Liver transplant selection criteria and outcomes in critically ill patients with ACLF.

Background & Aims: Retrospective studies have reported good results with liver transplantation (LTx) for acute-on-chronic liver failure (ACLF) in selected patients. The aim of this study was to evaluate the selection process for LTx in patients with ACLF admitted to the intensive care unit (ICU) and to assess outcomes. Methods: This prospective, non-interventional, single high-volume center study collected data on patients with ACLF admitted to the ICU between 2017-2020. Results: Among 200 patients (mean age: 55.0 ± 11.2 years and 74% male), 96 patients (48%) were considered potential candidates for LTx. Unfavourable addictology criteria (n = 76) was the main reason for LTx ineligibility. Overall, 69 patients were listed for LTx (34.5%) and 50 were transplanted (25% of the whole population). The 1-year survival in the LTx group was significantly higher than in the non-transplanted group (94% vs. 15%, p <0.0001). Among patients eligible for LTx, mechanical ventilation during the first 7 days of ICU stay and an increase in the number of organ failures at day 3 were associated with the absence of LTx or death (odds ratio 9.58; 95% CI 3.29-27.89; p <0.0001 for mechanical ventilation and odds ratio 1.87; 95% CI 1.08-3.24; p <0.027 for increasing organ failures). The probability of not being transplanted in patients with ACLF under mechanical ventilation is >85.4% in those experiencing an increase of 2 organ failures since admission or >91% if experiencing an increase >2 organ failures, at which point futility could be considered. Conclusion: This prospective analysis of outcomes of patients with ACLF admitted to the ICU highlights the drastic nature of selection in this setting. Unfavourable addictology criteria, mechanical ventilation and increasing number of organ failures since admission were predictive of absence of LTx, futility and death. Impact and implications: Liver transplantation (LT) is the best therapeutic option in selected cirrhotic patients admitted to the ICU with acute on chronic liver failure. However, the selection criteria are poorly described and based on retrospective studies. This is the first prospective study that aimed to describe the selection process for LT in a transplant center. Patients with ACLF should be admitted to the ICU and evaluated within a short period of time for LT. In the context of organ shortage, eligibility for LT and either absence of LT, futility of care or death are better clarified in our study. These are mainly determined by prolonged respiratory failure and worsening of organ failures since ICU admission. Considering worldwide variations in the etiology and definition of ACLF, transplant availability and a narrow therapeutic window for transplant further prospective studies are awaited.

New epidemiologic trends in cholangiocarcinoma.

Cholangiocarcinoma (CCA) is the most common biliary tract malignancy and the second most frequent primary hepatic malignancy after hepatocellular carcinoma. During the past three decades, the incidence of intrahepatic cholangiocarcinoma (iCCA) has risen in Western Europe, while the incidence of extrahepatic cholangiocarcinoma (eCCA) has remained stable or fallen. The mortality rates of iCCA, which are greater than those of eCCA, showed also an increasing trend, while those of eCCA remained stable. Well-known risk factors like hepatobiliary flukes, hepatolithiasis and choledochal cysts are important in the development of iCCA particularly in Asian countries. In Western countries, the primary sclerosing cholangitis is the most common risk factor for CCA. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and cirrhosis are considered to be risk factors for iCCA. Emergent risk factors such as obesity, diabetes and MAFLD are increasingly associated mostly with iCCA.

Progressive erythrocytosis under lenvatinib treatment in patients with advanced hepatocellular carcinoma.

PURPOSE: This manuscript reports on the occurrence of early and frequent erythrocytosis in advanced hepatocellular carcinoma (HCC) patients treated with lenvatinib. METHODS: A cohort of 23 patients with advanced HCC, treated with this antiangiogenic drug for at least one month, was retrospectively analyzed. RESULTS: These patients (82.7% men, median age 58.3, cirrhosis in 60.8%) were treated between October 2019 and September 2020 with lenvatinib, as first-line systemic therapy for 82.6% of them. For 20 patients (87%), an early and significant increase in hemoglobin (Hb) level, up to 1.41 g/dL (p < 0.001) was reported and remained elevated. Ten patients (43.5%), all men, reached erythrocytosis (Hb > 16.5 g/dL), 7 were treated with low-dose aspirin for primary thromboprophylaxis and 2 needed phlebotomy. None underwent thromboembolic complications. A significant Hb decrease was observed after treatment discontinuation (p < 0.05). Erythropoietin (EPO) serum levels also increased, which was attributed to HCC after immunostaining for EPO in liver biopsies. The Naranjo adverse drug reaction probability scale documented the relationship between erythrocytosis and lenvatinib and regression at treatment discontinuation. Erythrocytosis was hypothesized to be a class effect of anti-VEGF therapies, the magnitude of which might depend on the IC50 value of each molecule. CONCLUSION: This report documents the frequent occurrence of erythrocytosis during lenvatinib treatment for advanced HCC, likely secondary to EPO secretion by tumor cells through the antiangiogenic activity levatinib. An early and close monitoring of hematologic parameters is, thus, recommended, together with thromboprophylaxis by low-dose aspirin and phlebotomy in case of symptomatic erythrocytosis.

Influence of key histological characteristics on 18F-fluorodeoxyglucose /18F-choline positron emission tomography positivity in hepatocellular carcinoma: A machine learning study.

Purpose: To determine the characteristics influence of key histological on 18F-fluorodeoxyglucose (18F-FDG) and 18F-choline positron emission tomography (PET) positivity in hepatocellular carcinoma (HCC). Materials and methods: The 18F-FDG/18F-choline PET imaging findings of 103 histologically proven HCCs (from 62 patients, of which 47 underwent hepatectomy and 15 received liver transplantation) were retrospectively examined to assess the following key histological parameters: Grade, capsule, microvascular invasion (mVI), macrovascular invasion (MVI), and necrosis. Using a ratio of 70/30 for training and testing sets, respectively, a penalized classification model (Elastic Net) was trained using 100 repeated cross-validation procedures (10-fold cross-validation for hyperparameter optimization). The contribution of each histological parameter to the PET positivity was determined using the Shapley Additive Explanations method. Receiver operating characteristic curves with and without dimensionality reduction were finally estimated and compared. Results: Among the five key histological characteristics of HCC (Grade, capsule, mVI, MVI, and necrosis), mVI and tumor Grade (I-III) showed the highest relevance and robustness in explaining HCC uptake of 18F-FDG and 18F-choline. MVI and necrosis status both showed high instability in outcome predictions. Tumor capsule had a minimal influence on the model predictions. On retaining only mVI and Grades I-III for the final analysis, the area under the receiver operating characteristic (ROC) curve values were maintained (0.68 vs. 0.63, 0.65 vs. 0.64, and 0.65 vs. 0.64 for 18F-FDG, 18F-choline, and their combination, respectively). Conclusion: 18F-FDG/18F-choline PET positivity appears driven by both the Grade and mVI components in HCC. Consideration of the tumor microenvironment will likely be necessary to improve our understanding of multitracer PET positivity.

Is 18 F-FDG/ 18 F-Choline Dual-Tracer PET Behavior a Surrogate of Tumor Differentiation in Hepatocellular Carcinoma : A Tertiary Center Dedicated Study.

BACKGROUND: In hepatocellular carcinoma (HCC) setting, 18 F-FDG and 18 F-choline PET/CT radiotracers are classically considered surrogates of the degree of differentiation, a strong predictor of disease recurrence after curative treatment. Because the corresponding level of evidence has never been assessed as primary end point, the aim of this retrospective study was to specifically assess the relevance of 18 F-FDG combined to 18 F-choline PET imaging as a surrogate of tumor differentiation in HCC. PATIENTS AND METHODS: A total of 49 histologically proven HCCs (46 patients treated by surgery or liver transplantation) with available baseline 18 F-FDG and 18 F-choline PET/CT, dedicated liver contrast-enhanced CT scan, and histological key features were retrospectively reviewed. Hepatocellular carcinoma tumors with well, moderately, and poorly differentiation (grades I, II, and III of the World Health Organization classification) were compared on their PET findings (double-blinded visual analysis and 8 usual semiquantitative metrics) by using nonparametric Kruskal-Wallis analyses of variance. In the case of statistical significance, pairwise post hoc tests with family-wise error rate adjustment were performed. RESULTS: No statistical difference between the grades was observed for any of the patients' or lesions' characteristics ( P > 0.05), except for the macrovascular invasion between the grades I and II (adjusted P = 0.03). None of the PET findings showed statistical difference between the grades, except the tumor-to-background ratio of 18 F-FDG, higher for the grade III compared with grades I (adjusted P = 0.02) and II (adjusted P = 0.01). For less than one third of cases (14 lesions; 28.5%), the regional uptake was judged visually heterogeneous, but none of the related semiquantitative PET metrics were statistically discriminant ( P > 0.05). CONCLUSIONS: Contrary to a common belief, 18 F-FDG/ 18 F-choline dual-tracer PET behavior is not a relevant surrogate of tumor differentiation in HCC. Future multitracer PET studies are mandatory to refine our knowledges of their deep biological meaning in this field.

Resectable and transplantable hepatocellular carcinoma: Integration of liver stiffness assessment in the decision-making algorithm.

BACKGROUND: Liver resection is a curative treatment for hepatocellular carcinoma (HCC) and an alternative to liver transplantation (LT). However, post-liver resection recurrence rates remain high. This study aimed to determine whether liver stiffness measurement (LSM) correlated with recurrence and to propose a method for predicting HCC recurrence exclusively using pre-liver resection criteria. METHODS: This retrospective monocentric study included patients who had undergone LR liver resection for HCC between 2015 and 2018 and who had (1) preoperative alpha-fetoprotein scores indicating initial transplant viability and (2) available preoperative LSM data. We developed a predictive score for recurrence over time using Cox univariate regression and multivariate analysis with a combination plot before selecting the optimal thresholds (receiver operating characteristic curves + Youden test). RESULTS: Sixty-six patients were included. After an average follow-up of 40 months, the recurrence rate was 45% (n = 30). Three-year overall survival was 88%. Four preoperative variables significantly impacted the time to recurrence: age ≥70 years, LSM ≥11 kPa, international normalized ratio (INR) ≥1.2, and maximum HCC diameter ≥3 cm. By assigning 1 point per positive item, patients with a score <2 (n = 22) demonstrated greater mean overall survival (69.7 vs 54.8 months, P = .02) and disease-free survival (52.2 vs 34.7 months, P = .02) than those with a score ≥2. Patients experiencing early recurrence (<1 year) presented a significantly higher preoperative LSM (P = .06). CONCLUSION: We identified a simple preoperative score predictive of early hepatocellular carcinoma recurrence after liver resection, highlighting the role of liver stiffness. This score could help physicians select patients and make decisions concerning perioperative medical treatment.

18F-FDG /18F-Choline Dual-Tracer PET Behavior and Tumor Differentiation in HepatoCellular Carcinoma. A Systematic Review.

Background: Post-operative recurrence remains the strongest prognostic factor of resected hepatocellular carcinoma (HCC), making the accurate selection of patients with curable HCC a crucial issue. PET imaging combining both 18F-FDG and fatty acid synthase (FAS) radiotracers-such as Choline-has shown its interest for the initial staging and therapeutic management of patients with HCC, but its use is still not consensual. Importantly, the very first dual-tracer PET studies suggested 18F-FDG/FAS PET behavior be linked to the degree of differentiation of HCC, a major predictive factor of post-operative recurrence. Although this key molecular imaging concept may impact how dual-tracer PET will be used in early-stage HCC, its level of evidence remains largely unexplored. In this study, we conducted a systematic review of the available evidence-based data to clarify the relevance of dual 18F-FDG/18F-Choline PET in characterizing the degree of differentiation of HCC tumors. Methods: A systematic search of the PubMed/Medline and Embase databases was performed up to November 2021. A systematic review of the dual-tracer 18F-FDG/18F-Choline PET behavior of histology-proven HCC according to their degree of differentiation was conducted. The overall quality of the included studies was critically assessed based on the STROBE guidelines. Information on study date, design, patient cohort characteristics, grade of differentiation of HCC tumors, and the dual-tracer PET behavior per HCC was independently extracted and summarized. Results: From 440 records initially available, 6 full-text articles (99 histology-proven HCC) provided dual-tracer 18F-FDG/18F-Choline PET behavior per HCC tumor grade were included in the systematic review. Based on our analysis, 43/99 HCCs were reported to be well-differentiated, and 56/99 HCCs were reported to be less-differentiated tumors. In the well-differentiated subgroup, more than half were exclusively positive for 18F-Choline (51%), whereas 39% were positive for both 18F-FDG and 18F-Choline. In the less-differentiated subgroup, 37% of HCC patients were positive exclusively for FDG, 36% were positive for both 18F-FDG and 18F-Choline, and 25% were positive exclusively for 18F-Choline. Conclusion: The 18F-FDG/18F-Choline dual-tracer PET behavior of uptake shows high overlap between well- and less differentiated HCC, making the characterization of tumors challenging based on such PET combination alone. Given our growing knowledge of the molecular complexity of HCC, further studies are necessary to refine our understanding of radiotracers' behavior in this field and improve the usefulness of PET imaging in the clinical decision process of HCC.

Number of hepatocellular carcinoma nodules in patients listed for liver transplantation within alpha-fetoprotein score: a new prognostic risk factor.

In France, the listing for liver transplantation (LT) for hepatocellular carcinoma (HCC) requires an AFP score ≤2. This study evaluates whether the number of nodules assessed immediately before LT has a prognostic value among patients already listed within AFP score. Among 143 recipients transplanted with an AFP score ≤2 between 2013 and 2017 in our center, the number of nodules was considered at listing on the waiting list and at last imaging before LT. We compared the overall survival (OS) and disease-free survival (DFS) post-LT of patients with ≤3 and >3 nodules (current classification), and aimed to propose a new criteria to exclude patients on list at high risk of recurrence. The 3-year OS of patients with ≤3 HCC vs. >3 HCC at listing was of 90.3% vs. 67.3%, respectively (P = 0.04). At last imaging, eight listed patients presented ≥5 HCC nodules and had a significantly lower OS than <5 nodules patients (5-year OS: 24.4% vs. 78.1%; P = 0.01). Although the current AFP score offers satisfactory outcomes, we highlight the poorer outcomes when ≥5 nodules persist or appear after listing. A modification of the AFP score is mandatory to consider exclusion of high-risk patients already listed for LT program.

Predictive value of liver damage for severe early complications and survival after heart transplantation: A retrospective analysis.

BACKGROUND: Hepatic dysfunction is often associated with advanced heart failure. Its impact on complications following heart transplantation is not well known. We studied the influence of preoperative hepatic dysfunction on the results of heart transplantation with a specific priority access for critical patients. METHODS: Consecutive heart transplantation patients were retrospectively analyzed at listing to detect predictive factors for early complications and survival following heart transplantation. RESULTS: Among heart transplant candidates (n=384), median age was 52 years, dilated and ischemic cardiopathies were present in 44% and 32%, respectively. Clinical ascites was present in 15.6% and median MELD score was 13. A temporary circulatory support and a national priority access were necessary in 14.8% and 35% respectively. Whereas 12% of the global cohort died on the waiting list, 321 patients were transplanted, 34.2% suffered from severe early complications, 26.3% needed extracorporeal membrane oxygenation in postoperative period, 27.7% died before 3 months with a 5-year survival rate of 56%. At listing, clinical ascites, and creatinine were independently associated with specific early complications i.e. primary graft dysfunction and septic shock respectively. Bilirubin level was also an independent marker of other early complications. Finally, need for postoperative circulatory support and postoperative 90-day mortality were strongly and exclusively associated with clinical ascites and creatinine at listing. In a subgroup analysis, we predicted more accurately the postoperative survival at 3 months by combining MELD score and ascites. CONCLUSION: At listing, hepatic and renal dysfunctions are independent risk factors that could predict severe early complications and mortality following heart transplantation in the most severe patients.

Triple therapy with first generation HCV protease inhibitors: lead-in or no lead-in phase?

The standard therapeutic approach currently recommended for patients infected with genotype 1 hepatitis C virus (HCV) is the triple therapy combining pegylated interferon (PEG-IFN), ribavirin (RBV)and NS3/NS4 protease inhibitors, boceprevir or telaprevir [1]. Protease inhibitors (PIs) are direct acting antiviral drugs (DAA) which, when added to PEG-IFN and RBV, are able to achieve a significant gain in terms of sustained virological response (SVR), both in naïve and treatment-experienced patients [2­5]. The use of these new molecules, despite its in contestable benefits, reveals on the other hand new challenges: the emergence of variants with reduced sensitivity to PIs, the development of new or higher rate of side effects, drug to drug interactions, and significant increase in the overall cost of antiviral therapy. Among the two DAAs commonly used in combination with PEG-IFN and RBV (PEG-IFN/RBV) for the treatment of genotype 1 HCV patients, boceprevir has been licensed with a lead-in phase, while telaprevir has been licensed without. EMA approved regimens of both drugs are reported in Figs. 1 and 2. The lead-in phase represents an initial period of 4 weeks of dual therapy with PEG-IFN/RBV, in standard doses, followed by triple therapy. The concept of lead-in phase was initiated by the Schering­Plough company in order to improve efficacy of boceprevir-based triple therapy. Indeed, by lowering HCV RNA level, a short course of PEG-IFN/RBV may theoretically reduce the risk of viral breakthrough or resistance. However, there is still much controversy regarding the utility of the lead-in phase, some authors advocating its role in improving, and/or predicting triple therapy effectiveness, while others view it as a useless complication of the therapeutic regimen, its chief disadvantage being the inconvenience to the patient.

An overview of nonalcoholic steatohepatitis: past, present and future directions.

Nonalcoholic steatohepatitis (NASH) emerged from an anecdotal disease first described in 1981 to the most common cause of incident chronic liver disease at the end of the current decade. This article describes, from a historical perspective, some of the landmark changes in our perception and understanding of this disease. Natural history studies have shown the potential for serious liver damage and ultimately increased overall and liver-related mortality. The recognition of insulin resitance as an almost universal underlying condition in patients with NASH, its role as a major determinant of steatogenesis and possibly liver disease progression contributed to the identification of a probable cause for this disease, one that is amenable to therapeutic intervention. Consequently, screening for liver injury in patients with metabolic risk factors entered clinical practice in hepatology and endocrine diseases. NASH can coexist with other frequent liver diseases and often aggravate the course of liver injury; therefore it should be seen as an independent disease and not as an entity diagnosed only by exclusion of other hepatopathies. Finally, steatosis can have systemic consequences as it worsens insulin resistance, predicts the emergence of metabolic complications and increases the risk for cardiovascular events. Priorities for future research are the optimisation of non-invasive screening strategies, the identification of patients at risk of liver disease progression, the understanding of the hepatic carcinogenic potential and testing innovative pharmacological targets for therapy.