MRI for hepatocellular carcinoma and the role of abbreviated MRI for surveillance of hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma (HCC) constitutes the majority of liver cancers and significantly impacts global cancer mortality. While ultrasound (US) with or without alpha-fetoprotein is the mainstay for HCC surveillance, its limitations highlight the necessity for more effective surveillance tools. Therefore, this review explores evolving imaging modalities and abbreviated magnetic resonance imaging (MRI) (AMRI) protocols as promising alternatives, addressing challenges in HCC surveillance. AREAS COVERED: This comprehensive review delves into the evaluation and challenges of HCC surveillance tools, focusing on non-contrast abbreviated MRI (NC-AMRI) and contrast-enhanced abbreviated MRI protocols. It covers the implementation of AMRI for HCC surveillance, patient preferences, adherence, and strategies for optimizing cost-effectiveness. Additionally, the article provides insights into prospects for HCC surveillance by summarizing meta-analyses, prospective studies, and ongoing clinical trials evaluating AMRI protocols. EXPERT OPINION: The opinions underscore the transformative impact of AMRI on HCC surveillance, especially in overcoming US limitations. Promising results from NC-AMRI protocols indicate its potential for high-risk patient surveillance, though prospective studies in true surveillance settings are essential for validation. Future research should prioritize risk-stratified AMRI protocols and address cost-effectiveness for broader clinical implementation, alongside comparative analyses with US for optimal surveillance strategies.

Association between Liver Stiffness and Liver-Related Events in HCV-Infected Patients after Successful Treatment with Direct-Acting Antivirals.

Background and Objectives: Direct-acting antivirals (DAAs) are highly effective for the treatment of chronic hepatitis C virus (HCV) infection, but the risk of liver-related events and hepatocellular carcinoma (HCC) remains after successful therapy. We aimed to evaluate post-treatment changes in liver stiffness (LS) and identify a cut-off LS value for predicting such events in chronic HCV-infected patients receiving DAA. Materials and Methods: A total of 185 patients who had achieved sustained virologic response (SVR) after DAA therapy were included. Baseline characteristics and laboratory results were retrospectively abstracted. LS was measured by transient elastography at baseline, 12, 24, 48, and 96 weeks after SVR. FIB-4 index was assessed at baseline and 48 weeks after SVR. Development of liver-related events (hepatocellular carcinoma (HCC), portal-hypertension-related decompensation, listing for transplantation, and mortality) after SVR were identified. The association between liver fibrosis and the occurrence of liver-related events was analyzed using Cox regression analysis. Results: Significant differences in LS values were observed between baseline and 24, 48, 72, and 96 weeks after SVR. FIB-4 index at 48 weeks after SVR was significantly lower than the FIB-4 index at baseline. During the 41.6-month follow-up time, the incidence rates of all liver-related events and HCC were 2.36 and 1.17 per 100 person-years, respectively. Age, LS ≥8 kPa, and FIB-4 ≥1.35 at 48 weeks post-SVR were significantly associated with the occurrence of any liver-related events. By multivariate analysis, LS ≥8 kPa at 48 weeks post-SVR remained significantly associated with any liver-related events, with an adjusted hazard ratio (95%CI) of 5.04 (1.01-25.26), p = 0.049. Conclusions: Despite a significant reduction in LS after SVR, patients with LS ≥8 kPa at 48 weeks after SVR should be regularly monitored for liver-related complications, particularly HCC development.

Application of artificial intelligence in chronic liver diseases: a systematic review and meta-analysis.

BACKGROUND: The gold standard for the diagnosis of liver fibrosis and nonalcoholic fatty liver disease (NAFLD) is liver biopsy. Various noninvasive modalities, e.g., ultrasonography, elastography and clinical predictive scores, have been used as alternatives to liver biopsy, with limited performance. Recently, artificial intelligence (AI) models have been developed and integrated into noninvasive diagnostic tools to improve their performance. METHODS: We systematically searched for studies on AI-assisted diagnosis of liver fibrosis and NAFLD on MEDLINE, Scopus, Web of Science and Google Scholar. The pooled sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic odds ratio (DOR) with their 95% confidence intervals (95% CIs) were calculated using a random effects model. A summary receiver operating characteristic curve and the area under the curve was generated to determine the diagnostic accuracy of the AI-assisted system. Subgroup analyses by diagnostic modalities, population and AI classifiers were performed. RESULTS: We included 19 studies reporting the performances of AI-assisted ultrasonography, elastrography, computed tomography, magnetic resonance imaging and clinical parameters for the diagnosis of liver fibrosis and steatosis. For the diagnosis of liver fibrosis, the pooled sensitivity, specificity, PPV, NPV and DOR were 0.78 (0.71-0.85), 0.89 (0.81-0.94), 0.72 (0.58-0.83), 0.92 (0.88-0.94) and 31.58 (11.84-84.25), respectively, for cirrhosis; 0.86 (0.80-0.90), 0.87 (0.80-0.92), 0.85 (0.75-0.91), 0.88 (0.82-0.92) and 37.79 (16.01-89.19), respectively; for advanced fibrosis; and 0.86 (0.78-0.92), 0.81 (0.77-0.84), 0.88 (0.80-0.93), 0.77 (0.58-0.89) and 26.79 (14.47-49.62), respectively, for significant fibrosis. Subgroup analyses showed significant differences in performance for the diagnosis of fibrosis among different modalities. The pooled sensitivity, specificity, PPV, NPV and DOR were 0.97 (0.76-1.00), 0.91 (0.78-0.97), 0.95 (0.87-0.98), 0.93 (0.80-0.98) and 191.52 (38.82-944.81), respectively, for the diagnosis of liver steatosis. CONCLUSIONS: AI-assisted systems have promising potential for the diagnosis of liver fibrosis and NAFLD. Validations of their performances are warranted before implementing these AI-assisted systems in clinical practice. TRIAL REGISTRATION: The protocol was registered with PROSPERO (CRD42020183295).

COVID-19 vaccine acceptance, hesitancy, and determinants among physicians in a university-based teaching hospital in Thailand.

BACKGROUND: The COVID-19 vaccines provide renewed hope in the fight against the recent pandemic. To ensure widespread vaccination, it is crucial to analyze vaccine willingness and its determinants among physicians, key health care influencers. This study aimed to assess acceptance rate and identify factors associated with vaccine hesitancy among Thai physicians. METHODS: A cross-sectional online-based questionnaire was distributed to all physicians at King Chulalongkorn Memorial Hospital during March 31, 2021 to April 30, 2021 in order to assess their attitudes toward receiving the COVID-19 vaccine. Reasons for vaccine acceptance and refusal as well as predictors of vaccine hesitancy were analyzed by bivariate and multivariable analysis. RESULTS: A total of 705 complete responses were received with 95.6% (n = 675) of physicians expressing willingness to receive a COVID-19 vaccine. Only one of the 31 physicians (4.4%) who expressed a hesitancy or unwillingness to be vaccinated was a faculty member; the others were physicians-in-training. Approximately one-fifths of physicians surveyed were also not willing to recommend the vaccine to their family members (21.4%, n = 151) or patients (18.7%, n = 132). Using multivariable logistic regression, vaccine hesitancy was independently associated with preference for particular vaccines over the government allocated option, especially for mRNA vaccine (aOR 8.86; 95% CI 1.1-71.54; p = 0.041). Vaccine literacy showed an inverse relationship (aOR 0.34; 95% CI 0.13-0.9; p = 0.029) with vaccine hesitancy. Uncertainty of the vaccine efficacy (83.9%) and fear of adverse events (48.4%) were major concerns contributing to vaccine hesitancy. CONCLUSION: This study revealed a high rate of physician willingness to take the COVID-19 vaccine especially among staffs; however, a significant proportion would not currently suggest vaccination to their families or patients. Restrictions on vaccine choice and vaccine illiteracy, together with concerns over adverse effects and uncertainty of efficacy, were associated with negative attitudes toward vaccination. To raise acceptance of the vaccination program, efforts should be made to balance individual preference for vaccine type in addition to increasing the availability of accurate data on safety and efficacy for each vaccine.

Video-assisted liver ultrasound training for non-radiologists: protocol and preliminary results.

BACKGROUND: Ultrasound (US) is increasingly used as a bedside diagnostic tool, with training courses for non-radiologists being developed. However, the training time constraint is an important barrier for non-radiologists. We therefore created a short self-learning course for liver-US for non-radiologists. AIM: Assess the participants' ability in identifying the organ structures during a liver-US. METHOD: A short video-lecture on liver-US training and a portable guidebook for image acquisition were developed. Eighteen non-radiologist physicians studied the course and attended hands-on liver-US examinations to capture the assigned images and label the acquired organ/structures, which were evaluated by an expert radiologist. RESULT: 130 liver-US examinations were performed, 44 (33.8%) was cirrhosis. The overall of mean image acquisition score was 84.5 ± 9.7%. The mean score of the 1st examination was 75.2 ± 16.4. The mean score was >80% since the 2nd examination. The score was significant lower in cirrhotic cases as compared to non-cirrhotic cases (78.8 ± 17.3 vs. 88.3 ± 14.4, p = 0.001). The participants' year of study and experience in previous US training did not affect the image acquisition score. CONCLUSION: The liver-US training course in a short video format with a portable guidebook is effective and relatively low time-consuming for teaching non-radiologists to perform bedside liver-US.

Changes in inflammatory cytokines, antioxidants and liver stiffness after chelation therapy in individuals with chronic lead poisoning.

BACKGROUND: Chronic exposure to lead causes lead to accumulate mainly in the liver. In vivo studies have shown that lead toxicity is related to alterations in the inflammatory response. We aimed to evaluate the association between lead poisoning and liver fibrosis as well as the change in the degree of liver fibrosis, levels of inflammatory mediators and glutathione (GSH) after chelation therapy. METHODS: Workers from a battery factory who were exposed to lead for > 12 months and had a blood lead level (BLL) > 70 µg/dL were enrolled (n = 86) in the study. Participants underwent chelation therapy with intravenous CaNa2EDTA for 2 days followed by treatment with oral D-penicillamine for 90 days. The primary outcome was the change in the degree of liver fibrosis, which was presented as liver stiffness (LS) measured by FibroScan®. Secondary outcomes were the changes in the levels of serum GSH and inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) after chelation therapy. RESULTS: Among the 86 participants, there was a positive correlation between the duration of lead exposure and LS (r = 0.249, p = 0.021). To avoid the confounding effect of obesity-related steatosis, only 70 individuals who had controlled attenuation parameters < 296 dB/m, BMI < 25 kg/m2 and normal waist circumference were included in the interventional analysis. After chelation, the mean LS significantly decreased from 5.4 ± 0.9 to 4.8 ± 1.4 kPa (p = 0.001). Similarly, all of the inflammatory cytokines studied significantly decreased after chelation (p < 0.001); TNF-α decreased from 371.6 ± 211.3 to 215.8 ± 142.7; the levels of IL-1ß decreased from 29.8 ± 1.7 to 25.9 ± 4.3; and the levels of IL-6 decreased from 46.8 ± 10.2 to 35.0 ± 11.9. On the other hand, the mean GSH level increased significantly from 3.3 ± 3.3 to 13.1 ± 3.7 (p < 0.001) after chelation therapy. CONCLUSION: The duration of lead exposure was significantly correlated with the degree of liver fibrosis. Chelation treatment was associated with increased levels of GSH and decreased levels of proinflammatory cytokines and could potentially reduce the degree of LS. TRIAL REGISTRATION: This study was retrospectively registered and approved by the Thai Clinical Trial Registry (TCTR) on 2019-11-07. The TCTR identification number is TCTR20191108001 .

The incidence, etiologies, outcomes, and predictors of mortality of acute liver failure in Thailand: a population-base study.

BACKGROUND: Acute liver failure (ALF) is uncommon but progresses rapidly with high mortality. We investigated the incidence, etiologies, outcomes, and predictive factors for 30-day mortality in patients with ALF. METHODS: We conducted a population-based study of ALF patients hospitalized between 2009 and 2013 from the Thai Nationwide Hospital Admission database, which comprises 76% of all admissions from 858 hospitals across 77 provinces in Thailand. ALF was diagnosed using ICD-10 codes K72.0 and K71.11. Patients with liver cirrhosis were excluded. RESULTS: There were 20,589 patients diagnosed with ALF during the study period with 12,277 (59.6%) males and mean age of 46.6 ± 20.7 years. The incidence of ALF was 62.9 per million population per year. The most frequent causes of ALF were indeterminate (69.4%), non-acetaminophen drug-induced (26.1%), and viral hepatitis (2.5%). Acetaminophen was the presumptive cause in 1.7% of patients. There were 5502 patients (26.7%) who died within 30 days after admission. One patient (0.005%) underwent liver transplantation. The average hospital stay was 8.7 ± 13.9 days, and the total cost of management was 1075.2 ± 2718.9 USD per admission. The most prevalent complications were acute renal failure (ARF)(24.2%), septicemia (18.2%), and pneumonia (12.3%). The most influential predictive factors for 30-day mortality were ARF (HR = 3.64, 95% CI: 3.43-3.87, p < 0.001), malignant infiltration of the liver (HR = 3.37, 95% CI: 2.94-3.85, p < 0.001), and septicemia (HR = 1.96, 95%CI: 1.84-2.08, p < 0.001). CONCLUSIONS: ALF patients have poor outcomes with 30-day mortality of 26.7% and high economic burden. Indeterminate etiology is the most frequent cause. ARF, malignant infiltration of the liver, and septicemia are main predictors of 30-day mortality.

Uncomplicated common bile duct stone removal guided by cholangioscopy versus conventional endoscopic retrograde cholangiopancreatography.

BACKGROUND: Although previous studies have reported the possibility of therapeutic ERCP without fluoroscopy, more robust documentation of fluoroscopy-free common bile duct stone (CBDS) clearance is needed. Technically, "digital cholangioscopy" (DCS) may be used to confirm CBDS clearance. We aimed to compare the feasibility, safety, and radiation exposure between patients with CBDS undergoing stone removal by DCS and conventional ERCP (cERCP). METHODS: Fifty (50) consecutive patients with a CBDS size < 15 mm underwent DCS (SpyGlass DS Direct Visualization System, Boston Scientific, Marlboro, MA, USA) between December 2015 and October 2016. Of 202 consecutive patients undergoing cERCP during the same time frame, 50 matched pairs were created using propensity score matching analysis. In the DCS group, patients underwent biliary cannulation and CBDS removal without fluoroscopy followed by DCS to confirm complete CBDS clearance. A final occlusion cholangiogram was performed as the current standard of care to confirm CBDS clearance. RESULTS: Cannulation success rates were similar between the DCS and cERCP groups (98 vs. 98%). By intention-to-treat analysis, CBDS clearance in the DCS and cERCP groups was not different (90 vs. 98%; p = 0.20, respectively). DCS had successful CBDS removal in 45 cases, whereas 5 (10%) failed for clearance by DCS due to technical limitations. Adverse events were not different between both groups. CONCLUSIONS: In the management of uncomplicated CBDS, our data confirmed the feasibility of DCS for CBDS clearance as it showed efficacy and safety comparable to those of cERCP. Although certain conditions may limit its effectiveness, DCS offers the ability to perform CBDS clearance without the need for fluoroscopy unit and can avoid radiation exposure while ERCP under fluoroscopy remains the current standard of care in patients with CBDS.

Aspirin use and the risk of cholangiocarcinoma.

UNLABELLED: Whether aspirin use is protective against cholangiocarcinoma (CCA) remains unclear. We determined the association between aspirin use and other risk factors for each CCA subtype individually. In a hospital-based case-control study, 2395 CCA cases (1169 intrahepatic, 995 perihilar, and 231 distal) seen at the Mayo Clinic, Rochester, MN, from 2000 through 2014 were enrolled. Controls selected from the Mayo Clinic Biobank were matched two to one with cases by age, sex, race, and residence (n = 4769). Associations between aspirin use, other risk factors, and CCA risk were determined. Aspirin was used by 591 (24.7%) CCA cases and 2129 (44.6%) controls. There was a significant inverse association of aspirin use with all CCA subtypes, with adjusted odds ratios (AORs) of 0.35 (95% confidence interval [CI], 0.29-0.42), 0.34 (95% CI 0.27-0.42), and 0.29 (95% CI 0.19-0.44) for intrahepatic, perihilar, and distal CCA, respectively (P < 0.001 for all). Primary sclerosing cholangitis was more strongly associated with perihilar (AOR = 453, 95% CI 104-999) than intrahepatic (AOR = 93.4, 95% CI 27.1-322) or distal (AOR = 34.0, 95% CI 3.6-323) CCA, whereas diabetes was more associated with distal (AOR = 4.2, 95% CI 2.5-7.0) than perihilar (AOR = 2.9, 95% CI 2.2-3.8) or intrahepatic (AOR = 2.5, 95% CI 2.0-3.2) CCA. Cirrhosis not related to primary sclerosing cholangitis was associated with both intrahepatic and perihilar CCA, with similar AORs of 14. Isolated inflammatory bowel disease without primary sclerosing cholangitis was not associated with any CCA subtype. CONCLUSIONS: Aspirin use was significantly associated with a 2.7-fold to 3.6-fold decreased risk for the three CCA subtypes; our study demonstrates that individual risk factors confer risk of different CCA subtypes to different extents. (Hepatology 2016;64:785-796).

Circulating tumor cells are associated with poor overall survival in patients with cholangiocarcinoma.

UNLABELLED: Circulating tumor cells (CTCs) in blood are associated with poor survival of patients with breast, prostate, or colon cancer. We hypothesized that CTCs are associated with poor survival of patients with cholangiocarcinoma (CCA). Eighty-eight patients with CCA were prospectively enrolled at Mayo Clinic Rochester between June 2010 and September 2014. The CellSearch system by Veridex was used for detection of CTCs in peripheral blood. Associations between CTC, patient and tumor characteristics, and survival were examined using the Cox's proportional hazards model. Fifteen patients (17%) were positive for CTC ≥2 and 8 patients (9%) for CTC ≥5. CTCs were associated with tumor extent. CTC ≥2 (hazard ratio [HR]: 2.5; 95% confidence interval [CI]: 1.1-5.4; P = 0.02) and CTC ≥5 (HR, 4.1; 95% CI: 1.4-10.8; P = 0.01) were both independent predictors of survival. In subgroup analyses, CTC ≥2 (HR, 8.2; 95% CI: 1.8-57.5; P < 0.01) and CTC ≥5 (HR, 7.7; 95% CI: 1.4-42.9; P = 0.02) were both associated with shorter survival among patients with metastasis. There was a trend toward association of CTC ≥5 with shorter survival in patients with nonmetastatic CCA (HR, 4.3; 95% CI: 1.0-13.8; P = 0.06). CTC ≥2 (HR, 10.5; 95% CI: 2.2-40.1; P < 0.01) and CTC ≥5 (HR, 10.2; 95% CI: 1.5-42.3; P = 0.02) were both associated with shorter survival among patients with perihilar/distal CCA. CTC ≥5 was associated with shorter survival of patients with intrahepatic CCA (HR, 4.2; 95% CI: 1.1-14.1; P = 0.04). CONCLUSION: CTCs were associated with more-aggressive tumor characteristics and independently associated with survival in patients with CCA. Assessment of CTCs may be useful for identifying CCA patients at risk of early mortality.

Non-alcoholic fatty liver disease as a risk factor for cholangiocarcinoma: a systematic review and meta-analysis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has been recently identified as a risk factor of gastrointestinal tract cancers, especially hepatocellular carcinoma, and colorectal cancer. Whether NAFLD is a risk factor for cholangiocarcinoma (CCA) remains inconclusive. The aim of this study is to determine a potential association between NAFLD and CCA, stratifying by its subtypes; intrahepatic CCA (iCCA), and extrahepatic CCA (eCCA). METHODS: A search was conducted for relevant studies published up to April 2017 using MEDLINE, EMBASE, Scopus and Cochrane databases. Odds ratio (OR) and adjusted OR with 95% confidence interval (CI) were estimated using a random-effects model. Subgroup analyses were conducted with study characteristics. RESULTS: Seven case-control studies were included in the analysis, with a total of 9,102 CCA patients (5,067 iCCA and 4,035 eCCA) and 129,111 controls. Overall, NAFLD was associated with an increased risk for CCA, with pooled OR of 1.95 (95%CI: 1.36-2.79, I 2 =76%). When classified by subtypes, NAFLD was associated with both iCCA and eCCA, with ORs of 2.22 (95%CI: 1.52-3.24, I 2 =67%) and 1.55 (95%CI: 1.03-2.33, I 2 =69%), respectively. The overall pooled adjusted ORs were 1.97 (95%CI: 1.41-2.75, I 2 =71%), 2.09 (95%CI, 1.49-2.91, I 2 =42%) and 2.05 (95%CI, 1.59-2.64, I 2 =0%) for all CCAs, iCCA, and eCCA, respectively. CONCLUSIONS: This meta-analysis suggests that NAFLD may potentially increase the risk of CCA development. The magnitude of NAFLD on CCA risk is greater for iCCA than eCCA subtype, suggestive of a common pathogenesis of iCCA and hepatocellular carcinoma. Further studies to confirm this association are warranted. TRIAL REGISTRATION: The protocol for this study was registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42016046573).

A significant cancer burden and high mortality of intrahepatic cholangiocarcinoma in Thailand: a nationwide database study.

BACKGROUND: We aimed to examine the burden of intrahepatic cholangiocarcinoma (ICC) in Thailand and identify the prognostic factors for all-causes of death. METHODS: We conducted a population-based study of ICC patients admitted during 2009-2013 using the Nationwide Hospital Admission Database, the National Health Security Office (NHSO). There was an average of 1,051,146 patients/year with diagnosis of gastrointestinal diseases (GI). All patients with a diagnosis of ICC (ICD10- C221) were included from a total of 72,479 admissions from 858 hospitals. The surgical resection procedures such as the radical pancreaticoduodenectomy, subtotal and partial hepatectomy were analyzed. Data for all patients were censored 1 year post-study or death, whichever came first. RESULTS: A total of 34,325 patients with ICC during a 5-year study period (on average, 6865 patients/year, with the incidence rate of 14.6 per 100,000 population, per year. The ICC patients had a mean age of 63.8+/-11.6 years and 63% were males. The mean length of hospital stay was 6.4+/-7.3 days with a mean+/-SD cost of hospitalization of $595+/-$1160 USD per admission. There were 659 patients (1.9%) underwent surgical resection. The overall survival of ICC patients with surgery was significantly better than those patients without surgery. Hazard ratio of death for patients without surgery was 2.5 (95% CI of 2.3-2.7). Approximately 14% of the ICC patients died during hospitalization. The median overall survival of all patients after the first admission was 53 +/-0.6 days. From the multivariate analysis, factors related to all-causes of death were: patients' age >60 years (OR = 1.2, 95% CI; 1.1-1.3), length of hospital stay of >7 days (OR = 1.1, 95% CI; 1.02-1.2), male (OR = 1.3, 95% CI; 1.2-1.4), living in the northern part of Thailand (OR = 1.5, 95% CI; 1.3-1.8) and presence of complications during admission (OR = 1.3, 95% CI; 1.1-1.5). CONCLUSION: The disease burden of patients with ICC in Thailand is significant with the incidence rate of 14.6 per 100,000 population, per year during 2009-2013 and showed high mortality rate of 14%.

Surveillance for Hepatocellular Carcinoma Reduces Mortality: an Inverse Probability of Treatment Weighted Analysis.

BACKGROUND: Evidence supporting benefit of hepatocellular carcinoma (HCC) surveillance in reducing mortality is not well-established. The effect of HCC surveillance in reducing mortality was assessed by an inverse probability of treatment weighting (IPTW)-based analysis controlled for inherent bias and confounders in observational studies. MATERIAL AND METHODS: This retrospective cohort study was conducted on 446 patients diagnosed with HCC between 2007 and 2013 at a major referral center. Surveillance was defined as having at least 1 ultrasound test within a year before HCC diagnosis. Primary outcome was survival estimated using the Kaplan-Meier method with lead-time bias adjustment and compared using the log-rank test. Hazard ratio (HR) and 95% confidence interval (CI) were computed using conventional Cox and weighted Cox proportional hazards analysis with IPTW adjustment. RESULTS: Of the 446 patients, 103 (23.1%) were diagnosed with HCC through surveillance. The surveillance group had more patients with the Barcelona-Clinic Liver Cancer stage A (80.6% vs. 33.8%, P < 0.0001), more patients eligible for potentially curative treatment (73.8% vs. 44.9%, P < 0.0001), and longer median survival (49.6 vs. 15.9 months, P < 0.0001). By conventional multivariate Cox analysis, HR (95% CI) of surveillance was 0.63 (0.45-0.87), P = 0.005. The estimated effect of surveillance remained similar in the IPTW-adjusted Cox analysis (HR: 0.57; 95% CI: 0.43-0.76, P < 0.001). CONCLUSIONS: HCC surveillance by ultrasound is associated with a 37% reduction in mortality. Even though surveillance is recommended in all guidelines, but in practice, it is underutilized. Interventions are needed to increase surveillance rate for improving HCC outcome.

Silent Tyrosinemia Type I Without Elevated Tyrosine or Succinylacetone Associated with Liver Cirrhosis and Hepatocellular Carcinoma.

Tyrosinemia type I (TYRSN1, TYR I) is caused by fumarylacetoacetate hydrolase (FAH) deficiency and affects approximately one in 100,000 individuals worldwide. Pathogenic variants in FAH cause TYRSN1, which induces cirrhosis and can progress to hepatocellular carcinoma (HCC). TYRSN1 is characterized by the production of a pathognomonic metabolite, succinylacetone (SUAC) and is included in the Recommended Uniform Screening Panel for newborns. Treatment intervention is effective if initiated within the first month of life. Here, we describe a family with three affected children who developed HCC secondary to idiopathic hepatosplenomegaly and cirrhosis during infancy. Whole exome sequencing revealed a novel homozygous missense variant in FAH (Chr15(GRCh38):g.80162305A>G; NM_000137.2:c.424A > G; NP_000128.1:p.R142G). This novel variant involves the catalytic pocket of the enzyme, but does not result in increased SUAC or tyrosine, making the diagnosis of TYRSN1 problematic. Testing this novel variant using a rapid, in vivo somatic mouse model showed that this variant could not rescue FAH deficiency. In this case of atypical TYRSN1, we show how reliance on SUAC as a primary diagnostic test can be misleading in some patients with this disease. Augmentation of current screening for TYRSN1 with targeted sequencing of FAH is warranted in cases suggestive of the disorder.

An Optimized Set of Fluorescence In Situ Hybridization Probes for Detection of Pancreatobiliary Tract Cancer in Cytology Brush Samples.

BACKGROUND & AIMS: Pancreatobiliary cancer is detected by fluorescence in situ hybridization (FISH) of pancreatobiliary brush samples with UroVysion probes, originally designed to detect bladder cancer. We designed a set of new probes to detect pancreatobiliary cancer and compared its performance with that of UroVysion and routine cytology analysis. METHODS: We tested a set of FISH probes on tumor tissues (cholangiocarcinoma or pancreatic carcinoma) and non-tumor tissues from 29 patients. We identified 4 probes that had high specificity for tumor vs non-tumor tissues; we called this set of probes pancreatobiliary FISH. We performed a retrospective analysis of brush samples from 272 patients who underwent endoscopic retrograde cholangiopancreatography for evaluation of malignancy at the Mayo Clinic; results were available from routine cytology and FISH with UroVysion probes. Archived residual specimens were retrieved and used to evaluate the pancreatobiliary FISH probes. Cutoff values for FISH with the pancreatobiliary probes were determined using 89 samples and validated in the remaining 183 samples. Clinical and pathologic evidence of malignancy in the pancreatobiliary tract within 2 years of brush sample collection was used as the standard; samples from patients without malignancies were used as negative controls. The validation cohort included 85 patients with malignancies (46.4%) and 114 patients with primary sclerosing cholangitis (62.3%). Samples containing cells above the cutoff for polysomy (copy number gain of ≥2 probes) were classified as positive in FISH with the UroVysion and pancreatobiliary probes. Multivariable logistic regression was used to estimate associations between clinical and pathology findings and results from FISH. RESULTS: The combination of FISH probes 1q21, 7p12, 8q24, and 9p21 identified cancer cells with 93% sensitivity and 100% specificity in pancreatobiliary tissue samples and were therefore included in the pancreatobiliary probe set. In the validation cohort of brush samples, pancreatobiliary FISH identified samples from patients with malignancy with a significantly higher level of sensitivity (64.7%) than the UroVysion probes (45.9%) (P < .001) or routine cytology analysis (18.8%) (P < .001), but similar specificity (92.9%, 90.8%, and 100.0% respectively). Factors significantly associated with detection of carcinoma, in adjusted analyses, included detection of polysomy by pancreatobiliary FISH (P < .001), a mass by cross-sectional imaging (P < .001), cancer cells by routine cytology (overall P = .003), as well as absence of primary sclerosing cholangitis (P = .011). CONCLUSIONS: We identified a set of FISH probes that detects cancer cells in pancreatobiliary brush samples from patients with and without primary sclerosing cholangitis with higher levels of sensitivity than UroVysion probes. Cytologic brushing test results and clinical features were independently associated with detection of cancer and might be used to identify patients with pancreatobiliary cancers.

Fluorescence in situ hybridization compared with conventional cytology for the diagnosis of malignant biliary tract strictures in Asian patients.

BACKGROUND AND AIMS: Fluorescence in situ hybridization (FISH) has improved the diagnostic performance of cytology for the evaluation of malignant biliary strictures in the United States and Europe. The utility of FISH for the diagnosis of biliary strictures in Asia is currently unknown. We aimed to compare the sensitivity of FISH and conventional cytology for the diagnosis of malignant biliary strictures in Thai patients. METHODS: A prospective study was performed at 2 university hospitals between 2010 and 2013. Patients being evaluated for malignant-appearing biliary strictures were included (N = 99). Bile duct brushings were collected and assessed by cytology and FISH. Sensitivities with 95% confidence intervals of cytology and FISH were the main outcome measures. RESULTS: The overall sensitivities of cytology and FISH were 38% and 55%, respectively (P = .001). For those with a diagnosis of cancer based on clinical evidence without biopsy confirmation (n = 44), the sensitivities of cytology and FISH were 43% and 57%, respectively (P = .06). For the 49 patients for whom a cancer diagnosis was confirmed by pathology, FISH had a significantly higher sensitivity than cytology, with a sensitivity of 53% versus 33%, respectively (P = .008). CONCLUSIONS: FISH improves the diagnostic performance of cytology and can be used as a complementary tool to bile duct brushing and biopsy for the evaluation of malignancy in biliary strictures in Asian populations.

Update on biomarkers of hepatocellular carcinoma.

New biomarkers of hepatocellular carcinoma (HCC) have been identified using advanced genomic, proteomic, and metabolomics technologies. These are being developed not only for use in diagnosis of HCC, but also in prediction of patient and treatment outcomes and individualization of therapy. Some HCC biomarkers are currently used in surveillance to detect early stage HCCs and reduce mortality. Further studies are needed to determine whether the recently identified HCC biomarkers can be used in clinical practice; most are only in phase 1 or 2 studies. The diagnostic and predictive abilities of biomarkers are limited by the heterogeneous nature of HCCs; there is no perfect single biomarker of this tumor. To improve performance, combinations of biomarkers (panels), or combinations of biomarkers and clinical parameters or laboratory test results, might be required. We describe recently discovered biomarkers of HCC and discuss challenges to their development and application.

Combinations of biomarkers and Milan criteria for predicting hepatocellular carcinoma recurrence after liver transplantation.

Growing evidence suggests that pretransplant alpha-fetoprotein (AFP) predicts outcomes of hepatocellular carcinoma (HCC) patients treated with liver transplantation. We aimed to determine whether pretransplant AFP, Lens culinaris agglutinin-reactive alpha-fetoprotein (AFP-L3), and des-gamma-carboxyprothrombin (DCP) predicted HCC recurrence after transplantation. A retrospective cohort study of 313 HCC patients undergoing transplantation between 2000 and 2008 was conducted, and 48 (15.3%) developed recurrence during a median follow-up of 90.8 months. The 127 patients with available serum drawn before transplantation were included; they included 86 without recurrence and 41 with recurrence. Serum was tested for AFP, AFP-L3%, and DCP in a blinded fashion with the µTASWako i30 immunoanalyzer. All biomarkers were significantly associated with HCC recurrence. The hazard ratios (HRs) were 3.5 [95% confidence interval (CI), 1.9-6.7; P < 0.0001] for DCP ≥ 7.5 ng/mL and 2.8 (95% CI, 1.4-5.4; P = 0.002) for AFP ≥ 250 ng/mL. The HR increased to 5.2 (95% CI, 2.3-12.0; P < 0.0001) when AFP ≥ 250 ng/mL and DCP ≥7.5 ng/mL were considered together. When they were combined with the Milan criteria, the HR increased from 2.6 (95% CI, 1.4-4.7; P = 0.003) for outside the Milan criteria to 8.6 (95% CI, 3.0-24.6; P < 0.0001) for outside the Milan criteria and AFP ≥ 250 ng/mL and to 7.2 (95% CI, 2.8-18.1; P < 0.0001) for outside the Milan criteria and DCP ≥7.5 ng/mL. Our findings suggest that biomarkers are useful for predicting the risk of HCC recurrence after transplantation. Using both biomarkers and the Milan criteria may be better than using the Milan criteria alone in optimizing the decision of liver transplantation eligibility.

Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes.

UNLABELLED: The risks and benefits of metformin use in patients with cirrhosis with diabetes are debated. Although data on a protective effect of metformin against liver cancer development have been reported, metformin is frequently discontinued once cirrhosis is diagnosed because of concerns about an increased risk of adverse effects of metformin in patients with liver impairment. This study investigated whether continuation of metformin after cirrhosis diagnosis improves survival of patients with diabetes. Diabetic patients diagnosed with cirrhosis between 2000 and 2010 who were on metformin at the time of cirrhosis diagnosis were identified (n = 250). Data were retrospectively abstracted from the medical record. Survival of patients who continued versus discontinued metformin after cirrhosis diagnosis was compared using the log-rank test. Hazard ratio (HR) and 95% confidence interval (CI) were calculated using Cox's proportional hazards analysis. Overall, 172 patients continued metformin whereas 78 discontinued metformin. Patients who continued metformin had a significantly longer median survival than those who discontinued metformin (11.8 vs. 5.6 years overall, P < 0.0001; 11.8 vs. 6.0 years for Child A patients, P = 0.006; and 7.7 vs. 3.5 years for Child B/C patients, P = 0.04, respectively). After adjusting for other variables, continuation of metformin remained an independent predictor of better survival, with an HR of 0.43 (95% CI: 0.24-0.78; P = 0.005). No patients developed metformin-associated lactic acidosis during follow-up. CONCLUSION: Continuation of metformin after cirrhosis diagnosis reduced the risk of death by 57%. Metformin should therefore be continued in diabetic patients with cirrhosis if there is no specific contraindication.