The Young Investigator Committee of the International Xenotransplantation Association-Perspective of advancements in the field in 2023.

The 2023 IXA conference, hosted in San Diego, CA, brimmed with excitement against the backdrop of recent innovations in both the pre-clinical and clinical realms with several first-in-human applications of xenotransplantation. The theme, "Pigs are flying," alluded to the adage that xenotransplantation would only become a clinical reality "when pigs fly," suggesting a day that might never come. The event witnessed significant attendance, with 600 participants-the highest in the history of an IXA-IPITA joint congress. Among the attendees were members of the Food and Drug Administration (FDA), the National Institutes of Health (NIH), and corporate sponsors deeply engaged in the field. We summarize the latest topics from the congress, ranging from the pros/cons of decedent models of xenotransplantation and genetic engineering of porcine heart valves, solid organs, and cells for clinical translation and their regulatory and ethical landscape.

Can remote endarterectomy expand access to kidney transplantation in patients with severe iliac calcification?

Severe iliac artery calcification in patients with end-stage renal disease is a common barrier to listing for kidney transplant. While few surgical solutions to iliac calcification have been reported, improving treatment may thus improve access to transplant care. Here we present two cases of a novel application of remote endarterectomy of the external iliac artery to facilitate listing for renal transplant. Both patients were listed following remote endarterectomy, followed by successful renal transplants using the treated vessels.

Xenotransplantation literature update March 2021-March 2023.

After a significant hiatus imposed by the COVID-19 pandemic, we hereby restart Xenotransplantation literature updates. With the recently performed clinical xenotransplantation cases and the much-heightened interest in the field, we have determined that this is an optimal time to reinstate this section. There has been an invigorated focus on unique challenges posed by pig-to-human xenotransplantation, and specific attention will be given to this aspect. In this issue, we aimed to cover the gap and compiled the most relevant publications from March 2021 to March 2023.

Recent progress and remaining hurdles toward clinical xenotransplantation.

BACKGROUND: Xenotransplantation has made tremendous progress over the last decade. METHODS: We discuss kidney and heart xenotransplantation, which are nearing initial clinical trials. RESULTS: Life sustaining genetically modified kidney xenografts can now last for approximately 500 days and orthotopic heart xenografts for 200 days in non-human primates. Anti-swine specific antibody screening, preemptive desensitization protocols, complement inhibition and targeted immunosuppression are currently being adapted to xenotransplantation with the hope to achieve better control of antibody-mediated rejection (AMR) and improve xenograft longevity. These newest advances could probably facilitate future clinical trials, a significant step for the medical community, given that dialysis remains difficult for many patients and can have prohibitive costs. Performing a successful pig-to-human clinical kidney xenograft, that could last for more than a year after transplant, seems feasible but it still has significant potential hurdles to overcome. The risk/benefit balance is progressively reaching an acceptable equilibrium for future human recipients, e.g. those with a life expectancy inferior to two years. The ultimate question at this stage would be to determine if a "proof of concept" in humans is desirable, or whether further experimental/pre-clinical advances are still needed to demonstrate longer xenograft survival in non-human primates. CONCLUSION: In this review, we discuss the most recent advances in kidney and heart xenotransplantation, with a focus on the prevention and treatment of AMR and on the recipient's selection, two aspects that will likely be the major points of discussion in the first pig organ xenotransplantation clinical trials.

Pancreas collagen digestion during islet of Langerhans isolation-a prospective study.

The success of pancreas islet isolation largely depends on donor characteristics, including extracellular matrix composition of which collagen is the main element. We hypothesized that isolation yields are proportional to collagen digestion percentage, and aimed to determine a threshold that predicts isolation success. The amount of pancreas collagen (I-V) was determined using colorimetry prior to and after the digestion process in 52 human islet isolations. Collagen I-V and VI were also assessed histologically. We identified a collagen digestion threshold of ≥ 60% as an independent factor beyond which an islet preparation has a ninefold increased odds of yielding ≥ 250 000 islet equivalents (IEQ) (P = 0.009) and a sixfold increased odds of being transplanted (P = 0.015). Preparations with ≥ 60% collagen digestion (n = 35) yielded 283 017 ± 164 214 IEQ versus 180 142 ± 85 397 in the < 60% collagen digestion group (n = 17) (P = 0.016); respectively 62.9% versus 29.4% of those were transplanted (P = 0.024). Common donor characteristics, initial collagen content, enzyme blend, and digestion times were not associated with collagen digestion percentage variations. Donor age positively correlated with the amount of collagen VI (P = 0.013). There was no difference in islet graft survival between high and low digestion groups. We determined that a 60% pancreas collagen digestion is the threshold beyond which an islet isolation is likely to be successful and transplanted.

Randomized Controlled Trial of Enhanced Recovery Program Dedicated to Elderly Patients After Colorectal Surgery.

BACKGROUND: Enhanced recovery program is a multimodal, multidisciplinary-team, evidence-based care approach to reduce perioperative surgical stress, decrease morbidity and hospital stay, and improve recovery after surgery. This program may be most beneficial for elderly (≥70 y), but sparse series have investigated this question. OBJECTIVE: Feasibility and efficiency of a dedicated enhanced recovery program in the elderly as compared with standard care were studied. DESIGN: This was a nonblinded, randomized controlled study. SETTINGS: This study was conducted in a single high-volume university hospital. PATIENTS: A total of 150 eligible elderly patients undergoing elective colorectal surgery were included. INTERVENTIONS: Enhanced recovery after colorectal elective surgery in elderly patients was studied. MAIN OUTCOME MEASURES: The primary outcome was 30-day postoperative morbidity. Additional outcomes included hospital stay, readmission, postoperative pain, opioid consumption, independence preservation, and protocol compliance. RESULTS: An enhanced recovery program reduces postoperative morbidity according to Clavien-Dindo classification by 47% as compared with standard care (35% vs 65%; p = 0.0003), total number of complications (54 vs 118; p = 0.0003), and infectious complications (13 vs 29; p = 0.001). No anastomotic leak was recorded in the enhanced recovery group versus 5 for the standard group (p = 0.01). The enhanced recovery program resulted in shorter hospital stay (7 vs 12 d; p = 0.003) and better independence preservation (home discharge, 87% vs 67%; p = 0.005). A high protocol compliance of 77.2% could be achieved in this population. According to multivariate analysis, enhanced recovery program was strongly associated with reduced morbidity (OR = 0.23 (95% CI, 0.09-0.57); p = 0.001), less severe complications (OR = 0.36 (95% CI, 0.15-0.84); p = 0.02), and shorter hospital stay (OR = 2.07 (95% CI, 1.33-3.22); p = 0.001). LIMITATIONS: Limitations were a single-center recruitment and the impossibility of subject or healthcare professional blinding attributed to the nature of this multimodal program. CONCLUSIONS: Enhanced recovery program is safe and improves postoperative recovery in elderly patients with decreased morbidity, shorter hospital stay, and better maintenance of independence. It should therefore be considered as a standard of care for elective colorectal surgery in elderly patients. See Video Abstract at http://links.lww.com/DCR/A981. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01646190. ENSAYO CONTROLADO ALEATORIZADO DE UN PROGRAMA DE RECUPERACIÓN INTENSIFICADA DEDICADO A PACIENTES DE EDAD AVANZADA DESPUÉS DE CIRUGÍA COLORECTAL: El Programa de Recuperación Intensificada es un enfoque de atención multimodal, multidisciplinaria y basada en evidencia para reducir el estrés quirúrgico perioperatorio, disminuir la morbilidad y la estancia hospitalaria, y mejorar la recuperación después de la cirugía. Este programa puede ser más beneficioso para las personas mayores (≥70 años), pero pocas series han investigado esta pregunta. OBJETIVO: Viabilidad y eficiencia del Programa de Recuperación Intensificada dedicado en personas de edad avanzada en comparación con la atención estándar. DISEÑO:: Este fue un estudio controlado, aleatorizado, sin método ciego. ESCENARIO: Este estudio se realizó en un único hospital universitario de alto volumen. PACIENTES: Un total de 150 pacientes de edad avanzada elegibles sometidos a cirugía colorrectal electiva fueron incluidos. INTERVENCIONES: Recuperación Intensificada después de cirugía electiva colorrectal en pacientes de edad avanzada. PRINCIPALES MEDIDAS DE RESULTADO: El resultado primario fue la morbilidad postoperatoria a 30 días. Los resultados adicionales incluyeron estancia hospitalaria, reingreso, dolor postoperatorio, consumo de opioides, preservación de la independencia y cumplimiento del protocolo. RESULTADOS: El Programa de Recuperación Intensificada reduce la morbilidad postoperatoria según la clasificación de Clavien-Dindo en un 47% en comparación con la atención estándar (35% vs 65%; p = 0.0003), número total de complicaciones (54 vs 118; p = 0.0003) y complicaciones infecciosas (13 vs 29; p = 0.001). No se registró ninguna fuga anastomótica en el grupo de Recuperación Intensificada frente a 5 para el grupo estándar (p = 0.01). El Programa de Recuperación Intensificada dio como resultado una estancia hospitalaria más corta (7 contra 12 días; p = 0.003) y una mejor conservación de la independencia (alta hospitalaria: 87% vs 67%; p = 0.005). Se pudo lograr un alto cumplimiento del protocolo del 77.2% en esta población. De acuerdo con el análisis multivariable, el Programa de Recuperación Intensificada se asoció fuertemente con la reducción de morbilidad (OR = 0.23; IC 95%: 0.09-0.57; p = 0.001), menos complicaciones graves (OR = 0.36; IC 95%: 0.15-0.84; p = 0.02) y estancia hospitalaria más corta (OR = 2.07; IC 95%: 1.33-3.22; p = 0.001). LIMITACIONES: Las limitaciones fueron un centro único de reclutamiento y la imposibilidad de que los pacientes o el profesional de la salud tuvieran cegamiento debido a la naturaleza de este programa multimodal. CONCLUSIONES: El Programa de recuperación Intensificada es seguro y mejora la recuperación postoperatoria en pacientes de edad avanzada, con menor morbilidad, menor estancia hospitalaria y mejor mantenimiento de la independencia. Por lo tanto, debe considerarse como un estándar de atención para la cirugía colorrectal electiva en pacientes de edad avanzada. Vea el Resumen en video en http://links.lww.com/DCR/A981.

Interleukin-1 Receptor Antagonist Modulates Liver Inflammation and Fibrosis in Mice in a Model-Dependent Manner.

BACKGROUND: Interleukin-1 (IL-1)ß and IL-1 receptor antagonist (IL-1Ra) have been proposed as important mediators during chronic liver diseases. We aimed to determine whether the modulation of IL-1ß signaling with IL-1Ra impacts on liver fibrosis. METHODS: We assessed the effects of IL-1ß on human hepatic stellate cells (HSC) and in mouse models of liver fibrosis induced by bile duct ligation (BDL) or carbon tetrachloride treatment (CCl-4). RESULTS: Human HSCs treated with IL-1ß had increased IL-1ß, IL-1Ra, and MMP-9 expressions in vitro. HSCs treated with IL-1ß had reduced α-smooth muscle actin expression. These effects were all prevented by IL-1Ra treatment. In the BDL model, liver fibrosis and Kuppfer cell numbers were increased in IL-1Ra KO mice compared to wild type mice and wild type mice treated with IL-1Ra. In contrast, after CCl-4 treatment, fibrosis, HSC and Kupffer cell numbers were decreased in IL-1Ra KO mice compared to the other groups. IL-1Ra treatment provided a modest protective effect in the BDL model and was pro-fibrotic in the CCl-4 model. CONCLUSIONS: We demonstrated bivalent effects of IL-1Ra during liver fibrosis in mice. IL-1Ra was detrimental in the CCl-4 model, whereas it was protective in the BDL model. Altogether these data suggest that blocking IL-1-mediated inflammation may be beneficial only in selective liver fibrotic disease.

Xenotransplantation: back to the future?

The field of xenotransplantation has fluctuated between great optimism and doubts over the last 50 years. The initial clinical attempts were extremely ambitious but faced technical and ethical issues that prompted the research community to go back to preclinical studies. Important players left the field due to perceived xenozoonotic risks and the lack of progress in pig-to-nonhuman-primate transplant models. Initial apparently unsurmountable issues appear now to be possible to overcome due to progress of genetic engineering, allowing the generation of multiple-xenoantigen knockout pigs that express human transgenes and the genomewide inactivation of porcine endogenous retroviruses. These important steps forward were made possible by new genome editing technologies, such as CRISPR/Cas9, allowing researchers to precisely remove or insert genes anywhere in the genome. An additional emerging perspective is the possibility of growing humanized organs in pigs using blastocyst complementation. This article summarizes the current advances in xenotransplantation research in nonhuman primates, and it describes the newly developed genome editing technology tools and interspecific organ generation.

Pancreas preservation fluid microbial contamination is associated with poor islet isolation outcomes - a multi-centre cohort study.

The microbiological safety of islet preparations is paramount. Preservation medium contamination is frequent, and its impact on islet yield and function remains unclear. Microbiological samples collected during islet isolations from 2006 to 2016 were analyzed and correlated to isolation and allo- and autotransplantation outcomes. Microbial contamination of preservation medium was found in 64.4% of processed donor pancreases (291/452). We identified 464 microorganisms including Staphylococcus (253/464, 54.5%), Streptococcus (31/464, 6.7%), and Candida species (25/464, 5.4%). Microbial contamination was associated with longer warm and cold ischemia times and lower numbers of postpurification islet equivalents, purity, transplant rate, and stimulation index (all P < 0.05). Six percent of the preparations accepted for transplantation showed microbial contamination after isolation (12/200); 9 of 12 were Candida species. Six patients were transplanted with a sample with late microbial growth discovered after the infusion. Insulin independence rate was not affected. This risk of transplanting a contaminated islets preparation was reduced by half following the implementation of an additional sampling after 24 h of islet culture. Pancreas preservation fluid microbial contamination is associated with lower transplant rate and poorer in vitro function, but not with changes in graft survival. Culture medium testing 1 day after isolation reduces the risk of incidental transplantation with contaminated islets.

[Cystic lesions of the pancreas from the general practitioner's point of view]. / Les lésions kystiques du pancréas sous l'angle du médecin de premier recours.

The detection rate of cystic lesions of the pancreas has increased following the widespread use of high-resolution imaging technologies. CT-scan, MRI and echo-endoscopy are diagnostic modalities. Pseudocyst is the most common lesion. It is benign and can be managed with endoscopic treatment. Mucinous cystic neoplasia and Intraductal Papillary Mucinous Neoplasia (IPMN) carry a risk for malignant transformation. The surgical treatment of these lesions has to be discussed by a multidisciplinary board. Serous cystic neoplasia and pseudopapillar and solid neoplasia are two rare types of lesion. The aim of this article is to present the diagnostic pathway and the management of these lesions from the general practitioner point of view.

[Management of peritoneal carcinomatosis with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy]. / Prise en charge de la carcinose péritonéale par chirurgie cytoréductive et chimiothérapie hyperthermique intrapéritonéale.

In 2016, peritoneal carcinomatosis can be considered as a chronic disease that can be treated and sometimes cured. Hyperthermic Intra PEritoneal Chemotherapy (HIPEC) is a procedure developed in the eighties. Combined with CytoReductive (CR) surgery, this protocol underwent a considerable expansion in Washington Cancer Institute. CR combined with HIPEC was demonstrated to be the only curative treatment for PseudoMyxoma Peritonei syndrome (PMP). It is actually approved in the management of peritoneal carcinomatosis of ovarian, colorectal, or peritoneal primitive (mesothelioma) origin but is still studied for gastric cancer. CR/HIPEC is associated with an important mortality and morbidity. This article takes stock of indications to CR/HIPEC.

Microencapsulated human mesenchymal stem cells decrease liver fibrosis in mice.

BACKGROUND & AIMS: Mesenchymal stem cell (MSC) transplantation was shown to be effective for the treatment of liver fibrosis, but the mechanisms of action are not yet fully understood. We transplanted encapsulated human MSCs in two mouse models of liver fibrosis to determine the mechanisms behind the protective effect. METHODS: Human bone marrow-derived MSCs were microencapsulated in novel alginate-polyethylene glycol microspheres. In vitro, we analyzed the effect of MSC-conditioned medium on the activation of hepatic stellate cells and the viability, proliferation, cytokine secretion, and differentiation capacity of encapsulated MSCs. The level of fibrosis induced by bile duct ligation (BDL) or carbon tetrachloride (CCl4) was assessed after intraperitoneal transplantation of encapsulated MSCs, encapsulated human fibroblasts, and empty microspheres. RESULTS: MSC-conditioned medium inhibited hepatic stellate cell activation and release of MSC secreted anti-apoptotic (IL-6, IGFBP-2) and anti-inflammatory (IL-1Ra) cytokines. Viability, proliferation, and cytokine secretion of microencapsulated MSCs were similar to those of non-encapsulated MSCs. Within the microspheres, MSCs maintained their capacity to differentiate into adipocytes, chondrocytes, and osteocytes. 23% (5/22) of the MSC clones were able to produce anti-inflammatory IL-1Ra in vitro. Microencapsulated MSCs significantly delayed the development of BDL- and CCl4-induced liver fibrosis. Fibroblasts had an intermediate effect against CCl4-induced fibrosis. Mice transplanted with encapsulated MSCs showed lower mRNA levels of collagen type I, whereas levels of matrix metalloproteinase 9 were significantly higher. Human IL-1Ra was detected in the serum of 36% (4/11) of the mice transplanted with microencapsulated MSCs. CONCLUSIONS: MSC-derived soluble molecules are responsible for an anti-fibrotic effect in experimental liver fibrosis.

Improved liver function after portal vein embolization and an elective right hepatectomy.

BACKGROUND: Portal vein embolization (PVE) is used before extensive hepatic resections to increase the volume of the future remnant liver within acceptable safety margins (conventionally >0.6% of the patient's weight). The objective was to determine whether pre-operative PVE impacts on post-operative liver function independently from the increase in liver volume. METHODS: The post-operative liver function of patients who underwent an anatomical right liver resection with (n = 28) and without (n = 53) PVE were retrospectively analysed. Donors of the right liver were also analysed (LD) (n = 17). RESULTS: Patient characteristics were similar, except for age, weight and American Society of Anesthesiologists (ASA) score that were lower in LD. Post-operative factor V and bilirubin levels were, respectively, higher and lower in patients with PVE compared with patients without PVE or LD (P < 0.05). Patients with PVE had an increased blood loss, blood transfusions and sinusoidal obstruction syndrome. The day-3 bilirubin level was 40% lower in the PVE group compared with the no-PVE group after adjustment for body weight, chemotherapy, operating time, Pringle time, blood transfusions, remnant liver volume, pre-operative bilirubin level and pre-operative prothrombin ratio (P = 0.001). CONCLUSIONS: For equivalent volumes, the immediate post-operative hepatic function appears to be better in livers prepared with PVE than in unprepared livers. Future studies should analyse whether the conventional inferior volume limit that allows a safe liver resection may be lowered when a PVE is performed.

Islet of Langerhans isolation from pediatric and juvenile donor pancreases.

Islet grafts isolated from young donors allow superior functional outcomes but are often associated with poor islet isolation yields. The objective of this study was to comparatively analyze the outcomes of islet isolation between young and older donors. We retrospectively analyzed 564 pancreas isolations performed at our institution. Isolation outcomes were compared between donors aged ≤20 years (n = 42, YD) and >20 years (n = 522, OD). Isolation procedure was identical in both groups. Prepurification percentage of embedded islets was higher in YD (44.3 ± 22.7% vs. 24.9 ± 20.9%, P < 0.001). This led to a lower recovery rate in YD (48% vs. 76%, P = 0.002) and hence lower postpurification IEQ/g pancreas in YD (2 412 ± 1 789 IEQ/g vs. 3 194 ± 1 892 IEQ/g, P = 0.01). Final yield was 180 982 ± 128 073 IEQ in YD and 244 167 ± 134 137 IEQ in OD, (P = 0.006). In vitro function was markedly, albeit nonsignificantly, higher in YD (SI: 4.5 ± 5.1 vs. 3.0 ± 5.7, P = 0.350). Proportion of transplanted preparations was similar in both groups, 38% (16/42) in YD vs. 43% (224/522) in OD, P = 0.628. In spite of isolation and purification difficulties, pancreases from young donors allowed similar islet transplantation rates as older donors. Efforts should be directed at improving islet extraction in these donors to realize their full potential for islet transplantation.

Clinical outcome in acute small bowel obstruction after surgical or conservative management.

BACKGROUND: Small bowel obstruction (SBO) is characterized by a high rate of recurrence. In the present study, we aimed to compare the outcomes of patients managed either by conservative treatment or surgical operation for an episode of SBO. METHODS: The outcomes of all patients hospitalized at a single center for acute SBO between 2004 and 2007 were assessed. The occurrence of recurrent hospitalization, surgery, SBO symptoms at home, and mortality was determined. RESULTS: Among 221 patients admitted with SBO, 136 underwent a surgical procedure (surgical group) and 85 were managed conservatively (conservative group). Baseline characteristics were similar between treatment groups. The median follow-up time (interquartile range) was 4.7 (3.7-5.8) years. Nineteen patients (14.0 %) of the surgical group were hospitalized for recurrent SBO versus 25 (29.4 %) of the conservative group [hazard ratio (HR), 0.5; 95 % CI, 0.3-0.9]. The need for a surgical management of a new SBO episode was similar between the two groups, ten patients (7.4 %) in the surgical group and six patients (7.1 %) in the conservative group (HR, 1.1; 95 % CI, 0.4-3.1). Five-year mortality from the date of hospital discharge was not significantly different between the two groups (age- and sex-adjusted HR, 1.1; 95 % CI, 0.6-2.1). A follow-up evaluation was obtained for 130 patients. Among them, 24 patients (34.8 %) of the surgical group and 35 patients (57.4 %) of the conservative group had recurrent SBO symptoms (odds ratio, 0.4; 95 % CI, 0.2-0.8). CONCLUSIONS: The recurrence of SBO symptoms and new hospitalizations were significantly lower after surgical management of SBO compared with conservative treatment.

Liver Transplant Costs and Activity After United Network for Organ Sharing Allocation Policy Changes.

Importance: A new liver allocation policy was implemented by United Network for Organ Sharing (UNOS) in February 2020 with the stated intent of improving access to liver transplant (LT). There are growing concerns nationally regarding the implications this new system may have on LT costs, as well as access to a chance for LT, which have not been captured at a multicenter level. Objective: To characterize LT volume and cost changes across the US and within specific center groups and demographics after the policy implementation. Design, Setting, and Participants: This cross-sectional study collected and reviewed LT volume from multiple centers across the US and cost data with attention to 8 specific center demographics. Two separate 12-month eras were compared, before and after the new UNOS allocation policy: March 4, 2019, to March 4, 2020, and March 5, 2020, to March 5, 2021. Data analysis was performed from May to December 2022. Main Outcomes and Measures: Center volume, changes in cost. Results: A total of 22 of 68 centers responded comparing 1948 LTs before the policy change and 1837 LTs postpolicy, resulting in a 6% volume decrease. Transplants using local donations after brain death decreased 54% (P < .001) while imported donations after brain death increased 133% (P = .003). Imported fly-outs and dry runs increased 163% (median, 19; range, 1-75, vs 50, range, 2-91; P = .009) and 33% (median, 3; range, 0-16, vs 7, range, 0-24; P = .02). Overall hospital costs increased 10.9% to a total of $46 360 176 (P = .94) for participating centers. There was a 77% fly-out cost increase postpolicy ($10 600 234; P = .03). On subanalysis, centers with decreased LT volume postpolicy observed higher overall hospital costs ($41 720 365; P = .048), and specifically, a 122% cost increase for liver imports ($6 508 480; P = .002). Transplant centers from low-income states showed a significant increase in hospital (12%) and import (94%) costs. Centers serving populations with larger proportions of racial and ethnic minority candidates and specifically Black candidates significantly increased costs by more than 90% for imported livers, fly-outs, and dry runs despite lower LT volume. Similarly, costs increased significantly (>100%) for fly-outs and dry runs in centers from worse-performing health systems. Conclusions and Relevance: Based on this large multicenter effort and contrary to current assumptions, the new liver distribution system appears to place a disproportionate burden on populations of the current LT community who already experience disparities in health care. The continuous allocation policies being promoted by UNOS could make the situation even worse.

Matching for HLA-DR excluding diabetogenic HLA-DR3 and HLA-DR4 predicts insulin independence after pancreatic islet transplantation.

Introduction: In pancreatic islet transplantation, the exact contribution of human leukocyte antigen (HLA) matching to graft survival remains unclear. Islets may be exposed to allogenic rejection but also the recurrence of type 1 diabetes (T1D). We evaluated the HLA-DR matching, including the impact of diabetogenic HLA-DR3 or HLA-DR4 matches. Methods: We retrospectively examined the HLA profile in 965 transplant recipients and 2327 islet donors. The study population was obtained from patients enrolled in the Collaborative Islet Transplant Registry. We then identified 87 recipients who received a single-islet infusion. Islet-kidney recipients, 2nd islet infusion, and patients with missing data were excluded from the analysis (n=878). Results: HLA-DR3 and HLA-DR4 were present in 29.7% and 32.6% of T1D recipients and 11.6% and 15.8% of the donors, respectively. We identified 52 T1D islet recipients mismatched for HLA-DR (group A), 11 with 1 or 2 HLA-DR-matches but excluding HLA-DR3 and HLA- DR4 (group B), and 24 matched for HLA-DR3 or HLA-DR4 (group C). Insulin-independence was maintained in a significantly higher percentage of group B recipients from year one through five post-transplantation (p<0.01). At five-year post-transplantation, 78% of group B was insulin-independent compared to 24% (group A) and 35% (group C). Insulin-independence correlated with significantly better glycemic control (HbA1c <7%), fasting blood glucose, and reduced severe hypoglycemic events. Matching HLA-A-B-DR (≥3) independently of HLA- DR3 or HLA-DR4 matching did not improve graft survival. Conclusion: This study suggests that matching HLA-DR but excluding the diabetogenic HLA-DR3 and/or 4 is a significant predictor for long-term islet survival.

A new clinical severity score for the management of acute small bowel obstruction in predicting bowel ischemia: a cohort study.

BACKGROUND: Small bowel obstruction (SBO) is a common hospital admission diagnosis. Identification of patients who will require a surgical resection because of a nonviable small bowel remains a challenge. Through a prospective cohort study, the authors aimed to validate risk factors and scores for intestinal resection, and to develop a practical clinical score designed to guide surgical versus conservative management. PATIENTS AND METHODS: All patients admitted for an acute SBO between 2004 and 2016 in the center were included. Patients were divided in three categories depending on the management: conservative, surgical with bowel resection, and surgical without bowel resection. The outcome variable was small bowel necrosis. Logistic regression models were used to identify the best predictors. RESULTS: Seven hundred and thirteen patients were included in this study, 492 in the development cohort and 221 in the validation cohort. Sixty-seven percent had surgery, of which 21% had small bowel resection. Thirty-three percent were treated conservatively. Eight variables were identified with a strong association with small bowel resection: age 70 years of age and above, first episode of SBO, no bowel movement for greater than or equal to 3 days, abdominal guarding, C-reactive protein greater than or equal to 50, and three abdominal computer tomography scanner signs: small bowel transition point, lack of small bowel contrast enhancement, and the presence of greater than 500 ml of intra-abdominal fluid. Sensitivity and specificity of this score were 65 and 88%, respectively, and the area under the curve was 0.84 (95% CI: 0.80-0.89). CONCLUSION: The authors developed and validated a practical clinical severity score designed to tailor management of patients presenting with an SBO.

DCD liver transplant in patients with a MELD over 35.

Introduction: Donation after circulatory death (DCD) liver transplantation (LT) makes up well less than 1% of all LTs with a Model for End-Stage Liver Disease (MELD)≥35 in the United States. We hypothesized DCD-LT yields acceptable ischemia-reperfusion and reasonable outcomes for recipients with MELD≥35. Methods: We analyzed recipients with lab-MELD≥35 at transplant within the UCSF (n=41) and the UNOS (n=375) cohorts using multivariate Cox regression and propensity score matching. Results: In the UCSF cohort, five-year patient survival was 85% for DCD-LTs and 86% for matched-Donation after Brain Death donors-(DBD) LTs (p=0.843). Multivariate analyses showed that younger donor/recipient age and more recent transplants (2011-2021 versus 1999-2010) were associated with better survival. DCD vs. DBD graft use did not significantly impact survival (HR: 1.2, 95%CI 0.6-2.7). The transaminase peak was approximately doubled, indicating suggesting an increased ischemia-reperfusion hit. DCD-LTs had a median post-LT length of stay of 11 days, and 34% (14/41) were on dialysis at discharge versus 12 days and 22% (9/41) for DBD-LTs. 27% (11/41) DCD-LTs versus 12% (5/41) DBD-LTs developed a biliary complication (p=0.095). UNOS cohort analysis confirmed patient survival predictors, but DCD graft emerged as a risk factor (HR: 1.5, 95%CI 1.3-1.9) with five-year patient survival of 65% versus 75% for DBD-LTs (p=0.016). This difference became non-significant in a sub-analysis focusing on MELD 35-36 recipients. Analysis of MELD≥35 DCD recipients showed that donor age of <30yo independently reduced the risk of graft loss by 30% (HR, 95%CI: 0.7 (0.9-0.5), p=0.019). Retransplant status was associated with a doubled risk of adverse event (HR, 95%CI: 2.1 (1.4-3.3), p=0.001). The rejection rates at 1y were similar between DCD- and DBD-LTs, (9.3% (35/375) versus 1,541 (8.7% (1,541/17,677), respectively). Discussion: In highly selected recipient/donor pair, DCD transplantation is feasible and can achieve comparable survival to DBD transplantation. Biliary complications occurred at the expected rates. In the absence of selection, DCD-LTs outcomes remain worse than those of DBD-LTs.