Liver Transplantation Outcomes in a U.S. Multicenter Cohort of 789 Patients With Hepatocellular Carcinoma Presenting Beyond Milan Criteria.

BACKGROUND AND AIMS: The Organ Procurement and Transplantation Network recently approved liver transplant (LT) prioritization for patients with hepatocellular carcinoma (HCC) beyond Milan Criteria (MC) who are down-staged (DS) with locoregional therapy (LRT). We evaluated post-LT outcomes, predictors of down-staging, and the impact of LRT in patients with beyond-MC HCC from the U.S. Multicenter HCC Transplant Consortium (20 centers, 2002-2013). APPROACH AND RESULTS: Clinicopathologic characteristics, overall survival (OS), recurrence-free survival (RFS), and HCC recurrence (HCC-R) were compared between patients within MC (n = 3,570) and beyond MC (n = 789) who were down-staged (DS, n = 465), treated with LRT and not down-staged (LRT-NoDS, n = 242), or untreated (NoLRT-NoDS, n = 82). Five-year post-LT OS and RFS was higher in MC (71.3% and 68.2%) compared with DS (64.3% and 59.5%) and was lowest in NoDS (n = 324; 60.2% and 53.8%; overall P < 0.001). DS patients had superior RFS (60% vs. 54%, P = 0.043) and lower 5-year HCC-R (18% vs. 32%, P < 0.001) compared with NoDS, with further stratification by maximum radiologic tumor diameter (5-year HCC-R of 15.5% in DS/<5 cm and 39.1% in NoDS/>5 cm, P < 0.001). Multivariate predictors of down-staging included alpha-fetoprotein response to LRT, pathologic tumor number and size, and wait time >12 months. LRT-NoDS had greater HCC-R compared with NoLRT-NoDS (34.1% vs. 26.1%, P < 0.001), even after controlling for clinicopathologic variables (hazard ratio [HR] = 2.33, P < 0.001) and inverse probability of treatment-weighted propensity matching (HR = 1.82, P < 0.001). CONCLUSIONS: In LT recipients with HCC presenting beyond MC, successful down-staging is predicted by wait time, alpha-fetoprotein response to LRT, and tumor burden and results in excellent post-LT outcomes, justifying expansion of LT criteria. In LRT-NoDS patients, higher HCC-R compared with NoLRT-NoDS cannot be explained by clinicopathologic differences, suggesting a potentially aggravating role of LRT in patients with poor tumor biology that warrants further investigation.

Pathologic Response to Pretransplant Locoregional Therapy is Predictive of Patient Outcome After Liver Transplantation for Hepatocellular Carcinoma: Analysis From the US Multicenter HCC Transplant Consortium.

OBJECTIVE: The aim of the study was to determine the rate, predictors, and impact of complete pathologic response (cPR) to pretransplant locoregional therapy (LRT) in a large, multicenter cohort of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT). BACKGROUND: LRT is used to mitigate waitlist dropout for patients with HCC awaiting LT. Degree of tumor necrosis found on explant has been associated with recurrence and overall survival, but has not been evaluated in a large, multicenter study. METHODS: Comparisons were made among patients receiving pre-LT LRT with (n = 802) and without (n = 2637) cPR from the United States Multicenter HCC Transplant Consortium (UMHTC), and multivariable predictors of cPR were identified using logistic regression. RESULTS: Of 3439 patients, 802 (23%) had cPR on explant. Compared with patients without cPR, cPR patients were younger; had lower Model for End-stage Liver Disease (MELD) scores, AFP levels, and neutrophil-lymphocyte ratios (NLR); were more likely to have tumors within Milan criteria and fewer LRT treatments; and had significantly lower 1-, 3-, and 5-year incidence of post-LT recurrence (1.3%, 3.5%, and 5.2% vs 6.2%, 13.5%, and 16.4%; P < 0.001) and superior overall survival (92%, 84%, and 75% vs 90%, 78%, and 68%; P < 0.001). Multivariable predictors of cPR included age, sex, liver disease diagnosis, MELD, AFP, NLR, radiographic Milan status, and number of LRT treatments (C-statistic 0.67). CONCLUSIONS: For LT recipients with HCC receiving pretransplant LRT, achieving cPR portends significantly lower posttransplant recurrence and superior survival. Factors predicting cPR are identified, which may help prioritize patients and guide LRT strategies to optimize posttransplant cancer outcomes.

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.

Liver Resection and Transplantation for Patients With Hepatocellular Carcinoma Beyond Milan Criteria.

OBJECTIVES: To assess survival after liver resection and transplantation in patients with hepatocellular carcinoma (HCC) beyond Milan criteria. BACKGROUND: The role of liver resection and transplantation remains controversial for patients with HCC beyond Milan criteria. Resection of advanced tumors and transplantation using extended-criteria are pursued at select high-volume center. METHODS: Patients from 5 liver cancer centers in the United States who had liver resection or transplantation for HCC beyond Milan criteria between 1990 and 2011 were included in the study. Multivariable and propensity-matching analyses estimated the effects of clinical factors and operative selection on survival. RESULTS: Of 608 patients beyond Milan without vascular invasion, 480 (79%) patients underwent resection and 128 (21%) underwent transplantation. Clinicopathologic profiles between resection and transplant patients differed significantly. Hepatitis C and cirrhosis were more prevalent in transplantation group (P < 0.001). Resection patients had larger tumors [median 9 cm, interquartile range (IQR): 6.5-12.9 cm vs. median 4.1, IQR: 3.4-5.3 cm, P < 0.001]; transplant patients were more likely to have multiple tumors (78% vs 28%, P < 0.001).Overall (OS) and disease-free survival (DFS) were both greater after tumor downstaging and transplantation than resection (all P < 0.001). OS did not differ between liver transplant recipients who were not pretreated or pretreated and failed to downstage compared with propensity-matched liver resection patients (P ≥ 0.176); DFS in this propensity matched cohort was greater after liver transplantation (P ≤ 0.017). CONCLUSIONS: Liver resection and transplantation provide curative options for patients with HCC beyond Milan criteria. Further treatment strategies aimed at the efficiency and durability of tumor downstaging and expansion of the role of transplantation among suitable candidates could improve outcomes in patients with large or multifocal HCC.

Kidney clamp, perfuse, re-implant: a useful technique for graft salvage after vascular complications during kidney transplantation.

Although intra-operative vascular complications during renal transplantation are rare, injuries associated with prolonged ischemia may lead to graft threatening early and late complications. This series describes a novel technique for intra-operative repair of vascular complications in five patients over a three-yr period. The method consists of rapid graft nephrectomy and re-preservation of the graft with cold University of Wisconsin solution, which allows for controlled/precise back table repair of the vascular injury without incurring prolonged warm ischemia time. In three cases, the donor renal vein (2) and donor renal artery (1) were damaged and required back table reconstruction. In two cases, the recipient iliac artery needed reconstruction. Three of the five cases used deceased donor iliac vessels from another donor for reconstruction. Two patients required postoperative dialysis for delayed graft function for three to nine d (average six d) and two patients had slow graft function. All grafts were functioning at 17 months (mean) after transplant, with a median serum of 1.61 mg/dL (0.74-3.69). This series demonstrates the effectiveness of kidney clamp, perfuse, resuscitate as an effective intra-operative technique to salvage grafts after vascular injury. Although the grafts may suffer from delayed or slow graft function, excellent long-term function is attainable.

ECD kidney transplantation outcomes are improved when matching donors to recipients using a novel creatinine clearance match ratio (CCMR).

Improved outcomes have been associated with various methods of size matching between expanded criteria (ECD) donors and recipients. A novel method for improved functional based matching was developed utilizing manipulation of Cockcroft-Gault estimated creatinine clearances for donor and recipient. We hypothesized that optimal clearance-based matches would have superior outcomes for both immediate graft function and long-term graft survival. For the analysis, recipients of ECD kidneys in the Scientific Registry of Transplant Recipients (SRTR) transplanted between October 1, 1987 and August 31, 2011 were included. Univariate and multivariate analyses predicted the hazard ratio of graft failure and the odds ratio of requiring dialysis within the first week. A total of 25,640 ECD kidney transplants were analyzed. On multivariate analysis, higher creatinine clearance match ratio (CCMR) was associated with increased graft failure and odds of requiring dialysis within the first week (comparing highest ratio quintile versus lowest ratio quintile: HR 1.43, p < 0.001; OR 2.08, p < 0.001). This study suggests that ECD kidneys have improved outcomes when the recipient/donor CCMR is optimized.

Does the Surgical Approach Affect the Incidence of Post-Hepatectomy Liver Failure in Cirrhotic Patients? An Analysis of the NSQIP Database.

Background: The association between surgical approach and post-hepatectomy liver failure (PHLF) in cirrhotic patients is poorly understood. We hypothesize that patients will have similar rates of liver failure regardless of whether they undergo minimally invasive liver resection (MILR) or open liver resection (OLR) in major liver resections. In contrast, there will be lower rates of PHLF in patients undergoing minor hepatectomy via the MILR approach.Methods: Propensity score matching was used to analyze regression by matching the MILR to the OLR cohort. Patient demographics from the American College of Surgeons National Surgical Quality Improvement Program, including race, age, gender, and ethnicity, were matched. Chronic obstructive pulmonary disease, congestive heart failure, smoking, hypertension, diabetes, renal failure, dyspnea, dialysis dependence, body mass index, and American Society of Anesthesiologists (ASA) classification (>ASA III) were among the preoperative patient characteristics subject to matching. PHLF (Grade A vs B. vs C) was our primary outcome measure.Results: A total of 2129 cirrhotic patients were included in the study. In the minor hepatectomy group, patients undergoing an OLR were more likely to get discharged to a facility (7.0% vs 4.4%; P = .03), had greater hospital length of stay (5 vs 3 days; P = .02), and had a greater need for invasive postoperative interventions (10.7% vs 4.6%; P < .01). They were also noted to have higher rates of organ space superficial surgical infections (SSIs) (7.3% vs 3.7%; P = .003), Clostridium difficile infection (.9% vs .1%; P = .05), renal insufficiency (2.1% vs .1%; P < .01), unplanned intubations (3.1% vs 1.4%; P = .03), and Grade C liver failure (2.3% vs .9%; P = .03).Conclusion: A higher incidence of PHLF grade C was found in patients undergoing OLR in the minor hepatectomy group. Therefore, in cirrhotic patients who can tolerate minimally invasive approaches, MILR should be offered to prevent postoperative complications as part of their optimization plan.

Liver transplant versus liver resection in patients with multifocal hepatocellular carcinoma.

BACKGROUND: The optimal surgical option in patients with multifocal hepatocellular carcinoma (MHCC) is an area of active research. The preference varies based on geographic variations and institutional policies. We sought to determine long-term outcomes in patients with MHCC based on surgical treatment-liver transplant (LT) vs resection (LR). METHODS: We performed a retrospective analysis of the National Cancer Database (2004-2015) and identified patients with MHCC within Milan criteria. Patients with α-fetoprotein ≥ 1000 ng/mL and those who underwent ablation were excluded. The primary outcome measure was long-term survival in patients undergoing LT vs LR. The secondary aim of our study was to determine clinicodemographic factors associated with the receipt of LT and LR. RESULTS: A total of 1546 patients were included, of whom 1211 received LT and 335 underwent LR. Patients who were non-Hispanic White (70.8% vs 54.9%; P < .01), privately insured (53.7% vs 36.7%; P < .01), and treated at academic centers (85.4% vs 71.6%; P < .01) were more likely to receive an LT. Multivariable Cox analysis revealed LT was associated with improved survival compared with LR (hazard ratio, 0.34; 95% CI, 0.28-0.42). CONCLUSION: We described clinical and sociodemographic differences in LT and LR patients and found LT to be associated with a decreased mortality risk compared with LR. The study's findings should be interpreted in the context of several limitations, including the selection of MHCC criteria within Milan criteria.

Braun enteroenterostomy is associated with reduced delayed gastric emptying and early resumption of oral feeding following pancreaticoduodenectomy.

BACKGROUND AND OBJECTIVES: Morbidity rates following pancreaticoduodenectomy (PD) remain high with delayed gastric emptying (DGE) and slow resumption of oral diet contributing to increased postoperative length of stay. A Braun enteroenterostomy has been shown to decrease bile reflux following gastric resection. We hypothesize that addition of Braun enteroenterostomy during PD would reduce the sequelae of DGE. METHODS: From our PD database, patients were identified that underwent classic PD with partial gastrectomy from 2001 to 2006. All patients with reconstruction utilizing a single loop of jejunum at the University of Florida Shands Hospital were reviewed. Demographics, presenting signs and symptoms, pathologic diagnoses, and postoperative morbidity were compared in those patients undergoing reconstruction with an additional Braun enteroenterostomy (n = 70) to those not undergoing a Braun enteroenterostomy (n = 35). RESULTS: Patients undergoing a Braun had NG tubes removed earlier (Braun: 2 days, no Braun: 3 days, P = 0.002) and no significant change in postoperative vomiting (Braun: 27%, no Braun: 37%, P = 0.37) or NG tube reinsertion rates (Braun: 17%, no Braun: 29%, P = 0.21). Median postoperative day with tolerance of oral liquids (Braun: 5, no Braun: 6, P = 0.01) and solid diets (Braun: 7, no Braun: 9, P = 0.01) were significantly sooner in the Braun group. DGE defined by two criteria including the inability to have oral intake by postoperative day 10 (Braun: 10%, no Braun: 26%, P < 0.05) and the international grading criteria (grades B and C, Braun: 7% vs. no Braun: 31%, P = 0.003) were significantly reduced in those undergoing the Braun procedure. In addition, the median length of stay (Braun: 10 days, no Braun: 12 days, P < 0.05) was significantly reduced in those undergoing the Braun procedure. The rate of pancreatic anastomotic failure was similar in the two groups (Braun: 17% vs. no Braun: 14%, P = 0.79). Median bile reflux was 0% in those undergoing a Braun. CONCLUSIONS: The present study suggests that Braun enteroenterostomy can be safely performed in patients undergoing PD and may reduce the indicence of DGE and its sequelae. Further studies of Braun enteroenterostomy in larger randomized trials of patients undergoing PD are warranted.

Major hepatectomy induces phenotypic changes in circulating dendritic cells and monocytes.

INTRODUCTION: Patients undergoing major hepatectomy are at increased risk for post-operative morbidity and mortality, and changes in the phenotype of effector cells may predispose these patients to infectious sequelae. METHODS: To better understand post-hepatectomy immune responses, peripheral blood from 15 hepatectomy patients was drawn immediately before and after liver resection and on post-operative days 1, 3, and 5. Circulating monocytes and dendritic cells were analyzed by flow cytometry for quantity, phenotype, activation status, human leukocyte antigen DR (HLA-DR) expression, and toll-like receptor-2 and -4 expression. RESULTS: Major hepatectomy increased the numbers of activated CD16(bright) blood monocytes and the percentage of activated dendritic cells, although monocyte HLA-DR expression was reduced. These results may represent both dysfunctional antigen presentation and pending anergy, as well as cellular priming of immune effector cells. Better understanding of the alterations in innate immunity induced by hepatectomy may identify strategies to reduce infectious outcomes.

Hepatocellular carcinoma in a 10-month-old biliary atresia child.

We present a case of a 10-month-old boy with BA who developed HCC and was treated with liver transplantation. A four-month-old boy was referred to our institution because of persistent jaundice, hepatomegaly, and coagulopathy. He had been treated for the diagnosis of neonatal hepatitis at an outside hospital. He was evaluated and was accepted as a liver transplant candidate, and was subsequently transplanted with a deceased donor liver allograft at the age of 10 months. His native liver showed established cirrhosis because of BA with one focus of moderately differentiated HCC, measuring 0.7 cm in a diameter with microscopic vascular invasion in pathological study. The postoperative course was uneventful, and he is well without recurrence four months after liver transplantation. The occurrence of HCC in a child under one yr old is extremely rare, and only three cases are reported so far including our case.

Duplicate gallbladder arising from the left hepatic duct: report of a case.

Gallbladder duplication is a rare congenital biliary anomaly with different morphologies depending on events at embryogenesis. This case report describes a symptomatic duplicate gallbladder arising from the left intrahepatic duct 10 years after an open cholecystectomy: this is the rarest form of gallbladder duplication. The symptoms resolved following a second open cholecystectomy. This case illustrates the importance of preoperative imaging, intraoperative cholangiography, and a high index of suspicion of anomalous gallbladder anatomy in the diagnosis and management of this rare condition. We discuss the classification of anomalous gallbladder anatomy and review previous cases, to propose a modification of the common classification scheme.

Biliary Tract and Primary Liver Tumors: Who, What, and Why?

Biliary tract and primary liver tumors can be divided into intrahepatic and extrahepatic sites. Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma are the most common primary liver malignancies, making up 75% and 15% of cases, respectively. In the United States, there has been an increase in incidence of HCC and cholangiocarcinoma over the last 2 decades, and it is probable that the incidence of both will continue to climb. Gallbladder cancer, however, is the most frequent biliary tract cancer, comprising 80% to 90% of biliary tract cancers worldwide. Underlying epidemiology and cause are discussed.

Elevation of serum IgG4 in Western patients with autoimmune sclerosing pancreatocholangitis: a word of caution.

BACKGROUND: Autoimmune pancreatocholangitis is characterized by sclerosing inflammation of the biliary tree or pancreatic duct and can mimic pancreaticobiliary malignancy. Serum immunoglobin (Ig) G4 values seem to be helpful in distinguishing autoimmune pancreatocholangitis from pancreatic malignancy in the Japanese population; however, its significance in the Western population has not been well studied. METHODS: We report a retrospective analysis of 7 consecutive patients with autoimmune pancreatocholangitis and compare them to 23 patients with pancreatic malignancy. Clinical presentation, diagnostic tests, and preoperative IgG4 levels were reviewed in all patients. Presence of autoimmune pancreatocholangitis or pancreatic malignancy was determined by pathologic analysis in all patients and reviewed by a single pathologist. RESULTS: In all patients, autoimmune pancreatocholangitis manifested in a similar fashion to pancreatic malignancy. Median IgG4 levels were far lower in pancreatic cancer patients with localized, resectable disease (24 mg/dL), locally advanced disease (24 mg/dL), and metastatic disease (28 mg/dL) as compared with patients with autoimmune pancreatocholangitis (142 mg/dL, P < .05). Only one patient with pancreatic cancer had an IgG4 level that was >100 mg/dL. In contrast, all patients with autoimmune pancreatitis or cholangitis had levels >100 mg/dL. However, in five of these seven patients, IgG4 levels were below the upper limits of normal. CONCLUSIONS: Autoimmune pancreatocholangitis mimics pancreatobiliary malignancy. Serum IgG4 values seem to be helpful in distinguishing autoimmune pancreatocholangitis from malignancy in the Western population. However, absolute values seem to be lower in the United States compared with Japan. The upper limit of normal as reported in laboratories in the United States may not be useful in identifying abnormally high IgG4 values. A new upper limit of normal may need to be defined because IgG subclass determinations are being used more frequently in Western patients with biliary obstruction.

Liver transplantation from donation after cardiac death: a single center experience.

BACKGROUND: Liver transplantation (LT) from controlled donation after cardiac death (DCD) donors has increased steadily during the past decade because of the donor shortage in the United States. Although early reports of LT from DCD donors provided evidence for acceptable outcomes, long-term graft and patient survival rates from these procedures have been reviewed only recently. METHODS: From February 1990 to June 2006, 1209 LTs were performed from donation after brain death (DBD) donors, and 24 were performed from DCD donors at our institution. Detailed review of donor and recipient characteristics, and survival rates were evaluated in the two groups. RESULTS: One- and 3-year patient survival was similar in both groups, (DCD 86.8%, 81.7% vs. DBD 84.0%, 76.0%, respectively; P=0.713). Graft survival appeared inferior in the DCD group compared with the DBD group at 1 year (69.1% vs. 78.7%) and 3 years (58.6% vs. 70.2%), but there was no statistical difference (P=0.082). There were no significant differences in hepatic artery thrombosis, portal vein thrombosis, primary nonfunction, and biliary stricture between the two groups. All cases with biliary stricture in DCD group finally led to graft loss, and all survived with retransplantation. CONCLUSION: The outcome of LT from DCD donors remains acceptable in our institution. Although biliary complication rate was similar in two groups, the consequence of this complication in DCD was more severe and often led to graft loss. Close observation of biliary complications after LT from DCD donors would be beneficial.

Is early recurrence of hepatitis C associated with biliary anastomotic stricture after liver transplantation?

BACKGROUND: While the main effect of hepatitis C virus (HCV) is hepatitis, HCV is also known to cause a variety of systemic immunologic inflammatory abnormalities. The effect of HCV infection on the biliary tract after liver transplantation (LT) is not well understood. The aim of the current study is to determine if recurrence of hepatitis C affects biliary complications after LT, with special reference to late biliary anastomotic strictures (LBAS). METHODS: A total of 688 consecutive adult LT recipients with a choledochocholedochostomy without T-tube placement between 1990 and 2005 were reviewed. Biliary anastomotic stricture was confirmed by endoscopic retrograde cholangiopancreatography. LBAS was defined as stricture that occurred 30 days or more after LT. Early HCV recurrence was defined as recurrence within 6 months after LT. RESULTS: LBAS occurred in 55 patients (8% of total). Patients with HCV infection had a higher occurrence of LBAS than non-HCV patients (11% vs. 5%, P=0.0093). Among HCV patients, those with early HCV recurrence had an exceedingly high rate of LBAS (16%). In multivariate analyses, early recurrence of hepatitis C (P<0.0001), as well as occurrence of hepatic artery thrombosis (P=0.0018) and prolonged cold ischemic time (P=0.034), were independent risk factors affecting LBAS. Among HCV patients, those with LBAS had a significantly higher hepatitis activity index score (3.1 vs. 1.4, P<0.0001) and fibrosis stage (0.9 vs. 0.4, P<0.0001) as compared to patients without LBAS. CONCLUSION: Patients with early recurrence of HCV have increased occurrence of late biliary anastomotic stricture after liver transplantation.