Citations

Objective: To determine whether normothermic machine perfusion (NMP) mitigates the historical survival disadvantage of donation after circulatory death (DCD) liver transplantation compared with donation after brain death (DBD) livers. Summary Background Data: NMP has improved outcomes in DCD LT compared with static cold storage (SCS), but whether it eliminates the historical disparity relative to DBD transplantation remains uncertain. Methods: We performed a retrospective cohort study of adult LT at a high-volume US center between 2019 and 2024. Outcomes of DCD-NMP grafts were compared with DCD-SCS, DBD-SCS, and DBD-NMP grafts. Primary outcomes were 1-year graft and patient survival. Secondary outcomes included early allograft dysfunction (EAD), hepatic artery thrombosis (HAT), primary nonfunction (PNF), biliary anastomotic strictures (BAS), and ischemic cholangiopathy (IC). Results: Among 1338 liver transplants (DBD-SCS n=527; DBD-NMP n=142; DCD-SCS n=255; DCD-NMP n=414), DCD-NMP grafts had a significantly higher donor risk profile ( P <0.001) yet demonstrated survival comparable to DBD transplantation. One-year graft survival was 94% for DCD-NMP versus 93% for DBD grafts and 86% for DCD-SCS, and 1-year patient survival was 98% for DCD-NMP versus 94% to 95% for DBD grafts and 93% for DCD-SCS. In adjusted models, DCD-SCS was associated with increased hazards of graft loss (adjusted hazard ratio: 2.48; P <0.001) and death (adjusted hazard ratio: 2.39; P =0.004), whereas DBD groups did not differ from DCD-NMP. Incidence of EAD was lower with DCD-NMP (21.7%) than DCD-SCS (50.2%) and similar to DBD grafts (21.1%–26.4%); HAT and PNF were rare (≤1.3%). At 1 year, BAS occurred in 36% of DCD grafts versus 17% to 23% of DBD grafts. IC occurred in 7.7% of DCD-NMP compared with 22% of DCD-SCS and ≤1.5% of DBD grafts. Retransplantation due to IC was infrequent overall (1.3%), but more common in DCD-SCS (4.7%) than DCD-NMP (1.0%) and DBD grafts (≤0.4%). Conclusions: NMP enables safe utilization of DCD liver allografts and achieves graft and patient survival comparable to DBD LT, mitigating the historical disadvantage of DCD grafts. These findings support routine integration of NMP into clinical practice and efforts to standardize its implementation.

Normothermic machine perfusion (NMP) enables preservation and functional assessment of liver allografts, improving outcomes, particularly in marginal organs. However, the TransMedics Organ Care System (OCS) permits only single hepatic artery (HA) cannulation, limiting its use in grafts with variant arterial anatomy. Arterial reconstruction before NMP may overcome this limitation and expand the pool of grafts eligible for perfusion. We conducted a retrospective single-center cohort study of adult liver transplants utilizing OCS from January 2022 to September 2024. Allografts with variant hepatic artery anatomy requiring arterial reconstruction before NMP initiation were identified. Postoperative outcomes, including vascular and biliary complications, were compared between reconstructed and non-reconstructed grafts. Among 541 OCS-preserved grafts, 74 (13.7%) underwent arterial reconstruction. Compared with non-reconstructed grafts, reconstructed grafts had longer cross-clamp to cannulation time (2.8 vs. 2.4 h, p <0.001), but similar rates of early allograft dysfunction (23.0% vs. 20.8%, p =0.65), ischemic cholangiopathy (4.1% vs. 4.1%, p =1.00), and primary nonfunction (0.0% vs. 0.4%, p =1.00). Early (2.7% vs. 0.2%, p =0.05) and late hepatic artery thrombosis (HAT) (4.1% vs. 2.1%, p =0.40) were infrequent and not significantly different between non-reconstructed and reconstructed groups, respectively. Hepatic artery stenosis occurred more often in reconstructed grafts (12.2% vs. 4.1%, p =0.008), though most cases were managed with interventional radiology or surgical revision. Only one reconstructed graft required retransplantation due to vascular complications. Arterial reconstruction before NMP is safe and feasible, enabling successful perfusion and transplantation of liver allografts with variant HA anatomy. These findings support the broader application of NMP in anatomically complex donor livers.

Despite improvements in kidney transplantation rates, the shortage of donor kidneys remains a critical issue, exacerbated by non-utilization of recovered kidneys due to quality concerns, necessitating advancements in perfusion methods to enhance graft outcomes and usage. Although static cold storage remains the default standard for kidney preservation, newer methods like hypothermic machine perfusion have shown improved outcomes, including reduced delayed graft function and better survival rates. Hypothermic oxygenated machine perfusion and normothermic machine perfusion offer some potential clinical benefits but studies to date have demonstrated mixed results. In the United States, LifePort and the XVIVO’s Kidney Assist Transport are the most popular hypothermic perfusion devices, with NMP devices mostly in trials. Combining perfusion with biomarkers such as mitochondrial flavin mononucleotide, neutrophil gelatinase-associated lipocalin, and osteopontin shows promise in assessing kidney viability and predicting post-transplant outcomes, though further research is also needed. Emphasis on repair biomarkers, such as uromodulin and osteopontin, aims to better predict graft outcomes and develop new therapies. While notable advancements have been made in the use of machine perfusion and viability testing for liver transplantation, additional research with larger sample sizes is essential to substantiate these results and enhance kidney transplantation outcomes.

Background. Ex vivo machine perfusion (MP) has transformed organ preservation, offering significant benefits in liver transplantation (LT), particularly with high-risk donor grafts. However, adoption in the United States has been limited. We aimed to examine early adoption trends, surgeon perceptions, and barriers to implementing MP in the United States after Food and Drug Administration approval of MP platforms. Methods. A 23-question electronic survey was distributed to members of the American Society of Transplant Surgeons between October and November 2022, capturing attitudes and practices related to MP adoption. Responses from 96 surgeons representing 77 LT centers across 11 Organ Procurement and Transplantation Network regions were analyzed. Results. Forty-four respondents (48%) reported having an MP program at their institution. Adoption of MP was significantly more common in high-volume centers and those performing ≥20 donation after circulatory death (DCD) transplants annually (P < 0.001). MP utilization received strong support, with 88% endorsing its use for DCD liver allografts and 82% for donation after brain death allografts. Respondents cited MP’s ability to reduce ischemic cholangiopathy, enable graft repair, and facilitate viability assessment as key benefits. Normothermic MP was preferred for high-risk donor profiles, including DCD grafts, older donors, and steatotic livers, and was associated with an increased willingness to accept medically complex grafts compared with static cold storage. Barriers to MP utilization included program costs, personnel demands, and logistical complexities. Centers with higher proportions of privately insured patients were more likely to adopt MP. Despite these challenges, 84% of respondents expressed interest in future MP adoption. Conclusions. MP enhances graft utilization and outcomes, particularly for complex and high-risk donor livers, but widespread US adoption requires addressing financial and logistical barriers. Future efforts should focus on refining cost-effectiveness analyses, collaboration with organ procurement organizations and device companies, and developing standardized training to optimize MP integration and maximize its clinical impact on LT.

Abstract Background: Chimeric antigen receptor T-cell (CAR T) therapies have demonstrated significant clinical efficacy in hematologic malignancies, but have proven challenging in solid tumors, in part owing to a lack of tumor-specific targets and unmanageable toxicity. Mesothelin (MSLN) expression normally is limited to the mesothelium of major body cavities but can be upregulated in diverse solid tumor types (cancer.gov/tcga), making it a potential target for cancer therapy. MSLN-targeted cell therapy approaches, including CAR T and T-cell receptor fusion therapies, have shown promising clinical activity; however, on-target, off-tumor toxicity including fatal events have occurred (Beatty, et al. Gastroenterology. 2018.; Haas, et al. Mol Ther. 2023.; Hong, et al. ESMO 2021. Abstract 9590.). A2B694 is an autologous logic-gated, MSLN-targeted Tmod CAR T therapy that addresses the challenges of on-target, off-tumor toxicity by combining 2 CARs: an activating and blocking receptor. The activator recognizes MSLN present on the surface of both tumor and normal cells; the blocker inhibits the CAR T activator when it binds human leukocyte antigen (HLA)-A*02, which is present in normal cells and often lost in tumor cells. Thus, in patients with tumor-associated HLA-A*02 loss of heterozygosity (LOH), the blocker prevents on-target, off-tumor toxicity on normal cells owing to retained HLA-A*02 expression (Hamburger, et al. Mol Immunol. 2020). Through this unique selective mechanism, A2B694 may provide a therapeutic window to treat patients with MSLN-expressing solid tumors exhibiting HLA-A*02 LOH. Methods: EVEREST-2 (NCT06051695) is a first-in-human, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B694 in adults with recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression, including non-small cell lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, mesothelioma, or other solid tumors with MSLN expression. Eligible patients must have progressed following standard of care therapy. Enrollment to EVEREST-2 occurs through the prescreening study BASECAMP-1 (NCT04981119), which identifies patients with tumor-associated HLA-A*02 LOH via next-generation sequencing (Tempus AI, Inc). Eligible patients enroll in the BASECAMP-1 study and undergo leukapheresis. A2B694 is manufactured from cryopreserved T cells when clinically appropriate for patients. The primary objective of phase 1 is to evaluate the safety and tolerability of A2B694 and identify the recommended phase 2 dose (RP2D). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B694. Phase 2 will assess overall response rate per RECIST v1.1. The first patient was enrolled on EVEREST-2 in April 2024. Dose escalation is ongoing. Citation Format: Julian R. Molina, Antonious Hazim, Oliver Dorigo, Salman R. Punekar, Monica Avila, Diane M. Simeone, Kedar Kirtane, Gottfried E. Konecny, Jeffrey Ward, Matthew Block, Jennifer Specht, Leslie Boyd, Yanyan Lou, Jong Chul Park, Jacqueline D. Xuan, Ramez N. Eskander, Gayanie Ong, Marco Davila, Wendy Langeberg, Marcela Maus, Armen Mardiros, Frederick L. Locke, Andrea Wise, David G. Maloney, John Welch, J. Randolph Hecht. EVEREST-2: A seamless phase 1/2 study of A2B694, a logic-gated Tmod CAR T-cell therapy, in patients with mesothelin-expressing solid tumors with human leukocyte antigen-A*02 loss of heterozygosity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT186.

ABSTRACT Introduction Donation after circulatory death (DCD) allografts are underutilized in liver transplantation (LT) due to increased risk of complications. These risks stem from ischemic injury sustained during the total donor warm ischemia time (tDWIT), historically limited to 30 min. Normothermic machine perfusion (NMP) can mitigate these risks and facilitate LT of DCD grafts with extended tDWIT. We aimed to compare outcomes of DCD allografts with extended tDWIT preserved on NMP versus static cold storage (SCS). Methods This single‐center study included adult DCD LT with tDWIT ≥ 30 from 2019 to 2023. Outcomes of NMP and SCS were compared including EAD, IC, graft survival, and patient survival. Results Among 68 DCD LT with tDWIT ≥ 30, 64.7% ( n = 44) were preserved with NMP and 35.3% ( n = 24) with SCS. No differences in donor or recipient demographics were observed. The median tDWIT was 33 min for NMP and 30.5 min for SCS ( p < 0.01). Despite longer tDWIT, the NMP group had lower rates of EAD (4.5% vs. 66.7%, p < 0.01) and IC (2.3% vs. 29.2%, p < 0.01). One‐year graft survival was higher in NMP ( p < 0.01), and 1‐year patient survival was comparable between groups ( p = 0.18). Conclusion NMP challenges traditional tDWIT constraints and can increase the pool of viable DCD allografts for transplantation.

BACKGROUND: Although most transplant centers preferentially offer minimally invasive approaches to donor nephrectomies, there remains less standardization specific to the kidney extraction site. This study aimed to evaluate incisional hernia occurrence in living kidney donors based on kidney extraction site location. STUDY DESIGN: This was a retrospective study of all donors who underwent minimally invasive living donor nephrectomies at the Mayo Clinic Arizona between 2011 and 2023 with a 2-year external validation cohort from Mayo Clinic Florida and Mayo Clinic Minnesota. The cohort was divided into 2 groups based on the kidney extraction site type: midline infraumbilical and Pfannenstiel. RESULTS: In the primary cohort, incisional hernia occurrence was observed in 1.2% of donors with an infraumbilical midline kidney extraction site compared with 0.1% with a Pfannenstiel extraction site (p = 0.04). Donors with an infraumbilical midline kidney extraction site were more likely to be men (50.8% vs 23.3%, p < 0.0001), have a higher BMI (mean 27.2 vs 26 kg/m2, p < 0.0001), and have current or former tobacco use (p = 0.002). There were no differences in incisional hernia occurrence when comparing minimally invasive surgical techniques (p = 0.52). In the external validation cohort, hernia occurrence was observed in 4.5% of donors with a midline incision compared with 0.0% with a Pfannenstiel incision (p = 0.09). Using combined data from the 3 sites, the use of a Pfannenstiel incision as the extraction site was associated with significantly lower odds of developing a hernia compared with the infraumbilical midline incision (odds ratio 0.06, 95% CI 0.008 to 0.456). CONCLUSIONS: Although the risk of hernia in living kidney donors is generally low, the use of a Pfannenstiel incision for kidney extraction appears to offer an additional incremental reduction in risk.

Importance Normothermic machine perfusion (NMP) has been shown to reduce peritransplant complications. Despite increasing NMP use in liver transplant (LT), there is a scarcity of real-world clinical experience data. Objective To compare LT outcomes between donation after brain death (DBD) and donation after circulatory death (DCD) allografts preserved with NMP or static cold storage (SCS). Design, Setting, and Participants This single-center, retrospective observational cohort study included all consecutive adult LTs performed between January 2019 and December 2023 at the Mayo Clinic in Arizona. Data analysis was performed between February 2024 and June 2024. Outcomes of DBD-SCS, DBD-NMP, DCD-SCS, and DCD-NMP transplants were compared. Exposure DBD and DCD livers preserved on NMP or SCS. Main Outcomes and Measures The primary outcomes were early allograft dysfunction (EAD), intraoperative transfusion, and post-LT hospital resource use, including length of stay (LOS) and readmissions. Secondary outcomes included acute kidney injury (AKI) and 1-year graft and patient survival. Results A total of 1086 LTs were included in the following 4 groups: DBD-SCS (n = 480), DBD-NMP (n = 63), DCD-SCS (n = 264), and DCD-NMP (n = 279). Among LT recipients, median (IQR) age was 60.0 years (52.0-66.0); 399 LT recipients (36.7%) were female. DCD-NMP had the lowest EAD rate (17.5%), followed by DCD-SCS (50.0%), DBD-NMP (36.8%), and DBD-SCS (27.3%) ( P &amp;lt; .001). DCD-NMP had the lowest intraoperative transfusion requirement compared to all other groups. Hospital and intensive care unit (ICU) LOS were shortest in DCD-NMP (median [IQR] hospital LOS, 5.0 days [4.0-7.0]; P = .01; median [IQR] ICU LOS, 1.5 days [1.2-3.1]; P = .01). One-year cumulative readmission probability was 86% lower for DCD-NMP vs DCD-SCS (95% CI, 0.09-0.22; P &amp;lt; .001) and 53% lower for DBD-NMP vs DBD-SCS (95% CI, 0.26-0.87; P &amp;lt; .001). AKI events were lower in DCD-NMP (31.1%) vs DCD-SCS (47.4%) ( P = .001). Compared to SCS, the NMP group had a 78% overall reduction in graft failure (hazard ratio [HR], 0.22; 95% CI, 0.10-0.49; P &amp;lt; .001). For those receiving DCD allografts, the risk reduction was even more pronounced, with an 87% decrease in graft failure (HR, 0.13; 95% CI, 0.05-0.33; P &amp;lt; .001). NMP was significantly protective from patient mortality vs SCS (HR, 0.31; 95% CI, 0.12-0.80; P = .02). Conclusions and Relevance In this observational high-volume cohort study, NMP significantly improved LT clinical outcomes and reduced hospital resource use, especially in DCD allografts. NMP may enhance access to LT by addressing the challenges historically linked with DCD liver use.

TPS2699 Background: Despite the success in hematologic cancers, chimeric antigen receptor (CAR) T-cell therapies are challenging to implement in solid tumors owing to a lack of tumor-specific targets that discriminate cancer from normal cells. MSLN expression normally is limited to the mesothelium of major body cavities but can be upregulated in diverse solid tumor types (TCGA 2022), making it a potential target for cancer therapy. MSLN-targeted cell approaches, including CAR T-cell and T-cell receptor fusion therapies, have shown promising clinical activity; however, on-target, off-tumor toxicity including fatal events have occurred (1-3). A2B694 is an autologous logic-gated, MSLN-targeted Tmod CAR T-cell therapy that addresses the challenges of on-target, off-tumor toxicity by combining 2 CARs: an activating and blocking receptor. The activator recognizes MSLN present on the surface of both tumor and normal cells; the blocker binds HLA-A*02 and prevents CAR T-cell activity. Thus, in patients with both germline HLA-A*02 and tumor-associated HLA-A*02 LOH, the blocker prevents on-target, off-tumor toxicity on normal cells owing to retained HLA-A*02 expression (4). Through this unique discriminatory mechanism, A2B694 may provide a therapeutic window to treat patients with MSLN-expressing solid tumors exhibiting HLA-A*02 LOH. Methods: EVEREST-2 (NCT06051695) is a first-in-human, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B694 in adults with recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression, including non-small cell lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, mesothelioma, or other solid tumors with MSLN expression. Eligible patients should have received ≥1 line of prior therapy such as checkpoint inhibitor, molecular targeted, or chemotherapy. Enrollment to EVEREST-2 occurs through the prescreening study BASECAMP-1 (NCT04981119), which identifies patients with tumor-associated HLA-A*02 LOH via next-generation sequencing (Tempus AI, Inc.). Eligible patients enroll in the BASECAMP-1 study and undergo leukapheresis. A2B694 is manufactured from cryopreserved T cells when clinically appropriate for patients. The primary objective of phase 1 is to evaluate the safety and tolerability of A2B694 and identify the recommended phase 2 dose (RP2D). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B694. Phase 2 will assess overall response rate per RECIST v1.1. 1. Beatty, et al. Gastroenterology. 2018. 2. Haas, et al. Mol Ther. 2023. 3. Hong, et al. ESMO 2021. Abstract 9590. 4. Hamburger, et al. Mol Immunol. 2020. Clinical trial information: NCT06051695 .