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Cynthia De la Garza-Ramos,1 S Ali Montazeri,1 Kaitlyn R Musto,1 Melissa D Kapp,1 Andrew R Lewis,1 Gregory Frey,1 Ricardo Paz-Fumagalli,1 Sumera Ilyas,2 Denise M Harnois,3 Umair Majeed,4 Tushar Patel,3 Beau Toskich1 1Division of Interventional Radiology, Mayo Clinic Florida, Jacksonville, FL, USA; 2Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN, USA; 3Department of Transplant, Mayo Clinic, Florida, FL, USA; 4Division of Hematology and Medical Oncology, Mayo Clinic Florida, Jacksonville, FL, USACorrespondence: Beau Toskich, Division of Interventional Radiology, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA, Tel +1 904-953-1496, Email Toskich.Beau@mayo.eduPurpose: To compare the outcomes of radiation segmentectomy for early-stage hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD) versus hepatitis C virus (HCV).Materials and Methods: A retrospective analysis of consecutive patients with NAFLD- or HCV-related HCC treated with radiation segmentectomy from 01/2017-06/2022 was performed. Eligibility criteria included solitary tumor ≤ 8 cm or up to 3 HCC ≤ 3 cm, ECOG 0– 1, and absence of vascular invasion or extrahepatic spread. Imaging best response was assessed per modified Response Evaluation Criteria in Solid Tumors. Target tumor and overall progression, time-to-progression (TTP), and overall survival (OS) were calculated. All outcomes were censored for liver transplantation (LT). Complete pathologic response (CPN) was assessed in patients who underwent LT.Results: Of 142 patients included (NAFLD: 61; HCV: 81), most had cirrhosis (NAFLD: 87%; HCV: 86%) and small tumors (median size NAFLD: 2.3 cm; HCV: 2.5 cm). Patients with NAFLD had higher BMI (p< 0.001) and worse ALBI scores (p=0.003). Patients with HCV were younger (p< 0.001) and had higher AFP levels (p=0.034). Median radiation dose (NAFLD: 508 Gy; HCV: 452 Gy) and specific activity (NAFLD: 700 Bq; HCV: 698 Bq) were similar between cohorts. Objective response was 100% and 97% in the NAFLD and HCV cohorts, respectively. Target tumor progression occurred in 1 (2%) NAFLD and 8 (10%) HCV patients. Target tumor TTP was not met for either cohort. Overall progression occurred in 23 (38%) NAFLD and 39 (48%) HCV patients. Overall TTP was 17.4 months (95% CI 13.5– 22.2) in NAFLD and 13.5 months (95% CI 0.4– 26.6) in HCV patients (p=0.86). LT was performed in 27 (44%) NAFLD and 33 (41%) HCV patients, with a CPN rate of 63% and 54%, respectively. OS was not met in the NAFLD cohort and was 53.9 months (95% CI 32.1– 75.7) in the HCV cohort (p=0.15).Conclusion: Although NAFLD and HCV are associated with different mechanisms of liver injury, patients with early-stage HCC treated with radiation segmentectomy achieve comparable outcomes.Keywords: hepatocellular carcinoma, radiation segmentectomy, NAFLD, viral hepatitis

OBJECTIVE: To assess the association be tweencytomegalovirus (CMV) serology of donor and recipient and adverse outcomes afterliver transplantation in the era of effective antiviral chemoprophylaxis. PATIENTS AND METHODS: We performed a retrospective cohort study of 193 consecutive patients undergoing their first liver transplantation between February 1998 and July 2000 with targeted and preemptive ganciclovir chemoprophylaxis. Patients were divided into 4 groups by CMV serology of donor and recipient: donor-/recipient-; donor-/recipient+; donor+/recipient+; and donor+/recipient-. Survival to the end points of retransplantation, death, or survival to 1 year after transplantation (whichever occurred first) was assessed. Rates of bacterial, fungal, and CMV Infection and of CMV disease were recorded and compared. RESULTS: No significant differences were observed in the rates of retransplantation, death, or survival to 1 year among the 4 groups of patients. Despite significantly higher rates of CMV infection in the donor+ groups, there were no differences in the rates of bacterial or fungal Infection or of CMV disease. Rejection occurred least frequently in the donor-/recipient- group. CONCLUSION: The adverse effects of CMV on outcomes after liver transplantation have been diminished in the era of effective antiviral chemoprophylaxis. [ABSTRACT FROM AUTHOR]

Purpose: Hepatic venous transplant anastomotic pressure gradient measurement and transjugular liver biopsy are commonly used in clinical decision-making in patients with suspected anastomotic hepatic venous outflow obstruction. This investigation aimed to determine if sinusoidal dilatation and congestion on histology are predictive of hepatic venous anastomotic outflow obstruction, and if it can help select patients for hepatic vein anastomosis stenting., Materials and Methods: This is a single-center retrospective study of 166 transjugular liver biopsies in 139 patients obtained concurrently with transplant venous anastomotic pressure gradient measurement. Demographic characteristics, laboratory parameters, procedure and clinical data, and histology of time-zero allograft biopsies were analyzed., Results: No relationship was found between transplant venous anastomotic pressure gradient and sinusoidal dilatation and congestion (P = 0.92). Logistic regression analysis for sinusoidal dilatation and congestion confirmed a significant relationship with reperfusion/preservation injury and/or necrosis of the allograft at time-zero biopsy (OR 6.6 [1.3-33.1], P = 0.02)., Conclusion: There is no relationship between histologic sinusoidal dilatation and congestion and liver transplant hepatic vein anastomotic gradient. In this study group, sinusoidal dilatation and congestion is a nonspecific histopathologic finding that is not a reliable criterion to select patients for venous anastomosis stenting., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

Backgrounds/objectives: The escalating incidence of early-onset gastrointestinal cancers is becoming a primary global health concern. Biliary tract cancer (BTC) has been relatively understudied in this regard. We conducted an epidemiological study regarding the burden of this condition., Methods: We utilized data from the Global Burden of Disease Study 2019 to investigate the temporal trends in early-onset BTC (EOBTC), encompassing the estimation of frequencies and age-standardized rates (ASRs) of EOBTC incidence, mortality, and disability-adjusted life-years (DALYs), from 2010 to 2019., Results: EOBTC constituted nearly 7%of all BTC cases worldwide. The incidence rates of EOBTC decreased significantly in most regions, except in the Eastern Mediterranean (annual percentage change +1.04 %), where the incidence is rising. Stratified by the sociodemographic index (SDI), countries with low middle SDI (annual percentage change +0.5 %) show increasing incidence of EOBTC. The ASR of death and DALYs decreased in most regions. The ASR of EOBTC-related death and disability attributable to high body mass index increased in most regions, with the highest increase in Southeast Asia and low, middle SDI strata., Conclusions: There was a reduction in the burden of EOBTC globally, except for Eastern Mediterranean countries and low-middle SDI countries., Competing Interests: Cheng Han Ng has served as a consultant for Boxer Capital. Daniel Q. Huang has served as an advisory board member for Eisai and receives funding support from the Singapore Ministry of Health’s National Medical Research Council under its NMRC Research Training Fellowship (MOH-000595-01). Mazen Noureddin has been on the advisory board for 89BIO, Gilead, Intercept, Pfizer, Novo Nordisk, Blade, EchoSens, Fractyl, Terns, Siemens, and Roche diagnostic; has received research support from Allergan, BMS, Gilead, Galmed, Galectin, Genfit, Conatus, Enanta, Madrigal, Novartis, Pfizer, Shire, Viking and Zydus; and is a minor shareholder or has stocks in Anaetos, Rivus Pharma and Viking., (© 2023 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Autoimmune hepatitis is an immune-mediated inflammatory condition of the liver of undetermined cause that affects both sexes, all ages, races, and ethnicities. Its clinical presentation can be very broad, from having an asymptomatic and silent course to presenting as acute hepatitis, cirrhosis, and acute liver failure potentially requiring liver transplantation. The diagnosis is based on histological abnormalities (interface hepatitis), characteristic clinical and laboratory findings (increased aspartate aminotransferase, alanine aminotransferase, and serum IgG concentration), and the presence of one or more characteristic autoantibodies. The large heterogeneity of these clinical, biochemical, and histological findings can sometimes make a timely and proper diagnosis a difficult task. Treatment seeks to achieve remission of the disease and prevent further progression of liver disease. First-line therapy includes high-dose corticosteroids, which are later tapered to decrease side effects, and azathioprine. In the presence of azathioprine intolerance or a poor response to the standard of care, second-line therapy needs to be considered, including mycophenolate mofetil. AIH remains a diagnostic and therapeutic challenge, and a further understanding of the pathophysiological pathways of the disease and the implementation of randomized controlled trials are needed.

Background: Immune-mediated adverse effects of current systemic immunosuppression therapy compromise long-term survival of liver transplant recipients. Our recently observed results showed that intranodal delivery of sirolimus induced interleukin (IL)-10-driven CD4+ CD25+ Foxp3+ regulatory T cells. The present report investigated the feasibility of intra-nodal delivery of sirolimus ex vivo into a human liver common bile duct lymph node., Methods: We used a discarded donor human liver to directly administer sirolimus into a distal common bile duct lymph node. Sirolimus was injected once using an ultrasound-guided method., Results: The porta hepatis and its lymph node along the distal common bile duct were exposed. A handheld ultrasound probe (L15-7io, Koninklijke Philips N.V.) with a layer of standoff Aquasonic 100 Ultrasound Transmission Gel (Parker Laboratories, Inc) was applied to the exposed lymph node. Using a 1.0-mL 25G hypodermic needle, 0.05 mL of sirolimus solution was injected directly into the exposed lymph node., Conclusions: Under sonographic guidance, direct injection of sirolimus into a hepatic draining lymph node along the common bile duct is accomplished precisely and reliably. Direct administration of therapeutic agents into local lymph nodes is a viable approach for effective targeted immunotherapy., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare. Mayo Clinic does not endorse specific products or services included in this article., (Copyright © 2023. Published by Elsevier B.V.)

With donation after circulatory death (DCD) liver transplantation (LT), the goal of the recipient implantation procedure is to minimize surgical complexity to avoid a tenuous environment for an already marginal graft. The presence of portal vein thrombosis (PVT) at the time of LT adds surgical complexity, yet' to date, no studies have investigated the utilization of DCD liver grafts for patients with PVT., Methods: All DCD LT performed at Mayo Clinic-Florida, Mayo Clinic-Arizona, and Mayo Clinic-Rochester from 2006 to 2020 were reviewed (N = 771). Patients with PVT at the time of transplant were graded using Yerdel classification. A 1:3 propensity match between patients with PVT and those without PVT was performed., Results: A total of 91 (11.8%) patients with PVT undergoing DCD LT were identified. Grade I PVT was present in 62.6% of patients, grade II PVT in 27.5%, grade III in 8.8%, and grade 4 in 1.1%. At the time of LT, thromboendovenectomy was performed in 89 cases (97.8%). There was no difference in the rates of early allograft dysfunction (43.2% versus 52.4%; P = 0.13) or primary nonfunction (1.1% versus 1.1%; P = 0.41) between the DCD PVT and DCD without PVT groups, respectively. The rate of ischemic cholangiopathy was not significantly different between the DCD PVT (11.0%) and DCD without PVT groups (10.6%; P = 0.92). Graft ( P = 0.58) and patient survival ( P = 0.08) were similar between the 2 groups. Graft survival at 1-, 3-, and 5-y was 89.9%, 84.5%, and 79.3% in the DCD PVT group., Conclusions: In appropriately selected recipients with grades I-II PVT, DCD liver grafts can be utilized safely with excellent outcomes., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2022 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Introduction and Objectives: Renal dysfunction before liver transplantation (LT) is associated with higher post-LT mortality. We aimed to study if this association still persisted in the contemporary transplant era., Materials and Methods: We retrospectively reviewed data on 2871 primary LT performed at our center from 1998 to 2018. All patients were listed for LT alone and were not considered to be simultaneous liver-kidney (SLK) transplant candidates. SLK recipients and those with previous LT were excluded. Patients were grouped into 4 eras: era-1 (1998-2002, n = 488), era-2 (2003-2007, n = 889), era-3 (2008-2012, n = 703) and era-4 (2013-2018, n = 791). Pre-LT renal dysfunction was defined as creatinine (Cr) >1.5 mg/dl or on dialysis at LT. The effect of pre-LT renal dysfunction on post-LT patient survival in each era was examined using Kaplan Meier estimates and univariate and multivariate Cox proportional hazard analyses., Results: Pre-LT renal dysfunction was present in 594 (20%) recipients. Compared to patients in era-1, patients in era-4 had higher Cr, lower eGFR and were more likely to be on dialysis at LT (P < 0.001). Pre-LT renal dysfunction was associated with worse 1, 3 and 5-year survival in era-1 and era-2 (P < 0.005) but not in era-3 or era-4 (P = 0.13 and P = 0.08, respectively). Multivariate analysis demonstrated the lack of independent effect of pre-LT renal dysfunction on post-LT mortality in era-3 and era-4. A separate analysis using eGFR <60 mL/min/1.73 m 2 at LT to define renal dysfunction showed similar results., Conclusions: Pre-LT renal dysfunction had less impact on post-LT survival in the contemporary transplant era., (Copyright © 2021 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Purpose: Transarterial radioembolization can serve as an ablative therapy for early-stage hepatocellular carcinoma (HCC). Given the volumetric variability of liver segments, this study aimed to characterize the safety of ablative radioembolization by determining percent liver treated (%LT) thresholds associated with biochemical toxicity., Patients and Methods: Patients with HCC receiving a single ablative radioembolization treatment using glass microspheres from 2017 through 2020 were reviewed. %LT was calculated as treatment angiosome volume divided by whole liver volume. Biochemical toxicities were defined as increases in Albumin-Bilirubin (ALBI) grade or Child-Pugh (CP) class compared to baseline and albumin or bilirubin adverse events (AEs) per the Common Terminology Criteria for Adverse Events. Receiver operating characteristic curves and multivariate logistic regression analyses were performed to assess the impact of %LT on toxicities., Results: Of 141 patients analyzed, 53% (n=75) were ALBI 1, 45% (n=64) ALBI 2, 79% (n=111) CP-A, and 21% (n=30) CP-B. A %LT ≥14.5% was associated with grade/class increases in ALBI 2 ( p ≤0.01) and CP-B patients ( p =0.026). In multivariate analysis, a %LT ≥14.5% was an independent predictor of increases in the ALBI 2 and CP-B groups ( p <0.01). No significant %LT threshold was found for ALBI 1 and CP-A patients. No grade 3/4 albumin or bilirubin AEs were reported, while grade 2 AEs were related to an initial whole liver volume <1.3 L ( p ≤0.01)., Conclusion: Patients with ALBI 2 and CP-B liver function are less likely to have an increase in their respective grade/class when treating <14.5% of the liver using glass microspheres. ALBI 1 and CP-A patients showed no definitive %LT threshold for biochemical toxicity within the range of this study., Competing Interests: BB Toskich is an advisor for Boston Scientific, Sirtex Medical, Johnson and Johnson, AstraZeneca, Genentech, Eisai, HistoSonics and Turnstone Biologics. The authors reported no other potential conflicts of interest for this work., (© 2021 De la Garza-Ramos et al.)

Background: Recent studies have suggested an association between modest alcohol consumption and a decreased risk of advanced liver fibrosis among patients with nonalcoholic fatty liver disease (NAFLD) although the results are inconsistent. The current systematic review and meta-analysis was conducted to comprehensively investigate this possible association by identifying all the relevant studies and combining their results., Methods: A comprehensive literature review was conducted utilizing the MEDLINE and EMBASE databases through February 2019 to identify all cross-sectional studies that compared the prevalence of advanced liver fibrosis among NAFLD patients who were modest alcohol drinkers to NAFLD patients who were non-drinkers. Effect estimates from each study were extracted and combined together using the random-effect, generic inverse variance method of DerSimonian and Laird., Results: A total of 6 studies with 8,936 participants fulfilled the eligibility criteria and were included in the meta-analysis. The risk of advanced liver fibrosis among patients with NAFLD who were modest alcohol drinkers was significantly lower compared to patients with NAFLD who were non-drinkers with a pooled odds ratio of 0.51 (95% confidence interval [CI] 0.35-0.75; I 2 47%). The funnel plot was symmetric and was not suggestive of publication bias., Conclusion: A significantly lower risk of advanced liver fibrosis was observed among NAFLD patients who were modest alcohol drinkers compared to non-drinkers in this meta-analysis., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

Background/aims: The number of cases with coronavirus disease 2019 (COVID-19) has exceeded seven million worldwide. However, the data describing the global prevalence of liver injury associated with COVID-19 is lacking secondary to the novelty of this ongoing pandemic. Therefore, we conducted a meta-analysis to determine the association between COVID-19 and liver injury., Methods: A systematic literature search of indexed databases including, PubMed, Medline, and Embase databases from inception to 14 April 2020, was used to identify studies that reported data of liver chemistry in patients diagnosed with COVID 19. The overall prevalence of abnormal liver chemistry and relevant 95% confidence interval was used to estimate the pooled results studies., Results: Sixty-four studies with 11 245 patients with COVID-19 were included. The pattern of abnormal liver enzymes was notable for higher aspartate aminotransferase (AST) than alanine aminotransferase (ALT) levels. The overall global prevalence of elevated AST, ALT, total bilirubin, gamma-glutamyltransferase (GGT), and alkaline phosphatase was 23.2, 21.2, 9.7, 15.0, and 4.0%, respectively. The prevalence of elevated AST was substantially higher among those with severe cases (45.5%) compared to non-severe cases (15.0%). Co-existing chronic liver disease presented up to 37.6% of patients with COVID-19., Conclusion: A fourth of COVID-19 patients had elevated liver enzymes and associated with disease severity. Our study may be used as a guide for clinicians and epidemiologists to proactively identify other sources of injury and illness in patients diagnosed with COVID-19. Intensive monitoring for liver injury may be needed in cases with severe COVID-19., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background/objectives: Liver transplant recipients have an increased risk of Clostridioides difficile infection (CDI) which associated with higher morbidity and mortality. CDI in liver transplant has been argued to increase hospital costs, charges, and length of stay (LOS) in small studies. However, no recent nationwide analysis determines these outcomes., Methods: This is a retrospective cohort study using the National Inpatient Sample 2016. All patients with ICD10CM diagnostic codes for CDI were included. The cohort was stratified for the history of liver transplant and liver transplant index admission. The primary outcome was the odds of CDI in both patient cohorts to patients without liver transplant. Secondary outcomes were inpatient morbidity, mortality, resource utilization, colectomy rates, LOS, and total hospital costs and charges., Results: A total of 360 364 patients with CDI were identified, 1665 had a history of liver transplant and 155 had liver transplant during that admission. Patients with a history of liver transplant had increased odds of CDI compared to patients with no history of liver transplant (adjusted odds ratio 2.78; 95% confidence interval, 2.44-3.16). Patients with CDI had greater odds of shock, acute kidney injury, ICU stay, organ failure and significantly higher costs, charges and LOS., Conclusions: Patients with a history of liver transplant increased odds of CDI. CDI with history of liver transplant and the index admission for liver transplant had higher odds of morbidity and resource utilization. Clinicians must maintain a high index of suspicion for CDI for early diagnosis and appropriate initiation of treatment., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Objectives: Studies have suggested that smoking may accelerate the progression of fibrosis among patients with primary biliary cholangitis (PBC), although the data are limited. The current review was undertaken with the aim to comprehensively analyze this possible association by identifying all relevant studies and summarizing their results., Methods: A comprehensive literature review on MEDLINE and EMBASE databases was performed from inception through February 2019 to identify all relevant studies. Eligible studies included cross-sectional studies that recruited patients with PBC and collected data on the smoking status and presence or absence of advanced liver fibrosis for each participant. Odds ratios (OR) with 95 per cent confidence intervals (CI) was desirable for inclusion or sufficient raw data to calculate the same for this association. Adjusted point estimates from each study were extracted and combined together using the generic inverse variance method of DerSimonian and Laird. I 2 statistic, which quantifies the proportion of total variation across studies was used to determine the between-study heterogeneity., Results: Three cross-sectional studies with 544 participants were included. The pooled analysis found a significantly increased risk of advanced liver fibrosis among patients with PBC who were ever-smokers compared to those who were nonsmokers with the pooled OR of 3.00 (95% CI, 1.18-7.65). Statistical heterogeneity was high with I 2 of 89 per cent., Interpretation & Conclusions: This meta-analysis found that smoking is associated with a significantly higher risk of advanced liver fibrosis among patients with PBC. Further prospective studies are still required to determine whether this association is causal.

Background and Aims: Early detection of perihilar cholangiocarcinoma (CCA) among patients with primary sclerosing cholangitis (PSC) is important to identify more people eligible for curative therapy. While many recommend CCA screening, there are divergent opinions and limited data regarding the use of ultrasound or magnetic resonance imaging (MRI) for early CCA detection, and it is unknown whether there is benefit in testing asymptomatic individuals. Our aims were to assess the diagnostic performances and prognostic implications of ultrasound and MRI-based CCA detection., Approach and Results: This is a multicenter review of 266 adults with PSC (CCA, n = 120) who underwent both an ultrasound and MRI within 3 months. Images were re-examined by radiologists who were blinded to the clinical information. Respectively, MRI had a higher area under the curve compared with ultrasound for CCA detection: 0.87 versus 0.70 for the entire cohort; 0.81 versus 0.59 for asymptomatic individuals; and 0.88 versus 0.71 for those listed for CCA transplant protocol. The absence of symptoms at CCA diagnosis was associated with improved 5-year outcomes including overall survival (82% vs. 46%, log-rank P < 0.01) and recurrence-free survival following liver transplant (89% vs. 65%, log-rank P = 0.04). Among those with asymptomatic CCA, MRI detection (compared with ultrasound) was associated with reduction in both mortality (hazard ratio, 0.10; 95% confidence interval, 0.01-0.96) and CCA progression after transplant listing (hazard ratio, 0.10; 95% confidence interval, 0.01-0.90). These benefits continued among patients who had annual monitoring and PSC for more than 1 year before CCA was diagnosed., Conclusions: MRI is superior to ultrasound for the detection of early-stage CCA in patients with PSC. Identification of CCA before the onset of symptoms with MRI is associated with improved outcomes., (© 2020 by the American Association for the Study of Liver Diseases.)

The palatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 G allele is associated with nonalcoholic fatty liver disease (NAFLD), hepatocellular carcinoma, 1 and all-cause or cardiovascular mortality in the general population. 2 One recent Italian study reported an association between PNPLA3 polymorphism and liver-related events and mortality in biopsy-confirmed NAFLD. 3 Regarding extrahepatic cancer-related mortality, one study showed that only women carrying the G allele without hepatic steatosis had a 60% lower risk for cancer-related mortality. 4 However, owing to insufficient follow-up and selected populations, the results from these studies cannot generalize about the association between PNPLA3 polymorphism and liver- and extrahepatic cancer-related mortality at a population level. Thus, we investigated the association between PNPLA3 polymorphism and liver- and extrahepatic cancer-related mortality based on the presence of NAFLD in the U.S. general population., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Goals: We aimed to describe the diagnostic and prognostic performance of transient elastography (TE) and magnetic resonance elastography (MRE) in patients with primary biliary cholangitis (PBC)., Background: The diagnostic performance of TE and MRE in detecting advanced fibrosis in PBC and in predicting outcomes independent of existing serologic prognostic markers is incompletely understood., Materials and Methods: Five hundred thirty-eight consecutive patients with PBC at 3 centers with liver stiffness (LS) measurements by TE (n=286) or MRE (n=332) were reviewed. LS cutoffs for predicting fibrosis stages were determined by receiver operating characteristic curves among those with a liver biopsy (TE, n=63; MRE, n=98). Cox proportional hazard regression modeling was used to identify associations between covariates and hepatic decompensation., Results: The optimal LS thresholds for predicting histologic stage F4 were 14.40 kPa (area under the curve=0.94) for TE and 4.60 kPa (area under the curve=0.82) for MRE. Both TE and MRE outperformed biochemical markers for the prediction of histologic advanced fibrosis. Optimal LS thresholds to predict hepatic decompensation were 10.20 kPa on TE and 4.30 kPa on MRE. LS by TE and MRE (respectively) remained predictors of hepatic decompensation after adjusting for ursodeoxycholic acid responsiveness [hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.05-1.24 and HR, 1.68; 95% CI, 1.28-2.19] and the GLOBE score (HR, 1.13; 95% CI, 1.07-1.19 and HR, 2.09; 95% CI, 1.57-2.78)., Conclusion: LS measurement with either TE or MRE can accurately detect advanced fibrosis and offers additional prognostic value beyond existing serologic predictive tools., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background/objectives: Arthritis is a known manifestation of hereditary hemochromatosis. However, whether patients with hereditary hemochromatosis have an increased risk of having joint replacement surgery compared to the general population is still unknown. This meta-analysis was conducted to better characterize this risk., Methods: A comprehensive literature review was conducted utilizing the MEDLINE and EMBASE databases through September 2019 to identify all cohort studies that compared prevalence or incidence of joint replacement surgery (hip, ankle, or knee) between patients with hereditary hemochromatosis and individuals without hereditary hemochromatosis. Effect estimates from each study were extracted and combined together using the random-effect, generic inverse variance method of DerSimonian and Laird., Results: A total of five studies with 1 293 407 participants fulfilled the eligibility criteria and were included in the meta-analysis. Overall, the risk of having joint replacement surgery was significantly increased in patients with hereditary hemochromatosis compared to individuals without hereditary hemochromatosis with the pooled relative risk (RR) of 3.32 [95% confidence interval (CI), 1.60-6.86; I 88%]. Analysis by joint found a significantly increased risk of having hip and ankle replacement surgery among patients with hereditary hemochromatosis compared with the pooled RR of 2.62 (95% CI, 2.09-3.30; I 47%) and 8.94 (95% CI, 3.85-20.78; I 14%), respectively. The risk of having knee replacement surgery was also increased but was not statistically significant (pooled RR 1.57, 95% CI, 0.83-2.98; I 66%)., Conclusions: A significantly increased risk of needed joint replacement surgery among patients with hereditary hemochromatosis compared to patients without hereditary hemochromatosis was demonstrated in this study. Further studies are required to determine whether this association is causal.

Background and Aims: The use of statins has been shown to be associated with a decreased risk of cholangiocarcinoma (CCA) in many studies although the results have been inconsistent. We conducted this systematic review and meta-analysis to further investigate this possible association by identifying all relevant studies and combining their results together., Methods: A comprehensive literature review was conducted utilizing the MEDLINE and EMBASE databases through March 2020 to identify all studies that compared the risk of CCA among individuals who use statins with individuals who do not use statins. Effect estimates from each study were extracted and combined using the random-effect, generic inverse variance method of DerSimonian and Laird., Results: A total of seven studies with 6,251,187 participants fulfilled the eligibility criteria and were included in this meta-analysis. The pooled analysis found a significantly decreased risk of CCA among individuals who use statins compared with individuals who do not use statins with the pooled odds ratio of 0.68 (95% CI: 0.52-0.89; I 2 96%)., Conclusions: The current systematic review and meta-analysis found a significant association between the use of statins and a decreased risk of CCA.

Background: Currently, no surveillance guidelines for hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) exist. In this retrospective, multicenter study, we have investigated the role of surveillance imaging on postrecurrence outcomes., Methods: Patients with recurrent HCC after LT from 2002 to 2016 were reviewed from 3 transplant centers (University of California San Francisco, Mayo Clinic Florida, and University of Toronto). For this study, we proposed the term cumulative exposure to surveillance (CETS) as a way to define the cumulative sum of all the protected intervals that each surveillance test provides. In our analysis, CETS has been treated as a continuous variable in months., Results: Two hundred twenty-three patients from 3 centers had recurrent HCC post-LT. The median follow-up was 31.3 months, and median time to recurrence was 13.3 months. Increasing CETS was associated with improved postrecurrence survival (hazard ratio, 0.94; P < 0.01) as was treatment of recurrence with resection or ablation (hazard ratio, 0.31; P < 0.001). An receiver operating characteristic curve (area under the curve, 0.64) for CETS covariate showed that 252 days of coverage (or 3 surveillance scans) within the first 24 months provided the highest probability for aggressive postrecurrence treatment., Conclusions: In this review of 223 patients with post-LT HCC recurrence, we found that increasing CETS does lead to improved postrecurrence survival as well as a higher probability for aggressive recurrence treatment. We found that 252 days of monitoring (ie, 3 surveillance scans) in the first 24 months was associated with the ability to offer potentially curative treatment.

Background and Aim: The association between palatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) polymorphism and mortality is not well understood. We investigated the impact of PNPLA3 I148M (rs738409) polymorphism on overall and cardiovascular mortality based on the presence of nonalcoholic fatty liver disease (NAFLD)., Methods: The third National Health and Nutrition Examination Survey (NHANES) from 1991 to 1994 and National Health and Nutrition Examination Survey III-linked mortality data through 31 December 2015 were utilized in this study., Results: Of 4814 participants, 50.7% were homozygous for the C-allele and 12.6% were homozygous for the G-allele. During a follow up of 20 years, there were a total of 1255 deaths, 422 attributed to cardiovascular disease. There was a significant association with overall mortality among those with the PNPLA3 I148M (rs738409) GG genotype (hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.02-1.77) or G-allele (HR 1.22, 95% CI 1.09-1.36) in the general population. NAFLD with homozygous PNPLA3 I148M (rs738409) GG genotype had higher overall mortality after adjusting for multiple metabolic risk factors (HR 1.45, 95% CI 1.01-2.08). The PNPLA3 I148M (rs738409) G-allele had a tendency of increased cardiovascular mortality in the total population. This association was not noted in those with NAFLD., Conclusions: The homozygous PNPLA3 I148M (rs738409) GG genotype showed an increase in overall mortality in the general population and NAFLD independent of multiple metabolic risk factors., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aims: Recent studies have suggested an association between periodontitis and nonalcoholic fatty liver disease (NAFLD) although the results were inconsistent. The current systematic review and meta- analysis was conducted with the aim to comprehensively investigate this possible association by identifying all relevant studies and combining their results together., Methods: A comprehensive literature review was conducted utilizing the MEDLINE and EMBASE databases through December 2019 to identify all studies that compared the risk of NAFLD among patients with periodontitis to individuals without periodontitis. Effect estimates from each study were extracted and combined using the random-effect, generic inverse variance method of DerSimonian and Laird., Results: A total of five studies with 27,703 participants fulfilled the eligibility criteria and were included in the meta-analysis. All five studies reported the magnitude of association between NAFLD and periodontitis that was diagnosed based on the periodontal pocket depth of > 3.5-4 mm. The pooled OR of unadjusted analysis was 1.48 (95%CI: 1.15-1.89; I 2 92%). However, when adjusted results from the primary studies were used, pooled OR decreased to 1.13 and lost its statistical significance (95%CI: 0.95-1.35; I 2 67%). Three studies reported the magnitude of association between NAFLD and periodontitis that was diagnosed based on a clinical attachment level of ≥ 3 mm. The pooled OR of unadjusted analysis was 1.13 (95%CI: 1.07-1.20; I 2 0%). However, when adjusted results from the primary studied were used, pooled OR decreased to 1.08 and lost its statistical significance (95%CI: 0.94-1.24; I 2 58%)., Conclusions: The study found a significant association between periodontitis and NAFLD. However, the association lost its significance when various metabolic parameters were adjusted, suggesting that those metabolic conditions, not periodontitis itself, were predisposing factors for NAFLD.

Aim of the Study: Combined magnetic resonance imaging and magnetic resonance cholangiopancreatography (MRI/MRCP) can identify biliary strictures and diagnose primary sclerosing cholangitis (PSC). Diagnosis of cholangiocarcinoma in patients with PSC remains challenging, and the accuracy of MRI/MRCP has not been completely established. We aimed to determine the sensitivity and specificity of MRI/MRCP in the diagnosis of cholangiocarcinoma among patients with PSC from the published literature., Material and Methods: We searched Embase, PubMed, Cochrane, Scopus, ClinicalTrials.gov, and abstracts from relevant scientific meetings and performed a systematic review and meta-analysis to estimate the diagnostic yield of MRI/MRCP in patients with PSC. Sensitivity and specificity were calculated from pooled estimates of cholangiocarcinoma cases identified and lesions missed. Modifying variables were included in a meta-regression model., Results: Our literature search yielded 302 articles and 9 conference abstracts; 8 studies involving 846 liver patients from 5 countries were included in the final analysis. Of those, 531 had PSC and received MRI/MRCP. Thirty-six (6.8%) patients were diagnosed with cholangiocarcinoma (33 true positive, 3 false negative and 1 false positive). Pooled sensitivity was 98.9% (95% CI: 98.6-99.3%). Cholangiocarcinoma cases missed by MRI/MRCP were diagnosed as beading irregularities of the central hepatic ducts, or PSC-related diffuse stricture. Metaregression revealed that neither publication year, study design, nor sample size had a significant effect on observed cancer rates ( p = 0.9, 0.3, and 0.3, respectively)., Conclusions: MRI/MRCP followed by endoscopic retrograde cholangiopancreatography (ERCP) is a sensitive and specific tool to diagnose cholangiocarcinoma among patients with PSC. Further research should estimate MRI/MRCP diagnostic accuracy for cholangiocarcinoma using prospective methodology and longer term outcomes., Competing Interests: The authors report no conflict of interest., (Copyright: © 2020 Clinical and Experimental Hepatology.)

Objective: Cholangiocarcinoma (CCA) affects all ethnicities worldwide. The Hispanic population being the leading ethnic minority in the United States, its importance to the healthcare system cannot be understated. This study aims to assess the occurrence and outcomes of CCA in Hispanic patients in the United States., Methods: This is a case-control study using the National Inpatient Sample 2014. All patients with ICD-9 CM codes for CCA were included. Hispanic patients were identified from the ethnic categories within the database. The primary outcomes were the occurrence and odds of CCA in the Hispanic population when compared with other ethnicities. Secondary outcomes were inpatient mortality, morbidity, ICU stay, multiorgan failure, and resource utilization., Results: A total of 13 965 patients with CCA were identified, of which 2750 were propensity-matched to controls (1480 Hispanic). The inpatient occurrence of CCA in Hispanics relative to the national population was 2.73/100 000 persons, compared to 4.82/100 000 persons (39.9/100 000 relative to inpatient population) of all other ethnicities. After adjusting for confounders on multivariate analysis, Hispanic patients displayed adjusted propensity-matched odds of 1.28 (P < 0.01) of having CCA when compared with other ethnicities. Hispanics did not display different propensity-matched odds of inpatient mortality, morbidity, hospital length of stay, or resource utilization compared to non-Hispanic patients., Conclusion: This study demonstrated that the odds of CCA in admitted patients are higher for the Hispanic population. This difference with the prevalence potentially suggests the presence of social factors such as disparities in cancer prevention or detection in this group.

The need for liver transplantation (LT) among older patients is increasing, but the role of LT in the elderly (≥70 years) is not well defined. We retrospectively reviewed all primary LTs from 1998 through 2016 at our center. Survival and associated risk factors were analyzed with Cox regression and Kaplan-Meier methods for LT recipients in 3 age groups: <60, 60-69, and ≥70 years. Among 2281 LT recipients, the median age was 56 years (range, 15-80 years), and 162 were aged ≥70 years. The estimated 5- and 10-year patient survival probabilities for elderly LT recipients were lower (70.8% and 43.6%) than for recipients aged 60-69 years (77.2% and 64.6%) and <60 years (80.7% and 67.6%). Patient and graft survival rates associated with LT improved over time from the pre-Model for End-Stage Liver Disease era to Share 15, pre-Share 35, and Share 35 for the cohort overall (P < 0.001), but rates remained relatively stable in septuagenarians throughout the study periods (all P > 0.45). There was no incremental negative effect of age at LT among elderly patients aged 70-75 years (log-rank P = 0.32). Among elderly LT recipients, greater requirement for packed red blood cells and longer warm ischemia times were significantly associated with decreased survival (P < 0.05). Survival of LT recipients, regardless of age, markedly surpassed that of patients who were denied LT, but it was persistently 20%-30% lower than the expected survival of the general US population (P < 0.001). With the aging of the population, select older patients with end-stage liver diseases can benefit from LT, which largely restores their expected life spans., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Background: Sex differences in the incidences of cancers become a critical issue in both cancer research and the development of precision medicine. However, details in these differences have not been well reported. We provide a comprehensive analysis of sexual dimorphism in human cancers., Methods: We analyzed four sets of cancer incidence data from the SEER (USA, 1975-2015), from the Cancer Registry at Mayo Clinic (1970-2015), from Sweden (1970-2015), and from the World Cancer Report in 2012., Results: We found that all human cancers had statistically significant sexual dimorphism with male dominance in the United States and mostly significant in the Mayo Clinic, Sweden, and the world data, except for thyroid cancer, which is female-dominant., Conclusions: Sexual dimorphism is a clear but mostly neglected phenotype for most human cancers regarding the clinical practice of cancer. We expect that our study will facilitate the mechanistic studies of sexual dimorphism in human cancers. We believe that fully addressing the mechanisms of sexual dimorphism in human cancers will greatly benefit current development of individualized precision medicine beginning from the sex-specific diagnosis, prognosis, and treatment.

Background: The GALAD score is a serum biomarker-based model that predicts the probability of having hepatocellular carcinoma (HCC) in patients with chronic liver disease. We aimed to assess the performance of the GALAD score in comparison with liver ultrasound for detection of HCC., Methods: A single-center cohort of 111 HCC patients and 180 controls with cirrhosis or chronic hepatitis B and a multicenter cohort of 233 early HCC and 412 cirrhosis patients from the Early Detection Research Network (EDRN) phase II HCC Study were analyzed., Results: The area under the ROC curve (AUC) of the GALAD score for HCC detection was 0.95 [95% confidence interval (CI), 0.93-97], which was higher than the AUC of ultrasound (0.82, P <0.01). At a cutoff of -0.76, the GALAD score had a sensitivity of 91% and a specificity of 85% for HCC detection. The AUC of the GALAD score for early-stage HCC detection remained high at 0.92 (95% CI, 0.88-0.96; cutoff -1.18, sensitivity 92%, specificity 79%). The AUC of the GALAD score for HCC detection was 0.88 (95% CI, 0.85-0.91) in the EDRN cohort. The combination of GALAD and ultrasound (GALADUS score) further improved the performance of the GALAD score in the single-center cohort, achieving an AUC of 0.98 (95% CI, 0.96-0.99; cutoff -0.18, sensitivity 95%, specificity 91%)., Conclusions: The performance of the GALAD score was superior to ultrasound for HCC detection. The GALADUS score further enhanced the performance of the GALAD score., Impact: The GALAD score was validated in the United States., (©2018 American Association for Cancer Research.)

With recent changes in United Network for Organ Sharing policy, patients in the United States with hepatocellular carcinoma (HCC) are likely to spend more time on the liver transplantation (LT) waiting list. The increasing wait time will allow for an opportunity to assess tumor biology prior to LT. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) paradigm provides such a framework for this assessment, and yet little is understood of its utility as it would apply for patients listed for LT in the United States. Through a collaboration between the University of California, San Francisco, and the Mayo Clinic, Jacksonville, Florida, the experience of 772 patients listed for LT were retrospectively reviewed to study the impact of immediate mRECIST classification following locoregional therapy (LRT) on pre- and post-LT outcomes. Patients who had progression of disease (PD; n = 72), failed to respond to LRT (n = 89) at any time point, or did not achieve radiologic complete response (CR; n = 224) were all at significant risk for wait-list dropout (odds ratio [OR] = 12.11, 4.81, and 2.48; respectively). CR identified a cohort of patients who were at a reduced risk for wait-list dropout. However, 24.9% eventually required further intervention while waiting for transplant, and as many as 82.4% were found to have residual HCC on explant pathology. Failure to respond to LRT was associated with increased risk for recurrence (OR = 3.00) more so than PD (OR = 1.36), suggesting that despite PD, patients who eventually can respond to LRT may represent favorable candidates for LT. In conclusion, for patients awaiting LT, the mRECIST assessment provides critical guidance for patient management. Although PD portends a poor prognosis, our findings suggest that further aggressive LRT should be pursued because a response to LRT may yield acceptable results for patients awaiting LT as well as after LT., (Copyright © 2018 by the American Association for the Study of Liver Diseases.)

Gender differences in the incidences of cancers have been found in almost all human cancers. However, the mechanisms that underlie gender disparities in most human cancer types have been under-investigated. Here, we provide a comprehensive overview of potential mechanisms underlying sexual dimorphism of each cancer regarding sex hormone signaling. Fully addressing the mechanisms of sexual dimorphism in human cancers will greatly benefit current development of precision medicine. Our discussions of potential mechanisms underlying sexual dimorphism in each cancer will be instructive for future cancer research on gender disparities., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Volumetric laser endomicroscopy (VLE) provides circumferential images 3 mm into the biliary and pancreatic ducts. We aimed to correlate VLE images with the normal and abnormal microstructure of these ducts., Methods: Samples from patients undergoing hepatic or pancreatic resection were evaluated. VLE images were collected using a low-profile VLE catheter inserted manually into the biliary and pancreatic ducts ex vivo. Histological correlation was assessed by two unblinded investigators., Results: 25 patients (20 liver and 5 pancreatic samples) and 111 images were analyzed. VLE revealed three histological layers: epithelium, connective tissue, and parenchyma. It identified distinctive patterns for primary sclerosing cholangitis (PSC), pancreatic cysts, neuroendocrine tumor, and adenocarcinoma adjacent to the pancreatic duct or ampulla. VLE failed to identify dysplasia in a dominant stricture and inflammatory infiltrates in PSC. Reflectivity measurements of the liver parenchyma diagnosed liver cirrhosis with high sensitivity., Conclusions: VLE can identify histological changes in the biliary and pancreatic ducts allowing real-time diagnosis. Further studies are needed to measure the accuracy of VLE in a larger sample and to validate our findings in vivo., Competing Interests: Drs. H. C. Wolfsen and M. B. Wallace receive research support funding from NinePoint Medical, Inc. Dr. M. B. Wallace serves on the medical advisory board to NinePoint but receives no personal compensation. Compensation is paid to the Mayo Clinic Foundation. The other authors declare no conflict of interests., (© Georg Thieme Verlag KG Stuttgart · New York.)

Although hepatocellular carcinoma (HCC) has become a common indication for liver transplantation (LT), intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) are historically contraindicated due to their aggressive behavior. On the basis of recent experiences, some groups have proposed a clinical trial investigating the role of LT for patients with early cholangiocarcinoma (CCA), defined as a single lesion ≤ 2 cm. The purpose of this study is to assess the clinicopathologic features and outcomes following LT for patients who were initially diagnosed with HCC and subsequently found to have either ICC or cHCC-CCA on explant. Patients with the diagnosis of primary liver cancer (PLC) after LT from a single center were retrospectively reviewed. Outcomes for patients with early CCA were compared with patients with HCC within Milan criteria (MC). Out of 618 patients transplanted with PLC, 44 patients were found to have CCA on explant. On the basis of preoperative imaging, 12 patients met criteria for early CCA and were compared with 319 patients who had HCC within MC. The 1- and 5-year overall survival for early CCA versus HCC was 63.6% versus 90.0% and 63.6% versus 70.3% (log-rank, P = 0.25), respectively. Overall recurrence was 33.3% for early CCA versus 11% for HCC. On explant the patients with CCA were more likely understaged with higher tumor grade and vascular invasion. In conclusion, patients with CCA present a diagnostic challenge, which often leads to the finding of more aggressive lesions on explant after LT, higher recurrence rates, and worse post-LT survival. Careful consideration of this diagnostic conundrum needs to be made before a clinical trial is undertaken. Liver Transplantation 24 634-644 2018 AASLD., (© 2018 by the American Association for the Study of Liver Diseases.)

Portal hyperperfusion is detrimental to small-for-size livers (SFSLs) in liver transplantation. Surgical techniques modulating portal inflow provide the most effective approach to protect the SFSL. In this report, we describe a technique creating an allograft portacaval shunt that effectively attenuates portal inflow without a requirement of extensive surgical dissection in the recipient during the transplantation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aim: To assess the performance of BALAD, BALAD-2 and their component biomarkers in predicting outcome of hepatocellular carcinoma (HCC) patients after liver transplant., Methods: BALAD score and BALAD-2 class are derived from bilirubin, albumin, alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-gamma-carboxyprothrombin (DCP). Pre-transplant AFP, AFP-L3 and DCP were measured in 113 patients transplanted for HCC from 2000 to 2008. Hazard ratios (HR) for recurrence and death were calculated. Univariate and multivariate regression analyses were conducted. C-statistics were used to compare biomarker-based to predictive models., Results: During a median follow-up of 12.2 years, 38 patients recurred and 87 died. The HRs for recurrence in patients with elevated AFP, AFP-L3, and DCP defined by BALAD cut-off values were 2.42 (1.18-5.00), 1.86 (0.98-3.52), and 2.83 (1.42-5.61), respectively. For BALAD, the HRs for recurrence and death per unit increased score were 1.48 (1.15-1.91) and 1.59 (1.28-1.97). For BALAD-2, the HRs for recurrence and death per unit increased class were 1.45 (1.06-1.98) and 1.38 (1.09-1.76). For recurrence prediction, the combination of three biomarkers had the highest c-statistic of 0.66 vs. 0.64, 0.61, 0.53, and 0.53 for BALAD, BALAD-2, Milan, and UCSF, respectively. Similarly, for death prediction, the combination of three biomarkers had the highest c-statistic of 0.66 vs 0.65, 0.61, 0.52, and 0.50 for BALAD, BALAD-2, Milan, and UCSF. A new model combining biomarkers with tumor size at the time of transplant (S-LAD) demonstrated the highest predictive capability with c-statistics of 0.71 and 0.69 for recurrence and death., Conclusion: BALAD and BALAD-2 are valid in transplant HCC patients, but less predictive than the three biomarkers in combination or the three biomarkers in combination with maximal tumor diameter (S-LAD)., Competing Interests: Conflict-of-interest statement: Roberts LR has received grant funding from BTG, Gilead Sciences and Wako Life Sciences; Yamada H is an employee of Wako Life Sciences. There are no other potential conflicts of interest for the rest of the authors.

Small-for-size liver transplantation (SFS-LT) carries high morbidity and mortality after transplantation. SFS-LT is usually associated with living-donor or deceased-donor split LT; however its incidence and outcome are poorly defined in adult LT recipients who receive whole grafts (WLT). In this study, we retrospectively reviewed our cohort of 3,106 deceased-donor LT in adult recipients. We found that among the 31 split LTs, 11 (35.5%) were SFS. In contrast, there only 1.08% of the whole-graft transplants (31 out of 2,868) were SFS. Although less common, SFS-WLT is associated with poorer long-term outcome of both graft and patient survivals., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The utility of alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) surveillance is controversial. We aimed to identify factors associated with elevated AFP and define the patients for whom AFP is effective for surveillance. Methods: Data from the NCI Early Detection Research Network phase II HCC biomarker study (233 early-stage HCC and 412 cirrhotic patients) were analyzed. We analyzed 110 early-stage HCC and 362 cirrhotic hepatitis C virus (HCV) patients for external validation. Sensitivity, specificity, and area under the ROC curve (AUC) for HCC were calculated. Results: HCV etiology, non-White race, and serum alanine transaminase (ALT) predicted elevated AFP in cirrhotics. Non-White race and ALT predicted elevated AFP in HCC patients. Higher AUC of AFP for HCC was noted in patients with HBV (0.85) and alcohol (0.84), whereas it was lower in patients with hepatitis C virus (HCV; 0.80) and nonviral/alcohol etiology (0.76). The AUC was higher in HCV patients with serum ALT ≤40 U/L than patients with serum ALT >40 U/L (0.91 vs. 0.75, P < 0.01). At 90% specificity, the sensitivity of AFP increased from 44% to 74% in Whites with HCV and from 50% to 85% in non-Whites with HCV. There was a trend toward higher AUC in HCV patients with serum ALT ≤40 U/L than those with serum ALT >40 U/L (0.79 vs. 0.69, P = 0.10) in the validation cohort. Conclusions: The satisfactory performance of AFP in HCV patients with normal ALT should be further validated. Impact: The AFP may serve as a valuable surveillance test in HCV patients with normal ALT. Cancer Epidemiol Biomarkers Prev; 26(7); 1085-92. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Introduction and Aim: Liver transplantation (LT) provides durable survival for hepatocellular carcinoma (HCC). However, there is continuing debate concerning the impact of wait time and acceptable tumor burden on outcomes after LT. We sought to review outcomes of LT for HCC at a single, large U.S. center, examining the influence of wait time on post-LT outcomes., Material and Methods: We reviewed LT for HCC at Mayo Clinic in Florida from 1/1/2003 until 6/30/2014. Follow up was updated through 8/1/ 2015., Results: From 2003-2014, 978 patients were referred for management of HCC. 376 patients were transplanted for presumed HCC within Milan criteria, and the results of these 376 cases were analyzed. The median diagnosis to LT time was 183 days (8 - 4,337), and median transplant list wait time was 62 days (0 - 1815). There was no statistical difference in recurrence-free or overall survival for those with wait time of less than or greater than 180 days from diagnosis of HCC to LT. The most important predictor of long term survival after LT was HCC recurrence (HR: 18.61, p < 0.001). Recurrences of HCC as well as survival were predicted by factors related to tumor biology, including histopathological grade, vascular invasion, and pre-LT serum alpha-fetoprotein levels. Disease recurrence occurred in 13%. The overall 5-year patient survival was 65.8%, while the probability of 5-year recurrence-free survival was 62.2%., Conclusions: In this large, single-center experience with long-term data, factors of tumor biology, but not a longer wait time, were associated with recurrence-free and overall survival.

Importance: Several factors are associated with increased hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT), but no reliable risk score has been established to determine the individual risk for HCC recurrence., Objective: We aimed to develop and validate a Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score for patients with HCC meeting Milan criteria by imaging., Design, Setting, and Participants: Predictors of recurrence were tested in a development cohort of 721 patients who underwent LT between 2002 and 2012 at 3 academic transplant centers (University of California-San Francisco; Mayo Clinic, Rochester; and Mayo Clinic, Jacksonville) to create the RETREAT score. This was subsequently validated in a cohort of 341 patients also meeting Milan criteria by imaging who underwent LT at the University of Toronto transplant center using the C concordance statistic and net reclassification index., Main Outcomes and Measures: Characteristics associated with post-LT HCC recurrence., Results: A total of 1061 patients participated in the study; 77.8% (825) were men, and the median (IQR) age was 58.2 (53.3-63.9) years in the development cohort and 56.4 (51.7-61.0) years in the validation cohort (P < .001). In the development cohort of 721 patients (542 men), median α-fetoprotein (AFP) level at the time of LT was 8.3 ng/mL; 9.4% had microvascular invasion (n = 68), and 22.1% were beyond Milan criteria on explant (n = 159) owing to understaging by pretransplantation imaging. Cumulative probabilities of HCC recurrence at 1 and 5 years were 5.7% and 12.8%, respectively. On multivariable Cox proportional hazards regression, 3 variables were independently associated with HCC recurrence: microvascular invasion, AFP at time of LT, and the sum of the largest viable tumor diameter and number of viable tumors on explant. The RETREAT score was created using these 3 variables, with scores ranging from 0 to 5 or higher that were highly predictive of HCC recurrence (C statistic, 0.77). RETREAT was able to stratify 5-year post-LT recurrence risk ranging from less than 3% with a score of 0 to greater than 75% with a score of 5 or higher. The validation cohort (n = 340; 283 men) had significantly higher microvascular invasion (23.8% [n = 81], P < .001), explant beyond Milan criteria (37.3% [n = 159], P < .001), and HCC recurrence at 5 years (17.9% [n = 159], P = .03). RETREAT showed good model discrimination (C statistic, 0.82; 95% CI, 0.77-0.86) and superior recurrence risk classification compared with explant Milan criteria (net reclassification index, 0.40; P = .001) in the validation cohort., Conclusions and Relevance: We have developed and validated a simple and novel prognostic score that may improve post-LT HCC surveillance strategies and help identify patients who may benefit from future adjuvant therapies.

Background/aims: Inadequate bowel preparations can necessitate early repeat of colonoscopy and increased healthcare costs. Established risk factors for suboptimal bowel preparation are known, yet data are lacking in the specific subgroup of patients with decompensated cirrhosis. The primary aim of this study was to reduce inadequate bowel preparation rates in patients with decompensated cirrhosis undergoing evaluation for liver transplant via a quality improvement initiative targeting patient education., Methods: A total of 121 patients undergoing evaluation at our institution prior to implementation of the quality improvement initiative and 91 patients undergoing evaluation after implementation were included. The initiative was an educational intervention via a 6-minute colonoscopy and split-prep bowel preparation educational video during the initial liver transplantation evaluation visit for all patients with scheduled colonoscopy., Results: Inadequate bowel preparation was observed in 36 patients (29.8%) in the pre-intervention period compared to 29 patients (31.9%) in the post-intervention period. This corresponded to a lack of a significant difference in both single-variable analysis and multivariable analysis. Of note, there was a significantly higher rate of inadequate bowel preparation as ascites worsened (P=.028)., Conclusion: Patient educational video failed to improve bowel preparations in patients undergoing colonoscopy with decompensated cirrhosis., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Nurse practitioners (NPs) and physician assistants (PAs) are increasingly utilized in health care. However, their roles in liver transplantation (LT) have not been investigated., Materials and Methods: In this study, we reviewed the employment and development of NPs and PAs and their impact on our deceased-donor LT (DDLT) program., Results: We found a safe and efficient way to utilize NPs and PAs in a DDLT program. Since the beginning of our program, Model of End-Stage Liver Disease (MELD) scores have increased significantly, suggesting patients are sicker at the time of transplant, and wait times of patients have become longer. With the incorporation of NPs and PAs, we found that length of stay (LOS) was not affected. The overall median warm ischemic time did not increase. Outcomes of LT for both patient and graft survival actually improved and remain at or above the expected values. These results collectively support the usefulness and validity of NPs and PAs in a DDLT program., Conclusion: We have determined that surgical and medical NPs and PAs are essential for optimal patient outcomes. They facilitate a better learning experience for residents and fellows on their transplant rotations. Further investigations to assess the roles of these providers and their impact on the education of residents and fellows in transplantation are warranted. Further transplant hepatology education programs and/or fellowships are recommended to assist in the education and professional development of transplant NPs and PAs., (© 2016, NATCO.)

Aim: Patent foramen ovale (PFO) is a common atrial septal defect that is largely asymptomatic and often undiagnosed. The impact of a PFO in patients undergoing liver transplantation (LT) is unknown., Objective: Assess the impact of PFO and physiologic intrapulmonary shunt (IPS) on the perioperative outcomes of patients who underwent LT., Methods: We performed a retrospective, intention-to-treat analysis of patients with PFO and controls without PFO who underwent LT at Mayo Clinic in Florida between 2008 and 2013. Patients with physiologic IPS were also analyzed. The cohorts were compared for baseline characteristics, length of stay in the intensive care unit (ICU), postoperative oxygen requirements, 30-d cerebrovascular accidents, and mortality., Results: Of the 935 patients who underwent LT, 10.4% had proven PFO by pre-LT echocardiogram. Control patients (n = 101) were statistically older than PFO and IPS (n = 56) patients, but similar in sex, BMI, Model for End-stage Liver Disease score, American Society of Anesthesiologist score, and left ventricular ejection fraction. PFO and IPS patients had similar length of stay in the ICU, mechanical ventilation times, post-LT oxygen requirements, and 30-d mortality compared to controls. Subgroup analysis showed similar outcomes for large PFO and IPS patients to controls., Conclusions: The presence of PFO did not have a negative impact on perioperative LT outcomes., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Complications of cirrhosis may persist after liver transplantation. When indicated, partial splenic embolization (PSE) is an alternative to splenectomy but can cause severe infection. The identification of modifiable risk factors when performing PSE in immunocompromised liver transplant recipients may help reduce the risk of severe infection., Methods: Data were collected retrospectively for all PSE performed after liver transplantation at a single institution and included demographics, etiology of liver disease, indication for PSE, vaccination status, laboratory findings, procedural details, extent and pattern of splenic infarction, hospital length-of-stay, readmissions, procedural complications, and mortality. Statistical analysis included 2-tailed t test, Fisher exact test, and Kaplan-Meier survival curves, with significance defined as P < .05., Results: Sixteen patients received 22 embolizations, with 11 patients undergoing a single session and 5 patients undergoing multiple sessions. Indications included hypersplenism, gastrointestinal hemorrhage, ascites, and autoimmune hemolytic anemia. PSE produced significant and sustained cell count increases, improved ascites, and controlled hemorrhage. Splenic abscess, septic shock, need for splenectomy, and PSE-related mortality were seen in the group with large confluent splenic infarction but not in peripheral/wedge-shaped infarction. Multiple-session PSE exclusively using particles for embolization correlated with the pattern of peripheral/wedge-shaped infarction and avoided severe infection and PSE-related mortality., Conclusions: PSE in the immunosuppressed liver transplant recipient is an effective alternative to splenectomy, but carries substantial infectious risk. The risk is decreased when PSE performed with polyvinyl alcohol particles results in a pattern of peripheral/wedge-shaped infarction, which correlates with smaller infarction volumes, favorable length-of-stay, and minimal risk of abscess, sepsis, and mortality., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Graft-versus-host disease (GVHD) is a rare, fatal complication following orthotopic liver transplantation (OLT). To date, several risk factors have been proposed, but reports on these factors have been inconclusive. This is a retrospective, case-control study of prospectively collected data from 2775 OLTs performed at our institution. Eight cases of GVHD after OLT were diagnosed on the basis of the patient's clinical characteristics, and the findings were confirmed with skin and colonic biopsies. Each case was matched to three controls based on the diagnosis of liver disease, recipient's age, and blood group. Univariate and multivariate analyses were performed to identify risk factors associated with the development of GVHD after OLT. The univariate and multivariate analyses identified two main risk factors associated with development of GVHD in OLT recipients, a difference between recipient and donor age of >20 yr, and any human leukocyte antigen class I matches. Taking these two risk factors into consideration while matching prospective donors and recipients may reduce further incidence of GVHD in OLT patients. However, further studies are recommended to validate these findings., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hepatocellular carcinoma (HCC) recurrence in patients undergoing liver transplantation (LT) with donation after brain death (DBD) and donation after cardiac death (DCD) allografts has not previously been investigated. Rates and patterns of HCC recurrences were investigated in patients undergoing DBD (N = 1633) and DCD (N = 243) LT between 2003 and 2012. LT for HCC was identified in 397 patients (340 DBD and 57 DCD). No difference in tumor number (p = 0.26), tumor volume (p = 0.34) and serum alphafetoprotein (AFP) (p = 0.47) was seen between the groups. HCC recurrence was identified in 41 (12.1%) patients in the DBD group and 7 (12.3%) patients in the DCD group. There was no difference in recurrence-free survival (p = 0.29) or cumulative incidence of HCC recurrence (p = 0.91) between the groups. Liver allograft was the first site of recurrence in 22 (65%) patients in the DBD group and two (37%) patients in the DCD group (p = 0.39). LT for HCC with DBD and DCD allografts demonstrate no difference in the rate of HCC recurrence. Previously published differences in survival demonstrated between recipients with HCC receiving DBD and DCD allografts despite statistical adjustment can likely be explained by practice patterns not captured by variables contained in the SRTR database., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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., (© 2015 American Association for the Study of Liver Diseases.)