The tRNA(Ile) variant m.4309G>A may not cause Kearns Sayre syndrome No abstract available

EXPERIENCE WITH EARLY SORAFENIB TREATMENT WITH mTOR INHIBITORS IN HEPATOCELLULAR CARCINOMA RECURRING AFTER LIVER TRANSPLANTATION Background: Sorafenib (SOR) is currently used for hepatocellular carcinoma (HCC) recurring after liver transplantation (LT) when HCC is unsuitable for surgical/locoregional treatments. We evaluated safety and effectiveness of early introduction of SOR after HCC-recurrence. Methods: All patients with HCC-recurrence after LT treated with SOR in 2 centers were included (01/2008-06/2018). Baseline and on-treatment data were collected. Results: Fifty patients early treated with SOR for HCC-recurrence after LT (74% mammalian target of rapamycin inhibitor (mTORi), 54% HCC-treated at baseline) were enrolled. During 7.3 (0.3-88) months of SOR, all patients had at least one adverse event (AE), 56% graded 3-4. SOR was reduced in 68%, being AEs the main cause of reduction, and discontinued in 84% (60% symptomatic progression, 33% AE). Objective response was obtained in 16% and stable disease in 50%. Median time to radiological progression was 6 months (95% Confidence Interval [CI] 4-8). Thirty-three patients (69%) died, 94% for HCC progression. Median overall survival (OS) was 18 months (95%CI 8-27); 5-year OS was 18% (95%CI 4-32%). Baseline predictors of OS were SOR+mTORi (HR 0.4, 95%CI 0.2-0.9, p=0.04), previous curative treatments (HR 0.3, 95%CI 0.2-0.7, p=0.003) and alpha-fetoprotein>100ng/ml (HR 2.5, 95%CI 1.1-5.0, p=0.02). At multivariate analysis, HCC curative treatment was the only independent predictor (HR 0.4, 95%CI 0.2-1.0, p=0.04). Conclusions: Early and combined treatment with sorafenib and mTORi resulted in a favourable safety profile, while its effectiveness should be confirmed by meta-analysis of previous studies or by larger studies. Curative treatment for HCC resulted the only independent predictor of OS. Disclosures: Invernizzi F, speaker bureau for Abbvie; Iavarone M, speaker bureau for Bayer, Gilead Science, Janssen, BTG, Abbvie, MSD, consultant for BTG and Bayer; Donato MF, speaker bureau for BMS, Abbvie, MSD; Lampertico P, advisor and speaker bureau for Gilead, Roche, BMS, GSK, MSD, Arrowhead, Alnylam. The other authors have nothing to disclose. Funding: no financial support to be reported. Corresponding author: Massimo Iavarone, MD PhD, 1CRC “A. M. and A. Migliavacca” Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Via F. Sforza 28, 20122 Milan, Italy. Tel 39-0255035432, Fax 39-0250320410, E-mail massimo.iavarone@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Clinical relevance of arteriolar C4d staining in patients with chronic-active antibody-mediated rejection: A pilot study Introduction: C4d staining in peritubular capillaries (PTCs) is a well-established feature of antibody-mediated rejection (AMR). The relevance of C4d staining outside PTCs is not well understood. We investigated the significance of arteriolar C4d staining in c-aAMR. Methods: All for-cause renal allograft biopsies performed in 2007-2014 at the Erasmus MC and meeting the criteria for suspicious/diagnostic c-aAMR using the Banff Classification 2015, were included. For comparison, renal allograft biopsies from a matched control group and native renal biopsies were analyzed. Arteriolar C4d staining was semi-quantitatively scored as negative (0), small deposits in 1 arteriole (1+), small/large deposits in >1 arterioles (2+) or at least extensive deposits in most arterioles (3+). Results: Thirty-four of 40 (85%) patients with c-aAMR showed arteriolar C4d staining. A significant difference in arteriolar C4d score was observed between cases and matched controls (p=0.01) and a trend toward significance difference between cases and native renal biopsies (p=0.05). In the cases, arteriolar C4d staining was significantly associated with severity of arteriolar hyalinosis (ah) (p=0.004) and ≥2 arteriolar C4d staining was independently associated with better graft outcome in a multivariate Cox regression analysis (hazard ratio 0.260, 95%-Cl: 0.104-0.650, p=0.004). Conclusion: This pilot study shows that arteriolar C4d staining is more common in biopsies with c-aAMR compared to those without and that it is associated with ah. ≥2 arteriolar C4d staining is associated with superior graft outcome. However, larger studies are needed to examine these findings in more detail to asses if arteriolar C4d staining is truly related to antibody-mediated injury. Conflicts of interest: D.A. Hesselink has received lecture and consulting fees from Astellas Pharma and Chiesi Farmaceutici S.p.A., as well as grant support from Astellas Pharma, Bristol Myers-Squibb and Chiesi Farmaceutici S.p.A. (paid to the Erasmus MC). M.C. Clahsen-van Groningen received grant support from from Astellas Pharma (paid to the Erasmus MC). The other authors declare no conflicts of interest. Corresponding author: Malou L. H. Snijders, M.D., Dept. of Pathology, Room Be-230a, Erasmus MC, P.O. Box 2040, 3000 CA. Rotterdam, The Netherlands. Email: m.snijders@erasmusmc.nl Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Impact of donor hepatitis C virus on kidney transplant outcomes for hepatitis C positive recipients in the direct acting antiviral era: time to revise the kidney donor risk index? Introduction: Kidneys from donors with hepatitis C (HCV) infection are traditionally considered to be at risk for poorer survival outcomes, as reflected in the KDPI. Modern direct acting antivirals (DAAs) may modify this risk. Methods: Using UNOS data, HCV infected adult first time kidney transplant recipients from 2014-2017 were examined. Graft and patient survival were compared in a propensity matched cohort of recipients of HCV antibody(+) kidneys versus antibody(-) kidneys. Subsequent analysis was performed in a propensity matched cohort of recipients of HCV viremic (RNA positive) vs. HCV naive kidneys. Results: There were 379 recipients each in the matched cohort of recipients of HCV antibody(+) vs. HCV antibody(-) kidneys. Despite a higher KDPI (58.2% for HCV antibody(+) vs. 38.8% for HCV antibody(-)), 1 year patient and graft survival were similar in the HCV(+) and HCV(-) groups (95.4% and 94.9% vs 97.9% and 96.0%, p=0.543 and p=0.834, respectively). There were 200 recipients each in the cohort of recipients of HCV viremic vs. HCV naïve kidneys, with the KDPI again higher in the HCV viremic group (56.8% vs 35.2%). Baseline hazard ratios for graft failure (HR 4.69; p=0.009) and death (HR 7.60; p=0.003) were significantly elevated in the viremic group, but crossed 1 at 21 and 24 months, respectively. Conclusions: In the modern DAA era, calculated likely KDPI overestimates risk kidneys from HCV antibody(+) donors. Donor viremia conveys an early risk which appears to subside over time. These results suggest that it may be time to revise the kidney donor risk index. The authors have no conflicts of interest to declare, and there are no sources of funding to report. This work was presented at the 2019 American Transplant Congress, June 2, 2019, Boston MA. Corresponding Author: Robert M. Cannon, MD, 701 19th Street South, LHRB 748, Birmingham, AL 35294, Phone: 205-996-4249, rmcannon@uabmc.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Response to: The: tRNA(Ile: ) variant m.4309G>A may not cause Kearns Sayre syndrome No abstract available

A Comprehensive Review of Outcome Predictors in Low MELD Patients Risk scoring for patients with cirrhosis has evolved greatly over the last several decades. However, patients with low Model for End Stage Liver Disease – Sodium (MELD-Na) scores still suffer from liver-related morbidity and mortality. Unfortunately, it is not clear which of these low MELD-Na score patients would benefit from earlier consideration of liver transplantation. This paper reviews the literature of risk prediction in patients with cirrhosis, identifies which patients may benefit from earlier interventions such as transplantation, and proposes directions for future research. This manuscript has been reviewed and endorsed by the American Society of Transplantation Liver and Intestinal Community of Practice Disclosure: “The authors declare no conflicts of interest.” Funding: Dr. Mazumder is supported by an NIH T32 grant DK077662. Corresponding Author: Josh Levitsky, MD, MS, FAASLD, FAST, Professor of Medicine & Surgery, Program Director, Gastroenterology & Transplant Hepatology Fellowships, Director of Liver Research, Division of Gastroenterology & Hepatology, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, 676 N. St. Clair St., 19th Floor (19-045), Chicago, Illinois 60611, 312.926.9688 office, Josh.Levitsky@nm.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Executive Functioning in Pediatric Solid Organ Transplant Recipients: A Meta-Analytic Review Background: Examining executive functioning (EF) post-transplant has become increasingly prevalent, as EF deficits are associated with poor disease-related outcomes and psychosocial functioning. The purpose of the current meta-analysis was to compare overall and domain-specific EF between healthy youth and those with a kidney, heart, or liver transplant, and identify moderating variables related to EF differences between these two groups. Methods: A literature search of PsycINFO, Pubmed, and Medline was conducted for eligible articles published until January 2019. Twenty studies met eligibility criteria and were included in the present meta-analysis. Results: Results from the random effects model indicated a significant standardized mean difference in overall EF skills with transplant recipients demonstrating worse EF (g = .40, 95% CI = .29, .50) than healthy youth. Specifically, transplanted youth had worse working memory (g = .33, 95% CI = .01, .66), processing speed (g = .41, 95% CI = .19, .62), attentional control (g = .53, 95% CI = .33, .73), and metacognitive skills (g = .36, 95% CI = .18, .54). Assessment type and time since transplantation were not significant moderators. Conclusions: Pediatric solid organ transplant recipients demonstrate worse overall EF skills and deficits in working memory, processing speed, attentional control, and metacognitive skills. Many children who have undergone solid organ transplantation will require additional support in medical and academic settings due to deficits in various EF domains. Conflict of Interest: The authors declare no conflicts of interest. Funding Source: No funding was secured for this study. Address Correspondence to: Grace Cushman, Department of Psychology, University of Georgia, 125 Baldwin Street, Athens, GA 30602, gcushman@uga.edu. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

ITS finally here! The first International Transplant Science meeting jointly organized by AST, ESOT and TTS No abstract available

Ten Years of Kidney Paired Donation at Mayo Clinic: The Benefits of Incorporating ABO/HLA Compatible Pairs Background: We examined the 10 year experience of Mayo Clinic’s kidney paired donation (KPD).We aimed to determine the benefits for the recipients of enrolled ABO/HLA compatible pairs and determine the factors associated with prolonged KPD waiting time. Methods: We performed a retrospective study of 332 kidney transplants facilitated by the Mayo 3-site KPD program from 9/2007- 6/2018. Results: The median (IQR) time from KPD entry to transplantation was 89(42-187) days. The factors independently associated with receiving a transplant > 3 months after KPD entry included recipient blood type O and cPRA (calculated panel reactive antibodies) ≥ 98%. Fifty-four ABO/HLA compatible pairs participated in KPD for the following reasons: CMV mismatch [18.5 %(10/54)], EBV mismatch (EBV) [9.3 %(5/54)], age/size mismatch [51.9 %(28/54)] or altruistic reasons [20.3 %(11/54)]. CMV and EBV mismatch was avoided in 90 %(9/10) and 100 %(5/5) of cases. Recipients who entered KPD for age/size mismatch and altruistic reasons received kidneys from donors with lower Living Kidney Donor Profile Index (LKDPI) scores than their actual donor [median (IQR) 31.5(12.3, 47) p<.001, and 26(-1, 46), p=0.01 points lower, respectively]. Median time to transplant from KPD entry for compatible pair recipients was 70(41-163) days, and 44.4 %(24/54) of these transplants were preemptive. All chains/swaps incorporating compatible pairs included ABO/HLA incompatible pairs. Conclusion: KPD should be considered for all living donor/recipient pairs because the recipients of these pairs can derive personal benefit from KPD while increasing the donor pool for difficult to match pairs. Disclosures: The authors declare no conflicts of interest. Funding: This publication was supported by Clinical and Translational Science Awards Grant Number KL2 TR002379 from the National Center for Advancing Translational Sciences (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. Correspondence: Arpita Basu MD, MPH, Emory Transplant Center, 1365 Clifton Road NE, Clinic Bldg B- Suite 6100, Atlanta, GA 30322, Email: arpita.basu@emory.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The Challenges with the Cardiac Evaluation of Liver and Kidney Transplant Candidates Cardiovascular events are among the leading cause of mortality in kidney and liver transplant recipients. Thus, screening for cardiovascular disease and risk stratification for cardiovascular events constitute an important part of the pretransplant evaluation. In this overview, we first summarize current guidelines in the cardiac risk assessment of kidney and liver transplant candidates. We then elaborate on the limitations of these guidelines, summarize the current knowledge gaps and narrow down a spectrum of six themes that serves as challenges to research and practice development. This spectrum pertains to understanding the disease itself which is challenging due to the altered cardiac physiology in these patients and that current guidelines do not adequately account for nonischemic diseases and events. We then describe the challenges in assessing these patients, their symptoms, and individualizing their risk of cardiovascular events with a special consideration for non traditional risk factors. We also explore the limitations of the current and novel diagnostic tests and the lack of evidence of therapeutic efficacy in intervening in patients with asymptomatic disease. The transplant procedure itself can be a potential modifiable risk factor for cardiovascular events i.e. surgical technique, type of donor and induction immunosuppression. Lastly, we describe the potential issues with the current literature when defining cardiac diseases and events across different studies and shortcomings of extrapolating data from the nontransplant literature. We conclude by proposing research and practice implications of our discussion and that there is a need for evidence to guide the revision of current guidelines. Part of this manuscript was presented at the 27th International Congress of the Transplantation Society (Madrid June 30 – July 5, 2018) Disclosure: The authors declare no conflicts of interest Acknowledgments: This work was supported using clinical research funding from the Department of Medicine at the McGill University Health Center. Corresponding author: Marcelo Cantarovich, Royal Victoria Hospital Glen Site, D05-7176, 1001 boul. Decarie, Montreal, QC, Canada. H4A 3J1, Tel: (514) 934-1934 ext. 35203. Fax: (514) 938-7050. Email: marcelo.cantarovich@muhc.mcgill.ca Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.