Karim J. Halazun

Survival Outcomes Following Liver Transplantation (SOFT) Score: A Novel Method to Predict Patient Survival Following Liver Transplantation

It is critical to balance waitlist mortality against posttransplant mortality.

Negative Impact of Neutrophil-Lymphocyte Ratio on Outcome After Liver Transplantation for Hepatocellular Carcinoma

Background:The Milan criteria have been adopted by United Network for Organ Sharing (UNOS) to preoperatively assess outcome in patients with hepatocellular carcinoma (HCC) who receive orthotopic liver transplantation (OLT). These criteria rely solely on radiographic appearances of the tumor, providing no measure of tumor biology. Recurrence rates, therefore, remain around 20% for patients within the criteria. The neutrophil-lymphocyte ratio (NLR) is an indicator of inflammatory status previously established as a prognostic indicator in colorectal liver metastases. We aimed to determine whether NLR predicts outcome in patients undergoing OLT for HCC. Design:Analysis of patients undergoing OLT for HCC between 2001 and 2007 at our institution. A NLR ≥5 was considered to be elevated. Results:A total of 150 patients were identified, with 13 patients having an elevated NLR. Of these, 62% developed recurrence compared with 14% with normal NLR (P < 0.0001). The disease-free survival for patients with high NLR was significantly worse than that for patients with normal NLR (1-, 3-, and 5-year survivals of 38%, 25%, and 25% vs. 92%, 85%, and 75%, P < 0.0001). Patients with high NLR also had poorer overall survival (5-year survival, 28% vs. 64%, P = 0.001). Patients within Milan with an elevated NLR had significantly poorer disease-free survival than those with normal NLR within Milan (5-year survival, 30% vs. 81%, P < 0.0001). On univariate analysis, 9 factors including an NLR ≥5 were significant predictors of poor disease-free survival. However, only a raised NLR remained significant on multivariate analysis (P = 0.005, HR: 19.98). Conclusion:Elevated NLR significantly increases the risk for tumor recurrence and recipient death. Preoperative NLR measurement may provide a simple method of identifying patients with poorer prognosis and act as an adjunct to Milan in determining, which patients benefit most from OLT.

Preoperative prognostic score for predicting survival after hepatic resection for colorectal liver metastases

Background:Despite indications for resection of colorectal liver metastases having expanded, debate continues about identifying patients that may benefit from surgery. Methods:Clinicopathologic data from a total of 700 patients was gathered between January 1993 and January 2006 from a prospectively maintained dataset. Of these, 687 patients underwent resection for colorectal liver metastases. Results:The median age of patient was 64 years and 36.8% of patients had synchronous disease. The overall 5-year survival was 45%. The presence of an inflammatory response to tumor (IRT), defined by an elevated C-reactive protein (>10 mg/L) or a neutrophil/lymphocyte ratio of >5:1, was noted in 24.5% of cases. Only the number of metastases and the presence or absence of an IRT influenced both overall and disease-free survival on multivariable analysis. A preoperative prognostic score was derived: 0 = less than 8 metastases and absence of IRT; 1 = 8 or more metastases or IRT, and 2 = 8 or more metastases and IRT—from the results of the multivariable analysis. The 5-year survival of those scoring 0 was 49% compared with 34% for those scoring 1. None of the patients that scored 2 were alive at 5 years. Conclusion:The preoperative prognostic score is a simple and effective system allowing preoperative stratification.

The Combined Organ Effect : Protection Against Rejection?

Objectives:To further our understanding of the potential protective effects of one organ allograft for another in combined organ transplants by comparing rejection-free survival and the 1-year rejection rate of each type of combined organ transplant. Summary Background Data:Liver allografts have been thought to be immunoprotective of other donor-specific allografts. Recent observations have extended this property to other organs. Methods:Analysis of data from the United Network of Organ Sharing included recipients 18 years or older (except those receiving intestinal transplants) transplanted between January 1, 1994, and October 6, 2005, and excluded those with a previous transplant (n = 45,306), live-donor transplant (n = 80,850), or insufficient follow-up (n = 4304). Patients were followed from transplant until death (n = 41,524), retransplantation (n = 4649), or last follow-up (n = 87,243). Results:A total of 133,416 patients were analyzed. Rejection rates for allografts co-transplanted with donor-specific primary liver, kidney, and heart allografts are significantly lower than rejection rates for allografts transplanted alone. Allografts accompanying primary intestinal or pancreatic allografts did not have reduced rejection rates. A decreased rate of rejection was seen in interval kidney-heart transplants when allografts shared partial antigenic identity. Decreased rates of rejection were also seen in transplants of 2 donor-specific organs of the same type. Conclusions:In combined simultaneous transplants, heart, liver, and kidney allografts are themselves protected and protect the other organ from rejection. Analysis of interval heart-kidney allografts suggests the need for partial antigenic identity between organs for the immunoprotection to take effect. This was not demonstrated in interval liver-kidney transplants. Increased antigen load of identical antigens, as seen in double-lung and double-kidney transplants, also offers immunologic protection against rejection.

Diabetes, body mass index and outcomes in hepatocellular carcinoma patients undergoing liver transplantation

&NA; For many cancers, features of the metabolic syndrome, such as diabetes and obesity, have been associated with both increased risk of cancer development and poor outcomes. Methods We examined a large retrospective cohort of 342 consecutive patients who underwent liver transplantation for hepatocellular carcinoma between January 1999 and July 2010 at our institution. We evaluated the relationship between diabetes, obesity, hepatocellular carcinoma (HCC) recurrence, and overall survival. Results We found that a body mass index (BMI) higher than 30 was an independent predictor of poor overall survival in a multivariable Cox model, approximately doubling the risk of death after transplantation. A BMI higher than 30 was also a predictor of recurrent HCC, although this was of borderline statistical significance (hazard ratio for recurrence, 1.9; 95% confidence interval, 0.9–4.1). We also found increased BMI to be an independent predictor of microvascular invasion within HCC tumors, lending a possible explanation to these results. Those with diabetes showed worsened overall survival compared with those without diabetes in univariate but not multivariable analysis, possibly related to longer wait times. Conclusions Our findings suggest a relationship between higher BMI, tumor vascular invasion, increased recurrence, and worsened overall survival. These findings may help explain why those with high BMI have worse outcomes from their cancers. A better understanding of the role of obesity and diabetes in patients with cancer should help develop better predictors of outcome and improved treatment options for patients with HCC.

Right hepatic trisectionectomy for hepatobiliary diseases: results and an appraisal of its current role.

Objective:To assess the results of 275 patients undergoing right hepatic trisectionectomy and to clarify its current role. Summary Background Data:Right hepatic trisectionectomy is considered one of the most extensive liver resections, and few reports have described the long-term results of the procedure. Methods:Short- and long-term outcomes of 275 consecutive patients who underwent right hepatic trisectionectomy from January 1993 to January 2006 were analyzed. Results:Of the 275 patients, 160 had colorectal metastases, 49 had biliary tract cancers, 20 had hepatocellular carcinomas, 20 had other metastatic tumors, and 12 had benign diseases. Fourteen of the 275 patients underwent right hepatic trisectionectomy as part of auxiliary liver transplantation for acute liver failure and were excluded. Concomitant procedures were carried out in 192 patients: caudate lobectomy in 45 patients, resection of tumors from the liver remnant in 57 patients, resection of the extrahepatic biliary tree in 45 patients, and lymphadenectomy in 45 patients. One-, 3-, 5-, and 10-year survivals were 74%, 54%, 43%, and 36%, respectively. Overall hospital morbidity and 30-day and in-hospital mortalities were 41%, 7%, and 8%, respectively. Survivals for individual tumor types were acceptable, with 5-year survivals for colorectal metastasis and cholangiocarcinoma being 38% and 32%, respectively. Multivariate analysis disclosed the amount of intraoperative blood transfusion to be the sole independent predictor for the development of hospital morbidity. Age over 70 years, preoperative bilirubin levels, and the development of postoperative renal failure were found to be independent predictors of long-term survival. Conclusion:Right hepatic trisectionectomy remains a challenging procedure. The outcome is not influenced by additional concomitant resection of tumors from the planned liver remnant. Caution must be taken when considering patients older than 70 years for such resections.

Recurrence After Liver Transplantation for Hepatocellular Carcinoma: A New MORAL to the Story.

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 HCCs (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.

Obesity and Microvascular Invasion in Hepatocellular Carcinoma

ABSTRACT Background: We hypothesized that hepatocellular carcinoma (HCC) patients with higher Body Mass Index (BMI) might have more microvascular invasion (MVI) in their tumors. Methods: Records from 138 consecutive patients who underwent surgery at Columbia University Medical Center from January 1, 2002 to January 9, 2008 were evaluated. Results: 40 patients (29%) had MVI, including 14% with BMI <25, 31% with BMI = 25–30, and 40% with BMI >30 (p = .05). However, only maximum alpha-fetoprotein was significantly associated with overall mortality in a Cox model. Conclusions: MVI was associated with obesity. A better understanding of the mechanism of this association may lead to interventions for the treatment and prevention of HCC.

Leaning to the Left: Increasing the Donor Pool by Using the Left Lobe, Outcomes of the Largest Single-center North American Experience of Left Lobe Adult-to-adult Living Donor Liver Transplantation.

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.

Impact of Pretransplant Bridging Locoregional Therapy for Patients with Hepatocellular Carcinoma Within Milan Criteria Undergoing Liver Transplantation: Analysis of 3601 Patients from the US Multicenter HCC Transplant Consortium

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.