LIVER TRANSPLANTATION 21:991–1000, 2015

MEETING REPORT

Meeting Report of the 2014 Joint International Congress of the International Liver Transplantation Society, Liver Intensive Care Group of Europe, and European Liver and Intestinal Association Geraldine Diaz,1 Josh Levitsky,2 and Gabriel Oniscu3 Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL; 2Department of Gastroenterology and Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL; and 3Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom

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The 2014 Annual Meeting of the International Liver Transplantation Society was held in London, England. This was the 20th meeting of the Society and was marked by a joint meeting including the European Liver and Intestinal Association as well as the Liver Intensive Care Group of Europe. The meeting included symposia, invited lectures, debates, oral presentations, and posters. The principal themes were living donation, expanding the deceased donor pool, machine preservation, and new oral therapies for hepatitis C virus. This report highlights the scientific discussions of this meeting. Liver Transpl C 2015 AASLD. 21:991-1000, 2015. V Received February 11, 2015; accepted March 30, 2015. The 20th Annual Meeting of the International Liver Transplantation Society (ILTS) was held in London, England, from June 4-7, 2014. The meeting coincided with a joint meeting of European Liver and Intestinal Association (ELITA) and Liver Intensive Care Group of Europe (LICAGE). The major themes of the meeting were new therapies for the treatment of hepatitis C virus (HCV), the role of liver transplantation (LT) in the management of nonalcoholic steatohepatitis

(NASH), expansion of living donation, increasing allograft utilization, and the emerging role of machine preservation. These were addressed through a series of oral presentations, poster sessions, and interactive discussions. This report highlights the major themes by presenting key abstracts and discussion points. It is not a comprehensive review; rather, it is a guide to assist the reader in quickly identifying a source for further detailed information.

Abbreviations: AFP, alpha-fetoprotein; ALF, acute liver failure; AST, aspartate aminotransferase; AT, anaerobic threshold; BMI, body mass index; CNI, calcineurin inhibitor; CPET, cardiopulmonary exercise testing; CRR, cardiorespiratory reserve; DBD, donation after brain death; DCD, donation after cardiac death; ECD, extended criteria donor; ELITA, European Liver and Intestinal Association; ff-TEG, functional fibrinogen thromboelastography; GRWR, graft-to-recipient weight ratio; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HE, hepatic encephalopathy; HPS, hepatopulmonary syndrome; HTN, hypertension; ICH, intracranial hypertension; ICP, intracranial pressure; ILTS, International Liver Transplantation Society; INR, international normalized ratio; IS, immunosuppression; k-TEG, kaolin thromboelastography; LDLT, living donor liver transplantation; LICAGE, Liver Intensive Care Group of Europe; lncRNA, long noncoding RNA; LT, liver transplantation; MARS, Molecular Adsorbent Recirculating System; MELD, Model for End-Stage Liver Disease; MHV, middle hepatic vein; MPAP, mean pulmonary artery pressure; NASH, nonalcoholic steatohepatitis; NMP, normothermic machine preservation; NSQIP, National Surgical Quality Improvement Program; NRP, normothermic regional perfusion; PACE, predicting adverse cardiac event; PAH, pulmonary arterial hypertension; PEEP, positive end-expiratory pressure; POPH, portopulmonary hypertension; PTS, pretransplant sepsis; PVP, portal venous pressure; RBV, ribavirin; RPSG, right posterior sectoral liver graft; r-TEG, rapid thromboelastography; SDF, sidestream dark-field; SFS, small-forsize; SOF, sofosbuvir; SVR, sustained virological response; tDSE, target dobutamine stress testing; Treg, regulatory T cell. Address reprint requests to Geraldine Diaz, Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL. E-mail: [email protected] DOI 10.1002/lt.24144 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

C 2015 American Association for the Study of Liver Diseases. V

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VIRAL HEPATITIS A number of viral hepatitis studies with a focus on HCV in the pretransplant and posttransplant setting were reported. Afdahl et al.1 reported preliminary data on a randomized trial of sofosbuvir (SOF) 1 ribavirin (RBV) versus observation for HCV cirrhosis and portal hypertension (HTN) with and without decompensation. Results demonstrated more advanced disease patients, as evidenced by a higher Child-Pugh score, took longer to achieve viral clearance. In addition to laboratory improvement, ascites and encephalopathy also resolved with treatment. Afdahl et al.1 presented additional data on SOF 1 RBV before LT to prevent post-LT recurrence.2 Sixty-one patients were enrolled, and 43 were undetectable at the time of LT. The majority (70%) achieved post-LT sustained virological response (SVR) with the only significant predictor of relapse being not negative long enough before LT (30 days). Charlton reported on 40 well-compensated patients treated for recurrent HCV with SOF and RBV for 24 weeks.3 Overall, only 70% achieved SVR, and there were no obvious predictors of relapse. He also presented data on SOF for severe recurrent HCV including fibrosing cholestatic hepatitis after LT.4 Treatment of 104 patients in a compassionate program included 48 with severe early HCV recurrence and 56 with late cirrhosis and decompensation. Seventy-two completed therapy with only a 62% SVR. Although SVR rates have improved in the post-LT setting, newer therapies are needed to increase response rates. For monitoring of HCV after LT, Gambato et al.5 reported even though patients with mild HCV recurrence at 1 year after LT have good outcomes, cirrhosis still develops eventually in up to one-third of these patients. Crespo et al.6 reported a high sensitivity and negative predictive value for prediction of mild HCV recurrence with FibroScan, although it was not entirely predictive of those who develop more significant fibrosis. It remains unclear at this time whether all patients should be treated after LT or only those predicted to develop significant recurrence.

IMMUNOSUPPRESSION (IS), REJECTION, AND TOLERANCE IS minimization off calcineurin inhibitor (CNI) therapy and tolerance were the focus of a number of important abstracts. The everolimus H2304 study was discussed in 2 abstracts, demonstrating reasonable longterm outcomes for both the tacrolimus reduction/ everolimus and tacrolimus withdrawal arm, noting, however, that only a subset of each arm has undergone long-term follow-up.7,8 Genetic profiles that can predict successful withdraw of CNI with maintenance mycophenolate mofetil monotherapy were presented and may have a clinical impact similar to prediction of tolerance.9 Similarly, donor DNA as a marker of rejection was presented by the Gottingen group and may also serve as clinical markers of immune reactivity versus tolerance.10 Yamashita et al.11 next

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reported an update on their study of ex vivo regulatory T cell (Treg) generation and infusion in living donor liver transplantation (LDLT) to induce tolerance. Out of 10 patients, 7 are currently off IS, and 3 developed reversible rejection. Wozniak et al.12 reported on a series of 8 pediatric patients with antibody mediated rejection, 5 early and 3 late after LT. Most patients responded to antibody therapies including intravenous immunoglobulin and rituximab. Alternate IS approaches in select patients, either through augmented or reduced IS therapy, are emerging to improve long-term care and graft stability.

HEPATIC MALIGNANCY Substantial discussion centered on identification of patients at increased risk for hepatocellular carcinoma (HCC) recurrence after LT and strategies to decrease recurrence. In a multicenter study from Italy, Notarpaolo et al.13 investigated the utility of an alphafetoprotein (AFP) model in predicting HCC recurrence after LT. In comparison to Milan criteria, the AFP model (pretransplant AFP, size, and tumor number) had a better discriminative power. Those patients with an AFP score > 2 demonstrated a significantly higher risk of recurrence (40%) when compared with patients with AFP score < 2 (11%). A French multicenter study published similar results supporting the use of an AFP score in selection of candidates with HCC.14 The utility of AFP in predicting HCC recurrence was ~ ero et al.15 who devised a clinialso supported by Pin cal score combining the histological examination of the explanted liver (tumor number, presence of microvascular invasion, nuclear grade) with preoperative Milan staging and an AFP > 200 ng/mL. This clinical score may prove useful in selecting patients for closer monitoring or providing alternative IS therapies. Prolonged waiting time is considered detrimental for HCC candidates because of an increased risk of tumor progression and wait-list mortality. In a Brazilian cohort of 187 patients who underwent LT, Salvalaggio et al.16 discovered Model for End-Stage Liver Disease (MELD) score, over waiting time, had a greater influence on posttransplant survival and suggested allocation policies that prolong HCC candidate waiting times do not affect survival. In recent years, the correlation between the expression of long noncoding RNAs (lncRNAs) and HCC recurrence has been established.17,18 Yang et al.19 investigated a potential prognostic value for the lncRNA in predicting recurrence and identified 7 lncRNAs overexpressed in HCC. A Cox multivariate analysis revealed that in addition to tumor size and presence of vascular invasion, lncRNA signature was an independent prognostic factor for predicting tumor recurrence and overall survival after LT. Recurrencefree survival and overall survival in patients expressing a high level of lncRNA was significantly lower than those with low lncRNA expression. Strategies to reduce HCC recurrence are just emerging. One potential option is the use of sorafenib,

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which is now approved therapy for patients with advanced HCC. The role of sorafenib as neoadjuvant, adjuvant, or postrecurrence therapy in the context of LT has not been defined.20 Monsour et al.21 presented exciting data on the use of sorafenib to reduce HCC recurrence rates in HCC patients transplanted outside of Milan criteria. Their single-center study reported neoadjuvant sorafenib reduced recurrence in advanced HCC outside Milan criteria in 14 of 44 study patients. Overall recurrence was lower (7%) among patients receiving sorafenib when compared to those receiving no treatment (17%). However, these data are preliminary, and further clinical trials are needed. A new potential avenue was suggested by Du et al.22 who presented on a novel microRNA (Mir-126) that is decreased in HCC tissues and cells, correlating negatively with angiogenesis. This could be a potential target to inhibit tumor growth and vascularity as novel agents are developed. Finally, Hagness et al.23 reported on LT versus chemotherapy for nonresectable colorectal liver metastasis, showing 57% 5-year survival with LT versus 8.5% with chemotherapy. Although controversial, this reasonable 5-year survival may be acceptable enough to consider expanding selection criteria for LT.

LIVING DONATION AND SPLIT LT LDLT continues to represent an important topic at the annual meeting, in keeping with the increasing levels of activity in many countries, particularly in Asia. The focus of many presentations was an expansion of indications and the use of smaller grafts with modulation of vascular inflow. Rela discussed the role of portal venous pressure (PVP) in predicting postoperative complications after living donation in a cohort of 178 donors in 2 years.24 Middle hepatic vein (MHV) was included as necessary. PVP was measured before hilar dissection, before cross-clamp, and following the removal of the allograft. The PVP was not influenced by the removal of the MHV but correlated with residual liver volume 60 years) DCD donors suggesting that with

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careful donor and recipient selection, excellent outcomes are possible. In a study of 54 older DCD donors compared with 135 grafts from younger DCD donors and 125 grafts from older donation after brain death (DBD) donors (>60 years), the older DCD grafts achieved comparable 1- and 3-year survival. When considering ECD, donors who suffered hypoxic injuries represent a significant challenge because of the lack of prognostic factors for a successful outcome.48 Madanur et al.49 presented a series of 21 LTs from donors that suffered hypoxic injuries and compared them with elderly DBD donors as controls. The authors noted a downward trend in the level of liver enzymes after transplant with no difference between groups. Furthermore, the initial AST did not correlate with the AST on day 1 or day 7. These findings suggest although these grafts are high risk, a downward trend of the liver enzymes before retrieval allows selection of these livers for LT and achieves as good results as the grafts from older DBD donors.49

METABOLIC RESERVE IN LT Dr. William Bernal from King’s College discussed the topic “Should we set limits on an acceptable body mass index (BMI) for transplantation?” He discussed the limitations of BMI in the setting of liver disease and its relationship to surgical outcomes. High BMI has been associated with increased comorbidities, particularly cardiopulmonary dysfunction, but it is not an independent determinant of mortality.50 The satisfactory outcomes observed transplanting the morbidly obese are likely the result of selection bias as United Network for Organ Sharing data demonstrate obese patients with a BMI > 40 kg/m2 represent a much smaller percentage of transplant recipients relative to their proportion of the US population.51 In fact, NASH patients evaluated for LT were almost 3 times more likely to be excluded from listing than patients with HCV.52 Unique considerations of highBMI recipients include frequent ineligibility for crosssectional imaging, decreased efficacy of interventional radiologic procedures, and unique surgical considerations. Bernal noted current data do not support an absolute BMI cutoff for LT.53-55 Although BMI is not an independent predictor of outcome, prudence dictates careful preoperative evaluation for associated comorbidities be integrated with clinical judgment in determining the applicability of LT. Conversely, sarcopenia significantly increases mortality among LT recipients. Dr. Chris Snowden from Freeman Hospital Newcastle addressed sarcopenia in a featured symposium by discussing “Is the measurement of physiologic reserve the best predictor of outcomes?” He began by defining “frailty” as decreased physiologic reserve (muscular and cardiorespiratory) across multiple systems that increases patient vulnerability and decreases resistance to stressors. Sarcopenia is a component of frailty frequently associated with chronic liver disease and an independent

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predictor of pretransplant and posttransplant morbidity and mortality.56-58 Frailty may manifest as decreased muscular reserve as determined by low BMI or diminished cardiopulmonary reserve as determined by activity. Sarcopenia can be diagnosed at any BMI. Cardiorespiratory reserve (CRR) is independent of MELD and unrelated to the degree of liver disease. Poor CRR is associated with increased wait list mortality. Cardiopulmonary exercise testing (CPET) is the gold standard for evaluating CRR that involves testing specific isolated muscle groups to determine anaerobic threshold (AT) and maximum oxygen consumption.59 Where applicable, the bike test also is an excellent study of CRR. AT, as determined by CPET, was predictive of mortality in patients who did or did not undergo LT.60 However, Gupta et al.61 demonstrated CPET did not predict post-LT survival. The resolution of sarcopenia following LT is variable. The most effective strategy for LT among patients involves deferred listing until a proven response to therapy is observed. Targeted interventions such as exercise and lifestyle modification to improve CRR, termed prehabilitation, on wait-list mortality and posttransplant outcomes are just being investigated. In summary, the decision to list and proceed with LT requires interpolation of many nonspecific data points.

OUTCOMES MEASUREMENT Dr. Susan Mandell from the University of Colorado discussed measures of predicting short- and longterm outcomes. She began by introducing the concept of risk-adjusted outcomes, which are data standardized according to specific criteria to reduce the effect of heterogeneity and permit more detailed comparison of outcomes. Risk adjustment is essential for performance comparisons between centers. Mandell noted outcome measures may result from opportunity to treat (evidence-based practice) or aggregate score (practice-based evidence) designs. Evidence-based practice is derived from randomized controlled trials where patient populations and experimental conditions are tightly controlled. This limits applicability to a small segment of the population. Practice-based evidence is a different form of evidence that is applicable to a wider population. This outcome measure relies upon repeated clinical observations of patients. An example of practice-based evidence is the National Surgical Quality Improvement Program (NSQIP).62 The American Society of Transplant Surgeons (ASTS) is currently developing the Transplant Quality Improvement Program, which is also a practice-based model that will provide novel outcomes analysis for solid organ transplantation. Mandell recommended the utilization of both evidence-based and practice-based measures as it applies to our clinical practice. Finally, she emphasized outcomes should be shared across all disciplines and anesthesiologists must play an equal role in outcomes reporting.

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Gareth Ackland from University College London discussed the impact of early postoperative morbidity on long-term patient outcomes. He too used the NSQIP to demonstrate the effect of immediate postoperative complications on long-term outcomes. This occurs through a cascading effect where a deficiency in one system increases metabolic demands upon other systems increasing demand from a failing organ. This is particularly true for complications within the first 30 days following surgery. An example is the impact of infection and inflammation on tumor progression by impairing perioperative innate immunity. The NSQIP database is a valuable resource for improving outcomes.

ACUTE LIVER FAILURE (ALF) A featured symposium on ALF was began by Julia Wendon from King’s College who reported the incidence of intracranial hypertension (ICH) among ALF patients is decreasing. The risk of ICH in patients with grade III/IV hepatic encephalopathy (HE) secondary to ALF is approximately 10%. The etiology of ICH remains multifactorial; however, elevated ammonia levels are linked to decreased survival. Clinically, an inflammatory phenotype increases the risk for HE and ICH, as demonstrated by increased levels of interleukin-10 and tumor necrosis factor. Possible risk factors for developing ICH include the following: grade III/IV HE, young age, hemodynamic instability, fever, Systemic Inflammatory Response Syndrome (SIRS), hyponatremia, ammonia levels > 150 mmol/L renal failure, and acetaminophen-induced hepatic injury. Available interventions include the following: n-acetylcysteine, mannitol, hypertonic saline, and indomethacin in addition to supportive therapies such as sedation, elective ventilation for Glasgow Coma Scale (GCS) < 8-9, frequent neurologic examination, free water restriction, early renal replacement therapy, sepsis control, and hemodynamic optimization to maintain cerebral perfusion pressure.63 The insertion of an intracranial pressure (ICP) monitor should be considered in patients as mentioned above. ICP monitoring resulted in more interventions and a greater rate of transplantation.64 The risk of intracranial bleeding with ICP monitor insertion is estimated at 10%; however, mortality in patients who sustain an intracranial bleed is 50%.64 Identification of high-risk patients for development of ICH should prompt early radiologic evaluation and consideration of ICP monitoring. Survival in patients with ALF, even without LT, continues to improve as a result of early recognition and referral to specialty liver centers, abundant highquality intensive care unit care, and early initiation of treatment. Early referral and expeditious transport to a liver failure specialty center is essential. The decision to transplant a patient with ALF remains a clinical challenge. Professor Nigel Heaton from King’s College London discussed criteria for deferring LT in ALF. These include cardiovascular instability as manifest by increasing vasopressor requirements or deteriorating

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cardiac performance, respiratory failure defined as fraction of inspired oxygen requirements above 0.8 and positive end-expiratory pressure (PEEP) of 15-20 cm H2O, necrotizing pancreatitis, fixed and dilated pupils for >4 hours, and evolving sepsis, particularly fungal sepsis. The inherent danger of transporting the ALF patient and the need to limit low-yield testing was emphasized. Rapid deterioration of the ALF patient while awaiting a liver allograft is often secondary to sepsis. Supportive therapy is critical during this period. Critical points include maintaining head elevation and securing adequate vascular access preoperatively, early hepatic artery ligation with minimal handling of the liver until devascularized intraoperatively, and maintenance of core temperature throughout the procedure. In the setting of increasing acidosis, hypotension, and blunted response to vasopressors, total hepatectomy with porta-caval shunting should be considered. Saliba showed a benefit for Molecular Adsorbent Recirculating System (MARS) treatment in ALF, with lactate levels on admission predicting ALF requiring LT.65 However, the role of physiologic support devices such as MARS and extracorporeal membrane oxygenation remain under investigation. Professor Ton Lisman from the University of Groningen emphasized the concept of “hemostatic rebalance” in ALF.66 The risk of clinically significant bleeding in the setting of ALF is uncommon with an incidence of 15 mm Hg (age  64 years) or >20 mm Hg age (>64 years) or PaO2 < 80 mm Hg, and intrapulmonary vascular dilatation diagnosed by contrast echocardiography. HPS is a recognized MELD exception for LT with priority established at a PaO2 < 60 mm Hg.68 Outcomes for patients transplanted for HPS have been excellent.69 After careful review, the committee has

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recommended the threshold for exception be lowered to PaO2 < 55 mm Hg. Strategies endorsed by the committee but not included in the guidelines include the following: minimal PEEP with early extubation, inhaled nitric oxide/prostacyclin to improve Ventilation Perfusion (V-Q) mismatch, and avoidance of transjugular intrahepatic portocaval shunts before transplant.70 Recovery is expected, but the time course is variable. Angiogenesis blockade is an emerging therapy for HPS. Improved understanding of the pathophysiology of POPH has resulted from increased screening combined with the evolution of targeted medications. Three pathways are implicated in the development of POPH: pulmonary arterial obstruction, deficiency of endothelial prostacyclin synthase, and increased circulating endothelin-1.71 Pulmonary arterial obstruction may result from vasoconstriction, endothelial/ smooth muscle proliferation, or platelet aggregation.72 Diagnosis is by echocardiography that indicates pulmonary HTN Right Ventricular Systolic Pressure (RVSP) > 50 mm Hg) or right ventricular dysfunction/ enlargement with confirmation by right heart cardiac catheterization.73 The diagnostic criteria are mean pulmonary artery pressure (MPAP) > 25 mm Hg, Pulmonary Capillary Wedge Pressure (PCWP) < 15 mm Hg, and Pulmonary Vascular Resistance (PVR) > 3 Wood units.74 POPH is classified by the World Health Organization as a group I classification of pulmonary arterial hypertension (PAH) and resolution after transplant is variable.75 Multiple medications have been introduced or are expected in the near future to lower PAH. At present, there are no specific recommendations in the absence of randomized controlled trials but several pathways have been targeted. Prostacyclin deficiency has been targeted by epoprostenol, treprostinil, and iloprost. Endothelin receptor antagonists include bosentan, ambrisentan, and macisentan. Nitric oxide deficiency is targeted by sildenafil and tadalafil. The newest treatment pathway is soluble guanylate cyclase stimulation (Riociguat). POPH is not an established exception for MELD allocation. Thus, the strategy for pretransplant management is to initiate medical therapy early and frequently assess right ventricular performance. Pharmacologic therapy should be optimized to achieve MPAP < 35 mm Hg with a PVR < 5 Wood units. MPAPs exceeding 50 mm Hg remain a contraindication for LT. Right ventricular “conditioning” is demonstrated by improved right ventricular function, strain > -25%, and right index of myocardial performance (Tei Index) < 30. Responding patients are eligible for regional review board consideration or LT with an expanded donor criteria allograft. Intraoperatively, right ventricular function is continuously monitored by Transesophageal Echocardiogram (TEE) with a pulmonary arterial catheter to evaluate intracardiac pressures.73 Continuing the patients pretransplant regimen into the operating room with the addition of inhaled nitric oxide or milrinone infusion as needed is essential intraoperatively.

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The greatest risk for right ventricular failure is at allograft reperfusion. Following success in the operating room, continuous monitoring with a pulmonary arterial catheter should continue in the intensive care unit with extubation as soon as practical. Gradual weaning from medical therapy should only be attempted when the recipient is stable over a period of months.

ANESTHESIA/CRITICAL CARE MEDICINE The severity of POPH after LT was evaluated by Gallo de Moraes et al.76 from Mayo Clinic who reported early post-LT outcomes. Fourteen patients with POPH who underwent LT were included: 6 patients with POPH of MPAP > 45 mm Hg and 8 patients of POPH with MPAP < 45 mm Hg. Intensive care length of stay, days on mechanical ventilation, and vasopressor requirements were not significantly different between groups. The role of target dobutamine stress testing (tDSE) in predicting adverse cardiac events (PACE) within 1 year following LT was reported by Dr. Marina Gitman from Ochsner Medical Center.77 Their retrospective study demonstrated low sensitivity and positive predictive value for tDSE, but a specificity of >95%. As with previous cardiac assessments, successful screening for cardiac disease among LT candidates requires integration of multiple modalities. “The impact of early pre-transplant sepsis on post liver transplant outcomes in cirrhotic patients” was presented by Khoy-Ear et al.78 from Beaujon Hospital who conducted a retrospective observational single-center study to determine the effect of pretransplant sepsis (PTS) on posttransplant outcomes. Among their cohort, 21% had PTS that included spontaneous bacterial peritonitis, urinary tract infections, and pneumonia. Twenty-two percent were in septic shock, 24% required mechanical ventilation, and 22% required renal replacement therapy. The authors demonstrated that PTS resulted in increased posttransplant infections, vasopressor requirements, renal replacement therapy, days requiring mechanical ventilation, and hospital length of stay. The authors advocated for further study in identifying specific predictors to aid in the decision to offer transplantation in the presence of PTS.78 Blasi et al.79 from the University of Barcelona summarized pioneering work their group has performed on transplantation of allografts procured by uncontrolled donation after circulatory determination of death. In this study, the group’s experience with 39 Uncontrolled Donors after Cardiac Death (uDCD) donors was compared to a matched cohort of donation after neurologic death allograft recipients. The uDCD allograft recipients demonstrated lower mean arterial pressure and systemic vascular resistance upon reperfusion with a greater need for vasoactive support. Early allograft dysfunction was significantly greater in the uDCD group resulting in greater blood loss, higher transfusion requirements, an increased incidence for renal replacement therapy, a higher incidence of consumptive

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coagulopathy, and longer hospitalization. Long-term survival data of uDCD recipients were not presented. The authors concluded that although progress is occurring in the application of uDCD, perioperative management of these patients remains complex.79 “Applicability of rapid thromboelastography and functional fibrinogen assay in adult liver transplantation” by Lu et al.80 from the University of Pittsburgh was a prospective observational study comparing conventional kaolin thromboelastography (k-TEG) to the new thromboelastography variants, rapid thromboelastography (r-TEG), and functional fibrinogen thromboelastography (ff-TEG), in LT; rTEG demonstrated decreased test time but was associated with a higher incidence of measurement error compared to k-TEG. Functional fibrinogen TEG had a strong correlation with plasma fibrinogen level after induction of anesthesia, but this correlation declined postreperfusion. The effect of variation among the various modalities on clinical decision-making remained unclear. Prospective studies involving larger cohorts are necessary to define their applicability. The safety of epidural anesthesia in the performance of living donation was reported by Rajakumar et al.81 from Global Health City, India, where they have performed postoperative epidural anesthesia for 169 living donors. Their retrospective series comparing donors who received intravenous fentanyl infusion versus epidural anesthesia demonstrated significantly lower pain scores among epidural anesthesia recipients. Epidural catheters were removed on postoperative days 3 and 4 without neurologic sequelae. The authors concluded that appropriate timing of epidural placement and removal with respect to coagulation status may prevent complications.81 In conclusion, the 2014 Annual Meeting of the ILTS was well received by attendees. Significant new data were presented on the major themes of implementation of novel therapies for HCV, extension of living donation, expansion of the donor pool, and the emergence of machine preservation. These topics are certain to highlight the 2015 Annual Meeting of the ILTS in Chicago.

REFERENCES 1. Afdhal N, Everson G, Calleja JL, McCaughan G, Symonds WT, Denning J, et al. Sofosbuvir and ribavirin for the treatment of chronic HCV with cirrhosis and portal hypertension with and without decompensation: early virologic response and safety. Liver Transpl 2014; 20(suppl 1):S125. 2. Curry MP, Terrault N, O’Leary J, Forns X, Brown R Jr, Chung RT, et al. Sofosbuvir plus ribavirin before transplantation prevented HCV infection post-transplant in patients with HCV cirrhosis and HCC: results of an openlabel trial. Liver Transpl 2014;20(suppl 1):S150. 3. Charlton M, Samuel D, Gane E, Brown RS Jr, Curry MP, Kwo P, et al. Sofosbuvir and ribavirin for the treatment of recurrent hepatitis C infection after liver transplantation: results of a prospective, multicenter study. Liver Transpl 2014;20(suppl 1):S125. 4. Forns X, Prieto M, Charlton M, McHutchinson JG, Symonds WT, Denning J, et al. Sofosbuvir compassionate use program for patients with severe recurrent hepatits C

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including fibrosing cholestatic hepatitis following liver transplantation. Liver Transpl 2014;20(suppl 1):S150. 5. Gambato M, Crespo G, Londo~ no MC, Mari~ no Z, Lens S, Carri on JA, et al. Long term outcome of mild hepatitis C recurrence after liver transplantation: a large prospective study. Liver Transpl 2014;20(suppl 1):S121. 6. Crespo G, Gambato M, Mill an O, Casals G, Ruiz P, Forns X, et al. Usefulness of ELF, IP10, FibroScan and their combinations in the early prediction of severe hepatits C recurrence after liver transplantation. Liver Transpl 2014;20(suppl 1):S122. 7. De Simone P, Kaiser GM, De Carlis L, Metselaar HJ, Duvoux C, Nevens F, et al. The H2304E1 study: efficacy and safety of everolimus with reduced tacrolimus versus standard tacrolimus in de novo liver transplant recipients at 36 months. Liver Transpl 2014;20(suppl 1):S106. 8. Fung J, Metselaar HJ, Koneru B, Bartels M, McCaughan G, Chavin K, et al. Everolimus monotherapy after tacrolimus withdrawal at month 4 after liver transplantation: 3year results from the H2304 study extension. Liver Transpl 2014;20(suppl 1):S106. 9. Norero B, Serrano C, P erez RM, Duarte I, Arrese M, Soza A, et al. The expression of genes related to B cells are associated with a successful conversion from calcineurin inhibitor (CNI) based immunosuppresion to mycophenolate mofetil (MMF) monotherapy in liver transplant recipients. Liver Transpl 2014;20(suppl 1):S105. 10. Slotta JE, Beck J, Birau S, Balzer S, Andag R, Kanzaw P, et al. Quantification of donor DNA in the circulation after liver transplantation as a potential universal rejection biomarker using digital droplet PCR. Liver Transpl 2014; 20(suppl 1):S107. 11. Yamashita K, Zaitsu M, Nagatsu A, Goto R, Oura T, Watanabe M, et al. Successful withdrawal of immunosuppresion by a cell therapy using donor Ag-pulsed Tregs in living donor liver transplantation: an update on clinical trial. Liver Transpl 2014;20(suppl 1):S125. 12. Wozniak LJ, Venick RS, Bhattacharya S, Naini B, Reed EF, Farmer DG, et al. Treatment of donor specific antibodies: IVIG is efficacious for early but not late pediatric liver graft dysfunction. Liver Transpl 2014;20(suppl 1): S126. 13. Notarpaolo A, Bizouard G, Gambato M, Montalti R, Magini G, Miglioresi L, et al. Prediction of recurrence after liver transplantation for HCC: validation of the AFP model in an Italian cohort. Liver Transpl 2014;20(suppl 1):S132. 14. Duvoux C, Roudot-Thoraval F, Decaens T, Pessione F, Badran H, Piardi T, et al.; for Liver Transplantation French Study Group. Liver transplantation for hepatocellular carcinoma: a model including a-fetoprotein improves the performance of Milan criteria. Gastroenterology 2012;143:986-994. 15. Pi~ nero F, Marciano S, Ganem FO, Anders M, Zerega A, Cabrera CR, et al. Predicting recurrent hepatocellular carcinoma after liver transplantation with a new clinical score. Liver Transpl 2014;20(suppl 1):s135. 16. Salvalaggio PR, Felga GE, Della Guardia B, Almeida MD, Rezende MB. Prolonged waiting-list time does not have a negative impact in the post-transplant survival of patients with hepatocellular carcinoma. Liver Transpl 2014;20(suppl 1):S133. 17. Yang Z, Zhou L, Wu LM, Lai MC, Xie HY, Zhang F, Zheng SS. Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Ann Surg Oncol 2011;18:1243-1250. 18. Lai MC, Yang Z, Zhou L, Zhu QQ, Xie HY, Zhang F, et al. Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation. Med Oncol 2012;29:1810-1816.

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19. Yang Z, Zhou L, Ding C, Zheng Z, Wu L, Zheng S. A novel classification of hepatocellular carcinoma based on long noncoding RNA signature: implications for prognosis following liver transplantation. Liver Transpl 2014;20(suppl 1):S134. 20. Castelli G, Burra P, Giacomin A, Vitale A, Senzolo M, Cillo U, Farinati F. Sorafenib use in the transplant setting. Liver Transpl 2014;20:1021-1028. 21. Monsour HP Jr, Asham EH, Boktour M, Victor DW III, McFadden RS, Saharia A, et al. Sorafenib use pre transplant is associated with decreased post transplant recurrence rates in patients inside and outside the Milan criteria at 3 years. Liver Transpl 2014;20(suppl 1):S136. 22. Du C, Wu J, Lv Z, Cheng J, Xie H, Zheng S. The downregulation of Mir-126 promotes metastasis and angiogenesis in hepatocellular carcinoma. Liver Transpl 2014; 20(suppl 1):S149. 23. Hagness M, Solheim JM, Line PD, Foss AE, Dueland S. Liver transplantation or chemotherapy for non-resectable colorectal liver metastases? Liver Transpl 2014;20(suppl 1):S127. 24. Govil S, Shanmugam V, Safwan M, Ilias M, Olithselvan A, Narasimhan G, et al. Elevated portal venous pressure after living donor hepatectomy negatively influences postoperative synthetic liver function and increases postoperative complications. Liver Transpl 2014;20(suppl 1): S109. 25. Allard MA, Adam R, Bucur PO, Termos S, Cunha AS, Bismuth H, et al. Posthepatectomy portal vein pressure predicts liver failure and mortality after major liver resection on noncirrhotic liver. Ann Surg 2013;258:822-829. 26. Yamada T, Tanaka K, Uryuhara K, Ito K, Takada Y, Uemoto S. Selective hemi-portocaval shunt based on portal vein pressure for small-for-size graft in adult living donor liver transplantation. Am J Transplant 2008;8: 847-853. 27. Li H, Wei Y, Yan L, Wang W, Li B, Wen T. Using smallfor-size grafts in recipients with high MELD scores in living donor liver transplantation: our experience. Liver Transpl 2014;20(suppl 1):S110. 28. Kiuchi T, Tanaka K, Ito T, Oike F, Ogura Y, Fujimoto Y, Ogawa K. Small-for-size graft in living donor liver transplantation: how far should we go? Liver Transpl 2003;9: S29-S35. 29. Yi NJ, Suh KS, Lee HW, Shin WY, Kim J, Kim W, et al. Improved outcome of adult recipients with high Model for End-Stage Liver Disease score and a small-for-size graft. Liver Transpl 2009;15:496-503. 30. Olthoff KM, Merion RM, Ghobrial RM, Abecassis MM, Fair JH, Fisher RA, et al.; for A2ALL Study Group. Outcomes of 385 adult-to-adult living donor liver transplant recipients: a report from the A2ALL Consortium. Ann Surg 2005;242:314-323. 31. Bora G, Goyal N, Gupta S. Right posterior sector graft has fewer septic complications as compared to modified right lobe graft even when GRBWR is lesser. Liver Transpl 2014;20(suppl 1):S110. 32. Kokudo T, Hasegawa K, Sugawara Y, Kokudo N. Pitfall of right lateral sector graft procurement: supraportal right posterior hepatic artery. Transplantation 2013;96(12): e89-e91. 33. Yoshizumi T, Ikegami T, Kimura K, Uchiyama H, Ikeda T, Shirabe K, Maehara Y. Selection of a right posterior sector graft for living donor liver transplantation. Liver Transpl 2014;20:1089-1096. 34. Suh SW, Lee KW, Lee JM, Choi Y, Yi NJ, Suh KS. Clinical outcomes of and patient satisfaction with different incision methods for donor hepatectomy in living donor liver transplantation. Liver Transpl 2015;21:72-78.

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35. Kim SH, Lee SD, Kim YK, Park SJ. Pushing the frontiers of living donor right hepatectomy. World J Gastroenterol 2014;20:18,061-18,069. 36. Wu Y, Hu R. Robotic right lobectomy for living donor of liver. Liver Transpl 2014;20(suppl 1):S120. 37. Lin. Video presentation. In: The 2014 Joint International Congress of ILTS, ELITA & LICAGE. London, United Kingdom; 2014. 38. Bucur P, Allard M, Vignon-Clementel I, Audebert C, Drasdo D, Sebagh M, et al. Protection of the small remnant liver by portal pressure modulation with an adjustable vascular rIng (MID-AVR TM) after major hepatectomy in pigs. Liver Transpl 2014;20(suppl 1):S151. 39. Ravikumar R, Coussios CC, Holroyd D, Heaton N, Friend PJ, Jassem W. Human liver transplantation using normothermic machine preservation. Liver Transpl 2014; 20(suppl 1):S103. 40. Sutherland AI, Randle L, Muiesan P, Butler A, Perera T, Forsythe JRL, et al. Liver transplantation with allografts recovered from donors after circulatory death using insitu normothermic regional perfusion (NRP). Liver Transpl 2014;20(suppl 1):S104. 41. Jitaruch S, Dhawan A, Hughes RD, Filippi C, Soong D, Lehec S, Longhi MS, Mitry RR. Alginate microencapsulated human hepatocytes optimised for clinical transplantation. Liver Transpl 2014;20(suppl 1):S104. 42. Lu Z, Pan J, Yan S, Zheng S. Decellularized liver scaffolds preferentially induce Foxp31 regulatory T cells and inhibit allogenic T cell activation. Liver Transpl 2014; 20(suppl 1):S104. 43. Pulitano C, Ho P, Joseph D, Charbel S, Verran D, McCaughan G, et al. In vivo assessment of hepatic microcirculation using sidestream dark field imaging: an innovative method to predict early graft function after liver transplantation. Liver Transpl 2014;20(suppl 1): S119. 44. Uhlmann S, Uhlmann D, Spiegel HU. Evaluation of hepatic microcirculation by in-vivo microscopy. J Invest Surg 1999;12:179-193. 45. Puhl G, Schaser KD, Vollmar B, Menger MD, Settmacher U. Noninvasive in vivo analysis of the human hepatic microcirculation using orthogonal polarization spectral imaging. Transplantation 2003;75:756-761. 46. Lee KW, Simpkins CE, Montgomery RA, Locke JE, Segev DL, Maley WR. Factors affecting graft survival after liver transplantation from donation after cardiac death donors. Transplantation 2006;82:1683-1688. 47. Scalera I, Catalano G, Perera T, Mergental H, Mirza D, Bramhall S, et al. How far can we push the limit of donor age in DCD liver transplantation? Liver Transpl 2014; 20(suppl 1):S146. 48. Morrissey PE, Monaco AP. Donation after circulatory death: current practices, ongong challenges, and potential improvements. Transplantation 2014;97:258-264. 49. Madanur MA, Kontis E, Menon K, Stafford A, Jassem WM, Prachalias A, et al. Liver transplantation using preconditioned hypoxic donor livers is a safe way to increase the donor pool—a case controlled study. Liver Transpl 2014;20(suppl 1):S147. 50. Hakeem AR, Cockbain AJ, Raza SS, Pollard SG, Toogood GJ, Attia MA, et al. Increased morbidity in overweight and obese liver transplant recipients: a single-center experience of 1325 patients from the United Kingdom. Liver Transpl 2013;19:551-562. 51. Dick AA, Spitzer AL, Seifert CF, Deckert A, Carithers RL Jr, Reyes JD, Perkins JD. Liver transplantation at the extremes of the body mass index. Liver Transpl 2009;15: 968-977. 52. O’Leary JG, Landaverde C, Jennings L, Goldstein RM, Davis GL. Patients with NASH and cryptogenic cirrhosis

DIAZ ET AL. 999

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

are less likely than those with hepatitis C to receive liver transplants. Clin Gastroenterol Hepatol 2011;9:700-704. Pelletier SJ, Schaubel DE, Wei G, Englesbe MJ, Punch JD, Wolfe RA, et al. Effect of body mass index on the survival benefit of liver transplantation. Liver Transpl 2007; 13:1678-1683. Leonard J, Heimbach JK, Malinchoc M, Watt K, Charlton M. The impact of obesity on long-term outcomes in liver transplant recipients-results of the NIDDK liver transplant database. Am J Transplant 2008;8:667-672. Perez-Protto SE, Quintini C, Reynolds LF, You J, Cywinski JB, Sessler DI, Miller C. Comparable graft and patient survival in lean and obese liver transplant recipients. Liver Transpl 2013;19:907-915. Tandon P, Ney M, Irwin I, Ma MM, Gramlich L, Bain VG, et al. Severe muscle depletion in patients on the liver transplant wait list: its prevalence and independent prognostic value. Liver Transpl 2012;18:1209-1216. Kaido T, Ogawa K, Fujimoto Y, Ogura Y, Hata K, Ito T, et al. Impact of sarcopenia on survival in patients undergoing living donor liver transplantation. Am J Transplant 2013;13:1549-1556. DiMartini A, Cruz RJ Jr, Dew MA, Myaskovsky L, Goodpaster B, Fox K, et al. Muscle mass predicts outcomes following liver transplantation. Liver Transpl 2013;19:1172-1180. Wasserman K, Hansen JE, Sue DY, Stringer WW, Sietsema KE, Sun XG, Whipp BJ. Principles of Exercise Testing and Interpretation: Including Pathophysiology and Clinical Applications. 5th ed. Philadelphia, PA: Lippincott Williams & WIlkins; 2012. Bernal W, Martin-Mateos R, Lipcsey M, Tallis C, Woodsford K, McPhail MJ, et al. Aerobic capacity during cardiopulmonary exercise testing and survival with and without liver transplantation for patients with chronic liver disease. Liver Transpl 2014;20:54-62. Gupta A, Guha R, Cottam S. Cardiopulmonary exercise testing: can it really predict survival? Liver Transpl 2014;20(suppl 1):S149. Khuri SF, Daley J, Henderson W, Hur K, Demakis J, Aust JB, et al. The Department of Veterans Affairs’ NSQIP: The first national, validated, outcome-based, risk-adjusted, and peer-controlled program for the measurement and enhancement of the quality of surgical care. National VA Surgical Quality Improvement Program. Ann Surg 1998;228:491-507. Wang DW, Yin YM, Yao YM. Advances in the management of acute liver failure. World J Gastroenterol 2013;19: 7069-7077. Vaquero J, Fontana RJ, Larson AM, Bass NM, Davern TJ, Shakil AO, et al. Complications and use of intracranial pressure monitoring in patients with acute liver failure and severe encephalopathy. Liver Transpl 2005;11: 1581-1589. Saliba F, Dahlqvist G, Letierce A, Ichai P, Ruiz I, Coilly A, et al. Outcome of patients with acute liver failure meeting the criteria of liver transplantation in a recent cohort: impact of albumin dialysis with MARS and liver transplantation. Liver Transpl 2014;20(suppl 1):S141. Habib M, Roberts LN, Patel RK, Wendon J, Bernal W, Arya R. Evidence of rebalanced coagulation in acute liver injury and acute liver failure as measured by thrombin generation. Liver Int 2014;34:672-678. Lisman T, Bakhtiari K, Adelmeijer J, Meijers JC, Porte RJ, Stravitz RT. Intact thrombin generation and decreased fibrinolytic capacity in patients with acute liver injury or acute liver failure. J Thromb Haemost 2012;10:1312-1319. Iyer VN, Swanson KL, Cartin-Ceba R, Dierkhising RA, Rosen CB, Heimbach JK, et al. Hepatopulmonary

1000 DIAZ ET AL.

69.

70.

71. 72.

73.

74.

75.

syndrome: favorable outcomes in the MELD exception era. Hepatology 2013;57:2427-2435. Gupta S, Castel H, Rao RV, Picard M, Lilly L, Faughnan ME, Pomier-Layrargues G. Improved survival after liver transplantation in patients with hepatopulmonary syndrome. Am J Transplant 2010;10:354-363. Corley DA, Scharschmidt B, Bass N, Somberg K, Gold W. Lack of efficacy of TIPS for hepatopulmonary Syndrome. Gastroenterol 1997;113:728-730. Safdar Z, Bartolome S, Sussman N. Portopulmonary hypertension: an update. Liver Transpl 2012;18:881-891. Krowka MJ, Swanson KL, Frantz RP, McGoon MD, Wiesner RH. Portopulmonary hypertension: results from a 10-year screening algorithm. Hepatology 2006;44:1502-1510. Ramsay M. Portopulmonary hypertension and right heart failure in patients with cirrhosis. Curr Opin Anaestheiol 2010;23:145-150. Rodrıguez-Roisin R, Krowka MJ, Herv e P, Fallon MB; for ERS Task Force Pulmonary-Hepatic Vascular Disorders (PHD) Scientific Committee. Pulmonary-hepatic vascular disorders. Eur Respir J 2004;24:861-880. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009; 54(suppl):S43-S54.

LIVER TRANSPLANTATION, July 2015

76. Gallo de Moraes A, Cartin-Ceba R, Krowka MJ. Does the severity of portopulmonary hypertension (POPH) matter in the intensive care unit (ICU) post liver transplant (LT)? Liver Transpl 2014;20(suppl 1):S128. 77. Gitman M, Nicolau R, Ganier D, Sekar K, Nossaman B. Target dobutamine stress test (tDSE) in predicting adverse cardiac events (PACE) within one year following liver transplantation (LT). Liver Transpl 2014;20(suppl 1):S128. 78. Khoy-Ear L, P erier A, Eurin M, Toussaint A, Weiss E, Moreau R, et al. Impact of early pre-transplant sepsis on post liver-transplant outcome in cirrhotic patients. Liver Transpl 2014;20(suppl 1):S129. 79. Blasi A, Fondevila C, Hessheimer A, Fernandez J, Beltran J, Martinez-Palli G, et al. Liver transplant from uncontrolled DCD donors: a challenge in coagulation management. Liver Transpl 2014;20(suppl 1):S130. 80. Lu S, Tanaka KA, Abuelkasem E, Planinsik RM, Sakai T. Applicability of rapid thromboelastography and functional fibrinogen assay in adult liver transplantation. Liver Transpl 2014;20(suppl 1):S130. 81. Rajakumar A, Kaliamoorthy I, Gupta S, Reddy MS, Rela M. Epidural anaesthesia is safe and effective for donor hepatectomies - our experience with 169 cases. Liver Transpl 2014;20(suppl 1):S130.