Metastatic Merkel Cell Carcinoma After Simultaneous Pancreas-Kidney Transplantation: Fatal Outcomes.

Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous malignancy. Immunosuppression increases the risk of MCC and is associated with poor prognosis. Organ transplant recipients (OTR) have worse overall survival (OS) than patients with immunosuppression due to other causes. Treating MCC after organ transplantation is challenging, as checkpoint inhibitor immunotherapy, the standard of care for treating MCC, increases the risk of transplant rejection. This paper reviews the cases of two simultaneous pancreas-kidney transplant (SPKT) recipients with MCC and explores the role of immunosuppression in the development of MCC. Immunosuppression was discontinued and checkpoint inhibitor therapy was initiated in the first patient and considered by the second patient. In both cases, treatment failed, and the patients died shortly after developing metastatic MCC. These cases illustrate the need for improved multidisciplinary treatment regimens for MCC in OTRs. J Drugs Dermatol. 2024;23(5):376-377.     doi:10.36849/JDD.8234  .

Intestinal Transplantation: Include the Spleen with Intestinal Graft?

The traditional procedure for multivisceral transplant (MVT) is to transplant the stomach, pancreas, intestine, and liver en bloc. During surgery, the native spleen is routinely removed from the recipient, and it usually creates more space in the abdomen to insert the allogeneic graft. Thus, recipients often become asplenic after MVT. Considering all of the risks and benefits, we advocate that temporary transplant of the donor spleen could be the best option for MVT recipients; it could potentially reduce the rate of intestinal allograft rejection without increasing the risk for graft-versus-host disease.

From islet transplantation to beta-cell regeneration: an update on beta-cell-based therapeutic approaches in type 1 diabetes.

INTRODUCTION: Type 1 diabetes (T1D) mellitus is an autoimmune disease in which immune cells, predominantly effector T cells, destroy insulin-secreting beta-cells. Beta-cell destruction led to various consequences ranging from retinopathy and nephropathy to neuropathy. Different strategies have been developed to achieve normoglycemia, including exogenous glucose compensation, whole pancreas transplantation, islet transplantation, and beta-cell replacement. AREAS COVERED: The last two decades of experience have shown that indigenous glucose compensation through beta-cell regeneration and protection is a peerless method for T1D therapy. Tremendous studies have tried to find an unlimited source for beta-cell regeneration, on the one hand, and beta-cell protection against immune attack, on the other hand. Recent advances in stem cell technology, gene editing methods, and immune modulation approaches provide a unique opportunity for both beta-cell regeneration and protection. EXPERT OPINION: Pluripotent stem cell differentiation into the beta-cell is considered an unlimited source for beta-cell regeneration. Devising engineered pancreas-specific regulatory T cells using Chimeric Antigen Receptor (CAR) technology potentiates an effective immune tolerance induction for beta-cell protection. Beta-cell regeneration using pluripotent stem cells and beta-cell protection using pancreas-specific engineered regulatory T cells promises to develop a curative protocol in T1D.

Tacrolimus's Time Below Therapeutic Range Is Associated With Acute Pancreatic Graft Rejection and the Development of De Novo Donor-specific Antibodies.

Tacrolimus is pivotal in pancreas transplants but poses challenges in maintaining optimal levels due to recipient differences. This study aimed to explore the utility of time spent below the therapeutic range and intrapatient variability in predicting rejection and de novo donor-specific antibody (dnDSA) development in pancreas graft recipients. This retrospective unicentric study included adult pancreas transplant recipients between January 2006 and July 2020. Recorded variables included demographics, immunosuppression details, HLA matching, biopsy results, dnDSA development, and clinical parameters. Statistical analysis included ROC curves, sensitivity, specificity, and predictive values. A total of 131 patients were included. Those with biopsy-proven acute rejection (BPAR, 12.2%) had more time (39.9% ± 24% vs. 25.72% ± 21.57%, p = 0.016) and tests (41.95% ± 13.57% vs. 29.96% ± 17.33%, p = 0.009) below therapeutic range. Specific cutoffs of 31.5% for time and 34% for tests below the therapeutic range showed a high negative predictive value for BPAR (93.98% and 93.1%, respectively). Similarly, patients with more than 34% of tests below the therapeutic range were associated with dnDSA appearance (38.9% vs. 9.4%, p = 0.012; OR 6.135, 1.346-27.78). In pancreas transplantation, maintaining optimal tacrolimus levels is crucial. Suboptimal test percentages below the therapeutic range prove valuable in identifying acute graft rejection risk.

Abdominal Organ Transplantation: Noteworthy Literature in 2023.

This review highlights noteworthy literature published in 2023 and pertinent to anesthesiologists and critical care physicians caring for patients undergoing abdominal organ transplantation. We feature 9 studies from 593 peer-reviewed papers on pancreatic transplantation, 3 from 194 on intestinal transplantation, and 28 from over 4513 on kidney transplantation. The liver transplantation section includes a special focus on 20 studies from 5666 clinical trial publications. We explore a broad range of topics, including donor management, perioperative recipient management, and innovative pharmacologic and mechanical interventions tested for the improvement of patient and graft outcomes and survival.

The role of genetic risk factors, diet, and gut microbiota in type 1 diabetes mellitus, pancreas and pancreatic islet transplantation.

Despite advances in insulin delivery and glucose monitoring technology, prevention of the progression of secondary complications in patients with type 1 diabetes (T1DM) remains a challenge. Beta cell replacement therapy in the form of islet or pancreas transplantation can restore long-term normoglycaemia with sustained periods of insulin independence among T1DM patients. However, the same genetic, behavioural, or gut microbiota-related factors that promoted autoimmunity and primary islet destruction may also affect the function of transplanted islets and the ultimate results of transplant procedures. In such cases, identifying genetic risk factors and modifying behavioural factors and those related to gut microbiota may be beneficial for the outcomes of transplant procedures. Herein, we review related literature to the identified current gap in knowledge to be addressed in future clinical trials.

Assessing the influence of graft loss on 4-year patient survival after simultaneous pancreas-kidney transplantation: Kaplan-Meier versus Competing Risk Analysis model.

BACKGROUND: Graft loss increases the risk of patient death after simultaneous pancreas-kidney (SPK) transplantation. The relative risk of each graft failure is complex due to the influence of several competing events. METHODS: This retrospective, single-center study compared 4-year patient survival according to the graft status using Kaplan-Meier (KM) and Competing Risk Analysis (CRA). Patient survival was also assessed according to five eras (Era 1: 2001-2003; Era 2: 2004-2006; Era 3: 2007-2009; Era 4: 2010-2012; Era 5: 2012-2015). RESULTS: Between 2000 and 2015, 432 SPK transplants were performed. Using KM, patient survival was 86.5% for patients without graft loss (n = 333), 93.4% for patients with pancreas graft loss (n = 46), 43.7% for patients with kidney graft loss (n = 16), and 25.4% for patients with pancreas and kidney graft loss (n = 37). Patient survival was underestimated using KM versus CRA methods in patients with pancreas and kidney graft losses (25.4% vs. 36.2%), respectively. Induction with lymphocyte depleting antibodies was associated with 81% reduced risk (HR.19, 95% CI.38-.98, p = .0048), while delayed kidney function (HR 2.94, 95% CI 1.09-7.95, p = .033) and surgical complications (HR 2.94, 95% CI 1.22-7.08, p = .016) were associated with higher risk of death. Four-year patient survival increased from Era 1 to Era 5 (79% vs. 87.9%, p = .047). CONCLUSION: In this cohort of patients, kidney graft loss, with or without pancreas graft loss, was associated with higher mortality after SPK transplantation. Compared to CRA, the KM model underestimated survival only among patients with pancreas and kidney graft losses. Patient survival increased over time.

A Case Report of Modified Pancreatic Transplantation With a Limited Splenic Arteriovenous Fistula to Elude Thrombosis.

In classic pancreatic transplantation, the splenic artery and vein are ligated at the tail of the pancreas graft. This leads to slowed blood flow in the splenic vein and may cause thrombosis and graft loss. In this study, a patient received a pancreas after kidney transplantation. A modified surgical technique was used in the pancreatic graft preparation. The donor splenic artery and vein were anastomosed end to end at the tail of the pancreas. The splenic artery near the anastomosis was partially ligated, and an effective diameter of 2 mm was reserved to limit arterial blood pressure and flow. The patient recovered very well. Contrasted computed tomography scans on days 11 and 88 after pancreas transplantation indicated sufficient backflow of the splenic vein. We believe that this procedure may avoid the risk of splenic vein thrombosis after pancreas transplantation. This modified technique has not been reported in clinical cases previously and may help reduce the risk of thrombosis after pancreas transplantation.

[Diabetes and pancreas or islet transplantation: psychological issues]. / Diabète et transplantation du pancréas ou d'îlots de Langerhans : enjeux psychologiques.

Diabetes is a chronic and progressive disease that affects an increasing number of patients. The prevalence of associated psychological comorbidities is high and often requires the implementation of targeted psychological interventions. Pancreas or islet transplantation remains a therapeutic option to consider, for a part of patients with type 1 diabetes unstable disease or established complications. From the clinical indication to the waiting period for a transplantation, then to the postoperative and long-term care, the diabetic patient is found to experience perpetual changes that may test his adaptability. In this article, the psychological aspects of the pancreas or islet transplantation, as well as the role of a liaison psychiatrist in a transplantation unit will be discussed.

Le diabète est une maladie chronique et évolutive atteignant un nombre croissant de patients. La prévalence des comorbidités psychiques associées est élevée et nécessite souvent l'implémentation d'interventions psychologiques ciblées. La transplantation du pancréas ou d'îlots de Langerhans est une option thérapeutique à considérer pour certains patients avec un diabète de type 1 instable ou des complications installées. De l'indication clinique à la période d'attente pour une greffe, puis des suites postopératoires jusqu'à la vie d'après la greffe, le patient diabétique vit des transitions multiples le mettant à l'épreuve. Dans cet article, nous discutons les aspects psychologiques de ces transplantations ainsi que les interventions du psychiatre de liaison au sein d'un service de transplantation.

A New Mouse Model of Whole Pancreas Transplant With Graft Blood Through the Portal Vein.

OBJECTIVES: Pancreas transplant is currently the most effective method for maintaining physiological blood sugar levels and reversing small blood vessel injuries. Our team developed a model of whole pancreas transplant based on microsurgical techniques following the investigation of more than 300 mice. MATERIALS AND METHODS: A mouse pancreatic transplant model is required to investigate the pathophysiological process of pancreas transplant and pancreatic preservation technologies. Recently, the segment-neck pancreas transplant has been the most utilized mouse pancreatic transplant model. The innovative mouse pancreatic transplant modelthat we developed in this study uses the whole pancreas and returns heart blood flow into the liver via the portal vein. RESULTS: With our mouse pancreatic transplant model, the survivalrate of mice aftertransplant was >80%, and the success rate of pancreatic transplant was >90%. CONCLUSIONS: The segment-neck and the whole pancreas model can guarantee that the transplanted pancreas functions effectively, and both have excellent postoperative outcomes, survivalrates and pancreatic active rates.

Risk factors and outcomes of persistent post-transplant hypotension among simultaneous pancreas and kidney transplant recipients.

BACKGROUND: The risk factors and outcomes associated with post- transplant hypotension after simultaneous pancreas and kidney (SPK) Transplantation are poorly defined. METHODS: SPK recipients at our center between 2010 and 2021 with functioning pancreas and kidney grafts for >6 months were included. Recipients were then divided into three groups based on active medications for the treatment of hypo-or hypertension at 6-months post-transplant: those with normal blood pressure (NBP) not requiring medication (NBP group), those on antihypertensive medications (HTN group), and those on medications for hypotension (fludrocortisone and/or midodrine) (Hypotensive group). RESULTS: A total of 306 recipients were included in the study: 54 (18%) in the NBP group, 215 (70%) in the HTN group, and 37 (12%) in the Hypotensive group. On multivariate analysis, the use of T-depleting induction (aHR = 9.64, p = .0001, 95% Cl = 3.12-29.75), pre-transplant use of hypotensive medications (aHR = 4.53, p = .0003, 95% Cl = 1.98-10.38), and longer duration of dialysis (aHR = 1.02, p = .01, 95% Cl = 1.00-1.04) were associated with an increased risk of post-transplant hypotension. Post-transplant hypotension was not associated with an increased risk of death-censored kidney or pancreatic allograft failure, or patient death. CONCLUSION: Hypotension was common even 6 months post-SPK transplantation. With appropriate management, hypotension was not associated with detrimental graft or patient outcomes.

Incidental appendicectomy in pancreas transplantation: A single-center study.

BACKGROUND: Appendicitis in pancreatic transplant recipients can be challenging to diagnose and manage. Incidental appendicectomy (IA) during pancreas transplantation obviates the risk of appendicitis but potentially at the cost of increased operating time or early post-operative complications. This study reviewed the value of IA at a single center. METHODS: This was a retrospective study of patients who underwent a pancreas transplant in our unit from January 1st, 2012 to December 31st, 2020, with end of follow-up on May 21st, 2023; recipients were grouped by whether or not an IA was performed during pancreas transplantation. Donor, recipient, operative, and graft outcomes were compared between the two groups. Post-transplant complications related to appendiceal pathology (or IA) were recorded and classified. RESULTS: Two hundred forty-three patients underwent a pancreas transplant; 227 (93%) patients had an appendix in situ at transplantation, and of these 53 (23%) underwent an IA and 174 (77%) did not. There were no statistically significant differences in operative time (p = .06) or hospital stay (p = .50) between the two groups. In the IA cohort, there were no Clavien-Dindo Grade III-V complications relating to the appendicectomy. In those that did not undergo an IA, two patients (1%) subsequently required appendicectomy due to appendicitis. Comparison of pancreatic graft survival showed no statistically significant difference between the groups (p = .44). CONCLUSIONS: This study suggests that IA is effective at reducing risks of post-transplant appendiceal complications without significantly prolonging inpatient stay or impairing graft survival. These data support the consideration of undertaking an IA for all patients undergoing a pancreas transplant.

Risk of cytomegalovirus infection and subsequent allograft failure after pancreas transplantation.

Cytomegalovirus (CMV) is a common cause of infection after transplantation, but few studies have evaluated its epidemiology, risk factors, and outcomes among pancreas transplant recipients. We performed a retrospective cohort study of adults who underwent pancreas transplantation from January 1, 2010, through December 31, 2020, at 3 sites in Arizona, Florida, and Minnesota. The primary outcome was clinically significant CMV infection (csCMVi), defined as CMV disease or infection requiring antiviral therapy. The secondary outcome was pancreas allograft failure. Among 471 pancreas transplant recipients, 117 (24.8%) developed csCMVi after a median of 226 (interquartile range 154-289) days. CMV donor (D)+/R- patients had a significantly higher incidence of csCMVi (hazard ratio [HR] 4.01, 95% confidence interval [CI] 2.10-7.64; P < .001). In adjusted analysis, a lower absolute lymphocyte count (ALC) was associated with a greater risk of csCMVi among seropositive recipients (HR 1.39 per 50% decrease, 95% CI 1.13-1.73; P = .002) but not among D+/R- patients (HR 1.04 per 50% decrease, 95% CI 0.89-1.23; P = .595). csCMVi, lower ALC, and acute rejection (P < .001) were independently associated with pancreas allograft failure. In conclusion, CMV D+/R- was associated with csCMVi in pancreas recipients, although ALC was associated with csCMVi only among seropositive patients. The development of csCMVi in pancreas recipients was associated with poor pancreas allograft outcomes.

Donor noradrenaline use is associated with better allograft survival in recipients of pancreas transplantation.

INTRODUCTION: Outcomes following pancreas transplantation are suboptimal and better donor selection is required to improve this. Vasoactive drugs (VaD) are commonly used to correct the abnormal haemodynamics of organ donors in intensive care units. VaDs can differentially affect insulin secretion positively (dobutamine) or negatively (noradrenaline). The hypothesis was that some VaDs might induce beta-cell stress or rest and therefore impact pancreas transplant outcomes. The aim of the study was to assess relationships between VaD use and pancreas transplant graft survival. METHODS: Data from the UK Transplant Registry on all pancreas transplants performed between 2004 and 2016 with complete follow-up data were included. Univariable- and multivariable-adjusted Cox regression analyses determined risks of graft failure associated with VaD use. RESULTS: In 2,183 pancreas transplants, VaDs were used in the following numbers of donors: dobutamine 76 (3.5%), dopamine 84 (3.8%), adrenaline 161 (7.4%), noradrenaline 1,589 (72.8%) and vasopressin 1,219 (55.8%). In multivariable models, adjusted for covariates and the co-administration of other VaDs, noradrenaline use (vs non-use) was a strong predictor of better graft survival (hazard ratio [95% confidence interval] 0.77 [0.64-0.94], p = 0.01). CONCLUSIONS: Noradrenaline use was associated with better graft survival in models adjusted for donor and recipient variables - this may be related to inhibition of pancreatic insulin secretion initiating pancreatic beta-cell 'rest'. Further research is required to replicate these findings and establish whether relationships are causal. Identification of alternative methods of inducing beta-cell rest could be valuable in improving graft outcomes.

Innovative surgical techniques in the intestine and multivisceral transplant.

PURPOSE OF REVIEW: This timely review delves into the evolution of multivisceral transplantation (MVT) over the past six decades underscoring how advancements in surgical techniques and immunosuppression have driven transformation, to provide insight into the historical development of MVT, shedding light on its journey from experimentation to a valuable clinical approach. RECENT FINDINGS: The review presents contemporary enhancements in surgical methods within the context of intestinal transplantation. The versatility of MVT is emphasized, accommodating diverse organ combinations and techniques. Both isolated intestinal transplantation (IIT) and MVT have seen expanded indications, driven by improved parenteral nutrition, transplantation outcomes, and surgical innovations. Surgical techniques are tailored based on graft type, with various approaches for isolated transplantation. Preservation strategies and ostomy techniques are also covered, along with graft assessment advancements involving donor-specific antibodies. SUMMARY: This review's findings underscore the remarkable evolution of MVT from experimental origins to a comprehensive clinical practice. The progress in surgical techniques and immunosuppression has broadened the spectrum of patients who can benefit from intestinal transplant, including both IIT and MVT. The expansion of indications offers hope to patients with complex gastrointestinal disorders. The detection of donor-specific antibodies in graft assessment advances diagnostic accuracy, ultimately improving patient outcomes.

Impact of pancreas transplantation alone on kidney function: A multicenter clinical cohort study.

Pancreas transplantation alone (PTA) is a ß cell replacement option for selected patients with type 1 diabetes mellitus; concerns have been raised regarding deterioration in kidney function (KF) after PTA. This retrospective multicenter study assessed actual impact of transplantation and immunosuppression on KF in PTA recipients at three Transplant Centers. The primary composite endpoint 10 years after PTA was >50% eGFR decline, eGFR < 30 mL/min/1.73 m2 , and/or receiving a kidney transplant (KT). Overall, 822 PTA recipients met eligibility. Median baseline and 10-year eGFR (mL/min/1.73 m2 ) were 76.3 (58.1-100.8) and 51.3 (35.3-65.9), respectively. Primary composite endpoint occurred in 98 patients (53.5%) with 45 experiencing a >50% decrease in eGFR by 10 years post-transplant, 38 eGFR < 30 mL/min/1.73 m2 and 49 requiring KT. KF declined most significantly within 6 months post-PTA, more often in females and patients with better preserved GFR up to 5 years with 11.6% kidney failure at 10 years. Patient survival and death-censored graft survival were both 68% at 10 years with overall graft thrombosis rate 8%. KF declined initially after PTA but stabilized with further slow progression. In conclusion, prospective intervention studies are needed to test renal sparing interventions while gathering more granular data.