The First Collective Examination of Immunosuppressive Practices Among American Intestinal Transplant Centers.

Background: Unlike other solid organs, no standardized treatment algorithms exist for intestinal transplantation (ITx). We established a consortium of American ITx centers to evaluate current practices. Methods: All American centers performing ITx during the past 3 y were invited to participate. As a consortium, we generated questions to evaluate and collect data from each institution. The data were compiled and analyzed. Results: Ten centers participated, performing 211 ITx during the past 3 y (range, 3-46; mean 21.1). Induction regimens varied widely. Thymoglobulin was the most common, used in the plurality of patients (85/211; 40.3%), but there was no consensus regimen. Similarly, regimens for the treatment of acute cellular rejection, antibody-mediated rejection, and graft-versus-host disease varied significantly between centers. We also evaluated differences in maintenance immunosuppression protocols, desensitization regimens, mammalian target of rapamycin use, antimetabolite use, and posttransplantation surveillance practices. Maintenance tacrolimus levels, stoma presence, and scoping frequency were not associated with differences in rejection events. Definitive association between treatments and outcomes, including graft and patient survival, was not the intention of this initial collaboration and is prevented by the lack of patient-level data and the presence of confounders. However, we identified trends regarding rejection episodes after various induction strategies that require further investigation in our subsequent collaborations. Conclusions: This initial collaboration reveals the extreme heterogeneity of practices among American ITx centers. Future collaboration will explore patient-level data, stratified by age and transplant type (isolated intestine versus multivisceral), to explore the association between treatment regimens and outcomes.

Improving safety of robotic major hepatectomy with extrahepatic inflow control and laparoscopic CUSA parenchymal transection: technical description and initial experience.

BACKGROUND: Blood loss is a major determinant of outcomes following hepatectomy. Robotic technology enables hepatobiliary surgeons to mimic open techniques for inflow control and parenchymal transection during major hepatectomy, increasing the ability to minimize blood loss and perform safe liver resections. METHODS: Initial experience of 20 consecutive major robotic hepatectomies from November 2018 to July 2020 at two co-located institutions was reviewed. All cases were performed with extrahepatic inflow control and parenchymal transection with the laparoscopic cavitron ultrasonic surgical aspirator (CUSA), and a technical description is illustrated. Clinical characteristics, operative data, and surgical outcomes were retrospectively analyzed. RESULTS: The median (range) patient age was 58 years (20-76) and the majority of 14 (70%) patients were ASA III-IV. There were 12 (60%) resections for malignancy and the median tumor size was 6.2 cm (1.2-14.6). Right or extended right hepatectomy was the most common procedure (12 or 60% of cases). There were 7 (35%) left or extended left hepatectomies and 1 (5%) central hepatectomy. The median operative time was 420 (177-622) minutes. Median estimated blood loss was 300 mL (25-800 mL). One (5%) case was converted to open. Two (10%) patients required blood transfusion. The median length of stay was 3 (1-6) days. Major complications included 1 (5%) Clavien-Dindo IIIa bile leak requiring percutaneous drainage placement. There was no 90-day mortality. CONCLUSION: Advanced techniques to reduce blood loss in robotic hepatectomy may optimize safety and minimize morbidity in these complex minimally invasive procedures.

Impact of CMV Reactivation, Treatment Approaches, and Immune Reconstitution in a Nonmyeloablative Tolerance Induction Protocol in Cynomolgus Macaques.

BACKGROUND: Cytomegalovirus (CMV) infection is a serious complication in immunosuppressed patients, specifically transplant recipients. Here, we describe the development and use of an assay to monitor the incidence and treatment of CMV viremia in a Cynomolgus macaque model of bone marrow transplantation (BMT) for tolerance induction. We address the correlation between the course of viremia and immune reconstitution. METHODS: Twenty-one animals received a nonmyeloablative conditioning regimen. Seven received cyclosporine A for 28 days and 14 received rapamycin. A CMV polymerase chain reaction assay was developed and run twice per week to monitor viremia. Nineteen recipients were CMV seropositive before BMT. Immune reconstitution was monitored through flow cytometry and CMV viremia was tracked via quantitative polymerase chain reaction. RESULTS: Recipients developed CMV viremia during the first month post-BMT. Two animals developed uncontrollable CMV disease. CMV reactivation occurred earlier in cyclosporine A-treated animals compared with those receiving rapamycin. Post-BMT, T-cell counts remained significantly lower compared with pretransplant levels until CMV reactivation, at which point they increased during the viremic phase and approached pretransplant levels 3 months post-BMT. Management of CMV required treatment before viremia reached 10 000 copies/mL; otherwise clinical symptoms were observed. High doses of ganciclovir resolved the viremia, which could subsequently be controlled with valganciclovir. CONCLUSIONS: We developed an assay to monitor CMV in Cynomolgus macaques. CMV reactivation occurred in 100% of seropositive animals in this model. Rapamycin delayed CMV reactivation and ganciclovir treatment was effective at high doses. As in humans, CD8 T cells proliferated during CMV viremia.

Safety and pharmacodynamics of anti-CD2 monoclonal antibody treatment in cynomolgus macaques - an experimental study.

Anti-CD2 treatment provides targeted immunomodulatory properties that have demonstrated clinical usefulness to condition the immune system and to treat transplant rejection. The treatment is species-specific due to structural CD2 antigen differences between nonhuman primates and humans. Herein, we report the safety profile and efficacy of two modifications of the same anti-CD2 monoclonal antibody in cynomolgus macaques. Twelve subjects received one i.v. anti-CD2 (of rat or rhesus type) dose each, range 1-4 mg/kg, and were followed for 1-7 days. Treatment effects were evaluated with flow cytometry on peripheral blood and histopathological evaluation of secondary lymphoid organs. In vitro inhibitory activity on primary MHC disparate mixed lymphocyte reactions (MLRs) was determined. Upon anti-CD2 treatment, CD4+ , CD8+ memory subsets were substantially depleted. Naïve T cells and Tregs were relatively spared and exhibited lower CD2 expression than memory T cells. Early immune reconstitution was noted for naïve cells, while memory counts had not recovered after one week. Both antibodies displayed a concentration-dependent MLR inhibition. Lymph node examination revealed no significant lymphocyte depletion. None of the animals experienced any significant study drug-related adverse events. This study outlines the safety and pharmacodynamic profile of primate-specific anti-CD2 treatment, relevant for translation of anti-CD2-based animal models into clinical trials.

Xenotransplantation tolerance: applications for recent advances in modified swine.

PURPOSE OF REVIEW: The aim of this study was to review the recent progress in xenotransplantation achieved through genetic engineering and discuss the potential of tolerance induction to overcome remaining barriers to extended xenograft survival. RECENT FINDINGS: The success of life-saving allotransplantation has created a demand for organ transplantation that cannot be met by the supply of human organs. Xenotransplantation is one possible solution that would allow for a nearly unlimited supply of organs. Recent genetic engineering of swine has decreased the reactivity of preformed antibodies to some, but not all, potential human recipients. Experiments using genetically modified swine organs have now resulted in survival of life-supporting kidneys for over a year. However, the grafts show evidence of antibody-mediated rejection on histology, suggesting additional measures will be required for further extension of graft survival. Tolerance induction through mixed chimerism or thymic transplantation across xenogeneic barriers would be well suited for patients with a positive crossmatch to genetically modified swine or relatively negative crossmatches to genetically modified swine, respectively. SUMMARY: This review highlights the current understanding of the immunologic processes in xenotransplantation and describes the development and application of strategies designed to overcome them from the genetic modification of the source animal to the induction of tolerance to xenografts.

The use of vascular homografts in pediatric small bowel transplantation: Single-center experience over a decade.

Intestinal transplantation in children has evolved with more isolated small intestine transplants being performed compared to combined liver-intestine transplants. Consequently, surgical techniques have changed, frequently requiring the use of vascular homografts of small caliber to revascularize the isolated small intestine, the impact of which on outcomes is unknown. Among 106 pediatric intestine and multivisceral transplants performed at our center since 2003, 33 recipients of an isolated small intestine graft were included in this study. Outcome parameters were thrombotic complications, graft, and patient survival. A total of 29 of 33 (87.9%) patients required arterial and/or venous homografts from the same donor, mainly iliac or carotid artery and iliac or innominate vein, respectively (donor's median age 1.1 years [2 months to 23 years], median weight 10 kg [14.7-48.5]). Post-transplant, there were three acute arterial homograft thromboses and one venous thrombosis resulting in two peri-operative graft salvages and two graft losses. Three of four thromboses occurred in patients with primary hypercoagulable state, including the two graft losses. Overall, at a median of 4.1 years (1-10.2) from transplant, 29 of 33 (88%) patients are alive with 26 of 33 (79%) functioning grafts. The procurement of intact, size-matched donor vessels and the management of effective post-transplant anticoagulation are critical.

Apple peel deformity of the small bowel without atresia in a congenital mesenteric defect.

Congenital mesenteric defects are rare causes of bowel obstruction. Even rarer are mesenteric defects with an apple peel type of deformity, probably described definitively only once previously. We present a case of a 3 year old boy who presented with a septic-like picture of severe metabolic acidosis and lethargy from a bowel obstruction with bowel ischemia. At laparotomy he was found to have bowel infarction due to herniation through a congenital mesenteric defect with an apple peel type of deformity of the bowel without bowel atresia.