Mickael Lesurtel

Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report

Although liver transplantation is a widely accepted treatment for hepatocellular carcinoma (HCC), much controversy remains and there is no generally accepted set of guidelines. An international consensus conference was held on Dec 2-4, 2010, in Zurich, Switzerland, with the aim of reviewing current practice regarding liver transplantation in patients with HCC and to develop internationally accepted statements and guidelines. The format of the conference was based on the Danish model. 19 working groups of experts prepared evidence-based reviews according to the Oxford classification, and drafted recommendations answering 19 specific questions. An independent jury of nine members was appointed to review these submissions and make final recommendations, after debates with the experts and audience at the conference. This report presents the final 37 statements and recommendations, covering assessment of candidates for liver transplantation, criteria for listing in cirrhotic and non-cirrhotic patients, role of tumour downstaging, management of patients on the waiting list, role of living donation, and post-transplant management.

Resection Prior to Liver Transplantation for Hepatocellular Carcinoma

Objective: To evaluate the feasibility and postoperative course of liver transplantation (LT) in cirrhotic patients who underwent liver resection prior to LT for HCC. Summary Background Data: Although LT provides longer survival than liver resection for treatment of small HCCs, donor shortage and long LT wait time may argue against LT. The feasibility and survival following LT after hepatic resection have not been previously examined. Methods: Between 1991 and 2001, among 107 patients who underwent LT for HCC, 88 met Mazzaferos criteria upon pathologic analysis of the explant. Of these, 70 underwent primary liver transplantation (PLT) and 18 liver resection prior to secondary liver transplantation (SLT) for recurrence (n = 11), deterioration of liver function (n = 4), or high risk for recurrence (n = 3). Perioperative and postoperative factors and long-term survival were compared. Results: Comparison of PLT and SLT groups at the time of LT revealed similar median age (53 vs. 55 years), sex, and etiology of liver disease (alcohol/viral B/C/other). In the SLT group, the mean time between liver resection and listing for LT was 20 months (range 1–84 months). Overall time on LT waiting list of the two groups was similar (3 vs. 5 months). Pathologic analysis after LT revealed similar tumor size (2.2 vs. 2.3 cm) and number (1.6 vs. 1.7). Perioperative and postoperative courses were not different in terms of operative time (551 vs. 530 minutes), blood loss (1191 vs. 1282 mL), transfusion (3 vs. 2 units), ICU (9 vs. 10 days) or hospital stay (32 vs. 31 days), morbidity (51% vs. 56%) or 30-day mortality (5.7% vs. 5.6%). During a median follow-up of 32 months (3 to 158 months), 3 patients recurred after PLT and one after SLT. After transplantation, 3- and 5-year overall survivals were not different between groups (82 vs. 82% and 59 vs. 61%). Conclusions: In selected patients, liver resection prior to transplantation does not increase the morbidity or impair long-term survival following LT. Therefore, liver resection prior to transplantation can be integrated in the treatment strategy for HCC.

How Should Transection of the Liver Be Performed?: A Prospective Randomized Study in 100 Consecutive Patients: Comparing Four Different Transection Strategies

Objective:To identify the most efficient parenchyma transection technique for liver resection using a prospective randomized protocol. Summary Background Data:Liver resection can be performed by different transection devices with or without inflow occlusion (Pringle maneuver). Only limited data are currently available on the best transection technique. Methods:A randomized controlled trial was performed in noncirrhotic and noncholestatic patients undergoing liver resection comparing the clamp crushing technique with Pringle maneuver versus CUSA versus Hydrojet versus dissecting sealer without Pringle maneuver (25 patients each group). Primary endpoints were intraoperative blood loss, resection time, and postoperative liver injury. Secondary end points included the use of inflow occlusion, postoperative complications, and costs. Results:The clamp crushing technique had the highest transection velocity (3.9 ± 0.3 cm2/min) and lowest blood loss (1.5 ± 0.3 mL/cm2) compared with CUSA (2.3 ± 0.2 cm2/min and 4 ± 0.7 mL/cm2), Hydrojet (2.4 ± 0.3 cm2/min and 3.5 ± 0.5 mL/cm2), and dissecting sealer (2.5 ± 0.3 cm2/min and 3.4 ± 0.4 mL/cm2) (velocity: P = 0.001; blood loss: P = 0.003). Clamp crushing technique was associated with the lowest need for postoperative blood transfusions. The degree of postoperative reperfusion injury and complications were not significantly different among the groups. The clamp crushing technique proved to be most cost-efficient device and had a cost-saving potential of 600 &U20AC; to 2400 &U20AC; per case. Conclusions:The clamp crushing technique was the most efficient device in terms of resection time, blood loss, and blood transfusion frequency compared with CUSA, Hydrojet, and dissecting sealer, and proved to be also the most cost-efficient device.

ALPPS: from human to mice highlighting accelerated and novel mechanisms of liver regeneration.

Objectives:To develop a reproducible animal model mimicking a novel 2-staged hepatectomy (ALPPS: Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy) and explore the underlying mechanisms. Background:ALPPS combines portal vein ligation (PVL) with liver transection (step I), followed by resection of the deportalized liver (step II) within 2 weeks after the first surgery. This approach induces accelerated hypertrophy of the liver remnant to enable resection of massive tumor load. To explore the underlying mechanisms, we designed the first animal model of ALPPS in mice. Methods:The ALPPS group received 90% PVL combined with parenchyma transection. Controls underwent either transection or PVL alone. Regeneration was assessed by liver weight and proliferation-associated molecules. PVL-treated mice were subjected to splenic, renal, or pulmonary ablation instead of hepatic transection. Plasma from ALPPS-treated mice was injected into mice after PVL. Gene expression of auxiliary mitogens in mouse liver was compared to patients after ALPPS or PVL. Results:The hypertrophy of the remnant liver after ALPPS doubled relative to PVL, whereas mice with transection alone disclosed minimal signs of regeneration. Markers of hepatocyte proliferation were 10-fold higher after ALPPS, when compared with controls. Injury to other organs or ALPPS-plasma injection combined with PVL induced liver hypertrophy similar to ALPPS. Early initiators of regeneration were significantly upregulated in human and mice. Conclusions:ALPPS in mice induces an unprecedented degree of liver regeneration, comparable with humans. Circulating factors in combination with PVL seem to mediate enhanced liver regeneration, associated with ALPPS.

Efficacy of TachoSil a fibrin-based haemostat in different fields of surgery- a systematic review

Background: Proper haemostasis is an important prerequisite for a successful outcome in all operative fields. TachoSil® is used in many surgical specialties, especially for diffuse bleeding. However, TachoSil is not only used for haemostasis but also for closure of other anatomical structures. Objective: To review the literature concerning the efficacy of TachoSil, a topical fibrin-based haemostat. Methods: PubMed was searched for data on TachoSil and TachoComb from clinical trials and basic research. Results/conclusion: TachoSil is used in many surgical specialties and has proven to be a valuable tool for several indications. It also seems to be cost effective. Solid data from randomized controlled trials are available for liver surgery, thoracic surgery and urology where a positive value is clearly documented.

Prediction of Mortality After ALPPS Stage-1: An Analysis of 320 Patients From the International ALPPS Registry.

OBJECTIVES The aim of this study was to identify predictors of 90-day mortality after Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS), available after stage-1, either to omit or delay stage-2. BACKGROUND DATA ALPPS is a two-stage hepatectomy for patients with extensive liver tumors with predicted small liver remnants, which has been criticized for its high mortality rate. Risk factors for mortality are unknown. METHODS Patients in the International Registry undergoing ALPPS from April 2011 to July 2014 were analyzed. Primary outcome was 90-day mortality. Liver function after stage-1 was assessed using the criteria of the International Study Group for Liver Surgery (ISGLS) after stage-1 among others. A multivariable model was used to identify independent predictors of 90-day mortality. RESULTS Three hundred twenty patients registered by 55 centers worldwide were evaluated. Overall 90-day mortality was 8.8% (28/320). The predominant cause for 90-day mortality was postoperative liver failure in 75% of patients. Fourteen percent of patients developed liver failure according to ISGLS criteria already after stage-1 ALPPS. Those and patients with a model of end-stage liver disease (MELD) score more than 10 before stage-2 were at significantly higher risk for 90-day mortality after stage-2 with an odds ratio (OR) 3.9 [confidence interval (CI) 1.4-10.9, P = 0.01] and OR 4.9 (CI 1.9-12.7, P = 0.006), respectively. Other factors, such as size of future liver remnant (FLR) before stage-2 and time between stages, were not predictive. CONCLUSIONS This analysis of the largest cohort of ALPPS patients so far identifies those patients in whom stage-2 ALPPS surgery should be delayed or even denied. These findings may help to make ALPPS safer.

Adjuvant gemcitabine versus NEOadjuvant gemcitabine/oxaliplatin plus adjuvant gemcitabine in resectable pancreatic cancer: a randomized multicenter phase III study (NEOPAC study)

BackgroundDespite major improvements in the perioperative outcome of pancreas surgery, the prognosis of pancreatic cancer after curative resection remains poor. Adjuvant chemotherapy increases disease-free and overall survival, but this treatment cannot be offered to a significant proportion of patients due to the surgical morbidity. In contrast, almost all patients can receive (neo)adjuvant chemotherapy before surgery. This treatment is safe and effective, and has resulted in a median survival of 26.5 months in a recent phase II trial. Moreover, neoadjuvant chemotherapy improves the nutritional status of patients with pancreatic cancer. This multicenter phase III trial (NEOPAC) has been designed to explore the efficacy of neoadjuvant chemotherapy.Methods/DesignThis is a prospective randomized phase III trial. Patients with resectable cytologically proven adenocarcinoma of the pancreatic head are eligible for this study. All patients must be at least 18 years old and must provide written informed consent. An infiltration of the superior mesenteric vein > 180° or major visceral arteries are considered exclusion criteria. Eligible patients will be randomized to surgery followed by adjuvant gemcitabine (1000 mg/m2) for 6 months or neoadjuvant chemotherapy (gemcitabine 1000 mg/m2, oxaliplatin 100 mg/m2) followed by surgery and the same adjuvant treatment. Neoadjuvant chemotherapy is given four times every two weeks. The staging as well as the restaging protocol after neoadjuvant chemotherapy include computed tomography of chest and abdomen and diagnostic laparoscopy. The primary study endpoint is progression-free survival. According to the sample size calculation, 155 patients need to be randomized to each treatment arm. Disease recurrence will be documented by scheduled computed tomography scans 9, 12, 15, 21 and thereafter every 6 months until disease progression. For quality control, circumferential resection margins are marked intraoperatively, and representative histological sections will be centrally reviewed by a dedicated pathologist.DiscussionThe NEOPAC study will determine the efficacy of neoadjuvant chemotherapy in pancreatic cancer for the first time and offers a unique potential for translational research. Furthermore, this trial will provide the unbiased overall survival of all patients undergoing surgery for resectable cancer of the pancreatic head.Trial registrationclinicalTrials.gov NCT01314027

Activation of serotonin receptor-2B rescues small-for-size liver graft failure in mice.

The implantation of grafts below 30% of the normal liver volume is associated with a high risk of failure known as small‐for‐size (SFS) syndrome. Strategies to rescue small grafts may have a dramatic impact on organ shortage. Serotonin is a potent growth factor for the liver. The goal of this study was to determine whether enhanced serotonin signaling could prevent the deleterious effects of SFS syndrome. We performed 30% normal liver volume transplantations in wild‐type C57/BL6 and interleukin‐6 (IL‐6)−/− mice. Some animals received α‐methyl‐5‐HT (DOI), an agonist of serotonin receptor‐2 (5‐HT2B). Endpoints included long‐term survival, serum and hepatic markers of liver injury and regeneration, assessment of hepatic microcirculation by intravital fluorescence microscopy and scanning electron microscopy, and transcript levels of a variety of serotonin receptors, tumor necrosis factor α, and IL‐6. All recipients of small grafts (controls) died within 2‐4 days of transplantation, whereas half of those receiving DOI survived permanently. Control animals disclosed major liver injury, including diffuse microvesicular steatosis in hepatocytes, impairment of microcirculation, and a failure of regeneration, whereas these parameters were dramatically improved in animals subjected to DOI. Blockage of 5‐HT2B blunted the protective effects of DOI. Whereas IL‐6 levels were higher in DOI‐treated animals, IL‐6−/− mice were still protected by DOI, suggesting a protective pathway independent of IL‐6. Conclusion: Serotonin through its action on receptor‐2B protects SFS liver grafts from injury and prevents microcirculation and regeneration. The mechanism of hepato‐protection is independent of IL‐6. (Hepatology 2011;)

Randomized clinical trial of ischaemic preconditioning in major liver resection with intermittent Pringle manoeuvre.

Vascular inflow occlusion is effective in avoiding excessive blood loss during hepatic parenchymal transection but may cause ischaemic damage to the remnant liver. Intermittent portal triad clamping (IPTC) is superior to continuous hepatic pedicle clamping as it avoids severe ischaemia–reperfusion (IR) injury in the liver remnant. Ischaemic preconditioning (IPC) before continuous Pringle manoeuvre may protect against IR during major liver resection.

Protection of pharmacological postconditioning in liver surgery: results of a prospective randomized controlled trial.

Objectives:To elucidate the possible organ-protective effect of pharmacological postconditioning in patients undergoing liver resection with inflow occlusion. Background:Inflow occlusion reduces blood loss during liver transection in selected patients but is potentially harmful due to ischemia-reperfusion injury. Preventive strategies include the use of repetitive short periods of ischemia interrupted by a reperfusion phase (intermittent clamping), application of a short period of ischemia before transection (ischemic preconditioning), or pharmacological preconditioning before transection. Whether intervention after resection (postconditioning) may confer protection is unknown. Methods:A 3 arm, prospective, randomized trial was designed for patients undergoing liver resection with inflow occlusion to compare the effects of pharmacological postconditioning with the volatile anesthetic agent sevoflurane (n = 48), intermittent clamping (n = 50), or no protective intervention (continuous inflow occlusion, n = 17). Endpoints included peak serum aspartate transaminase level, postoperative complications, and hospital stay. All patients were intravenously anesthetized with propofol. In patients with postconditioning, propofol infusion was stopped upon reperfusion and replaced with sevoflurane for 10 minutes. Results:Compared with the control group, both postconditioning (P = 0.044) and intermittent clamping (P = 0.015) significantly reduced aspartate transaminase levels. The risk of complications was significantly decreased by postconditioning, odds ratio, 0.08 [95% confidence interval (CI), 0.02–0.36; P = 0.001]) and intermittent clamping, odds ratio, 0.50 [95% CI, 0.26–0.96; P = 0.038], compared with controls. Both interventions reduced length of hospital stay, postconditioning −4 days [95% CI, −6 to −1; P = 0.009], and intermittent clamping −2 days, [95% CI, −4 to 0; P = 0.019]. Conclusions:Pharmacological postconditioning reduces organ injury and postoperative complications. This easily applicable strategy should be used in patients with prolonged continuous inflow occlusion.