Glenda Meeberg

Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma.

An increasing number of patients with hepatocellular carcinoma (HCC) are undergoing evaluation for listing for liver transplantation. Criteria for selection require ongoing review for suitability. A consecutive series of 40 patients with HCC within the standard Milan criteria (single tumors n = 19 <5 cm, or up to 3 tumors <3 cm) and beyond (Extended Criteria; single tumors n = 21 <7.5 cm, multiple tumors <5 cm) underwent liver transplant with a sirolimus‐based immunosuppressive protocol designed to minimize exposure to calcineurin inhibitors and steroids. At 44.3 ± 19.3 months (mean ± standard deviation) follow‐up, 1‐ and 4‐year survivals (Kaplan‐Meier) are 94.1 ± 5.7% and 87.4 ± 9.3%, in the Milan group, respectively, and 90.5 ± 6.4% and 82.9 ± 9.3% in the Extended Criteria group, respectively. Five patients died during follow‐up, only 1 from recurrent HCC. Five tumor recurrences have occurred at median 17 (mean 22 ± 17) months posttransplant, 1 in the Milan group and 4 in the Extended Criteria group. Median survival in the patients with recurrent tumor is 42 months (mean 45 ± 25), and the median postrecurrence survival is 15.5 months (mean 23 ± 16). The rate of patients who were alive and free of tumor at 1 and 4 years is 94.1 ± 5.7% and 81.1 ± 9.9%, respectively, in the Milan group and is 90.5 ± 6.4% and 76.8 ± 10.5%, respectively, in the Extended Criteria group. Five patients had sirolimus discontinued for toxicity, while 24 of 35 surviving patients have sirolimus monotherapy immunosuppression. In conclusion, the Milan criteria for liver transplantation in the presence of HCC can be carefully extended without compromising outcomes. This sirolimus based immunosuppression protocol appears to have beneficial effects on tumor recurrence and survival with an acceptable rate of rejection and toxicity. (Liver Transpl 2004;10:1301–1311.)

De novo sirolimus-based immunosuppression after liver transplantation for hepatocellular carcinoma: Long-term outcomes and side effects

Background. We report long-term outcomes and side effects after transplantation for hepatocellular carcinoma (HCC) using de novo, sirolimus-based immunosuppression (IS). Methods. A total of 70 patients with HCC (mean age: 54.4±7 years, female/male: 12/58) were transplanted and included in the study. Immunosuppression included de novo sirolimus, low-dose calcineurin inhibitor for 6 to 12 months, with short-course (3 months) or no steroids. Results. After 49 months-median follow-up, eight patients have experienced an HCC recurrence, 2 of 34 when Milan criteria were respected (6%) and 6 of 36 when beyond Milan criteria (17%). One- and 4-year tumor-free survivals were 85 and 73%, when Milan criteria were respected and 82% and 75% when they were not, respectively. (P=0.9). After recurrence, mean survival was 23±28 months. Half (35 of 70) of the patients experienced a rejection. Incisional hernia (24 of 70, 34%), wound infection (12 of 70, 17%), anemia (39 of 70, 56%), leucopenia (39 of 70, 56%), high triglyceride (43 of 70, 61%), and cholesterol (28 of 70, 40%) levels and mouth ulcers (20 of 70, 29%) were among the most frequent complications. No hepatic artery thrombosis was observed. Conclusions. These data suggest that de novo sirolimus-based immunosuppression is associated with satisfactory outcomes after transplantation, even in selected patients beyond Milan criteria. The protocol has proven safe, with an acceptable side-effect profile. This study supports the conduct of larger randomized trials investigating sirolimus after transplantation for HCC.

ABO-incompatible liver transplantation for critically ill adult patients

ABO incompatible (ABO‐In) liver transplant remains a controversial solution to acute liver failure in adults. Adult liver recipients with acute liver failure or severely decompensated end‐stage disease, intubated and/or in the intensive care unit, were grouped as ABO‐In (n = 14), ABO‐compatible (n = 29, ABO‐C) and ABO‐identical (n = 65, ABO‐Id). ABO‐In received quadruple immunosuppression with antibody‐depleting induction agents (except two), calcineurin inhibitors, antimetabolites and steroids. No significant difference of patient and graft survivals was observed among ABO‐In, ABO‐C and ABO‐Id: graft survivals were 64%, 62% and 67%, respectively, in 1 year and 56%, 54% and 60%, respectively, in 5 years; patient survivals 86%, 69% and 67%, respectively, in 1 year and 77%, 61% and 62%, respectively, in 5 years. Three ABO‐In grafts were lost (one hyper‐acute rejection and two hepatic artery thrombosis). Surgical and infectious complications were similarly distributed between groups, except the hepatic artery thrombosis, more frequent in ABO‐In (2, 14%) than ABO‐I (1, 1.5%, P < 0.05). In contrast to previous studies, no significant difference of patient and graft survivals could be observed among all ABO‐compatibility settings. Our results suggest that ABO‐incompatible transplants should be viewed as an important therapeutic option in adult patients with acute liver failure awaiting an emergency procedure.

Total tumor volume and alpha-fetoprotein for selection of transplant candidates with hepatocellular carcinoma: A prospective validation.

The selection of liver transplantation (LT) candidates with hepatocellular carcinoma (HCC) is currently validated based on Milan criteria. The use of extended criteria has remained a matter of debate, mainly because of the absence of prospective validation. The present prospective study recruited patients according to the previously proposed total tumor volume (TTV; ≤115 cm3)/alpha‐fetoprotein (AFP; ≤400 ng/mL) score. Patients with AFP >400 ng/mL were excluded, and, as such, the Milan group was modified to include only patients with AFP <400 ng/mL; these patients were compared to patients beyond Milan, but within TTV/AFP. From January 2007 to March 2013, 233 patients with HCC were listed for LT. Of them, 195 patients were within Milan and 38 beyond Milan, but within TTV/AFP. The average follow‐up from listing was 33.9 ± 24.9 months. Risk of dropout was higher for patients beyond Milan, but within TTV/AFP (16 of 38; 42.1%), than for those within Milan (49 of 195 [25.1%]; P = 0.033). In parallel, intent‐to‐treat survival from listing was lower in patients beyond Milan (53.8% vs. 71.6% at 4 years; P < 0.001). After a median waiting time of 8 months, 166 patients were transplanted, 134 within Milan criteria, and 32 beyond Milan but within TTV/AFP. They demonstrated acceptable and similar recurrence rates (4.5% vs. 9.4%; P = 0.138) and post‐transplant survivals (78.7% vs. 74.6% at 4 years; P = 0.932). Conclusion: Based on the present prospective study, HCC LT candidate selection could be expanded to the TTV (≤115 cm3)/AFP (≤400 ng/mL) criteria in centers with at least 8‐month waiting time. An increased risk of dropout on the waiting list can be expected, but with equivalent and satisfactory post‐transplant survival. (Hepatology 2015;62:158‐165)

A shorter duration of pre-transplant abstinence predicts problem drinking after liver transplantation.

OBJECTIVES:Liver transplantation for alcoholic liver disease (ALD) can be complicated by abusive or “problem” drinking (PD) after transplant. There are limited data for evaluating the effect of pre-transplant abstinence on post-transplant PD. Few existing studies have included a substantial number of patients with co-existing causes of hepatic dysfunction, and the effect of PD on survival in recent European studies has been controversial. We hypothesized that a longer duration of pre-transplant abstinence would lead to less PD after transplantation. Accordingly, the objectives of this study are to analyze a North American cohort of patients with ALD with or without a secondary diagnosis of liver disease to estimate (i) the incidence of PD and its predictors, as well as (ii) the effect of PD on patient survival.METHODS:We conducted a retrospective review of all patients transplanted for ALD surviving for more than 3 months after transplant. PD was defined as either any drinking (AD) to the point of intoxication or drinking above the toxic threshold (>20 g/day in women and >40 g/day in men) on at least two separate occasions. We used Coxs proportional hazards regression to estimate risk ratios and Kaplan–Meier curves with log-rank analysis to compare survival.RESULTS:Of 213 eligible transplant patients, 42 were excluded. Of the 171 remaining patients, 78% were male; mean age was 52 years. Overall 53% of patients had co-existing causes of liver dysfunction. The mean follow-up was 64.8 months. The median pre-transplant abstinence was 19 months. In all patients, the risk of AD was 24% and PD 13%. Pre-transplant abstinence duration was the only independent predictor of PD after transplant. For every 1-month increment in pre-transplant abstinence, there was a 5% decrease in the adjusted relapse rate. There was no survival difference noted between problem drinkers and non-drinkers.CONCLUSIONS:The risk of PD decreased with increasing pre-transplant abstinence. Our data support pre-transplant abstinence as an important predictor of post-transplant recidivism; however, the optimal period of abstinence remains unclear. Patients with <18 months of abstinence may benefit from more intensive follow-up and rehabilitation after transplant.

The impact of sirolimus on hepatitis C recurrence after liver transplantation

BACKGROUND While some immunosuppression strategies may accelerate hepatitis C virus (HCV) recurrence after liver transplantation (LT), the impact of sirolimus (SRL) is not known. OBJECTIVE To assess the risk of biopsy-proven HCV recurrence and patient survival using known and suspected risk factors for HCV recurrence as covariates. METHODS A retrospective analysis of 141 consecutive patients, including 88 who received de novo SRL therapy, who had undergone a first LT for HCV cirrhosis was conducted. Known and suspected risk factor covariates including transplant era, donor and recipient age, Model for End-stage Liver Disease score, cold ischemia time, immunosuppressive drugs and steroid treatment rejection rates were used in the assessment. RESULTS Overall, 72.3% of the cohort developed biopsy-proven HCV recurrence. The incidence of HCV recurrence was not significantly different for patients treated with SRL (75% versus 69.8%; P=0.5). There was no difference found for time to recurrence, nor did mean activity or fibrosis scores differ at the time of initial recurrence. However, on follow-up using serial biopsies in patients with recurrence, the mean activity and fibrosis scores were significantly lower in the SRL group. Donor age and acute rejection episodes were the only factors affecting the HCV recurrence rate (expB 1.02 [95% CI 1.01 to 1.03]); P=0.03; and expB 2.8 [95% CI 1.8 to 4.3]; P<0.01], respectively). SRL treatment did not alter patient survival rates. Among patients treated with SRL-based immunosuppression, higher drug area under the curve levels were associated with a trend to lower disease activity and fibrosis at diagnosis; however, higher SRL levels were associated with shorter recurrence-free survival (P=0.038). CONCLUSION Results of the present analysis suggest that de novo SRL-based immunosuppression can be safely used in patients undergoing LT for HCV-associated liver disease; however, SRL-based immunosuppression did not significantly affect the timing or severity of post-transplant HCV recurrence. HCV recurrence in SRL-treated patients had lower progressive activity and fibrosis levels on serial biopsy.

Alcohol Use While on the Liver Transplant Waiting List: A Single-Center Experience

Alcoholic liver disease (ALD) is a leading indication for liver transplantation. Our center has randomly checked blood alcohol levels (BALs) in ALD patients on the waiting list since 2004. We aimed to identify the incidence and predictors of inactivation on the transplant list due to alcohol use and to determine the utility of BAL‐screening in this process. We conducted a retrospective review of patients with ALD listed for liver transplantation with at least 3 months of postlisting follow‐up. Alcohol use while on the transplant list was defined as a positive BAL, an admission of alcohol use, or refusal to perform screening within 12 hours of request. Cox proportional hazards regression was used to estimate risk ratios (RRs). Of 134 patients meeting eligibility criteria, 78% were male, and mean age was 52 years. Alcohol use was documented in 23 patients (17%). Of these, 12 refused to have a random screen, 8 had detectable serum ethanol levels, and 3 had self‐reported alcohol use. On multivariable analysis, a higher number of random BAL‐checks [RR = 0.63(0.52, 0.76), P = 0.001] and a longer duration of prelisting abstinence [RR = 0.88(0.83, 0.94), P = 0.001] independently reduced the risk of alcohol use by patients while on the waiting list. None of the patients with >24 months of prelisting abstinence had a positive screen. In conclusion, this study supports random BAL‐screening before transplantation and reinforces the importance of abstinence duration as a predictor of relapse. For patients with <24 months of prelisting abstinence, our center will increase the frequency of random BAL screening and increase the rehabilitation requirements to include an intensive 3‐week rehabilitation program. We hope that these measures will reduce the rate of relapse to alcohol use post‐transplantation. Liver Transpl 16:91–97, 2010.

Multicentric outcome analysis of sirolimus‐based immunosuppression in 252 liver transplant recipients

The use of sirolimus (SRL) in orthotopic liver transplantation (OLT) has been controversial after experimental data suggested an increased risk of hepatic artery thrombosis (HAT). To assess the safety and efficacy of SRL as de novo immunosuppression in OLT recipients. Outcomes of 252 OLT patients who received SRL were compared with outcomes of 291 OLT recipients who received calcineurin inhibitor in a retrospective study. Primary outcomes of this study were: patient‐ and graft survivals, vascular, biliary, wound complications and rejection rates. Secondary outcomes were: postoperative infection rate, bone marrow and renal function and changes of lipid levels. Patient‐ and graft survivals, rejection and infection rates were similar. In the SRL group, HAT occurred in 1.2%, biliary complications in 19.4%, and incisional hernias in 9.1%. In the control group the incidence of HAT was 5.8% (P = 0.004), biliary complications 18.5% (P = NS) and incisional hernias 7.2% (P = NS). Patients on SRL experienced significantly higher levels of serum triglycerides but fewer acute cellular rejections. Bone marrow and renal functions were similar in both the groups. Our findings would suggest that SRL is safe and effective for very selected OLT recipients. Randomized controlled trials are necessary to confirm our results.

Validation of the five‐variable Model for End‐stage Liver Disease (5vMELD) for prediction of mortality on the liver transplant waiting list

Modifications to the Model for End‐Stage Liver Disease (MELD) have been proposed to improve prioritization of liver transplant (LT) candidates. Using a U.S. database, we derived a revised MELD including sodium and albumin [5‐variable MELD (5vMELD)] that improved prediction of waiting list mortality. Our objectives were to confirm the association between hypoalbuminaemia and mortality and to externally validate 5vMELD in Canadian LT candidates.

Cardiac work-up protocol for liver transplant candidates: experience from a single liver transplant centre.

BACKGROUND Ischemic cardiac events can cause significant morbidity and mortality postliver transplantation; however, no validated protocols to screen patients before transplantation exist. OBJECTIVES To report the introduction of a noninvasive cardiac screening protocol used at the Liver Unit, University of Calgary (Calgary, Alberta); to determine whether the protocol decreases use of coronary angiograms; and to compare cardiac outcomes using the new protocol with an appropriately matched historical control group. METHODS A new cardiac screening protocol was introduced into the program in 2005, which uses perfusion scintigraphy to screen high-risk cardiac patients, reserving coronary angiograms for abnormal results. Transplanted patients screened using this protocol were compared with matched historical controls. Electronic charts were reviewed for cardiac outcomes intra- and postliver transplantation. RESULTS A total of 396 patients were screened between April 2005 and February 2009. Eighty-two were transplanted by February 2009 and included in the study. Eighty-one patients were successfully matched according to age, sex, cardiac history and presence of diabetes. Twelve of 82 (14.6%) and 11 of 81 (13.6%) in the study and control groups, respectively, underwent coronary angiograms (P=0.85). Coronary artery disease was found in six of 12 (50.0%) study patients and three of 11 (27.3%) control patients who underwent coronary angiography (P=0.27). The mean (± SD) length of the follow-up period was 1.87±0.91 years and 4.45±1.89 years in the study and control groups, respectively. One of 81 in the control group and zero of 82 in the study group experienced an acute coronary syndrome event postoperatively. CONCLUSIONS Coronary events are infrequent in liver transplant recipients. The described protocol is an effective method of coronary artery disease screening before liver transplant but does not reduce the number of cardiac investigations performed.