R. W. Busuttil

Liver Transplantation Criteria For Hepatocellular Carcinoma Should Be Expanded: A 22-Year Experience With 467 Patients at UCLA

Objective:To assess the efficacy of orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) and the impact of current staging criteria on long term survival. Summary Background Data:HCC is becoming an increasingly common indication for OLT. Medicare approves OLT only for HCCs meeting the Milan criteria, thus limiting OLT for an expanding pool of potential liver recipients. We analyzed our experience with OLT for HCC to determine if expansion of criteria for OLT for HCC is warranted. Methods:All patients undergoing OLT for HCC from 1984 to 2006 were evaluated. Outcomes were compared for patients who met Milan criteria (single tumor ≤5 cm, maximum of 3 total tumors with none >3 cm), University of California, San Francisco (UCSF) criteria (single tumor <6.5 cm, maximum of 3 total tumors with none >4.5 cm, and cumulative tumor size <8 cm), or exceeded UCSF criteria. Results:A total of 467 transplants were performed for HCC. At mean follow up of 6.6 ± 0.9 years, recurrence rate was 21.2%, and overall 1, 3, and 5-year survival was 82%, 65%, and 52%, respectively. Patients meeting Milan criteria had similar 5-year post-transplant survival to patients meeting UCSF criteria by preoperative imaging (79% vs. 64%; P = 0.061) and explant pathology (86% vs. 71%; P = 0.057). Survival for patients with tumors beyond UCSF criteria was significantly lower and was below 50% at 5 years. Multivariate analysis showed that tumor number (P < 0.001), lymphovascular invasion (P < 0.001), and poor differentiation (P = 0.002) independently predicted poor survival. Conclusions:This largest single institution experience with OLT for HCC demonstrates prolonged survival after liver transplantation for tumors beyond Milan criteria but within UCSF criteria, both when classified by preoperative imaging and by explant pathology. Measured expansion of OLT criteria is justified for tumors not exceeding the UCSF criteria.

Pretransplant Model to Predict Posttransplant Survival in Liver Transplant Patients

ObjectiveTo develop a prognostic model that determines patient survival outcomes after orthotopic liver transplantation (OLT) using readily available pretransplant variables. Summary Background DataThe current liver organ allocation system strongly favors organ distribution to critically ill recipients who exhibit poor survival outcomes following OLT. A severely limited organ resource, increasing waiting list deaths, and rising numbers of critically ill recipients mandate an organ allocation system that balances disease severity with survival outcomes. Such goals can be realized only through the development of prognostic models that predict survival following OLT. MethodsVariables that may affect patient survival following OLT were analyzed in hepatitis C (HCV) recipients at the authors’ center, since HCV is the most common indication for OLT. The resulting patient survival model was examined and refined in HCV and non-HCV patients in the United Network for Organ Sharing (UNOS) database. Kaplan-Meier methods, univariate comparisons, and multivariate Cox proportional hazard regression were employed for analyses. ResultsVariables identified by multivariate analysis as independent predictors for patient survival following primary transplantation of adult HCV recipients in the last 10 years at the authors’ center were entered into a prognostic survival model to predict patient survival. Accordingly, mortality was predicted by 0.0293 (recipient age) + 1.085 (log10 recipient creatinine) + 0.289 (donor female gender) + 0.675 urgent UNOS - 1.612 (log10 recipient creatinine times urgent UNOS). The above variables, in addition to donor age, total bilirubin, prothrombin time (PT), retransplantation, and warm and cold ischemia times, were applied to the UNOS database. Of the 46,942 patients transplanted over the last 10 years, 25,772 patients had complete data sets. An eight-factor model that accurately predicted survival was derived. Accordingly, the mortality index posttransplantation = 0.0084 donor age + 0.019 recipient age + 0.816 log creatinine + 0.0044 warm ischemia (in minutes) + 0.659 (if second transplant) + 0.10 log bilirubin + 0.0087 PT + 0.01 cold ischemia (in hours). Thus, this model is applicable to first or second liver transplants. Patient survival rates based on model-predicted risk scores for death and observed posttransplant survival rates were similar. Additionally, the model accurately predicted survival outcomes for HCV and non-HCV patients. ConclusionsPosttransplant patient survival can be accurately predicted based on eight straightforward factors. The balanced application of a model for liver transplant survival estimate, in addition to disease severity, as estimated by the model for end-stage liver disease, would markedly improve survival outcomes and maximize patients’ benefits following OLT.

Liver transplantation for nonalcoholic steatohepatitis: the new epidemic.

Objective:To analyze incidence, outcomes, and utilization of health care resources in liver transplantation (LT) for nonalcoholic steatohepatitis (NASH). Summary of Background Data:With the epidemic of obesity and metabolic syndrome in nearly 33% of the US population, NASH is projected to become the leading indication for LT in the next several years. Data on predictors of outcome and utilization of health care resources after LT in NASH is limited. Methods:We conducted an analysis from our prospective database of 144 adult NASH patients who underwent LT between December 1993 and August 2011. Outcomes and resource utilization were compared with other common indications for LT. Independent predictors of graft and patient survival were identified. Results:The average Model for End-Stage Liver Disease score was 33. The frequency of NASH as the primary indication for LT increased from 3% in 2002 to 19% in 2011 to become the second most common indication for LT at our center behind hepatitis C. NASH patients had significantly longer operative times (402 vs 322 minutes; P < 0.001), operative blood loss (18 vs 14 packed red blood cell units; P = 0.001), and posttransplant length of stay (35 vs 29 days; P = 0.032), but 1-, 3-, and 5-year graft (81%, 71%, 63%) and patient (84%, 75%, 70%) survival were comparable with other diagnoses. Age greater than 55 years, pretransplant intubation, dialysis, hospitalization, presence of hepatocellular carcinoma on explant, donor age greater than 55 years, and cold ischemia time greater than 550 minutes were significant independent predictors of survival for all patients, whereas body mass index greater than 35 was a predictor in NASH patients only. Conclusions:We report the largest single institution experience of LT for NASH. Over a 10-year period, the frequency of LT for NASH has increased 5-fold. Although outcomes are comparable with LT for other indications, health care resources are stressed significantly by this new and increasing group of transplant candidates.

The evolution of liver transplantation during 3 decades: analysis of 5347 consecutive liver transplants at a single center.

Objective:To analyze a 28-year single-center experience with orthotopic liver transplantation (OLT) for patients with irreversible liver failure. Background:The implementation of the model for end-stage liver disease (MELD) in 2002 represented a fundamental shift in liver donor allocation to recipients with the highest acuity, raising concerns about posttransplant outcome and morbidity. Methods:Outcomes and factors affecting survival were analyzed in 5347 consecutive OLTs performed in 3752 adults and 822 children between 1984 and 2012, including comparisons of recipient and donor characteristics, graft and patient outcomes, and postoperative morbidity before (n = 3218) and after (n = 2129) implementation of the MELD allocation system. Independent predictors of survival were identified. Results:Overall, 1-, 5-, 10-, and 20-year patient and graft survival estimates were 82%, 70%, 63%, 52%, and 73%, 61%, 54%, 43%, respectively. Recipient survival was best in children with biliary atresia and worst in adults with malignancy. Post-MELD era recipients were older (54 vs 49, P < 0.001), more likely to be hospitalized (50% vs 47%, P = 0.026) and receiving pretransplant renal replacement therapy (34% vs 12%, P < 0.001), and had significantly greater laboratory MELD scores (28 vs 19, P < 0.001), longer wait-list times (270 days vs 186 days, P < 0.001), and pretransplant hospital stays (10 days vs 8 days, P < 0.001). Despite increased acuity, post-MELD era recipients achieved superior 1-, 5-, and 10-year patient survival (82%, 70%, and 65% vs 77%, 66%, and 58%, P < 0.001) and graft survival (78%, 66%, and 61% vs 69%, 58%, and 51%, P < 0.001) compared with pre-MELD recipients. Of 17 recipient and donor variables, era of transplantation, etiology of liver disease, recipient and donor age, prior transplantation, MELD score, hospitalization at time of OLT, and cold and warm ischemia time were independent predictors of survival. Conclusions:We present the worlds largest reported single-institution experience with OLT. Despite increasing acuity in post-MELD era recipients, patient and graft survival continues to improve, justifying the “sickest first” allocation approach.

Endoscopic treatment of postorthotopic liver transplantation anastomotic biliary strictures with maximal stent therapy (with video)

BACKGROUNDnThe optimal endoscopic protocol for treating postorthotopic liver transplantation (OLT) anastomotic biliary strictures (ABSs) has not been established.nnnOBJECTIVEnTo review the technique and outcomes of endoscopic retrograde cholangiopancreatography (ERCP) with maximal stenting for post-OLT ABSs at our institution.nnnDESIGNnRetrospective study.nnnSETTINGnTertiary-care center.nnnPATIENTSnEighty-three patients with a diagnosis of ABS.nnnINTERVENTIONSnERCP with balloon dilation and maximal stenting.nnnMAIN OUTCOME MEASUREMENTSnStricture resolution, stricture recurrence, and complication rates.nnnRESULTSnOf 83 patients, 69 completed treatment, of whom 65 (94%) achieved resolution and 4 (6%) required hepaticojejunostomy (HJ). The remaining 14 patients who did not achieve a study endpoint were excluded (9 deaths or redo OLT unrelated to biliary disease, and 5 without follow-up). Comparing the resolution group and the HJ group, there were, respectively, 8.0 and 3.5 total stents (P = .021), 2.5 and 1.3 stents per ERCP (P = .018) (maximum = 9), 4.2 and 2.8 ERCPs (P = .15), and 20 and 22 months from OLT to ABS diagnosis (P = .19). There were 2 cases of ERCP pancreatitis (0.7%) and 2 cases of periprocedural bacteremia of 286 total ERCPs and no episodes of cholangitis caused by stent occlusion. In a median follow-up of 11 months (range 0-39), 2 (3%) patients had ABS recurrence that was successfully re-treated with ERCP. A multivariate Cox model demonstrated that treatment success was directly related to the number of stents used in total and per ERCP.nnnLIMITATIONSnRetrospective study, single endoscopist.nnnCONCLUSIONSnOur maximal stenting protocol for ABSs is effective, safe, rarely associated with ABS recurrence, and conducive to less frequent stent exchange and therefore fewer ERCPs compared with conventional treatment.

The correlation of intragraft cytokine expression with rejection in rat small intestine transplantation.

Rejection continues to be a major cause of graft Ion in small intestine transplantation (SIT). We have studied, by semiquantitative reverse transcriptase PCR (rtPCR), the intragraft expression of cytokines relevant to rejection in a rat model. Heterotopic SIT grafts were performed from Lewis x Brown Norway F1 donors into Lewis recipients. The isograft control was Lewis into Lewis. Five animals in each isograft and allograft group were sacrificed on POD 3, 5, 7, 8, 9, 10, 12, and 14. mRNA was isolated from portions of the terminal ileum and rtPCR performed to amplify message for interleukin-2 (IL-2), IL-2 receptor (IL-2R), interleukin-6 (IL-8), tumor necrosis factor α (TNF-α), and interferon gamma (IFN-γ). Semiquantitative analysis was performed using 32P radionuclide incorporation and scintillation counting. The results were expressed as percent activity compared with β-actin. Histologic correlation with cytokine expression was made. On POD 3 after SIT there was no evidence of rejection by histology and all cytokines studied showed no difference between the-isograft and the allograft. On POD 5 the first evidence of mild rejection was seen on histology and IL-6, IFN-γ, TNF-α showed a significant up regulation in the allograft that persisted through POD 14. mRNA for IL-2 was not significantly upregulated until POD 7 and persisted until POD 14. IL-2R was constitutively expressed in both isograft and allograft and was not a reliable predictor of rejection. Histologic rejection was moderately severe by POD 7 and severe between POD 8 and 14 correlating with the increasing expression of IL-8, IFN-γ, and TNF-α. In summary, we have shown that increasing expression of mRNA for IL-6, IFN-γ, and TNF-α not only correlated with severity of rejection but that upregulation began early when histologic evidence of rejection first occurred.

AASLD/ILTS transplant course: is there an extended donor suitable for everyone?

1 The clinical success of liver transplantation coupled with the current era of organ shortage has caused many centers to expand their criteria for acceptable donors. 2 The definition of “Extended Criteria Donor” (ECD) is becoming better understood and quantified. 3 Recipient factors that portend poor outcome must be recognized and factored in as well. Grafts and recipients must be “matched” to manage and minimize the risk from ECDs. 4 Maintaining acceptable outcomes as ECD concepts evolve is paramount. 5 Absolute risk factors for poor graft function still exist and must be respected, but relative risk factors are now well identified, quantified, accepted, and managed as an alternative to high waiting list mortality. (Liver Transpl 2005;11:S2–S5.)

Complete pathologic response to pretransplant locoregional therapy for hepatocellular carcinoma defines cancer cure after liver transplantation: analysis of 501 consecutively treated patients.

OBJECTIVESnTo evaluate the rate, effect, and predictive factors of a complete pathologic response (cPR) in patients with hepatocellular carcinoma (HCC) undergoing locoregional therapy (LRT) before liver transplantation (LT).nnnBACKGROUNDnEligible patients with HCC receive equal model for end-stage liver disease prioritization, despite variable risks of tumor progression, waitlist dropout, and posttransplant recurrence. Pretransplant LRT mitigates these risks by inducing tumor necrosis.nnnMETHODSnComparisons were made among HCC recipients with cPR (n = 126) and without cPR (n = 375) receiving pre-LT LRT (1994-2013). Multivariable predictors of cPR were identified.nnnRESULTSnOf 501 patients, 272, 148, and 81 received 1, 2, and 3 or more LRT treatments. The overall, recurrence-free, and disease-specific survival at 1-, 3-, and 5 years was 86%, 71%, 63%; 84%, 67%, 60%; and 97%, 90%, 87%. Compared with recipients without cPR, cPR patients had significantly lower laboratory model for end-stage liver disease scores, pretransplant alpha fetoprotein, and cumulative tumor diameters; were more likely to have 1 lesion, tumors within Milan/University of California, San Francisco (UCSF) criteria, LRT that included ablation, and a favorable tumor response to LRT; and had superior 1-, 3-, and 5-year recurrence-free survival (92%, 79%, and 73% vs 81%, 63%, and 56%; P = 0.006) and disease-specific survival (100%, 100%, and 99% vs 96%, 89%, and 86%; P < 0.001) with only 1 cancer-specific death and fewer recurrences (2.4% vs 15.2%; P < 0.001). Multivariate predictors of cPR included a favorable post-LRT radiologic/alpha fetoprotein tumor response, longer time interval from LRT to LT, and lower model for end-stage liver disease score and maximum tumor diameter (C-statistic 0.75).nnnCONCLUSIONSnAchieving cPR in patients with HCC receiving LRT strongly predicts tumor-free survival. Factors predicting cPR are identified, allowing for differential prioritization of HCC recipients based on their variable risks of post-LT recurrence. Improving LRT strategies to maximize cPR would enhance posttransplant cancer outcomes.

Balloon-Occluded Retrograde Transvenous Obliteration (BRTO) for Treatment of Gastric Varices: Review and Meta-Analysis

AimTo perform a systematic review and meta-analysis of the effectiveness and complications of BRTO for gastric varices.Materials and MethodsA systematic review was performed to identify relevant articles. Inclusion criteria were applied to select studies with at least ten patients with acute bleeding or at-risk gastric varices treated with BRTO. Meta-analysis with random effects model was performed to calculate data for immediate technical success, clinical success, and complications.ResultsA total of 1,016 Patients from 24 studies met inclusion criteria. Technical success rate for BRTO was 96.4xa0% (95xa0% CI 93.7, 98.3xa0%; Qxa0=xa03,269.26, pxa0<xa00.01, I2xa0=xa099.39xa0%). Clinical success (defined as no recurrence or rebleed of gastric varices, or complete obliteration of varices on subsequent imaging) rate was 97.3xa0% (95xa0% CI 95.2, 98.8xa0%; Qxa0=xa03,105.91, pxa0<xa00.01, I2xa0=xa099.29xa0%). Major complication rate was 2.6xa0% (95xa0% CI 1.1, 4.6xa0%; Qxa0=xa03,348.98, pxa0<xa00.01, I2xa0=xa099.34xa0%). Esophageal variceal recurrence rate was 33.3xa0% (95xa0% CI 24.6, 42.6xa0%; Qxa0=xa07,291.75, pxa0<xa00.01, I2xa0=xa099.74xa0%).ConclusionBRTO is safe and efficacious for gastric varices, and current best evidence suggests that BRTO could be considered as therapy for patients with gastric varices.

Perforin and granzyme B. Cytolytic proteins up-regulated during rejection of rat small intestine allografts.

Perforin and granzyme B are 2 cytolytic proteins specific to activated killer cells, particularly CTL. We have studied the mRNA expression of these 2 proteins by a reverse transcriptase polymerase chain reaction method in a unidirectional model of rat small intestine transplant rejection. The allograft group consisted of Lewis x Brown Norway F1 donors into Lewis recipients. The isograft controls were Lewis donors into Lewis recipients. Grafts were placed heterotopically and no immunosuppression was given. Five animals in each group were killed at postoperative days (POD) 3, 5, 7, 8, 9, 10, 12, and 14. mRNA was extracted and a semiquantitative reverse transcriptase polymerase chain reaction was performed. For the semiquantitative analysis, we compared scintillation counts from excised bands. Results were expressed as a percent activity compared with beta-actin. From the same tissue samples, a histologic evaluation was made and rejection was graded according to severity. The isograft controls showed no evidence of histologic rejection and a very low expression of mRNA for perforin and granzyme B from POD 3-14. In contrast, the allograft group began to show histologic evidence of mild rejection on POD 5. By day 7, rejection was moderately severe and associated with a significant up-regulation of perforin and granzyme B in the allografts compared with the controls (P < 0.01), which persisted through POD 14. Peak expression for perforin and granzyme B was on POD 10 and 8, respectively. We conclude that the up-regulation of perforin and granzyme B in rat small intestine transplant allografts is a useful marker of clinically important rejection.