Pierre-Alain Clavien

Playing Play-Doh to prevent postoperative liver failure: the "ALPPS" approach.

opital Paul Brousse in Paris, France, with the introduction of sequential operations, referred to as “2-stage hepatectomy” to stepwise remove multiple liver tumors, with the aim of allowing the liver to regenerate between both procedures. 4 Additional PVE was also used in a few patients. Soon after, Daniel Jaeck and his colleagues from Strasbourg, France, developed another 2-stage approach for bilateral (predominantly right) tumor involvement. Using routine right PVE, after the initial removal of tumors located in the left hemiliver, the resulting hypertrophy of the left part of the liver (free of tumor) allowed a safer curative right or extended-right hemihepatectomy. 5 Finally, the group from Zurich modified this approach by applying concomitant right portal vein ligation with wedge resections of all left-sided tumors during the first surgery, followed a few weeks later by an extended righthepatectomy. 1 Thismodificationwasbasedonevidencethatportalveinligationtriggersasimilar or better regenerative response than PVE 6,7 and could be safely applied, even in combination with partial hepatectomies of the left hemiliver. In a few patients with intact primary neuroendocrine or colorectal tumors, Belghiti and colleagues have also used portal vein ligation along with resection of the primary tumor. 8 In many patients, those developments led to the successful removal of multiple, often bilateral, liver lesions otherwise felt to be unresectable. The drawback, however, was the need for long intervals between the 2 surgeries. The earlier techniques, without the use of selective portal vein occlusion, required a delay of 2 to 13 months before completing the second hepatectomy. 4 The majority of patients in whom this approach failed, did so because they had developed disease progression in the meantime. 4 With the advent of PVE, this period was dramatically shortened to 2 to 4 months, 5 and with concomitant portal vein ligature to about 4 weeks. 1 Other shortcomings included the insufficient hypertrophy of a putative remnant liver, preventing curative resection or, if performed, leading to postoperative failure due to “small for size” syndrome. 3 In Figure 1, we show the development of the various types of staged hepatectomies. The article in this issue of Annals of Surgery by Schnitzbauer and coworkers call out ref. 9 introduces a novel concept representing one of the most promising advances in oncological liver surgery so far. Contrary to many surgical innovations, this one was somehow developed by chance. In 2007, Dr Hans Schlitt from Regensburg, Germany, was planning an extended right hepatectomy in a patient with perihilar cholangiocarcinoma, but he realized intraoperatively that the future cholestatic liver remnant was too small to sustain the patient postoperatively. He took a good, but uncommon surgical decision, by performing only a selective hepatico-jejunostomy on the left biliary system. For the optimal positioning of the hepatico-jejunostomy, he had to divide the liver parenchyma along the falciform ligament, thereby completely devascularizing segment IV, that is, an in-situ split as performed for pediatric liver transplantation. Finally, he ligated the right portal vein to induce hypertrophy of segments II to III. Out of curiosity, he performed a CT scan on postoperative day 8 and, to his surprise, found that the left liver had grown enormously. He decided to proceed with the removal of the diseased liver. The patient, who had been at risk of liver failure a week prior, tolerated the removal just fine. After this successful case, Dr Schlitt deliberately applied this approach in a patient with extensive colorectal liver metastases and in another patient with a large cholangiocarcinoma. The enthusiasm for this approach was then shared with other surgeons, mostly from Germany, who used

Early survival and safety of ALPPS: first report of the International ALPPS Registry.

Objectives:To assess safety and outcomes of the novel 2-stage hepatectomy, Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS), using an international registry. Background:ALPPS induces accelerated growth of small future liver remnants (FLR) to allow curative resection of liver tumors. There is concern about safety based on reports of higher morbidity and mortality. Methods:A Web-based data entry system was created with password access and data pseudoencryption (NCT01924741). All patients with complete 90-day data were included. Multivariate logistic regression analysis was performed to identify independent risk factors for severe complications and mortality and volume growth of the FLR. Results:Complete data were available for 202 patients. A total of 141 (70%) patients had colorectal liver metastases (CRLM). Median starting standardized future liver remnants of 21% increased by 80% within a median of 7 days. Ninety-day mortality was 19/202 (9%). Severe complications including mortalities (Clavien-Dindo ≥IIIb) occurred in 27% of patients. Independent factors for severe complications were red blood cell transfusion [odds ratio (OR), 5.2), ALPPS stage I operating time greater than 300 minutes (OR, 4.4), age more than 60 years (OR, 3.8), and non-CRLM (OR, 2.7). Age, use of Pringle maneuver, and histologic changes led to less volume growth. In patients younger than 60 years with CRLM, 90-day mortality was similar to conventional 2-stage hepatectomies for CRLM. Conclusions:This is the first analysis of the ALPPS registry showing that ALPPS has increased perioperative morbidity and mortality in older patients but better outcomes in patients with CRLM.

Challenges to Liver Transplantation and Strategies to Improve Outcomes

Liver transplantation (LT) is a highly successful treatment for many patients with nonmalignant and malignant liver diseases. However, there is a worldwide shortage of available organs; many patients deteriorate or die while on waiting lists. We review the important clinical challenges to LT and the best use of the scarce organs. We focus on changes in indications for LT and discuss scoring systems to best match donors with recipients and optimize outcomes, particularly for the sickest patients. We also cover controversial guidelines for the use of LT in patients with hepatocellular carcinoma and cholangiocarcinoma. Strategies to increase the number of functional donor organs involve techniques to perfuse the organs before implantation. Partial LT (living donor and split liver transplantation) techniques might help to overcome organ shortages, and we discuss small-for-size syndrome. Many new developments could increase the success of this procedure, which is already one of the major achievements in medicine during the second part of the 20th century.

Fasting protects liver from ischemic injury through Sirt1-mediated downregulation of circulating HMGB1 in mice

BACKGROUND & AIMS Fasting and calorie restriction are associated with a prolonged life span and an increased resistance to stress. The protective effects of fasting have been exploited for the mitigation of ischemic organ injury, yet the underlying mechanisms remain incompletely understood. Here, we investigated whether fasting protects liver against ischemia reperfusion (IR) through energy-preserving or anti-inflammatory mechanisms. METHODS Fasted C57BL6 mice were subjected to partial hepatic IR. Injury was assessed by liver enzymes and histology. Raw264-7 macrophage-like cells were investigated in vitro. Sirt1 and HMGB1 were inhibited using Ex527 and neutralizing antibodies, respectively. RESULTS Fasting for one, but not two or three days, protected from hepatic IR injury. None of the investigated energy parameters correlated with the protective effects. Instead, inflammatory responses were dampened in one-day-fasted mice and in starved macrophages. Fasting alone led to a reduction in circulating HMGB1 associated with cytoplasmic HMGB1 translocation, aggregate formation, and autophagy. Inhibition of autophagy re-elevated circulating HMGB1 and abolished protection in fasted mice, as did supplementation with HMGB1. In vitro, Sirt1 inhibition prevented HMGB1 translocation, leading to elevated HMGB1 in the supernatant. In vivo, Sirt1 inhibition abrogated the fasting-induced protection, but had no effect in the presence of neutralizing HMGB1 antibody. CONCLUSIONS Fasting for one day protects from hepatic IR injury via Sirt1-dependent downregulation of circulating HMGB1. The reduction in serum HMGB1 appears to be mediated by its engagement in the autophagic response. These findings integrate Sirt1, HMGB1, and autophagy into a common framework that underlies the anti-inflammatory properties of short-term fasting.

Hypothermic Oxygenated Perfusion (HOPE) downregulates the immune response in a rat model of liver transplantation.

Objective:To evaluate the impact of a novel oxygenated perfusion approach on rejection after orthotopic liver transplantation (OLT). Background:Hypothermic oxygenated perfusion (HOPE) was designed to prevent graft failure after OLT. One of the mechanisms is downregulation of Kupffer cells (in situ macrophages). We, therefore, designed experiments to test the effects of HOPE on the immune response in an allogeneic rodent model of nonarterialized OLT. Methods:Livers from Lewis rats were transplanted into Brown Norway rats to induce liver rejection in untreated recipients within 4 weeks. Next, Brown Norway recipients were treated with tacrolimus (1 mg/kg), whereas in a third group, liver grafts from Lewis rats underwent HOPE or deoxygenated machine perfusion for 1 hour before implantation, but recipients received no immunosuppression. In a last step, low-dose tacrolimus treatment (0.3 mg/kg) was assessed with and without HOPE. Results:Allogeneic OLT without immunosuppression led to death within 3 weeks after nonarterialized OLT due to severe acute rejection. Full-dose tacrolimus prevented rejection, whereas low-dose tacrolimus led to graft fibrosis within 4 weeks. HOPE treatment without immunosuppression also protected from lethal rejection. The combination of low-dose tacrolimus and 1-hour HOPE resulted in 100% survival within 4 weeks without any signs of rejection. Conclusions:We demonstrate that allograft treatment by HOPE not only protects against preservation injury but also impressively downregulates the immune system, blunting the alloimmune response. Therefore, HOPE may offer many beneficial effects, not only to rescue marginal grafts but also by preventing rejection and the need for immunosuppression.

Systemic protection through remote ischemic preconditioning is spread by platelet-dependent signaling in mice

Remote ischemic preconditioning (RIPC), the repetitive transient mechanical obstruction of vessels at a limb remote to the operative site, is a novel strategy to mitigate distant organ injury associated with surgery. In the clinic, RIPC has demonstrated efficacy in protecting various organs against ischemia reperfusion (IR), but a common mechanism underlying the systemic protection has not been identified. Here, we reasoned that protection may rely on adaptive physiological reponses toward local stress, as is incurred through RIPC. Standardized mouse models of partial hepatic IR and of RIPC to the femoral vascular bundle were applied. The roles of platelets, peripheral serotonin, and circulating vascular endothelial growth factor (Vegf) were studied in thrombocytopenic mice, Tph1−/− mice, and through neutralizing antibodies, respectively. Models of interleukin‐10 (Il10) and matrix metalloproteinase 8 (Mmp8) deficiency were used to assess downstream effectors of organ protection. The protection against hepatic IR through RIPC was dependent on platelet‐derived serotonin. Downstream of serotonin, systemic protection was spread through up‐regulation of circulating Vegf. Both RIPC and serotonin‐Vegf induced differential gene expression in target organs, with Il10 and Mmp8 displaying consistent up‐regulation across all organs investigated. Concerted inhibition of both molecules abolished the protective effects of RIPC. RIPC was able to mitigate pancreatitis, indicating that it can protect beyond ischemic insults. Conclusions: We have identified a platelet‐serotonin‐Vegf‐Il10/Mmp8 axis that mediates the protective effects of RIPC. The systemic action, the conservation of RIPC effects among mice and humans, and the protection beyond ischemic insults suggest that the platelet‐dependent axis has evolved as a preemptive response to local stress, priming the body against impending harm. (Hepatology 2014;60:1409–1417)

Platelet-derived serotonin: translational implications for liver regeneration.

I n this issue of HEPATOLOGY, Starlinger et al. present a successful example of translational research 7 years following the discovery in mice that plateletderived serotonin mediates liver regeneration in vivo. Effectively, they provide the first evidence that plateletderived serotonin plays a critical role in liver regeneration in humans following a hepatectomy and that low preoperative serotonin in platelets is associated with delayed postoperative liver regeneration as well as poorer clinical outcomes. During the last 20 years, liver surgery has benefited from a number of breakthroughs, which have broadened the indications for liver resection, in order to increase the chances of curing many patients with malignant liver tumors. One of the most significant advances has been a better understanding of the mechanisms of liver regeneration. New knowledge in this area has led to innovative strategies to perform safer extended hepatectomies (more that 70% of the liver volume) often through the manipulation of the portal flow prior to resection to allow efficient hypertrophy of the future liver remnant. In liver transplantation, partial grafts from cadaveric donors (split liver) or from living donors have enabled increasing the pool of available organs for transplantation. In living donor liver transplantation, for example, the donor operation involves a major liver resection (up to 60% of the liver) in a healthy adult, whose remnant liver regenerates to almost its normal size within 4 to 6 weeks. In the recipient, the graft also increases rapidly in volume in order to overcome the metabolic function of the diseased native liver. Major liver resection, however, exposes patients to postoperative liver failure because of insufficient liver mass. Below a certain threshold of the liver remnant volume (about 20-25% of the native liver volume) and depending of the quality of the liver parenchyma (e.g., underlying fibrosis or steatosis), the remnant liver may not regenerate, leading to liver failure, so-called small-for-size syndrome (SFSS). This widely used term in the surgical literature means that a liver remnant is too small for the size of an individual. From a molecular point of view, liver regeneration encompasses the activation of many intraand extracellular pathways. The current understanding is that liver regeneration after partial hepatectomy involves a large number of genes organized into three networks: cytokines (e.g., tumor necrosis factor-a [TNF-a] and interleukin 6 [IL-6]), growth factors (e.g., hepatocyte growth factor [HGF], epidermal growth factor [EGF], vascular endothelial growth factor [VEGF], and platelet-derived growth factor [PDGF]), and metabolic, although marked redundancy exists among them. Many factors pertaining to liver regeneration have been extensively studied, among which platelets and platelet-derived serotonin appeared in the forefront of the early activation triggering hepatocyte proliferation. Our interest in the impact of platelets on the liver dates back to the early 1990s when platelets were found to contribute to reperfusion injury after cold preservation of the liver as well as normothermic ischemia. Subsequently, we developed an interest in liver regeneration, which has led us to investigate platelets and factors stored by them in relation to hepatocyte proliferation in vivo. We observed that liver regeneration was significantly impaired following a partial hepatectomy in mice subjected to immune thrombocytopenia. Similar results were documented after applying an inhibitor of platelet aggregation (clopidogrel), suggesting that a factor released by platelets may induce or maintain liver regeneration. We then identified platelet-derived serotonin as a new mediator of regeneration in vivo. Figure 1 illustrates the Abbreviations: EGF, epidermal growth factor; HGF, hepatocyte growth factor; IGF-1, insulin-like growth factor-1; IL, interleukin; IP 5-HT, intraplatelet pool of serotonin; PDGF, platelet-derived growth factor; SFSS, small-for-size syndrome; SSRIs, selective serotonin reuptake inhibitors; TNF-a, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor. Received January 3, 2014; accepted February 7, 2014. Micka€el Lesurtel is supported by a professorship grant No. PP00P3_128475 from the Swiss National Science Foundation. Pierre-Alain Clavien is supported by the grant No. 32003B-109906 from the Swiss National Science Foundation and by the Clinical Research Priority Program of the University of Zurich “Non-resectable liver tumors: from palliation to cure.” Address reprint requests to: Pierre-Alain Clavien, M.D., Ph.D., Department of Surgery, University Hospital of Zurich, Raemistrasse 100, 8091 Z€ urich, Switzerland. E-mail: clavien@access.uzh.ch; fax: 141 44 255 44 49. Copyright VC 2014 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27067 Potential conflict of interest: Nothing to report.

Commentary on "Happy marriage or "dangerous liaison": ALPPS and the anterior approach".

T he interesting letter by Dr Chan et al1 refers to the inaugural publications of the new ALPPS (Associating Liver Partition and Portal vein ligation for Staged hepatectomy) technique in this journal.2,3 With the anterior approach, that is, parenchymal transection without prior mobilization of the right lobe or visualization of the vena cava, usually for large right hemi-liver hepatomas, the group from Hong Kong pioneered a new technique and set the standard in surgical oncology for hepatomas.4 They have now caught interest of the ALPPS technique to induce rapid hypertrophy and used the anterior approach in 2 patients, one with fibrosis from chronic hepatitis B, and the other in a child with hepatoblastoma. The rising interest in ALPPS has, and will further, lead to technical modifications such as the use of the anterior approach to address the initial concern about higher complication rates and to improve long-term survival.5 It has been established that the anterior approach confers oncological advantages in conventional liver surgery and is readily applicable to ALPPS. The anterior approach is, however, not necessary in all patients, especially those with multifocal colorectal metastases. We have used the anterior approach in Buenos Aires, Argentina, and Zurich, Switzerland, along with the hanging maneuver,6 in about half of our 54 patients undergoing ALPPS. With the letter by Chan et al in hand, we analyzed the International ALPPS Registry (www.alpps.net) and found that in 37% (66/175) patients underwent transection during the first step of ALPPS using the anterior approach and in 42% of the patients (74/175), the hanging maneuver was used with or without anterior approach. Further analyses revealed that the anterior approach was used in 31% of patients with hemiliver hepatoma and 38% of patients with CLRM. The next step ought to be an analysis of safety and long-

Solutions to shortage of liver grafts for transplantation

The success of liver transplantation has resulted in a demand for grafts that exceeds the number of available organs. Organ donation is therefore crucial. This rate of donation depends on numerous factors, including intensive care capacity, funding for organ donation programmes and public awareness. In addition, legislation regarding potential organ donors (opting out or opting in to donation) can influence the number of available organs in a country, although the association between a legislative framework and the level of acceptance rates or absolute number of donors remains unclear1. A well organized donation infrastructure along with local commitment for maximizing donation appears to be much more important than any other strategies, but this is a difficult goal to achieve. Other measures have therefore been proposed to increase the pool of available organs. Among those approaches are donation after cardiac death (DCD), the use of fatty or older livers, or the acceptance of donors presenting with a history of cancer. In this issue of BJS, three articles attempt to address the impact of donor age on DCD liver grafts2, the baseline cellular energy status of DCD liver grafts3 and the risk of cancer transmission in donors with a history of cancer4.

A challenging hernia: primary venous aneurysm of the proximal saphenous vein.

IntroductionPrimary venous aneurysm is a rare, but essential consideration in the differential diagnosis of an inguinal and femoral hernia.MethodsWe report a case of a 43-year-old man who was referred for evaluation and treatment of a femoral hernia.ResultsThe patient presented with a 3-month history of an asymptomatic tumor on his right upper inner thigh. Physical examination noted a non-tender, non-indurated tumor.ConclusionSurgical exploration demonstrated a primary venous aneurysm of the proximal saphenous vein.