High-risk Transplant Research Articles

Post-Transplantation Cyclophosphamide Versus Low Doses ATG Fresenius As Part of Two Immunosuppression Regimens for Graft Versus Host Disease Prophylaxis: Low Severe Graft Versus Host Disease (GVHD) Incidence and y Similar Gvhd-Free and Relapse-Free Survival (GRFS)

BACKGROUND AND OBJECTIVES.Post transplantation High dose Cyclophosphamide (PTCY) used in haploidentical hematopoietic transplantations, has a high effectivity in acute Graft versus Host Disease (aGVHD), and chronic Graft versus Host Disease prophylaxis (cGVHD), however it is associated with high relapse rates. On the other hand, Anti-T-Lymphocyte Globulin (ATG-Fresenius ®) is also effective as immunosuppressive (IS) drug, but its benefit on Overall Survival (OS) and Relapse Free Survival (RFS) is unclear.The aim of this study was to compare the effectiveness of two GVHD prophylaxis regimes used in high risk transplantation: PTCY used in Haploidentical transplantation and ATG used for peripheral blood, non-related, related and mismatched donors.The primary endpoint was to evaluate the incidence of aGVHD and cGVHD, and its severity in both groups. As secondary endpoints we analyse the OS, RFS and GRFS (recorded adverse events include grade 3-4 aGVHD, systemic therapy-requiring cGVHD, relapse or death during median follow-up). We also consider transplantation related mortality (TRM) and post-transplantation complications.PATIENTS AND METHODS.We retrospectively analyse 111 allo-transplantations performed at our institution between 2012 and 2017. We analyse two cohorts: 49 haploidentical transplantation with PTCY (50 mg/kg, on day +3, +4) followed by Tacrolimus and Mycophenolate; and 62 peripheral blood related, non-related and mismatched with low dose ATG Fresenius (7mgr/Kg on days -3, -2, -1) associated with Tacrolimus/Cyclosporine starting on day -1 with a short course Methotrexate (on day +1, +3, +6) or Mycophenolate. Mycophenolate was stopped on day +28 and Cyclosporine or Tacrolimus were tapered on day +50.RESULTS.There were no differences in patients' age (49 vs 51), sex or pre-transplantation HCTI-score ≥ 3 (30 vs 26) between PTCY and ATG groups. We found differences between diagnosis (lymphoproliferative disorders (16 vs 4, p= 0.003), high DRI-score (18 vs 11, p = 0.04), number of previous transplantations (12 vs 5, p= 0.02), reduced intensity conditioning regimen (36 vs 20, p < 0.001) and bone marrow as stem cells source (38 vs 9, p < 0.001) between PTCY and ATG groups.The median time to neutrophil engraftment (>500/uL) was similar: 17 days [13-34] for PTCY and 16 days [9-33] for ATG. Median time to platelet recovery was higher in PTCY cohort (33 vs 18 days, p= 0.016). There were 3 secondary graft failures in PTCY group vs 4 graft failures in ATG (3 primary, 1 secondary).The were no differences in grade 2 - 4 aGVHD incidence between groups (PTCY:30.6% vs ATG:36.4%), but we found differences in grades 3 - 4 aGVHD (PTCY:4.1% vs ATG: 9%, p=ns).The global incidence of any NIH grade cGVHD was 56.1% in PTCY vs 66% in ATG group. Mild, moderate and severe cGVHD incidence were 31.7%, 19.5% and 4.8% for PTCY vs 28%, 26% and 12% in ATG (p=ns).The median duration of IS in alive patients with cGVHD was 6.5 months [3-19] in PTCY patients and 10 [3-34] in ATG group. Among moderate and severe forms, the median IS duration was 10 and 5 months in PTCY group vs 13 and 12 months in ATG respectively.PTCY cohort developed more non-infectious complications, especially, cardiac, lung, digestive and neurologic complications, (p=0.086), however there were not differences in infectious complications (Table 1).TRM was similar between groups, 18.4% for PTCY vs 22.5% for ATG, (p=0.250). We didn´t find differences in early toxic mortality (<100 days): 16.3% for PTCY and 14.5% for ATG (p=0,421).With a median follow-up of 27 months in alive patients (28 months for PTCY and 22 months for ATG) we report an 67.8 % and 61% OS at 12 and 24 months for PTCY and 68.8% and 59.9% for ATG (Log Rank=0.971). Relapse free survival at 12 and 24 months was 61% and 57.9% for PTCY and 69% and 54% for ATG (Log Rank=0.839).GRFS at 12 and 24 months was 46.5% and 42.9% for PTCY patients and 40.7% and 33% for ATG patients, (Log Rank = 0.433).CONCLUSIONS.Regardless the different scenarios between transplantation cohorts, the use of PTCY and low dose ATG are equally effective in the prophylaxis of severe forms of aGVHD and cGVHD, offering similar GRFS. PTCY shows higher early toxicity but a similar rate of infectious events. In order to validate these results, it would be necessary to carry out a randomized controlled trial. DisclosuresNo relevant conflicts of interest to declare.

A Phase II Study of Decitabine Followed By Allogeneic Hematopoietic Stem Cell Transplantation in High-Risk Patients with Myeloid Malignancies

Introduction:Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for myelodysplastic syndrome (MDS) and high-risk acute myeloid leukemia (AML). Patients with high-risk disease have a markedly increased risk of relapse and death following transplant (Armand et al, Blood, 2014). Those who remain disease-free are at risk of severe morbidity from graft-versus- host-disease (GvHD). These issues highlight the importance of improved allo-HSCT platforms designed to reduce relapse rate without increasing risk of GvHD. Decitabine has minimal non-hematologic toxicity and proven efficacy in myeloid diseases (Blum et al, PNAS, 2010). Use of post-transplant cyclophosphamide has demonstrated improved rates of GvHD following allo-HSCT using haplo-identical donors (Bashey et al, JCO, 2013). No studies have reported on outcomes in patients undergoing decitabine immediately prior to transplantation followed by post-transplant cyclophosphamide (PTCy). We hypothesized that the combination of decitabine induction prior to transplant and PTCy would be safe and result in improved disease control with low rates of GVHD, translating into improved survival in a high-risk transplant cohort.MethodsIn this single-arm, single institution trial, eligible patients received 10 days of IV decitabine at 20mg/m2 no sooner than 24 days and no later than 17 days prior to conditioning. Myeloablative conditioning included fludarabine (50mg/m2 day-5-2), busulfan (IV 3.2mg/kg/day -5-2), and 4 Gy total body irradiation on day -1. Patients above age 65 received a 25% busulfan dose reduction. Patients received a fully or partially matched related bone marrow graft on day 0. GvHD prophylaxis included 50mg/kg of IV cyclophosphamide on day +3-4. Patients with fully matched donors received only PTCy while those with partially matched donors also received mycophenolate mofetil through day +35 and tacrolimus through day +180.ResultsWe enrolled 20 patients, fifteen patients with AML and 5 with MDS. The cohort had a median age of 64 (29-73) and was predominantly male (14/20, 70%). Eight (40%) patients scored as high risk by the HSCT comorbidity index. Eighteen patients (90%) had a high or very high-risk score by the refined disease risk index.All patients received decitabine and 18/20 (90%) underwent transplantation; 2 patients did not receive a transplant due to infectious complications. The majority of patients received a haplo-identical graft (13/18, 72%), and the remaining 5 received a matched related graft.Outcomes are reported in table 2 and figure 1. There were no engraftment failures. Five patients, 3 MDS and 2 AML, are long-term survivors with median follow-up over 3 years. One patient developed donor derived MDS and required a second transplant. Most transplanted patients (13/18, 72%) survived to day 100 with a median post-transplant survival of 138 days. There were 15 deaths on study with the majority due to underlying disease. Six patients (6/20, 30%) died of infectious complications or did not receive a transplant due to infection. Incidence of grade 3-4 acute GvHD was low among those surviving at least 40 days from transplant (3/17, 17%). There were also low rates of chronic GvHD among the 12 patients alive without ongoing GvHD at day 100 (2/12, 17%).ConclusionsDecitabine induction followed by myeloablative conditioning in this high-risk population resulted in a high treatment related mortality of 40%. Still, outcomes fell into an expected range for high-risk myeloid disease in an elderly and comorbid population. Based on expected outcomes for high-risk patients from the literature (Armand et al, Blood, 2014), decitabine did not markedly improve overall survival outcomes, recognizing that no direct comparisons are available in our limited study population. Decitabine may increase the risk of peri-transplant infections by contributing to a cumulative immunologic insult combined with disease-related immunosuppression and transplant-related toxicity, highlighting the importance of strict vigilance for infections within this setting. Diligent monitoring may improve infectious outcomes as shown in the second half of the cohort; only two out of the latter 10 patients on protocol died of treatment related complications. There were no cases of engraftment failure. Rates of acute and chronic GvHD using a PTCy platform were low and support other studies reporting this benefit. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

1134. Novel T2Candida Panel Assay Compared With Blood Cultures for Detection of Candidemia in Transplant and Non-Transplant Patients

BackgroundBlood culture (BC) the current “gold” standard for detection of candidemia has a sensitivity of ~50% and turnaround time (TAT) of 2–5 days. T2Candida Panel (T2) a magnetic resonance nano-diagnostic test done directly on blood samples detects C. albicans/C. tropicalis, C. krusei/C. glabrata, and C. parapsilosis. Clinical trials of T2 showed good sensitivity, specificity, NPV 99% and TAT of 3–5 hours. The performance of T2 in high-risk transplant (Tx) population is unknown. T2 was implemented at our institution in October 2015. We evaluated the performance characteristics of T2 and BC in our Tx and non-transplant (non-Tx) patient populations.MethodsThis was an observational, retrospective, cross-sectional evaluation of patients with suspected candidemia that had T2 done from October 2015 to October 2017 at a multihospital healthcare system in Detroit, MI. Performance characteristics of the T2 and BC in Tx and non-Tx patients were compared. BC obtained within 7 days before or after the T2 test were included in the analysis. TAT, sensitivity, specificity, PPV and NPV were calculated using positive BC as the standard. Differences between groups were assessed using two sample proportions testing at α = 0.05.ResultsA total of 1,272 patients with suspected candidemia had T2 done: 1,162 (91%) non-Tx and 110 (9%) Tx patients. Average TAT for T2 was 13 hours (5–41) vs. 34 hours (21–109) to initial positive BC result and 4 days (3–13) to species-specific BC result. In four non-Tx patients with negative T2, C. lusitaniae, C. dubliniensis, and C. kefyr were isolated in BC. Performance characteristics of T2 and BC in the two groups is shown (Table 1). Of the T2+/BC− cases (n = 102), 9% had retinitis and 9% had invasive candidiasis.ConclusionThe rapid TAT, good sensitivity, and high NPV of T2 in Tx patients has clinical implications and can help support antifungal stewardship efforts in this population. The clinical significance of T2 positivity in the presence of negative BC needs further investigation.Table1: Performance Characteristics of T2 Compared with BC (N = 1,272)Tx (n = 110)Non-Tx (n = 1162) P-valueT2 + and blood culture +5 (4.5%)35 (3.01%)0.3917T2 + and blood culture −19 (17.3%)86 (7.4%)0.0003T2 - and blood culture +1 (0.9%)41 (3.5%)0.1431Sensitivity83.3%46.1%Specificity81.9%92.4%PPV20.8%28.9%NPV98.8%96.2%Disclosures G. Alangaden, T2 Biosystems: Speaker’s Bureau, Educational grant and Speaker honorarium.

1564. Lower Rates of Epstein–Barr Virus (EBV) Viremia in Pediatric Solid Organ Transplant (SOT) Recipients Who Received Valganciclovir Prophylaxis

BackgroundAntiviral prophylaxis to prevent PTLD remains controversial, but some data suggest that valganciclovir or ganciclovir ([val]ganciclovir) use in EBV high-risk pediatric renal transplants reduces EBV viremia. We evaluated the impact of [val]ganciclovir on EBV viremia and post-transplant lymphoproliferative disease (PTLD) in pediatric nonrenal SOT recipients.MethodsRetrospective study of 100 patients who underwent a first heart, liver, lung, intestine, or multivisceral SOT between November 2013 and November 2016 at Boston Children’s Hospital who survived without re-transplantation for at least 30 days. Data collected included EBV donor/recipient serostatus, donor’s age >2 years-old (to avoid misclassification of EBV risk due to maternal antibody), antiviral use ([val]ganciclovir or acyclovir), time to EBV viremia (>1,000 copies/mL by whole blood PCR), and time to development of PTLD. EBV high-risk patients were those with donor EBV positive [D+]/recipient EBV negative [R–] serologies; intermediate-risk were EBV R+; low risk were EBV D–/R–. Time-to-event analysis using the Kaplan–Meier method was performed and significance (P = 0.05) was evaluated using the log-rank test.ResultsHigh (n = 45) or intermediate (n = 27) EBV risk was associated with increased EBV viremia (P = 0.007, table). EBV viremia was significantly decreased in the subgroup of high-risk patients with donors >2 years old who received [val]ganciclovir vs. those who received no antiviral (n = 23, n = 4, P = 0.03, Figure 1). Most PTLD cases (8/9) occurred in the high-risk group (P = 0.03, Figure 2). Overall, patients who received [val]ganciclovir had less PTLD than those who did not (P = 0.03), but this was not significant in the high-risk subgroup (P = 0.14, Figure 3).ConclusionLower rates of EBV viremia occurred in high EBV risk transplant recipients who received [val]ganciclovir, possibly by preventing primary EBV infection. Recipients with high EBV risk have the highest rate of PTLD.cases=100EBV RiskOutcomeOrganUnknownLowIntermediateHighViremiaPTLDHeart581320185Liver11101862Lung114462Intestine10Multivisceral11Dual organ31Total7212745439AntiviralNo Antiviral6652Acyclovir213873[Val]ganciclovir5132431314OutcomeViremia2214259PTLD189 Disclosures F. M. Marty, Merck: Consultant and Investigator, Consulting fee, Research support and Speaker honorarium; Astellas: Consultant and Investigator, Consulting fee and Research support; Chimerix: Consultant and Investigator, Consulting fee and Research support; Fate Therapeutics: Consultant, Consulting fee; GlaxoSmithKline: Consultant, Consulting fee; LFB: Consultant, Consulting fee; Roche Molecular Diagnostics: Consultant, Consulting fee; Shire: Consultant and Investigator, Consulting fee and Research support.

Third-Party Allogeneic Mesenchymal Stromal Cells Prevent Rejection in a Pre-sensitized High-Risk Model of Corneal Transplantation

High-risk cornea transplant recipients represent a patient population with significant un-met medical need for more effective therapies to prevent immunological graft rejection due to heightened anti-donor immune response. In this study, a rat model of pre-existing anti-donor immunity was developed in which corneal allografts were rejected earlier than in non-pre-sensitized recipients. In this model, third-party (non-donor, non-recipient strain) allogeneic mesenchymal stromal cells (allo-MSC) were administered intravenously 7 and 1 days prior to transplantation. Rejection-free graft survival to 30 days post-transplant improved from 0 to 63.6% in MSC-treated compared to vehicle-treated control animals (p = < 0.0001). Pre-sensitized animals that received third-party allo-MSC prior to transplantation had significantly higher proportions of CD45+CD11b+ B220+ monocytes in the lungs 24 h after the second MSC injection and significantly higher proportions of CD4+ FoxP3+ regulatory T cells in the graft-draining lymph nodes at the average day of rejection of control animals. In in vitro experiments, third-party allo-MSC polarized primary lung-derived CD11b/c+ myeloid cells to a more anti-inflammatory phenotype, as determined by cytokine profile and conferred them with the capacity to suppress T cell activation via prostaglandin E2 and TGFβ1. In experiments designed to further validate the clinical potential of the protocol, thawed cryopreserved, third-party allo-MSC were shown to be similarly potent at prolonging rejection-free corneal allograft survival as their freshly-cultured counterparts in the pre-sensitized high-risk model. Furthermore, thawed cryopreserved third-party allo-MSC could be co-administered with mycophenolate mofetil without adversely affecting their immunomodulatory function. In conclusion, a clinically-relevant protocol consisting of two intravenous infusions of third-party allo-MSC during the week prior to transplantation, exerts a potent anti-rejection effect in a pre-sensitized rat model of high-risk corneal allo-transplantation. This immune regulatory effect is likely to be mediated in the immediate post-transplant period through the promotion, by allo-MSC, of alternatively-activated macrophages in the lung and, later, by enhanced regulatory T-cell numbers.

Usefulness of the preoperative prognostic nutritional index score as a predictor of the outcomes of lung transplantation: A single-institution experience

There is increasing evidence that preoperative nutritional status is a predictor of disease severity and mortality after lung transplantation (LTX). This study aimed to evaluate preoperative nutritional assessment as a predictor of LTX outcomes. We included 132 patients who underwent single or double LTX at Severance Hospital, Yonsei University, between October 2010 and April 2016. The Prognostic Nutritional Index (PNI) scores were calculated as follows: 10 × serum albumin value (g/dL)+0.005 × peripheral lymphocyte count (/mm3). The optimal cut-off PNI score for the prediction of postoperative overall survival was set at 41.15 using receiver operating characteristics analysis. The efficacies of PNI and other clinical factors in predicting LTX outcomes were determined using univariate and multivariate Cox proportional hazard analyses. Patients with PNI <41.15 (PNI-low group) were older, had higher preoperative C-reactive protein levels, and had lower nutritional status scores than did those in the PNI-high group (PNI≥41.15). Based on Kaplan-Meier analysis, the overall survival rate was significantly better in the PNI-high group (78.3%) than in the PNI-low group (28.6%) (P<0.001). Age, sex, body mass index, use of preoperative mechanical ventilation, C-reactive protein level, neutrophil-to-lymphocyte ratio, and PNI score were independent prognostic factors. Survival was significantly higher in the PNI-high group (hazard ratio: 0.220; P<0.001) than in the PNI-low group, and incidence of complications≥grade IV was higher in the PNI-low group than in the PNI-high group (P<0.001). Multivariate regression analysis showed that preoperative PNI score was significantly associated with postoperative survival, even after adjusting for other confounding factors. Our findings suggest that PNI is a useful prognostic marker for the identification of high-risk lung transplant recipients. Preoperative nutritional assessment using PNI may provide useful information for reducing postoperative morbidity and mortality.

Understanding the Fontan Procedure in Congenital Heart Disease Patients and the Importance of Early Hepatology Referrals: A Case Study.

Patients with congenital heart disease are surviving into adulthood because of new surgeries developed over the recent decades. One surgery is the Fontan procedure, which is used in patients with only one functioning ventricle. Although it has been saving lives, in the recent years multiple complications have been noted. To discuss the Fontan procedure and inform nurse practitioners in the primary care setting the importance of early screening and referral because of increasing number of liver complications in these patients. This case study highlights the dilemmas a patient with the Fontan procedure faces as a young adult. Evidence-based articles from the PubMed and Embase databases were used to support the case study. Patients with the low-pressure Fontan circulation are under chronic passive congestion and have known liver complications such as liver fibrosis, cirrhosis, and protein-losing enteropathy. This can lead to a high-risk dual organ heart-liver transplant. Early screening and referral to a hepatologist are critical in these patients. Since patients with congenital heart disease often present to the primary care setting, nurse practitioners in this area should understand the Fontan procedure and its associated complications so they can effectively manage these patients.

Organ transplant recipients express enhanced skin autofluorescence and pigmentation at skin cancer sites

BackgroundSkin autofluorescence and pigmentation can estimate photodamage and sun exposure. These techniques may quantify differences in actinic damage between high-risk organ transplant recipients (OTRs) and immunocompetent patients. MethodsAge and gender-matched OTRs (n = 15) and immunocompetent controls (n = 15) with a new keratinocyte carcinoma (KC) were included. We measured skin autofluorescence (370 nm excitation, F370) and skin pigmentation at five standardized body sites; and determined black light-evaluated solar lentigines on the shoulders and photosensitivity to UVA and simulated solar radiation (SSR) as minimal erythema doses (MED). ResultsF370 autofluorescence values were enhanced at KC site versus other body sites in OTRs (2208 vs. 1458–1898 AU, p < 0.05). Compared with non-OTRs, OTRs expressed higher F370 autofluorescence at KC site (2208 vs. 1385 arbitrary units AU, p = 0.01) and the shoulder (1898 vs. 1525, p = 0.05). Likewise, OTRs had increased skin pigmentation (25.0 vs. 20.8 pigment%, p = 0.05) and solar lentigines (3.5 vs. 3.0, p = 0.048) on the shoulders. MED tests showed increased UVA photosensitivity in OTRs (2.4 vs. 1.7 times higher than expected, p = 0.03), whereas SSR photosensitivity was similar. ConclusionQuantified F370 autofluorescence, skin pigmentation, and density of solar lentigines could serve to assess photodamage in OTR. Increased UVA photosensitivity may account for higher skin photodamage.

Invited Commentary

Models of posttransplant mortality are common. They are used frequently: for prognostic information for providers and families, benchmarking of individual center results, and public reporting of those results. Each model or score has strengths and weaknesses that are predominantly determined by the data source and the methodology. The score presented in this issue of The Annals of Thoracic Surgery by O’Connor and colleagues [1O'Connor M.J. Glatz A.C. Rossano J.W. et al.Cumulative effect of preoperative risk factors on mortality after pediatric heart transplantation.Ann Thorac Surg. 2018; 106: 561-567Abstract Full Text Full Text PDF Scopus (6) Google Scholar] is paradigmatic of both the potential and the limitations of a single-center retrospective study. By identifying a series of risk factors unavailable to larger datasets, it demonstrates how the use of large dataset models of posttransplant mortality has the potential to dissuade centers from transplanting high-risk pediatric patients. Most prior models and scores predicting posttransplant mortality in children have been developed using large datasets, commonly either the Pediatric Heart Transplant Study or the Organ Procurement and Transplantation Network/United Network for Organ Sharing data [2Almond C.S. Gauvreau K. Canter C.E. Rajagopal S.K. Piercey G.E. Singh T.P. A risk-prediction model for in-hospital mortality after heart transplantation in US children.Am J Transplant. 2012; 12: 1240-1248Crossref PubMed Scopus (66) Google Scholar, 3Schumacher K.R. Almond C. Singh T.P. et al.Predicting graft loss by 1 year in pediatric heart transplantation candidates: an analysis of the Pediatric Heart Transplant Study database.Circulation. 2015; 131: 890-898Crossref PubMed Scopus (49) Google Scholar, 4Davies R.R. Russo M.J. Mital S. et al.Predicting survival among high-risk pediatric cardiac transplant recipients: an analysis of the United Network for Organ Sharing database.J Thorac Cardiovasc Surg. 2008; 135 (155.e1–2): 147-155Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar]. Organ Procurement and Transplantation Network/United Network for Organ Sharing data underlie the risk prediction models utilized by the Scientific Registry of Transplant Recipients to develop the publicly available program-specific reports (PSRs) evaluating individual center performance. These large-dataset models have the advantage of large sample sizes from multiple centers, but often lack relevant clinical information. Using a single-center retrospective analysis, O’Connor and colleagues [1O'Connor M.J. Glatz A.C. Rossano J.W. et al.Cumulative effect of preoperative risk factors on mortality after pediatric heart transplantation.Ann Thorac Surg. 2018; 106: 561-567Abstract Full Text Full Text PDF Scopus (6) Google Scholar] have identified several risk factors for posttransplant mortality that are not available in larger datasets, including single ventricle congenital heart disease, pulmonary vein stenosis, a history of greater than or equal to 4 prior sternotomies, and referral from another cardiac surgical center. Unfortunately, the methodology limits the practical applicability of the resultant score: the score is unvalidated, it suffers from the biases of the center (eg, there was only a single patient with renal insufficiency), and the increase in mortality occurred predominantly among patients with 4 or 5 risk factors (78% versus 7% to 14% in those with 0 to 3 risk factors). As the authors note, further study and validation of the score is required. However, the inclusion of these granular and specific clinical risk factors does point to the limitations of the current system of public reporting and program monitoring. Accurate models require accounting for all relevant risk models. The Scientific Registry of Transplant Recipients models used in generating PSRs fail to account for many factors that this study and others suggest are associated with high post-transplant mortality: pulmonary vein stenosis, specific congenital diagnoses, a high number of prior sternotomies, and other anatomic abnormalities. When PSRs and similar modeling are used for public reporting, regulatory oversight, and insurance contracting, centers become incentivized to avoid transplanting candidates whose risk factors are not accounted for in the modeling. Thus, while the specific score developed by O’Connor and colleagues [1O'Connor M.J. Glatz A.C. Rossano J.W. et al.Cumulative effect of preoperative risk factors on mortality after pediatric heart transplantation.Ann Thorac Surg. 2018; 106: 561-567Abstract Full Text Full Text PDF Scopus (6) Google Scholar] may have limited wider applicability, the identification of these granular risk factors and their inclusion in modeling is critical both to maximizing individual outcomes and to maintaining access to transplantation among high-risk patients. Cumulative Effect of Preoperative Risk Factors on Mortality After Pediatric Heart TransplantationThe Annals of Thoracic SurgeryVol. 106Issue 2PreviewRisk assessment in heart transplantation is critical for candidate selection, but current models inadequately assess individual risk of postoperative mortality. We sought to identify risk factors and develop a scoring system to predict mortality after heart transplantation in children. Full-Text PDF

Abstract 2377: Design, synthesis, and characterization of 4-aminopyrazole quinazolines as potent inhibitors of G protein-coupled receptor kinase GRK6 for the potential treatment of multiple myeloma

Abstract Multiple myeloma (MM) is one of the most common hematological malignancies, but current therapeutic options are limited to high-dose chemotherapy or high-risk stem-cell transplantation. In a kinome-wide RNAi study by Tiedemann and colleagues (2010), the G-protein coupled receptor kinase GRK6 was identified as a critical kinase required for survival of MM cells. This study also suggests that MM cells, but not other cell types, are dependent on GRK6; and that gene silencing by shRNA or siRNA of GRK6, but not other members of the GRK family, results in decreased survival. Through gene silencing techniques, we determined that a functional GRK6 kinase domain is required for survival of MM cells. These findings helped validate that the kinase domain of GRK6 is a promising target for MM, and therefore encouraged us to embark on an effort to identify potent small molecule kinase inhibitors of GRK6. Toward that end, by screening a focused kinase-directed library of small molecule inhibitors, compounds with moderate potency against GRK6 in biochemical assays were identified. Through this exercise, we discovered that two structurally distinct aminopyrazoles AZ-960 and ASC-082 had modest inhibition of GRK6. By combining structural features of these hits and further optimization we identified the quinazoline analogue OICR9945, a potent GRK6 inhibitor with good selectivity against a panel of diverse kinases and anti-proliferative activity against MM cell lines. Herein, we describe the design, synthesis and early pharmacological characterization of OICR9945 along with structure activity relationships (SAR) of this series against GRK6 and other kinases. Citation Format: David Uehling, Babu Joseph, Carly Griffin, Ratheesh Subramaniam, Ayome Abibi, Richard Marcellus, Michael Prakesch, Gennadiy Poda, Methvin Isaac, Chungyee Leung-Hagesteijn, Rodger Tiedemann, Rima Al-awar. Design, synthesis, and characterization of 4-aminopyrazole quinazolines as potent inhibitors of G protein-coupled receptor kinase GRK6 for the potential treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2377.

Sa1515 - High-Risk Non-Alcoholic Steatohepatitis Liver Transplant Candidates have Inferior Post-Transplantation Survival and Greater Waiting-List Mortality

Sa1515 - High-Risk Non-Alcoholic Steatohepatitis Liver Transplant Candidates have Inferior Post-Transplantation Survival and Greater Waiting-List Mortality

Tu1470 - Reducing Hospital Readmissions: Screening and Referral of High-Risk Liver Transplant Patients to a Transitional Care Coordination(TCC) Program

Tu1470 - Reducing Hospital Readmissions: Screening and Referral of High-Risk Liver Transplant Patients to a Transitional Care Coordination(TCC) Program

Editorial introductions

Editorial introductions

HEART TRANSPLANTATION IN DIABETIC RECIPIENTS

Diabetes mellitus is one of the most prevalent chronic metabolic disorders. Its role in patients with heart transplantation is not unifi ed. According to some authors, post-transplantation diabetes mellitus increases the risk of acute rejections and infections, increases the incidence of coronary artery disease of the graft and reduces long-term survival of patients with heart transplantation. On the other hand other studies did not confi rm these fi ndings. However, when diabetic patients were stratifi ed by disease severity, recipients with less severe disease achieved better survival. Accordingly, posttransplant survival was not signifi cantly different between recipients with uncomplicated diabetes and nondiabetic recipients. Diabetes alone should not be a contraindication to heart transplantation. Well-selected diabetic patients achieve the same survival as nondiabetic patients. Conversely, patients with complicated diabetes have signifi cantly worse survival. Therefore, given the critical shortage of transplantable organs, maximal benefi t may be achieved by exploring alternative treatment options in individuals with severe diabetes. These include use of high-risk transplant lists and destination therapy.

Complications in pediatric intestine transplantation in the absence of peri‐operative donor or recipient bowel decontamination

This study reports the clinical complication and infection rates of an active pediatric IT program that has never utilized bowel decontamination in either the donor or the recipient. All patients undergoing IT from 2003 to 2015 at a single pediatric IT center were reviewed. Post-transplant surgical, infectious, and immunosuppressive complications are reported. There were 52 patients who underwent IT during the study period. Among these patients, 4% developed a postoperative abscess, one developed an enteric fistula (2%), and one had an enteric or anastomotic leak (2%). The rate of any bacterial infection was 90% in the first year, with a wound infection rate of 23%. Any fungal infection occurred in 25% of patients. Any viral infection occurred in 75% of patients. Gastrointestinal viruses were diagnosed in 52% of patients, and cytomegalovirus infections occurred in 17%. Rejection rates were 39% at any time post-transplant (isolated 44% and 35% for multivisceral patients). At this center in which no bowel decontamination was used, rates of surgical complications, infections, and rejection were similar to those reported by other centers. These findings suggest bowel decontamination may provide no significant benefit in this population of high-risk transplant patients.

Chemoprevention of Skin Carcinomas in High-Risk Transplant Recipients.

Long-term immunosuppressive therapy, as provided to solid organ transplant recipients, inevitably results in a significant inhibition of immune defenses; this leads to frequent skin infections and malignancies, which represent an important cause of morbidity and mortality for transplanted patients. The incidence and risk of skin carcinomas are elevated in solid organ transplant recipients in comparison with the general population, with a 10-fold increased risk for basal cell carcinoma and a 50-100-fold for squamous cell carcinoma. The schedule of immunosuppressive drugs influences the type and timing of skin malignancies, but a crucial role is also played by endogenous and exogenous risk factors. Here, we will review the state-of-the-art in chemoprevention of epidermal carcinomas in order to provide useful information for clinicians involved in the management of transplant recipients. One-hundred and forteen paper, published on peerreviewed journals, has been included. Chemoprevention would be key in controlling skin carcinogenesis in high-risk patients.

414 - Prevention of Veno-Occlusive Disease (VOD) with Defibrotide in High-Risk Pediatric Hematopoietic Stem Cell Transplant Patients

414 - Prevention of Veno-Occlusive Disease (VOD) with Defibrotide in High-Risk Pediatric Hematopoietic Stem Cell Transplant Patients

Aquaporin 4 blockade improves survival of murine heart allografts subjected to prolonged cold ischemia.

Prolonged cold ischemia storage (CIS) is a leading risk factor for poor transplant outcome. Existing strategies strive to minimize ischemia-reperfusion injury in transplanted organs, yet there is a need for novel approaches to improve outcomes of marginal allografts and expand the pool of donor organs suitable for transplantation. Aquaporins (AQPs) are a family of water channels that facilitate homeostasis, tissue injury, and inflammation. We tested whether inhibition of AQP4 improves the survival of fully MHC-mismatched murine cardiac allografts subjected to 8hours of CIS. Administration of a small molecule AQP4 inhibitor during donor heart collection and storage and for a short-time posttransplantation improves the viability of donor graft cells, diminishes donor-reactive T cell responses, and extends allograft survival in the absence of other immunosuppression. Furthermore, AQP4 inhibition is synergistic with cytotoxic T lymphocyte-associated antigen 4-Ig in prolonging survival of 8-hour CIS heart allografts. AQP4 blockade markedly reduced T cell proliferation and cytokine production in vitro, suggesting that the improved graft survival is at least in part mediated through direct effects on donor-reactive T cells. These results identify AQPs as a promising target for diminishing donor-specific alloreactivity and improving the survival of high-risk organ transplants.

Impact of CYP3A5 genomic variances on clinical outcomes among African American kidney transplant recipients.

Little is known about the impact of CYP3A5 polymorphisms on transplantation outcomes among African American (AA) kidney transplant recipients (KTRs). To assess this issue, clinical outcomes were compared between AA CYP3A5*1 expressers and nonexpressers. This retrospective cohort study analyzed AA KTRs. Biopsy-proven acute rejection (BPAR), delayed graft function (DGF), glomerular filtration rate (GFR), infections, and tacrolimus dosing requirements were examined in 106 immunologically high-risk AA kidney transplant patients over a 2-year follow-up period. In CYP3A5*1 expressers compared to nonexpressers, the incidence of BPAR was significantly higher in the first 6months (13% vs 0%; P=.016) compared to 24months (13% vs 7%; P=.521). Tacrolimus total daily dose at first therapeutic level was significantly higher in CYP3A5*1 expressers (12mg/day) compared to nonexpressers (8mg/day; P<.001). Compared to CYP3A5*1 nonexpressers, DGF incidence was significantly higher among CYP3A5*1 expressers (27.6% vs 6.7%; P=.006). By contrast, median GFR was significantly higher in CYP3A5*1 expressers compared to nonexpressers (54.5mL/min vs 50.0mL/min; P=.003) at 24months. The findings from this retrospective study suggest that AAs with CYP3A5*1 expression require 50% more tacrolimus and have an increased incidence of DGF and acute rejection.

Orthotopic Kidney Transplantation in an Elderly Patient With Various Severe Comorbid Conditions: A Case Report

In recent years, the frequency of high-risk kidney transplantations has increased. We report a case in which a 72-year-old man with various severe comorbidities (prostate cancer, diabetes mellitus, complete atrioventricular block, coronary artery stenosis, severe stenosis of the popliteal arteries, and severe calcification of the iliac arteries) who received an orthotopic kidney transplantation. To prevent the occurrence of acute limb ischemia due to the steal phenomenon (caused by the kidney graft), we decided that a heterotopic kidney transplantation involving the iliac arteries was not an appropriate option. Therefore, as an alternative, left native nephrectomy was performed followed by an orthotopic kidney transplantation to the native renal artery and renal vein through a left subcostal incision. Postoperative ureteral stenosis occurred, and so stent exchange was required every 6 months. Despite the ureteral complication, the patient's serum creatinine level was 1.5 mg/dL at 2 years after the procedure.