Addition of interleukin-6 receptor blockade to carfilzomib-based desensitization in a highly sensitized nonhuman primate model.

Sensitized patients, those who had prior exposure to foreign human leukocyte antigens, are transplanted at lower rates due to challenges in finding suitable organs. Desensitization strategies have permitted highly sensitized patients to undergo kidney transplantation, albeit with higher rates of rejection. This study assesses targeting plasma cell and interleukin (IL)-6 receptor for desensitization in a sensitized nonhuman primate kidney transplantation model.

A novel method for in vitro culture and expansion of nonhuman primate B cells.

Background: Given the role of B cells in sensitization and antibody-mediated rejection pathogenesis, the ability to identify, isolate, and study B cells in vitro is critical for understanding these processes and developing novel therapeutics. While in vivo nonhuman primate models have been used to this end, an in vitro nonhuman primate model of B cell activation and proliferation has not been developed.

Methods: CD20 B cells and CD3 T cells were isolated using magnetic bead separation from the peripheral blood of naive and skin allograft sensitized nonhuman primates.

Anti-thymoglobulin induction improves neonatal porcine xenoislet engraftment and survival.

Porcine islet xenotransplantation is a viable strategy to treat diabetes. Its translation has been limited by the pre-clinical development of a clinically available immunosuppressive regimen. We tested two clinically relevant induction agents in a non-human primate (NHP) islet xenotransplantation model to compare depletional versus nondepletional induction immunosuppression.

Decline of increased risk donor offers increases waitlist mortality in paediatric heart transplantation.

Background: Increased risk donors in paediatric heart transplantation have characteristics that may increase the risk of infectious disease transmission despite negative serologic testing. However, the risk of disease transmission is low, and refusing an IRD offer may increase waitlist mortality. We sought to determine the risks of declining an initial IRD organ offer.

Emerging New Approaches in Desensitization: Targeted Therapies for HLA Sensitization.

There is an urgent need for therapeutic interventions for desensitization and antibody-mediated rejection (AMR) in sensitized patients with preformed or donor-specific HLA antibodies (DSA). The risk of AMR and allograft loss in sensitized patients is increased due to preformed DSA detected at time of transplant or the reactivation of HLA memory after transplantation, causing acute and chronic AMR. Alternatively, DSA that develops post-transplant due to inadequate immunosuppression and again may lead to acute and chronic AMR or even allograft loss.

Preoperative carfilzomib and lulizumab based desensitization prolongs graft survival in a sensitized non-human primate model.

Sensitized patients are difficult to transplant due to pre-formed anti-donor immunity. We have previously reported successful desensitization using carfilzomib and belatacept in a non-human primate (NHP) model. Here we evaluated selective blockade of the co-stimulatory signal (CD28-B7) with Lulizumab, which preserves the co-inhibitory signal (CTLA4-B7).

Targeting Calcium Release-activated Calcium Channel Is Not Sufficient to Prevent Rejection in Nonhuman Primate Kidney Transplantation.

Background: Calcineurin inhibitors successfully control rejection of transplanted organs but also cause nephrotoxicity. This study, using a rhesus monkey renal transplantation model, sought to determine the applicability of a new immunomodulatory drug inhibiting the store-operated calcium release-activated calcium channel of lymphocytes to control transplant rejection without nephrotoxicity.

Methods: Animals underwent kidney transplantation and were treated with tacrolimus alone (n = 3), a CRACM1 inhibitor (PRCL-02) (n = 6) alone, or with initial tacrolimus monotherapy followed by gradual conversion at 3 weeks to PRCL-02 alone (n = 3).

Evolution of minimally invasive surgery for rectal cancer: update from the national cancer database.

Background: As the use of minimally invasive techniques in colorectal surgery has become increasingly prevalent, concerns remain about the oncologic effectiveness and long-term outcomes of minimally invasive low anterior resection (MI-LAR) for the treatment of rectal cancer.

Study Design: The 2010-2015 National Cancer Database (NCDB) Participant Data Use File was queried for patients undergoing elective open LAR (OLAR) or MI-LAR for rectal adenocarcinoma. A 1:1 propensity match was performed on the basis of demographics, comorbidity, and tumor characteristics.

Kidney Donor Profile Index Is a Reliable Alternative to Liver Donor Risk Index in Quantifying Graft Quality in Liver Transplantation.

Background: The most established metric for estimating graft survival from donor characteristics in liver transplantation is the liver donor risk index (LDRI). The LDRI is calculated from donor and transplant-related variables, including cold ischemic time. Because cold ischemic time is unknown at the time of organ offer, LDRI is not available for organ acceptance decisions.

Pretransplant Desensitization with Costimulation Blockade and Proteasome Inhibitor Reduces DSA and Delays Antibody-Mediated Rejection in Highly Sensitized Nonhuman Primate Kidney Transplant Recipients.

Background: Patients with broad HLA sensitization have poor access to donor organs, high mortality while waiting for kidney transplant, and inferior graft survival. Although desensitization strategies permit transplantation lowering of donor-specific antibodies, the B cell-response axis from germinal center activation to plasma cell differentiation remains intact.

Methods: To investigate targeting the germinal center response and plasma cells as a desensitization strategy, we sensitized maximally MHC-mismatched rhesus pairs with two sequential skin transplants.

Daratumumab in Sensitized Kidney Transplantation: Potentials and Limitations of Experimental and Clinical Use.

Background: Donor-specific antibodies are associated with increased risk of antibody-mediated rejection and decreased allograft survival. Therefore, reducing the risk of these antibodies remains a clinical need in transplantation. Plasma cells are a logical target of therapy given their critical role in antibody production.

Secondary lymphoid tissue and costimulation-blockade resistant rejection: A nonhuman primate renal transplant study.

Naïve T cell activation requires antigen presentation combined with costimulation through CD28, both of which optimally occur in secondary lymphoid tissues such as lymph nodes and the spleen. Belatacept impairs CD28 costimulation by binding its ligands, CD80 and CD86, and in doing so, impairs de novo alloimmune responses. However, in most patients belatacept is ineffective in preventing allograft rejection when used as a monotherapy, and adjuvant therapy is required for control of costimulation-blockade resistant rejection (CoBRR).

Elevated Donor Hemoglobin A1C Impairs Kidney Graft Survival From Deceased Donors With Diabetes Mellitus: A National Analysis.

Objectives: Kidney transplant is the optimal therapy for patients with end-stage renal disease. The presence of donor diabetes mellitus is a recognized risk factor for impaired kidney graft survival and is incorporated into the Kidney Donor Profile Index. At present, however, there are limited assessments of the severity of this risk factor.

A Propensity-matched Survival Analysis: Do Simultaneous Liver-lung Transplant Recipients Need a Liver?

Background: There is debate whether simultaneous lung-liver transplant (LLT) long-term outcomes warrant allocation of 2 organs to a single recipient. We hypothesized that LLT recipients would have improved posttransplant survival compared with matched single-organ lung recipients with an equivalent degree of liver dysfunction.

Methods: The Organ Procurement and Transplant Network/United Network for Organ Sharing STAR file was queried for adult candidates for LLT and isolated lung transplantation from 2006 to 2016.

Cervical seatbelt sign is not associated with blunt cerebrovascular injury in children: A review of the national trauma databank.

Background: Blunt cerebrovascular injury (BCVI) is a rare consequence of blunt trauma. There appears to be benefit to an aggressive approach to screening for BCVI due to catastrophic sequelae of unrecognized injury. However, screening for BCVI carries extensive cost and oncologic risk to young patients.

Improved contemporary outcomes of liver transplantation for pediatric hepatoblastoma and hepatocellular carcinoma.

Purpose: Improvement in outcomes of LT for pediatric HB and HCC has been reported in small series. We analyzed national outcomes and changes in donor, recipient, and perioperative factors over time that may contribute to survival differences.

Methods: The UNOS database was queried for patients age <21 years that underwent LT for a primary diagnosis of HB or HCC (1987-2017).

Improved survival in simultaneous lung-liver recipients and candidates in the modern era of lung allocation.

Background: Liver-lung transplantation (LLT) is a rare procedure performed for patients with end-stage liver and lung disease. The lung allocation score (LAS), introduced in 2005, guides lung allocation including those receiving LLT. However, the impact of the LAS on outcomes in LLT is currently unknown.

Dual targeting: Combining costimulation blockade and bortezomib to permit kidney transplantation in sensitized recipients.

Previous evidence suggests that a homeostatic germinal center (GC) response may limit bortezomib desensitization therapy. We evaluated the combination of costimulation blockade with bortezomib in a sensitized non-human primate kidney transplant model. Sensitized animals were treated with bortezomib, belatacept, and anti-CD40 mAb twice weekly for a month (n = 6) and compared to control animals (n = 7).

Local excision results in comparable survival to radical resection for early-stage rectal carcinoid.

Background: Controversy exists regarding current National Comprehensive Cancer Network guidelines, which recommend local excision for rectal carcinoids ≤2 cm and radical resection for tumors >2 cm. Given the limited data examining optimal surgical approach for these lesions, we queried a national database to determine the impact of extent of resection on survival.

Methods: Patients undergoing treatment for clinical stage I and II rectal carcinoid (RC) were identified from the National Cancer Data Base (1998-2012).

Single-Center Long-Term Analysis of Combined Liver-Lung Transplant Outcomes.

Background: Combined lung-liver transplantation (LLT) applies 2 technically challenging transplants in 1 patient with severe 2-organ failure.

Methods: Institutional medical records and United Network for Organ Sharing database were queried for patients at our institution that underwent LLT from 2000 to 2016.

Results: Twelve LLTs were performed from 2000 to 2016 including 9 male and 3 female recipients with a median age of 28.

Contemporary Strategies and Barriers to Transplantation Tolerance.

The purpose of this review is to discuss immunologic tolerance as it applies to solid organ transplantation and to identify barriers that hinder the achievement of this long-term goal. First, the definition of tolerance and an introduction of mechanisms by which tolerance exists or can be achieved will be discussed. Next, a review of contemporary attempts at achieving transplant tolerance will be described.

Outcomes of laparoscopic resection of Meckel's diverticulum are equivalent to open laparotomy.

Purpose: Meckel's diverticulum (MD) is a common congenital anomaly caused by failure of involution of the omphalomesenteric duct. Enthusiasm for minimally invasive surgery (MIS) in children has burgeoned as technologies have advanced, but the outcomes of laparoscopic resection in comparison to open laparotomy for MD remain poorly defined. We queried a large national database to compare current practice patterns and clinical outcomes between surgical approaches for MD in the pediatric population.

Pediatric phyllodes tumors: A review of the National Cancer Data Base and adherence to NCCN guidelines for phyllodes tumor treatment.

Background: Phyllodes tumors are fibroepithelial breast lesions that are uncommon in women and rare among children. Due to scarcity, few large pediatric phyllodes tumor series exist. Current guidelines do not differentiate treatment recommendations between children and adults.

Successful desensitization with proteasome inhibition and costimulation blockade in sensitized nonhuman primates.

The detrimental effects of donor-directed antibodies in sensitized transplant patients remain a difficult immunologic barrier to successful organ transplantation. Antibody removal is often followed by rebound. Proteasome inhibitors (PIs) deplete antibody-producing plasma cells (PCs) but have shown marginal benefit for desensitization.

Solid Pseudopapillary Neoplasm of the Pancreas in Children and Adults: A National Study of 369 Patients.

Background: Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare tumor in children, with current evidence limited to single-center studies. We examined treatment and clinical outcomes for pediatric and adult SPN with a national data set.

Methods: The 2004 to 2013 National Cancer Data Base was queried to identify all patients diagnosed with SPN.