W. Kenneth Washburn

Corticosteroid‐free immunosuppression with daclizumab in HCV+ liver transplant recipients: 1‐year interim results of the HCV‐3 study

This work is a 1‐yr interim analysis of a prospective, randomized, multicenter trial evaluating the effect of corticosteroid‐free immunosuppression on hepatitis C virus–positive (HCV+) liver transplant recipients following liver transplantation (LT). Patients received tacrolimus and corticosteroids (Arm 1; n = 80); tacrolimus, corticosteroids, and mycophenolate mofetil (MMF) (Arm 2; n = 79); or daclizumab induction, tacrolimus, and MMF (Arm 3; n = 153). At 1 yr, 64.1%, 63.4%, and 69.4% of patients achieved the composite primary endpoint of freedom from rejection, freedom from HCV recurrence, and freedom from treatment failure, respectively. Excellent patient and graft survival did not differ significantly among treatment arms. Freedom from HCV recurrence at 1 yr was 61.8 ± 6.2%, 60.1 ± 6.1%, and 67.0 ± 4.3% in Arms 1, 2, and 3, respectively (P = not significant). Freedom from rejection was significantly higher in Arm 3 compared to Arm 1 (93.0 ± 2.2% vs. 81.9 ± 4.4%; P = 0.011). Multivariate analysis identified acute rejection (hazard ratio = 2.692; P = 0.001) and donor age (hazard ratio = 1.015; P = 0.001) as significant risk factors for HCV recurrence. HCV recurrence was not influenced by recipient demographics, HCV genotype, or immunosuppression. In conclusion, these results suggest that a corticosteroid‐free regimen of tacrolimus and MMF following daclizumab induction is safe and effective in HCV+ liver transplant recipients. Liver Transpl 13:1521–1531, 2007.

Graft Function And Outcome Of Older (≥60 Years) Donor Livers

Livers from donors > or = 60 years of age are often considered inadequate for transplantation by many centers. With waiting times exceeding 1 year in our region, we have aggressively used livers from this donor age group. Between 1990 and 1994, 209 patients received 223 liver grafts at our institution. Of these, 29 (13%) were from donors > or = 60 years of age (group A) and 194 (87%) were from donors < 60 years of age (group B). The two groups were matched for recipient diagnosis and severity of disease. Group A and B donors had similar liver, renal, and hematologic studies prior to donation. Weight, sex, race and vasopressor requirement were also similar. Postoperative alanine aminotransferase, aspartate aminotransferase,and prothrombin time were not significantly different over the first 10 postoperative days. Group A grafts were significantly more cholestatic than group B grafts on postoperative days 6-10. The retransplantation rate for primary graft nonfunction was not significantly different from group A (6.7%) and group B (3.4%; P=0.04). Patient and graft survival rates at 1 year were 58.6 % and 44.8% for group A and 79.2% and 74.5% for group B (P<0.001 for both). Four of 12 deaths in the first year in group A were completely unrelated to graft function. If these are excluded, patient and graft survival rates were 68% and 52%, which are better but still significantly less than in group B. Initial graft function of older donor livers are similar to that of the matched younger group. However, patient and graft survival rates were significantly worse for the older donors, even when corrected for unrelated deaths. Livers should not be discarded based on age alone without inspection and/or biopsy to rule out significant steatosis. Prompt retransplantation for primary graft nonfunction of older donors are generally more cholestatic than those from the younger donor age group; however, many of them function quite well. At the present time, given the inability to identify donor variables associated with decreased recipient survival, we recommend cautious use of older liver grafts in healthier recipients.

Radiofrequency tissue ablation: Effect of hepatic blood flow occlusion on thermal injuries produced in cirrhotic livers

AbstractBackground: Radiofrequency thermal ablation has been used as a treatment for several types of hepatic malignancies. Many of these lesions exist in the presence of cirrhosis. Limitations exist to the size of the ablations and, subsequently, the efficacy of treatment. Hepatic vascular inflow occlusion has been advocated as an adjunctive measure to increase the efficacy of the ablation. We present a model in the human cirrhotic liver that demonstrates the advantage of blood flow occlusion during radiofrequency ablation. Methods: Five patients with advanced endstage liver disease scheduled to have orthotopic liver transplantation were enrolled in this study. After laparotomy and before hepatectomy, radiofrequency ablation was performed without and with hepatic blood flow occlusion. After hepatectomy, the liver was sectioned, the area of ablation was measured in three dimensions, and the volume of ablation calculated. Results: Three of the patients had had previously placed transjugular intrahepatic portosystemic shunt. The mean volume of the ablation without blood flow occlusion was 22.5 ± 7.4 cm3 and that with blood flow occlusion was 48.4 ± 24.0 cm3 (P = .05). Conclusions: Ablation area is increased significantly with hepatic blood flow occlusion in the human cirrhotic liver. This result may have application in the treatment of larger (>3 cm) hepatic malignancies.

Factors influencing liver transplant length of stay at two large‐volume transplant centers

Length of stay (LOS) is considered a reliable surrogate for liver transplant resource utilization. Little information exists about how donor and recipient variables interact to affect transplant LOS. Data for adult, non–status 1 transplants (1998–2005), including the donor risk index (DRI) and Model for End‐Stage Liver Disease (MELD) scores, were collected from 2 institutions (n = 745 for center A and n = 710 for center B). Cox proportional hazards models identified variables associated with LOS for the separate and combined cohorts. The cohorts differed significantly in donor, recipient, and transplant factors. DRI (1.46 for center A and 1.40 for center B, P = 0.0013) and MELD (22.4 for center A and 20.4 for center B, P = 0.046) were both higher at center A, but LOS was comparable (13.7 days for center A and 13.3 days for center B, P = 0.052). Three factors at center A (nonlocal donor, recipient age, and MELD) and 7 factors at center B (donor age and weight, recipient female gender, retransplant status, international normalized ratio, MELD, and cold ischemia time) were associated with transplant LOS. For the combined cohort, donor age, weight, nonlocal status, recipient age, female gender, retransplant status, MELD, and transplant center were LOS risk factors. In conclusion, the impact of donor and recipient variables on LOS varies by institution. However, the MELD score exerts a potent and consistent effect across institutions, emphasizing the dominant role of disease severity in liver transplant resource utilization. Liver Transpl 15:1570–1578, 2009.

Geographic disparities in deceased donor liver transplantation within a single UNOS region

Although the Model for End‐Stage Liver Disease (MELD) scoring system has improved the ability to measure medical urgency for transplantation, geographic disparities in the probability of being delisted as a result of complications of end‐stage liver disease or death and in the probability of orthotopic liver transplantation (OLT) remain. The purpose of the current study was to identify factors associated with these variations among donor service areas (DSAs) in one United Network for Organ Sharing (UNOS) region. Data for 2,948 candidates listed for OLT within 4 DSAs in UNOS region 4 between February 2002 and November 2005 were obtained from UNOS. Multivariate regression models were used to identify study factors associated with delisting (due to deterioration or death) and likelihood of OLT. After risk adjustment for candidate characteristics, those listed in DSA‐3 and DSA‐4 were at significantly higher risk of delisting than candidates listed in DSA‐2 (hazard ratio, 1.22 and 1.10 vs. 0.87 for DSA‐2; P = 0.01 and 0.05, respectively). In addition, the likelihood of OLT was significantly higher for candidates listed in DSA‐1 than in DSA‐2, DSA‐3 or DSA‐4 (hazard ratio, 1.00 compared with 0.45, 0.77, and 0.51; P < 0.001 for all pairwise comparisons). Despite the implementation of the MELD system, great geographic disparities exist in the likelihood of delisting and for OLT, suggesting the need for further refinement in regional allocation strategies. Liver Transpl 13:747–751, 2007.

Conversion from twice daily tacrolimus capsules to once daily extended‐release tacrolimus (LCP‐Tacro): Phase 2 trial of stable liver transplant recipients

LCP‐Tacro is an extended‐release formulation of tacrolimus designed for once‐daily dosing. Studies in renal transplantation demonstrate greater bioavailability with similar safety and efficacy vs. twice‐daily tacrolimus capsules. In this phase 2 study, adult stable liver transplant patients on tacrolimus capsules (Prograf) twice‐daily were converted to tacrolimus tablets (LCP‐Tacro) once‐daily; patients continued on LCP‐Tacro once‐daily for days 8–21; target trough levels were 5–15 ng/mL; 24‐hour pharmacokinetic (PK) assessments were done on days 7 (baseline pre‐switch), 14, and 21. A 6 month extension study phase evaluated PK and safety following a total of 52 weeks of LCP‐Tacro. Fifty‐seven patients completed LCP‐Tacro dosing in the core study; 43 completed the extension phase. The mean conversion ratio was 0.71 (Prograf:LCP‐Tacro). PK data demonstrated consistent exposure (AUC) at the lower conversion dose. Cmax, Cmax/Cmin ratio, percent fluctuation and swing were significantly (P<0.001) lower and Tmax significantly (P<0.001) longer for LCP‐Tacro vs. Prograf. AUC24 and Cmin correlation coefficients after 7 and 14 days of therapy were ≥0.93. There were no significant differences in PK parameters at week 26 vs. 14. One patient experienced an unrelated serious adverse event (SAE) during the core study and discontinued. There were six unrelated SAEs in the extension and 1 possibly related (rejection) that resolved; there were 3 discontinuations due to AEs during the extension. In this study, patients were safely converted from Prograf twice‐daily to LCP‐Tacro. The greater bioavailability of LCP‐Tacro allowed for once‐daily dosing and similar (AUC) exposure at a dose approximately 30% less than the total daily dose of Prograf. LCP‐Tacro displayed significantly lower peak and peak‐trough fluctuations. LCP‐Tacro administered over one year was well tolerated with no new safety concerns. Liver Transpl 20:564–575, 2014.

Split-Liver Transplantation Using the Left Lateral Segment: A Collaborative Sharing Experience Between Two Distant Centers

Split‐liver transplantation (SLT) increases the pool of organs for pediatric orthotopic liver transplantation (pOLT). With increased collaboration and organ sharing, transplant centers can fully maximize the use of all split donor allografts. Herein, we report the collaborative results between two distant centers involved in a sharing alliance.

A regional experience with emergency liver transplantation.

Liver transplantation for patients requiring life-support results in the lowest survival and highest costs. A ten year (1983-1993) regional experience with liver transplantation for critically ill patients was undertaken to ascertain the fate of several subgroups of patients. Of the 828 liver transplants performed at six transplant centers within the region over this period, 168 (20%) were done in patients who met todays criteria for a United Network of Organ Sharing (UNOS) status 1 (emergency) liver transplant candidate. Recipients were classified according to chronicity of disease and transplant number (primary-acute, primary-chronic, reTx-acute, reTx-chronic). Overall one-year survival was 50% for all status 1 recipients. The primary-acute subgroup (n = 63) experienced a 57% one-year survival compared with 50% for the primary-chronic (n = 51) subgroup (P = 0.07). Of the reTx-acute recipients (n = 43), 44% were alive at one year in comparison with 20% for the reTx-chronic (n = 11) group (P = 0.18). There was no significant difference in survival for the following: transplant center, blood group compatibility with donors, age, preservation solution, or graft size. For patients retransplanted for acute reasons (primary graft nonfunction (PGNF) or hepatic artery thrombosis [HAT]), survival was significantly better if a second donor was found within 3 days of relisting (52% vs. 20%; P = 0.012). Over the study period progressively fewer donor organs came from outside the region. No strong survival-based argument can be made for separating, in allocation priority, acute and chronic disease patients facing the first transplant as a status 1 recipient. Clearly patients suffering from PGNF or HAT do far better if retransplanted within 3 days. Establishing an even higher status for recipients with PGNF, perhaps drawing from a supraregional donor pool, would allow surgeons to accept more marginal donors, thus potentially expanding the pool, without significantly compromising patient survival. Retransplantation of the recipient with a chronically failing graft who deteriorates to the point of needing life-support is nearly futile, and in todays health care climate, not an optimal use of scarce donor livers.

High-grade microsteatosis and delay in hepatic function after orthotopic liver transplantation

Macrovesicular steatosis may be used to exclude potential donor livers from use in transplantation. Livers with more than 50% macrovesicular steatosis are believed to be at risk for delayed graft function and primary graft nonfunction. However, the significance of even extensive microsteatosis is uncertain. The hematoxylin and eosin-stained slides of postperfusion donor liver biopsies from 161 transplants were examined. The type of steatosis (macrovesicular, low-grade microvesicular, and high-grade microvesicular ) was determined, and the extent of each type was semiquantitated into 3 groups (none, ≤50%, and >50%). These were analyzed in conjunction with the donor and recipient age and the recipients sex and MELD score against postoperative outcome parameters, including serial measures of serum lactate, days in the intensive care unit and overall in hospital, and death less than 3 months posttransplant. High-grade microsteatosis usually coexisted with macrosteatosis and infrequently with low-grade microsteatosis. There was no significant association between the extent of either macrosteatosis or low-grade microsteatosis (even when >50%) and any of the outcome parameters. In contrast, the presence of high-grade microsteatosis was significantly associated with delayed hepatic function, but not with the other outcome parameters. Donor age greater than 60 years was associated with late postoperative rise in serum lactate, and higher recipient MELD score was associated with extended stay in the intensive care unit and in the hospital. In this patient population, the association of steatosis with adverse outcomes was largely restricted to delay in postoperative hepatic function, and was due to the subgroup that displayed high-grade microsteatosis.

An early look at the OPTN explant pathology form data

In April 2012, the Organ Procurement and Transplantation Network (OPTN) implemented an online explant pathology form for recipients of liver transplantation who received additional wait‐list priority for their diagnosis of hepatocellular carcinoma (HCC). The purpose of the form was to standardize the data being reported to the OPTN, which had been required since 2002 but were submitted to the OPTN in a variety of formats via facsimile. From April 2012 to December 2014, over 4500 explant forms were submitted, allowing for detailed analysis of the characteristics of the explanted livers. Data from the explant pathology forms were used to assess agreement with pretransplant imaging. Explant data were also used to assess the risk of recurrence. Of those with T2 priority, 55.7% were found to be stage T2 on explant. Extrahepatic spread (odds ratio [OR] = 6.8; P < 0.01), poor tumor differentiation (OR = 2.8; P < 0.01), microvascular invasion (OR = 2.6; P < 0.01), macrovascular invasion (OR = 3.2; P < 0.01), and whether the Milan stage based on the number and size of tumors on the explant form was T4 (OR = 2.4; P < 0.01) were the strongest predictors of recurrence. In conclusion, this analysis confirms earlier findings that showed an incomplete agreement between pretransplant imaging and posttransplant pathology in terms of HCC staging, though the number of patients with both no pretransplant treatment and no tumor in the explant was reduced from 20% to <1%. In addition, several factors were identified (eg, tumor burden, age, sex, region, ablative therapy, alpha‐fetoprotein, Milan stage, vascular invasion, satellite lesions, etc.) that were predictive of HCC recurrence, allowing for more targeted surveillance of high‐risk recipients. Continued evaluation of these data will help shape future guidelines or policy recommendations. Liver Transplantation 22 757–764 2016 AASLD.