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Background Treatment of hepatocellular carcinoma (HCC) is predicated on early diagnosis such that ‘curative therapies’ can be successfully applied. The term ‘curative’ is, however, poorly quantitated. We aimed to complement our previous work by developing a statistical model to predict cure after ablation and to use this analysis to compare the true curative potential of the various ‘curative’ therapies. Methods We accessed data from 1571 HCC patients treated in 5 centres receiving radiofrequency (RFA) or microwave (MWA) ablation and used flexible parametric modelling to determine the curative fraction. The results of this analysis were then combined with our previous estimations to provide a simple calculator applicable to all patients undergoing potentially curative therapies. Results The cure fraction was 18.3% rising to about 40% in patients with good liver function and very small tumours. Conclusion Cure for HCC treated with ablation occurs in the order of 20% to 30%, similar to that achievable by resection but much inferior to transplantation where the analogous figure is >70%. We provide a ‘calculator’ that permits clinicians to estimate the chance of cure for any individual patient, based on readily available clinical features.

Limited information is available regarding endothelial glycocalyx degradation during sepsis in horses. Plasma syndecan-1 concentrations are increased in consequence of sepsis in other species and have been useful for prognostication.To determine whether plasma syndecan-1 levels are increased in adult horses affected with sepsis.Retrospective cohort study.Adult horses were assigned to one of three groups based on results of physical and laboratory examinations, clinical diagnosis, and results of previously described SIRS classification: Group 1 horses included healthy, nonseptic horses; Group 2 included horses in which clinical illness was identified but that were not considered to be septic; Group 3 included horses with a clinical diagnosis of sepsis. Plasma syndecan-1 concentration was determined in blood obtained at admission into the hospital for each horse, using an equine specific ELISA. Data were analysed using ANOVA and linear regression (p ≤ 0.05).One hundred and ninety-one horses were included and divided into three groups. Scores for SIRS were highest for Group 3 horses and lowest in Groups 1 and 2. Plasma syndecan-1 concentrations in Group 3 horses (50.73 ± 84.24 μg/ml; n = 42) were greater than those for Group 1 (15.69 ± 11.28 μg/ml; n = 66) and Group 2 (16.88 ± 15.30 μg/ml; n = 83). There was no difference regarding syndecan concentrations between Groups 1 and 2.Retrospective study design, solitary time point of measurement for each patient, and lack of a widely accepted consensus regarding definitive diagnosis of sepsis in adult horses.Circulating plasma levels of syndecan-1, a biochemical marker of endothelial glycocalyx damage, are increased in septic adult horses.

In collaboration with the American College of Veterinary Pathologists

The article focuses on the Considerations related to the use of molecular diagnostic tests in veterinary clinical and regulatory practice . Topics discussed include technological advances are creating an ever widening array of options for detecting pathogens and diagnosing diseases of concern in clinical and regulatory veterinary medicine;and new technology can facilitate timelier responses and, in some instances, move assays from laboratory-based to patient-side.

Inflammation and apoptosis in the hoof lamellar interface both contribute to the early stages of sepsis-associated laminitis, but it is not clear whether apoptosis is occurring before the onset of inflammation or is being provoked by inflammation. Apoptosis and inflammation were therefore measured in lamellar tissues obtained at different time points throughout the early stages of experimentally induced laminitis. Apoptotic cells and leukocyte were enumerated in archived paraffin embedded lamellar tissue samples from previous experiments in which acute laminitis was induced using Black Walnut Extract (BWE) or starch (CHO). BWE-derived samples from 20 horses were allocated into four groups: Control (CON = 5); Early Time Point (ETP, 1.5 h after induction, n = 5); Developmental Time Point (DTP, 3-4 h after induction, n = 5); Obel Grade 1 (OG1, Onset of Lameness, n = 5). CHO-derived samples from 25 horses were allocated into four groups: CON (n = 8); DTP (10-12 h after induction, n = 6); OG 1 (n = 6); Obel 3 (OG3, lameness progression, n = 5). Apoptotic cells were enumerated using a horse validated TUNEL technique. Compared to controls, significant increases in apoptotic cell counts were not detected in lamellar epithelial cells during the developmental phase or at the onset of lameness during laminitis induction. A negative correlation between apoptosis and leukocyte infiltration was detected in the BWE model (P 0.05). In conclusion, apoptosis does not play an important role in the initial stages of sepsis-related laminitis.

In patients with hepatitis C virus (HCV) infection and decompensated cirrhosis (DC), it is uncertain whether viral clearance is clinically meaningful and whether it decreases liver-related and non-liver-related mortality. The aim of this study was to assess whether viral eradication reduced liver-related and non-liver-related mortality in patients with HCV infection and DC. To clarify the impact of viral eradication on liver-related and non-liver-related mortality, 364 patients with DC who received direct-acting antivirals (DAAs) and achieved sustained virological response (SVR) in the UK (DAA group) were compared with 249 patients with DC who did not receive DAAs and who underwent symptomatic treatment in Japan (non-DAA group). Propensity score matching and inverse probability weighting (IPW) were performed to adjust the baseline characteristics in the DAA and non-DAA groups. Liver-related and non-liver-related mortality were analyzed using the competing risks IPW cumulative incidence functions estimator. The cumulative all-cause mortality rate in the DAA group was significantly lower than that in the non-DAA group (p

OBJECTIVE To determine the following: (1) whether an irrigation solution that is hyperosmolar (HYPER) relative to synovial fluid decreases tissue extravasation during an arthroscopic protocol when compared to a relatively hypoosmolar solution, (2) the safety of a HYPER solution based on viability of joint tissues following joint irrigation, and (3) if the use of a HYPER solution decreases water content in stifle joint tissue. ANIMALS 8 adult horses. PROCEDURES A prospective, blinded, randomized controlled trial was performed to compare lactated Ringer’s solution (LRS; 273 mOsm/L) and a HYPER (600 mOsm/L) irrigation solution for routine medial femorotibial joint (MFTJ) arthroscopy. Primary outcomes included quantification of periarticular fluid retention based on measured changes in defined stifle joint girth and ultrasonographic (US) criteria. Water content of tissue samples was assessed. The viability of articular cartilage was determined using a microscopic fluorescent cell viability staining system. RESULTS No significant difference in postprocedural joint swelling was observed between LRS and HYPER treatment groups. Percent increments in femorotibial joint dimensions (mean ± SD) were seen in both treatment groups based on US (LRS, 83.9 ± 84.6%; HYPER, 131.2 ± 144.9%) and caliper measurements (LRS 5.5 ± 4.3%; HYPER 7.5 ± 5.8%) (P ≤ .05). Chondrocyte viability and tissue water content were maintained in both treatment groups, and differences were not statistically significant. CLINICAL RELEVANCE Doubling the osmolarity of an irrigation solution used routinely for arthroscopy does not result in detrimental effects on chondrocyte viability or tissue water content. However, use of a relatively HYPER irrigation solution did not attenuate procedural tissue swelling of the equine stifle joint.

© 2020 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd Whilst the benefit of direct-acting antiviral agents (DAAs) in achieving sustained virological response (SVR) is now well-accepted, their impact on liver function, particularly in relation to achievement of SVR, has not been well documented. We studied 2394 patients with chronic HCV infection, 1276 receiving DAAs and 1118 interferon-based therapy. Liver function was assessed by the albumin-bilirubin (ALBI) score or grade. Overall survival according to SVR status and baseline ALBI grade was examined. We also studied time to first decompensation according to ALBI grade, as well as longitudinal changes in ALBI score over time according to SVR. Among the patients receiving DAAs, 89% achieved SVR (Japan=99%, UK=78%). Amongst the decompensated patients in the UK cohort, three distinct risk groups according to ALBI grade at baseline were observed. The UK patients receiving DAAs, who had predominantly decompensated disease, showed clear evidence of improvement of liver function detectable within 2years of the start of treatment, especially in those achieving SVR. These early changes in liver function were very similar to those observed in the first 2-3years after interferon-based therapy. DAAs improve liver function especially in those with decompensated disease who achieve SVR. Experience with interferon-based therapy suggests that failure to achieve SVR is associated with long-term decline in liver function and, in contrast, patients who do achieve SVR can expect long-term disease improvement and subsequent stabilization of liver function. Our initial analysis suggests that those receiving DAAs are likely, in the long term, to follow a similar course.

PurposeHepatic function is a key prognostic marker in patients with hepatocellular cancer (HCC) and central to patient selection for transarterial chemoembolization (TACE). We investigated the clinical utility of the Albumin-Bilirubin (ALBI) grade, an emerging prognostic model, in this heterogenous cohort via a meta-analysis of published studies.MethodsPublications including full text articles and abstracts regarding ALBI grade were sourced by two independent researchers from databases including PubMed, Embase, Medline and Cochrane Library. Studies analysing patients with HCC undergoing TACE treatment were systematically screened utilising the PRISMA tool for data extraction and synthesis, after exclusion of duplicates, irrelevant studies and overlapping cohorts. The primary outcome was overall survival (OS), as determined by ALBI grade and assessed by hazard ratio (HRs) with 95% confidence intervals (CIs), with analysis of collated data using comprehensive meta-analysis, version 3.0 software.ResultsEight studies were included, with a pooled population of 6538 patients with HCC that underwent TACE treatment. Higher pre-treatment grade was associated with poor OS, with median OS of 12.0 months (P ConclusionsHigh pre-treatment ALBI grade is associated with poorer prognosis in patients with HCC undergoing TACE therapy. The ALBI grade demonstrates clinical utility for clinical prognostication and patient selection for TACE.

The incidence of hepatocellular carcinoma (HCC) in the United Kingdom has increased 60% in the past 10 years. The epidemics of obesity and type 2 diabetes are contributing factors. In this article, we examine the impact of diabetes and glucose-lowering treatments on HCC incidence and overall survival (OS).Data from 1064 patients diagnosed with chronic liver disease (CLD) (n = 340) or HCC (n = 724) were collected from 2007 to 2012. Patients with HCC were followed up prospectively. Univariate and multivariate logistic regression determined HCC risk factors. Kaplan-Meier curves were used to examine survival and Cox proportional hazards analysis estimated hazard ratios (HRs) for death according to use of glucose-lowering therapies.Diabetes prevalence was 39.6% and 10.6% within the HCC and CLD cohorts, respectively. The odds ratio for having HCC in patients with diabetes was 5.55 (P0.001). Univariate analysis found an increased association of HCC with age, sex, cirrhosis, hemochromatosis, alcohol abuse, diabetes, and Child's Pugh score. In multivariate analysis age, sex, cirrhosis, Child's Pugh score, diabetes status, and insulin use retained significance. Diabetes status did not significantly affect OS in HCC; however, in people with diabetes and HCC, metformin treatment was associated with improved OS (mean survival, 31 vs 24 months; P =0.016; HR for death = 0.75; P = 0.032).Diabetes is significantly associated with HCC in the United Kingdom. Metformin treatment is associated with improved OS after HCC diagnosis. Treatment of diabetes should be appropriately reviewed in high-risk populations, with specific consideration of the potential hepatoprotective effects of metformin in HCC.

Soluble epoxide hydrolase (sEH) inhibitors are novel anti-inflammatory and analgesic agents that could improve pain management in horses. The objective of the present study was to evaluate the anti-nociceptive effect of a single-dose intravenous administration of the sEH inhibitor trans-4-{4-[3-(4-trifluro-methoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (t-TUCB) using an adjustable heart bar shoe (a-HBS) model of lameness. We hypothesized that t-TUCB would improve objective and subjective lameness measures compared to the control.Reversible lameness was induced in 8 horses for 24 h using an a-HBS in a randomized, crossover design. A vehicle-control placebo (DMSO) or t-TUCB (1 mg/kg) was intravenously administered at time 0 following a baseline induced lameness evaluation. Blood was collected and lameness was objectively measured with an inertial sensor system at 0-, 1-, 3-, 6-, 12-, and 24-h time points. Front-facing videos were obtained at each time point for subjective evaluation by three blinded evaluators using a visual analog scale (VAS).Treatment with t-TUCB significantly decreased (i.e. improved) lameness compared to placebo at 1-h and compared to baseline at 1-, 3-, and 6-h following administration. Lameness significantly increased (i.e. worsened) from baseline in placebo-treated horses 12 h after administration. All horses returned to baseline soundness within 24 h of reversing lameness.Treatment with single-dose IV administration of t-TUCB improved lameness induced by the a-HSB, suggesting that t-TUCB has anti-nociceptive effects in horses.The soluble epoxide hydrolase inhibitor, t-TUCB, is a promising novel analgesic for horses.

Background The therapeutic value of repeat hepatic resection (rHR) or radiofrequency ablation (RFA) for recurrent hepatocellular carcinoma (HCC) is unknown. This study aimed to investigate the safety and efficacy of rHR or RFA. Methods This was a retrospective multicentre study of patients with recurrent HCC within the Milan criteria who underwent rHR or RFA at nine university hospitals in China and Italy between January 2003 and January 2018. Survival after rHR or RFA was examined in unadjusted analyses and after propensity score matching (1 : 1). Results Of 847 patients included, 307 and 540 underwent rHR and RFA respectively. Median overall survival was 73.5 and 67.0 months after rHR and RFA respectively (hazard ratio 1.01 (95 per cent c.i. 0.81 to 1.26)). Median recurrence-free survival was longer after rHR versus RFA (23.6 versus 15.2 months; hazard ratio 0.76 (95 per cent c.i. 0.65 to 0.89)). These results were confirmed after propensity score matching. RFA was associated with lower morbidity of grade 3 and above (0.6 versus 6.2 per cent; P Conclusion rHR was associated with longer recurrence-free survival but not overall survival compared with RFA.

Background and aims The aMAP score is a model that predicts risk of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis. Its performance in a ‘real world’ surveillance setting has not yet been ascertained. Patients and methods We had access to a cohort of 3473 individuals enrolled in a rigorously implemented and prospectively accrued surveillance programme (patients undergoing regular ultrasound and biomarker examination between 1998 and 2021). During this period 445 had HCC detected. Of these, 77.8% had early stage disease (within Milan criteria), permitting potentially curative therapy to be implemented in nearly 70% of cases. We applied the recently developed aMAP score to classify patients according to their initial aMAP score in to low, medium and high-risk groups as proposed in the original publication. The performance of the aMAP score was assessed according to the concordance-index and calibration (i.e. agreement between observed and predicted risk). Allowance was made for competing causes of death. Results The aMAP score achieved an overall C-index of 0.81 (95% CI: 0.79–0.82) consistent with the initial report and was unaffected by allowance for competing causes of death. Sub-group analysis showed that the results did not change significantly according to gender, or aetiology. However, aMAP discrimination was greater for younger individuals (versus older individuals), and also for individuals without cirrhosis. The HCC incidence rate was 0.98, 7.05 and 29.1 events per 1000 person-years in the low-, moderate- and high-risk aMAP groups, respectively. Conclusions The results from this ‘real-world’ cohort demonstrate that risk stratification is a realistic prospect and that identification of a subgroup of chronic liver disease patients who have a very low risk of HCC is feasible.

International guidelines recommend six monthly ultrasounds as the primary surveillance tool for patients at risk of hepatocellular carcinoma (HCC). The dominant driver of liver disease in HCC surveillance populations is shifting, particularly in Europe and the United States, from chronic viral hepatitis (B or C), towards non-alcoholic fatty liver disease (NAFLD). Today, the population requiring HCC surveillance is also characterised by a high prevalence of overweight/obesity. These patient characteristics significantly impair ultrasound quality which can impede the detection of early HCC lesions. This diagnostic limitation has significant implications considering that eligibility for curative treatment depends upon the stage at which the cancer is detected. In this narrative review, we provide a comprehensive overview of the published evidence and national/international guidelines regarding ultrasound surveillance for HCC in people with NAFLD. We examine ultrasound sensitivity in this cohort for the detection of all stage and early HCC, the impact of steatosis and abdominal obesity on ultrasound performance, evidence for the addition of serum alpha-fetoprotein measurement, optimal timing of surveillance, emerging modalities for risk stratification and screening, and outline the challenges of case finding and surveillance eligibility criteria in this patient cohort. Finally, amalgamating all available evidence, we propose a pragmatic surveillance pathway for patients with NAFLD.

Background & Aims Sorafenib has been the standard of care for patients with advanced hepatocellular carcinoma and although immunotherapeutic approaches are now challenging this position, it retains an advantage in HCV-seropositive patients. We aimed to quantify the rate of tumour progression in patients receiving sorafenib and relate this figure to survival, both overall, and according to viral status. Methods Using serial data from an international clinical trial we applied a joint model to combine survival and progression over time in order to estimate the rate of tumour growth as assessed by tumour burden and serum alpha-fetoprotein, and the impact of treatment on liver function. Results High tumour burden at baseline was associated with an increased risk of death. In patients still alive at the end of the study, the progression in relation to tumour burden was very low compared to those who died within the study. Overall, the change in mean tumour burden was 0.12 mm per day or an absolute growth rate of 3.6 mm/month. Median doubling time was 665 days. For those who progressed above 0.12 mm per day or the 12% rate, median survival was 234 days compared to 384 days if the rate was below 12%. Tumour growth rate and serum alpha-fetoprotein rise were significantly lower in those who were HCV seropositive as was the rate of decline in liver function. These results were replicated in 2 independent patient groups. Conclusion Our analysis suggests that sorafenib treatment is associated with improved survival in patients with advanced hepatocellular carcinoma mainly by decreasing the rate of tumour growth and liver function deterioration among patients with HCV infection. Lay summary Among patients receiving sorafenib for advanced hepatocellular carcinoma the rate of tumour growth (as assessed by changes in tumour size and the biomarker alpha-fetoprotein) and the deterioration of liver function is less in those who have the hepatitis C virus, than in those who do not.

BackgroundLocoregional treatments (LRT) including radioembolisation (SIRT), transarterial chemo-embolisation (TACE), hepatic arterial infusion (HAI) of chemotherapy, external beam radiotherapy (EBRT) and ablation have been studied for the management of intrahepatic cholangiocarcinoma (iCC). The aim of this systematic review was to provide outcome benchmarks for clinical trial design.MethodsIdentification of studies reporting outcomes of patients treated with LRT for iCC was performed using PubMed and Embase. Pooled weighted means were calculated for progression-free survival (PFS) and overall survival (OS); meta-analysis of proportions was used for estimation of pooled response rate.Results6325 entries were reviewed; 93 studies were eligible, representing 101 cohorts and 3990 patients: 15 cohorts (645 patients) for ablation, 18 cohorts (541 patients) for EBRT, 27 cohorts (1232 patients) for SIRT, 22 cohorts (1145 patients) for TACE, 16 cohorts (331 patients) for HAI and 3 cohorts (96 patients) not pooled. 74% of the studies were retrospective, 99% non-randomised.The pooled mean weighted OS was 30.2 months (95% confidence interval (CI): 21.8–38.6) for ablation, 18.9 (14.2–23.5) for EBRT, 14.1 (12.1–16.0) for SIRT, 15.9 (12.9–19.0) for TACE and 21.3 (15.4–27.1) for HAI. The pooled complete response rate was 93.9% for ablation. When analysed together, SIRT, TACE and HAI had a pooled mean weighted OS of 15.7 months, and 25.2 months for patients treated in first-line with concomitant systemic chemotherapy.ConclusionsAvailable literature on LRT for iCC was heterogeneous and of insufficient quality to make strong recommendations. Ablation achieved satisfactory outcomes, and may be recommended when surgery is not feasible.

High-grade dysplasia carries significant risk of transformation to hepatocellular carcinoma (HCC). Despite this, at the current standard of care, all non-malignant hepatic nodules including high-grade dysplastic nodules are managed similarly. This is partly related to difficulties in distinguishing high-risk pathology in the liver. We aimed to identify chromosome arm-level somatic copy number alterations (SCNAs) that characterise the transition of liver nodules along the cirrhosis-dysplasia-carcinoma axis. We validated our findings on an independent cohort using blood-derived cell-free DNA. A repository of non-cancer DNA sequences obtained from patients with HCC (n = 389) was analysed to generate cut-off thresholds aiming to minimise false-positive SCNAs. Tissue samples representing stages from the multistep process of hepatocarcinogenesis (n = 184) were subjected to low-pass whole genome sequencing. Chromosome arm-level SCNAs were identified in liver cirrhosis, dysplastic nodules, and HCC to assess their discriminative capacity. Samples positive for 1q+ or 8q+ arm-level duplications were likely to be either HCC or high-grade dysplastic nodules as opposed to low-grade dysplastic nodules or cirrhotic tissue with an odds ratio (OR) of 35.5 (95% CI 11.5-110) and 16 (95% CI 6.4-40.2), respectively (p

Background: The ‘Prediction Of Survival in Advanced Sorafenib-treated HCC’ (PROSASH) model addressed the heterogeneous survival of patients with hepatocellular carcinoma (HCC) treated with sorafenib in clinical trials but requires validation in daily clinical practice. This study aimed to validate, compare and optimize this model for survival prediction. Methods: Patients treated with sorafenib for HCC at five tertiary European centres were retrospectively staged according to the PROSASH model. In addition, the optimized PROSASH-II model was developed using the data of four centres (training set) and tested in an independent dataset. These models for overall survival (OS) were then compared with existing prognostic models. Results: The PROSASH model was validated in 445 patients, showing clear differences between the four risk groups (OS 16.9-4.6months). A total of 920 patients (n=615 in training set, n=305 in validation set) were available to develop PROSASH-II. This optimized model incorporated fewer and less subjective parameters: the serum albumin, bilirubin and alpha-foetoprotein, and macrovascular invasion, extrahepatic spread and largest tumour size on imaging. Both PROSASH and PROSASH-II showed improved discrimination (C-index 0.62 and 0.63, respectively) compared with existing prognostic scores (C-index ≤0.59). Conclusions: In HCC patients treated with sorafenib, individualized prediction of survival and risk group stratification using baseline prognostic and predictive parameters with the PROSASH model was validated. The refined PROSASH-II model performed at least as good with fewer and more objective parameters. PROSASH-II can be used as a tool for tailored treatment of HCC in daily practice and to define pre-planned subgroups for future studies.

Hepatocellular Carcinoma (HCC) is the fourth most common cause of cancer deaths worldwide, and its early detection is a critical determinant of whether curative treatment is achievable. Early stage HCC is typically asymptomatic. Thus, screening programmes are used for cancer detection in patients at risk of tumour development. Radiological screening methods are limited by imperfect data, cost and associated risks, and additionally are unable to detect lesionsuntil they have grown to a certain size. Therefore, some screening programmes use additional blood/serum biomarkers to help identify individuals in whom to target diagnostic cancer investigations. The GALAD score, combining the levels of several blood biomarkers, age and sex, has been developed to identify patients with early HCC. Here we propose a Bayesian hierarchical model for an individual's longitudinal GALAD scores whilst in HCC surveillance to identify potentially significant changes in the trend of the GALAD score, indicating the development of HCC, aiming to improve early detection compared to standard methods. An absorbent two-state continuous-time hidden Markov model is developed for the individual level longitudinal data where the states correspond to the presence/absence of HCC. The model is additionally informed by the information on the diagnosis by standard clinical practice, taking into account that HCC can be present before the actual diagnosis so that there may be false negatives within the diagnosis data. We fit the model to a Japanese cohort of patients undergoing HCC surveillance and show that the detection capability of this proposal is greater than using a fixed cut-off point.

Autophagy is a well-conserved self-eating mechanism of cell survival during periods of nutrient deprivation, stress and injury. Autophagy is implicated in many pathophysiological conditions across all organ systems. The cornea is an avascular transparent tissue that is prone to damage by trauma, injury and infection. Following insult, the cornea undergoes a complex wound healing process, which is regulated by multiple factors including autophagy. The involvement of autophagy in keratoconus and HSV-1 infection has been demonstrated, underlining the importance of this mechanism in corneal disorders. However, the role of autophagy in corneal wound repair, fibrosis and angiogenesis is still unclear. Recently, we characterized the expression of autophagy-related genes in cornea and are studying their role in the modulation of corneal conditions including fibrosis and dystrophies. Preliminary results presented within this review article support further investigation of the dynamic modulation of autophagy-related genes in corneal health and disease. This article provides an overview of how autophagy modulates corneal function.

Despite vaccination programs and direct antiviral treatments, the incidence of virus-related hepatocellular carcinoma (HCC) remains high, while ultrasound-based detection rates for early-stage HCC is continuously low. To address this insufficiency, we set out to characterize whether the GALAD score, which incorporates gender, age, and serum levels of AFP, AFP isoform L3 (AFP-L3), and des-gamma-carboxy-prothrombin (DCP), can improve early-stage HCC detection in a Caucasian HBV/HCV cohort. In a retrospective German single-center study, 182 patients with HBV, 223 with HCV and 168 with other etiology (OE) of chronic liver disease (CLD) were enrolled. HCC was confirmed in 52 HBV, 84 HCV and 60 OE CLD patients. The diagnostic performance of the single biomarkers in HCC detection was compared to the GALAD model. At initial diagnosis, most patients were at (very) early BCLC 0 (n = 14/7%) or A (n = 56/29%) or intermediate stage BCLC B (n = 93/47%) HCC in all three subgroups. In the BCLC 0/A cohort, GALAD exhibited an AUC of 0.94 discriminating HCC from non-HCC, surpassing AFP (AUC 0.86), AFP-L3 (AUC 0.83) and DCP (AUC 0.83). In the HBV population, GALAD achieved an AUC of 0.96, in HCV an AUC of 0.98 and in OE an AUC of 0.99, clearly superior to the biomarkers alone. Furthermore, in HCV patients GALAD showed a significantly higher specificity (89%) versus AFP (64%) alone. In chronic viral hepatitis, the GALAD model showed superior performance in detection of early-stage HCC, while exhibiting higher specificity in HCV patients compared to AFP alone. We conclude that the GALAD score shows potential for HCC surveillance in Caucasian HBV/HCV patients.

Background & Aims: Hepatocellular carcinoma (HCC) is the leading cause of death in patients with chronic hepatitis. In this international collaboration, we sought to develop a global universal HCC risk score to predict the HCC development for patients with chronic hepatitis.Methods: A total of 17,374 patients, comprising 10,578 treated Asian patients with chronic hepatitis B (CHB), 2,510 treated Caucasian patients with CHB, 3,566 treated patients with hepatitis C virus (including 2,489 patients with cirrhosis achieving a sustained virological response) and 720 patients with non-viral hepatitis (NVH) from 11 international prospective observational cohorts or randomised controlled trials, were divided into a training cohort (3,688 Asian patients with CHB) and 9 validation cohorts with different aetiologies and ethnicities (n = 13,686).Results: We developed an HCC risk score, called the aMAP score (ranging from 0 to 100), that involves only age, male, albumin–bilirubin and platelets. This metric performed excellently in assessing HCC risk not only in patients with hepatitis of different aetiologies, but also in those with different ethnicities (C-index: 0.82–0.87). Cut-off values of 50 and 60 were best for discriminating HCC risk. The 3- or 5-year cumulative incidences of HCC were 0–0.8%, 1.5–4.8%, and 8.1–19.9% in the low- (n = 7,413, 43.6%), medium- (n = 6,529, 38.4%), and high-risk (n = 3,044, 17.9%) groups, respectively. The cut-off value of 50 was associated with a sensitivity of 85.7–100% and a negative predictive value of 99.3–100%. The cut-off value of 60 resulted in a specificity of 56.6–95.8% and a positive predictive value of 6.6–15.7%.Conclusions: This objective, simple, reliable risk score based on 5 common parameters accurately predicted HCC development, regardless of aetiology and ethnicity, which could help to establish a risk score-guided HCC surveillance strategy worldwide.Lay summary: In this international collaboration, we developed and externally validated a simple, objective and accurate prognostic tool (called the aMAP score), that involves only age, male, albumin–bilirubin and platelets. The aMAP score (ranged from 0 to 100) satisfactorily predicted the risk of hepatocellular carcinoma (HCC) development among over 17,000 patients with viral and non-viral hepatitis from 11 global prospective studies. Our findings show that the aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk among all the cohorts irrespective of aetiology and ethnicity.© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. This is an open access article under the CC BY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background We conducted a prospective study using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-MRI) to determine whether sustained virological response (SVR) by direct-acting anti-viral (DAA) drugs suppresses hepatocarcinogenesis in patients with hepatitis C virus (HCV) infection. Aim To use serial Gd-EOB-MRI to assess the impact of DAAs on hepatocarcinogenesis. Methods Between February 2008 and December 2018, 1083 consecutive patients with HCV infection underwent Gd-EOB-MRI. Of these, 719 patients were enrolled, including 210 patients in the 'Non-DAA group', who did not receive DAAs before the introduction of DAAs, and 509 patients in the 'DAA group', who achieved SVR after the introduction of DDAs. Factors associated with hepatocarcinogenesis were analysed by a Cox proportional hazard model. In addition, hepatocarcinogenesis was classified into two types, 'multistep' and 'de novo', on the basis of Gd-EOB-MRI findings. Factors associated with each type were analysed by Fine and Gray proportional hazards models. Results Hepatocarcinogenesis was observed in 67 of 719 (9.3%) patients. Factors associated with hepatocarcinogenesis were male gender, albumin-bilirubin (ALBI) grade 2 or 3, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) ≥5%, the presence of nonhypervascular hypointense nodules (NHHNs) and Non-DAA group. Of 67 patients, multistep hepatocarcinogenesis occurred in 58 patients (86.6%) and de novo hepatocarcinogenesis occurred in nine patients (13.4%). Factors associated with multistep hepatocarcinogenesis were male gender and Non-DAA group. Conclusion The eradication of HCV by DAA therapy reduces multistep hepatocarcinogenesis.

Background & Aims Ultrasound (US)-based screening has been recommended for patients with an increased risk of hepatocellular carcinoma (HCC). US analysis, however, is limited in patients who are obese or have small tumors. The addition of serum level of α-fetoprotein (AFP) measurements to US analysis can increase detection of HCC. We analyzed data from patients with chronic liver disease, collected over 15 years in an HCC surveillance program, to develop a model to assess risk of HCC. Methods We collected data from 3450 patients with chronic liver disease undergoing US surveillance in Japan from March 1998 through April 2014, and followed them up for a median of 8.83 years. We performed longitudinal discriminant analysis of serial AFP measurements (median number of observations/patient, 56; approximately every 3 months) to develop a model to determine the risk of HCC. We validated the model using data from 2 cohorts of patients with chronic liver disease in Japan (404 and 2754 patients) and 1 cohort in Scotland (1596 patients). Results HCC was detected in 413 patients (median tumor diameter, 1.8 cm), during a median follow-up time of 6.60 years. In the development data set, the model identified patients who developed HCC with an area under the curve of 0.78; it correctly identified 74.3% of patients who did develop HCC, and 72.9% of patients who did not. Overall, 73.1% of patients were classified correctly. The model could be used to assign patients to a high-risk group (27.5 HCCs/1000 patient-years) vs a low-risk group (4.9 HCCs/1000 patient-years). A similar performance was observed when the model was used to assess patients with cirrhosis. Analysis of the validation cohorts produced similar results. Conclusions We developed and validated a model to identify patients with chronic liver disease who are at risk for HCC based on change in serum AFP level over time. The model could be used to assign patients to high-risk vs low-risk groups, and might be used to select patients for surveillance.

Background: Targeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung. Parasympathetic input to the heart originating from the lungs contributes to respiratory sinus arrhythmia (RSA) and disruption of pulmonary nerves via TLD may impact RSA. Objective: The aim of this study was to assess the potential of TLD to affect RSA in sheep and humans. Methods: TLD was performed in 5 sheep and 9 humans using a novel lung denervation system (Nu­vaira Inc., Minneapolis, MN, USA) with an electrocardiogram collected before and after the procedure. Frequency domain analysis of heart rate variability was performed in 5 sheep and 6 humans with presence of RSA approximated as high-frequency power (HF power). Results: HF power decreased in 3 of 5 sheep with 1 animal reaching less than 7% of its baseline HF power 30 days after TLD. The average treatment location was more distal in the remaining 2 animals, which did not exhibit RSA attenuation, suggesting diminished denervation. HF power decreased in 5 of 6 humans, with 3 subjects reaching less than 50% of their baseline HF power 90 days after TLD. Conclusions: TLD appeared to attenuate RSA in both sheep and human cohorts of this sub-study. Further confirmation in humans is necessary to allow for RSA attenuation to be used as a marker of successful lung denervation via TLD.

Parasympathetic efferent innervation of the lung is the primary source of lung acetylcholine. Inhaled long-acting anticholinergics improve lung function and symptoms in patients with chronic obstructive pulmonary disease. Targeted lung denervation (TLD), a bronchoscopic procedure intended to disrupt pulmonary parasympathetic inputs, is an experimental treatment for chronic obstructive pulmonary disease. The physiologic and histologic effects of TLD have not previously been assessed. Eleven sheep and two dogs underwent circumferential ablation of the main bronchi with simultaneous balloon surface cooling using a lung denervation system (Nuvaira, Inc., Minneapolis, MN). Changes in pulmonary air flow resistance were monitored before and following TLD. Four animals were assessed for the presence or abolishment of the sensory axon-mediated Hering-Breuer reflex before and following TLD. Six sheep were histologically evaluated 30 days post-TLD for the extent of lung denervation (axonal staining) and effect on peribronchial structures near the treatment site. No adverse clinical effects were seen in any treated animals. TLD produced a ~30% reduction in pulmonary resistance and abolished the sensory-mediated Hering-Breuer reflex. Axonal staining was consistently decreased 60% at 30 days after TLD. All treated airways exhibited 100% epithelial integrity. Damage to other peribronchial structures was minimal. Tissue 1 cm proximal and distal to the treatment was normal, and the esophagus and periesophageal vagus nerve branches were unaffected. TLD treatment effectively denervates the lung while protecting the bronchial epithelium and minimizing effects on peribronchial structures. NEW & NOTEWORTHY The feasibility of targeted lung denervation, a new minimally invasive therapy for obstructive lung disease, has been demonstrated in humans with preliminary clinical studies demonstrating improvement in symptoms, pulmonary function, and exercise capacity in patients with chronic obstructive pulmonary disease. This preclinical animal study demonstrates the ability of targeted lung denervation to disrupt vagal inputs to the lung and details its physiologic and histopathologic effects.