Impact of simultaneous heart procurement on outcomes of donation after circulatory death lung transplantation.

Donation after circulatory death (DCD) heart procurement is done using either direct procurement (DP) or thoracoabdominal normothermic machine perfusion (TA-NRP). Both approaches could impact lung transplant outcomes with combined heart and lung procurements from the same donor. The impact of such practice on DCD lung transplant remains unstudied. We performed a retrospective analysis using the United Network for Organ Sharing (UNOS) dataset, identifying DCD lung transplants where the donor also donated the heart (cardia lung donor [CD]). A cohort of noncardiac DCD lung donors (noncardiac lung donor [NCD]) from the same era, matched for donor and recipient characteristics, was used as a comparison group. Both immediate and long-term outcomes were examined. A subanalysis was performed comparing the distinct impact of DP or TA-NRP on DCD lung transplant outcomes. Overall graft survival did not significantly differ between CD and NCD. However, recipients in the CD group trended toward a lower P/F ratio at 72 hours (CD vs NCD: 284 vs 3190; P = .054). In the subanalysis, we identified 40 DP donors and 22 TA-NRP donors. We found the both cohorts had lower P/F ratio at 72 hours than the NCD control (P = .04). Overall, 1-year graft survival was equivalent among the TA-NRP, DP, and NCD cohorts.

The impact of IdeS (imlifidase) on allo-specific, xeno-reactive, and protective antibodies in a sensitized rhesus macaque model.

BACKGROUND: Highly sensitized patients face many barriers to kidney transplantation, including higher rates of antibody-mediated rejection after HLA-incompatible transplant. IdeS, an endopeptidase that cleaves IgG nonspecifically, has been trialed as desensitization prior to kidney transplant, and successfully cleaves donor-specific antibody (DSA), albeit with rebound. METHODS: IdeS was generated and tested (2 mg/kg, IV) in two naïve and four allosensitized nonhuman primates (NHP). Peripheral blood samples were collected at regular intervals following IdeS administration. Total IgG, total IgM, and anti-CMV antibodies were quantified with ELISA, and donor-specific antibody (DSA) and anti-pig antibodies were evaluated using flow cytometric crossmatch. B cell populations were assessed using flow cytometry. RESULTS: IdeS successfully cleaved rhesus IgG in vitro. In allosensitized NHP, robust reduction of total, DSA, anti-pig, and anti-CMV IgG was observed within one day following IdeS administration. Rapid rebound of all IgG antibody populations was observed, with antibody levels returning to baseline around day 14 post-infusion. Total IgM level was not affected by IdeS. Interestingly, a comparable reduction in antibody populations was observed after the second dose of IdeS. However, we have not observed any significant modulation of B cell subpopulations after IdeS. CONCLUSIONS: This study evaluated efficacy of IdeS in the allosensitized NHP in IgG with various specificities, mirroring antibody kinetics in human patients. The efficacy of IdeS on preexisting anti-pig antibodies may be useful in clinical xenotransplantation. However, given the limitation of IdeS on its durability as a monotherapy, optimization of IdeS with other agents targeting the humoral response is further needed.

Attitudes of patients with renal disease on xenotransplantation: A systematic review.

BACKGROUND: Recent years have seen major advancements in xenotransplantation: the first pig-to-human heart transplant, the development of a brain-dead recipient model for kidney xenotransplantation, and the registration of the first xenokidney clinical trial. The attitudes of patients with kidney disease or transplants on xenotransplantation and an assessment of their reservations and considerations regarding the technology are crucial to successful clinical translation and eventual widespread implementation. METHODS: This systematic review was registered through PROSPERO (CRD42022344581) prior to initiation of the study and reported using the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. We included studies that evaluated attitudes towards and willingness to undergo xenotransplantation in patients with end-stage renal disease (ESRD), including those who had already undergone transplantation. MEDLINE (via Ovid), Embase (via Elsevier), and Web of Science (via Clarivate) were searched from database inception to July 15, 2022 by an experienced medical librarian for studies on xenotransplantation and attitudes. Abstracts and full text were screened using Covidence software and data items regarding study methodology, patient demographics, and attitudes regarding xenotransplantation were extracted using Microsoft Excel. Risk of bias assessments were performed using the Critical Appraisal Skills Programmed and National Institute of Health study quality assessment tools. RESULTS: Of 1992 studies identified, 14 studies met the inclusion criteria. These studies were conducted across eight countries, four in the United States, for a total of 3114 patients on the kidney waitlist or with a kidney transplant. All patients were over 17 years old and 58% were male. Acceptance of a xenotransplant was assessed using surveys in 12 studies. Sixty-three percent (n = 1354) of kidney patients reported that they would accept a xenotransplant with function comparable to that of an allotransplant. Acceptance of xenografts with inferior function to allografts (15%) or as bridge organs (35%) to allotransplantation was lower. Specific concerns expressed by patients included graft function, infection, social stigma, and animal rights. Subgroup analyses showed higher acceptance in already transplanted compared to waitlist patients and white compared to Black Americans. CONCLUSION: An understanding of patient attitudes and reservations is key to the successful execution of the first xenotransplantation clinical trials. This study compiles important factors to consider, such as patient concerns, attitudes regarding practical clinical scenarios for the use of xenotransplantation, and the impact of demographic factors on acceptance of this emerging technology.

Creation of an asynchronous faculty development curriculum on well-written narrative assessments that avoid bias.

BACKGROUND: The COVID-19 pandemic in parallel with concerns about bias in grading resulted in many medical schools adopting pass/fail clinical grading and relying solely on narrative assessments. However, narratives often contain bias and lack specificity. The purpose of this project was to develop asynchronous faculty development to rapidly educate/re-educate > 2000 clinical faculty spread across geographic sites and clinical disciplines on components of a well-written narrative and methods to minimize bias in the assessment of students. METHODS: We describe creation, implementation, and pilot data outcomes for an asynchronous faculty development curriculum created by a committee of volunteer learners and faculty. After reviewing the literature on the presence and impact of bias in clinical rotations and ways to mitigate bias in written narrative assessments, the committee developed a web-based curriculum using multimedia learning theory and principles of adult learning. Just-in-time supplemental materials accompanied the curriculum. The Dean added completion of the module by 90% of clinical faculty to the department chairperson's annual education metric. Module completion was tracked in a learning management system, including time spent in the module and the answer to a single text entry question about intended changes in behavior. Thematic analysis of the text entry question with grounded theory and inductive processing was used to define themes of how faculty anticipate future teaching and assessment as a result of this curricula. OUTCOMES: Between January 1, 2021, and December 1, 2021, 2166 individuals completed the online module; 1820 spent between 5 and 90 min on the module, with a median time of 17 min and an average time of 20.2 min. 15/16 clinical departments achieved completion by 90% or more faculty. Major themes included: changing the wording of future narratives, changing content in future narratives, and focusing on efforts to change how faculty teach and lead teams, including efforts to minimize bias. CONCLUSIONS: We developed a faculty development curriculum on mitigating bias in written narratives with high rates of faculty participation. Inclusion of this module as part of the chair's education performance metric likely impacted participation. Nevertheless, time spent in the module suggests that faculty engaged with the material. Other institutions could easily adapt this curriculum with provided materials.

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

Sensitized patients, those who had prior exposure to foreign human leukocyte antigens, are transplanted at lower rates due to challenges in finding suitable organs. Desensitization strategies have permitted highly sensitized patients to undergo kidney transplantation, albeit with higher rates of rejection. This study assesses targeting plasma cell and interleukin (IL)-6 receptor for desensitization in a sensitized nonhuman primate kidney transplantation model. All animals were sensitized using two sequential skin transplants from maximally major histocompatibility complex-mismatched donors. Carfilzomib (CFZ)/tocilizumab (TCZ) desensitization (N = 6) successfully decreased donor-specific antibody (DSA) titers and prevented the expansion of B cells compared to CFZ monotherapy (N = 3). Dual desensitization further delayed, but did not prevent humoral rebound, as evidenced by a delayed increase in post-kidney transplant DSA titers. Accordingly, CFZ/TCZ desensitization conferred a significant survival advantage over CFZ monotherapy. A trend toward increased T follicular helper cells was also observed in the dual therapy group along the same timeline as an increase in DSA and subsequent graft loss. Cytomegalovirus reactivation also occurred in the CFZ/TCZ group but was prevented with ganciclovir prophylaxis. In accordance with prior studies of CFZ-based dual desensitization strategies, the addition of IL-6 receptor blockade resulted in desensitization with further suppression of posttransplant humoral response compared to CFZ monotherapy.

Coagulation Abnormalities and Clinical Complications in Children With SARS-CoV-2: A Systematic Review of 48,322 Patients.

Given the limited information on the coagulation abnormalities of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in pediatric patients, we designed a systematic review to evaluate this topic. A comprehensive literature search was conducted for "SARS-CoV-2," "coagulopathy," and "pediatrics." Two authors independently screened the articles that the search returned for bleeding, thrombosis, anticoagulant and/or antiplatelet usage, and abnormal laboratory markers in pediatric patients with SARS-CoV-2, and the authors then extracted the relevant data. One hundred twenty-six publications were included. Thirty-four (27%) studies reported thrombotic complications in 504 patients. Thirty-one (25%) studies reported bleeding complications in 410 patients. Ninety-eight (78%) studies reported abnormal laboratory values in 6580 patients. Finally, 56 (44%) studies reported anticoagulant and/or antiplatelet usage in 3124 patients. The variety of laboratory abnormalities and coagulation complications associated with SARS-CoV-2 presented in this review highlights the complexity and variability of the disease presentation in infants and children.

Regional anesthesia does not decrease inpatient or outpatient opioid demand in distal femur fracture surgery.

INTRODUCTION: Regional anesthesia (RA) is sometimes used to decrease pain and opioid consumption in distal femur fractures. However, the real-world impact of RA on inpatient opioid consumption and outpatient opioid demand is not well known. The hypothesis of this study is that RA would be associated with decreased inpatient opioid consumption and outpatient opioid demand. METHODS: This study evaluated inpatient post-operative opioid consumption (0-24 h, 24-48 h, 48-72 h) and outpatient opioid demand (discharge to 2 weeks, 6 weeks, and 90 days) in all patients ages 18 and older undergoing operative treatment of distal femur fractures at a single institution from 7/2013 to 7/2018 (n = 230). Unadjusted and adjusted multivariable models were used to evaluate the impact of RA and other baseline patient and operative characteristics on inpatient opioid consumption and outpatient opioid demand. RESULTS: Adjusted models demonstrated a small, significant increase in inpatient opioid consumption in patients with RA compared to no RA (4.7 estimated OE's without RA vs 6.2 OE's with RA from 24- to 48-h post-op, p < 0.05) but otherwise no significant differences at other timepoints (6.7 estimated OE's without RA vs 6.9 OE's with RA from 0- to 24-h post-op and 4.5 vs 4.4 from 48- to 72-h post-op, p > 0.05). Estimated cumulative outpatient opioid demand was significantly higher in patients with RA from discharge to 6 weeks and to 90 days (55.8 OE's without RA vs 63.9 with RA from discharge to 2 weeks, p > 0.05; 74.9 vs 95.1 OE's to 6 weeks, and 85 vs 113.1 OE's to 90 days, p < 0.05). DISCUSSION: In distal femur fracture surgery, RA was associated with increased inpatient and outpatient opioid demand after adjusting for baseline patient and treatment characteristics. These results call into question the routine use of RA in distal femur fractures. LEVEL OF EVIDENCE: Level III, retrospective, therapeutic cohort study.

Interleukin-6 as a Biomarker of Early-Onset Neonatal Sepsis.

OBJECTIVE: The aim of this study is to determine the utility of C reactive protein (CRP) and interleukin (IL)-6 in the diagnosis of neonatal sepsis (NS) in a neonatal intensive care unit (NICU) in the south of Colombia. STUDY DESIGN: A nonmatched case-control study was conducted. Convenience sampling was performed. Data were obtained from clinical records. IL-6 levels were determined using enzyme-linked immunosorbent assay. Receiver operator characteristic (ROC) curve analysis and Youden's index were used to determine the optimal cutoffs for CRP and IL-6 levels in diagnosing NS, early-onset NS (EONS), and late-onset NS (LONS). RESULTS: Data from 31 cases and 62 controls were included. History of chorioamnionitis (infinite odds ratio [OR] [3.07-infinity]), and the presence of meconium-stained amniotic fluid during birth (OR: 9.04 [1.35-112]) were identified as risk factors for NS. Differences in CRP (p < 0.0001) and IL-6 (p < 0.0485) levels were also found, more significantly for LONS and EONS patients, respectively. In the diagnosis of LONS using CRP levels, the area under the ROC curve (AUC) was 0.8371 (p < 0.0001). The optimal cutoff was 0.53 mg/dL. For EONS diagnosis using IL-6, the AUC was 0.6869 (p = 0.0315) and the optimal cutoff was 17.75 pg/mL. CONCLUSION: Differences between CRP and IL-6 levels were found between control and NS groups. Furthermore, CRP showed greater potential diagnostic utility in the LONS group, whereas IL-6 showed greater potential utility in the EONS group. KEY POINTS: · NS is a major morbimortality cause worldwide. · CRP and IL-6 levels may be useful NS biomarkers. · No biomarker alone is enough for the diagnosis of NS.

Legislation Only Limiting Opioid Prescription Length Has Minimal Impact on Prescribing in Orthopaedic Trauma.

This study evaluates the efficacy of North Carolina's Strengthen Opioid Misuse Prevention (STOP) Act in reducing the volume and rate of 90-day perioperative opioid prescribing to patients ages 18 and older after orthopaedic trauma surgery. Patients undergoing fracture surgery from January 2017 to June 2017 (pre-STOP) were compared with patients undergoing fracture surgery from January 2018 to June 2018 (post-STOP). Adjusted analyses demonstrated that patients undergoing surgery after the STOP Act (n = 730) were prescribed significantly lower volume of opioids in the discharge to 2-week time frame and at the first postoperative prescription (7.3 and 5.8 fewer oxycodone, respectively). Otherwise, there were no significant differences between the two cohorts in adjusted volume or rates of 90-day opioid prescribing. The STOP act has had only a minor impact on early post-discharge opioid prescribing in patients undergoing fracture surgery. These findings question the efficacy of this type of legislation in combating opioid overprescribing in orthopaedic trauma. (Journal of Surgical Orthopaedic Advances 30(2):101-107, 2021).

Locally-secreted interleukin-6 is related with radiological severity in smear-negative pulmonary tuberculosis.

Pulmonary tuberculosis (PTB) has been identified as a substantial public health threat and diagnostic challenge. A large proportion of patients exhibit negative smear tests despite active infection. The role of cytokines in the pathophysiology and clinical severity of PTB remains a controversial question. We evaluated the pattern of cytokines presents locally in patients with smear-negative PTB. Levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, IL-4, IL-6, IL-10, and IL-17 in bronchoalveolar lavage fluid (BALf) from patients with smear-negative PTB, as well as in those with other pulmonary diseases and controls, were performed by flow cytometry. ROC curve and a radiological severity scale were used to establish the potential diagnosis use and the relationship of the cytokine levels with disease severity, respectively. The levels of IL-6 were higher in the PTB (P = 0.0249) and pneumonia (P = 0.0047) groups compared to controls. Low to undetectable levels of TNF-α, IFN-γ, IL-2, IL-4, IL-10, and IL-17 were found in BALf, even after sample concentration using filtration columns and centrifugation. IL-6 levels measured in BALf could distinguish PTB patients or pneumonia patients from controls (AUC: 0.91, P = 0.002 and AUC: 0.86, P = 0.001, respectively), but not patients with PTB from those with pneumonia (AUC: 0.51, P = 0.86). IL-6 levels were related with the severity of PTB, as levels were higher in patients with higher radiological severity. These results confirm the importance of IL-6 in the immunopathology of smear-negative PTB.

Quality improvement initiative to increase radial artery usage as a second arterial conduit in coronary artery bypass grafting.

OBJECTIVES: Use of radial artery as a second arterial graft, compared to a saphenous vein, in coronary artery bypass grafting (CABG) can improve late outcomes. However, the radial artery remains underutilized. We initiated a quality improvement (QI) initiative to increase the usage of radial artery grafts. METHODS: During our 4-month lead period, we disseminated evidence for radial artery graft usage to surgeons, developed a radial artery decision-making algorithm and adopted endoscopic harvesting. Our QI initiative was conducted over a 6-month period and included a postoperative survey of decision-making for graft selection and obstacles to radial artery usage. RESULTS: Over the 6-month study period, 247 patients received isolated CABG which included 98 (40%) with radial arteries as a second arterial graft and 144 (58%) with greater saphenous veins. Radial artery usage increased with QI initiative implementation by 67% compared to 6 months prior to the study period (60 radial arteries/252 isolated CABG, 24%) (P = 0.006). The survey response rate was 93% (231/247). Barriers to radial artery graft usage were poor quality target vessel or stenosis <80% (24%), patient age >75 years (20%), ejection fraction ≤35% (8%) and renal insufficiency/dialysis (7%). No patients experienced significant complications from radial artery harvest. CONCLUSIONS: Our institutional QI initiative was successful in (i) increasing the usage of radial artery as a second arterial graft and (ii) understanding barriers to radial artery graft usage. Implementation of a QI program can improve radial artery usage in CABG with low risk of patient morbidity from radial artery harvest.

Defining the learning curve for robotic pancreaticoduodenectomy for a single surgeon following experience with laparoscopic pancreaticoduodenectomy.

Robotic pancreaticoduodenectomy (RPD) has a learning curve of approximately 30-250 cases to reach proficiency. The learning curve for laparoscopic pancreaticoduodenectomy (LPD) at Duke University was previously defined as 50 cases. This study describes the RPD learning curve for a single surgeon following experience with LPD. LPD and RPD were retrospectively analyzed. Continuous pathologic and perioperative metrics were compared and learning curve were defined with respect to operative time using CUSUM analysis. Seventeen LPD and 69 RPD were analyzed LPD had an inverted learning curve possibly accounting for proficiency attained during the surgeon's fellowship and acquisition of new skills coinciding with more complex patient selection. The learning curve for RPD had three phases: accelerated early experience (cases 1-10), skill consolidation (cases 11-40), and improvement (cases 41-69), marked by reduction in operative time. Compared to LPD, RPD had shorter operative time (379 vs 479 min, p < 0.005), less EBL (250 vs 500, p < 0.02), and similar R0 resection. RPD also had improved LOS (7 vs 10 days, p < 0.007), and lower rates of surgical site infection (10% vs 47%, p < 0.002), DGE (19% vs 47%, p < 0.03), and readmission (13% vs 41%, p < 0.02). Experience in LPD may shorten the learning curve for RPD. The gap in surgical quality and perioperative outcomes between LPD and RPD will likely widen as exposure to robotics in General Surgery, Hepatopancreaticobiliary, and Surgical Oncology training programs increase.

Gene delivery followed by ex vivo lung perfusion using an adeno-associated viral vector in a rodent lung transplant model.

OBJECTIVE: Ex vivo lung perfusion has emerged as a platform for organ preservation, evaluation, and restoration. Gene delivery using a clinically relevant adeno-associated vector during ex vivo lung perfusion may be useful in optimizing donor allografts while the graft is maintained physiologically active. We evaluated the feasibility of adeno-associated vector-mediated gene delivery during ex vivo lung perfusion in a rat transplant model. Additionally, we assessed off-target effects and explored different routes of delivery. METHODS: Rat heart-lung blocks were procured and underwent 1-hour ex vivo lung perfusion. Before ex vivo lung perfusion, 4e11 viral genome luciferase encoding adeno-associated vector 9 was administered via the left bronchus (Br group, n = 4), via the left pulmonary artery (PA group, n = 3), or directly into the circuit (Circuit group, n = 3). Donor lungs in the Control group (n = 3) underwent ex vivo lung perfusion without adeno-associated vector 9. Only the left lung was transplanted. Animals underwent bioluminescence imaging weekly before being killed at 2 weeks. Tissues were collected for luciferase activity measurement. RESULTS: All recipients tolerated the transplant well. At 2 weeks post-transplant, luciferase activity in the transplanted lung was significantly higher among animals in the Br group compared with the other 3 groups (Br: 1.1 × 106 RLU/g, PA: 8.3 × 104 RLU/g, Circuit: 3.8 × 103 RLU/g, Control: 2.5 × 103 RLU/g, P = .0003). No off-target transgene expression was observed. CONCLUSIONS: In this work, we demonstrate that a clinically relevant adeno-associated vector 9 vector mediates gene transduction during ex vivo lung perfusion in rat lung grafts when administered via the airway and potentially the pulmonary artery. Our preliminary results suggest a higher transduction efficiency when adeno-associated vector 9 was delivered via the airway, and delivery during ex vivo lung perfusion reduces off-target effects after graft implant.

Prolonged xenokidney graft survival in sensitized NHP recipients by expression of multiple human transgenes in a triple knockout pig.

Genetic modification of porcine donors, combined with optimized immunosuppression, has been shown to improve outcomes of experimental xenotransplant. However, little is known about outcomes in sensitized recipients, a population that could potentially benefit the most from the clinical implementation of xenotransplantation. Here, five highly allosensitized rhesus macaques received a porcine kidney from GGTA1 (α1,3-galactosyltransferase) knockout pigs expressing the human CD55 transgene (1KO.1TG) and were maintained on an anti-CD154 monoclonal antibody (mAb)-based immunosuppressive regimen. These recipients developed de novo xenoreactive antibodies and experienced xenograft rejection with evidence of thrombotic microangiopathy and antibody-mediated rejection (AMR). In comparison, three highly allosensitized rhesus macaques receiving a kidney from GGTA1, CMAH (cytidine monophospho-N-acetylneuraminic acid hydroxylase), and b4GNT2/b4GALNT2 (ß-1,4-N-acetyl-galactosaminyltransferase 2) knockout pigs expressing seven human transgenes including human CD46, CD55, CD47, THBD (thrombomodulin), PROCR (protein C receptor), TNFAIP3 (tumor necrosis factor-α-induced protein 3), and HMOX1 (heme oxygenase 1) (3KO.7TG) experienced significantly prolonged graft survival and reduced AMR, associated with dampened post-transplant humoral responses, early monocyte and neutrophil activation, and T cell repopulation. After withdrawal of all immunosuppression, recipients who received kidneys from 3KO.7TG pigs rejected the xenografts via AMR. These data suggest that allosensitized recipients may be suitable candidates for xenografts from genetically modified porcine donors and could benefit from an optimized immunosuppression regimen designed to target the post-transplant humoral response, thereby avoiding AMR.

Allosensitisation in NHP results in cross-reactive anti-SLA antibodies not detected by a lymphocyte-based flow cytometry crossmatch.

Xenotransplantation is a potential option for individuals for whom an acceptable human allograft is unavailable. Individuals with broadly reactive HLA antibodies due to prior exposure to foreign HLA are potential candidates for a clinical xenotransplant trial. It remains controversial if allosensitisation results in the development of cross-reactive antibodies against SLA. This may require increased histocompatibility scrutiny for highly sensitised individuals prior to enrollment in a clinical trial. Serum samples were obtained from non-human primates sensitised via serial skin transplantation from maximally MHC-mismatched donor, as reported. Sera from pre- and post-allosensitisation timepoints were assessed in a flow crossmatch (FXM) for IgM and IgG binding to pig splenocytes with or without red blood cell adsorption. Xenoreactive antibodies were eluted from pig splenocytes and screened on a single antigen HLA bead assay. A MHC Matchmaker algorithm was developed to predict potential conserved amino acid motifs among the pig, NHP, and human. Our sensitised NHP model was used to demonstrate that allosensitisation does not result in an appreciable difference in xenoreactive antibody binding in a cell-based FXM. However, antibody elution and screening on single antigen HLA beads suggest the existence of potential cross-reactive antibodies against SLA. The cross-reactive IgG after allosensitisation were predicted by comparing the recipient Mamu alleles against its previous allograft donor Mamu alleles and the donor pig SLA alleles. Our study suggests that allosensitisation could elevate cross-reactive antibodies, but a more sensitive assay than a cell-based FXM is required to detect them. The MHC Matchmaker algorithm was developed as a potential tool to help determine amino acid motif conservation and reactivity pattern.

Impact of Tumor Size and Management on Survival in Small Gastric Gastrointestinal Stromal Tumors.

BACKGROUND: Society guidelines remain inconsistent on the role of endoscopic and radiographic surveillance as an alternative to surgical resection of small gastric gastrointestinal stromal tumors (GISTs). Herein, we aimed to assess survival among patients with gastric GISTs undergoing observation versus surgical resection, stratified by tumor size. METHODS: The National Cancer Database (NCDB) was queried for gastric GISTs < 2 cm diagnosed from 2010-2017. Patients were stratified by management strategy-observation vs surgical resection. The primary outcome, overall survival (OS), was examined with Kaplan-Meier and multivariable Cox proportional hazard methods. Subgroup analyses were conducted on tumors < 1 cm and 1-2 cm in size. RESULTS: Altogether, 1208 patients were identified: 439 (36.3%) undergoing observation and 769 (63.7%) receiving surgical resection. In the overall cohort, patients undergoing surgical resection demonstrated improved survival (93.6 vs. 88.8% 5-year OS, p=0.02). In multivariable analysis, upfront surgical resection was not associated with a reduction in mortality; however, there was a significant interaction with tumor size. For patients with tumors < 1 cm, there was no difference in survival based on management strategy. However, resection of tumors 1-2 cm was associated with improved survival relative to surveillance. CONCLUSIONS: While surgical resection and surveillance were associated with similar survival for patients with gastric GISTs < 1 cm, this NCDB analysis suggests that patients with tumor size ≥ 1 cm may benefit from upfront surgical resection. Prospective studies comparing these two approaches and their impact on recurrence-free and disease-specific survival are needed to better align consensus guidelines and recommendations.

Desensitization and belatacept-based maintenance therapy in pregnancy-sensitized monkeys receiving a kidney transplant.

Among sensitized patients awaiting a transplant, females are disproportionately represented, partly because of pregnancy-induced sensitization. Using female NHPs sensitized by pregnancy alone, we examined the efficacy of costimulation blockade and proteasome inhibition for desensitization. Three animals received no desensitization (control), and seven animals received weekly carfilzomib (27 mg/m2) and belatacept (20 mg/kg) before kidney transplantation. All animals received renal allografts from crossmatch-positive/maximally MHC-mismatched donors. Controls and three desensitized animals received tacrolimus-based immunosuppression. Four desensitized animals received additional belatacept with tacrolimus-based immunosuppression. Multiparous females had less circulating donor-specific antibody when compared to skin-sensitized males before transplantation. While females receiving desensitization showed only a marginal survival benefit over control females (MST = 11 days versus 63 days), additional belatacept to posttransplant maintenance significantly prolonged graft survival (MST > 164 days) and suppressed posttransplant DSA and circulating follicular helper T-like cells. This combination of therapies demonstrates great potential to reduce antibody-mediated rejection in sensitized recipients.

The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates.

Prior studies of anti-CD40 ligand (CD40L)-based immunosuppression demonstrated effective prevention of islet and kidney allograft rejection in nonhuman primate models; however, clinical development was halted because of thromboembolic complications. An anti-CD40L-specific monoclonal antibody, AT-1501 (Tegoprubart), was engineered to minimize risk of thromboembolic complications by reducing binding to Fcγ receptors expressed on platelets while preserving binding to CD40L. AT-1501 was tested in both a cynomolgus macaque model of intrahepatic islet allotransplantation and a rhesus macaque model of kidney allotransplantation. AT-1501 monotherapy led to long-term graft survival in both islet and kidney transplant models, confirming its immunosuppressive potential. Furthermore, AT-1501-based regimens after islet transplant resulted in higher C-peptide, greater appetite leading to weight gain, and reduced occurrence of cytomegalovirus reactivation compared with conventional immunosuppression. These data support AT-1501 as a safe and effective agent to promote both islet and kidney allograft survival and function in nonhuman primate models, warranting further testing in clinical trials.

Belatacept and carfilzomib-based treatment for antibody-mediated rejection in a sensitized nonhuman primate kidney transplantation model.

Introduction: One-third of HLA-incompatible kidney transplant recipients experience antibody mediated rejection (AMR) with limited treatment options. This study describes a novel treatment strategy for AMR consisting of proteasome inhibition and costimulation blockade with or without complement inhibition in a nonhuman primate model of kidney transplantation. Methods: All rhesus macaques in the present study were sensitized to maximally MHC-mismatched donors by two sequential skin transplants prior to kidney transplant from the same donor. All primates received induction therapy with rhesus-specific ATG (rhATG) and were maintained on various immunosuppressive regimens. Primates were monitored postoperatively for signs of acute AMR, which was defined as worsening kidney function resistant to high dose steroid rescue therapy, and a rise in serum donor-specific antibody (DSA) levels. Kidney biopsies were performed to confirm AMR using Banff criteria. AMR treatment consisted of carfilzomib and belatacept for a maximum of four weeks with or without complement inhibitor. Results: Treatment with carfilzomib and belatacept was well tolerated and no treatment-specific side effects were observed. After initiation of treatment, we observed a reduction of class I and class II DSA in all primates. Most importantly, primates had improved kidney function evident by reduced serum creatinine and BUN as well as increased urine output. A four-week treatment was able to extend graft survival by up to two months. Discussion: In summary, combined carfilzomib and belatacept effectively treated AMR in our highly sensitized nonhuman primate model, resulting in normalization of renal function and prolonged allograft survival. This regimen may translate into clinical practice to improve outcomes of patients experiencing AMR.