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Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

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., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Extracellular vesicles (EVs) are major contributors to immunological responses following solid organ transplantation. Donor derived EVs are best known for their role in transplant rejection through transferring donor major histocompatibility complex proteins to recipient antigen presenting cells, a phenomenon known as ‛cross-decoration'. In contrast, donor liver-derived EVs are associated with organ tolerance in small animal models. Therefore, the cellular source of EVs and their cargo could influence their downstream immunological effects. To investigate the immunological effects of EVs released by the liver in a physiological and transplant-relevant model, we isolated EVs being produced during normothermic ex vivo liver perfusion (NEVLP), a novel method of liver storage prior to transplantation. We found EVs were produced by the liver during NEVLP, and these EVs contained multiple anti-inflammatory miRNA species. In terms of function, liver-derived EVs were able to cross-decorate allogeneic cells and suppress the immune response in allogeneic mixed lymphocyte reactions in a concentration-dependent fashion. In terms of cytokine response, the addition of 1 × 10 9 EVs to the mixed lymphocyte reactions significantly decreased the production of the inflammatory cytokines TNF-α, IL-10 and IFN-γ. In conclusion, we determined physiologically produced liver-derived EVs are immunologically regulatory, which has implications for their role and potential modification in solid organ transplantation., (© 2024 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

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., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

End-stage kidney disease patients who are referred for transplant undergo an extensive evaluation process to ensure their health prior to transplant due in part to the shortage of available organs. Although management and surveillance guidelines exist for malignancies identified in the transplant and waitlist populations, less is written about the management of premalignant lesions in this population. This review covers the less common premalignant lesions (intraductal papillary mucinous neoplasm, gastrointestinal stromal tumor, thymoma, and pancreatic neuroendocrine tumor) that can be found in the transplant candidate population. High-level evidence for the management of these rarer premalignant lesions in the transplant population is lacking, and this review extrapolates evidence from the general population and should not be a substitute for a multidisciplinary discussion with medical and surgical oncologists., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., (© 2023 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Nodular regenerative hyperplasia (NRH) is a primary disease of the liver that may cause noncirrhotic portal hypertension. Common causes include autoimmune, hematologic, immune deficiency, and myeloproliferative disorders. Given the limited data regarding the development of NRH in contemporary immunosuppressive protocols and the occurrence of NRH post-liver transplantation, we systematically reviewed NRH as it pertains to liver transplantation. We performed a comprehensive search for NRH and transplantation. Nineteen studies were identified with relevant data for NRH as an indication for a liver transplant. Thirteen studies were identified with relevant data pertaining to NRH development after liver transplant. Pooled analysis revealed 0.9% of liver transplant recipients had NRH. A total of 113 patients identified with NRH underwent liver transplantation. Most series report transplants done after the failure of endoscopic banding and TIPS management of portal hypertension. Reported 5-year graft and patient survival ranged from 73%-78% and 73%-90%. The pooled incidence of NRH after liver transplant for all indications was 2.9% and caused complications of portal hypertension. Complications related to portal hypertension secondary to NRH are a rare indication for a liver transplant. NRH can develop at any time after liver transplantation often without an identifiable cause, which may lead to portal hypertension requiring treatment or even re-transplantation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors PS and DA declared that they were editorial board members of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2023 Biesterveld, Schroder, Hitchcock, Bolognese, Kim and Al-Adra.)

Hepatocellular carcinoma (HCC) is one of the most fatal cancers in the world. There is an urgent need to understand the molecular background of HCC to facilitate the identification of biomarkers and discover effective therapeutic targets. Published transcriptomic studies have reported a large number of genes that are individually significant for HCC. However, reliable biomarkers remain to be determined. In this study, built on max-linear competing risk factor models, we developed a machine learning analytical framework to analyze transcriptomic data to identify the most miniature set of differentially expressed genes (DEGs). By analyzing 9 public whole-transcriptome datasets (containing 1184 HCC samples and 672 nontumor controls), we identified 5 critical differentially expressed genes (DEGs) (ie, CCDC107, CXCL12, GIGYF1, GMNN, and IFFO1) between HCC and control samples. The classifiers built on these 5 DEGs reached nearly perfect performance in identification of HCC. The performance of the 5 DEGs was further validated in a US Caucasian cohort that we collected (containing 17 HCC with paired nontumor tissue). The conceptual advance of our work lies in modeling gene-gene interactions and correcting batch effect in the analytic framework. The classifiers built on the 5 DEGs demonstrated clear signature patterns for HCC. The results are interpretable, robust, and reproducible across diverse cohorts/populations with various disease etiologies, indicating the 5 DEGs are intrinsic variables that can describe the overall features of HCC at the genomic level. The analytical framework applied in this study may pave a new way for improving transcriptome profiling analysis of human cancers., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Patients with acute and chronic liver disease present with a wide range of disease states and severity that may require liver transplantation (LT). Physiologic alterations occur that are dynamic throughout all phases of perioperative care, creating complex management scenarios that necessitate multidisciplinary clinical care. Specifically, alterations in hemostasis in liver disease can be pronounced and evolve with disease progression over time. Recent studies and society guidance address this emerging paradigm and offer recommendations to assist with hemostatic management in patients with liver disease. However, patients undergoing LT are unique and diverse, often with unstable disease that requires specialized approaches. Our aim is to provide a focused review of hemostatic management of the LT patient, distinguish unique aspects of the three main phases of care (before LT, perioperative, and after LT), and identify knowledge gaps and critical areas of future research., (© 2022 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Unanticipated transfusion requirements during liver transplantation can delay lifesaving intraoperative resuscitation and strain blood bank resources. Risk-stratified preoperative blood preparation can mitigate these deleterious outcomes., Study Design and Methods: A two-tiered blood preparation protocol for liver transplantation was retrospectively evaluated. Eleven binary variables served as criteria for high-risk (HR) allocation. Primary outcomes included red blood cell (RBC), plasma (FFP), and platelet (Plt) utilization. Secondary outcomes included product under- and overpreparation. Contingency tables for transfusion requirements above the population means were generated using 15 clinical variables. Modified protocols were developed and retrospectively optimized using the study population., Results: Of 225 recipients, 102 received HR preoperative orders, which correlated to higher intraoperative transfusion requirements. However, univariate analysis identified only two statistical risk factors per product: Hgb ≤7.8 g/dl (p < .001) and MELD ≥38 (p = .035) for RBCs, Hgb ≤7.8 g/dl (p = .002) and acute alcoholic hepatitis (p = 0.015) for FFP, and Hgb ≤7.8 g/dl (p = .001) and normothermic liver preservation (p = .037) for Plts. Based on these findings, we developed modified protocols for individual products, which were evaluated retrospectively for their effectiveness at reducing under-preparatory events while limiting product overpreparation. Cohort statistics were used to define the preparation strategy for each protocol. Retrospective comparative analysis demonstrated the superiority of the modified protocols by improving the under-preparation rate from 24% to <10% for each product, which required a 1.56-fold and 1.44-fold increase in RBC and FFP overpreparation, respectively. Importantly, there was no difference in Plt overpreparation., Discussion: We report translatable data-driven blood bank preparation protocols for liver transplantation., (© 2022 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Enteric drainage in pancreas transplantation is complicated by an enteric leak in 5%-8%, frequently necessitating pancreatectomy. Pancreatic salvage outcomes are not well studied. Risk factors for enteric leak were examined and outcomes of attempted graft salvage were compared to immediate pancreatectomy. Pancreas transplants performed between 1995 and 2018 were reviewed. Donor, recipient, and organ variables including demographics, donor type, ischemic time, kidney donor profile index, and pancreas donor risk index were analyzed. Among 1153 patients, 33 experienced enteric leaks (2.9%). Donors of allografts that developed leak were older (37.9y vs. 29.0y, p = .001), had higher KDPI (37% vs. 24%, p < .001), higher pancreas donor risk index (1.83 vs. 1.32, p < .001), and longer cold ischemic time (16.5 vs. 14.8 h, p = .03). Intra-abdominal abscess and higher blood loss decreased the chance of successful salvage. Enteric leak increased 6-month graft loss risk (HR 13.9[CI 8.5-22.9], p < .001). However, 50% (n = 12) of allografts undergoing attempted salvage survived long-term. After 6 months of pancreas graft survival, salvage and non-leak groups had similar 5-year graft survival (82.5% vs. 81.5%) and mortality (90.9% vs. 93.5%). Enteric leaks remain a challenging complication. Pancreatic allograft salvage can be attempted in suitable patients and accomplished in 50% of cases without significantly increased graft failure or mortality risk., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Dysregulation of expression of functional genes and pathways plays critical roles in the etiology and progression of hepatocellular carcinoma (HCC). Next generation-based RNA sequencing (RNA-seq) offers unparalleled power to comprehensively characterize HCC at the whole transcriptome level. In this study, 17 fresh-frozen HCC samples with paired non-neoplastic liver tissue from Caucasian patients undergoing liver resection or transplantation were used for RNA-seq analysis. Pairwise differential expression analysis of the RNA-seq data was performed to identify genes, pathways, and functional terms differentially regulated in HCC versus normal tissues. At a false discovery rate (FDR) of 0.10, 13% (n = 4335) of transcripts were up-regulated and 19% (n = 6454) of transcripts were down-regulated in HCC versus non-neoplastic tissue. Eighty-five Kyoto Encyclopedia of Genes and Genomes pathways were differentially regulated (FDR, <0.10), with almost all pathways (n = 83) being up-regulated in HCC versus non-neoplastic tissue. Among the top up-regulated pathways was oxidative phosphorylation (hsa00190; FDR, 1.12E-15), which was confirmed by Database for Annotation, Visualization, and Integrated Discovery (DAVID) gene set enrichment analysis. Consistent with potential oxidative stress due to activated oxidative phosphorylation, DNA damage-related signals (e.g., the up-regulated hsa03420 nucleotide excision repair [FDR, 1.14E-04] and hsa03410 base excision repair [FDR, 2.71E-04] pathways) were observed. Among down-regulated genes (FDR, <0.10), functional terms related to cellular structures (e.g., cell membrane [FDR, 3.05E-21] and cell junction [FDR, 2.41E-07], were highly enriched, suggesting compromised formation of cellular structure in HCC at the transcriptome level. Interestingly, the olfactory transduction (hsa04740; FDR, 1.53E-07) pathway was observed to be down-regulated in HCC versus non-neoplastic tissue, suggesting impaired liver chemosensory functions in HCC. Our findings suggest oxidative phosphorylation and the associated DNA damage may be the major driving pathologic feature in HCC., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Tissue-resident dendritic cells (DCs) are essential for immunological homeostasis and hold promise for a variety of therapeutic interventions. The rare nature of tissue-resident DCs and their suboptimal description in the lab rat model has limited their characterization. To address this limitation, FMS-like tyrosine kinase 3 ligand (FLT3L) has been utilized to expand these population in vitro and in vivo for investigative or therapeutic purposes. However, conflicting reports have suggested that FLT3L can either promote immune tolerance or enhance immunogenicity, necessitating clarification of the effects of FLT3L on DC phenotype and functionality. We first paired single-cell RNA sequencing with multicolour spectral flow cytometry to provide an updated strategy for the identification of tissue-resident classical and plasmacytoid DCs in the rat model. We then administered FLT3L to Lewis rats in vivo to investigate its effect on tissue-resident DC enumeration and phenotype in the liver, spleen, and mesenteric lymph nodes. We found that FLT3L expands classical DCs (cDCs) 1 and 2 in a dose-dependent manner and that cDC1 and cDC2 in secondary lymphoid organs had altered MHC I, MHC II, CD40, CD80, CD86, and PD-L1 cell-surface expression levels following FLT3L administration. These changes were accompanied by an increase in gene expression levels of toll-like receptors 2, 4, 7, and 9 as well as inflammatory cytokines IL-6 and TNF-α. In conclusion, FLT3L administration in vivo increases cDC enumeration in the liver, spleen, and mesenteric lymph nodes accompanied by a tissue-restricted alteration in expression of antigen presentation machinery and inflammatory mediators., (© 2022 The Scandinavian Foundation for Immunology.)

Introduction: Normothermic ex vivo liver perfusion (NEVLP) is an organ preservation method that allows liver graft functional assessment prior to transplantation. One key component of normothermic perfusion solution is an oxygen carrier to provide oxygen to the liver to sustain metabolic activities. Oxygen carriers such as red blood cells (RBCs) or hemoglobin-based oxygen carriers have an unknown effect on the liver-resident immune cells during NEVLP. In this study, we assessed the effects of different oxygen carriers on the phenotype and function of liver-resident immune cells., Methods: Adult Lewis rat livers underwent NEVLP using three different oxygen carriers: human packed RBCs (pRBCs), rat pRBCs, or Oxyglobin (a synthetic hemoglobin-based oxygen carrier). Hourly perfusate samples were collected for downstream analysis, and livers were digested to isolate immune cells. The concentration of common cytokines was measured in the perfusate, and the immune cells underwent phenotypic characterization with flow cytometry and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The stimulatory function of the liver-resident immune cells was assessed using mixed lymphocyte reactions., Results: There were no differences in liver function, liver damage, or histology between the three oxygen carriers. qRT-PCR revealed that the gene expression of nuclear factor κ light chain enhancer of activated B cells (NF-kB), Interleukin (IL-1β), C-C motif chemokine ligand 2 (CCL2), C-C motif chemokine ligand 7 (CCL7), and CD14 was significantly upregulated in the human pRBC group compared with that in the naive, whereas the rat pRBC and Oxyglobin groups were not different from that of naive. Flow cytometry demonstrated that the cell surface expression of the immune co-stimulatory protein, CD86, was significantly higher on liver-resident macrophages and plasmacytoid dendritic cells perfused with human pRBC compared to Oxyglobin. Mixed lymphocyte reactions revealed increased allogeneic T-cell proliferation in the human and rat pRBC groups compared to that in the Oxyglobin group., Conclusions: Liver-resident immune cells are important mediators of rejection after transplantation. In this study, we show that the oxygen carrier used in NEVLP solutions can affect the phenotype of these liver-resident immune cells. The synthetic hemoglobin-based oxygen carrier, Oxyglobin, showed the least amount of liver-resident immune cell activation and the least amount of allogeneic proliferation when compared to human or rat pRBCs. To mitigate liver-resident immune cell activation during NEVLP (and subsequent transplantation), Oxyglobin may be an optimal oxygen carrier., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jennings, Carlson, Little, Verhagen, Nagendran, Liu, Verhoven, Zeng, McMorrow, Chlebeck and Al-Adra.)

Introduction: The significance of bile duct tumor-associated thrombi in patients undergoing transplantation for hepatocellular carcinoma (HCC) is controversial. Therefore, we performed a systematic review of the literature with pooled analysis to investigate the impact of biliary invasion on HCC recurrence and patient survival., Methods: Of 1,584 references screened, eight were included for analysis. Demographics, patient and tumor factors, recurrence, and survival data were analyzed. Time to recurrence and death were extracted from each paper by cross-referencing survival curves., Results: A total of 35 patients across eight studies were pooled for analysis when follow-up data were available. At 1 year, 92.9% of patients undergoing transplantation for HCC with bile duct thrombi were alive. Overall survival at 3 and 5 years was 65.5 and 49.6%, respectively. At 1 year, 21.6% of patients had recurrence of their disease, while at 3 years, 50.4% of patients had recurrence. Of those patients with recurrence in the first year, 71.4% recurred within the first 3 months after transplantation., Conclusion: Overall patient survival decreased within the first 5 years, but then stabilized. The 5-year survival rate of 49.6% in this pooled analysis is lower than that reported for patients undergoing transplantation for HCC within the Milan criteria (50-78%) or recent reports in patients with portal vein involvement (63.6%), though data is limited by a lack of long-term follow-up in this understudied population. Transplantation for patients with HCC with bile duct involvement may be a viable treatment option, warranting further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kim, Bolognese, Little, Hitchcock, Leverson and Al-Adra.)

CD8 T cells play a key role in cancer immunotherapy and allograft rejection. However, it is not clear how they kill cells and tissues that do not have the agonist peptide-major histocompatibility complex (MHC) on their surface, as in the settings of MHC class I deficient tumors and indirect rejection of MHC-mismatched transplants. CD8 T cells might respond to agonist antigen cross-presented on hematopoietic cells, leading to a "bystander" rejection. Alternatively, they may recognize agonist antigen cross-presented on recipient endothelial cells and kill the tissue's vital blood supply. The latter mechanism predicts that all non-vascularized grafts, grafts dependent on in-growth of recipient blood vessels, will be susceptible to CD8 T cell mediated indirect rejection. In contrast, we show here that non-vascularized transplants, bearing the same agonist antigen, are not universally susceptible to this rejection pathway. Non-vascularized skin, but not islet or heart tissue transplants were indirectly rejected by CD8 T cells. Furthermore, CD8 T cells were able to indirectly reject skin grafts when recipient MHC class I expression was restricted to bone marrow derived cells but not when it was restricted to radioresistant cells (e.g. endothelial cells). These findings argue against a major role for endothelial cell cross-presentation in killing of tissue that does not present the agonist peptide-MHC class I. Instead, the data suggests that cross-presentation by recipient hematopoietic cells underlies the CD8 T cell mediated killing of tissue that is unable to directly present the target peptide-MHC class I.

Background: The use of Hepatitis C (HCV) NAT positive allografts remains unusual and is clustered at few centers. We conducted a contemporary literature review to assess whether patient and clinician attitudes toward viremic organs impact acceptance., Methods: Databases including PubMed, MEDLINE, and SCOPUS databases were reviewed to identify studies focused on evaluating patient and provider perceptions of HCV NAT positive organ use within the DAA era (January 2015-April 2021). Search included MeSH terms related to Hepatitis C, transplantation, and patient and clinician attitudes. Two investigators extracted study characteristics including information on willingness to accept viremic organs, HCV-specific outcomes knowledge, HCV-specific concerns, and factors that contributed to acceptance or non-acceptance., Results: Eight studies met all inclusion criteria. These included three pretransplant patient-directed studies, two post-transplant patient-directed studies, one pre- and post-transplant patient-directed study, and two clinician-directed studies. Common themes identified were concerns regarding HCV cure rates, viremic organ quality, DAA cost, stigma, and the possibility of HCV transmission to household members. The perception of decreased waitlist time was associated with viremic organ acceptance. Physician trust played a mixed role in acceptance patterns., Conclusions: Knowledge of high cure rates, shorter waitlist times, and higher organ quality appear to have the highest impact on organ acceptance., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Normothermic ex vivo liver perfusion (NEVLP) is a novel system for organ preservation that may improve over static cold storage clinically and offers the chance for graft modification prior to transplantation. Although recent studies have shown the presence of inflammatory molecules during perfusion, none have yet shown the effects of NEVLP on liver-resident immune cell activation. We investigated the effects of NEVLP on liver-resident immune cell activation and assessed the ability of anti-inflammatory cytokines interleukin 10 (IL10) and transforming growth factor β (TGF-β) to improve organ function and reduce immune activation during perfusion. Rat livers were perfused for 4 hours at 37°C with or without the addition of 20 ng/mL of each IL10 and TGF-β (n = 7). Naïve and cold storage (4 hours at 4°C) livers served as controls (n = 4). Following preservation, gene expression profiles were assessed through single-cell RNA sequencing; dendritic cell and macrophage activation was measured by flow cytometry; and cytokine production was assessed by enzyme-linked immunosorbent assay. NEVLP induced a global inflammatory gene expression signature, most notably in liver-resident macrophages and dendritic cells, which was accompanied by an increase in cell-surface levels of major histocompatibility complex (MHC) II, CD40, and CD86. Immune activation was partially ameliorated by IL10 and TGF-β treatment, but no changes were observed in inflammatory cytokine production. Overall levels of liver damage and cellular apoptosis from perfusion were low, and liver function was improved with IL10 and TGF-β treatment. This is the first study to demonstrate that liver-resident immune cells gain an activated phenotype during NEVLP on both the gene and protein level and that this activation can be reduced through therapeutic intervention with IL10 and TGF-β., (Copyright © 2021 by the American Association for the Study of Liver Diseases.)

Objectives: The use of deceased after circulatory death liver allografts in patients with primary sclerosing cholangitis is controversial, given the increased risk of graft complications in patients with primary sclerosing cholangitis. We hypothesized that transplant of deceased after circulatory death livers into recipients with primary sclerosing cholangitis when appropriately selected using the UK deceased after circulatory death scoring system is not associated with increased graft failure and mortality., Materials and Methods: We analyzed 99 229 transplants (between January 2001 and December 2018) from the Organ Procurement and Transplantation Network database. Deceased after circulatory death transplants were stratified by the UK scoring system as low risk or high risk. We identified 3958 patients with primary sclerosing cholangitis who received deceased after brain death transplant and 95 patients with primary sclerosing cholangitis who received deceased after circulatory death transplant., Results: As expected, 5-year graft survival was lower in the circulatory death recipient group (69.0% vs 78.4%; P = .02). However, 5-year graft survival was significantly lower in the high-risk versus low-risk UK scoring system group (60.0% vs 75.4%; P = .02), with rate in the low-risk group similar to the brain death recipient group (78.4% vs 75.4%; P = .52). On multivariate analysis, the high-risk group had significantly increased risk of graft loss (hazard ratio of 1.92; P = .01). However, the low-risk group had equivalent graft survival to the brain death recipient group (hazard ratio of 1.23; P = .31)., Conclusions: Graft failure was higher in patients with primary sclerosing cholangitis who received livers from deceased after circulatory death donors; however, the risk of graft loss was abrogated using appropriately matched donor and recipient combinations.

Objectives: Despite advances in surgical techniques and organ preservation, transplant ureteric strictures remain a common complication in kidney transplantation. A variety of endourological and surgical techniques have been utilized; however, there is a lack of consensus on the optimal modality in dealing with these complex cases., Materials and Methods: We present challenging ureteral reconstruction cases after failed attempts at ureteral dilatation, failed conventional open repairs, and/or with bladder dysfunction., Results: All renal allografts were salvaged by successful use of bladder Boari flap and intestinal segment interpositions/diversions., Conclusions: Operative repair remains the most durable and successful approach, and minimally invasive options should be reserved for nonsurgical candidates, with consideration of a single attempt in patients with early, distal, short (<2 cm), nonischemic strictures.

Aim: The impact of pre-transplant (pre-TXP) bariatric surgery (BS) on outcomes after liver transplant (LTX) has not been completely elucidated. Roux-en Y gastric bypass (RYGB) is one of the most common BS procedures. The primary objective of this study was to identify the risk of infection in LTX recipients with pre-TXP RYGB., Methods: Adult patients with LTX between 1/1/2001 and 9/30/2018 at our center were screened for pre-TXP RYGB; patients with gastrectomy via sleeve or banding were excluded. Patients with no history of BS pre- or post-transplant were placed in a comparator group, matched 2:1 via incidence density sampling on age epoch., Results: There were 16 LTX recipients with pre-TXP RYGB matched to 32 controls. Median time from RYGB to transplant was 11.7 years. Mean weight loss was 66 ± 19 kg. There were significantly more women with pre-TXP RYGB than in the matched control (RYGB:68.8% vs control:25%, P = .009). Demographics were otherwise similar between groups. Pre-TXP RYGB did not significantly increase hospital or ICU length of stay (P = .5, P = .3) but was associated with a significantly increased rate of fungal infection at 1 year (RYGB:33.4% vs control:9.7%, P = .01), and a numerical trend to increased bacterial infection (RYGB:56.2% vs control:32.2%, P = .09)., Conclusion: Despite the substantial weight loss attributed to BS, patients with pre-TXP RYGB demonstrated increased rates of fungal infection after transplant and trended toward increased bacterial infection. While the anatomical complexity associated with LTX surgery after RYGB did not appear to significantly affect ICU or hospital length of stay, it may have contributed to overall infectious risk, and possibly to impaired survival. Additionally, bypass of the host natural barrier defenses of the stomach could also have contributed to infectious risk. Our findings highlight the complexity of this patient population. Future prospective studies are needed to investigate risk of infection after LTX in the setting of pre-Txp BS. Potential modification in fungal prophylaxis protocols to include pre-TXP RYGB may be warranted., (© 2020 Wiley Periodicals LLC.)

Ex vivo machine perfusion (EVMP) has gained revitalized interest in recent years due to the increasing use of marginal organs which poorly tolerate the standard preservation method static cold storage (SCS). EVMP improves on SCS in a number of ways, most notably by the potential for reconditioning of the donor organ prior to transplantation without the ethical concerns associated with organ modulation before procurement. Immunomodulatory therapies administered during EVMP can influence innate and adaptive immune responses to reduce production of inflammatory molecules and polarize tissue-resident immune cells to a regulatory phenotype. The targeted inhibition of an inflammatory response can reduce ischemia-reperfusion injury following organ reoxygenation and therefore reduce incidence of graft dysfunction and rejection. Numerous approaches to modulate the inflammatory response have been applied in experimental models, with the ultimate goal of clinical translatability. Strategies to target the innate immune system include inhibiting inflammatory signaling pathways, upregulating anti-inflammatory mediators, and decreasing mitochondrial damage while those which target the adaptive immune system include mesenchymal stromal cells. Inhibitory RNA approaches target both the innate and adaptive immune systems with a focus on MHC knock-down. Future studies may address issues of therapeutic agent delivery through use of nanoparticles and explore novel strategies such as targeting co-inhibitory molecules to educate T-cells to a tolerogenic state. In this review, we summarize the cellular and acellular contributors to allograft dysfunction and rejection, discuss the strategies which have been employed pre-clinically during EVMP to modulate the donor organ immune environment, and suggest future directions for immunomodulatory EVMP studies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Patients undergoing evaluation for solid organ transplantation (SOT) often have a history of malignancy. Although the cancer has been treated in these patients, the benefits of transplantation need to be balanced against the risk of tumor recurrence, especially in the setting of immunosuppression. Prior guidelines of when to transplant patients with a prior treated malignancy do not take in to account current staging, disease biology, or advances in cancer treatments. To develop contemporary recommendations, the American Society of Transplantation held a consensus workshop to perform a comprehensive review of current literature regarding cancer therapies, cancer stage-specific prognosis, the kinetics of cancer recurrence, and the limited data on the effects of immunosuppression on cancer-specific outcomes. This document contains prognosis based on contemporary treatment and transplant recommendations for breast, colorectal, anal, urological, gynecological, and nonsmall cell lung cancers. This conference and consensus documents aim to provide recommendations to assist in the evaluation of patients for SOT given a history of a pretransplant malignancy., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Patients undergoing evaluation for solid organ transplantation (SOT) frequently have a history of malignancy. Only patients with treated cancer are considered for SOT but the benefits of transplantation need to be balanced against the risk of tumor recurrence, taking into consideration the potential effects of immunosuppression. Prior guidelines on timing to transplant in patients with a prior treated malignancy do not account for current staging, disease biology, or advances in cancer treatments. To update these recommendations, the American Society of Transplantation (AST) facilitated a consensus workshop to comprehensively review contemporary literature regarding cancer therapies, cancer stage specific prognosis, the kinetics of cancer recurrence, as well as the limited data on the effects of immunosuppression on cancer-specific outcomes. This document contains prognosis, treatment, and transplant recommendations for melanoma and hematological malignancies. Given the limited data regarding the risk of cancer recurrence in transplant recipients, the goal of the AST-sponsored conference and the consensus documents produced are to provide expert opinion recommendations that help in the evaluation of patients with a history of a pretransplant malignancy for transplant candidacy., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Pharmaceuticals to inhibit mammalian target of rapamycin (mTOR) protein, which plays an integral role in T cell survival and function, have been used to prevent complications associated with organ transplantation. Although studies have individually shown that resveratrol can inhibit mTOR and that inhibiting mTOR leads to attenuated immune function, no studies to date have examined these two functions conjointly under one study. Therefore, we hypothesize that resveratrol will decrease mTOR activation and expression as well as attenuate stimulated T cell activation and proliferation in peripheral blood mononuclear cells (PBMC)., Methods and Materials: Human PBMC were isolated and cultured. The cells were pre-treated with resveratrol (50 μM) overnight (18 hrs) before stimulation. The cells were collected for subsequent biochemical analysis after 1, 3, and 5 days. Additionally, the cells were stained with proliferation dye and cultured for 24 hours in PMA/Ionomycin with resveratrol for flow cytometry analysis., Results: Resveratrol treated stimulated PBMCs displayed a significant decrease in activated phosphorylation of mTOR at days 1, 3, and 5 (P < 0.0329). Markers of T cell activation, tumour necrosis factor-alpha (TNF-α) and interferon-gamma (INF-γ), were also significantly reduced along with T cell proliferation following stimulated PBMC resveratrol treatment when compared to vehicle-treated controls (P < 0.01)., Conclusion: Taken together, our data suggest that resveratrol can decrease the immune response of stimulated T-cells and inhibit the expression and activation of mTOR mediated cellular signalling under the same study setting. Therefore, resveratrol proposes a possible adjunctive therapy option for patients undergoing organ transplantation., Competing Interests: None., (AJCEI Copyright © 2020.)

Despite good organ quality, pancreata from extremely small pediatric donors (<30 kg) are generally avoided by many centers because of concerns of reduced islet cell mass and early technical failure. Therefore, we sought to compare the outcomes of small pancreas grafts (<30 kg) to those from higher weight donors from transplants performed between 1994 and 2015 (n = 1183). A total of 33 pancreata were from donors' ≤30 kg (3%), with a mean weight of 23.8 kg and mean age of 7.8 years. Patient survival was similar at 1, 5, and 10 years between recipients of ≤30 and >30 kg donors (≤30 kg: 96.8%, 86.8%, and 78.1% vs. >30 kg: 96.8%, 89.5%, and 79.1%, P = 0.5). Pancreas graft survival at 1, 5, and 10 years was also similar, ≤30 kg: 93.9%, 73.2%, and 61.0% vs. >30 kg: 87%, 73.3%, and 58.3% (P = 0.7). This graft survival pattern was also seen when comparing pancreata from ≤20 kg donors to those from >20 to 30 kg. Cause of graft loss, and metabolic and physiologic outcomes did not differ between the groups. After assessing the impact of donor weight as a continuous variable and calculating recipient-to-donor weight ratio (RDWR), we observed no effect of donor weight on patient and graft outcomes., (© 2020 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Longterm liver graft dysfunction and immunological rejection remain common adverse events, in part due to early acute rejection episodes initiated by ischemia/reperfusion injury (IRI) immediately following transplantation. Novel treatment methods are therefore required to ameliorate liver IRI and to promote longterm allograft acceptance. Extracellular vesicles (EVs) derived from tolerogenic phenotype cells may serve as a novel therapeutic option in liver transplantation due to their immunomodulatory and proregenerative effects. Studies of hepatic IRI along with animal liver allograft models have demonstrated that EVs isolated from mesenchymal stem/stromal cells, immature dendritic cells, and hepatocytes can reduce graft injury through mechanisms including enhancement of mitochondrial autophagy, inhibition of immune response, and promotion of tissue regeneration. These preclinical models may soon move translationally into clinical practice, necessitating the generation of robust methods to generate clinical-grade EVs. These methods must address issues of reproducibility and ability to scale up the tolerogenic cell cultivation, EV isolation, and EV characterization. Once generated, the efficient delivery of EVs to the donor organ prior to transplantation remains an issue that could be resolved through the novel organ storage method ex vivo machine perfusion (EVMP). In this review, we summarize studies that have used tolerogenic cell-derived EVs to ameliorate hepatic IRI and promote liver allograft acceptance, discuss the steps toward generation of clinical-grade EVs, and introduce EVMP as a novel method to efficiently deliver EVs., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

The acceptable threshold remains unknown for the percentage of macrosteatosis (MaS) and microsteatosis (MiS) to yield optimal outcomes after donation after circulatory death (DCD) liver transplantation (LT). The purpose of this analysis was to determine the impact of donor liver MaS and MiS on DCD LT outcomes. Using the Organ Procurement and Transplantation Network database, we analyzed pretransplant biopsy results from adult, solitary, DCD livers transplanted between January 1, 2006, and December 31, 2017. Kaplan-Meier analysis was used to assess graft and patient survival based on MaS and MiS severity. MiS was divided into the groups MiS ≤10% and >10%. MaS was divided into the groups MaS ≤15% and >15%. Of 7757 recovered DCD livers, 11.4% (n = 885) were biopsied and transplanted. Patients who received DCD livers with MaS >15% had significantly worse patient survival (P < 0.04), and those with MiS >10% demonstrated inferior graft and patient survival (P < 0.02). In multivariate analyses including known risk factors, both MaS >15% and MiS >10% were associated with increased risk of graft failure and patient mortality (P < 0.03). Recipient and donor age >60 years were also associated with increased risk of graft failure and patient death. This analysis demonstrates that MaS >15% and MiS >10% are additional risk factors for graft loss and patient mortality in DCD LT., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

Purpose: The effect of living donor kidney allograft size on recipient outcomes is not well understood. In this study, we sought to investigate the relationship between preoperatively measured donor kidney volume and recipient estimated glomerular filtration rate (eGFR) in living donor kidney transplantation (LDKT)., Methods: We studied computed tomography (CT) donor kidney volumes and recipient outcomes for 438 LDKTs at the Toronto General Hospital between 2007 and 2016. Estimated glomerular filtration rate (eGFR) was calculated at 1, 3, and 6 months and a multivariable linear regression model was fitted to study the effect of donor kidney volume on recipient eGFR., Results: The mean volume and weight of the donated kidneys were 157.3 (± 32.3) cc and 186.7 (± 48.7) g, respectively. Kidney volume was significantly associated with eGFR on multivariable analysis (P < 0.001). Specifically, for every 10 cc increase in kidney volume, there was a 1.68 mL/min, 1.25 mL/min and 0.97 mL/min rise in recipient eGFR at 1, 3, and 6 months, respectively., Conclusions: Donor kidney volume is a strong independent predictor of recipient eGFR in LDKT, and therefore, may be a valuable addition to predictive models of eGFR after transplant. Further research may determine if the inclusion of donor kidney volume in matching algorithms can improve recipient outcomes.

Background: The use of venovenous bypass in liver transplantation has declined over time. Few studies have examined the impact of surgical approach in cases performed exclusively without venovenous bypass. We hypothesized that advances in liver transplant anesthesia and perioperative care have minimized the importance of surgical approach in the modern era., Methods: Deceased donor liver transplants at the University of Toronto from 2000 to 2015 were reviewed, all performed without venovenous bypass. First, an unadjusted analysis was performed comparing perioperative outcomes and graft/patient survival for 3 different liver transplant techniques (caval interposition, piggyback, side-to-side cavo-cavostomy). Second, a propensity-matched analysis was performed comparing caval interposition to caval-preserving techniques., Results: One thousand two hundred thirty-three liver transplants were included in the study. On unadjusted analysis, blood loss, transfusion requirement, postoperative complications, and graft/patient survival were equivalent for the 3 different techniques. To account for possible confounding patient variables, propensity matching was performed. Analysis of the propensity-matched cohorts also demonstrated similar outcomes for caval interposition versus caval-preserving approaches., Conclusions: In the modern era at centers with a multidisciplinary team, the importance of specific liver transplant technique is minimized. Full or partial cross-clamping of the inferior vena cava is feasible without the use of venovenous bypass., Competing Interests: The authors declare no funding or conflicts of interest.

Background: Liver resection (LR) and radiofrequency ablation (RFA) are curative-intent therapies for early stages of hepatocellular carcinoma (HCC). If HCC recurs, salvage liver transplant (SLT) may constitute a treatment option., Objective: We aimed to compare the outcomes of patients transplanted for recurrent HCC after curative-intent therapies with those transplanted as initial therapy., Methods: We conducted a matched-control (1:1) cohort study comparing patients with HCC treated with primary liver transplant (PLT) with SLT after HCC recurrence. Matching was performed according to the size and number of viable tumors at explant pathology following liver transplant., Results: Between November 1999 and December 2014, 687 patients with HCC were listed for transplant at our institution. A total of 559 patients were transplanted; 509 patients were treated with PLT and 50 patients were treated with SLT for HCC recurrence after primary treatment with LR (n = 25) or RFA (n = 25). The median length of follow-up from transplant was 64 months (0.5-195), and the median time from curative-intent treatment of HCC with RFA or LR to recurrence was 9.5 months (1-36) and 14.5 months (3-143), respectively (p = 0.04). The matched cohort was composed of 48 SLT patients (23 LR and 25 RFA) and 48 PLT patients. The 5-year risk of recurrence after LT was 22% in the PLT group versus 32% in the SLT group (p = 0.53), while the 5-year actuarial patient survival after PLT was 69% versus 70% in the SLT group (p = 1)., Conclusion: Liver transplant is an effective treatment for patients with HCC recurrence following RFA or LR. Outcomes are similar in both groups.

Cystic fibrosis (CF) affects multiple organs including the lung, liver, and pancreas. Lung transplant, liver transplant, and combined lung-liver transplant have become well-established therapies for CF patients with end-stage organ failure. Thus far, however, there has been limited experience with pancreas transplantation in CF. In this report, we detail the clinical history, transplant procedure, and post-operative recovery of a patient who underwent combined lung-liver-pancreas transplant for advanced CF., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Although the primary indication for pancreas transplantation is type I diabetes, a small number of patients requires pancreas transplantation to manage combined endocrine and exocrine insufficiency that develops after extensive native pancreatic resection. The objective of this case report was to describe the operative and clinical course in 3 such patients and present an alternative technical approach., Competing Interests: The authors declare no funding or conflicts of interest.

Background: In parallel with the obesity epidemic, liver transplantation for nonalcoholic steatohepatitis (NASH) is increasing dramatically in North America. Although survival outcomes are similar to other etiologies, liver transplantation in the NASH population has been associated with significantly increased resource utilization. We sought to compare outcomes between live donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT) at a high volume North American transplant center, with a particular focus on resource utilization., Methods: The study population consists of primary liver transplants performed for NASH at Toronto General Hospital from 2000 to 2014. Recipient characteristics, perioperative outcomes, graft and patient survivals, and resource utilization were compared for LDLT versus DDLT., Results: A total of 176 patients were included in the study (48 LDLT vs 128 DDLT). LDLT recipients had a lower model for end-stage liver disease score and were less frequently hospitalized prior to transplant. Estimated blood loss and early markers of graft injury were lower for LDLT. LDLT recipients had a significantly shorter hospitalization (intensive care unit, postoperative, and total hospitalization)., Conclusions: LDLT for NASH facilitates transplantation of patients at a less severe stage of disease, which appears to promote a faster postoperative recovery with less resource utilization., Competing Interests: The authors declare no funding or conflicts of interest.

Radioembolization with yttrium-90 microspheres offers an alternative treatment option for patients with unresectable intrahepatic cholangiocarcinoma (ICC). However, the rarity and heterogeneity of ICC makes it difficult to draw firm conclusions about treatment efficacy. Therefore, the goal of the current study is to systematically review the existing literature surrounding treatment of unresectable ICCs with yttrium-90 microspheres and provide a comprehensive review of the current experience and clinical outcome of this treatment modality. We performed a comprehensive search of electronic databases for ICC treatment and identified 12 studies with relevant data regarding radioembolization therapy with yttrium-90 microspheres. Based on pooled analysis, the overall weighted median survival was 15.5 months. Tumour response based on radiological studies demonstrated a partial response in 28% and stable disease in 54% of patients at three months. Seven patients were able to be downstaged to surgical resection. The complication profile of radioembolization is similar to that of other intra-arterial treatment modalities. Overall survival of patients with ICC after treatment with yttrium-90 microspheres is higher than historical survival rates and shows similar survival to those patients treated with systemic chemotherapy and/or trans-arterial chemoembolization therapy. Therefore, the use of yttrium-90 microspheres should be considered in the list of available treatment options for ICC. However, future randomized trials comparing systemic chemotherapy, TACE and local radiation will be required to identify the optimal treatment modality for unresectable ICC., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

Background: Islet transplantation is a recognized treatment option for select patients with type I diabetes mellitus. However, islet infusions from multiple donors are often required to achieve insulin independence. Ideally, insulin independence would be achieved routinely with only a single donor. Identification of factors associated with insulin independence after single-donor islet transplantation may help to select recipient-donor combinations with the highest probability of success., Methods: Subjects undergoing islet transplantation at a single center (Edmonton, Canada) between March 1999 and August 2013 were included. Recipient, donor, and transplant characteristics were collected and compared between recipients who became insulin independent after one islet transplantation and those who did not., Results: Thirty-one patients achieved insulin independence after a single-donor islet transplantation, and 149 did not. Long-term insulin-free survival was not different between the groups. Factors significantly associated with single-donor success included recipient age, insulin requirement at baseline, donor weight, donor body mass index, islet transplant mass, and peritransplant heparin and insulin administration. On multivariate analysis, pretransplantation daily insulin requirements, the use of peritransplantation heparin and insulin infusions, and islet transplant mass remained significant., Conclusion: We have identified clinically relevant differences defining the achievement of insulin independence after single-donor transplantation. Based on these differences, a preoperative insulin requirement of less than 0.6 U/kg per day and receiving more than 5,646 islet equivalents (IEQ)/kg have a sensitivity of 84% and 71% and specificity of 50% and 50%, respectively, for insulin independence after single-donor islet transplantation. With ideal patient selection, this finding could potentially increase single-donor transplantation success and may be especially relevant for presensitized subjects or those who may subsequently require renal replacement.

Mixed chimerism is a promising approach toward generating donor-specific immunological tolerance. However, chimerism induction can be toxic; therefore, there is an effort to develop non-myeloablative, minimal intensity protocols that can generate chimerism without the toxic side effects. Recently, with the goal of creating a minimalistic chimerism induction protocol in the tolerance resistant non-obese diabetic (NOD) mouse model, we identified pre-existing T cells as cells that resist fully allogeneic chimerism. With monoclonals targeting NOD T cells, we showed that long-term chimerism and tolerance toward donor islets could be established. However, this promising new protocol relied on the administration of a single dose of anti-CD40 ligand, which is not clinically applicable. In refining protocols to move even closer to clinical utility, we report here initial success at generating fully allogeneic mixed chimerism in NOD mice by adding cyclophosphamide to the conditioning regimen in place of anti-CD40 ligand antibodies.

Donor-specific tolerance induced by mixed chimerism is one approach that may eliminate the need for long-term immunosuppressive therapy, while preventing chronic rejection of an islet transplant. However, even in the presence of chimerism it is possible for certain donor tissues or cells to be rejected whereas others from the same donor are accepted (split tolerance). We previously developed a nonmyeloablative protocol that generated mixed chimerism across full major histocompatability complex plus minor mismatches in NOD (nonobese diabetic) mice, however, these chimeras demonstrated split tolerance. In this study, we used radiation chimeras and found that the radiosensitive component of NOD has a greater role in the split tolerance NOD mice develop. We then show that split tolerance is mediated primarily by preexisting NOD lymphocytes and have identified T cells, but not NK cells or B cells, as cells that both resist chimerism induction and mediate split tolerance. Finally, after recognizing the barrier that preexisting T cells impose on the generation of fully tolerant chimeras, the chimerism induction protocol was refined to include nonmyeloablative recipient NOD T cell depletion which generated long-term mixed chimerism across fully allogeneic barriers. Furthermore, these chimeric NOD mice are immunocompetent, diabetes free and accept donor islet allografts., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Worldwide, more than 1.7 billion individuals may be classified as overweight and are in need of appropriate medical and surgical treatments. The primary goal of a comprehensive weight management program is to produce sustainable weight loss. However, for such a program to be effective, the patient must complete it. We analyzed attrition rates and predictors of attrition within a publicly funded, multidisciplinary adult weight management program., Methods: We retrospectively reviewed charts from an urban multidisciplinary adult weight management clinic program database. Patients received medical or surgical treatment with appropriate follow-up. We collected information on demographics and comorbidities. Patients in the surgical clinics received either laparoscopic gastric band insertion or gastric bypass. We conducted univariate analysis and multivariate analyses on predictors of attrition., Results: A total of 1205 patients were treated in the weight management program: 887 in the medical clinic and 318 with surgery and follow-up in a surgical clinic. Overall, 516 patients left the program or were lost to follow-up (attrition rate 42.8%). The attrition rate was 53.9% in the medical clinic and 11.9% in the surgical clinic. Multivariate analyses identified participation in the medical clinic, younger patient age and lower body mass index as predictors of attrition., Conclusion: We found lower attrition rates among surgically than medically treated patients in a multidisciplinary weight management clinic. Further research is needed to understand those variables that lead to improved attrition rates.

Purpose: Acute appendicitis remains the common gastrointestinal emergency in adults. Single-incision laparoscopic appendectomy (SILA) has been proposed as the next evolution in minimally invasive surgery. SILA is postulated to reduce postoperative pain and enhance cosmesis, while effectively removing an inflamed appendix. However, the efficacy and benefits of SILA compared with conventional laparoscopic appendectomy (CLA) remain to be determined. Our objectives were to systematically review the literature comparing SILA with CLA for acute appendicitis and perform a pooled analysis on the efficacy of SILA., Methods: Published English-language manuscripts were considered for review inclusion. A comprehensive search of electronic databases (eg, MEDLINE, EMBASE, SCOPUS, BIOSIS Previews, and the Cochrane Library) using broad search terms was completed. All comparative studies were included if they incorporated adult patients undergoing appendectomy for acute appendicitis by SILA. The primary outcomes of interest were operative time and length of hospital stay., Results: From a total of 366 articles, 34 articles were identified. A total of 9 comparative studies were included for pooled analysis. There was no significant difference in operative time, length of stay, pain scores, and conversion or complication rates between SILA and CLA for acute appendicitis., Conclusions: This systematic review and pooled analysis demonstrates that SILA is comparable to CLA for acute appendicitis in adults. However, this review identifies the need for randomized controlled trials to clarify the efficacy of SILA compared with CLA.

Osteoarthritis is a common progressive disease leading to joint pain and severe disability. It is a complex multifactorial disease leading to damage of cartilage, deposition of subchondral bone matrix and release of pro-inflammatory cytokines. Obesity is an emerging epidemic and also an important risk factor for osteoarthritis. Weight loss has been shown to improve pain and function in hip and knee joints with osteoarthritis. Bariatric surgery currently is the only evidence-based approach to marked weight loss in obese individuals. However, there is currently limited literature to evaluate the role of bariatric surgery in hip and knee osteoarthritis. The objective of the present study was to systematically review the literature regarding the effectiveness of bariatric surgery in obese adult patients in improving large weight-bearing joint (hip and knee) osteoarthritis. Published English-language manuscripts were considered for review inclusion. A comprehensive search of electronic databases using broad search terms was completed. From a total of 400 articles, eight articles were identified. A total of six studies were included for qualitative analysis. A general trend was identified indicating improved hip and knee osteoarthritis following marked weight loss secondary to bariatric surgery. This systematic review demonstrates that bariatric surgery may benefit obese patients with hip or knee osteoarthritis. However, this review identifies the need for randomized controlled trials to clarify the role and indications for bariatric surgery., (© 2011 The Authors. obesity reviews © 2011 International Association for the Study of Obesity.)

Background: Induction of allogeneic hematopoietic chimerism is a promising strategy to induce tolerance to donor islets for treating type 1 diabetes. Successful induction of chimerism requires overcoming host alloimmunity. In diabetes-prone nonobese diabetic (NOD) mice, this is challenging due to their general tolerance resistance. Although the adaptive alloimmunity of NOD mice is a known barrier to allogeneic chimerism, whether NOD natural killer (NK) cells are an additional barrier has not been examined. Because NOD NK cells exhibit functional defects, they may not inhibit chimerism generation., Methods: Antibody depletion of NK cells in vivo, or transplantation of F1 hybrid donor cells to eliminate the "missing-self" trigger of NK cells, was preformed to test the NK-mediated rejection of donor bone marrow cells. We also studied the capacity of rapamycin to block the NK cell response against allogeneic cells in vivo., Results: Depleting NK cells or rendering them unresponsive to the donor greatly improved the level of chimerism obtained in NOD mice. Rapamycin significantly reduced the resistance to allogeneic chimerism mounted by NOD NK cells; however, it was much less effective than NK cell depletion by antibodies., Conclusions: Contrary to the view that NOD NK cells are defective, we found these cells to be a substantial barrier to allogeneic chimerism in the presence or absence of adaptive immunity. Moreover, rapamycin will need to be combined with other approaches to fully overcome the NK cell barrier.

Gastric cancer with peritoneal carcinomatosis has an extremely poor prognosis, which may be improved with cytoreductive surgery (CRS) combined with heated intraperitoneal chemotherapy (HIPEC). We systematically reviewed the literature regarding the efficacy of CRS + HIPEC in these patients. Electronic databases were searched from 2000 to 2010. Following CRS + HIPEC, overall median survival was 7.9 months and improved to 15 months for patients with completeness of cytoreduction scores of 0/1, however with a 30-day mortality rate of 4.8%., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: As laparoscopic surgical procedures increase in complexity, surgeons may find themselves with the laparoscope opposite to their laparoscopic instruments, thus creating the paradoxical viewpoint. We assessed whether surgical task performance in the paradoxical viewpoint would be improved by digitally altering the image or by changing the camera orientation., Methods: Sixty-one laparoscopically naïve operators performed a Peg Transfer task using a trainer box. In the first "round," naïve operators were block-randomized to perform the Peg-Transfer task either in the standard view or the paradoxical view. In the second "round," naïve operators were positioned in the paradoxical view and block-randomized to having the monitor image as paradoxical (n = 19) or altered by being digitally flipped (mirror-image) (n = 22) or inverted (n = 20). The task consisted of transferring six plastic objects in 5 min (300 s). Scoring was based on the formula of total time = time to completion (max = 300 s) + penalty time (50 s/peg not transferred)., Results: In the first round, average total time to perform the Peg Transfer task using the standard view was 215 ± 20 s, which was significantly less (P < 0.001) than the 563 ± 13 s for the paradoxical view. In the second round (with all naïve operators in the paradoxical viewpoint), the total time for the paradoxical image, digitally flipped image (mirror-image), and inverted image were 561 ± 12, 449 ± 25, and 259 ± 37 s, respectively. The total time for the inverted image was significantly less than both the paradoxical image and digitally flipped image (P < 0.001). The total time for the digitally flipped image was also less than paradoxical image (P < 0.05). The group with the paradoxical image completed 0.8 ± 0.2 peg transfers, which was less than both the digitally flipped and inverted-view groups (P < 0.05)., Conclusions: This is the first study to demonstrate that when in the paradoxical viewpoint, altering the image on the video monitor, either by digitally flipping or inverting the image, can improve surgical task performance.

Establishing hematopoietic mixed chimerism can lead to donor-specific tolerance to transplanted organs and may eliminate the need for long-term immunosuppressive therapy, while also preventing chronic rejection. In this review, we discuss central and peripheral mechanisms of chimerism induced tolerance. However, even in the long-lasting presence of a donor organ or donor hematopoietic cells, some allogeneic tissues from the same donor can be rejected; a phenomenon known as split tolerance. With the current goal of creating mixed chimeras using clinically feasible amounts of donor bone marrow and with minimal conditioning, split tolerance may become more prevalent and its mechanisms need to be explored. Some predisposing factors that may increase the likelihood of split tolerance are immunogenicity of the graft, certain donor-recipient combinations, prior sensitization, location and type of graft and minimal conditioning chimerism induction protocols. Additionally, split tolerance may occur due to a differential susceptibility of various types of tissues to rejection. The mechanisms involved in a tissue's differential susceptibility to rejection include the presence of polymorphic tissue-specific antigens and variable sensitivity to indirect pathway effector mechanisms. Finally, we review the clinical attempts at allograft tolerance through the induction of chimerism; studies that are revealing the complex relationship between chimerism and tolerance. This relationship often displays split tolerance, and further research into its mechanisms is warranted.

Background: Bariatric laparoscopic surgery has been shown to lead to sustainable weight-loss in obese individuals. Robotic-assisted laparoscopic surgery is proposed as the next major evolution in minimally invasive surgery. This study systematically reviews the literature regarding the feasibility and safety of robotic-assisted bariatric surgery in obese patients., Methods: A comprehensive search of electronic databases was completed for the period 2003 to 2010. Two independent reviewers assessed the studies for relevance, inclusion, and extracted data., Results: After an initial screen of 297 titles, 22 studies met the inclusion criteria. A total of 1253 patients with a mean preoperative body mass index of 46.6 kg/m(2) were obtained from 13 included studies. Major complications of malabsorptive procedures included eight anastomotic leaks (2.4%), bleeding (7/349 patients = 2%) and strictures/stenosis (13/430 patients = 3%). There were no reported deaths., Conclusions: This systematic review demonstrates that robotic-assisted bariatric surgery is both a safe and feasible option for severely obese patients., (Copyright © 2011 John Wiley & Sons, Ltd.)

Background: Postoperative wound infection is the most common complication following abdominal surgery and leads to delayed wound healing, prolonged hospital length of stay (LOS), and causes morbidity. Povidone-Iodine (PVI) is a broad-spectrum anti-septic and disinfectant solution, and can be used intra-operatively to irrigate subcutaneous tissues prior to abdominal skin closure. We systematically reviewed the literature regarding the efficacy of intra-operative PVI irrigation of subcutaneous tissues following elective colorectal surgery., Methods: A comprehensive search of electronic databases and various grey literature sources was completed. Unpublished and non-English-language results were included. All clinical controlled trials involving PVI solution in adult colorectal surgery were included. Two independent reviewers assessed the studies for relevance, inclusion, methodological quality and extracted data from the full versions of the manuscripts. Disagreements were resolved by re-extraction or third party adjudication. Data for dichotomous outcomes are reported as relative risks (RR) with 95% confidence intervals (CI). For continuous data, mean differences (MD) are reported with 95% CIs., Results: Five randomized controlled trials (RCTs) involving 205 patients comparing PVI solution or spray to a control group following abdominal fascial closure in elective colorectal or clean-contaminated operations were identified. Pooled results demonstrated a reduction in surgical site infection for patients treated with PVI (RR = 1.97; 95% CI: 1.22 to 3.17) compared to controls., Conclusions: Irrigation of subcutaneous tissues with PVI following abdominal fascial closure is associated with a reduced incidence of surgical site infection. Due to the small number of included trials and patients, additional robust randomized trials are needed.