Analyzing Mitochondrial Bioenergetics to Improve Organ Hibernation Methods.

β-hydroxybutyrate is a molecule synthesized in the liver that can be used as an alternative to glucose in cellular metabolism. BHB metabolism does not produce lactic acidosis which makes it an optimal source of energy for tissues in an ischemic state. Melatonin is a hormone produced in the pineal gland that aids in slowing the metabolic rate. Both BHB and Melatonin have antioxidant properties that assist in relieving oxidative stress due to an increased metabolic rate during post-ischemic reperfusion. Testing consisted of infusing donor pigs with either BHB/M or a vehicle control. The pigs were then made brain-dead and their hearts were harvested under standard conditions and placed in a UW solution or a UW+BHB/M solution under static cold conditions. Tissue samples were then analyzed immediately after harvest, 2 days, and 8 days post-harvest using a Seahorse XFe96 Flux Analyzer. This test analyzed the oxygen consumption rate in order to show mitochondrial function. We hypothesize that the BHB/M solution will aid in mitochondrial function while the tissues are in an ischemic state. We believe this will prolong the viability of harvested organs in order to increase the amount of available organs for transplantation. We also believe that future testing will show that the BHB/M will relieve the effects of oxidative stress during reperfusion of the tissues which will decrease the risk or organ failure post-transplantation.https://digitalcommons.unmc.edu/surp2023/1005/thumbnail.jp

Predictors of in-hospital mortality and complications in very elderly patients undergoing emergency surgery

INTRODUCTION: With the increasing aging population demographics and life expectancies the number of very elderly patients (age ≥ 80) undergoing emergency surgery is expected to rise. This investigation examines the outcomes in very elderly patients undergoing emergency general surgery, including predictors of in-hospital mortality and morbidity. METHODS: A retrospective study of patients aged 80 and above undergoing emergency surgery between 2008 and 2010 at a tertiary care facility in Canada was conducted. Demographics, comorbidities, surgical indications, and perioperative risk assessment data were collected. Outcomes included length of hospitalization, discharge destination, and in-hospital mortality and morbidity. Multivariable logistic regression was used to identify predictors of in-hospital mortality and complications. RESULTS: Of the 170 patient admissions, the mean age was 84 years and the in-hospital mortality rate was 14.7%. Comorbidities were present in 91% of this older patient population. Over 60% of the patients required further services or alternate level of care on discharge. American Society of Anesthesiologist Physical Status (ASA) Classification (OR 5.30, 95% CI 1.774-15.817, p = 0.003) and the development of an in-hospital complications (OR 2.51, 95% CI 1.210-5.187, p = 0.013) were independent predictors of postoperative mortality. Chronological age or number of comorbidities was not predictive of surgical outcome. CONCLUSIONS: Mortality, complication rates and post-discharge care requirements were high in very elderly patients undergoing emergency general surgery. Advanced age and medical comorbidities alone should not be the limiting factors for surgical referral or treatment. This study illustrates the importance of preventing an in-hospital complication in this very vulnerable population. ASA class is a robust tool which is predictive of mortality in the very elderly population and can be used to guide patient and family counseling in the emergency setting

Repeated metastasectomy in an adolescent with fibrolamellar hepatocellular carcinoma: A case report

The fibrolamellar variant of hepatocellular carcinoma (FL-HCC) is a primary malignancy of the liver classically identified in the non-cirrhotic liver. By virtue of the non-cirrhotic liver background, patients with FL-HCC are more likely to be selected for surgical resection as primary treatment than in classic HCC. Synchronous and metachranous metastasis of FL-HCC can be treated with either resection, chemotherapy, or both. We present here an adolescent who underwent resection of a large FL-HCC following neo-adjuvant chemotherapy. The patient went on to receive surveillance and resection of five serially identified metastasis. Despite repeated aggressive metastasectomy, we observed survival in this case surpassing the median reported survival for adolescents with FL-HCC. This case supports the hypothesis proposed previously that aggressive surgical resection, including metastasectomy in the thoracic and abdominal cavity, should be offered to patients with this rare tumor

Costimulatory blockade with belatacept in clinical and experimental transplantation - a review

BACKGROUND: Current maintenance immunosuppression agents have been critical to the improved graft and patient survival rates in solid organ transplantation observed over the past decade. However, long-term follow-up has revealed that these agents are associated with troublesome side effects and chronic toxicity, contributing to graft loss and death. OBJECTIVES: Costimulation blockade has long been recognized as an important target for immunomodulation in solid organ transplantation. Belatacept, a high-affinity chimeric fusion protein that binds to CD80/CD86 on antigen-presenting cells, has shown great promise in renal transplantation and is now in Phase III trials. METHODS: This review explores the development and efficacy of belatacept, compared with currently approved immunosuppressive agents used in transplantation. RESULTS: Belatacept seems to be an effective alternative to current maintenance immunosuppressive therapies, with no apparent end organ toxicity and a minimal side-effect profile. This agent works best when used in combination with therapies that target different pathways of T-cell activation, but the optimal regimen has not yet been identified. Data generated in ongoing clinical trials will be essential in validating previous studies and for further development of belatacept-based combinatorial strategies

Total pancreatectomy and autoislet transplant for chronic recurrent pancreatitis in a 5-year-old boy

Childhood chronic pancreatitis is a rare disorder, which can lead to a chronically debilitating condition. The etiology of recurrent hereditary pancreatitis, which previously was classified as idiopathic, has now been attributed in certain cases to specific genetic mutations including abnormalities in the PRSS gene. We describe here the use of total pancreatectomy and autoislet transplant in a 5-year-old with chronic pancreatitis. This represents the youngest patient undergoing the procedure at our institution. The early successful outcomes for this patient, both of symptom relief and glycemic control are detailed

Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma

Liver transplantation is an important treatment option for selected patients with nonresectable hepatocellular carcinoma (HCC). Several reports have suggested a lower risk of posttransplant tumor recurrence with the use of sirolimus and a higher one with calcineurin inhibitors, but the selection of an ideal immunosuppression protocol is still a matter of debate. The aim of this study was to define the immunosuppression associated with the best survival after liver transplantation for HCC. It was based on the Scientific Registry of Transplant Recipients and included 2,491 adult recipients of isolated liver transplantation for HCC and 12,167 for non-HCC diagnoses between March 2002 and March 2009. All patients remained on stable maintenance immunosuppression protocols for at least 6 months posttransplant. In a multivariate analysis, only anti-CD25 antibody induction and sirolimus-based maintenance therapy were associated with improved survivals after transplantation for HCC (hazard ratio [HR] 0.64, 95% confidence interval [CI]: 0.45-0.9, P ≤ 0.01; HR 0.53, 95% CI: 0.31-0.92, P ≤ 0.05, respectively). The other studied drugs, including calcineurin inhibitors, did not demonstrate a significant impact. In an effort to understand whether the observed effects were due to a direct impact of the drug on tumor or more on liver transplant in general, we conducted a similar analysis on non-HCC patients. Although anti-CD25 induction was again associated with a trend toward improved survival, sirolimus showed a trend toward lower rates of survival in non-HCC recipients, confirming the specificity of its beneficial impact to cancer patients. Conclusion: According to these data, sirolimus-based immunosuppression has unique posttransplant effects on HCC patients that lead to improved survival

The impact of waiting list alpha-fetoprotein changes on the outcome of liver transplant for hepatocellular carcinoma

Liver transplantation is a recognized treatment for selected patients with hepatocellular carcinoma (HCC), but transplant criteria still need to be refined, especially in the case of more advanced or downstaged tumors

The caspase selective inhibitor EP1013 augments human islet graft function and longevity in marginal mass islet transplantation in mice

OBJECTIVE: Clinical islet transplantation can provide insulin independence in patients with type 1 diabetes, but chronic graft failure has been observed. This has been attributed in part to loss of ≥ 60% of the transplanted islets in the peritransplant period, resulting in a marginal implant mass. Strategies designed to maximize survival of the initial islet mass are likely to have major impact in enhancing long-term clinical outcomes. EP1013 (N-benzyloxycabonyl-Val Asp-fluoromethyl ketone [zVD-FMK]), is a broad-spectrum caspase selective inhibitor with no observed toxicity in rodents. RESEARCH DESIGN AND METHODS: The therapeutic benefit of EP1013 was examined in a syngeneic rodent islet transplant model using deceased donor human islets to determine whether the amount of tissue required to restore euglycemia in diabetic animals could be reduced. RESULTS: EP1013 (combined pretransplant islet culture for 2 h and in vivo treatment for days 0-5 posttransplant) significantly improved marginal islet mass function following syngeneic islet transplantation in mice, even at lower doses, compared with previous studies using the pan-caspase inhibitor N-benzyloxycabonyl-Val Ala-Asp-fluoromethyl ketone (zVAD-FMK). EP1013 supplementation in vitro improved human islet yields following prolonged culture and reversed diabetes following implantation of a marginal human islet mass (80-90% reduction) into mice. CONCLUSIONS: Our data suggest that EP1013 therapy will markedly reduce the islet mass required in clinical islet transplantation, improving insulin independence rates following single-donor infusion