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Background: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Current guidelines for HCC management recommend surveillance of high-risk patients every 6 mo using ultrasonography. Serum biomarkers, like alpha-fetoprotein (AFP), protein induced by vitamin K absence/antagonist-II (PIVKA-II) and lectin-reactive AFP, show suboptimal performance for detection of HCC, which is crucial for successful resection or treatment. Thus, there is a significant need for new biomarkers to aid early diagnosis of HCC. Studies have shown that the expression level of human microRNAs (miRNAs), a small, non-coding RNA species released into the blood, can serve as an early marker for various diseases, including HCC., Aim: To evaluate the diagnostic role of miRNAs in HCC as single markers, signatures or in combination with known protein biomarkers., Methods: Our prospective, multicenter, case-control study recruited 660 participants (354 controls with chronic liver disease and 306 participants with HCC) and employed a strategy of initial screening by two independent methods, real-time quantitative PCR ( n = 60) and next-generation sequencing ( n = 100), to assess a large number of miRNAs. The results from the next-generation sequencing and real-time quantitative PCR screening approaches were then combined to select 26 miRNAs (including two putative novel miRNAs). Those miRNAs were analyzed for their diagnostic potential as single markers or in combination with other miRNAs or established protein biomarkers AFP and PIVKA-II via real-time quantitative PCR in training ( n = 200) and validation cohorts ( n = 300)., Results: We identified 26 miRNAs that differentiated chronic liver disease controls from (early) HCC via two independent discovery approaches. Three miRNAs, miR-21-5p (miR-21), miR-320a and miR-186-5p, were selected by both methods. In the training cohort, only miR-21, miR-320d and miR-423 could significantly distinguish ( Q < 0.05) between the HCC and chronic liver disease control groups. In the multivariate setting, miR-21 with PIVKA-II was selected as the best combination, resulting in an area under the curve of 0.87 for diagnosis and area under the curve of 0.74 for early diagnosis of HCC. In the validation cohort, only miR-21 and miR-423 could be confirmed as potential HCC biomarkers. A combination of miRNAs did not perform better than any single miRNA. Improvement of PIVKA-II performance through combination with miRNAs could not be confirmed in the validation panel. Two putative miRs, put-miR-6 and put-miR-99, were tested in the training and validation panels, but their expression could only be detected in very few samples and at a low level (cycle threshold between 31.24 and 34.97)., Conclusion: miRNAs alone or as a signature in combination with protein biomarkers AFP and PIVKA-II do not improve the diagnostic performance of the protein biomarkers., Competing Interests: Conflict-of-interest statement: Malik J, Klammer M, Rolny V and Swiatek-de Lange M are employees of Roche Diagnostics GmbH and shareholders in Roche Diagnostics., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Aim: To determine the role of screening and surveillance of hepatocellular carcinoma (HCC) in treatment-naïve chronic hepatitis B (CHB) patients., Methods: We recruited 2293 CHB patients (both males and females; aged 20-65 years). All patients were screened and underwent surveillance using abdominal ultrasonography (AUS) and serum alpha-fetoprotein (AFP) assay every 6 mo. The diagnosis, staging and treatment of HCC followed the American Association for the Study of Liver Diseases practice guidelines and the Barcelona Clinic Liver Cancer guidelines. The exclusion criteria included: decompensated cirrhosis; a history of any cancer in the last 5 years; previous antiviral treatment for CHB; concurrent infection with hepatitis C virus or human immunodeficiency virus; a Karnofsky Performance Status score < 60%; or any medical condition preventing eligibility to complete the protocol. The prevalence and incidence rates of HCC were determined; survival rates were calculated at 3-year post HCC diagnosis. The sensitivity and specificity were calculated on a per-patient basis., Results: Among 2293 treatment-naïve CHB patients, seven cases had HCC at initial screening, giving a prevalence rate of 305 per 100000 persons; 3.3% were diagnosed with liver cirrhosis, all of which were Child-Pugh class A. With a median follow-up time of 42 (range, 3-48) mo, 10 additional cases were diagnosed with HCC, resulting in an incidence rate of 143 per 100000 persons per year. This burden was as high as that reported in other studies from East Asian countries. All HCC patients were aged ≥ 40 years. Most were at an early stage (Stage 0, A or B); 14/17 cases were successfully treated with surgical resection or radiofrequency ablation, with a high 3-year survival rate of 90%. Hemangioma was the most common focal liver lesion in CHB patients detected by AUS; the main causes of AFP elevation at the initial screening were cirrhosis, increased alanine aminotransferase level and HCC. AUS detected 16/17 HCC cases whereas AFP levels ≥ 20 μg/L at diagnosis were observed in only 7/17 patients, most with a tumor size > 5 cm. For HCC screening and surveillance, AUS had a sensitivity and specificity of 94% and 82%, respectively, whereas the sensitivity and specificity of AFP at a cut-off value of ≥ 20 μg/L were 41% and 98%, respectively. Combined use of AUS and AFP assay did not improve effectiveness., Conclusion: Implementation of active screening and surveillance using AUS to detect early-stage HCC in naïve CHB patients aged ≥ 40 years in an endemic area is of benefit., Competing Interests: Conflict-of-interest statement: The authors of this manuscript declare that they have no conflicts of interest to disclose.

Aim: To examined the efficacy and safety of treatment with boceprevir, PEGylated-interferon and ribavirin (PR) in hepatitis C virus genotype 1 (HCVGT1) PR treatment-failures in Asia., Methods: The Boceprevir Named-Patient Program provided boceprevir to HCVGT1 PR treatment-failures. Participating physicians were invited to contribute data from their patients: baseline characteristics, on-treatment responses, sustained virological response at week 12 (SVR12), and safety were collected and analysed. Multivariate analysis was performed to determine predictors of response., Results: 150 patients were enrolled from Australia, Malaysia, Singapore and Thailand (Asians = 86, Caucasians = 63). Overall SVR12 was 61% (Asians = 59.3%, Caucasians = 63.5%). SVR12 was higher in relapsers (78%) compared with non-responders (34%). On-treatment responses predicted SVR, with undetectable HCVRNA at week 4, 8 and 12 leading to SVR12s of 100%, 87%, and 82% respectively, and detectable HCVRNA at week 4, 8 and 12, leading to SVR12s of 58%, 22% and 6% respectively. Asian patients were similar to Caucasian patients with regards to on-treatment responses. Patients with cirrhosis (n = 69) also behaved in the same manner with regards to on-treatment responses. Those with the IL28B CC genotype (80%) had higher SVRs than those with the CT/TT (56%) genotype (P = 0.010). Multivariate analysis showed that TW8 and TW12 responses were independent predictors of SVR. Serious adverse events occurred in 18.6%: sepsis (2%), decompensation (2.7%) and blood transfusion (14%). Discontinuations occurred in 30.7%, with 18.6% fulfilling stopping rules., Conclusion: Boceprevir can be used successfully in PR treatment failures with a SVR12 > 80% if they have good on-treatment responses; however, discontinuations occurred in 30% because of virological failure or adverse events.

Aim: To characterize the effects of age on clinical presentations and endoscopic diagnoses and to determine outcomes after endoscopic therapy among patients aged ≥ 65 years admitted for acute upper gastrointestinal bleeding (UGIB) compared with those aged < 65 years., Methods: Medical records and an endoscopy data-base of 526 consecutive patients with overt UGIB ad-mitted during 2007-2009 were reviewed. The initial presentations and clinical course within 30 d after endoscopy were obtained., Results: A total of 235 patients aged ≥ 65 years constituted the elderly population (mean age of 74.2 ± 6.7 years, 63% male). Compared to young patients, the elderly patients were more likely to present with melena (53% vs 30%, respectively; P < 0.001), have comorbidities (69% vs 54%, respectively; P < 0.001), and receive antiplatelet agents (39% vs 10%, respectively; P < 0.001). Interestingly, hemodynamic instability was observed less in this group (49% vs 68%, respectively; P < 0.001). Peptic ulcer was the leading cause of UGIB in the elderly patients, followed by varices and gastropathy. The elderly and young patients had a similar clinical course with regard to the utilization of endoscopic therapy, requirement for transfusion, duration of hospital stay, need for surgery [relative risk (RR), 0.31; 95% confidence interval (CI), 0.03-2.75; P = 0.26], rebleeding (RR, 1.44; 95% CI, 0.92-2.25; P = 0.11), and mortality (RR, 1.10; 95% CI, 0.57-2.11; P = 0.77). In Cox's regression analysis, hemodynamic instability at presentation, background of liver cirrhosis or disseminated malignancy, transfusion requirement, and development of rebleeding were significantly associated with 30-d mortality., Conclusion: Despite multiple comorbidities and the concomitant use of antiplatelets in the elderly patients, advanced age does not appear to influence adverse outcomes of acute UGIB after therapeutic endoscopy.

Aim: To assess the clinical, biochemical, and virological outcome during long-term follow-up of chronic hepatitis C patients with sustained virological response following effective antiviral therapy., Methods: This study was a retrospective cohort study including 171 sustained responders defined as HCV RNA PCR negative at 6 mo after the end of effective antiviral treatment (SVR-6). Clinical signs and symptoms, biochemical hepatic parameters, ultrasonography and HCV RNA PCR were followed., Results: Mean follow-up period was 35.38 +/- 22.2 mo after the end of treatment. Twenty-seven (15.8%) responders had evidence of cirrhosis before treatment. Forty-eight (28.1%), 107 (62.6%) and 6 (3.5%) patients were genotype 1, 3, and 6 respectively, while 10 patients (5.8%) were unclassified. There were no virological and biochemical relapses during the period of follow-up. None of the patients showed evidence of hepatic decompensation. However, there were 3 patients (1.8%) developing hepatocellular carcinoma at 14, 18, 29 mo after treatment discontinuation, two of whom had evidence of cirrhosis prior to therapy., Conclusion: The study shows that during a follow-up interval for about 3 years in 171 chronic hepatitis C patients with sustained viral response after effective antiviral treatment there were no evident signs of either biochemical or clinical relapse of liver disease in all but three patients who developed hepatocellular carcinoma.