Faculty Bibliography

OBJECTIVE:To evaluate the effect of pretransplant bridging locoregional therapy (LRT) on hepatocellular carcinoma (HCC) recurrence and survival after liver transplantation (LT) in patients meeting Milan criteria (MC). SUMMARY BACKGROUND DATA:Pre-LT LRT mitigates tumor progression and waitlist dropout in HCC patients within MC, but data on its impact on post-LT recurrence and survival remain limited. METHODS:Recurrence-free survival and post-LT recurrence were compared among 3601 MC patients with and without bridging LRT utilizing competing risk Cox regression in consecutive patients from 20 US centers (2002-2013). RESULTS:Compared with 747 LT recipients not receiving LRT, 2854 receiving LRT had similar 1, 3, and 5-year recurrence-free survival (89%, 77%, 68% vs 85%, 75%, 68%; P = 0.490) and 5-year post-LT recurrence (11.2% vs 10.1%; P = 0.474). Increasing LRT number [3 LRTs: hazard ratio (HR) 2.1, P < 0.001; 4+ LRTs: HR 2.5, P < 0.001), and unfavorable waitlist alphafetoprotein trend significantly predicted post-LT recurrence, whereas LRT modality did not. Treated patients achieving complete pathologic response (cPR) had superior 5-year RFS (72%) and lower post-LT recurrence (HR 0.52, P < 0.001) compared with both untreated patients (69%; P = 0.010; HR 1.0) and treated patients not achieving cPR (67%; P = 0.010; HR 1.31, P = 0.039), who demonstrated increased recurrence compared with untreated patients in multivariate analysis controlling for pretransplant and pathologic factors (HR 1.32, P = 0.044). CONCLUSIONS:Bridging LRT in HCC patients within MC does not improve post-LT survival or HCC recurrence in the majority of patients who fail to achieve cPR. The need for increasing LRT treatments and lack of alphafetoprotein response to LRT independently predict post-LT recurrence, serving as a surrogate for underlying tumor biology which can be utilized for prioritization of HCC LT candidates.

OBJECTIVE:Marginal livers (ML) have been used to expand the donor pool. National utilization of MLs is variable, and in some centers, they are never used. We examined the outcomes of MLs in the largest single center series of MLs used to date and compared outcomes to standard (SL) and living donor (LD) livers. METHODS:Analysis of a prospectively maintained database of all liver transplants performed at our institution from 1998 to 2016. ML grafts were defined as livers from donors >70, livers discarded regionally and shared nationally, livers with cold ischemic time >12 hours, livers from hepatitis C virus positive donors, livers from donation after cardiac death donors, livers with >30% steatosis, and livers split between 2 recipients. RESULTS:A total of 2050 liver transplant recipients were studied, of these 960 (46.8%) received ML grafts. ML recipients were more likely to have lower MELDs and have hepatocellular carcinoma. Most MLs used were from organs turned down regionally and shared nationally (69%) or donors >70 (22%). Survival of patients receiving MLs did not significantly differ from patients receiving SL grafts (P = 0.08). ML and SL recipients had worse survival than LDs (P < 0.01). Despite nearly half of our recipients receiving MLs, overall survival was significantly better than national survival over the same time period (P = 0.04). Waitlist mortality was significantly lower in our series compared with national results (19% vs 24.0%, P < 0.0001). CONCLUSIONS:Outcomes of recipients of ML grafts are comparable to SL transplants. Despite liberal use of these grafts, we have been able to successfully reduce waitlist mortality while exceeding national post-transplant survival metrics.

BACKGROUND:Low case volume has been associated with worse survival outcomes in solid organ transplantation. Our aim was to analyze wait-list outcomes in conjunction with posttransplant outcomes. METHODS:We studied a cohort of 11,488 candidates waitlisted in the Organ Procurement and Transplantation Network (OPTN) for pediatric kidney transplant between 2002 and 2014, including both deceased- and living-donor transplants; 8757 (76 %) candidates received a transplant. Candidates were divided into four groups according to the average volume of yearly transplants performed in the listing center over a 12-year period: more than ten, six to nine, three to five, and fewer than three. We used multivariate Cox regression analysis to identify independent risk factors for wait list and posttransplant mortality. RESULTS:Twenty-seven percent of candidates were listed at low-volume centers in which fewer than three transplants were performed annually. These candidates had a limited transplant rate; only 49 % received a transplant versus 88 % in high-volume centers (more than ten transplants annually) (p < 0.001). Being listed at a low-volume center showed a fourfold increased risk for death while on the wait list [hazard ratio (HR) 4.0 in multivariate Cox regression and 6.1 in multivariate competing risk regression]. It was not a significant risk factor for posttransplant death in multivariate Cox regression. CONCLUSIONS:Pediatric transplant candidates are listed at low-volume transplant centers are transplanted less frequently and have a much greater risk of dying while on the wait list. Further studies are needed to elucidate the reasons behind the significant outcome differences.

OBJECTIVE:We sought to develop a "Model Of Recurrence After Liver transplant" (MORAL) for hepatocellular carcinoma (HCC). BACKGROUND:The Milan criteria are used to allocate livers to patients with HCC requiring liver transplantation (LT) but do not include objective measures of tumor biology. Biological markers including the neutrophil-lymphocyte ratio (NLR) and alpha-fetoprotein (AFP) have been associated with recurrence risk. METHODS:Prospective cohort study of adults undergoing LT for HCC between January 2001 and December 2012. RESULTS:A total of 339 patients were included. On multivariable Cox regression analysis, 3 preoperatively available factors were independent predictors of worse recurrence-free survival (RFS), namely, an NLR ≥ 5 (P < 0.0001, hazard ratio, HR: 6.2), AFP > 200 (P < 0.0001, HR: 3.8), and Size >3 cm (P < 0.001, HR: 3.2). The Pre-MORAL score was constructed from the hazard ratios and assigning patients points in an additive fashion, with a minimum of 0 points (no factors) and a maximum of 13 points (all 3 factors). The highest risk patients in the Pre-MORAL had a 5-year RFS of 17.9% compared with 98.6% for the low risk group (P < 0.0001). The post-MORAL was constructed similarly using the 4 postoperatively available independent predictors of worse RFS, grade 4 HCC's (P < 0.0001, HR: 5.6), vascular invasion (P = 0.019, HR: 2.0), size >3 cm (P < 0.0001, HR: 3.2) and number >3 (P = 0.048, HR: 1.8). The pre- and post-MORAL were superior to Milan at predicting recurrence with c-statistics of 0.82 and 0.87, compared with 0.63, respectively. We then combined the scores to produce a combo-MORAL, with a c-statistic of 0.91 for predicting recurrence. CONCLUSIONS:The MORAL score provides a simple, highly accurate tool for predicting recurrence and risk-stratification pre- and postoperatively.

Since the advent of the Milan criteria in 1996 and its widespread adoption for selection of patients with hepatocellular carcinoma (HCC) who would benefit from transplant, there has been an extensive hunt for the ideal clinical biomarker to predict HCC recurrence. This is because Milan lack does not include tumor biology indices and recurrence rates remain in the 15-20% range worldwide. While a 'silver-bullet' biomarker has not been found, several useful inflammatory markers have been identified and used in scoring systems that supersede Milan in their ability to predict HCC recurrence post liver transplantation (LT). In this review, we aim to summarize the role of inflammatory markers paly in the selection of HCC patients awaiting LT.

OBJECTIVE:Centers offering adult living donor liver transplantation (LDLT) mostly use right lobe grafts due to fears of providing recipients with insufficient hepatic volume, and the technical challenges presented by using left lobe grafts (LLGs). LLGs therefore represent approximately 5% of adult LDLTs performed in the United States. Here we present the largest North American experience with the use of LLG for adult LDLT. METHODS:Analysis of a prospectively maintained database of LDLTs performed from 1998 to 2015 at our institution. RESULTS:A total of 214 adult LDLTs were studied. Fifty-six patients (26%) received LLG. LLG recipients were more likely to be women, had significantly lower BMI, graft weight, and graft-weight-recipient-weight ratios (P < 0.05 for all). There were no significant differences in vascular or biliary complication between the groups. No significant differences existed in patient or graft survival at 1, 3, and 5 years (P = 0.747 and P = 0.398 respectively). Despite significantly increased risk of small-for-size syndrome in LLG, there was no increased risk of retransplant within 90-days or perioperative mortality in LLG recipients (P = 0.308 and P = 0.932 respectively). Graft type did not predict patient or graft outcomes on regression analysis (P = 0.857 and 0.399 respectively). CONCLUSIONS:Despite smaller graft sizes, outcomes of adult LDLT using LLG are comparable to right lobe grafts transplants. Left lobes can provide an important resource in an era of severe organ shortages, and these data should serve to allay the concerns of the transplant community in the United States.

Allocation policies for liver transplantation underwent significant changes in June 2013 with the introduction of Share 35. We aimed to examine the effect of Share 35 on regional variation in posttransplant outcomes. We examined two patient groups from the United Network for Organ Sharing dataset; a pre-Share 35 group composed of patients transplanted between June 17, 2012, and June 17, 2013 (n = 5523), and a post-Share group composed of patients transplanted between June 18, 2013, and June 18, 2014 (n = 5815). We used Kaplan-Meier and Cox multivariable analyses to compare survival. There were significant increases in allocation Model for End-stage Liver Disease (MELD) scores, laboratory MELD scores, and proportions of patients in the intensive care unit and on mechanical, ventilated, or organ-perfusion support at transplant post-Share 35. We also observed a significant increase in donor risk index in this group. We found no difference on a national level in survival between patients transplanted pre-Share 35 and post-Share 35 (p = 0.987). Regionally, however, posttransplantation survival was significantly worse in the post-Share 35 patients in regions 4 and 10 (p = 0.008 and p = 0.04), with no significant differences in the remaining regions. These results suggest that Share 35 has been associated with transplanting "sicker patients" with higher MELD scores, and although no difference in survival is observed on a national level, outcomes appear to be concerning in some regions.

BACKGROUND: Low case volume has been associated with poorer surgical outcomes in a multitude of surgical procedures. We studied the association among low case volume, outcomes, and the likelihood of pediatric liver transplantation. METHODS: We studied a cohort of 6628 candidates listed in the Organ Procurement and Transplantation Network for primary pediatric liver transplantation between 2002 and 2012; 4532 of the candidates went on to transplantation. Candidates were divided into groups according to the average volume of yearly transplants performed in the listing center over 10 years: >15, 10 to 15, 5 to 9, and <5. We used univariate and multivariate Cox regression analyses with bootstrapping on transplant recipient data and identified independent recipient and donor risk factors for wait-list and posttransplant mortality. RESULTS: 38.5% of the candidates were listed in low-volume centers, those in which <5 transplants were performed annually. These candidates had severely reduced likelihood of transplantation with only 41% receiving a transplant. For the remaining candidates, listed at higher volume centers, the transplant rate was 85% (P < .001). Being listed at a low-volume center was a significant risk factor in multivariate Cox regression analysis for both wait-list mortality (hazard ratio, 3.27; confidence interval, 2.53-4.23) and posttransplant mortality (hazard ratio, 2.21; confidence interval, 1.43-3.40). CONCLUSIONS: 38.5% of pediatric transplant candidates are listed in low-volume transplant centers and have lower likelihood of transplantation and poorer outcomes. If further studies substantiated these findings, we would advocate consolidating pediatric liver transplantation in higher volume centers.

Living donor liver transplantation has failed to become a major means of transplantation in the United States, where <5% of the transplants are performed with living donors. At least 30% to 50% of the complications of donor hepatectomy appear to be related to abdominal wall trauma, including hernia, bowel obstruction, and chronic abdominal discomfort. We analyzed our experience with laparoscopically procured donor hepatectomy. We compared 22 full laparoscopic donor hepatectomies to 20 open/hybrid hepatectomies over an 11-year period. Donor and recipient demographics, complications, and graft and recipient outcomes were analyzed. All 22 laparoscopically procured liver allografts were transplanted successfully. The laparoscopically procured grafts took longer to procure (7 hours 58 minutes versus 6 hours 38 minutes; P < 0.001). The laparoscopically procured cases had lower blood loss (177.3 versus 3753 cc; P < 0.001), a shorter length of stay, and significantly reduced days off work (P = .01). The 1-year graft survival was not different (90% in the laparoscopic group and 85% in the open group; P = 0.70). The 1-year patient survival was not different (95% in the laparoscopic group and 85% in the open group; P = 0.32). There was a trend toward lower wound issues in the laparoscopic group, but this did not reach significance (the hybrid/open group had a 15% hernia rate versus 5% for the laparoscopic group). In experienced living donor centers, laparoscopic liver donation appears to be feasible for all pediatric recipients and some adult recipients. Outcomes for the recipients of laparoscopically procured grafts do not appear significantly different from outcomes with hybrid/open techniques.