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In Italy, since August 2014, liver transplant (LT) candidates with model for end-stage liver disease (MELD) scores ≥30 receive national allocation priority. This multicenter cohort study aims to evaluate time on the waiting list, dropout rate, and graft survival before and after introducing the macro-area sharing policy. A total of 4,238 patients registered from 2010 to 2018 were enrolled and categorized into an ERA-1 Group (n = 2,013; before August 2014) and an ERA-2 Group (n = 2,225; during and after August 2014). A Cox proportional hazards model was used to estimate the hazard ratio (HR) of receiving a LT or death between the two eras. The Fine-Gray model was used to estimate the HR for dropout from the waiting list and graft loss, considering death as a competing risk event. A Fine-Gray model was also used to estimate risk factors of graft loss. Patients with MELD ≥30 had a lower median time on the waiting list (4 vs.12 days, p < 0.001) and a higher probability of being transplanted (HR 2.27; 95% CI 1.78–2.90; p = 0.001) in ERA-2 compared to ERA-1. The subgroup analysis on 3,515 LTs confirmed ERA-2 (odds ratio 0.56; 95% CI 0.46–0.68; p = 0.001) as a protective factor for better graft survival rate. The protective variables for lower dropouts on the waiting list were: ERA-2, high-volume centers, no competition centers, male recipients, and hepatocellular carcinoma. The protective variables for graft loss were high-volume center and ERA-2, while MELD ≥30 remained related to a higher risk of graft loss. The national MELD ≥30 priority allocation was associated with improved patient outcomes, although MELD ≥30 was associated with a higher risk of graft loss. Transplant center volumes and competition among centers may have a role in recipient prioritization and outcomes. NCT04530240 Italy introduced a new policy in 2014 to give national allocation priority to patients with a model for end-stage liver disease (MELD) score ≥30 (i.e. very sick patients). This policy has led to more liver transplants, fewer dropouts, and shorter waiting times for patients with MELD ≥30. However, a higher risk of graft loss still burdens these cases. Transplant center volumes and competition among centers may have a role in recipient prioritization and outcomes. [Display omitted] • Priority allocation for liver transplantation has been given to MELD ≥30 candidates in Italy since 2014 (ERA-2). • Donor age, MELD ≥30 and ERA-1 were independent predictors of worse graft survival. • MELD ≥30 patients had a lower median time on the waiting list in ERA-2. • Low-volume and multiple regional transplant centres were independent predictors of higher dropout rate. [ABSTRACT FROM AUTHOR]

Summary: The practice of treating candidates for liver transplantation (LT) for hepatocellular carcinoma (HCC), with locoregional therapies, is common in most transplant centers. However, for T1 tumors and expected waiting times to LT <6months, there is no evidence that these treatments are beneficial. For T2 tumors and for longer waiting times, neo-adjuvant treatments are usually performed with transarterial chemoembolization (TACE), ablation techniques and liver resection in selected cases. The treatment choice should be based on the BCLC staging system. At present, there is no evidence of the superiority of ablation/resection vs. TACE, but some studies showed better results of the former in achieving a complete response. The response to neo-adjuvant treatments should be evaluated through mRECIST criteria, but few studies adopted these criteria and properly analyzed factors affecting response. The simultaneous evaluation of the impact of neo-adjuvant therapies on dropout rate, post-LT HCC recurrence and patient survival is rarely reported. Tumor stage and volume, alpha-fetoprotein levels, response to treatments and liver function affect pre-LT outcomes. These same factors, together with vascular invasion and poor tumor differentiation, are major determinants of poor post-LT outcomes. Due to the low number of prospective studies with well-defined entry criteria and the variability of results, the role of downstaging is still to be defined. Novel molecular markers seem promising for the estimation of prognosis and/or response to treatments. With a persistent scarcity of organ donors, neo-adjuvant treatments can help identify patients with different probabilities of cancer progression, and consequently balance the priority of HCC and non-HCC-candidates through revised additional scores for HCC. [ABSTRACT FROM AUTHOR]

Liver stiffness measurement (LSM), assessed by transient elastography (Fibroscan), has been demonstrated to predict post-hepatectomy liver failure in patients who undergo hepatic resection for hepatocellular carcinoma (HCC). However, other complications are also likely to be related to the underlying grade of liver fibrosis. Herein, we aimed to identify predictors of postoperative complications and to build and develop a novel nomogram able to identify patients at risk of developing severe complications. Data from patients who underwent hepatectomy for HCC between 2006 and 2016 at 2 referral centres were retrospectively reviewed. All surgical complications were recorded and scored using the comprehensive complication index (CCI), ranging from 0 (uneventful course) to 100 (death). A CCI ≥26.2 was used as a threshold to define severe complications. During the study period, 471 patients underwent hepatic resection for HCC. Among them, 50 patients (10.6%) had a CCI ≥26.2. Age, model for end-stage liver disease (MELD) score and LSM values, together with serum albumin, were independent predictors of high CCI. The nomogram built on these variables was internally validated and showed good performance (optimism-corrected c-statistic = 0.751). A regression equation to predict the CCI was also established by multiple linear regression analysis: [LSM (kPa) × 0.254] + [age (years) × 0.118] + [MELD score (pt.) × 1.050] − [albumin (g/dl) × 2.395] − 3.639. A novel nomogram, combining LSM values, age and liver function tests provided an excellent preoperative prediction of high CCI in patients with resectable HCC. This predictive model could be used as a reference for clinicians and surgeons to help them in clinical decision-making. Liver stiffness measurement is increasingly being used to assess the degree of liver fibrosis in patients with cirrhosis and/or chronic hepatitis. Using Fibroscan, we developed a novel nomogram to predict severe complications following liver resection for hepatocellular carcinoma, according to the new comprehensive complication index. This tool could be used as a reference for clinicians and surgeons to help them in clinical decision-making. • Liver stiffness measurement (LSM) is emerging as the most promising non-invasive test to predict decompensation after resection. • Little is known about the predictive role of LSM on the occurrence of other complications after resection. • A novel nomogram based on LSM, liver function tests and age was built to predict severe postoperative complications. • This nomogram will serve as a reference for clinicians and surgeons to help them with pre-operative decision-making. [ABSTRACT FROM AUTHOR]

In the context of liver transplantation (LT) for hepatocellular carcinoma (HCC), prediction models are used to ensure that the risk of post-LT recurrence is acceptably low. However, the weighting that 'response to neoadjuvant therapies' should have in such models remains unclear. Herein, we aimed to incorporate radiological response into the Metroticket 2.0 model for post-LT prediction of "HCC-related death", to improve its clinical utility. Data from 859 transplanted patients (2000-2015) who received neoadjuvant therapies were included. The last radiological assessment before LT was reviewed according to the modified RECIST criteria. Competing-risk analysis was applied. The added value of including radiological response into the Metroticket 2.0 was explored through category-based net reclassification improvement (NRI) analysis. At last radiological assessment prior to LT, complete response (CR) was diagnosed in 41.3%, partial response/stable disease (PR/SD) in 24.9% and progressive disease (PD) in 33.8% of patients. The 5-year rates of "HCC-related death" were 3.1%, 9.6% and 13.4% in those with CR, PR/SD, or PD, respectively (p <0.001). Log 10 AFP (p <0.001) and the sum of number and diameter of the tumour/s (p <0.05) were determinants of "HCC-related death" for PR/SD and PD patients. To maintain the post-LT 5-year incidence of "HCC-related death" <30%, the Metroticket 2.0 criteria were restricted in some cases of PR/SD and in all cases with PD, correctly reclassifying 9.4% of patients with "HCC-related death", at the expense of 3.5% of patients who did not have the event. The overall/net NRI was 5.8. Incorporating the modified RECIST criteria into the Metroticket 2.0 framework can improve its predictive ability. The additional information provided can be used to better judge the suitability of candidates for LT following neoadjuvant therapies. In the context of liver transplantation for patients with hepatocellular carcinoma, prediction models are used to ensure that the risk of recurrence after transplantation is acceptably low. The Metroticket 2.0 model has been proposed as an accurate predictor of "tumour-related death" after liver transplantation. In the present study, we show that its accuracy can be improved by incorporating information relating to the radiological responses of patients to neoadjuvant therapies. • Combining morphology and biology represents the most useful approach to select candidates for LT in the context of HCC. • To maintain post-LT 5-year incidence of "HCC-related death" <30%, Metroticket 2.0 criteria had to be restricted in some cases. • Adding mRECIST criteria to Metroticket 2.0 led to correct reclassification of 9.4% of patients with "HCC-related death". • This additional information can be used to better judge the suitability of candidates for LT following neoadjuvant therapies. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is characterized by a low mutation burden and a relatively low number of tumor-infiltrating lymphocytes (TILs), making still difficult to identify targets for specific therapies. The aim of this study was the identification of the prognostic role of TILs in HCC, focusing on their distribution and status of activation. We retrospectively enrolled 41 patients, undergone to liver resection for HCC. A significant increase of CD8 + intratumoral lymphocytes was observed in HCCs with prevalent solid architecture, but with a higher PD-1/TIA1 ratio, suggesting that HCCs with solid architecture have more peri-tumoral lymphocytes, but with minor functionality. At multivariate and univariate analyses, TIA1/CD8 ratio correlated with tumor recurrence, meaning that HCC with more activated TILs are characterized by a higher tumor aggressiveness. The use of a feasible and cheap immunohistochemical panel can help in post-surgical prognostic stratification, focusing not only in the raw number and density of TILs, but more on their state of activation and morphology. [ABSTRACT FROM AUTHOR]

Background & Aims: Knowledge of pre-operative tumour grade is crucial in the management of hepatocellular carcinoma (HCC) because it can influence recurrence and survival after surgery. The accuracy of pre-operative needle core biopsy (NCB) in tumour grading has been assessed in only a few studies with conflicting results. Our aim was to determine the long-term safety and the overall accuracy of NCB in assessing tumour grading in subjects who had undergone liver resection for a single HCC. Methods: Eighty-one cirrhotic patients with HCC who had undergone NCB before liver resection were selected. Only patients with a single HCC and with at least a five-year-follow-up were included. Tumour grading was scored according to a modified Edmondson–Steiner classification: well/moderately (low grade) vs poorly-differentiated (high grade). Results: In the 81 patients with a solitary HCC (mean size 4.1±2.3cm) tumour grade was correctly identified by NCB in 74 out of 81 (91.4%) HCCs. NCB overall sensitivity and specificity were 65% and 98.1%, respectively, with a PPV of 92% and an NPV of 91%. No major complications (in particular tumour seeding) were observed. The overall survival rates at 1, 3, and 5years were 83%, 62%, and 44%, respectively; the recurrence rate after a 5-year-follow-up was 56.2% for low grade and 82.3% for high grade tumours (p <0.007). Conclusions: Pre-operative NCB can be performed on early (<5cm) HCC cirrhotic patients because it provides histologically useful information for HCC management with good accuracy and a low complication rate. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatocellular carcinoma (HCC) prognosis strongly depends upon nuclear grade and the presence of microscopic vascular invasion (MVI). The aim of this study was to develop an artificial neural network (ANN) that is able to predict tumour grade and MVI on the basis of non-invasive variables. Methods: Clinical, radiological, and histological data from 250 cirrhotic patients resected (n =200) or transplanted (n =50) for HCC were analyzed. ANN and logistic regression models were built on a training group of 175 randomly chosen patients and tested on the remaining testing group of 75. Receiver operating characteristics curve (ROC) and k-statistics were used to analyze model accuracy in the prediction of the final histological assessment of tumour grade (G1–G2 vs. G3–G4) and MVI (absent vs. present). Results: Pathologic examination showed G3–G4 in 69.6% of cases and MVI in 74.4%. Preoperative serum alpha-fetoprotein (AFP), tumour number, size, and volume were related to tumour grade and MVI (p <0.05) and were used for ANN building, whereas, tumour number did not enter into the logistic models. In the training group, ANN area under ROC curves (AUC) for tumour grade and MVI prediction were 0.94 and 0.92, both higher (p<0.001) than those of logistic models (0.85 for both). In the testing group, ANN correctly identified 93.3% of tumour grades (k =0.81) and 91% of MVI (k =0.73). Logistic models correctly identified 81% of tumour grades (k =0.55) and 85% of MVI (k =0.57). Conclusion: ANN identifies HCC tumour grades and MVI on the basis of preoperative variables more accurately than the conventional linear model and should be used for tailoring clinical management. [Copyright &y& Elsevier]

Nowadays, the major limit to the immunohistochemical (IHC) analysis of tissue PD-L1 is the high variability of the monoclonal antibodies commercially available. Aims of the present paper are to assess the best clone and the most suitable scoring for PD-L1 IHC determination on human hepatocellular carcinoma (HCC) among three commercially available clones, and to evaluate which PD-L1 clone is the best in predicting HCC aggressiveness in vivo. We built a tissue microarray (TMA) with 60 retrospective HCC cases, including the correspondent non-tumoral tissue. IHC was automatically performed using the following anti-PD-L1 clones: 28.8, SP142, and SP263. As results, we did not find any immunoreactivity for PD-L1 in both neoplastic and normal hepatocytes included in the TMA using the three antibodies. Positivity for PD-L1 was exclusively seen in inflammatory cells within the HCC tissue and in cirrhotic parenchyma. When a gold standard was assessed, the sensitivity of SP142, 28.8 and SP263 was 46 %, 54 % and 85 % respectively. Using the SP263 clone, the absolute number of PD-L1-positive inflammatory cells in the HCC cores was paired with the number of PD-L1-positive inflammatory cells in the corresponding non-tumoral tissue (P = 0.001). Finally, using SP263, the mean number of PD-L1-positive cells was 11.3 ± 12.6 in HCC from deceased patients, versus 4.7 ± 5.2 in alive patients (p = 0.039). SP263 is the most sensitive clone for PD-L1 IHC tissue determination in HCC, as well as the best antibody for the assessment of its biological behavior. [ABSTRACT FROM AUTHOR]