Transplant benefit for patients with hepatocellular carcinoma

Although liver transplantation is theoretically the best treatment for hepatocellular carcinoma(HCC),it is limited by the realities of perioperative complications,and the shortage of donor organs.Furthermore,in many cases there are available alternative treatments such as resection or locoregional therapy.Deciding upon the best option for a patient with HCC is complicated,involving numerous ethical principles including:urgency,utility,intention-to-treat survival,transplant benefit,harm to candidates on waiting list,and harm to living donors.The potential contrast between different principles is particularly relevant for patients with HCC for several reasons:(1)HCC candidates to liver transplantation are increasing;(2)the great prognostic heterogeneity within the HCC population;(3)in HCC patients tumor progression before liver transplantation may significantly impair post transplant outcome;and(4)effective alternative therapies are often available for HCC candidates to liver transplantation.In this paper we suggest that allocating organs by transplant benefit could help balance these competing principles,and also introduce equity between patients with HCC and nonmalignant liver disease.We also propose a triangular equipoise model to help decide between deceased donor liver transplantation,living donor liver transplantation,or alternative therapies.

Prediction of hepatocellular carcinoma biological behaviorin patient selection for liver transplantation

Morphological criteria have always been considered the benchmark for selecting hepatocellular carcinoma(HCC)patients for liver transplantation(LT).These criteria,which are often inappropriate to express the tumor’s biological behavior and aggressiveness,offer only a static view of the disease burden and are frequently unable to correctly stratify the tumor recurrence risk after LT.Alpha-fetoprotein(AFP)and its progression as well as AFP-m RNA,AFP-L3%,des-γ-carboxyprothrombin,inflammatory markers and other serological tests appear to be correlated with post-transplant outcomes.Several other markers for patient selection including functional imaging studies such as18F-FDG-PET imaging,histological evaluation of tumor grade,tissue-specific biomarkers,and molecular signatures have been outlined in the literature.HCC growth rate and response to pre-transplant therapies can further contribute to the transplant evaluation process of HCC patients.While AFP,its progression,and HCC response to pretransplant therapy have already been used as a part of an integrated prognostic model for selecting patients,the utility of other markers in the transplant setting is still under investigation.This article intends to review the data in the literature concerning predictors that could be included in an integrated LT selection model and to evaluate the importance of biological aggressiveness in the evaluation process of these patients.

Role of blood AFP mRNA and tumor grade in the preoperative prognostic evaluation of patients with hepatoceiluiar carcinoma

AIM: To explore the potential prognostic role of preoperative tumor grade and blood AFP mRNA in a cohort of patients with hepatocellular carcinoma (HCC)eligible for radical therapies according to a well-defined treatment algorithm not including nodule size and number as absolute selection criteria.METHODS: Fifty patients with a diagnosis of HCC were prospectively enrolled in the study. Inclusion criteria were: (1) histological assessment of tumor grade by means of percutaneous biopsies; (2) determination of AFP mRNA status in the blood; (3) patient's eligibility for radical therapies.RESULTS: At preoperative evaluation, 54% of the study group had a well-differentiated HCC, 42% had AFP mRNA in the blood, 40% had a tumor larger than 5 cm and 56% had more than one nodule. Surgery (resection or liver transplantation) was performed in 29 patients,while 21 had percutaneous ablation procedures. After a median follow-up of 28 mo, 12-, 24-, and 36-mo survival rates were 78%, 58%, and 51%, respectively. Surgical therapy, performance status and three tumor-related variables (AFP mRNA, HCC grade and gross vascular invasion) resulted as significant survival predictors at univariate analysis. Nodule size and number did not perform as significant prognosticators. Multivariate study selected only surgical therapy and a biologically early HCC profile (AFP mRNA negative and well-differentiated tumor without gross vascular invasion) as independent survival variables.CONCLUSION: The preoperative determination of tumor grade and blood AFP mRNA status may potentially refine the prognostic evaluation of HCC patients and improve the selection process for radical therapies.

Management of hepatitis C infection before and after liver transplantation

Chronic hepatitis C(CHC) is the most common indication for liver transplantation(LT). Aggressive treatment of hepatitis C virus(HCV) infection before cirrhosis development or decompensation may reduce LT need and risk of HCV recurrence post-LT. Factors associated with increased HCV risk or severity of recurrence include older age, immunosuppression, HCV genotype 1 and high viral load at LT. HCV recurrence post-LT leads to accelerated liver disease and cirrhosis development with reduced graft and patient survival. Currently, interferon(IFN)-based regimens can be used in dualagent regimens with ribavirin, in triple-agent antiviral strategies with direct-acting antivirals(e.g., protease inhibitors telaprevir or boceprevir), or before transplant in compensated patients to reduce HCV viral load to prevent or reduce the risk of post-LT recurrence and complications; they cannot be used in patients with decompensated cirrhosis. IFN-based regimens are used in less than half of HCV-infected patients waiting for LT due to extremely low efficacy and poor tolerability. However, antiviral therapy is indicated after LT in patients with histologically confirmed CHC despite tolerability issues. Improvements in side effect management have increased survival in patients achieving therapeutic targets. HCV treatment pre- and post-LT results in significant health care costs especially when lack of efficacy leads to disease worsening, although studies have shown sofosbuvir treatment before LT vs conventional post-LT dual antiviral is cost effective. The suboptimal efficacy and tolerability of IFN-based therapies, plus the significant economic burden, means the need for effective and well tolerated IFN-free antiHCV therapy for pre- and post-LT remains high.

BCLC staging system and liver transplantation:From a stage to a therapeutic hierarchy

The Barcelona Clinic Liver Cancer(BCLC)system was proposed in 1999 with the intent to improve a therapeutic algorithm for the management of patients with hepatocellular carcinoma(HCC)[1].Both the European and the American Guidelines on the Treatment of HCC have endorsed the BCLC as the standard staging algorithm with prognostic and therapeutic implications[2,3].The BCLC staging system stratifies HCC patients into five stages(0,A,B,C and D).According to the algorithm,liver transplantation(LT)is indicated only in patients in the stages BCLC 0 and A,special situations provided.

Molecular Mechanism of the Specificity of Protein Import into Chloroplasts and Mitochondria in Plant Cells

Plants possess both types of endosymbiotic organelles, chloroplasts and mitochondria. Transit peptides and presequences function as signal sequences for specific import into chloroplasts and mitochondria, respectively. However, how these highly similar signal sequences confer the protein import specificity remains elusive. Here, we show that mitochondrial- or chloroplast-specific import involves two distinct steps, specificity determination and translocation across envelopes, which are mediated by the N-terminal regions and functionally interchangeable C-terminal regions, respectively, of transit peptides and presequences. A domain harboring multiple-arginine and hydrophobic sequence motifs in the N-terminal regions of presequences was identified as the mitochondrial specificity factor. The presence of this domain and the absence of arginine residues in the N-terminal regions of otherwise common targeting signals confers specificity of protein import into mitochondria and chloroplasts, respectively. AtToc159, a chloroplast import receptor, also contributes to determining chloroplast import specificity. We propose that common ancestral sequences were functionalized into mitochondrial- and chloroplast-specific signal sequences by the presence and absence, respectively, of multiple-arginine and hydrophobic sequence motifs in the N-terminal region.

Protein Domains Involved in Assembly in the Endoplasmic Reticulum Promote Vacuolar Delivery when Fused to Secretory GFP, Indicating a Protein Quality Control Pathway for Degradation in the Plant Vacuole

The correct folding and assembly of newly synthesized secretory proteins are monitored by the protein quality control system of the endoplasmic reticulum （ER）. Through interactions with chaperones such as the binding protein （BiP） and other folding helpers, quality control favors productive folding and sorts for degradation defective proteins. A major route for quality control degradation identified in yeast, plants, and animals is constituted by retrotranslocation from the ER to the cytosol and subsequent disposal by the ubiquitin/proteasome system, but alternative routes involving the vacuole have been identified in yeast. In this study, we have studied the destiny of sGFP418, a fusion between a secretory form of GFP and a domain of the vacuolar protein phaseolin that is involved in the correct assembly of phaseolin and in BiP recognition of unassembled subunits. We show that sGFP418, despite lacking the phaseolin vacuolar sorting signal, is delivered to the vacuole and fragmented, in a process that is inhibited by the secretory traffic inhibitor brefeldin A. Moreover, a fusion between GFP and a domain of the maize storage protein γ-zein involved in zein polymerization also undergoes post-translational fragmentation similar to that of sGFP418. These results show that defective secretory proteins with permanently exposed sequences normally involved in oligomerization can be delivered to the vacuole by secretory traffic. This strongly suggests the existence of a plant vacuolar sorting mechanism devoted to the disposal of defective secretory proteins.

Effects of calibration process on the simulation of rear-end conflicts at roundabouts

A methodology for calibrating and validating VISSIM simulation model is presented that allows to replicate the observed vehicles conflicts. A roundabout case study has been selected to test the usefulness of a combined approach of VISSIM simulation package and the surrogate safety assessment model(SSAM) for providing reliable estimates of traffic conflicts. Safety performance has been assessed from the field by video-recording vehicle interactions at the roundabout, and then expressed in terms of time to collision(TTC)values.The proposed calibration procedure has been performed by a multistage methodology involving microscopic drivers' car following behavior parameters to enhance the correlation between observed and simulated queue lengths at the roundabout's entries. The calibration procedure is based on a statistical screening of inputs leading to a linear expression relating significant parameters to the queue length. The best estimates of the model's parameters have been determined using a genetic algorithm technique.The spatial distribution of the rear-end conflicts and the TTC values determined by SSAM have been finally compared with the observed ones to analyze the capability of the model of replicating rear-end conflicts.The results suggest to this calibration procedure impacts positively on the estimate of the safety performance measures obtained through the simulation processes.Notwithstanding the good results in the evaluation of the model's accuracy, the simulation seems to fail in reproducing the traffic phenomena linked to unusual driving behavior, and therefore it is not able to replicate forced drivers' maneuvers that can lead to a conflict situation.

Role of laparoscopic and robotic liver resection compared to open surgery in elderly hepatocellular carcinoma patients: a systematic review and meta-analysis

Aim:This study aimed to compare mini-invasive liver resection(MILR)(laparoscopic/robotic approach)and open liver resection(OLR)for hepatocellular carcinoma(HCC)in elderly patients with regard to clinical and oncological outcomes through a comprehensive systematic review.Methods:The MEDLINE and Cochrane Library electronic databases were systematically searched from 2009 to December 2019 to identify relevant English written studies comparing MILR and OLR.The main endpoints were Child-Pugh score,serum total bilirubin level,comorbidity,presence/absence of cirrhosis,minor/major resection,challenge segment approach,operative time,estimated intraoperative blood loss,liver failure rate,morbidity according to the Clavien-Dindo classification,length of hospital stay(LOS),postoperative mortality,number of lesions,tumor size,readmission rate,recurrence rate and survival at 1,3 and 5 years after operation.Meta-analyses provided pooled relative risks and mean differences for these outcomes.Cut-off for"elderly age"was set at 65 years old.Results:Eight studies that evaluated 3051 patients who underwent liver resection for HCC,with 950 undergoing MILR and 2101 OLR,were included after the screening process.Blood loss,morbidity,and LOS showed statistical significance in favor of MILR.In particular,with respect to OLR,MILR decreased on average blood loss by 161.43 mL(95%CI:250.24-72.61),risk of morbidity by 42%(P<0.01),LOS by 4 days(95%CI:7-2),postoperative mortality risk by 47%(although not significantly,P=0.06).Major resections were significantly more common in the OLR group(P<0.0001).Recurrence,although not significant(P=0.06),must also be emphasized.The two surgical approaches were comparable with regard to the other outcomes investigated.Conclusion:Meta-analyses confirmed the advantages of MILR in terms of short perioperative outcomes,where it may promote the extension of liver resection to HCC patients with borderline liver function.MILR may be considered an important treatment option with significant benefits in the elderly and fragile patients.However,large well-designed prospective comparative studies or randomized controlled trials would be necessary to further confirm our conclusions.