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Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication of organ transplantation, commonly diagnosed after patients present with nonspecific constitutional symptoms and/or transplant organ dysfunction. In this article, we report a case of a kidney transplant recipient who was found to have highly elevated circulating donor-derived cell-free DNA (dd-cfDNA) levels on routine serum surveillance for allograft rejection, initially without organ dysfunction or evidence of allograft rejection on biopsy. Later, for cause imaging revealed retroperitoneal lymphadenopathy and an allograft hilar mass, which was biopsied to show PTLD/diffuse large B cell lymphoma. The elevated circulating dd-cfDNA levels in this patient prompted targeted next-generation sequencing of the same 266 single-nucleotide polymorphisms used to detect dd-cfDNA on the diffuse large B cell lymphoma, which identified it as derived from the donor. The patient achieved complete remission with retained allograft kidney function after reduced immunosuppression and 6 cycles of immunochemotherapy. This case suggests that dd-cfDNA may be an early detection tool in rare but potentially life-threatening cases of donor-derived malignancy, such as donor-derived PTLD., Competing Interests: Declaration of competing interests The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Harm reduction has become increasingly influential in drug policy and practice, but has developed primarily around adult drug use. Theoretical, practical, ethical and legal issues pertaining to children and adolescents under the age of majority - both relating to their own use and the effects of drug use among parents or within the family - are less clear. This commentary proposes a sub-field of drug policy at the intersection of harm reduction and childhood which we refer to as 'child-centred harm reduction'. We provide a definition and conceptual model, as well as illustrative questions that emerge through a child-centred harm reduction lens. Many people in different countries are already working on these kinds of issues, whose work needs greater recognition, analysis and support. In beginning to name and define this sub-field we hope to improve this situation, and inspire further international debate, collaboration, and innovation., Competing Interests: Declarations of Interest The authors declare no competing interests., (Copyright © 2022. Published by Elsevier B.V.)

Background: Portal venous reconstruction (PVR) is often needed during resection of hepatopancreato-biliary (HPB) malignancies. Primary repair (PR), autologous vein (AV), or cryopreserved cadaveric vein (CCV) are frequently utilized, however relative patency is not well studied., Methods: All patients undergoing PVR between 2007-2019 at our center were identified. 3-year primary patency (PP), overall survival (OS), and survival-adjusted patency (SAP) were evaluated with Kaplan-Meier and Cox proportional hazards modeling., Results: One-hundred-twenty patients were identified with a median follow-up of 11 months. PR, AV, and CCV reconstruction were used in 28 (23%), 35 (29%), and 57 (48%) patients, respectively, with two (7%), four (11%), and 29 (51%) thromboses, respectively. 3-year PP was greater for both primary repair (90%) and AV (83%) compared to CCV (33%, both p<0.001). On multivariable analysis, CCV had worse 3-year PP (HR 7.89, p=0.005) and SAP (HR 2.09, p=0.02) compared to PR; AV reconstruction had equivalent oncologic and patency-related outcomes to PR (p>0.4 for both comparisons)., Conclusions: Primary patency for PR and AV reconstruction is superior to CCV for PVR during resection of HPB malignancies. AV conduit should be the preferred choice of reconstruction when PR is not achievable. Surgeons should only use CCV when factors preclude PR/AV reconstruction., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Intraoperative autologous transfusion (IAT) of salvaged blood is a common method of resuscitation during liver transplantation (LT), however concern for recurrence in recipients with hepatocellular carcinoma (HCC) has limited widespread adoption., Methods: A review of patients undergoing LT for HCC between 2008 and 2018 was performed. Clinicopathologic and intraoperative characteristics associated with inferior recurrence-free (RFS) and overall survival (OS) were identified using Kaplan-Meier analysis and uni-/multi-variable Cox proportional hazards modeling. Propensity matching was utilized to derive clinicopathologically similar groups for subgroup analysis., Results: One-hundred-eighty-six patients were identified with a median follow up of 65 months. Transplant recipients receiving IAT (n = 131, 70%) also had higher allogenic transfusions (median 5 versus 0 units, P < 0.001). There were 14 recurrences and 46 deaths, yielding an estimated 10-year RFS and OS of 89% and 67%, respectively. IAT was not associated with RFS (HR 0.89/liter, P = 0.60), or OS (HR 0.98/liter, P = 0.83) pre-matching, or with RFS (HR 0.97/liter, P = 0.92) or OS (HR 1.04/liter, P = 0.77) in the matched cohort (n = 49 per group)., Conclusion: IAT during LT for HCC is not associated with adverse oncologic outcomes. Use of IAT should be encouraged to minimize the volume of allogenic transfusion in patients undergoing LT for HCC., (Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Graft-versus-host disease after liver transplantation (LT-GVHD) is rare, frequently fatal, and associated with bone marrow failure (BMF), cytopenias, and hyperferritinemia. Given hyperferritinemia and cytopenias are present in hemophagocytic lymphohistiocytosis (HLH), and somatic mutations in hematopoietic cells are associated with hyperinflammatory responses (clonal hematopoiesis of indeterminate potential, CHIP), we identified the frequency of hemophagocytosis and CHIP mutations in LT-GVHD. We reviewed bone marrow aspirates and biopsies, quantified blood/marrow chimerism, and performed next-generation sequencing (NGS) with a targeted panel of genes relevant to myeloid malignancies, CHIP, and BMF. In all, 12 marrows were reviewed from 9 LT-GVHD patients. In all, 10 aspirates were evaluable for hemophagocytosis; 7 had adequate DNA for NGS. NGS was also performed on marrow from an LT cohort (n = 6) without GVHD. Nine of 10 aspirates in LT-GVHD patients showed increased hemophagocytosis. Five (71%) of 7 with LT-GVHD had DNMT3A mutations; only 1 of 6 in the non-GVHD LT cohort demonstrated DNMT3A mutation (p = .04). Only 1 LT-GVHD patient survived. BMF with HLH features was associated with poor hematopoietic recovery, and DNMT3A mutations were over-represented, in LT-GVHD patients. Identification of HLH features may guide prognosis and therapeutics. Further studies are needed to clarify the origin and impact of CHIP mutations on the hyperinflammatory state., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: We hypothesized hepato-pancreato-biliary (HPB) surgery patients are more likely to be hypercoagulable than hypocoagulable, and that bleeding risks from VTE chemoprophylaxis are low. This study sought to use thromboelastography (TEG) to compare coagulation profiles with bleeding/thrombotic events in HPB patients receiving standardized perioperative chemoprophylaxis., Methods: Consecutive patients undergoing HPB resections by three surgeons at one institution (January 2014-December 2015) received preoperative and early postoperative VTE chemoprophylaxis and were evaluated with TEGs. Coagulation profiles were compared to bleeding/thrombotic events., Results: Of 87 total patients, 83 (95.4%) received preoperative chemoprophylaxis and 100% received it postoperatively. Median estimated blood loss was 190 ml. Only 2 (2.3%) patients received intraoperative transfusions. None required transfusions at 72-hours. Only 2 were transfused within 30 days. There was 1 (1.1%) 30-day VTE event. Of 83 preoperative TEGs, 29 (34.9%) were hypercoagulable and only 8 (9.6%) were hypocoagulable/fibrinolytic. Of 73 postoperative TEGs, 34 (46.6%) were hypercoagulable and just 8 (11.0%) were hypocoagulable/fibrinolytic. ., Conclusion: With routine perioperative chemoprophylaxis, both VTE and bleeding events were negligible. Perioperative TEG revealed a considerable proportion (46.6%) of HPB patients were hypercoagulable. HPB patients can receive standardized preoperative/early postoperative VTE chemoprophylaxis with effective results and minimal concern for perioperative hemorrhage., (Copyright © 2016 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Mixed hepatocellular and cholangiocarcinoma (HCC-CC) have been associated with a poor prognosis after liver transplantation (LT). We aimed to evaluate long-term outcomes in patients undergoing LT for HCC-CC versus patients with hepatocellular carcinoma (HCC) or cholangiocarcinoma (CC)., Methods: Retrospective analysis of the United Network for Organ Sharing (UNOS) database from 1994-2013. Overall survival (OS) in patients with HCC-CC, HCC, and CC, were compared., Results: We identified 4049 patients transplanted for primary malignancy (94 HCC-CC; 3515 HCC; 440 CC). Mean age of patients with HCC-CC was 57 ± 10 years, and 77% were male. MELD score did not differ among the groups (p = 0.637). Hepatitis C virus was the most common secondary diagnosis within the HCC-CC (44%) and HCC (36%) cohorts, with primary sclerosing cholangitis in the CC (16%) cohort. OS rates at 1, 3 and 5 years for HCC-CC (82%, 47%, 40%) were similar to CC (79%, 58%, 47%), but significantly worse than HCC (86%, 72%, and 62% p = 0.002)., Discussion: Patients undergoing LT for HCC had significantly better survival compared to those transplanted for HCC-CC and CC. LT for mixed HCC-CC confers a survival rate similar to selected patients with CC. Efforts should be made to identify HCC-CC patients preoperatively., (Copyright © 2015. Published by Elsevier Ltd.)

Autosomal dominant mutations in BTB and Kelch domain containing 13 protein (KBTBD13) are associated with a new type of Nemaline Myopathy (NEM). NEM is a genetically heterogeneous group of muscle disorders. Mutations causing phenotypically distinct NEM variants have previously been identified in components of muscle thin filament. KBTBD13 is a muscle specific protein composed of an N terminal BTB domain and a C terminal Kelch-repeat domain. The function of this newly identified protein in muscle remained unknown. In this study, we show that KBTBD13 interacts with Cullin 3 (Cul3) and the BTB domain mediates this interaction. Using ubiquitination assays, we determined that KBTBD13 participates in the formation of a Cul3 based RING ubiquitin ligase (Cul3-RL) capable of ubiquitin conjugation. Confocal microscopy of transiently expressed KBTBD13 revealed its co-localization with ubiquitin. Taken together, our results demonstrate that KBTBD13 is a putative substrate adaptor for Cul3-RL that functions as a muscle specific ubiquitin ligase, and thereby implicate the ubiquitin proteasome pathway in the pathogenesis of KBTBD13-associated NEM., (Published by Elsevier Inc.)

The Ets transcription factors regulate a wide variety of biologic processes. Several members have been shown to play a role in regulating angiogenesis and vascular development. For example, the Ets factor ELF-1 is enriched in the developing vasculature of the embryo, where it regulates the expression of the Tie2 gene. We have determined that ELF-1 and Tie2 expression is also enriched in tumor blood vessels, and have identified a short peptide, 34 amino acids in length, corresponding to the terminal portion of the highly conserved ETS domain that potently blocks the function of ELF-1. A tailored ELF-1 blocking peptide, containing a 12-amino acid HIV-1 TAT protein, readily crosses the cell membrane and enters into the nucleus of endothelial cells, leading to a marked reduction in the expression of ELF-1 gene targets including Tie2 and endothelial nitric oxide synthase. Furthermore, the ELF-1 blocking peptide potently inhibits angiopoietin-1-mediated endothelial cell migration. Systemic administration of this peptide markedly attenuates B16 melanoma tumor growth and tumor-associated angiogenesis in nude mice. These results support the function of ELF-1 in the regulation of Tie2 gene expression during the development of tumor angiogenesis.

The Port Pirie Lead Program commenced in 1984. The abatement program involves identification of children with elevated blood lead levels, house decontamination, soil treatment, development of heavily vegetated buffer zones around the smelter, family education and support and community education. Since 1984 the smelter has also implemented substantial new emission controls and environmental improvements. Blood lead and air monitoring programs as well as investigations of emission sources, ongoing household contamination and infant exposure mechanisms are in place. Although capillary blood lead monitoring has shown a significant decrease in the mean blood lead levels of the children, 61% of children aged 1-4 years still exceed 10 microg/dl, with 28% at or above 15 microg/dl. Re-entrainment of lead from the contaminated areas within the city is only a small contributor to air-borne lead levels compared with that from the smelter and its environs. The smelter has undertaken extensive work to reduce windborne fugitive emissions. While attempts to demonstrate reductions in air lead have been hampered by large annual variations in wind speed and direction, air lead studies have confirmed that only small losses are now arising from the stockpile area of the smelter site. Evidence suggests that worker hygiene improvements, relocation of children to lower exposure suburbs, community education, house decontamination, specific measures for individual children with elevated blood lead, and avoidance of tank rainwater have all been partially successful. A substantial investigation program has refocused intervention efforts towards reducing exposure from indoor environments during the first year of life and contributed to improved identification and ranking of ongoing smelter emission sources.