Evolution of Pancreas Transplantation At A Single Institution-50+ Years and 2,500 Transplants.

OBJECTIVE: To describe the evolution of pancreas transplantation, including improved outcomes and factors associated with improved outcomes over the past five decades. BACKGROUND: The world's first successful pancreas transplant was performed in December 1966 at the University of Minnesota. As new modalities for diabetes treatment mature, we must carefully assess the current state of pancreas transplantation to determine its ongoing role in patient care. METHODS: A single-center retrospective review of 2,500 pancreas transplants performed over >50 years in bivariate and multivariable models. Transplants were divided into six eras; outcomes are presented for the entire cohort and by era. RESULTS: All measures of patient and graft survival improved progressively through the six transplant eras. The overall death censored (DC) pancreas graft half-lives were >35 years for simultaneous pancreas and kidney (SPK), 7.1 years for pancreas after kidney (PAK), and 3.3 years for pancreas transplants alone (PTA). The 10-year DC pancreas graft survival rate in the most recent era was 86.9% for SPK recipients, 58.2% for PAK recipients, and 47.6% for PTA. Overall graft loss was most influenced by patient survival in SPK transplants, whereas graft loss in PAK and PTA recipients was more often due to graft failures. Predictors of improved pancreas graft survival were primary transplants, bladder drainage of exocrine secretions, younger donor age, and shorter preservation time. CONCLUSIONS: Pancreas outcomes have significantly improved over time via sequential, but overlapping, advances in surgical technique, immunosuppressive protocols, reduced preservation time, and the more recent reduction of immune-mediated graft loss.

Adenovirus causing hepatic abscess formation and unexplained fever in adult liver transplant recipients.

Adenovirus infection is commonly associated with self-limited respiratory and gastrointestinal illnesses. However, infection in immunocompromised individuals, such as transplant recipients, can cause severe life-threatening illness including pneumonitis, hemorrhagic cystitis, nephritis, hepatitis, and enterocolitis. In orthotopic liver transplant recipients, adenovirus viremia can cause hepatitis leading to marked transaminitis, allograft loss, and death. Although hepatic abscesses mediated by adenovirus have been described in other immunosuppressed patient populations, it has very rarely been described in liver transplant recipients. Here, we report two adult cases of hepatic abscesses following liver transplantation secondary to adenovirus infection and describe the successful treatment of these patients. Adenovirus should be considered as an uncommon etiology of hepatic abscess and unexplained fevers in adults following liver transplantation.

Evaluating living donor kidney transplant rates: Are you reaching your potential?

BACKGROUND: Traditionally, living donor kidney transplant (LDKT) rate has been calculated as a percentage of total kidney transplant volume. We believe this calculation to be inherently flawed because the number of deceased donor kidney transplants has no bearing on the number of LDKT performed. We propose an alternative calculation of LDKT rate as a percentage of the number of new waitlist registrants. METHODS: We evaluated 192 adult transplant centers in the United States with respect to their LDKT rate according to both the traditional and proposed calculations, using data from the scientific registry of transplant recipients between July 2014 and June 2015. RESULTS: The median LDKT rate for every 100 new waitlist registrants was 12.3, compared to 27.9 for every 100 total kidney transplants. Based on our proposed calculation of LDKT rate, 16.7% of transplant centers were misevaluated when compared to the national mean using the traditional method. CONCLUSIONS: A new calculation of LDKT rate based on new waitlist registrants, and not total kidney transplants, is necessary to eliminate the bias associated with the traditional method, allowing for the identification of centers for improvement as well as each individual center's true potential based on their patient demographics.

Donor Lymphocyte Infusion-Mediated Graft-versus-Host Responses in a Preclinical Swine Model of Haploidentical Hematopoietic Cell Transplantation.

We previously described successful hematopoietic stem cell engraftment across MHC barriers in miniature swine without graft-versus-host disease (GVHD) using novel reduced-intensity conditioning regimens consisting of partial transient recipient T cell-depletion, thymic or low-dose total body irradiation, and a short course of cyclosporine A. Here we report that stable chimeric animals generated with these protocols are strongly resistant to donor leukocyte infusion (DLI)-mediated GVH effects. Of 33 total DLIs in tolerant chimeras at clinical doses, 21 failed to induce conversion to full donor hematopoietic chimerism or cause GVHD. We attempted to overcome this resistance to conversion through several mechanisms, including using sensitized donor lymphocytes, increasing the DLI dose, removing chimeric host peripheral blood cells through extensive recipient leukapheresis before DLI, and using fully mismatched lymphocytes. Despite our attempts, the resistance to conversion in our model was robust, and when conversion was achieved, it was associated with GVHD in most animals. Our studies suggest that delivery of unmodified hematopoietic stem cell doses under reduced-intensity conditioning can induce a potent, GVHD-free, immune tolerant state that is strongly resistant to DLI.

Effect of Irradiation on Incidence of Post-Transplant Lymphoproliferative Disorder after Hematopoietic Cell Transplantation in Miniature Swine.

Post-transplant lymphoproliferative disease (PTLD) is a major complication of clinical organ and cell transplantation. Conditioning and immunosuppressive regimens that significantly impair T cell immunity, including depleting antibodies and calcineurin inhibitors, increase the risk of PTLD after transplantation. Swine PTLD has been shown to closely resemble human PTLD in morphology, histology, and viral-driven reactivation of B cells. Previously, we reported high incidences of PTLD after hematopoietic cell transplantation (HCT) in miniature swine recipients conditioned with thymic irradiation (TI) in addition to T cell depletion and cyclosporine A monotherapy after transplantation. Replacement of TI with 100 cGy of total body irradiation resulted in similar numbers of B cells early post-transplantation, greater numbers of T cells at day 0, and markedly decreased incidence of PTLD, suggesting that a threshold number of T cells may be necessary to prevent subsequent B cell proliferation and development of overt PTLD. Results from this large cohort of animals provide insight into the important effect of irradiation and T cell immunity on the incidence of PTLD after HCT and reinforce the pig model as a valuable tool for the study of PTLD and HCT.

Eliminating financial disincentives to living kidney donation - a call to action.

The incidence of end stage renal disease (ESRD) in the United States (US) is increasing each year. The lone curative treatment for ESRD remains kidney transplantation. Despite the demonstrated medical and economic benefits, living donor kidney transplantation (LDKT) only accounts for a small number of kidney transplantations each year. Direct and indirect costs exist that disincentivize potential living kidney donors from coming forward, such as the cost of travel and lodging, risk of death, potential loss of income due to an extended recovery time, and the inability to donate to a relative in the future if needed. Herein, we advocate for policy changes that make living kidney donation (LKD) a financially neutral process thereby incentivizing increased LDKT and mitigating the kidney donor shortage.

Surgical management of a giant hepatic metastasis from a cranial meningioma 10 years after resection.

Meningiomas are the most common type of primary brain tumor; they have a low risk for extracranial metastases, which are primarily associated with increased tumor grade. Hepatic metastases from cranial meningiomas are extremely rare, with only a paucity of cases reported in the literature and no standardized approach to management. Herein, we report a case of an incidentally discovered giant (>20 cm) metastatic meningioma to the liver treated with surgical resection 10 years following resection of a low-grade cranial meningioma. This report also highlights the use of (68Ga) DOTATATE PET/CT as the diagnostic imaging modality of choice when evaluating for meningioma metastases. To our knowledge, this report describes the largest hepatic metastasis from a cranial meningioma to undergo surgical resection in the literature.

Operative Outcomes for Polycystic Liver Disease: Results of a Large Contemporary Series.

INTRODUCTION: Persistent symptoms of pain, early satiety, dyspnea, and gastrointestinal reflux due to significant liver enlargement are indications for surgical debulking in patients with polycystic liver disease (PCLD) due to the lack of effective medical therapies; however, few data exist on outcomes of surgical intervention for PCLD. METHODS: We conducted a retrospective analysis of consecutive patients who underwent operative intervention due to persistent symptoms secondary to PCLD. Preoperative patient characteristics, 30-day postoperative outcomes, and long-term postoperative outcomes, including complications and symptom resolution, were analyzed. RESULTS: We identified 50 patients who underwent hepatic resection for symptomatic PCLD. Nine patients (19%) had concomitant polycystic kidney disease, and 14 (28%) had previously undergone interventions for PCLD management. The overall complication rate was 30%, with 8 patients (16%) experiencing Clavien-Dindo Grade III-V complications and no mortalities. The median relative reduction in liver volume was 41%. At a median follow-up of 2 years, 94% has sustained symptom resolution. CONCLUSIONS: This is among the largest case series exploring PCLD operative outcomes, revealing that surgical intervention for debulking for advanced PCLD is safe and effective for symptom management. Furthermore, patients with PCLD undergoing hepatectomy tolerate significant liver volume loss without evidence of impaired hepatic function.

Successful Liver Transplantation from a Deceased Donor After Ethylene Glycol Ingestion: A Case Report and Review of the Literature of Organ Donation from Poisoned Donors.

Despite the increase in deceased organ donation over the past ten years, the gap between patients awaiting transplant and available organs continues to widen. Deceased donors secondary to acute fatal poisonings represent less than 1% of all organ donors. Organs from poisoned donors have largely been discarded due to concerns of toxin transmission and poor organ function as well as the paucity of data that exists regarding this donor population. Here, we report a case of a 40-year-old male who underwent successful liver re-transplantation from a donor who died following ethylene glycol ingestion. To our knowledge this case report is the first to describe successful re-transplantation from an ethylene glycol-poisoned donor. We also provide a comprehensive review of the literature describing organ donation from poisoned donors.

The MHC-characterized Miniature Swine: Lessons Learned From a 40-Year Experience in Transplantation.

Over the last 40 y, a specialized herd of miniature swine has been intentionally bred to develop lines of animals homozygous for the swine major histocompatibility complex (MHC), which have facilitated transplantation studies across reproducible MHC and minor antigen mismatch barriers. These MHC-characterized miniature swine (Mc-MS) have been used for the study of novel surgical techniques, various approaches to tolerance induction of solid organ and vascularized composite allografts, as well as studies of the immunobiology of allografts and xenografts. Mc-MS possess characteristics that are highly advantageous to these studies, and their continued use will likely continue to play an important role in bridging "bench-to-cage-to bedside" therapies in the field of transplantation. In this review, we highlight the seminal contributions of the Mc-MS model to the field and analyze their role in the broader context of large animal models in transplantation research.

Extracorporeal Liver Support: A Bridge to Somewhere.

Content available: Audio Recording.

Cellular Immunotherapies in Preclinical Large Animal Models of Transplantation.

Hematopoietic stem cell (HSC) transplantation and solid organ transplantation remain the only curative options for many hematologic malignancies and end-stage organ diseases. Unfortunately, the sequelae of long-term immunosuppression, as well as acute and chronic rejection, carry significant morbidities, including infection, malignancy, and graft loss. Numerous murine models have demonstrated the efficacy of adjunctive cellular therapies using HSCs, regulatory T cells, mesenchymal stem cells, and regulatory dendritic cells in modulating the alloimmune response in favor of graft tolerance; however, translation of such murine approaches to other preclinical models and in the clinic has yielded mixed results. Large animals, including nonhuman primates, swine, and canines, provide a more immunologically rigorous model in which to test the clinical translatability of these cellular therapies. Here, we highlight the contributions of large animal models to the development and optimization of HSCs and additional cellular therapies to improve organ transplantation outcomes.

Non-invasive imaging for the diagnosis of acute rejection in transplantation: The next frontier.

Acute rejection is a leading cause of organ transplant failure and the most common indication for re-transplantation. Clinically, suspicion of acute rejection is often dependent upon serum laboratory values which may only manifest after organ injury. The gold standard for diagnosis requires an invasive biopsy which can carry serious clinical risks including bleeding and graft loss as well as the possibility of sampling error. The use of noninvasive imaging modalities to monitor transplanted organs is of great clinical value, particularly as a tool for early detection of graft dysfunction or acute rejection. Herein, we provide an overview of the existing literature evaluating noninvasive imaging modalities of solid organ and cellular allografts after transplantation, including both preclinical and clinical studies.

Large Animal Models of Vascularized Composite Allotransplantation: A Review of Immune Strategies to Improve Allograft Outcomes.

Over the past twenty years, significant technical strides have been made in the area of vascularized composite tissue allotransplantation (VCA). As in solid organ transplantation, the allogeneic immune response remains a significant barrier to long-term VCA survival and function. Strategies to overcome acute and chronic rejection, minimize immunosuppression and prolong VCA survival have important clinical implications. Historically, large animals have provided a valuable model for testing the clinical translatability of immune modulating approaches in transplantation, including tolerance induction, co-stimulation blockade, cellular therapies, and ex vivo perfusion. Recently, significant advancements have been made in these arenas utilizing large animal VCA models. In this comprehensive review, we highlight recent immune strategies undertaken to improve VCA outcomes with a focus on relevant preclinical large animal models.

Biliary Complications Following Adult Deceased Donor Liver Transplantation: Risk Factors and Implications at a High-volume US Center.

Biliary leaks and anastomotic strictures comprise the majority of biliary complications (BCs) following liver transplantation (LT). Currently, there are few large contemporary case series of BCs in adult deceased donor liver transplant (DDLT) recipients in the literature. The purpose of this study was to examine the pretransplant and intraoperative risk factors associated with BCs at a high-volume tertiary care center and determine the impact of these BCs on their posttransplant course and long-term transplant outcomes. METHODS: We retrospectively reviewed all adult patients undergoing a DDLT from a donor after brain death (DBD) at Emory University between January 2015 and December 2019. RESULTS: A total of 647 adult patients underwent DDLT from a DBD during the study period and were included in analyses. The median length of follow-up posttransplant was 2.5 y. There were a total of 27 bile leaks (4.2%) and 69 biliary strictures (10.7%). Recipient age and cold ischemic time were identified as risk factors for biliary leak, whereas alcoholic cirrhosis as transplant indication was a risk factor for biliary stricture. Placement of a biliary stent was associated with the development of both biliary leaks and anastomotic strictures. Posttransplant, biliary leaks were a significant risk factor for future episodes of acute rejection but did not impact overall survival. In contrast, biliary strictures were associated with a significantly reduced overall survival at 1- and 4-y post DDLT. CONCLUSIONS: BCs are a major source of morbidity and mortality following DDLT, with strictures and leaks associated with distinct posttransplant complications.

Outcomes and implications of a single brain death examination policy on organ donation outcomes at a high-volume trauma center.

BACKGROUND: Despite current neurological guidelines that a single brain death examination (SBDE) is sufficient to determine brain death, a vast majority of hospitals still use a two brain death examination (TBDE) policy based on historical practice. The purpose of this study was to analyze the outcomes and implications of an SBDE policy compared with a TBDE policy with respect to organ donation outcomes. METHODS: We retrospectively reviewed all adult patients declared dead by neurological criteria between 2010 and 2018 at a high-volume trauma center. The study population was divided into SBDE and TBDE cohorts. Primary outcomes included time to organ donation, terminal donor creatinine and bilirubin, and number of procured and transplanted organs. RESULTS: A total of 327 patients comprised the study population: 66.7% SBDE (n = 218 of 327 patients) and 33.3% TBDE (n = 109 of 327 patients). The SBDE group had a shorter median time from examination to procurement (38 vs. 44 hours, p = 0.02) as well as lower terminal donor creatinine (1.1 vs. 1.35 mg/dL, p = 0.004) and bilirubin (0.8 vs. 1.1 mg/dL, p = 0.04). Furthermore, the SBDE group had a significantly greater proportion of kidneys (90.6% vs. 81.6%, p = 0.02), lungs (11.8% vs. 4.6%, p = 0.02), and total organs (58.2% vs. 46.6%; p = 0.0001) procured with intent to transplant and a greater proportion of total organs transplanted (53.1% vs. 42.4%, p = 0.0004). Multivariable regression analysis confirmed that SBDE was independently associated with a shorter time to procurement, lower terminal creatinine, and increased number of procured organs. CONCLUSION: These data highlight the potential benefit of an SBDE policy with regards to organ donation outcomes at a high-volume trauma center and should facilitate future randomized prospective studies to more rigorously test this hypothesis. LEVEL OF EVIDENCE: Therapeutic/Care Management, level IV.

Cellular Therapies for the Treatment of Hematological Malignancies; Swine Are an Ideal Preclinical Model.

The absence of clinically relevant large animal tumor models has historically forced experimental cellular therapies for hematological malignancies to translate directly from murine models to clinical trials. However, recent advances highlight swine as an ideal large animal model to demonstrate the safety of murine proof of concept studies prior to their implementation clinically. The availability of the MHC defined MGH miniature swine herd has been key for the development of novel approaches for hematopoietic cell and solid organ transplantation. New spontaneously arising hematological malignancies in these swine, specifically myeloid leukemias and B cell lymphomas, resemble human malignancies, which has allowed for development of immortalized tumor cell lines and has implications for the development of a large animal transplantable tumor model. The novel development of a SCID swine model has further advanced the field of large animal cancer models, allowing for engraftment of human tumor cells in a large animal model. Here, we will highlight the advantages of the swine pre-clinical model for the study of hematological malignancies. Further, we will discuss our experience utilizing spontaneously arising tumors in MGH swine to create a transplantable tumor model, describe the potential of the immunodeficient swine model, and highlight several novel cellular and biological therapies for the treatment of hematological malignancies in swine as a large animal pre-clinical bridge.

Development of a Transplantable GFP+ B-Cell Lymphoma Tumor Cell Line From MHC-Defined Miniature Swine: Potential for a Large Animal Tumor Model.

The lack of a reliable and reproducible large animal tumor model for the study of hemolymphatic malignancies limits the ability to explore the underlying pathophysiology and testing of novel therapies. The goal of this study was to develop an aggressive, trackable swine tumor cell line in mice for adoptive transfer into MHC matched swine. Two tumor cell lines, post-transplant lymphoproliferative disease (PTLD) 13271 and chronic myelogenous leukemia (CML) 14736, were previously established from the Massachusetts General Hospital (MGH) miniature swine herd. PTLD 13271 is a swine B-cell lymphoma line originating from an animal that developed PTLD following hematopoietic cell transplantation (HCT), while CML 14736 was generated from a swine that spontaneously developed CML. In order to select for aggressive tumor variants, both lines were passage into NOD/SCID IL-2 receptor γ-/- (NSG) mice. Tumor induced mortality in mice injected with CML14736 was 68% while 100% of mice injected with PTLD 13271 succumbed to PTLD by day 70. Based on aggressiveness, PTLD 13271 was selected for further development and re-passage into NSG mice resulting in increased tumor burden and metastasis. Transduction of the PTLD 13271 cell line with a green fluorescent protein (GFP)-expressing lentivirus facilitated tumor tracking when re-passaged in mice. Utilizing a tolerance induction strategy, GFP+ tumors were injected into an MHC matched miniature swine and successfully followed via flow cytometry for 48 h in circulation, although tumor engraftment was not observed. In summary, we report the development of an aggressive GFP+B-cell lymphoma cell line which has the potential for facilitating development of a large animal tumor model.

Survival of Allogeneic Self-Assembled Cultured Skin.

BACKGROUND: Deficiency of autologous skin for reconstruction of severe wounds is a major problem in plastic surgery. Autologous substitutes can provide additional coverage, but due to the duration of production, treatment is significantly delayed. The allogeneic approach offers a potential of having an off-the-shelf solution for the immediate application. METHODS: In this study, we assess the engraftment and immunogenicity of allogeneic bilayered bioengineered skin prepared by a self-assembly method. Bioengineered skin has the potential immunological advantage of lacking passenger leukocytes including antigen-presenting cells. The skin constructs were transplanted across major histocompatibility complex (MHC) barriers in a porcine animal model. Animals received a second grafting of the same skin construct 7 weeks after the first set of grafts together with MHC-matched constructs to assess for clinical sensitization. RESULTS: All alloconstructs successfully engrafted with histologic evidence of neovascularization by day 4. Complete cellular rejection and tissue loss occurred by day 8 for most grafts. After the second application, accelerated rejection (<4 days) took place with the development of swine MHC-specific cytotoxic alloantibody. CONCLUSIONS: These data demonstrate preclinically that self-assembled allogeneic constructs engraft and reject similar to allogeneic skin despite the absence of professional donor antigen-presenting cells.