Faculty Bibliography

Pancreatic ductal adenocarcinoma (PDAC) is refractory to most therapies, including immunotherapies, for which reinvigoration of CD8 T cells through immune checkpoint blockade is insufficient to induce long-term, durable remissions. Direct KRAS inhibitors (KRASi) have shown clinical promise, although acquired resistance is common. We modeled KRASi response and relapse in mice and demonstrated that, unlike chemotherapy or combinations with checkpoint blockade, an interleukin (IL)-21 cytokine mimic (21h10) induced long-term, durable remissions. Its efficacy depends on T helper 1 (Th1)-polarized CD4 T cells, but not on CD8 T cells or tumor cell expression of major histocompatibility complex class I (MHC class I). Specifically, CD4 T cells primed by type 2 conventional dendritic cells (cDC2s) produce interferon γ (IFN-γ), which promotes macrophage-mediated phagocytosis of tumor cells. Ex vivo treatment of human PDAC specimens with 21h10 induces IFN-γ production by infiltrating T cells. Thus, IL-21-elicited CD4 T cells exert antitumor activity in mice and potentially in humans, converting transient responses to KRAS inhibition into durable remissions.

Kidneys from donation after circulatory death (DCD) donors historically had lower recovery and utilization than kidneys from donation after brain death (DBD) donors. However, the organ shortage and advances in organ preservation have increased interest in DCD transplantation. We used OPTN data to study temporal changes in U.S. DCD kidney recovery and transplantation. The percent DCD among kidney donors increased from 21.0% (Era1: 2016-2019) to 30.6% (Era2: 2020-2022) and 42.4% (Era3: 2023-2025). By 2025Q2, more than half (50.4%) of kidney donors were DCDs. Wide variability persisted across eras in percent DCD by recovering OPO (Era1 range: 0%-38%, Era2: 0%-49%, Era3: 0.4%-60%) and by transplanting center (Era1 range: 0%-48%, Era2: 0%-58%, Era3: 0%-60%). Transplanted DCD kidneys in Era3 (vs Era1 & Era2) were more likely to have donor age >60, diabetes, hypertension, obesity, and death due to cardiovascular disease or stroke; 86.8% were pumped. Though the recovered DCD kidney nonuse rate rose from 20.8% (Era1) to 29.9% (Era2) and 35.4% (Era3), nonused DCD kidney donors were age and had more comorbidities in Era 3 compared to earlier eras. Given that half of kidney donors are now DCD, refinements in DCD donor selection and management are needed to optimize recovery and utilization.

BACKGROUND/UNASSIGNED:Normothermic regional perfusion (NRP) increases the availability of quality transplantable organs. However, there are unresolved ethical challenges and variability in approaches to NRP facilitation across U.S. organ procurement organizations (OPOs). We sought to assess the landscape of OPO member perceptions on facilitating NRP. METHODS/UNASSIGNED:Semi-structured interviews with OPO executives assessed their experiences collaborating with hospital partners, communicating with donor families, and training hospital personnel to implement NRP. Qualitative themes were elicited through deductive and inductive thematic content analysis. RESULTS/UNASSIGNED:Twenty executives participated (53% participation rate). Five themes emerged: 1) comfort with allowing NRP procedures varied across and within donor hospitals and recipient transplant centers; 2) most participating OPOs lacked standardized operating procedures regarding case protocols and data collection protocols for NRP cases; 3) OPOs disclosed varied information about NRP during authorization conversations with donor families; 4) OPOs collaborated with donor hospitals and recipient transplant centers before, during, and after NRP cases; and 5) OPOs engaged in proactive educational efforts about NRP with partner hospitals before NRP cases are presented. CONCLUSIONS/UNASSIGNED:Our findings suggest that proactive, consistent, and cross-organization collaboration may help hospitals decide whether and how to adopt NRP and may help OPOs more effectively address challenges regarding the implementation of NRP. Future research should empirically assess NRP-related OPO practices.

Normothermic regional perfusion (NRP) is a novel organ procurement strategy used for donation after circulatory death (DCD) involving in situ organ perfusion. This cross-sectional survey study assesses US public attitudes toward organ donation and willingness to donate organs after DCD-NRP, standard DCD and after brain death, comparing registered donors (registrants) and non-registered participants (non-registrants). More registrants agreed with having trust in the medical system and registrants were more likely to agree with donation in every scenario. Almost half of respondents agreed that a person must be dead to donate their vital organs. This study found that willingness to donate was associated with donor registration and trust in the medical system. A secondary finding was that there is not universal understanding of the dead donor rule and implications of first-person authorization. Overall, our findings suggest that public support for donation remains strong, and that NRP utilization does not diminish that support.

BACKGROUND:Medical assistance in dying (MAiD) is legally permitted in a growing number of jurisdictions, and in 6, it can currently be followed by organ donation. Organ donation following MAiD offers patients an opportunity to address transplant needs as a final act of altruism, but it also raises complex ethical questions that require strong safeguards to protect patients, professionals, and public trust. METHODS:We identified key ethical issues and safeguards by analyzing guidelines and protocols from the 6 countries where organ donation following MAiD is performed: Australia, Belgium, Canada, the Netherlands, New Zealand, and Spain. This article was developed under the auspices of the Ethics Committee of The Transplantation Society with medical, ethical, and legal experts from these countries. RESULTS:Three domains of ethical concern emerged: (1) safeguarding the integrity of patients' decision-making (voluntariness, informed consent, and how and when information is presented); (2) ethical governance of donation following MAiD (adherence to the Dead Donor Rule, death determination, and consent for premortem interventions); and (3) implications for care relationships and professional practice (end-of-life impacts, recipient information and donor anonymity, and professional support, including conscientious objection). Key recommendations include clear and consistent policies; a patient-centered, nondirective approach; rigorous eligibility and voluntariness assessments; and strict separation between MAiD and donation/transplantation teams. CONCLUSIONS:These recommendations provide practical guidance for implementing organ donation following MAiD in jurisdictions where it is practiced or being considered. They support patients' end-of-life wishes while safeguarding ethical and legal standards and maintaining trust in both MAiD and organ transplantation.

INTRODUCTION/BACKGROUND:Media messaging offers insight into the informational context that may shape the public's acceptance of xenotransplantation (XTx). The purpose of this study was to characterize the media's portrayal of the initiation of contemporary in-human XTx and assess both the accuracy and the ethical valence of XTx messaging. METHODS:This study employed a summative qualitative content analysis of online print media coverage of the first contemporary experimental pig-to-human transplants in the United States. A comprehensive search of the 50 most-trafficked online news sources in the US was conducted for print articles pertaining to XTx published between July 13, 2021 and July 13, 2022. All articles in the sample were coded using qualitative data analysis software. Using a combined deductive and inductive approach to analysis, codes were grouped into topical categories representing patterns of meaning and subsequently interpreted into overarching themes. RESULTS:The search yielded 208 unique print-based articles. The top five most prevalent codes were "genetically modified," "reference to animal organ," "XTx rejection possibility," "novelty of the procedure," and "XTx as a 'success'/extending life." Code patterns were interpreted into the following overarching themes: (1) value judgments about XTx, (2) justifications for XTx, and (3) emphasis on technical details. CONCLUSIONS:Results suggest that media reporting on XTx during this time period frequently employed incomplete and hyperbolic narratives to support and justify XTx. As the field of XTx evolves with the initiation of human clinical trials, efforts to communicate accurate, balanced information to the general public should be prioritized.

PURPOSE OF REVIEW/OBJECTIVE:The science and practice of xenotransplantation is advancing more rapidly than the regulatory infrastructure that will be necessary to ensure the promise of alleviating the organ shortage can be safely and equitably met. RECENT FINDINGS/RESULTS:While countries leading the way have developed some regulatory guidance to support first in human "compassionate use" xenotransplant interventions and the first clinical trials, existing legislative, regulatory, and operational frameworks for human allotransplantation have not been explicitly extended to nonhuman animal organs. SUMMARY/CONCLUSIONS:To address safety concerns and other ethics challenges unique to xenotransplantation, existing policies must be amended and new policies must be implemented to protect patients and ensure equitable access to xenotransplantation.

With U.S. Food and Drug Administration (FDA) clearance of clinical trials of kidney xenotransplantation (XTx) in living humans, understanding the recipient experience is critical. Semi-structured interviews with the three living XTx recipients identified core domains of the recipient experience, including quality of life (QoL), fears about XTx, and healthcare team communication and support. Transcribed interviews were analyzed by two qualitative researchers using an inductive thematic approach and were mapped onto the Warwick Patient Experience Model, a validated framework to assess key aspects of patient satisfaction with the healthcare experience. All three recipients (53-year-old female; 66-year-old male; 54-year old male) described a restoration of hope, contrasted with their poor quality of life on dialysis. They emphasized that access to XTx and graft survival requires mutual confidence and commitment between recipients and healthcare teams. XTx recipients use dialysis as a point of reference when describing changes in their post-transplant QoL and seemed well-situated to handle the possibility of graft failure. These insights may aid in the creation of decision aids and educational materials tailored to the specific needs of XTx recipients.