Quirino Lai

Alpha-fetoprotein and modified response evaluation criteria in Solid Tumors progression after locoregional therapy as predictors of hepatocellular cancer recurrence and death after transplantation.

Locoregional therapy (LRT) is being increasingly used for the management of hepatocellular cancer (HCC) in patients listed for liver transplantation (LT). Although several selection criteria have been developed, stratifications of survival according to the pathology of explanted livers and pre‐LT LRT are lacking. Radiological progression according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) and alpha‐fetoprotein (AFP) behavior was reviewed for 306 patients within the Milan criteria (MC‐IN) and 116 patients outside the Milan criteria (MC‐OUT) who underwent LRT and LT between January 1999 and March 2010. A prospectively collected database originating from 6 collaborating European centers was used for the study. Sixty‐one patients (14.5%) developed HCC recurrence. For both MC‐IN and MC‐OUT patients, an AFP slope > 15 ng/mL/month and mRECIST progression were unique independent risk factors for HCC recurrence and patient death. When the radiological Milan criteria (MC) status was combined with radiological and biological progression, MC‐IN and MC‐OUT patients without risk factors had similarly excellent 5‐year tumor‐free and patient survival rates. MC‐IN patients with at least 1 risk factor had worse outcomes, and MC‐OUT patients with at least 1 risk factor had the poorest survival (P < 0.001). In conclusion, both radiological and biological modifications permit documentation of the response to LRT in patients waiting for LT. According to these 2 parameters, tumor progression significantly increases the risk of recurrence and patient death not only for MC‐OUT patients but also for MC‐IN patients. The monitoring of both parameters in combination with the initial radiological MC status is an essential element for further refining the selection criteria for potential liver recipients with HCC. Liver Transpl 19:1108‐1118, 2013.

Neutrophil and platelet-to-lymphocyte ratio as new predictors of dropout and recurrence after liver transplantation for hepatocellular cancer.

There is increasing evidence that systemic inflammation markers like neutrophil (NLR) and platelet‐to‐lymphocyte ratios (PLR) may play a role in the outcome of hepatocellular cancer (HCC). Between January 1994 and March 2012, 181 patients with HCC were registered on the transplant waiting list: 35 (19.3%) patients dropped out during the waiting period and 146 (80.7%) patients underwent liver transplantation (LT). The median follow‐up of this patient cohort was 4.2 years (IQR: 1.8–8.3). On c‐statistics, the last NLR (AUROC = 67.4; P = 0.05) was the best predictor of dropout. The last PLR had an intermediate statistical ability (AUROC = 66.1; P = 0.07) to predict post‐LT tumor recurrence. Patients with a NLR value >5.4 had poor 5‐year intention‐to‐treat (ITT) survival rates (48.2 vs. 64.5%; P = 0.02). Conversely, PLR better stratified patients in relation to tumor‐free survival (TFS) (80.7 vs. 91.6%; P = 0.02). NLR is a good predictor for the risk of dropout, while PLR is a good predictor for the risk of post‐LT recurrence. Use of these markers, which are all available before LT, may represent an additional tool to refine the selection criteria of HCC liver recipients.

Liver transplantation for hepatocellular cancer : UCL experience in 137 adult cirrhotic patients. Alpha-foetoprotein level and locoregional treatment as refined selection criteria.

Liver transplantation (LT) is a validated treatment for selected cirrhotics with hepatocellular cancer (HCC). A retrospective single center study including 137 recipients having proven HCC was done to refine inclusion criteria for LT as well as to look at impact of locoregional treatment (LRT) on outcome. At pre‐LT imaging, 42 (30.6%) patients were Milan criteria (MC)‐OUT; 28 (20.4%) were University of California San Francisco criteria (UCSFC)‐OUT. Pre‐LT LRT was performed in 109 (79.6%) patients. Multivariate analysis identified four factors to be independently predictive of recurrence: tumour number >3, AFP level ≥400 ng/ml, microvascular invasion and rejection needing anti‐lymphocytic antibodies. When considering pre‐transplant variables only, AFP level ≥400 ng/ml (HR = 5.13; P < 0.0001) was the unique risk factor for recurrence; conversely, application of LRT was protective (HR = 0.42; P = 0.04). MC‐IN patients having LRT (n = 79) had the best 5‐year tumour‐free survival (TFS) (91.6%). MC‐IN patients without LRT (n = 16) and MC‐OUT patients with LRT (n = 30) had similar good TFS (72.7% vs.77.5%); finally MC‐OUT patients without LRT (n = 12) had the worst results (45.0%; vs. 1st group: P < 0.0001). Immediate pre‐LT AFP and aggressive pre‐transplant LRT strategy, especially in MC‐OUT patients, are both important elements to further expand inclusion criteria without compromising long‐term results of HCC liver recipients.

Combination of biological and morphological parameters for the selection of patients with hepatocellular carcinoma waiting for liver transplantation

Lai Q, Avolio AW, Manzia TM, Sorge R, Agnes S, Tisone G, Berloco PB, Rossi M. Combination of biological and morphological parameters for the selection of patients with hepatocellular carcinoma waiting for liver transplantation. 
Clin Transplant 2011 DOI: 10.1111/j.1399‐0012.2011.01572.x. 
© 2011 John Wiley & Sons A/S.

Alpha-Fetoprotein and Novel Tumor Biomarkers as Predictors of Hepatocellular Carcinoma Recurrence after Surgery: A Brilliant Star Raises Again

Alpha-fetoprotein (AFP), des-γ-carboxy prothrombin (DCP), and lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) have been developed with the intent to detect hepatocellular carcinoma (HCC) and for the surveillance of at-risk patients. However, at present, none of these tests can be recommended to survey cirrhotic patients at risk for HCC development because of their suboptimal ability for routine clinical practice in HCC diagnosis. Starting from these considerations, these markers have been therefore routinely and successfully used as predictors of survival and HCC recurrence in patients treated with curative intent. All these markers have been largely used as predictors in patients treated with hepatic resection or locoregional therapies, mainly in Eastern countries. In recent studies, AFP has been proposed as predictor of recurrence after liver transplantation and as selector of patients in the waiting list. Use of AFP modification during the waiting list for LT is still under investigation, potentially representing a very interesting tool for patient selection. The development of a new predictive model combining radiological and biological features based on biological markers is strongly required. New genetic markers are continuously discovered, but they are not already fully available in the clinical practice.

Risk factors and surgical management of anastomotic biliary complications after pediatric liver transplantation.

Biliary complications (BCs) still remain the Achilles heel of liver transplantation (LT) with an overall incidence of 10% to 35% in pediatric series. We hypothesized that (1) the use of alternative techniques (reduced size, split, and living donor grafts) in pediatric LT may contribute to an increased incidence of BCs, and (2) surgery as a first treatment option for anastomotic BCs could allow a definitive cure for the majority of these patients. Four hundred twenty‐nine primary pediatric LT procedures, including 88, 91, 47, and 203 whole, reduced size, split, and living donor grafts, respectively, that were performed between July 1993 and November 2010 were retrospectively reviewed. Demographic and surgical variables were analyzed, and their respective impact on BCs was studied with univariate and multivariate analyses. The modalities of BC management were also reviewed. The 1‐ and 5‐year patient survival rates were 94% and 90%, 89% and 85%, 94% and 89%, and 98% and 94% for whole, reduced size, split, and living donor liver grafts, respectively. The overall incidence of BCs was 23% (n = 98). Sixty were anastomotic complications [47 strictures (78%) and 13 fistulas (22%)]. The graft type was not found to be an independent risk factor for the development of BCs. According to a multivariate analysis, only hepatic artery thrombosis and acute rejection increased the risk of anastomotic BCs (P < 0.001 and P = 0.003, respectively). Anastomotic BCs were managed primarily with surgical repair in 59 of 60 cases with a primary patency rate of 80% (n = 47). These results suggest that (1) most of the BCs were anastomotic complications not influenced by the type of graft, and (2) the surgical management of anastomotic BCs may constitute the first and best therapeutic option. Liver Transpl 20:893‐903, 2014.

Hepatocellular cancer: how to expand safely inclusion criteria for liver transplantation.

Purpose of reviewThe Milan criteria are still considered to be the best ones to select patients with hepatocellular cancer (HCC) for liver transplantation. Although the Milan criteria allowed lowering the incidence of tumor recurrence to a remarkable 10%, there is growing evidence that high numbers of patients were unrightfully excluded from a curative liver transplantation when exceeding these criteria. New strategies have been advocated during recent years with the intent not only to enlarge the number of potential transplant candidates, but also to select recipients with the lowest biological risk of recurrence. Recent findingsDifferent ‘biological’ and ‘dynamic’ parameters have been proposed both in western and eastern scenarios, such as &agr;-fetoprotein dynamics, radiological response to locoregional treatments and several inflammatory markers, the neutrophil-to-lymphocyte ratio being the most promising one. SummaryThe paradigm that HCC patients should be selected according to morphological aspects (tumor numbers and diameters) only, based on the almost 20-year old success story of the Milan criteria, should be modified by combining these parameters with newer biological tumor markers in order to further refine the selection for liver transplantation. Such therapeutic algorithm will allow to further improve selection for and thus outcome after liver transplantation for HCC patients.

Predictive criteria for the outcome of patients with acute liver failure treated with the albumin dialysis molecular adsorbent recirculating system.

The aim of this study was to evaluate the improvement of prognostic parameters after treatment with the molecular adsorbent recirculating system (MARS) in patients with fulminant hepatitis (FH). The parameters conducive to a positive prognosis include: Glasgow Coma Scale (GCS) score ≥11, intracranial pressure (ICP) <15 mm Hg or an improvement of the systolic peak flow of 25–32 cm/s via Doppler ultrasound in the middle cerebral artery, lactate level <3 mmol/L, tumor necrosis factor‐α <20 pg/mL, interleukin (IL)‐6 <30 pg/mL, and a change in hemodynamic instability from hyperkinetic to normal kinetic conditions, and so define the timing (and indeed the necessity) of a liver transplant (LTx). From 1999 to 2008 we treated 45 patients with FH with MARS in the intensive care unit of our institution. We analyzed all the parameters that were statistically significant using univariate analysis and considered the patients to be candidates for inclusion in a multivariate logistic regression analysis. Thirty‐six patients survived: 21 were bridged to liver transplant (the BLT group) and 15 continued the extracorporeal method until native liver recovery (the NLR group) with a positive resolution of the clinical condition. Nine patients died before transplantation due to multi‐organ failure. We stratified the entire population into three different groups according to six risk factors (the percentage reduction of lactate, IL‐6 and ICP, systemic vascular resistance index values, GCS <9, and the number of MARS treatments): group A (0–2 risk factors), group B (3–4 risk factors), and group C (5–6 risk factors). Analyzing the prevalence of these parameters, we noted that group A perfectly corresponded to the NLR group, group B corresponded to the BLT group, and group C was composed of patients from the non‐survival group; thus, we were able to select the patients who could undergo a LTx using the predictive criteria. For patients with an improvement of neurological status, cytokines, lactate, and hemodynamic parameters, LTx was no longer necessary and their treatment continued with MARS and standard medical therapy.

Risk analysis of ischemic‐type biliary lesions after liver transplant using octogenarian donors

The use of octogenarian donors to increase the donor pool in liver transplantation (LT) is controversial because advanced donor age is associated with a higher risk of ischemic‐type biliary lesions (ITBL). The aim of this study was to investigate retrospectively the role of a number of different pre‐LT risk factors for ITBL in a selected population of recipients of octogenarian donor grafts. Between January 2003 and December 2013, 123 patients underwent transplantation at our institution with deceased donor grafts from donors of age ≥80 years. Patients were divided into 2 groups based on the presence of ITBL in the posttransplant course. Exclusion criteria were retransplantations, presence of vascular complications, and no availability of procurement liver biopsy. A total of 88 primary LTs were included, 73 (83.0%) with no posttransplant ITBLs and 15 (17.0%) with ITBLs. The median follow‐up after LT was 2.1 years (range, 0.7‐5.4 years). At multivariate analysis, donor hemodynamic instability (hazard ratio [HR], 7.6; P = 0.005), donor diabetes mellitus (HR, 9.5; P = 0.009), and donor age–Model for End‐Stage Liver Disease (HR, 1.0; P = 0.04) were risk factors for ITBL. Transplantation of liver grafts from donors of age ≥80 years is associated with a higher risk for ITBL. However, favorable results can be achieved with accurate donor selection. Donor hemodynamic instability, a donor history of diabetes mellitus, and allocation to higher Model for End‐Stage Liver Disease score recipient all increase the risk of ITBL and are associated with worse graft survival when octogenarian donors are used. Liver Transplantation 22 588‐598 2016 AASLD.

Tumor growth pattern as predictor of colorectal liver metastasis recurrence

BACKGROUND Surgical resection is the gold standard therapy for the treatment of colorectal liver metastases (CRM). The aim of this study was to investigate the impact of tumor growth patterns on disease recurrence. METHODS We enrolled 91 patients who underwent CRM resection. Pathological specimens were prospectively evaluated, with particular attention given to tumor growth patterns (infiltrative vs pushing). RESULTS Tumor recurrence was observed in 65 patients (71.4%). According to multivariate analysis, 3 or more lesions (P = .05) and the infiltrative tumor margin type (P = .05) were unique independent risk factors for recurrence. Patients with infiltrative margins had a 5-year disease-free survival rate significantly inferior to patients with pushing margins (20.2% vs 40.5%, P = .05). CONCLUSIONS CRM patients with pushing margins presented superior disease-free survival rates compared with patients with infiltrative margins. Thus, the adoption of the margin pattern can represent a tool for improved selection of patients for adjuvant treatment.