in a medical center and 8449 population-based participants in Taiwan Biobank (TWB). Clinic-based cases were ascertained by neurologists. Participants in Taiwan Biobank were interviewed by a structured questionnaire including headache and migraine history; among them, 2394 had headache or migraine history while 6055 were free of headache and served as controls. All subjects were genotyped by Axiom Genome-Wide Single Nucleotide Polymorphism Arrays and imputed for eight classical human leukocyte antigen genes. Human leukocyte antigen frequencies were compared between clinic-based and self-reported patients and controls. We utilized likelihood ratio tests to examine human leukocyte antigen-disease associations and logistic regressions to estimate the effect of human leukocyte antigen alleles on migraine.

Results: Human leukocyte antigen and showed significant associations with clinic-based migraine (-value < 0.05). Human leukocyte antigen, human leukocyte antigen, human leukocyte antigen and human leukocyte antigen were significantly associated with migraine, with age and sex-adjusted odds ratios (95% CIs) of 1.80 (1.28-2.53), 1.50 (1.15-1.97), 1.36 (1.14-1.62) and 1.36 (1.14-1.62), correspondingly. Clinic-based migraineurs carrying human leukocyte antigen or human leukocyte antigen had 1.63 (1.11-2.39) -fold likelihood to have chronic migraine with medication-overuse headache compared to episodic migraine. However, no human leukocyte antigen genes were associated with self-reported headache or migraine in the community.

Conclusions: Human leukocyte antigen class I genetic variants are positively associated with risk of clinic-based migraine but not self-reported migraine or headache and may contribute to migraine chronification and medication overuse.
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http://dx.doi.org/10.1177/0333102420902228DOI Listing
April 2020

Predicting Lung Cancer Occurrence in Never-Smoking Females in Asia: TNSF-SQ, a Prediction Model.

Cancer Epidemiol Biomarkers Prev 2020 02 17;29(2):452-459. Epub 2019 Dec 17.

Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.

Background: High disease burden suggests the desirability to identify high-risk Asian never-smoking females (NSF) who may benefit from low-dose CT (LDCT) screening. In North America, one is eligible for LDCT screening if one satisfies the U.S. Preventive Services Task Force (USPSTF) criteria or has model-estimated 6-year risk greater than 0.0151. According to two U.S. reports, only 36.6% female patients with lung cancer met the USPSTF criteria, while 38% of the ever-smokers ages 55 to 74 years met the USPSTF criteria.

Methods: Using data on NSFs in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma and the Taiwan Biobank before August 2016, we formed an age-matched case-control study consisting of 1,748 patients with lung cancer and 6,535 controls. Using these and an estimated age-specific lung cancer 6-year incidence rate among Taiwanese NSFs, we developed the Taiwanese NSF Lung Cancer Risk Models using genetic information and simplified questionnaire (TNSF-SQ). Performance evaluation was based on the newer independent datasets: Taiwan Lung Cancer Pharmacogenomics Study (LCPG) and Taiwan Biobank data after August 2016 (TWB2).

Results: The AUC based on the NSFs ages 55 to 70 years in LCPG and TWB2 was 0.714 [95% confidence intervals (CI), 0.660-0.768]. For women in TWB2 ages 55 to 70 years, 3.94% (95% CI, 2.95-5.13) had risk higher than 0.0151. For women in LCPG ages 55 to 74 years, 27.03% (95% CI, 19.04-36.28) had risk higher than 0.0151.

Conclusions: TNSF-SQ demonstrated good discriminative power. The ability to identify 27.03% of high-risk Asian NSFs ages 55 to 74 years deserves attention.

Impact: TNSF-SQ seems potentially useful in selecting Asian NSFs for LDCT screening.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1221DOI Listing
February 2020
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