Jean Hardwigsen

Liver transplantation for hepatocellular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria.

BACKGROUND & AIMS The aim of this study was to generate an improved prognostic model for predicting recurrence in liver transplant candidates with hepatocellular carcinoma (HCC). METHODS Predictors of recurrence were tested by a Cox model analysis in a training cohort of 537 patients transplanted for HCC. A prognostic score was developed and validated in a national cohort of 435 patients followed up prospectively. RESULTS α-Fetoprotein (AFP) independently predicted tumor recurrence and correlated with vascular invasion and differentiation. At a Cox score threshold of 0.7 (area under the receiver operating characteristic curve, 0.701; 95% confidence interval, 0.63-0.76; accuracy, 75.8%), a model combining log(10) AFP, tumor size, and number was highly predictive of tumor recurrence and death. By using a simplified version of the model, with untransformed AFP values, a cut-off value of 2 was identified. In the validation cohort, a score greater than 2 predicted a marked increase in 5-year risk of recurrence (50.6% ± 10.2% vs 8.8% ± 1.7%; P < .001) and decreased survival (47.5% ± 8.1% vs 67.8% ± 3.4%; P = .002) as compared with others. Among patients exceeding Milan criteria, a score of 2 or lower identified a subgroup of patients with AFP levels less than 100 ng/mL with a low 5-year risk of recurrence (14.4% ± 5.3% vs 47.6% ± 11.1%; P = .006). Among patients within Milan criteria, a score greater than 2 identified a subgroup of patients with AFP levels greater than 1000 ng/mL at high risk of recurrence (37.1% ± 8.9% vs 13.3% ± 2.0%; P < .001). Net reclassification improvement showed that predictability of the AFP model was superior to Milan criteria. CONCLUSIONS Prediction of tumor recurrence is improved significantly by a model that incorporates AFP. We propose the adoption of new selection criteria for HCC transplant candidates, taking into account AFP.

Impact of pretransplantation transarterial chemoembolization on survival and recurrence after liver transplantation for hepatocellular carcinoma.

The actual impact of transarterial chemoembolization before liver transplantation (LT) for hepatocellular carcinoma (HCC) on patient survival and HCC recurrence is not known. Between 1985 and 1998, 479 patients with HCC in 14 French centers were evaluated for LT. Among these 479 patients, this case‐control study included 100 patients who received transarterial chemoembolization before LT (TACE group) and 100 control patients who did not receive chemoembolization (no‐TACE group). Patients and controls were matched for the pre‐LT tumor characteristics, the period of transplantation, the time spent on the waiting list, and pre‐ and posttransplantation treatments. Kaplan‐Meier estimates were calculated 5 years after LT and were compared with the log‐rank test. The mean waiting time before LT was 4.2 ± 3.2 months in the TACE group and 4.3 ± 4.4 months in the no‐TACE group. The median number of TACE procedures was 1 (range: 1‐12). Demographic data, median alpha‐fetoprotein level (21.6 ng/mL and 22.0 ng/mL, respectively), and pre‐ and post‐LT morphologic characteristics of the tumors did not differ in the TACE and no‐TACE groups. Overall 5‐year survival was 59.4% with TACE and 59.3% without TACE (ns). Survival rates did not differ significantly between the two groups with respect to the time on the waiting list, the tumor diameter, or the type of TACE (selective or nonselective). In the TACE group, 30 patients had tumor necrosis ≥80% on the liver explant with a 5‐year survival rate of 63.2%, compared with 54.2% among their matched controls (P = 0.9). In conclusion, with a mean waiting period of 4.2 months and 1 TACE procedure, pre‐LT TACE does not influence post‐LT overall survival and disease‐free survival. (Liver Transpl 2005;11:767–775.)

Impact of UCSF criteria according to pre‐ and post‐OLT tumor features: Analysis of 479 patients listed for HCC with a short waiting time

Orthotopic liver transplantation (OLT) indication for hepatocellular carcinoma (HCC) is currently based on the Milan criteria. The University of California, San Francisco (UCSF) recently proposed an expansion of the selection criteria according to tumors characteristics on the explanted liver. This study: 1) assessed the validity of these criteria in an independent large series and 2) tested for the usefulness of these criteria when applied to pre‐OLT tumor evaluation. Between 1985 and 1998, 479 patients were listed for liver transplantation (LT) for HCC and 467 were transplanted. According to pre‐OLT (imaging at date of listing) or post‐OLT (explanted liver) tumor characteristics, patients were retrospectively classified according to both the Milan and UCSF criteria. The 5‐yr survival statistics were assessed by the Kaplan‐Meier method and compared by the log‐rank test. Pre‐OLT UCSF criteria were analyzed according to an intention‐to‐treat principle. Based on the pre‐OLT evaluation, 279 patients were Milan+, 44 patients were UCSF+ but Milan− (subgroup of patients that might benefit from the expansion), and 145 patients were UCSF− and Milan−. With a short median waiting time of 4 months, 5‐yr survival was 60.1 ± 3.0%, 45.6 ± 7.8%, and 34.7 ± 4.0%, respectively (P < 0.001). The 5‐yr survival was arithmetically lower in UCSF+ Milan− patients compared to Milan+ but this difference was not significant (P = 0.10). Based on pathological features of the explanted liver, 5‐yr survival was 70.4 ± 3.4%, 63.6 ± 7.8%, and 34.1 ± 3.1%, in Milan+ patients (n = 184), UCSF+ Milan− patients (n = 39), and UCSF− Milan− patients (n = 238), respectively (P < 0.001). However, the 5‐yr survival did not differ between Milan+ and UCSF+ Milan− patients (P = 0.33). In conclusion, these results show that when applied to pre‐OLT evaluation, the UCSF criteria are associated with a 5‐yr survival below 50%. Their applicability is therefore limited, despite similar survival rates compared to the Milan criteria, when the explanted liver is taken into account. Liver Transpl 12:1761‐1769, 2006.

Resection of the Inferior Vena Cava for Neoplasms With or Without Prosthetic Replacement: A 14-Patient Series

ObjectiveTo review the outcome of resection of the suprarenal or infrarenal inferior vena cava (IVC) and possible indications for prosthetic replacement. Summary Background DataInvolvement of the IVC has long been considered a limiting factor for curative surgery for advanced tumors because the surgical risks are high and the long-term prognosis is poor. Prosthetic replacement of the IVC is controversial. MethodsThe authors retrospectively reviewed a 7-year series of 14 patients who underwent en bloc resection including a circumferential segment of the IVC. The tumor was malignant in 12 patients and benign in 2. The resected segment of the IVC was located above the kidneys in eight patients and below in six. Resection was performed without extracorporeal circulation in all patients. ResultsIn all but one patient, IVC resection was associated with multivisceral resection, including extended nephrectomy (n = 8), major hepatic resection (n = 3), digestive resection (n = 3), and infrarenal aortic replacement (n = 2). Prosthetic replacement of the IVC was performed in eight patients cases and was more common after resection of a suprarenal (6/8) than an infrarenal segment of the IVC (2/6). One patient died of multiorgan failure. Major complications occurred in 29% of patients. Symptomatic complications of prosthetic replacement occurred in one patient (acute postoperative thrombosis, successfully treated by surgical disobstruction). Graft-related infection was not observed. Marked symptoms of venous obstruction developed in three of the six patients who did not undergo venous replacement. In patients undergoing surgery for malignant disease, the estimated median survival was 37 months and the actuarial survival rate was 67% at 1 year. ConclusionMultivisceral resection including a segment of IVC is justified to achieve complete extirpation in selected patients with extensive abdominal tumors. Prosthetic replacement of the IVC may be required, particularly in cases of suprarenal resection. It is a safe procedure with a low complication rate and good functional results.

Conversion from a calcineurin inhibitor to everolimus therapy in maintenance liver transplant recipients: a prospective, randomized, multicenter trial.

Calcineurin inhibitors (CNIs) contribute to renal dysfunction following liver transplantation. This prospective, randomized, multicenter, 6‐month study (with an additional 6 months of follow‐up) evaluated whether everolimus with CNI reduction or discontinuation would improve renal function in maintenance liver transplant recipients experiencing CNI‐related renal impairment. Patients started everolimus therapy with CNI reduction or discontinuation (n = 72) or continued receiving standard‐exposure CNI (n = 73). At month 6, 80% of the patients who had converted to everolimus had discontinued the CNI. The mean change in creatinine clearance (CrCl) from baseline to month 6 was similar between groups (everolimus, 1.0 ± 10.2 mL/minute; controls, 2.3 ± 7.8 mL/minute; P = 0.46), so the primary study endpoint (8 mL/minute difference in the change in CrCl) was not achieved. Among patients who continued everolimus according to the protocol, the mean increase in CrCl was 2.1 (n = 53) and 3.8 mL/minute (n = 38) at months 6 and 12, respectively, versus 2.4 (n = 68) and 3.5 mL/minute in controls (n = 51). The high frequency of CNI dose reductions in controls (77% of the patients) and the relatively long mean time post‐transplant (>3 years) likely contributed to the small difference in CrCl. Biopsy‐proven acute rejection occurred in 1.4% of the patients in each group, with no graft losses. Study drug discontinuation was higher in everolimus‐treated patients, and adverse events were more frequent. These data demonstrate that everolimus allows for discontinuation or a major reduction of CNI exposure in liver allograft recipients suffering CNI‐related renal dysfunction without a loss of efficacy. Trials targeting earlier conversion post‐transplantation are required to confirm the efficacy and safety of everolimus for improving renal function after liver transplantation. Liver Transpl 15:1262–1269, 2009.

Resection of hepatocellular carcinoma with tumor thrombus in the major vasculature. A European case-control series

Tumor thrombus in major vasculature is a frequent finding with a poor long-term prognosis in patients with hepatocellular carcinoma (HCC). The utility of surgical resection is still controversial. This study compared morbidity and survival after resection for HCC with and without tumor thrombus. Data of 108 patients who underwent major hepatic resection for HCC were prospectively recorded. Patients were divided into two groups. The venous thrombectomy (VT) group included 26 patients who had HCC with tumor thrombus in the portal or hepatic veins. The matched control group included 82 patients who had HCC without tumor thrombus. Surgical technique, early outcome, and late survival were analyzed in each group. Multivariate analysis was performed to assess the prognostic value of this feature. Surgical technique was comparable in the VT and control group with regard to extent of hepatectomy, procedure duration, and transfusion requirements. Early postoperative outcome was also comparable. Actuarial survival at 1, 3, and 5 years was 38%, 20%, and 13%, respectively, in the VT group (median: 9 months) versus 74%, 56%, and 33%, respectively, in the control group (median: 41 months). In the subgroup of patients with tumor thrombus limited to the portal vein, actuarial survival at 1, 3, and 5 years was 50%, 26%, and 17%, respectively, (median: 12 months) and two patients lived longer than 5 years. Multivariate analysis showed that incomplete resection, alphafetoprotein level greater than 100 N, more than two tumor nodules, and tumor thrombus in major vasculature were independent factors of poor prognosis. Survival after resection for HCC with tumor thrombus in the major vasculature is poorer than after resection for HCC without tumor thrombus. However, an aggressive surgical strategy can provide significant survival with comparable morbidity in selected cases, that is, tumor thrombus located in the portal vein only and expected complete resection of the lesions.

Morbidity of Major Hepatic Resections: a 100-Case Prospective Study

OBJECTIVE To assess the morbidity and its main risk factors after major hepatic resection. DESIGN Retrospective study of prospectively collected data. SETTING University hospital, France. SUBJECTS 100 consecutive patients who underwent major hepatic resections, 1989-95. INTERVENTIONS Major hepatic resection, defined as resection involving 3 or more segments according to Couinauds classification, in all cases. MAIN OUTCOME MEASURES All complications that affected outcome or prolonged hospital stay. Risk factors identified by univariate and multivariate analysis. RESULTS 45 patients developed at least 1 complication and 7 died. The most common complications were: pleural effusion (n = 21), hepatic failure (n = 12), and ascites (n = 9). Univariate analysis showed that the following variables were significantly related to the morbidity: age >55 years, American Society of Anesthesiologists (ASA) grade II or more, bilirubin >80 micromol/L, alkaline phosphatase activity more than double the reference range, malignant tumours, abnormal liver parenchyma, simultaneous surgical procedures, operative time >4 hours, and perioperative blood transfusion > or =600 ml. The extent of resection did not correlate with postoperative complications. Multivariate analysis showed that volume of blood transfusion > or =600 ml and simultaneous surgical procedures were the most important independent risk factors for complicated outcome. CONCLUSIONS The morbidity associated with major hepatic resections remains high, and the main determinants of outcome are intraoperative surgeon-related factors.

Conversion to everolimus in maintenance liver transplant patients: a multicenter, retrospective analysis.

Data on the conversion of patients to everolimus after liver transplantation are sparse. A multicenter, retrospective study followed 240 maintenance liver transplant patients to analyze the current indications for everolimus conversion, the employed regimens and exposure levels, and the impact on efficacy and safety. The mean time from transplantation to the introduction of everolimus was 4.9 ± 5.2 years. The mean everolimus trough level was 7.3 ± 4.1 ng/mL at month 1 and 8.1 ± 4.7 ng/mL at month 12. At 12 months, 61.6% of the patients were no longer receiving calcineurin inhibitor (CNI) therapy. The mean estimated glomerular filtration rate (eGFR) according to the Cockcroft‐Gault formula was 64.2 ± 30.0 mL/minute on day 0 and 68.4 ± 32.5 mL/minute at month 12 (P = 0.007). Among patients with baseline serum creatinine levels ≥ 130 μmol/L, the eGFR values were 44.3 ± 15.7 mL/minute on day 0 and 53.7 ± 26.0 mL/minute at month 12 (P = 0.003). Four patients (1.6%) developed mild or moderate biopsy‐proven acute rejection. Adverse events led to everolimus discontinuation in 12.9% of the patients. After the initiation of everolimus, the mean white blood cell count decreased significantly, and the total cholesterol and triglyceride levels increased significantly. In this retrospective analysis of the largest cohort of maintenance liver transplant patients analyzed after their conversion to everolimus, more than 60% of the patients were kept free of CNIs with a very low risk of acute rejection and with an acceptable safety profile. Randomized trials in which maintenance liver transplant patients are switched to everolimus in response to clinical indications or preemptively are warranted. Liver Transpl 17:905–913, 2011.

Mapping of NKp46+ cells in healthy human lymphoid and non-lymphoid tissues

Understanding Natural Killer (NK) cell anatomical distribution is key to dissect the role of these unconventional lymphocytes in physiological and disease conditions. In mouse, NK cells have been detected in various lymphoid and non-lymphoid organs, while in humans the current knowledge of NK cell distribution at steady state is mainly restricted to lymphoid tissues. The translation to humans of findings obtained in mice is facilitated by the identification of NK cell markers conserved between these two species. The Natural Cytotoxicity Receptor (NCR) NKp46 is a marker of the NK cell lineage evolutionary conserved in mammals. In mice, NKp46 is also present on rare T cell subsets and on a subset of gut Innate Lymphoid Cells (ILCs) expressing the retinoic acid receptor-related orphan receptor γt (RORγt) transcription factor. Here, we documented the distribution and the phenotype of human NKp46+ cells in lymphoid and non-lymphoid tissues isolated from healthy donors. Human NKp46+ cells were found in splenic red pulp, in lymph nodes, in lungs, and gut lamina propria, thus mirroring mouse NKp46+ cell distribution. We also identified a novel cell subset of CD56dimNKp46low cells that includes RORγt+ ILCs with a lineage−CD94−CD117brightCD127bright phenotype. The use of NKp46 thus contributes to establish the basis for analyzing quantitative and qualitative changes of NK cell and ILC subsets in human diseases.

Long term results of liver transplantation for Wilson’s disease: Experience in France

BACKGROUND & AIMS Liver transplantation (LT) is the therapeutic option for severe complications of Wilsons disease (WD). We aimed to report on the long-term outcome of WD patients following LT. METHODS The medical records of 121 French patients transplanted for WD between 1985 and 2009 were reviewed retrospectively. Seventy-five patients were adults (median age: 29 years, (18-66)) and 46 were children (median age: 14 years, (7-17)). The indication for LT was (1) fulminant/subfulminant hepatitis (n = 64, 53%), median age = 16 years (7-53), (2) decompensated cirrhosis (n = 50, 41%), median age = 31.5 years (12-66) or (3) severe neurological disease (n = 7, 6%), median age = 21.5 years (14.5-42). Median post-transplant follow-up was 72 months (0-23.5). RESULTS Actuarial patient survival rates were 87% at 5, 10, and 15 years. Male gender, pre-transplant renal insufficiency, non elective procedure, and neurological indication were significantly associated with poorer survival rate. None of these factors remained statistically significant under multivariate analysis. In patients transplanted for hepatic indications, the prognosis was poorer in case of fulminant or subfulminant course, non elective procedure, pretransplant renal insufficiency and in patients transplanted before 2000. Multivariate analysis disclosed that only recent period of LT was associated with better prognosis. At last visit, the median calculated glomerular filtration rate was 93 ml/min (33-180); 11/93 patients (12%) had stage II renal insufficiency and none had stage III. CONCLUSIONS Liver failure associated with WD is a rare indication for LT (<1%), which achieves an excellent long-term outcome, including renal function.