Croome, Kris P

Normothermic regional perfusion (NRP) adoption for donation after circulatory death (DCD) liver transplantation in the United States has been growing, but there remains a higher rate of non-utilization of NRP DCD liver grafts as compared with donation after brain death liver grafts. Six transplant centers and 1 organ procurement organization (OPO) with substantial NRP liver procurement experience performed retrospective reviews of all NRP procurement attempts from September 1, 2021, until March 1, 2024, identifying opportunities for utilization. Five of the 6 transplant centers had prospectively collected data on all accepted livers with NRP intent. The transplant center's intention to utilize DCD donors included 329 livers accepted for transplantation before withdrawal, 252 (76.6%) potential donors expired within the hospital timeframe for donation, and 168 (66.7%) livers were transplanted. Fifty-seven opportunities for utilization were identified by transplant centers, plus 11 from the OPO: most were due to exceeding a functional warm ischemic time limit (n=26), other reasons (n=17), and functional assessment (n=16). The lessons learned by centers in this study provide guidance for newer NRP centers and for OPOs in identifying opportunities for utilization of NRP DCD grafts that have historically been declined.

Liver transplantation has emerged as a curative treatment option for selected patients with unresectable hepatic malignancies beyond hepatocellular carcinoma, marking a paradigm shift in transplant oncology. For colorectal cancer liver metastases (CRLM), prospective trials have demonstrated that highly selected patients achieve 5-year OS rates of 60–83%, with the Oslo score identifying optimal candidates for transplantation. Perihilar cholangiocarcinoma (pCCA) has been successfully treated using strict patient selection criteria combined with neoadjuvant therapy, achieving 5-year OS rates of 50–68%, though emerging data suggests chemotherapy-based approaches may be preferable to radiation in selected cases. Intrahepatic cholangiocarcinoma (iCCA), previously considered a contraindication to transplantation, can now achieve excellent long-term outcomes (79.5% 5-year OS) in patients demonstrating sustained response to neoadjuvant chemotherapy and radioembolization, with metabolic tumor volume < 70 cm3 serving as an objective prognostic marker. Across these three emerging indications, successful outcomes depend on strict patient selection based on tumor biology, intensive multimodal neoadjuvant therapy, multidisciplinary evaluation in high-volume centers, and careful observation during treatment to exclude patients with aggressive disease. This evolution in transplant practice offers curative intent therapy to patients that previously only had palliative therapeutic options, fundamentally transforming hepatobiliary and oncologic surgery.

ABSTRACT During normothermic regional perfusion (NRP), lactate is the most commonly used liver viability marker. Lactate production from pyruvate breakdown in erythrocytes is not suspended during pRBC storage. By transfusing blood at a variety of stored ages, variable amounts of lactate are added to the NRP circuit and may influence serial lactate measurements. Sixteen DCD donors undergoing NRP were enrolled in a prospective study. Samples were drawn from pRBC bags prior to use in the NRP circuit and were tested for lactate values. Lactate values of the NRP circuit perfusate were also assessed Q15 min. Lactate values of the pRBCs varied from 4.4 mmol/L to >20 mmol/L and were strongly correlated with the age of the stored blood ( r 2 = 0.74). Donors in which the pRBCs were > = 20‐days from expiration (Newer Blood group) had a significantly lower lactate at 60 min of NRP compared to donors in which pRBCs were <20 day from expiration (Older Blood group) (4.0±2.0 mg/dL vs. 6.3±2.3 mg/dL; p = 0.048). If the lactate is not decreasing as anticipated, transfusion of older pRBC should be entertained as one possible explanation. In cases where the liver seems acceptable for transplantation, additional lactate testing with longer time on NRP or sequential NRP/NMP should be considered in lieu of declining the liver outright.

ABSTRACTThe incidence of ischemic cholangiopathy (IC) is expected to remain significant due to rising rates of transplants performed with livers donated after circulatory death (DCD), despite the use of machine perfusion. Absent established pharmacologic interventions against this progressive etiology of allograft dysfunction and failure, we describe the use of fenofibrate—a cheap and widely‐accessible peroxisome proliferator‐activated receptor agonist that downregulates bile acid production—to impede IC progression in 15 DCD liver recipients who were not responding to reactive, standard‐of‐care management. All patients were undergoing serial endoscopic retrograde cholangiopathy (ERC) to maintain biliary patency but demonstrated progressive cholestasis, with serum alkaline phosphatase (ALP) rising 70.3% over the 90 days preceding fenofibrate. Cholestasis improved in all patients after fenofibrate initiation, with a 63.9% reduction in mean ALP at 90 days, maintained at 270 days (p = 0.02) and 360 days (p = 0.06). ALP improvement was associated with reduced ERC frequency during and after fenofibrate treatment, and this improvement was independent of concurrent ERC or ursodeoxycholic acid use during fenofibrate treatment. In patients who stopped treatment, ALP increased. No fenofibrate‐associated adverse events were seen. These preliminary data support the further study of agents that downregulate bile acid production as a means of impeding IC in DCD livers.

Intrahepatic cholangiocarcinoma is an aggressive malignancy with rising incidence and poor outcomes. This review examines recent advancements in locoregional therapies for unresectable intrahepatic cholangiocarcinoma, focusing on external beam radiotherapy, transarterial radioembolization (TARE), hepatic artery infusion pump (HAIP) chemotherapy, and liver transplantation. Stereotactic body radiation therapy and proton beam therapy have shown promise in achieving local control and improving survival. TARE, with personalized dosimetry, has demonstrated encouraging results in select patient populations. HAIP chemotherapy, primarily studied using floxuridine, has yielded impressive survival outcomes in phase II trials. Liver transplantation, once contraindicated, is now being reconsidered for carefully selected patients with localized disease. While these locoregional approaches show potential, randomized controlled trials comparing them to standard systemic therapy are lacking. Patient selection remains crucial, with factors such as liver function, tumor burden, and molecular profile influencing treatment decisions. Ongoing research aims to optimize treatment sequencing, explore combination strategies with systemic therapies, and refine phenotype identification and patient selection criteria. As the landscape of intrahepatic cholangiocarcinoma management evolves, a multidisciplinary approach is essential to tailor treatment strategies and improve outcomes for patients with this challenging disease.

Background. The availability of in situ normothermic regional perfusion (NRP) or ex situ normothermic machine perfusion (NMP) has revolutionized donation after circulatory death (DCD) liver transplant (LT). While some have suggested that NRP and NMP may represent competing technologies for DCD LT, there are many scenarios where these technologies can function in a complementary manner. Methods. Between January 2022 and March 2024, 83 DCD LTs were performed using NRP (62 NRP alone and 21 NRP + NMP) and were compared with 297 static cold storage (SCS) DCD LTs. NRP + NMP was used in scenarios with (1) long travel distances, (2) complicated transplant recipients, or (c) the need for additional liver graft recovery in “marginal” cases. Results. Ischemic cholangiopathy was lower in the NRP alone group (0%) and the NRP + NMP group (0%) compared with the SCS group (16.8; P < 0.001 and P = 0.04, respectively). In addition, early allograft dysfunction, number of packed red blood cells transfused, and acute kidney injury were lower in the NRP alone and NRP + NMP groups compared with the SCS group. Graft survival was higher in cases where NRP was used than in cases where SCS was used ( P = 0.016). In all the cases where lactate remained elevated at the end of NRP (mean 8.2 ± 2.0), it ultimately normalized at the end of NMP (0.92 ± 0.56). Conclusions. The present study demonstrates lower rates of ischemic cholangiopathy and improved graft survival with NRP alone or NRP + NMP compared with SCS when using liver grafts from DCD donors. It also demonstrates that excellent outcomes can be achieved with sequential NRP + NMP in cases with prolonged travel distances, complicated recipients, or when there is a need for additional liver recovery in “marginal” cases.

There is a paucity of data on the impact of cold ischemia time before the initiation of normothermic machine perfusion (NMP), particularly in more susceptible organs such as livers from donation after circulatory death (DCD) donors. The present analysis aimed to investigate the impact of prolonged time from cross-clamp until NMP start on early allograft dysfunction and other peri–liver transplant (LT) outcomes. All DCD LT performed and placed on NMP at Mayo Clinic Arizona, Florida, and Rochester from January 2022 to March 2024 were included. The decision was made a priori to divide the population into 2 groups based on terciles: typical cross-clamp to on-pump time (lower 2 terciles) versus prolonged cross-clamp to on-pump time (upper tercile; >2 h 45.6 min). Three hundred eighty-four DCD LT undergoing NMP met the inclusion criteria. The rate of early allograft dysfunction was significantly higher in the prolonged cross-clamp to on-pump group (51.2%) compared to the typical cross-clamp to on-pump group (37.6%) (p = 0.01). The prolonged cross-clamp to on-pump group also had higher rates of acute kidney injury and the number of packed red blood cells transfused during LT. No significant difference in ischemic cholangiopathy (2.4% vs. 3.1%; p = 0.68) or graft survival at 12 months was seen between the prolonged cross-clamp to on-pump and typical cross-clamp to on-pump group, respectively. Following cross-clamp, DCD liver grafts should be placed on the NMP pump as quickly as is safely and logistically possible. In cases where delays are unavoidable, such as waiting for biopsy results or liver reallocation with another center, acceptable results can still be achieved, and therefore, livers with prolonged times should still be used.

Importance Despite the unmet need for donor organs, organ use from donation after circulatory determination of death (DCD) donors has been limited by inferior transplant outcomes. Normothermic regional perfusion (NRP) improves recipient outcomes and organ utilization from DCD donors. There is variability in NRP policies and experience among US organ procurement organizations (OPOs). Objectives To determine OPO experience, identify operational inconsistencies, and explore needs related to NRP. Design, Setting, and Participants This survey study included 55 OPOs in the US that had recovered DCD organs and completed a survey on operational, administrative, and educational components related to NRP in November to December 2023. Data analysis was performed from February to April 2024. Main Outcome and Measures The primary outcome was the number of OPOs participating in and/or anticipating NRP participation. Secondary outcomes were NRP implementation barriers, OPO education practices, and future needs regarding consensus NRP recommendations and standards. Results Of 55 respondents, 11 (20%) were chief executive officers, 8 (15%) were chief operating officers, and 36 (65%) were medical directors or chief clinical officers. Forty-nine OPOs facilitated NRP cases: 26 OPOs (53%) facilitated both thoracoabdominal NRP (TA-NRP) and abdominal NRP (A-NRP) cases, 16 OPOs (33%) facilitated only TA-NRP, and 7 OPOs (14%) facilitated only A-NRP. OPOs reported 606 NRP cases (421 TA-NRP [69%], 185 A-NRP [31%]); median (range) case experience was 8 (1-52). Fifty-two of 55 OPOs (95%) thought standardized guidance documents would be helpful. All 49 OPOs facilitated NRP at a transplant center’s request; 39 (80%) had NRP initiated by a nonlocal transplant center. Twenty-three of 49 OPOs (47%) participated in NRP without a policy and without a policy pending approval. Positive donor hospital feedback was received by 29 OPOs (59%), primarily focused on increased organs transplanted and prerecovery communication. Allocation challenges were experienced by 21 OPOs (43%); their median (range) case volume was higher than those with no reported allocation challenges (11 [3-52] vs 6.5 [1-29]; P = .03). Eleven OPOs (22%) had incorporated NRP into general donor hospital education. Conclusions In this survey study of US OPOs, wide variation existed with respect to NRP experience and practice. Allocation challenges occurred more frequently with increased NRP experience. NRP guidelines and standardization were desired by most OPOs to decrease allocation challenges and maximize the gift of organ donation.

Background. Normothermic regional perfusion (NRP) has emerged as a vital technique in organ procurement, particularly in donation after circulatory death (DCD) cases, offering the potential to optimize organ utilization and improve posttransplant outcomes. Recognizing its significance, the American Society of Transplant Surgeons (ASTS) convened a work group to develop standardized recommendations for abdominal NRP in the United States. Methods. The workgroup, comprising experts in NRP, DCD, and transplantation, formulated recommendations through a collaborative process involving revisions and approvals by relevant committees and the ASTS council. Four key areas were identified for standardization: Preprocedure communication, NRP procedure, Terminology and documentation, and Mentorship/credentialing. Results. The recommendations encompass a range of considerations, including preprocedure communication protocols to facilitate informed decision-making by transplant centers and organ procurement organizations, procedural guidelines for NRP teams, uniform terminology to clarify the NRP process, and standards for mentorship and credentialing of NRP practitioners. Specific recommendations address logistical concerns, procedural nuances, documentation requirements, and the importance of ongoing quality assurance. Conclusions. The standardized recommendations for abdominal NRP presented in this article aim to ensure consistency, safety, and efficacy in the organ procurement process. By establishing clear protocols and guidelines, the ASTS seeks to enhance organ utilization, honor donor wishes, and uphold public trust in the donation process. Implementation of these recommendations can contribute to the advancement of NRP practices and improve outcomes for transplant recipients.