Background. We previously reported that 100% of HLA-identical siblings and 50% of HLA-haploidentical donor-recipient pairs exhibited bidirectional immunoregulation (BDIR) before living-related renal transplantation. BDIR predicted successful transplant outcomes. However, at the time, we were unaware of the role of the cytokine interleukin-35 (IL35) in immunoregulation, and we now appreciate exosomes as a means of confining immunoregulation to the transplanted tissue. Here we show that HLA-identical sibling transplants use IL35 in posttransplant BDIR. Methods. We analyzed the posttransplant IL35 response using the trans-vivo delayed type hypersensitivity assay in HLA-identical sibling transplants, using anti-IL35 antibodies to block immune-regulatory function as measured by either (1) inhibition of the tetanus toxoid/diphtheria toxoid recall response or (2) uncovering of direct response, in both the donor anti-recipient and the recipient anti-donor (minor H) antigen directions. Results. We found that minor antigen-specific human regulatory T cells, known to be present in peripheral blood mononuclear cell of HLA-identical siblings pretransplant, also caused BDIR via production of IL35 posttransplant. Conclusions. We conclude that human IL35 is a component of BDIR in HLA-identical sibling transplantation. Since IL35 is one of a subclass of exosome-delivered cytokines, this means that human IL35 could sustain local BDIR within the transplant itself. It follows that local BDIR would persist indefinitely if donor leukocytes were allowed to stably engraft. This may account for the success of combined total lymphoid irradiation/bone marrow transplantation/renal transplantation induction of stable tolerance in HLA-identical sibling transplant recipients.

Importance:Ischemia-reperfusion injury contributes to graft dysfunction after liver transplant. Hypothermic oxygenated perfusion (HOPE) has been shown to improve liver function, but its benefit in extended criteria donors in a US population remains unclear. Objective:To assess whether back-to-base portal-venous HOPE impacts outcomes after liver transplant in the US. Design, Setting, and Participants:The Bridge to HOPE Trial is a multicenter, randomized, open-label trial with 1-year follow-up. The study took place at 15 US liver transplant centers and patients were enrolled between January 2021 and May 2023. Central assessment of complications and cholangiograms for nonanastomotic biliary strictures (NAS) was blinded to treatment arm. Participants included 219 recipients of extended-criteria donor livers after brain death (DBD) and after circulatory death (DCD) who were randomized 1:1 to HOPE after static cold storage (SCS) (n = 109) or SCS only (n = 110). Randomization was performed after liver inspection and acceptance for transplant. Data were analyzed from December 2024 to July 2025. Intervention:After SCS and transport, livers underwent portal-venous HOPE until implant, using the VitaSmart HOPE System. Main Outcomes and Measures:The primary efficacy end point was early allograft dysfunction (EAD). Other main outcomes included model for early allograft function (MEAF) score, hospital length of stay (LOS), patient and graft survival, and biliary complications. Additional post hoc analyses were performed. Results:Overall, 219 patients (82 female [37.4%] and 137 male[62.6%]) were included (DCD, 57 of 219 [26%]) with 97% (212 of 219) completing 12-month follow-up. EAD incidence was 20.2% (22 of 109) with HOPE vs 37.3% (41 of 110) with SCS (rate difference, -17.1%; 95% CI, -27.2 to -7.0; noninferiority P < .001; superiority P = .005). HOPE treatment led to significantly lower MEAF mean (SD) scores (HOPE group, 4.28 [1.75]; control group, 4.82 [1.85]; mean difference, -0.54; 95% CI, -1.02 to -0.06; P = .03) and shorter median LOS (hazard ratio, 1.32; 95% CI, 1.01-1.73; P = .04). NAS on imaging and 1-year survivals were comparable between groups (patients: HOPE group, 106 of 109 [97.2%] vs SCS, 106 of 110 [96.4%]; graft: HOPE group, 104 of 109 [95.4%] vs SCS, 102 of 110 [92.7%]). Post hoc analyses showed numerically less graft loss due to NAS after HOPE (4 vs 1) and less major complications (Clavien-Dindo classification ≥IIIa) per patient, respectively. Conclusions and Relevance:Back-to-base portal-venous HOPE was compared with SCS alone for extended risk DBD and DCD livers. The HOPE approach was safe and associated with reduced EAD, MEAF score, and LOS. These findings support the use of HOPE as a pragmatic strategy to improve early posttransplant outcomes. Trial Registration:ClinicalTrials.gov Identifier: NCT05045794.

ImportanceThe indications, safety, and efficacy of chemical venous thromboembolism prophylaxis (cVTE) in pediatric trauma patients remain unclear. A set of high-risk criteria to guide cVTE use was recently recommended; however, these criteria have not been evaluated prospectively.ObjectiveTo examine high-risk criteria and cVTE use in a prospective multi-institutional study of pediatric trauma patients.Design, Setting, and ParticipantsThis cohort study was completed between October 2019 and October 2022 in 8 free-standing pediatric hospitals designated as American College of Surgeons level I pediatric trauma centers. Participants were pediatric trauma patients younger than 18 years who met defined high-risk criteria on admission. It was hypothesized that cVTE would be safe and reduce the incidence of VTE.ExposuresReceipt and timing of chemical VTE prophylaxis.Main Outcomes and MeasuresThe primary outcome was overall VTE rate stratified by receipt and timing of cVTE. The secondary outcome was safety of cVTE as measured by bleeding or other complications from anticoagulation.ResultsAmong 460 high-risk pediatric trauma patients, the median (IQR) age was 14.5 years (10.4-16.2 years); 313 patients (68%) were male and 147 female (32%). The median (IQR) Injury Severity Score (ISS) was 23 (16-30), and median (IQR) number of high-risk factors was 3 (2-4). A total of 251 (54.5%) patients received cVTE; 62 (13.5%) received cVTE within 24 hours of admission. Patients who received cVTE after 24 hours had more high-risk factors and higher ISS. The most common reason for delayed cVTE was central nervous system bleed (120 patients; 30.2%). There were 28 VTE events among 25 patients (5.4%). VTE occurred in 1 of 62 patients (1.6%) receiving cVTE within 24 hours, 13 of 189 patients (6.9%) receiving cVTE after 24 hours, and 11 of 209 (5.3%) who had no cVTE (P = .31). Increasing time between admission and cVTE initiation was significantly associated with VTE (odds ratio, 1.01; 95% CI, 1.00-1.01; P = .01). No bleeding complications were observed while patients received cVTE.Conclusions and RelevanceIn this prospective study, use of cVTE based on a set of high-risk criteria was safe and did not lead to bleeding complications. Delay to initiation of cVTE was significantly associated with development of VTE. Quality improvement in pediatric VTE prevention may center on timing of prophylaxis and barriers to implementation.

BACKGROUND:In the United States, hepatitis C virus-associated hepatocellular carcinoma incidence and mortality are highest among minorities. Socioeconomic constraints play a major role in inequitable treatment. We evaluated the association between race/ethnicity and outcomes in a population that overcame treatment barriers. METHODS:We report a retrospective cohort study of 666 patients across 20 institutions in the United States Hepatocellular Carcinoma Liver Transplantation Consortium from 2015 to 2019 with hepatitis C virus-associated hepatocellular carcinoma who completed direct-acting antiviral therapy and underwent liver transplantation. Patients were excluded if they had a prior liver transplantation, hepatocellular carcinoma recurrence, no prior liver-directed therapy, or if race/ethnicity data were unavailable. Patients were stratified by race/ethnicity. Primary outcomes were recurrence-free survival and overall survival, and secondary outcome was major postoperative complication. RESULTS:Race/ethnicity was not associated with differences in 5-year recurrence-free survival (White 90%, Black 88%, Hispanic 92%, Other 87%; p = 0.85), overall survival (White 85%, Black 84%, Hispanic 84%, Other 93%; p = 0.70), or major postoperative complication. CONCLUSIONS:Race/ethnicity was not associated with worse oncologic or postoperative outcomes among those who completed direct-acting antiviral therapy and underwent liver transplantation, suggesting that overcoming socioeconomic constraints equalizes outcomes across racial/ethnic groups. Eliminating barriers that prohibit care access among minorities must be a priority.

Background. Solid organ transplantation is a risk predictor for virally-mediated anal squamous intraepithelial lesions and cancer (anal disease). Precancerous squamous intraepithelial lesions can be detected by screening, and treatment may prevent cancer progression. Screening recommendations are not well defined. We aim to define prevalence and describe risk predictors for anal disease in a large population of solid organ transplant recipients. Methods. Retrospective single-center cohort analysis included solid organ transplant recipients cared for between 2001 and 2022 (N = 15 362). The cohort of recipients who developed anal disease was compared with those who did not. Greedy propensity score matching was performed for organ-specific recipients, and time-to-event analysis for the development of anal disease was performed in those with genitourinary human papilloma virus (HPV) disease versus those without. Results. Prevalence of anal disease was 0.6% (cancer 0.2%). The average years from transplant to the diagnosis of anal disease was 11.67. Anal disease was more common in women (68.5% versus 31.5%, P < 0.001), patients who had other HPV-related genitourinary diseases (40.4% versus 0.6%, P < 0.001), who were of younger age at transplant (39.62 versus 46.58, P < 0.001), and had increased years from transplant (17.06 versus 12.57, P < 0.001). In multivariate analysis, the odds of anal disease increased by 4% each year posttransplant. History of genitourinary HPV disease (odds ratio 69.63) and female sex (odds ratio 1.96) were the most significant risk predictors for anal disease. Conclusions. The prevalence of anal cancer among solid organ transplant recipients was equal to the general population (0.2%). Due to the low prevalence of overall disease, these data suggest that anal screenings in transplant recipients should be targeted to higher-risk subsets: female recipients farther out from transplant and patients with genitourinary HPV-related diseases.

To the Editor: In their review on liver transplantation, Lucey et al. (Nov. 16 issue)1 discuss sentinel events warranting evaluation for liver transplantation. The onset of a decompensating condition, such as ascites, was considered to be such an event. However, in most countries, Model for End-Stage Liver Disease (MELD) scores or variants of such scores are used for the allocation of donated livers and for decisions about whether to screen patients for liver transplantation. Lucey et al. do not discuss whether such scores limit access to liver transplantation in patients with acute-on-chronic liver failure.2 Patients with some types of cirrhosis, . . .

Study Design. Prospective randomized controlled trial. Objective. Compare range of motion (ROM) and adjacent segment degeneration (ASD) following cervical disc arthroplasty (CDA) versus anterior cervical discectomy and fusion (ACDF) at 20-year follow-up. Summary of Background Data. ACDF is the standard of treatment for single-level cervical disc degeneration causing radiculopathy. CDA is claimed to reduce shear strain and adjacent-level ROM changes hypothesized to hasten ASD with ACDF. Methods. This study collected data on 47 patients randomized to ACDF or CDA. Lateral cervical spine radiographs were evaluated preoperatively, postoperatively, and at 20-years for alignment, ROM, ASD, and heterotopic ossification. Results. Eighty-two percent (18/22) of CDA patients and 84% (21/25) of ACDF patients followed up at 20 years. At 20 years, total cervical (C2-C7) ROM was statistically different between the CDA and fusion groups (47.8° vs. 33.4°, P =0.005). Total cervical ROM was not significantly different between preoperative and 20-year periods following CDA (45.6° vs. 47.4°, P =0.772) or ACDF (40.6° vs. 33.0°, P =0.192). Differences in postoperative and 20-year index-level ROM following CDA were not significant (10.1° vs. 10.2°, P =0.952). Final ASD grading was statistically lower following CDA versus ACDF at both adjacent levels ( P <0.005). Twenty-year adjacent level ossification development was increased following ACDF versus CDA ( P <0.001). Polyethylene mean thickness decreased from 9.4 mm immediately postoperatively to 9.1 mm at 20-year follow up ( P =0.013). Differences in adjacent level ROM from preoperative to 20-year follow-up in both the ACDF and CDA groups did not meet statistical significance ( P >0.05). Conclusions. CDA maintains index-level and total cervical ROM at very long-term follow-up. Total cervical ROM was higher at 20 years in CDA relative to ACDF. CDA results in lower rates of adjacent segment degeneration and adjacent level ossification development than ACDF.

Existing literature offers conflicting conclusions about whether early acute cellular rejection influences long-term outcomes in liver transplantation. We retrospectively collected donor and recipient data on all adult, first-time liver transplants performed at a single center between 2008 and 2020. We divided this population into two cohorts based on the presence of early biopsy-proven acute cellular rejection (EBPR) within the first 90 days post-transplant and compared outcomes between the groups. There were 896 liver transplants that met inclusion criteria with 112 cases (12.5%) of EBPR. Recipients who developed EBPR had higher biochemical Model for End-Stage Liver Disease scores (28 vs. 24, p < .01), but other donor and recipient characteristics were similar. Recipients with EBPR had similar overall survival compared to patients without EBPR (p = .09) but had decreased graft survival (p < .05). EBPR was also associated with decreased time to first episode of late (> 90 days post-transplant) rejection (p < .0001) and increased vulnerability to bacterial and viral infection (p < .05). In subgroup analysis of recipients with autoimmune indications for liver transplantation, EBPR had a more pronounced association with patient death (hazard ratio [HR] 3.9, p < .05) and graft loss (HR 4.0, p < .01). EBPR after liver transplant is associated with inferior graft survival, increased susceptibility to late rejections, and increased vulnerability to infection.

Background. Kidney transplant outcomes have dramatically improved since the first successful transplant in 1954. In its early years, kidney transplantation was viewed more skeptically. Today it is considered the treatment of choice among patients with end-stage kidney disease. Methods. Our program performed its first kidney transplant in 1966 and recently performed our 12 000th kidney transplant. Here, we review and describe our experience with these 12 000 transplants. Transplant recipients were analyzed by decade of date of transplant: 1966–1975, 1976–1985, 1986–1995, 1996–2005, 2006–2015, and 2016–2022. Death-censored graft failure and mortality were outcomes of interest. Results. Of 12 000 kidneys, 247 were transplanted from 1966 to 1975, 1147 from 1976 to 1985, 2194 from 1986 to 1995, 3147 from 1996 to 2005, 3046 from 2006 to 2015, and 2219 from 2016 to 2022 compared with 1966–1975, there were statistically significant and progressively lower risks of death-censored graft failure at 1 y, 5 y, and at last follow-up in all subsequent eras. Although mortality at 1 y was lower in all subsequent eras after 1986–1995, there was no difference in mortality at 5 y or the last follow-up between eras. Conclusions. In this large cohort of 12 000 kidneys from a single center, we observed significant improvement in outcomes over time. Kidney transplantation remains a robust and ever-growing and improving field.

With improved medical treatments, the prognosis for many malignancies has improved, and more patients are presenting for transplant evaluation with a history of treated cancer. Solid organ transplant (SOT) recipients with a prior malignancy are at higher risk of posttransplant recurrence or de novo malignancy, and they may require a cancer surveillance program that is individualized to their specific needs. There is a dearth of literature on optimal surveillance strategies specific to SOT recipients. A working group of transplant physicians and cancer-specific specialists met to provide expert opinion recommendations on optimal cancer surveillance after transplantation for patients with a history of malignancy. Surveillance strategies provided are mainly based on general population recurrence risk data, immunosuppression effects, and limited transplant-specific data and should be considered expert opinion based on current knowledge. Prospective studies of cancer-specific surveillance models in SOT recipients should be supported to inform posttransplant management of this high-risk population.

BACKGROUND:Liver transplantation (LT) is the treatment of choice for end-stage liver disease and certain malignancies such as hepatocellular carcinoma (HCC). Data on the surgical management of de novo or recurrent tumors that develop in the transplanted allograft are limited. This study aimed to investigate the perioperative and long-term outcomes for patients undergoing hepatic resection for de novo or recurrent tumors after liver transplantation. METHODS:The study enrolled adult and pediatric patients from 12 centers across North America who underwent hepatic resection for the treatment of a solid tumor after LT. Perioperative outcomes were assessed as well as recurrence free survival (RFS) and overall survival (OS) for those undergoing resection for HCC. RESULTS:Between 2003 and 2023, 54 patients underwent hepatic resection of solid tumors after LT. For 50 patients (92.6 %), resection of malignant lesions was performed. The most common lesion was HCC (n = 35, 64.8 %), followed by cholangiocarcinoma (n = 6, 11.1 %) and colorectal liver metastases (n = 6, 11.1 %). The majority of the 35 patients underwent resection of HCC did not receive any preoperative therapy (82.9 %) or adjuvant therapy (71.4 %), with resection their only treatment method for HCC. During a median follow-up period of 50.7 months, the median RFS was 21.5 months, and the median OS was 49.6 months. CONCLUSION:Hepatic resection following OLT is safe and associated with morbidity and mortality rates that are comparable to those reported for patients undergoing resection in native livers. Hepatic resection as the primary and often only treatment modality for HCC following LT is associated with acceptable RFS and OS and should be considered in well selected patients.

Background. Here we test the hypothesis that, like CD81-associated “latent” IL35, the transforming growth factor (TGF)β:latency-associated peptide (LAP)/glycoprotein A repetitions predominant (GARP) complex was also tethered to small extracellular vesicles (sEVs), aka exosomes, produced by lymphocytes from allo-tolerized mice. Once these sEVs are taken up by conventional T cells, we also test whether TGFβ could be activated suppressing the local immune response. Methods. C57BL/6 mice were tolerized by i.p. injection of CBA/J splenocytes followed by anti-CD40L/CD154 antibody treatment on days 0, 2, and 4. On day 35, spleen and lymph nodes were extracted and isolated lymphocytes were restimulated with sonicates of CBA splenocytes overnight. sEVs were extracted from culture supernatants by ultracentrifugation (100 000g) and assayed for (a) the presence of TGFβ:LAP associated with tetraspanins CD81,CD63, and CD9 by enzyme-linked immunosorbent assay; (b) GARP, critical to membrane association of TGFβ:LAP and to activation from its latent form, as well as various TGFβ receptors; and (c) TGFβ-dependent function in 1° and 2° immunosuppression of tetanus toxoid-immunized B6 splenocytes using trans-vivo delayed–type hypersensitivity assay. Results. After tolerization, CBA-restimulated lymphocytes secreted GARP/TGFβ:LAP-coated extracellular vesicles. Like IL35 subunits, but unlike IL10, which was absent from ultracentrifuge pellets, GARP/TGFβ:LAP was mainly associated with CD81+ exosomes. sEV-bound GARP/TGFβ:LAP became active in both 1° and 2° immunosuppression, the latter requiring sEV uptake by “bystander” T cells and reexpression on the cell surface. Conclusions. Like other immune-suppressive components of the Treg exosome, which are produced in a latent form, exosomal GARP/TGFβ:LAP produced by allo-specific regulatory T cells undergoes either immediate activation (1° suppression) or internalization by naive T cells, followed by surface reexpression and subsequent activation (2°), to become suppressive. Our results imply a membrane-associated form of TGFβ:LAP that, like exosomal IL35, can target “bystander” lymphocytes. This new finding implicates exosomal TGFβ:LAP along with Treg-derived GARP as part of the infectious tolerance network.

Despite the increased usage of livers from donation after circulatory death (DCD) donors in the last decade, many patients remaining on the waitlist who need a liver transplant. Recent efforts have focused on maximizing the utilization and outcomes of these allografts using advances in machine perfusion technology and other perioperative strategies such as normothermic regional perfusion (NRP). In addition to the standard donor and recipient matching that is required with DCD donation, new data regarding the impact of graft steatosis, extensive European experience with NRP, and the increasing use of normothermic and hypothermic machine perfusion have shown immense potential in increasing DCD organ overall utilization and improved outcomes. These techniques, along with viability testing of extended criteria donors, have generated early promising data to consider the use of higher-risk donor organs and more widespread adoption of these techniques in the United States. This review explores the most recent international literature regarding strategies to optimize the utilization and outcomes of DCD liver allografts, including donor–recipient matching, perioperative strategies including NRP versus rapid controlled DCD recovery, viability assessment of discarded livers, and postoperative strategies including machine perfusion versus pharmacologic interventions.