A Prospective Study of the Effect of Gastroduodenal Artery Reconstruction on Duodenal Oxygenation and Enzyme Content After Pancreas Transplantation.

BACKGROUND: Whole pancreas transplantation provides durable glycemic control and can improve survival rate; however, it can carry an increased risk of surgical complications. One devastating complication is a duodenal leak at the site of enteroenteric anastomosis. The gastroduodenal artery (GDA) supplies blood to the donor duodenum and pancreas but is commonly ligated during procurement. Since we have not had expressive changes in pancreatic back table surgical techniques in the recent decades, we hypothesized whether back table GDA reconstruction, improving perfusion of the donor duodenum and head of the pancreas, could lead to fewer surgical complications in simultaneous pancreas-kidney (SPK) transplants. MATERIAL AND METHODS: Between 2017 and 2021, we evaluated demographic information, postoperative complications, intraoperative donor duodenum, recipient bowel O2 tissue saturation, and patient morbidity through the Comprehensive Complication Index (CCI®). RESULTS: A total of 26 patients were included: 13 underwent GDA reconstruction (GDA-R), and 13 had GDA ligation (GDA-L). There were no pancreatic leaks in the GR group compared to 38% (5/13) in the GDA-L group (p = 0.03913). Intraoperative tissue oxygen saturation was higher in the GDA-R group than in the GDA-L (95.18 vs.76.88%, p < 0,001). We observed an increase in transfusion rate in GDA-R (p < 0.05), which did not result in a higher rate of exploration (p = 0.38). CCI® patient morbidity was also significantly lower in the GDA-R group (s < 0.05). CONCLUSIONS: This study identified improved intraoperative duodenal tissue oxygen saturation in the GDA-R group with an associated reduction in pancreatic leaks and CCI® morbidity risk. A larger prospective multicenter study comparing the two methods is warranted.

Autoantibodies to LG3 are associated with poor long-term survival after liver retransplantation.

Autoantibodies are detrimental to the survival of organ transplantation. We demonstrated that Angiotensin II Type I Receptor agonistic autoantibodies (AT1R-AA) were associated with poor outcomes after liver retransplantation. To examine the effect of other autoantibodies, we studied a retrospective cohort of 93 patients who received a second liver transplant. Pre-retransplant sera were tested with Luminex-based solid-phase assays. Among 33 tested autoantibodies, 15 were significantly higher in 48 patients who lost their regrafts than 45 patients whose regrafts were still functioning. Specifically, patients with autoantibodies to the C-terminal laminin-like globular domain of Perlecan (LG3) experienced significantly worse regraft survival (p = .002) than those with negative LG3 autoantibodies (LG3-A). In multivariate analysis, LG3-A (HR = 2.35 [1.11-4.98], p = .027) and AT1R-AA (HR = 2.09 [1.07-4.10], p = .032) remained significant predictors of regraft loss after adjusting for recipient age and sex. There were synergistic deleterious effects on regraft survival in patients who were double-positive for LG3-A and donor-specific antibody (DSA) (HR = 5.26 [2.15-12.88], p = .001), or LG3-A and AT1R-AA (HR = 3.23 [1.37-7.66], p = .008). All six double-positive patients lost their liver regrafts. In conclusion, LG3-A is associated with inferior long-term outcomes of a second liver transplant. Screening anti-HLA antibodies and autoantibodies such as LG3-A/AT1R-AA identifies patients with a higher risk for liver transplantation.

Chronic stress physically spares but functionally impairs innate-like invariant T cells.

The deleterious effects of psychological stress on mainstream T lymphocytes are well documented. However, how stress impacts innate-like T cells is unclear. We report that long-term stress surprisingly abrogates both T helper 1 (TH1)- and TH2-type responses orchestrated by invariant natural killer T (iNKT) cells. This is not due to iNKT cell death because these cells are unusually refractory to stress-inflicted apoptosis. Activated iNKT cells in stressed mice exhibit a "split" inflammatory signature and trigger sudden serum interleukin-10 (IL-10), IL-23, and IL-27 spikes. iNKT cell dysregulation is mediated by cell-autonomous glucocorticoid receptor signaling and corrected upon habituation to predictable stressors. Importantly, under stress, iNKT cells fail to potentiate cytotoxicity against lymphoma or to reduce the burden of metastatic melanoma. Finally, stress physically spares mouse mucosa-associated invariant T (MAIT) cells but hinders their TH1-/TH2-type responses. The above findings are corroborated in human peripheral blood and hepatic iNKT/MAIT cell cultures. Our work uncovers a mechanism of stress-induced immunosuppression.

Circular RNA in colorectal cancer.

Circular RNA (circRNA) is a highly abundant type of single-stranded non-coding RNA. Novel research has discovered many roles of circRNA in colorectal cancer (CRC) including proliferation, metastasis and apoptosis. Furthermore, circRNAs also play a role in the development of drug resistance and have unique associations with tumour size, staging and overall survival in CRC that lend circRNAs the potential to serve as diagnostic and prognostic biomarkers. Among cancers worldwide, CRC ranks second in mortality and third in incidence. In order to have a better understanding of the influence of circRNA on CRC development and progression, this review summarizes the role of specific circRNAs in CRC and evaluates their potential value as therapeutic targets and biomarkers for CRC. We aim to provide insight in the development of therapy and clinical decision-making.

A tribute to Dr. Roger Keith (1940-2020).

Dr. Roger Keith, a former co-editor of the Canadian Journal of Surgery who died recently in Saskatoon, was a Canadian ambassador for surgery and one of its leaders in North America. His career spans a period when surgery made the greatest progress in its history.

Circular RNA Foxo3 in cardiac ischemia-reperfusion injury in heart transplantation: A new regulator and target.

Ischemia-reperfusion (I/R) injury occurring in heart transplantation (HT) remains as a leading cause of transplant heart graft failure. Circular RNAs (circRNAs) play important roles in gene regulation and diseases. However, the impact of circRNAs on I/R injury during HT remains unknown. This study aims to investigate the role of circular RNA Foxo3 (circFoxo3) in I/R injury in HT. Using an in vivo mouse HT model and an in vitro cardiomyocyte culture model, we demonstrated that circFoxo3 is significantly upregulated in I/R-injured hearts and hypoxia/reoxygenation (H/R)-damaged cardiomyocytes. Knockdown of circFoxo3 using siRNA not only reduces cell apoptosis and death, mitochondrial damage, and expression of apoptosis/death-related genes in vitro, but also protects heart grafts from prolonged cold I/R injury in HT. We also show that circFoxo3 interacts with Foxo3 proteins and inhibits the phosphorylation of Foxo3 and that it indirectly affects the expression of miR-433 and miR-136. In conclusion, circRNA is involved in I/R injury in HT and knockdown of circFoxo3 with siRNA can reduce I/R injury and improve heart graft function through interaction with Foxo3. This study highlights that circRNA is a new type of molecular regulator and a potential target for preventing I/R injury in HT.

An Addition of U0126 Protecting Heart Grafts From Prolonged Cold Ischemia-Reperfusion Injury in Heart Transplantation: A New Preservation Strategy.

BACKGROUND: Ischemia-reperfusion injury (IRI) is the major cause of primary graft dysfunction in organ transplantation. The mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) signaling pathway plays a crucial role in cell physiological and pathological processes including IRI. This study aims to investigate whether inhibition of ERK signaling with U0126 can prevent prolonged cold IRI in heart transplantation. METHODS: Rat cardiac cell line H9c2 cells were treated with U0126 before exposure to hypothermic hypoxia/reoxygenation (H/R) conditions. The effect of U0126 on H9c2 cells in response to H/R stress was determined by measuring cell death, reactive oxygen species production, mitochondrial membrane potential, and ERK signaling activation. Mouse syngeneic heterotopic heart transplantation was conducted, where a donor heart was preserved in the University of Wisconsin (UW) solution supplemented with U0126 for 24 hours at 4°C before transplantation. Heart graft function, histopathologic changes, apoptosis, and fibrosis were measured to assess IRI. RESULTS: Phosphorylated ERK was increased in both in vitro H/R-injured H9c2 cells and in vivo heart grafts with IRI. Pretreatment with U0126 inhibited ERK phosphorylation and prevented H9c2 cells from cell death, reactive oxygen species generation, and mitochondrial membrane potential loss in response to H/R. Preservation of donor hearts with U0126-supplemented solution improved graft function and reduced IRI by reductions in cell apoptosis/death, neutrophil infiltration, and fibrosis of the graft. CONCLUSIONS: Addition of U0126 to UW solution reduces ERK signal activation and attenuates prolonged cold IRI in a heart transplantation model. ERK inhibition with U0126 may be a useful strategy to minimize IRI in organ transplantation.

Elevated C-peptide Levels Are Associated With Acute Rejection in Kidney Pancreas Transplantation.

BACKGROUND: We assessed whether allograft rejection or failure can be predicted by an acute increase in C-peptide production from the transplanted pancreas. METHODS: Patients with a minimum of 5 years of follow-up post simultaneous pancreas-kidney transplant were identified. C-peptide levels were obtained during clinic visits routinely. Graft failure was defined as return to dependence on insulin therapy or return to dialysis for pancreas and kidney grafts, respectively. Protocol kidney allograft biopsies were performed at 3 and 12 months. For-cause biopsies were also performed. RESULTS: Acute rejections were detected in 11 patients on biopsy results of the renal allograft. C-peptide levels drawn prior to documented rejections were significantly higher in patients with acute rejection than patients with borderline or no rejection (P = .006). Receiver operating characteristics curves for C-peptide indicated greater accuracy in predicting rejection than simultaneously drawn serum creatinine or lipase. CONCLUSIONS: Higher C-peptide levels in simultaneous pancreas-kidney recipients is associated with acute rejection vs nonrejection.

Effect of PET-CT on disease recurrence and management in patients with potentially resectable colorectal cancer liver metastases. Long-term results of a randomized controlled trial.

BACKGROUND: Preoperative evaluation of resectable colorectal cancer liver metastases with positron emission tomography (PET) combined with computed tomography (PET-CT) is used extensively. The PETCAM trial evaluated the effect of PET-CT (intervention) vs no PET-CT (control) on surgical management. PET-CT resulted in 8% change in surgical management, therefore, we aimed to compare long-term outcomes (disease-free [DFS], overall survival [OS]). METHODS: Trial recruitment (2005-2010) had prospective follow-up until 2013. Events from 2013 to 2017 were collected retrospectively. Survival was described by the Kaplan-Meier method and compared with log-rank test. Oncologic risk factors were calculated using Cox proportional hazard models. RESULTS: Among 404 patients randomized, there were no differences in DFS (hazard ratio [HR] = 1.13; 95% confidence interval [CI], 0.89 to 1.43) or OS (HR, 1.02; 95% CI, 0.78-1.32) between groups. For all patients randomized, median DFS (PET-CT vs no PET-CT) was 16 months (95% CI, 13-18) and 15 months (95% CI, 11-22), P = .33. For patients who underwent liver resection (n = 368), DFS (17 vs 16 months, P = .51) and OS (58 months vs 52 months, P = .90) were similar between groups, respectively. Risk factors for DFS and OS were age, tumor size, node-positive disease, extrahepatic metastases and disease-free duration. CONCLUSION: Preoperative PET-CT changes surgical management in a small percentage of cases, without effect on recurrence rates or long-term survival.

Angiotensin II type I receptor agonistic autoantibodies are associated with poor allograft survival in liver retransplantation.

Angiotensin II type I receptor (AT1R) agonistic autoantibodies (AT1R-AA) are detrimental to kidney transplantation. Early studies suggested a similar negative effect in primary liver transplantation. Here, we studied AT1R-AA in a retrospective cohort of 94 patients who received a second liver transplant to determine their prevalence and effects. The concentrations of preformed AT1R-AA before transplantation were higher (P = .019) in the 48 patients who lost their liver grafts than in the 46 patients whose grafts survived. About half (48/94, 51.1%) of the patients were positive for AT1R-AA >17 U/mL before the second liver transplantation. In 22 (23.4%) patients, strong positive AT1R-AA (defined as >40 U/mL) were detected, of whom 16 (72.7%) patients lost their grafts. Based on Kaplan-Meier analysis, patients with strong positive AT1R-AA had significantly worse graft survival than those with AT1R-AA <40 U/mL (P = .035). In multivariate Cox models that included confounders such as sex and age, either AT1R-AA >40 U/mL (HR = 1.999 [1.085-3.682], P = .026) or increased concentrations of AT1R-AA (HR = 1.003 [1.001-1.006] per incremental U/mL, P = .019) were significantly associated with elevated risk for graft loss. In conclusion, our data indicate that there is a high prevalence of AT1R-AA in candidates for second liver transplantation and that their presence is associated with inferior long-term outcomes of the second graft.

Vascular trauma: Does experience in the United States apply to a Canadian centre?

Summary: Trauma care has evolved similarly in the United States and Canada over the last 3 decades. Like much of modern trauma care, management of vascular trauma has been influenced by combat surgery experiences in recent wars. The American Association for the Surgery of Trauma sponsored the Prospective Observational Vascular Injury Treatment (PROOVIT) registry to document changes in the treatment of vascular trauma and determine outcomes in the US. However, differences in trauma populations and trauma systems between Canada and the US need to be considered. Here we compare the vascular trauma experience at a Canadian level I trauma centre over a 5-year period to the data in the PROOVIT registry.

Risk factors for survival following recurrence after first liver resection for colorectal cancer liver metastases.

BACKGROUND: Management of recurrence following liver resection for colorectal cancer metastases is a topic of debate. We determined risk factors for survival following recurrence after liver resection. METHODS: Long-term follow-up of patients in the PETCAM trial who had recurrence following liver resection. Risk groups were created according to their survival risk. Differences in overall survival (OS) between groups were estimated. Disease-free survival (DFS), patterns of disease recurrence and management were determined. Cox proportional hazard models, Kaplan-Meier method, and the log-rank test were used. RESULTS: Among 368 patients who underwent liver resection, 264 (72%) experienced disease recurrence (51% lung and 41% liver). Following liver resection, DFS: 17 months (95% CI, 14-19); OS: 57 months (95% CI, 46-70). In those who recurred, 120 (45%) received chemotherapy only, and 112 (42%) underwent second surgical resection. Among patients who experienced recurrence (n = 264), the high-risk group (more than one site of recurrence or disease-free duration < 5 months and node-positive disease) had median OS: 19 months (95% CI, 15-23) vs 36 months (95% CI, 30-48) for patients in the low-risk group (HR = 2.9, 95% CI, 2.2-3.9). CONCLUSION: Recurrence following liver resection is common. Following recurrence after liver resection, patients should be carefully selected for surgical re-resection based on risk factors.

Reconstitution of T-Cell Subsets Following Thymoglobulin-Induced Depletion in High Immunologic Risk and Donation After Cardiac Death Renal Transplant Recipients.

INTRODUCTION: Depletion therapy in high immunologic risk (HR) patients by antithymocyte globulin (rATG) induces lymphopenia and subsequent compartmental repopulation of T-cell subsets. rATG is also given to patients receiving kidneys from donations after cardiac death (DCDs) to mitigate innate immune activation associated with the DCD process. METHODS: We compared the T-cell response with rATG in both HR and DCD kidney recipients. We examined the reconstitution of T-cell subsets after rATG treatment in HR and DCD recipients (n = 19 per group) by multicolor flow cytometry. RESULTS: Following treatment, there was a rapid drop in the frequency of T cells in both groups, which persisted over 28 days. HR patients had an early surge in the frequency of CD4+ naïve, effector-memory, and regulatory T cells. Although we found a significant proliferation of the T cells in both groups, the DCD cohort had a blunted response as well as reduced CD4+ T-cell immune-reactivity compare with the HR group. CONCLUSIONS: Our data suggest that there is a lack of significant homeostatic proliferative response in DCD recipients following rATG, and CD4+ T cells may be less reactive in the DCD group than previously thought, indicating that rATG treatment may not have to be considered a first-line induction therapy in DCD recipients.

The impact of alloantibodies directed against the second donor on long-term outcomes of repeat liver transplantation.

BACKGROUND: Despite reports that associate donor specific antibody (DSA) with rejection after liver transplantation, grafts are still allocated according to blood group (ABO) but not human leukocyte antigen (HLA) compatibility, possibly due to the absence of an easily discernible clinical association between adverse recipient outcome and DSA. Re-transplantation provides a test environment where the presence of preformed DSA is prevalent and its effect on outcome should be apparent. METHODS: All patients undergoing a second liver transplantation with available pre-operative serum were included with the exception of ABO incompatible or multiple organ transplants. Banked sera were tested for anti-HLA antibodies with Luminex-based solid phase assays. Anti-HLA antibodies to the second donor (D2SA) were determined using antibodies specificity and HLA typing of 2nd liver donor. RESULTS: Preformed HLA antibodies directed to second liver transplantation (D2SA) were found in 31 (39%) of the 79 patients that were included in the study. Primary and re-transplantation characteristics were similar in both subgroups except first graft survival which was significantly shorter in recipients who are negative for D2SA. Mean survival of the second graft was similar in D2SA+ and D2SA- cohorts [8.55 (range, 0.01-24.74) vs. 7.56 (range, 0-23.53) years respectively, P=0.574]. Mean patient survival after 2nd liver transplantation was similar in D2SA+ and D2SA- cohorts [9.11 (range, 0.01-24.74) vs. 8.10 (range, 0-23.53) years respectively, P=0.504]. Subgroup univariate analysis demonstrated no detrimental effect of class, locus, or strength of D2SA on survival of the second liver transplant. In multivariate cox regression model, neither class I D2DSA (HR =1.101, P=0.92) nor class II D2SA (HR =1.74, P=0.359) were significant risks of graft failure. CONCLUSIONS: Presence of D2SA was not found to be associated with inferior outcomes in this retrospective cohort study of liver re-transplantation suggesting that changes to the allocation system are not required.

Bidirectional graft-host hematological traffic in liver transplantation.

The highly complex immuno-hematological system of the recipient has to rebalance itself when the liver is replaced with a graft that has its own system. This gives us an opportunity for observation. Here we consider the graft-to-recipient direction with passenger lymphocyte syndrome (PLS) as well as the recipient-to-graft direction with Factor VIII (FVIII) inhibitors, paroxysmal nocturnal hemoglobinuria (PNH) and graft endothelial replacement with liver transplantation. PLS extends beyond the ABO blood groups to any situation where the donor has been sensitized to a recipient antigen. PLS directed against ABO or minor blood group antigens is usually self limiting whereas Rhesus (Rh) PLS persists with life threatening immune hemolysis. Human platelet antigen (HPA) 1A PLS results in life threatening immune thrombocytopenia. Treatments of severe PLS may include reduction in immunosuppression, anti-B-cell therapy, plasmapheresis and splenectomy. Liver transplantation into recipients with FVIII inhibitors has been difficult. Donors with acquired hemophilia may transmit the capacity to make FVIII inhibitors by PLS and should be avoided. Patients with PNH have been transplanted successfully but a considerable cost in the continued use of high dose eculizumab. We speculate that combined bone marrow and liver transplantation would be a better option for recipients with FVIII inhibitors or PNH. Replacement of liver graft endothelium with recipient cells is common and may explain relative transplant tolerance that is believed to occur with liver transplantation.

Anti-donor immunoglobulin G subclass in liver transplantation.

Immunoglobulin G (IgG) subclasses in human health and immunity have only be sporadically studied in the half century since their discovery. Different patterns of IgG subclass production are seen if the immune response is deviated towards type 1 versus type 2. The current state of our knowledge of IgG subclasses in liver transplantation is reviewed here. While several studies have been conducted in liver disease, only four relatively small studies have been undertaken in liver transplant recipients. Total IgG4 elevation in serum is related to sclerosing pancreatico-cholangiopathy that is sensitive to treatment with steroids. Conventional immunosuppressive regimes, especially with a combination of tacrolimus and sirolimus, reduce the production of all IgG subclasses after transplantation but it is not known if they deviate the immune response. Presence of anti-donor IgG3 before transplantation, or its expansion after transplantation, has been associated with rejection and liver graft loss. Anti-GSTT1 IgG4 production after transplantation is associated with de-novo immune hepatitis. Greater knowledge of anti-donor IgG subclass responses after transplantation will allow us tailor novel treatments for greater effect.