Pediatric living donor liver transplantation with large-for-size left lateral segment grafts.

Usage of "large-for-size" left lateral segment (LLS) liver grafts in children with high graft to recipient weight ratio (GRWR) is controversial due to concerns about increased recipient complications. During the study period, 77 pediatric living donor liver transplantations (LDLTs) with LLS grafts were performed. We compared recipients with GRWR ≥2.5% (GR-High = 50) vs GRWR <2.5% (GR-Low = 27). Median age was higher in the GR-Low group (40 vs 8 months, P> .0001). Graft (GR-High: 98%, 98%, 98% vs GR-Low: 96%, 93%, 93%) and patient (GR-High: 98%, 98%, 98% vs GR-Low: 100%, 96%, 96%) survival at 1, 3, and 5 years was similar between groups (P = NS). Overall complications were also similar (34% vs 30%; P = .8). Hepatic artery and portal vein thrombosis following transplantation was not different (P = NS). Delayed abdominal fascia closure was more common in GR-High patients (17 vs 1; P = .002). Subgroup analysis comparing recipients with GRWR ≥4% (GR-XL = 20) to GRWR <2.5% (GRWR-Low = 27) revealed that delayed abdominal fascia closure was more common in the GR-XL group, but postoperative complications and graft and patient survival were similar. We conclude that pediatric LDLT with large-for-size LLS grafts is associated with excellent clinical outcomes. There is an increased need for delayed abdominal closure with no compromise of long-term outcomes. The use of high GRWR expands the donor pool and improves timely access to the benefits of transplantation without extra risks.

Renal Dysfunction After Liver Transplantation: Effect of Donor Type.

Recipients of donation after circulatory death (DCD) grafts are reportedly at higher risk of developing renal dysfunction after liver transplantation (LT). We compared the development of acute kidney injury (AKI) and chronic kidney disease (CKD) after LT in recipients of DCD versus donation after brain death (DBD) or living donor liver transplantation (LDLT) livers. Adult recipients of DBD, LDLT, and DCD between 2012 and 2016 at Toronto General Hospital were included. AKI was defined as a post-LT increase of serum creatinine (sCr) ≥26.5 µmol/L within 48 hours or a ≥50% increase from baseline, and CKD was defined as an estimated glomerular filtration rate <60 mL/minute for >3 months. A total of 681 patients (DCD, n = 57; DBD, n = 446; and LDLT, n = 178) with similar baseline comorbidities were included. Perioperative AKI (within the first 7 postoperative days) was observed more frequently in the DCD group (61%; DBD, 40%; and LDLT, 44%; P = 0.01) and was associated with significantly higher peak AST levels (P < 0.001). Additionally, patients in the DCD group had a significantly higher peak sCr (P < 0.001) and a trend toward higher rates of AKI stage 3 (DCD, 33%; DBD, 21%; LDLT, 21%; P = 0.11). The proportions of recovery from AKI (DCD, 77%; DBD, 72%; LDLT, 78%; P = 0.45) and patients developing CKD (DCD, 33%; DBD, 32%; LDLT, 32%; P = 0.99) were similar. Nevertheless, patients who received DCD or DBD LT and required perioperative renal replacement therapy showed significantly lower patient survival in multivariate analysis (hazard ratio, 7.90; 95% confidence interval, 4.51-13.83; P < 0.001). In conclusion, recipients of DCD liver grafts experience higher rates of short-term post-LT renal dysfunction compared with DBD or LDLT. Additional risk factors for the development of severe kidney injury, such as high Model for End-Stage Liver Disease score, massive transfusions, or donor age ≥60 years should be avoided.

Predictor parameters of liver viability during porcine normothermic ex situ liver perfusion in a model of liver transplantation with marginal grafts.

Normothermic ex situ liver perfusion (NEsLP) offers the opportunity to assess biomarkers of graft function and injury. We investigated NEsLP parameters (biomarkers and markers) for the assessment of liver viability in a porcine transplantation model. Grafts from heart-beating donors (HBD), and from donors with 30 minutes (donation after cardiac death [DCD]30'), 70 minutes (DCD70'), and 120 minutes (DCD120') of warm ischemia were studied. The HBD, DCD30', and DCD70'-groups had 100% survival. In contrast, 70% developed primary nonfunction (PNF) and died in the DCD120'-group. Hepatocellular function during NEsLP showed low lactate (≤1.1 mmol/L) in all the groups except the DCD120'-group (>2 mmol/L) at 4 hours of perfusion (P = .04). The fold-urea increase was significantly lower in the DCD120'-group (≤0.4) compared to the other groups (≥0.65) (P = .01). As for cholangiocyte function, bile/perfusate glucose ratio was significantly lower (<0.6) in all the groups except the DCD120'-group (≥0.9) after 3 hours of perfusion (<0.01). Bile/perfusate Na+ ratio was significantly higher (≥1.2) after 3 hours of perfusion in all the groups except for the DCD120'-group (≤1) (P < .01). Three hours after transplantation, the DCD120'-group had a significantly higher international normalized ratio (>5) compared to the rest of the groups (≤1.9) (P = .02). Rocuronium levels were higher at all the time-points in the animals that developed PNF during NEsLP and after transplantation. This study demonstrates that biomarkers and markers of hepatocellular and cholangiocyte function during NEsLP correlate with the degree of ischemic injury and posttransplant function.

Live donor liver transplantation for patients with hepatocellular carcinoma offers increased survival vs. deceased donation.

BACKGROUND & AIMS: There are conflicting reports on the outcomes after live donor liver transplantation in patients with hepatocellular carcinoma (HCC). We aimed to compare the survival of patients with HCC, with a potential live donor (pLDLT) at listing vs. no potential donor (pDDLT), on an intention-to-treat basis. METHODS: All patients with HCC listed for liver transplantation between 2000-2015 were included. The pLDLT group was comprised of recipients with a potential live donor identified at listing. Patients without a live donor were included in the pDDLT group. Survival was assessed by the Kaplan-Meier method. Multivariable Cox regression was applied to identify potential predictors of mortality. RESULTS: A total of 219 patients were included in the pLDLT group and 632 patients in the pDDLT group. In the pLDLT group, 57 patients (26%) were beyond the UCSF criteria whereas 119 patients (19%) in the pDDLT group were beyond (p = 0.02). Time on the waiting list was shorter for the pLDLT than the pDDLT group (4.8 [2.9-8.5] months vs. 6.2 [3.0-12.0] months, respectively, p = 0.02). The dropout rate was 32/219 (14.6%) in the pLDLT and 174/632 (27.5%) in the pDDLT group, p <0.001. The 1-, 3- and 5-year intention-to-treat survival rates were 86%, 72% and 68% in the pLDLT vs. 82%, 63% and 57% in the pDDLT group, p = 0.02. Having a potential live donor was a protective factor for death (hazard ratio [HR] 0.67; 95% CI 0.53-0.86). Waiting times of 9-12 months (HR 1.53; 95% CI 1.02-2.31) and ≥12 months (HR 1.69; 95% CI 1.23-2.32) were predictors of death. CONCLUSION: Having a potential live donor at listing was associated with a significant decrease in the risk of death in patients with HCC in this intention-to-treat analysis. This benefit is related to a lower dropout rate and a shorter waiting period. LAY SUMMARY: Liver transplantation (LT) offers the best chance of survival for patients with hepatocellular carcinoma and can be performed using grafts from deceased donors or live donors. In this work, we aimed to assess the differences in survival after live donor LT when compared to deceased donor LT. We studied 219 patients listed for live donor LT and 632 patients listed for deceased donor LT. Patients who had a potential live donor at the time of listing had a higher survival rate. Therefore, being listed for a live donor LT was a protective factor against death.

Outcomes of radiofrequency ablation as first-line therapy for hepatocellular carcinoma less than 3 cm in potentially transplantable patients.

BACKGROUND & AIMS: Radiofrequency ablation (RFA) is an effective treatment for single hepatocellular carcinoma (HCC) ≤3 cm. Disease recurrence is common, and in some patients will occur outside transplant criteria. We aimed to assess the incidence and risk factors for recurrence beyond Milan criteria in potentially transplantable patients treated with RFA as first-line therapy. METHODS: We performed a retrospective cohort study of potentially transplantable patients with new diagnoses of unifocal HCC ≤3 cm that underwent RFA as first-line therapy between 2000-2015. We defined potentially transplantable patients as those aged <70 years without any comorbidities that would preclude transplant surgery. Incidence of recurrence beyond Milan criteria was compared across 2 groups according to HCC diameter at the time of ablation: (HCC ≤2 cm vs. HCC >2 cm). Competing risks Cox regression was used to identify predictors of recurrence beyond Milan criteria. RESULTS: We included 301 patients (167 HCC ≤2 cm and 134 HCC >2 cm). Recurrence beyond Milan criteria occurred in 36 (21.6%) and 47 (35.1%) patients in the HCC ≤2 cm and the HCC >2 cm groups, respectively (p = 0.01). The 1-, 3- and 5-year actuarial survival rates after RFA were 98.2%, 86.2% and 79.0% in the HCC ≤2 cm group vs. 93.3%, 77.6% and 70.9% in the HCC >2 cm group (p = 0.01). Tumor size >2 cm (hazard ratio 1.94; 95%CI 1.25-3.02) and alpha-fetoprotein levels at the time of ablation (100-1,000 ng/ml: hazard ratio 2.05; 95%CI 1.10-3.83) were found to be predictors of post-RFA recurrence outside Milan criteria. CONCLUSION: RFA for single HCC ≤3 cm provides excellent short- to medium-term survival. However, we identified patients at higher risk of recurrence beyond Milan criteria. For these patients, liver transplantation should be considered immediately after the first HCC recurrence following RFA. LAY SUMMARY: Radiofrequency ablation and liver transplantation are treatment options for early stages of hepatocellular carcinoma (HCC). After ablation some patients will experience recurrence or metastatic spread of the initial tumor or may develop new tumors within the liver. Despite close follow-up, these recurrences can progress rapidly and exceed transplant criteria, preventing the patient from receiving a transplant. We identified that patients with HCC >2 cm and higher serum alpha-fetoprotein are at greater risk of recurrence beyond the transplant criteria. These data suggest that liver transplantation should be considered immediately after the first HCC recurrence for these patients.

Passenger Lymphocyte Syndrome After Pediatric Liver Transplantation.

BACKGROUND: Passenger lymphocyte syndrome (PLS) is a less known etiology of acute onset anemia following ABO-compatible (ABO-c) liver transplantation (LT). Available literature on PLS after pediatric LT is limited. Therefore, we evaluated the prevalence, clinical course, and risk factors of PLS in children following ABO-c LT. METHODS: A single-center retrospective review of all children who underwent LT between 2000 and 2017 was performed. PLS was defined as a drop-in hemoglobin >20 g/L within 30 days of LT, with positive direct antiglobulin test and 1 laboratory test confirming hemolysis. Chi square and student t tests compared variables between subjects with and without PLS. RESULTS: Amongst 333 pediatric LT performed, 51 children received an ABO-c graft. PLS was diagnosed in 7 (14%) subjects at a median of 10 days after LT. There were no significant differences in patient demographics, graft type, or immunosuppression between those who did and did not develop PLS. Recipient blood group A+ receiving a donor O+ graft was a risk factor for PLS (P = 0.015). All PLS subjects recovered with blood transfusions (median 2), and no additional interventions. Three subjects initially received recipient (instead of donor) blood group red cells. CONCLUSIONS: We report a 14% prevalence of PLS following pediatric ABO-c LT. Recipient blood group A+ receiving a donor O+ graft is a risk factor for PLS. Recognition of PLS as a cause of early acute anemia in pediatric ABO-c LT enables timely transfusion with donor (rather than recipient) blood group red cells.

Defining Benchmarks in Liver Transplantation: A Multicenter Outcome Analysis Determining Best Achievable Results.

: This multicentric study of 17 high-volume centers presents 12 benchmark values for liver transplantation. Those values, mostly targeting markers of morbidity, were gathered from 2024 "low risk" cases, and may serve as reference to assess outcome of single or any groups of patients. OBJECTIVE: To propose benchmark outcome values in liver transplantation, serving as reference for assessing individual patients or any other patient groups. BACKGROUND: Best achievable results in liver transplantation, that is, benchmarks, are unknown. Consequently, outcome comparisons within or across centers over time remain speculative. METHODS: Out of 7492 liver transplantation performed in 17 international centers from 3 continents, we identified 2024 low risk adult cases with a laboratory model for end-stage liver disease score ≤20 points, a balance of risk score ≤9, and receiving a primary graft by donation after brain death. We chose clinically relevant endpoints covering intra- and postoperative course, with a focus on complications graded by severity including the complication comprehensive index (CCI). Respective benchmarks were derived from the median value in each center, and the 75 percentile was considered the benchmark cutoff. RESULTS: Benchmark cases represented 8% to 49% of cases per center. One-year patient-survival was 91.6% with 3.5% retransplantations. Eighty-two percent of patients developed at least 1 complication during 1-year follow-up. Biliary complications occurred in one-fifth of the patients up to 6 months after surgery. Benchmark cutoffs were ≤4 days for ICU stay, ≤18 days for hospital stay, ≤59% for patients with severe complications (≥ Grade III) and ≤42.1 for 1-year CCI. Comparisons with the next higher risk group (model for end stage liver disease 21-30) disclosed an increase in morbidity but within benchmark cutoffs for most, but not all indicators, while in patients receiving a second graft from 1 center (n = 50) outcome values were all outside of benchmark values. CONCLUSIONS: Despite excellent 1-year survival, morbidity in benchmark cases remains high with half of patients developing severe complications during 1-year follow-up. Benchmark cutoffs targeting morbidity parameters offer a valid tool to assess higher risk groups.

Expanding the donor pool: Donation after circulatory death and living liver donation do not compromise the results of liver transplantation.

Because of the shortfall between the number of patients listed for liver transplantation (LT) and the available grafts, strategies to expand the donor pool have been developed. Donation after circulatory death (DCD) and living donor (LD) grafts are not universally used because of the concerns of graft failure, biliary complications, and donor risks. In order to overcome the barriers for the implementation of using all 3 types of grafts, we compared outcomes after LT of DCD, LD, and donation after brain death (DBD) grafts. Patients who received a LD, DCD, or DBD liver graft at the University of Toronto were included. Between January 2009 through April 2017, 1054 patients received a LT at our center. Of these, 77 patients received a DCD graft (DCD group); 271 received a LD graft (LD group); and 706 received a DBD graft (DBD group). Overall biliary complications were higher in the LD group (11.8%) compared with the DCD group (5.2%) and the DBD group (4.8%; P < 0.001). The 1-, 3-, and 5-year graft survival rates were similar between the groups with 88.3%, 83.2%, and 69.2% in the DCD group versus 92.6%, 85.4%, and 84.7% in the LD group versus 90.2%, 84.2%, and 79.9% in the DBD group (P = 0.24). Furthermore, the 1-, 3-, and 5-year patient survival was comparable, with 92.2%, 85.4%, and 71.6% in the DCD group versus 95.2%, 88.8%, and 88.8% in the LD group versus 93.1%, 87.5%, and 83% in the DBD group (P = 0.14). Multivariate Cox regression analysis revealed that the type of graft did not impact graft survival. In conclusion, DCD, LD, and DBD grafts have similar longterm graft survival rates. Increasing the use of LD and DCD grafts may improve access to LT without affecting graft survival rates. Liver Transplantation 24 779-789 2018 AASLD.

Living Donor Liver Transplantation Using Selected Grafts With 2 Bile Ducts Compared With 1 Bile Duct Does Not Impact Patient Outcome.

The outcome after living donor liver transplantation (LDLT) using grafts with multiple bile ducts (BDs) remains unclear. We analyzed 510 patients who received an adult-to-adult right lobe LDLT between 2000 and 2015 and compared outcome parameters of those receiving grafts with 2 BDs (n = 169) with patients receiving grafts with 1 BD (n = 320). Additionally, patients receiving a graft with 3 BDs (n = 21) were analyzed. Demographic variables and disease severity were similar between the groups. Roux-en-Y reconstruction was significantly more common in the 2 BD group (77% versus 38%; P < 0.001) compared with the 1 BD group. No difference was found in biliary complication rates within 1 year after LDLT (1 BD versus 2 BD groups, 18% versus 21%, respectively; P = 0.46). In the 2 BD group, 82/169 (48.5%) patients were reconstructed with 2 anastomoses. The number of anastomoses did not negatively impact biliary complication rates. Recipients' major complication rate (Clavien ≥ 3b) was similar between both groups (1 BD versus 2 BD groups, 21% versus 24%, respectively; P = 0.36). Furthermore, no difference could be found between the 1 BD, the 2 BD, and the 3 BD groups in the frequency of developing biliary complications within 1 year (18%, 21%, 14%, respectively; P = 0.64), BD strictures (15%, 15%, 5%, respectively; P = 0.42), or BD leaks (10%, 11%, 10%, respectively; P = 0.98). In addition, the 1-year (90% versus 91%), 5-year (82% versus 77%), and 10-year (70% versus 66%) graft survival rates as well as the 1-year (92% versus 93%), 5-year (84% versus 80%), and 10-year (75% versus 76%) patient survival rates were comparable between the 1 BD and the 2 BD groups (P = 0.41 and P = 0.54, respectively). In conclusion, this study demonstrates that selected living donor grafts with 2 BDs can be used safely without negatively impacting biliary complication rates and graft or patient survival rates.

Liver Transplantation is Equally Effective as a Salvage Therapy for Patients with Hepatocellular Carcinoma Recurrence Following Radiofrequency Ablation or Liver Resection with Curative Intent.

BACKGROUND: Liver resection (LR) and radiofrequency ablation (RFA) are curative-intent therapies for early stages of hepatocellular carcinoma (HCC). If HCC recurs, salvage liver transplant (SLT) may constitute a treatment option. OBJECTIVE: We aimed to compare the outcomes of patients transplanted for recurrent HCC after curative-intent therapies with those transplanted as initial therapy. METHODS: We conducted a matched-control (1:1) cohort study comparing patients with HCC treated with primary liver transplant (PLT) with SLT after HCC recurrence. Matching was performed according to the size and number of viable tumors at explant pathology following liver transplant. RESULTS: Between November 1999 and December 2014, 687 patients with HCC were listed for transplant at our institution. A total of 559 patients were transplanted; 509 patients were treated with PLT and 50 patients were treated with SLT for HCC recurrence after primary treatment with LR (n = 25) or RFA (n = 25). The median length of follow-up from transplant was 64 months (0.5-195), and the median time from curative-intent treatment of HCC with RFA or LR to recurrence was 9.5 months (1-36) and 14.5 months (3-143), respectively (p = 0.04). The matched cohort was composed of 48 SLT patients (23 LR and 25 RFA) and 48 PLT patients. The 5-year risk of recurrence after LT was 22% in the PLT group versus 32% in the SLT group (p = 0.53), while the 5-year actuarial patient survival after PLT was 69% versus 70% in the SLT group (p = 1). CONCLUSION: Liver transplant is an effective treatment for patients with HCC recurrence following RFA or LR. Outcomes are similar in both groups.

Live donor liver transplantation with older donors: Increased long-term graft loss due to HCV recurrence.

Using our prospectively collected database all adult hepatitis C virus (HCV)-positive patients receiving an adult-to-adult LDLT between October 2000 and May 2014 were identified. Outcome of LDLT with grafts from younger (<50 years=128) vs older donors (≥50 years=31) was compared. Post-transplant graft function, postoperative complications and incidence of HCV recurrence were evaluated. Long-term graft and patient survival was calculated. No difference in graft function was observed between younger and older grafts. Overall complications were similar between both groups. The severity of complications determined by the Dindo-Clavien score was similar. Graft loss from HCV recurrence was significantly less frequent in younger grafts (18% vs 62%, P = 0.001). Young vs older livers had a trend toward improved 1-, 5-, and 10-year graft survival (89% vs 87%, 77% vs 69%, 70% vs 55%, P = 0.096), while patient survival was comparable between both groups (91% vs 90%, 78% vs 69%, 71% vs 60%, P = 0.25). In conclusion, LDLT with older vs younger grafts are more frequently associated with long-term graft loss due to HCV recurrence. Differences in graft survival might be more prominent with prolonged (≥5-year) follow-up. Living donor-recipient matching is particularly important for younger HCV-positive recipients.

Stereotactic body radiotherapy vs. TACE or RFA as a bridge to transplant in patients with hepatocellular carcinoma. An intention-to-treat analysis.

BACKGROUND & AIMS: There is limited information on the use of stereotactic body radiotherapy (SBRT) as a bridge to liver transplantation for hepatocellular carcinoma and no study comparing its efficacy to transarterial chemoembolization (TACE) and radiofrequency ablation (RFA). We aimed to ascertain the safety and efficacy of SBRT on an intention-to-treat basis compared with TACE and RFA as a bridge to liver transplantation in a large cohort of patients with hepatocellular carcinoma. METHODS: Outcomes between groups were compared from the time of listing and from the time of transplant. Between July 2004 and December 2014, 379 patients were treated with either SBRT (n=36, SBRT group), TACE (n=99, TACE group) or RFA (n=244, RFA group). RESULTS: The drop-out rate was similar between groups (16.7% SBRT group vs. 20.2% TACE group and 16.8% RFA group, p=0.7); 30 patients were transplanted in the SBRT group, 79 in the TACE group and 203 in the RFA group. Postoperative complications were similar between groups. Patients in the RFA group had more tumor necrosis in the explant. The 1-, 3- and 5-year actuarial patient survival from the time of listing was 83%, 61% and 61% in the SBRT group vs. 86%, 61% and 56% in the TACE group, and 86%, 72% and 61% in the RFA group, p=0.4. The 1-, 3- and 5-year survival from the time of transplant was 83%, 75% and 75% in the SBRT group vs. 96%, 75% and 69% in the TACE group, and 95%, 81% and 73% in the RFA group, p=0.7. CONCLUSIONS: In conclusion, SBRT can be safely utilized as a bridge to LT in patients with HCC, as an alternative to conventional bridging therapies. LAY SUMMARY: Patients with liver cancer included in the waiting list for liver transplantation are at risk of tumor progression and death. Stereotactic body radiotherapy may be a good alternative to conventional therapies to reduce this risk.

The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: A prospective validation study.

The selection of liver transplant candidates with hepatocellular carcinoma (HCC) relies mostly on tumor size and number. Instead of relying on these factors, we used poor tumor differentiation and cancer-related symptoms to exclude patients likely to have advanced HCC with aggressive biology. We initially reported similar 5-year survival for patients whose tumors exceeded (M+ group) and were within (M group) the Milan criteria. Herein, we validate our original data with a new prospective cohort and report the long-term follow-up (10-years) using an intention-to-treat analysis. The previously published study (cohort 1) included 362 listed (294 transplanted) patients from January 1996 to August 2008. The validation cohort (cohort 2) includes 243 listed (105 M+ group, 76 beyond University of California San Francisco criteria; 210 transplanted) patients from September 2008 to December 2012. Median follow-up from listing was 59.7 (26.8-103) months. For the validation cohort 2, the actuarial survival from transplant for the M+ group was similar to that of the M group at 1 year, 3 years, and 5 years: 94%, 76%, and 69% versus 95%, 82%, and 78% (P = 0.3). For the combined cohorts 1 and 2, there were no significant differences in the 10-year actuarial survival from transplant between groups. On an intention-to-treat basis, the dropout rate was higher in the M+ group and the 5-year and 10-year survival rates from listing were decreased in the M+ group. An alpha-fetoprotein level >500 ng/mL predicted poorer outcomes for both the M and M+ groups. CONCLUSION: Tumor differentiation and cancer-related symptoms of HCC can be used to select patients with advanced HCC who are appropriate candidates for liver transplantation; alpha-fetoprotein level limitations should be incorporated in the listing criteria for patients within or beyond the Milan criteria. (Hepatology 2016;64:2077-2088).

Liver Transplantation is a Preferable Alternative to Palliative Therapy for Selected Patients with Advanced Hepatocellular Carcinoma.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) beyond the traditional criteria (advanced HCC) are typically offered palliation, which is associated with a 3-year survival rate lower than 30%. This study aimed to describe the outcomes for a subset of patients with advanced HCC who satisfied the Extended Toronto Criteria (ETC) and were listed for liver transplantation (LT). METHODS: All patients listed in the Toronto liver transplantation program with HCC beyond both the Milan and University of California, San Francisco criteria were included in this study. Data were extracted from the prospectively collected electronic database. All radiologic images were reviewed by two independent radiologists. The primary end point was patient survival. RESULTS: Between January 1999 and August 2014, 96 patients with advanced HCC were listed for LT, and 62 (65%) of these patients received bridging therapy while on the waiting list. Bridging therapy led to a significant reduction in tumor progression (p = 0.02) and tumor burden (p < 0.001). The majority of those listed underwent LT (n = 69, 72%). Both tumor progression on waiting list (hazard ratio [HR] 4.973; range1.599-15.464; p = 0.006) and peak alpha-fetoprotein (AFP) at 400 ng/ml or higher (HR, 4.604; range 1.660-12.768; p = 0.003) were independently associated with waiting list dropout. Post-LT HCC recurrence occurred in 35% of the patients (n = 24). Among those with HCC recurrence, survival was significantly better for those who received curative treatment (p = 0.004). The overall actuarial survival rates from the listing were 76% at 1 year, 56% at 3 years, and 47% at 5 years, and the corresponding rates from LT were 93, 71, and 66%. CONCLUSION: Liver transplantation provides significantly better survival rates than palliation for patients with selected advanced HCC.

Characteristics of liver transplant candidates delisted following recompensation and predictors of such delisting in alcohol-related liver disease: a case-control study.

Whether and when recovery beyond the need for transplant may occur in patients listed for decompensation remains unclear. This study aimed to investigate the characteristics of patients delisted following recompensation. Seventy-seven patients who were listed between 2005 and 2015 for decompensation, but later delisted following recompensation were included. Alcohol-related liver disease (ALD) was the underlying etiology in the majority (n = 47, 61%). Listing characteristics of these patients were compared with those of decompensated ALD patients who either underwent deceased donor liver transplantation or died on the waiting list. The model for end-stage liver disease (MELD) score <20 and serum albumin ≥32 g/l at listing were the only independent predictors of recompensation/delisting in ALD. The probability of recompensation was 70% when both factors were present at listing. Interestingly, about a tenth of decompensated ALD patients who died on the waiting list (median duration on waiting list 11 months) and a quarter of decompensated ALD patients who underwent living donor liver transplantation (median duration on waiting list 2 months) also had both factors at listing. In conclusion, ALD seems to be the most favorable etiology for recompensation beyond the need for transplantation. Both MELD and serum albumin at listing independently predict recompensation/delisting in ALD. It seems advisable to implement a period of observation for ALD patients with both favorable factors, before embarking on living donor liver transplantation.

Live Donor Liver Transplantation With Older (≥50 Years) Versus Younger (<50 Years) Donors: Does Age Matter?

OBJECTIVE: To compare the outcome of adult live donor liver transplantation (LDLT) with grafts from older versus younger donors. INTRODUCTION: Using older donor grafts for adult LDLT may help expand the donor pool. However, the risks of LDLT with older donors remain controversial, and many centers are reluctant to use live donors aged 45 years or older for adult LDLT. METHODS: Outcomes of patients receiving a LDLT graft from donors aged 50 years or older (n = 91) were compared with those receiving a live donor graft from donors younger than 50 years (n = 378). RESULTS: Incidences of biliary (LDLT <50: 24% vs LDLT ≥50: 23%; P = 0.89) and major complications (LDLT <50: 24% vs LDLT ≥50: 24%; P = 1) were similar between both groups of recipients. No difference was observed in 30-day recipient mortality (LDLT <50: 3% vs LDLT ≥50: 0%; P = 0.13). The 1- (90% vs 90%), 5- (82% vs 73%), and 10- (71% vs 58%) year graft survival was statistically similar between both groups (P = 0.075). Likewise, patient survival after 1- (92% vs 96%), 5- (83% vs 79%), and 10- (76% vs 69%) years was also similar (P = 0.686). Overall, donors rate of major complications (Dindo-Clavien ≥3b) within 30 days was low (n = 2.3%) and not different in older versus younger donors (P = 1). Donor median hospital stay in both groups was identical [LDLT <50: 6 (4-17) vs LDLT ≥50: 6 (4-14) days; P = 0.65]. No donor death occurred and all donors had full recovery and returned to baseline activity. CONCLUSIONS: Right lobe LDLT with donors aged 50 years or older results in acceptable recipient outcome without increased donor morbidity or mortality. Potential live donors should not be declined on the basis of age alone.

Defining Benchmarks for Major Liver Surgery: A multicenter Analysis of 5202 Living Liver Donors.

OBJECTIVE: To measure and define the best achievable outcome after major hepatectomy. BACKGROUND: No reference values are available on outcomes after major hepatectomies. Analysis in living liver donors, with safety as the highest priority, offers the opportunity to define outcome benchmarks as the best possible results. METHODS: Outcome analyses of 5202 hemi-hepatectomies from living donors (LDs) from 12 high-volume centers worldwide were performed for a 10-year period. Endpoints, calculated at discharge, 3 and 6 months postoperatively, included postoperative morbidity measured by the Clavien-Dindo classification, the Comprehensive Complication Index (CCI), and liver failure according to different definitions. Benchmark values were defined as the 75th percentile of median morbidity values to represent the best achievable results at 3 month postoperatively. RESULTS: Patients were young (34 ± [9] years), predominantly male (65%) and healthy. Surgery lasted 7 ± [2] hours; 2% needed blood transfusions. Mean hospital stay was 11.7± [5] days. 12% of patients developed at least 1 complication, of which 3.8% were major events (≥grade III, including 1 death), mostly related to biliary/bleeding events, and were twice higher after right hepatectomy. The incidence of postoperative liver failure was low. Within 3-month follow-up, benchmark values for overall complication were ≤31 %, for minor/major complications ≤23% and ≤9%, respectively, and a CCI ≤33 in LDs with complications. Centers having performed ≥100 hepatectomies had significantly lower rates for overall (10.2% vs 35.9%, P < 0.001) and major (3% vs 12.1%, P < 0.001) complications and overall CCI (2.1 vs 8.5, P < 0.001). CONCLUSIONS: The thorough outcome analysis of healthy LDs may serve as a reference for evaluating surgical performance in patients undergoing major liver resection across centers and different patient populations. Further benchmark studies are needed to develop risk-adjusted comparisons of surgical outcomes.

Anti-inflammatory signaling during ex vivo liver perfusion improves the preservation of pig liver grafts before transplantation.

Normothermic ex vivo liver perfusion (NEVLP) improves graft preservation by avoiding cold ischemia injury. We investigated whether the protective effects of NEVLP can be further improved by applying strategies targeted on reducing the activation of proinflammatory cytokines during perfusion. Livers retrieved under heart-beating conditions were perfused for 4 hours. Following the preservation period, a pig liver transplantation was performed. In group 1 (n = 5), anti-inflammatory strategies (alprostadil, n-acetylcysteine, carbon monoxide, sevoflurane, and subnormothermic temperature [33°C]) were applied. This was compared with a perfused control group (group 2) where livers (n = 5) were perfused at 37°C without anti-inflammatory agents, similar to the setup used in current European clinical trials, and to a control group preserved with static cold storage (group 3). During 3-day follow-up, markers of reperfusion injury, bile duct injury, and liver function were examined. Aspartate aminotransferase (AST) levels during perfusion were significantly lower in the study versus control group at 1 hour (52 ± 6 versus 162 ± 86 U/L; P = 0.01), 2 hours (43 ± 5 versus 191 ± 111 U/L; P = 0.008), and 3 hours (24 ± 16 versus 218 ± 121 U/L; P = 0.009). During perfusion, group 1 versus group 2 had reduced interleukin (IL) 6, tumor necrosis factor α, and galactosidase levels and increased IL10 levels. After transplantation, group 1 had lower AST peak levels compared with group 2 and group 3 (1400 ± 653 versus 2097 ± 1071 versus 1747 ± 842 U/L; P = 0.47) without reaching significance. Bilirubin levels were significantly lower in group 1 versus group 2 at day 1 (3.6 ± 1.5 versus 6.60 ± 1.5 µmol/L; P = 0.02) and 3 (2 ± 1.1 versus 9.7 ± 7.6 µmol/L; P = 0.01). A trend toward decreased hyaluronic acid, as a marker of improved endothelial cell function, was observed at 1, 3, and 5 hours after reperfusion in group 1 versus group 2. Only 1 early death occurred in each group (80% survival). In conclusion, addition of anti-inflammatory strategies further improves warm perfused preservation. Liver Transplantation 22 1573-1583 2016 AASLD.

Subnormothermic ex vivo liver perfusion is a safe alternative to cold static storage for preserving standard criteria grafts.

We developed a novel technique of subnormothermic ex vivo liver perfusion (SNEVLP) for the storage of liver grafts before transplantation. To test the safety of SNEVLP for the nonextended criteria grafts (standard grafts), we compared it to a control group with minimal cold static storage (CS) time. Heart-beating pig liver retrieval was performed. Grafts were either stored in cold unmodified University of Wisconsin solution (CS-1), in cold University of Wisconsin solution with ex vivo perfusion additives (CS-2), or preserved with a sequence of 3 hours CS and 3 hours SNEVLP (33°C), followed by orthotopic liver transplantation. Liver function tests and histology were investigated. Aspartate aminotransferase (AST) levels during SNEVLP remained stable (54.3 ± 12.6 U/L at 1 hour to 47.0 ± 31.9 U/L at 3 hours). Posttransplantation, SNEVLP versus CS-1 livers had decreased AST levels (peak at day 1, 1081.9 ± 788.5 versus 1546.7 ± 509.3 U/L; P = 0.14; at day 2, 316.7 ± 188.1 versus 948.2 ± 740.9 U/L; P = 0.04) and alkaline phosphatase levels (peak at day 1, 150.4 ± 19.3 versus 203.7 ± 33.6 U/L; P = 0.003). Bilirubin levels were constantly within the physiological range in the SNEVLP group, whereas the CS-1 group presented a large standard deviation, including pathologically increased values. Hyaluronic acid as a marker of endothelial cell (EC) function was markedly improved by SNEVLP during the early posttransplant phase (5 hours posttransplant, 1172.75 ± 598.5 versus 5540.5 ± 2755.4 ng/mL). Peak international normalized ratio was similar between SNEVLP and CS-1 groups after transplantation. Immunohistochemistry for cleaved caspase 3 demonstrated more apoptotic sinusoidal cells in the CS-1 group when compared to SNEVLP grafts 2 hours after reperfusion (19.4 ± 19.5 versus 133.2 ± 48.8 cells/high-power field; P = 0.002). Adding normothermic CS-2 had no impact on liver injury or function after transplantation when compared to CS-1. In conclusion, SNEVLP is safe to use for standard donor grafts and is associated with improved EC and bile duct injury even in grafts with minimal CS time.

Normothermic ex vivo liver perfusion using steen solution as perfusate for human liver transplantation: First North American results.

The European trial investigating normothermic ex vivo liver perfusion (NEVLP) as a preservation technique for liver transplantation (LT) uses gelofusine, a non-US Food and Drug Administration-approved, bovine-derived, gelatin-based perfusion solution. We report a safety and feasibility clinical NEVLP trial with human albumin-based Steen solution. Transplant outcomes of 10 human liver grafts that were perfused on the Metra device at 37 °C with Steen solution, plus 3 units of erythrocytes were compared with a matched historical control group of 30 grafts using cold storage (CS) as the preservation technique. Ten liver grafts were perfused for 480 minutes (340-580 minutes). All livers cleared lactate (final lactate 1.46 mmol/L; 0.56-1.74 mmol/L) and produced bile (61 mL; 14-146 mL) during perfusion. No technical problems occurred during perfusion, and all NEVLP-preserved grafts functioned well after LT. NEVLP versus CS had lower aspartate aminotransferase and alanine aminotransferase values on postoperative days 1-3 without reaching significance. No difference in postoperative graft function between NEVLP and CS grafts was detected as measured by day 7 international normalized ratio (1.1 [1-1.56] versus 1.1 [1-1.3]; P = 0.5) and bilirubin (1.5; 1-7.7 mg/dL versus 2.78; 0.4-15 mg/dL; P = 0.5). No difference was found in the duration of intensive care unit stay (median, 1 versus 2 days; range, 0-8 versus 0-23 days; P = 0.5) and posttransplant hospital stay (median, 11 versus 13 days; range, 8-17 versus 7-89 days; P = 0.23). Major complications (Dindo-Clavien ≥ 3b) occurred in 1 patient in the NEVLP group (10%) compared with 7 (23%) patients in the CS group (P = 0.5). No graft loss or patient death was observed in either group. Liver preservation with normothermic ex vivo perfusion with the Metra device using Steen solution is safe and results in comparable outcomes to CS after LT. Using US Food and Drug Administration-approved Steen solution will avoid a potential regulatory barrier in North America. Liver Transplantation 22 1501-1508 2016 AASLD.