Neeta Vachharajani

Outcomes of neoadjuvant transarterial chemoembolization to downstage hepatocellular carcinoma before liver transplantation.

Purpose:To evaluate outcomes of downstaging patients with advanced (American liver tumor study group stage III/IV) hepatocellular carcinoma (HCC) with transarterial chemoembolization (TACE) to allow eligibility for orthotopic liver transplant (OLT). Methods:From 1999 to 2006, 202 patients with HCC were referred for transplant evaluation. Seventy-six (37.6%) patients with stage III/IV HCC were potential transplant candidates if downstaging was achieved by TACE. OLT was considered based on follow-up imaging findings. The number of patients who were successfully downstaged within the Milan criteria, tumor response using Response Evaluation Criteria in Solid Tumors criteria, findings at explant, and outcomes after transplant were tracked. Results:Eighteen of 76 (23.7%) patients had adequate downstaging to qualify for OLT under the Milan criteria. By Response Evaluation Criteria in Solid Tumors, 27/76 (35.5%) patients had a partial response, 22/76 (29%) had stable disease, and 27/76 (35.5%) had progressive disease. Seventeen of 76 (22.4%) patients who met other qualifications underwent OLT after successful downstaging (13/38 stage III;4/38 stage IV). Explant review demonstrated 28 identifiable tumors in which post-TACE necrosis was greater than 90% in 21 (75%). At a median of 19.6 months (range 3.6–104.7), 16/17 (94.1%) patients who underwent OLT are alive. One patient expired 11 months after OLT secondary to medical comorbidities. One of 17 (6%) OLT patients had recurrent HCC. This patient underwent resection of a pulmonary metastasis and is alive, 63.6 months from OLT. Conclusion:Selected patients with stage III/IV HCC can be downstaged to Milan criteria with TACE. Importantly, patients who are successfully downstaged and transplanted have excellent midterm disease-free and overall survival, similar to stage II HCC.

Advanced Donor Age Alone Does Not Affect Patient or Graft Survival after Liver Transplantation

BACKGROUND Individuals greater than 60 years old donate an important portion of the organs available for orthotopic liver transplantation (OLT), but use of donors in this age group remains controversial. We hypothesized that proper selection of donors older than age 60 would not disadvantage recipients in terms of patient and graft survival. STUDY DESIGN All OLTs performed at our center between January 1, 1990, and July 31, 2007, were divided into groups based on donor age: donors 60 years old or more and donors less than 60 years old. Recipients in each group were compared based on graft and patient survival at 1, 3, and 5 years, Model for End-Stage Liver Disease (MELD) scores, cold ischemic times, and era of transplant (before or after 2001). RESULTS There were 741 recipients who met inclusion criteria. Ninety-one patients received livers from donors 60 years old or older, and 650 patients had donors younger than 60 years old. Overall patient survival rates in the group using donors 60 or older were 86.8%, 72.6%, and 67.6% at 1, 3, and 5 years, respectively, and did not differ significantly from survival in the group receiving transplants from donors less than 60 (87.1%, 81.8%, and 75.5%; p=0.39). The 1-, 3-, and 5-year graft survivals in patients receiving transplants from donors 60 or older were 82.4%, 65%, and 62.5%, respectively, and were not significantly different from those in the group using donors younger than 60 (84%, 78.6%, and 72.3%, respectively; p=0.39). Neither patient survival nor graft survival in recipients of organs from donors 60 or older was affected by Model of End-Stage Liver Disease score. Recipients of older-donor livers had improved outcomes after 2001, which correlated with significant improvements in cold ischemic times. CONCLUSIONS Our data suggest that age alone does not adversely affect recipient outcomes. When properly selected, donors older than 60 represent an important and safe increase in the liver donor pool.

Morbid obesity in liver transplant recipients adversely affects longterm graft and patient survival in a single-institution analysis

OBJECTIVE The effects of obesity in liver transplantation remain controversial. Earlier institutional data demonstrated no significant difference in postoperative complications or 1-year mortality. This study was conducted to test the hypothesis that obesity alone has minimal effect on longterm graft and overall survival. METHODS A retrospective, single-institution analysis of outcomes in patients submitted to primary adult orthotopic liver transplantation was conducted using data for the period from 1 January 2002 to 31 December 2012. Recipients were divided into six groups by pre-transplant body mass index (BMI), comprising those with BMIs of <18.0 kg/m(2) , 18.0-24.9 kg/m(2) , 25.0-29.9 kg/m(2) , 30.0-35.0 kg/m(2) , 35.1-40.0 kg/m(2) and >40 kg/m(2) , respectively. Pre- and post-transplant parameters were compared. A P-value of <0.05 was considered to indicate statistical significance. Independent predictors of patient and graft survival were determined using multivariate analysis. RESULTS A total of 785 patients met the study inclusion criteria. A BMI of >35 kg/m(2) was associated with non-alcoholic steatohepatitis (NASH) cirrhosis (P < 0.0001), higher Model for End-stage Liver Disease (MELD) score, and longer wait times for transplant (P = 0.002). There were no differences in operative time, intensive care unit or hospital length of stay, or perioperative complications. Graft and patient survival at intervals up to 3 years were similar between groups. Compared with non-obese recipients, recipients with a BMI of >40 kg/m(2) showed significantly reduced 5-year graft (49.0% versus 75.8%; P < 0.02) and patient (51.3% versus 78.8%; P < 0.01) survival. CONCLUSIONS Obesity increasingly impacts outcomes in liver transplantation. Although the present data are limited by the fact that they were sourced from a single institution, they suggest that morbid obesity adversely affects longterm outcomes despite providing similar short-term results. Further analysis is indicated to identify risk factors for poor outcomes in morbidly obese patients.

Short- and long-term outcomes after steatotic liver transplantation.

OBJECTIVE To determine if the use of steatotic grafts adversely affects outcomes in liver transplantation. DESIGN A retrospective review of a prospectively maintained database. SETTING A single center. PATIENTS Four hundred ninety adults who underwent liver transplantation from January 1, 2002, to December 31, 2008, at a single center. Graft biopsies were available in 310 (63.3%) cases. Grafts were classified based on amount of macrovesicular steatosis: 5% or less (n = 222), more than 5% to less than 35% (n = 66), and 35% or more (n = 22). MAIN OUTCOME MEASURES Recipient demographics, Model for End-Stage Liver Disease (MELD) score, patient/graft survival, complications, transfusion rates, and liver function test results. RESULTS One-, 3-, and 5-year patient and graft survivals, respectively, were similar (90.38%, 84.7%, and 74.4%, respectively, P = .3; and 88.7%, 82.5%, and 73.3%, respectively, P = .15). Median follow-up was 25 months. Recipient age, sex, body mass index, laboratory MELD score, and ischemia times were similar among all groups. Packed red blood cell (3 vs 8 U, P < .001), fresh frozen plasma (2 vs 4 U, P = .007), and cryoprecipitate transfusion rates were significantly increased in grafts with 35% or more steatosis. Intensive care unit (5 vs 11 days, P = .02) and hospital (11 vs 21 days, P < .001) stay was also increased in those with grafts with 35% or more steatosis compared with those with 5% or less steatosis. The grafts with 35% or more steatosis had higher transaminase peaks and longer times for bilirubin to normalize (P < .001). CONCLUSIONS Use of carefully selected steatotic grafts was not associated with higher rates of primary nonfunction or poorer outcomes. However, the use of steatotic grafts is associated with increased resource use in the perioperative period.

Outcomes Using Grafts from Donors after Cardiac Death

BACKGROUND Previous reports suggest that donation after cardiac death (DCD) liver grafts have increased primary nonfunction (PNF) and cholangiopathy thought to be due to the graft warm ischemia before cold flushing. STUDY DESIGN In this single-center, retrospective study, 866 adult liver transplantations were performed at our institution from January 2005 to August 2014. Forty-nine (5.7%) patients received DCD donor grafts. The 49 DCD graft recipients were compared with all recipients of donation after brain death donor (DBD) grafts and to a donor and recipient age- and size-matched cohort. RESULTS The DCD donors were younger (age 28, range 8 to 60 years) than non-DCD (age 44.3, range 9 to 80 years) (p < 0.0001), with similar recipient age. The mean laboratory Model for End-Stage Liver Disease (MELD) was lower in DCD recipients (18.7 vs 22.2, p = 0.03). Mean cold and warm ischemia times were similar. Median ICU and hospital stay were 2 days and 7.5 days in both groups (p = 0.37). Median follow-ups were 4.0 and 3.4 years, respectively. Long-term outcomes were similar between groups, with similar 1-, 3- and 5-year patient and graft survivals (p = 0.59). Four (8.5%) recipients developed ischemic cholangiopathy (IC) at 2, 3, 6, and 8 months. Primary nonfunction and hepatic artery thrombosis did not occur in any patient in the DCD group. Acute kidney injury was more common with DCD grafts (16.3% of DCD recipients required dialysis vs 4.1% of DBD recipients, p = 0.01). An increased donor age (>40 years) was shown to increase the risk of IC (p = 0.006). CONCLUSIONS Careful selection of DCD donors can provide suitable donors, with results of liver transplantation comparable to those with standard brain dead donors.

Liver Transplantation for Hepatocellular Carcinoma: Long-Term Results Suggest Excellent Outcomes

BACKGROUND Selected 5-year survival results after liver transplantation for hepatocellular carcinoma (HCC) have been reported to be 70%. Our hypothesis was that liver transplantation is effective for long-term cancer control for HCC. STUDY DESIGN A 20-year retrospective review of a prospectively collected database was carried out. Demographic data and patient survival were calculated. RESULTS There were 1,422 liver transplantations performed between January 1990 and April 2011. Of these, 264 had HCC and 157 (59%) were pretreated with transarterial chemoembolization. Recipient age was 55.9 (± 7.9) years and 208 (79%) of patients were male. The underlying disease was hepatitis C virus in 155 (58.7%), hepatitis B virus in 16 (6%), alcohol in 21 (8%), and miscellaneous in the remaining 72 cases. The mean number of tumors was 1.8 (± 1.7) and the mean largest tumor diameter was 2.3 (± 1.3) cm in the explanted liver. One, 5, and 10-year patient survival was 88.5%, 69.1%, and 40.5%, respectively; disease-specific survival was 99.1%, 94.4% and 87.9%; and disease-free survival was 86.0%, 64.6%, and 40.1%. One, 5, and 10-year graft survival was 87.3%, 68.0%, and 41.8%. Nine (3.4%) patients required retransplantation; 75 patients (28.4%) have died, but only 10 of 75 (13.3%) died of recurrent HCC (3.7% of all HCC patients receiving a transplant) and 6 (8%) died of recurrent viral hepatitis. An additional 9 recipients developed recurrence (total HCC recurrence, n = 19 [7%]), 4 of whom died of causes other than HCC. The remaining 5 are disease-free post-treatment (mean 5.5 years after orthotopic liver transplantation). CONCLUSIONS Orthotopic liver transplantation offers an effective treatment strategy for HCC in the setting of cirrhosis, even in the setting of hepatitis C virus. Hepatocellular carcinoma recurrence is uncommon in properly selected patients and disease-specific long-term survival approaches 90%.

Donor graft steatosis influences immunity to hepatitis C virus and allograft outcome after liver transplantation.

Background. Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is universal, often with accelerated allograft fibrosis. Donor liver steatosis is frequently encountered and often associated with poor early postoperative outcome. The aim of this study was to test the hypothesis that allograft steatosis alters immune responses to HCV and self-antigens promoting allograft fibrosis. Methods. Forty-eight HCV OLT recipients (OLTr) were enrolled and classified based on amount of allograft macrovesicular steatosis at time of OLT. Group 1: no steatosis (0%–5% steatosis, n=21), group 2: mild (5%–35%, n=16), and group 3: moderate (>35%, n=11). Cells secreting interleukin (IL)-17, IL-10, and interferon gamma (IFN-&ggr;) in response to HCV antigens were enumerated by Enzyme Linked Immunospot Assay. Serum cytokines were measured by Luminex, antibodies to Collagen I, II, III, IV, and V by ELISA. Results. OLTr of moderate steatotic grafts had the highest incidence of advanced fibrosis in protocol 1 year post-OLT biopsy (10.8% vs. 15.8% vs. 36.6%, r=0.157, P<0.05). OLTr from groups 2 and 3 had increased HCV-specific IL-17 (P<0.05) and IL-10 (P<0.05) with reduced IFN-&ggr; (P<0.05) secreting cells when compared with group 1. This was associated with increase in serum IL-17, IL-10, IL-1&bgr;, IL-6, IL-5, and decreased IFN-&ggr;. In addition, there was development of antibodies to Collagen I, II, III and V in OLTr with increased steatosis (P<0.05). Conclusion. The results demonstrate that allograft steatosis influences post-OLT HCV-specific immune responses leading to an IL-17 T-helper response and activation of humoral immune responses to liver-associated self-antigens that may contribute to allograft fibrosis and poor outcome.

Surgical Treatment of Hepatocellular Carcinoma in North America: Can Hepatic Resection Still Be Justified?

BACKGROUND The incidence of hepatocellular cancer (HCC) is increasing dramatically worldwide. Optimal management remains undefined, especially for well-compensated cirrhosis and HCC. STUDY DESIGN This retrospective analysis included 5 US liver cancer centers. Patients with surgically treated HCC between 1990 and 2011 were analyzed; demographics, tumor characteristics, and survival rates were included. RESULTS There were 1,765 patients who underwent resection (n = 884, 50.1%) or transplantation (n = 881, 49.9%). Overall, 248 (28.1%) resected patients were transplant eligible (1 tumor <5 cm or 2 to 3 tumors all <3 cm, no major vascular invasion); these were compared with 496 transplant patients, matched based on year of transplantation and tumor status. Overall survivals at 5 and 10 years were significantly improved for transplantation patients (74.3% vs 52.8% and 53.7% vs 21.7% respectively, p < 0.001), with greater differences in disease-free survival (71.8% vs 30.1% at 5 years and 53.4% vs 11.7% at 10 years, p < 0.001). Ninety-seven of the 884 (11%) resected patients were within Milan criteria and had cirrhosis; these were compared with the 496 transplantation patients, with similar results to the overall group. On multivariate analysis, type of surgery was an independent variable affecting all survival outcomes. CONCLUSIONS The increasing incidence of HCC stresses limited resources. Although transplantation results in better long-term survival, limited donor availability precludes widespread application. Hepatic resection will likely remain a standard therapy in selected patients with HCC. In this large series, only about 10% of patients with cirrhosis were transplant-eligible based on tumor status. Although liver transplantation results are significantly improved compared with resection, transplantation is available only for a minority of patients with HCC.

A Novel Organ Donor Facility: A Decade of Experience With Liver Donors

Transplant surgeons have historically traveled to donor hospitals, performing complex, time‐sensitive procedures with unfamiliar personnel. This often involves air travel, significant delays, and frequently occurs overnight. In 2001, we established the nations first organ recovery center. The goal was to increase efficiency, reduce costs and reduce surgeon travel. Liver donors and recipients, donor costs, surgeon hours and travel time, from April 1, 2001 through December 31, 2011 were analyzed. Nine hundred and fifteen liver transplants performed at our center were analyzed based on procurement location (living donors and donation after cardiac death donors were excluded). In year 1, 36% (9/25) of donor procurements occurred at the organ procurement organization (OPO) facility, rising to 93% (56/60) in the last year of analysis. Travel time was reduced from 8 to 2.7 h (p < 0.0001), with a reduction of surgeon fly outs by 93% (14/15) in 2011. Liver organ donor charges generated by the donor were reduced by 37% overall for donors recovered at the OPO facility versus acute care hospital. Organs recovered in this novel facility resulted in significantly reduced surgeon hours, air travel and cost. This practice has major implications for cost containment and OPO national policy and could become the standard of care.

SALL4 immunoreactivity predicts prognosis in Western hepatocellular carcinoma patients but is a rare event: a study of 236 cases.

Prognostic biomarkers that stratify patients with cancer are needed. Recent studies from Asia have implicated SALL4, a stem cell marker, as useful in identifying aggressive cases of hepatocellular carcinoma (HCC), and >50% of the cases tested had upregulation by microarray or dense immunoreactivity. Given the differences in predominant etiologic factors between the Asian and Western HCC, we sought to determine the prevalence of SALL4 immunoreactivity and its clinical relevance in Western HCC patients. We constructed tissue microarrays from 236 adult HCCs. Two cores each of tumor and nontumor tissue were included for each case. SALL4 immunohistochemistry was scored in a semiquantitative manner and the results correlated with recurrence-free and overall survival, in addition to standard demographics. Among the 236 cases, 165 (70.0%) were male. The median age was 59 years (range: 19 to 83 y). The majority (78.4%) of patients were white, followed by African American (15.7%), Asian (3.8%), Hispanic (1.7%), and Native American (0.4%). The majority of patients had hepatitis C (42.8%), followed by alcoholic liver disease and hepatitis B (both 8.9%), and nonalcoholic steatohepatitis (3.8%). SALL4 immunoreactivity was detected in a total of 3 cases (1.3%), and nonreactivity was validated on tissue sections from 73 cases. By univariate analysis, the SALL4-positive cases had significantly higher tumor grade (P=0.0251), more frequent lymphovascular invasion (P=0.0150), and shorter recurrence-free survival (7.90 vs. 57.54 mo; P=0.0115) and overall survival (7.90 vs. 64.87 mo; P=0.0018). Although SALL4 immunoreactivity in Western HCC is correlated with higher grade and poor prognosis, this is a rare event. Therefore, universal application of SALL4 as a biomarker for HCC should be performed with caution.