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The Nuffield Department of Surgical Sciences is the academic department of surgery at the University of Oxford, and hosts a multidisciplinary team of senior clinical academic surgeons, senior scientists, junior clinicians and scientists in training.
Risk analysis for deterioration of renal function after pancreas alone transplant
The risk of progression to renal replacement after pancreas transplant alone (PTA) is a concern in patients with pre-transplant estimated glomerular filtration rate (eGFR) <70mL/min/1.73m2. This is a retrospective, single-center risk analysis of potential factors affecting renal function after PTA. Twenty-four patients, transplanted over a three-yr period, with functioning pancreatic grafts at the study's end point were included. High tacrolimus levels (>12mg/dL) at sixmonths post-transplant was the only independent risk factor identifying a substantial decline in native renal function by Cox regression analysis (HR=14.300, CI=1.271-160.907, p=0.031). The presence of severe pre-transplant proteinuria (urine Pr/Cr ≥100mg/mmol) marginally failed to reach significance (p=0.056). Low eGFR levels alone (≤45 and ≤40mL/min/1.73m2) at the time of transplant did not correlate with substantial decline in renal function. Our data suggest that PTA is a justifiable therapy for patients with hypoglycemia unawareness or other life-threatening diabetic complications, even in those with borderline renal function, provided that they do not suffer from severe proteinuria and appropriate monitoring and tailoring of immunosuppression is ensured. © 2012 John Wiley & Sons A/S.
Pancreas transplantation
Pancreas transplantation is now the standard of care for selected patients with diabetes and end-stage renal failure, with clear benefits in duration and quality of life. The indication for transplantation in patients with other severe diabetic complications are less clearly defined and the benefits less certain. The criteria for donor selection are more rigorous than for kidney and liver transplantation; selection of suitable organs and surgical retrieval technique are critical to success as the transplanted pancreas is vulnerable to preservation injury and post-transplant pancreatitis. Modern immunosuppressive strategies have reduced rejection rates and lowered the need for steroids; this has enabled surgical developments, particularly the enteric drainage of exocrine secretions, which have further reduced postoperative complications. As well as data relating to greater life expectancy, there is increasing evidence of stabilisation or long-term improvement in retinal, cardiovascular and neurological complications of diabetes. In patients with normal renal function, pancreatic islet transplantation may provide similar benefits without the morbidity of whole organ transplantation; this may be offered to patients suffering from life-threatening episodes of hypoglycaemic unawareness. © 2011 Elsevier Ltd. All rights reserved.
Splenectomy improves survival of hDAF transgenic pig kidneys in primates
The production of transgenic pigs expressing a human regulator of complement activation (decay accelerating factor, hDAF) has allowed to abrogate hyperacute rejection after organ transplantation into primates and to achieve prolonged survival. In this study hDAF transgenic porcine kidneys were transplanted into cynomolgus monkeys in a life-supporting model (the native kidneys were removed). Immunosuppression consisted of an induction therapy with cyclophosphamide and maintenance with cyclosporin A, mycophenolate mofetil and steroids. The additional effect of concomitant splenectomy was investigated in a second group. Splenectomy prolonged survival from 17 days to 43 days (median) without any effect on the incidence of rejection. In the absence of rejection episodes transgenic kidneys maintained normal serum homeostasis and fluid balance. Improved immunosuppressive combinations may enable long-term survival of transgenic kidneys in primates in the near future.
Blood usage for liver transplantation in infants and children
Nineteen patients, aged 2 1/2 years or younger, underwent liver transplantation at the Indiana University Medical Center. Three required a second graft and one required a third. The transfusion requirements of these children were compared with the needs of adults receiving liver allografts at the same institution. When expressed as units of blood components transfused per kilogram of patient weight, the intraoperative use for the two groups was similar. After surgery, pediatric patients required the greatest hemotherapy support and received considerably larger doses of fresh frozen plasma than did adults. Thus, in contrast to adults, who require greater hemotherapy support during surgery, these pediatric patients required the greatest amount of blood components posttransplantation. Ten of the 19 pediatric patients were cytomegalovirus (CMV) -seronegative before transplantation. Three of the 10 seroconverted after transplantation. Two had received organ grafts from CMV-seropositive donors, but the third received a liver graft and cellular blood components from only CMV-seronegative donors. The cause of this patient's seroconversion was unknown.
Emergency rescue hepatic transplantation following shunt surgery for Budd-Chiari syndrome
Objective: Assessment and optimal surgical treatment of a patient with Budd-Chiari syndrome. Design: A single patient case report with a brief review of the literature regarding choice of surgical treatment: shunt surgery versus orthotopic liver transplantation. Setting: Departments of medicine and surgery in two university hospitals. Patient: A 20-year-old woman presented with a 4-week history of ascites. The patient was diagnosed as having Budd-Chiari syndrome. There was no hepatic fibrosis on histology and synthetic function was well preserved. She fulfilled the published criteria for shunt surgery. Despite anticoagulation treatment over 4 weeks, she experienced mild deterioration. Shunt surgery resulted in fulminant hepatic failure requiring liver transplantation. Interventions: Porto-caval shunt surgery with subsequent emergency orthotopic liver transplantation. Outcome: The patient died. Conclusions: Clinical deterioration, even if apparently mild, may indicate a need to re-evaluate the choice of surgery. Surgical treatment should occur in centres where liver transplantation is available. © 1994 Current Science Ltd.
Liver transplantation for hepatic cirrhosis in cystic fibrosis
Five children with cystic fibrosis complicated by hepatic cirrhosis received liver grafts. They all had portal hypertension with varices and three had variceal bleeding; respiratory function was only moderately impaired, but four were colonised with pseudomonas and one with aspergillus. Liver transplantation was well tolerated and there was no increase in respiratory or other early postoperative complications. Four of the children were fully well from 14 to 35 months after transplantation; the most recently transplanted had problems from a biliary stricture. In spite of the need for immunosuppression there was no increase in infection and respiratory function improved or remained stable. Once the children were stabilised after transplantation their nutrition and general health were greatly improved.
Monoclonal antibodies that recognize activated human lymphocytes - Experimental and clinical studies
The objective of this study was to evaluate, in an experimental model, three monoclonal antibodies that recognize antigens whose expression on the surface of human T lymphocytes is either specific to activation or greatly increased on activation and to proceed to clinical studies if an antibody were shown to have significant immunosuppressive properties. The experimental study demonstrated substantial immunosuppressive properties of Campath-6 and YTH 655 as shown by a doubling of the survival times of renal allografts between strongly mismatched baboons. Campath-2 was not shown to have any immunosuppressive effect; there are various possible explanations for this including rapid modulation or failure to direct baboon effector mechanisms. Campath-6 and YTH 655 are effective only by blocking functional molecules rahter than by cell deletion. The clinical pilot study of Campath-6, being both small and uncontrolled, does not provide unequivocal evidence of any beneficial effect of Campath-6. However, this group of patients was unusually free of early acute cellular rejection, and no patients was seen to have any ill effects or reactions after treatment (as was also the case in baboons). On this basis, we have proceeded to design a randomized, controlled trial of Campath-6 used prohylactically after liver transplantation; this is currently in progress.
FK506 in experimental renal allografts in dogs and primates
The immunosuppressive potency in renal allografts and the toxicity of FK506 (FK) in two large animal models, the dog and baboon, are reported. FK is a fermentation product isolated from Streptomyces tsukubaensis that has been shown to be immunosuppressive both in vitro and in rats where it has prolonged skin, heart, and kidney allografts. In dogs FK has serious side effects due to a widespread vasculitis at a dose that was only minimally immunosuppressive. When FK was given to renal allograft recipient dogs at the minimally immunosuppressive dose of 0.5 mg/kg orally daily together with cyclosporine A, 10 mg/kg orally daily, the severe vasculitic lesions were still seen in three of four animals at days 5, 9, and 22. In baboons FK proved to be a powerful immunosuppressive agent but with a serious side effect that required dose reduction to a nonimmunosuppressive level to prevent a diabetogenic effect. The presence of insulin granules within the islets and raised levels of circulating insulin suggests a possible peripheral insulin resistance induced by FK that is reversible by dose reduction. Although FK is immunosuppressive, it appears to induce various significant side effects in the different species we have studied. A reliable assay of blood drug levels may have been beneficial in allowing adjustment of the dose. This should be made available during any future studies.
Biologics for chronic rhinosinusitis.
BACKGROUND: This living systematic review is one of several Cochrane Reviews evaluating the medical management of patients with chronic rhinosinusitis. Chronic rhinosinusitis is common. It is characterised by inflammation of the nasal and sinus linings, nasal blockage, rhinorrhoea, facial pressure/pain and loss of sense of smell. It occurs with or without nasal polyps. 'Biologics' are medicinal products produced by a biological process. Monoclonal antibodies are one type, already evaluated in related inflammatory conditions (e.g. asthma and atopic dermatitis). OBJECTIVES: To assess the effects of biologics for the treatment of chronic rhinosinusitis. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; CENTRAL (2019, Issue 9); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 16 September 2019. SELECTION CRITERIA: Randomised controlled trials (RCTs) with at least three months follow-up comparing biologics (currently, monoclonal antibodies) against placebo/no treatment in patients with chronic rhinosinusitis. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Our primary outcomes were disease-specific health-related quality of life (HRQL), disease severity and serious adverse events (SAEs). The secondary outcomes were avoidance of surgery, extent of disease (measured by endoscopic or computerised tomography (CT) score), generic HRQL and adverse events (nasopharyngitis, including sore throat). We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included eight RCTs. Of 986 adult participants, 984 had severe chronic rhinosinusitis with nasal polyps; 43% to 100% of participants also had asthma. Three biologics, with different targets, were evaluated: dupilumab, mepolizumab and omalizumab. All the studies were sponsored or supported by industry. Anti-IL-4Rα mAb (dupilumab) versusplacebo/no treatment (all receiving intranasal steroids) Three studies (784 participants) evaluated dupilumab. Disease-specific HRQL was measured with the SNOT-22 (score 0 to 110; minimal clinically important difference (MCID) 8.9 points). At 24 weeks, the SNOT-22 score was 19.61 points lower (better) in participants receiving dupilumab (mean difference (MD) -19.61, 95% confidence interval (CI) -22.54 to -16.69; 3 studies; 784 participants; high certainty). Symptom severity measured on a 0- to 10-point visual analogue scale (VAS) was 3.00 lower in those receiving dupilumab (95% CI -3.47 to -2.53; 3 studies; 784 participants; moderate certainty). The risk of serious adverse events may be lower in the dupilumab group (risk ratio (RR) 0.45, 95% CI 0.28 to 0.75; 3 studies; 782 participants; low certainty). The number of participants requiring nasal polyp surgery (actual or planned) during the treatment period is probably lower in those receiving dupilumab (RR 0.17, 95% CI 0.05 to 0.52; 2 studies; 725 participants; moderate certainty). Change in the extent of disease using the Lund Mackay computerised tomography (CT) score (0 to 24, higher = worse) was -7.00 (95% CI -9.61 to -4.39; 3 studies; 784 participants; high certainty), a large effect favouring the dupilumab group. The EQ-5D visual analogue scale (0 to 100, higher = better; MCID 8 points) was used to measure change in generic quality of life. The mean difference favouring dupilumab was 8.59 (95% CI 5.31 to 11.86; 2 studies; 706 participants; moderate certainty). There may be little or no difference in the risk of nasopharyngitis (RR 0.95, 95% CI 0.72 to 1.25; 3 studies; 783 participants; low certainty). Anti-IL-5 mAb (mepolizumab) versusplacebo/no treatment (all receiving intranasal steroids) Two studies (137 participants) evaluated mepolizumab. Disease-specific HRQL measured with the SNOT-22 at 25 weeks was 13.26 points lower (better) in participants receiving mepolizumab (95% CI -22.08 to -4.44; 1 study; 105 participants; low certainty; MCID 8.9). It is very uncertain whether there is a difference in s ymptom severity: on a 0- to 10-point VAS symptom severity was -2.03 lower in those receiving mepolizumab (95% CI -3.65 to -0.41; 1 study; 72 participants; very low certainty). It is very uncertain if there is difference in the risk of serious adverse events (RR 1.57, 95% CI 0.07 to 35.46; 2 studies; 135 participants, very low certainty). It is very uncertain whether or not the overall risk that patients still need surgery at trial end is lower in the mepolizumab group (RR 0.78, 95% CI 0.64 to 0.94; 2 studies; 135 participants; very low certainty). It is very uncertain whether mepolizumab reduces the extent of disease as measured by endoscopic nasal polyps score (scale range 0 to 8). The mean difference was 1.23 points lower in the mepolizumab group (MD -1.23, 95% -1.79 to -0.68; 2 studies; 137 participants; very low certainty). The difference in generic quality of life (EQ-5D) was 5.68 (95% CI -1.18 to 12.54; 1 study; 105 participants; low certainty), favouring the mepolizumab group. This difference is smaller than the MCID of 8 points. There may be little or no difference in the risk of nasopharyngitis (RR 0.73, 95% 0.36 to 1.47; 2 studies; 135 participants; low certainty). Anti-IgE mAb (omalizumab) versus placebo/no treatment (all receiving intranasal steroids) Three very small studies (65 participants) evaluated omalizumab. We are very uncertain about the effect of omalizumab on disease-specific HRQL, severe adverse events, extent of disease (CT scan scores), generic HRQL and adverse effects. AUTHORS' CONCLUSIONS: In adults with severe chronic rhinosinusitis and nasal polyps, using regular topical nasal steroids, dupilumab improves disease-specific HRQL compared to placebo, and reduces the extent of the disease as measured on a CT scan. It probably also improves symptoms and generic HRQL and there is no evidence of an increased risk of serious adverse events. It may reduce the need for further surgery. There may be little or no difference in the risk of nasopharyngitis. In similar patients, mepolizumab may improve both disease-specific and generic HRQL. It is uncertain whether it reduces the need for surgery or improves nasal polyp scores. There may be little or no difference in the risk of nasopharyngitis. It is uncertain if there is a difference in symptom severity and the risk of serious adverse events. We are uncertain about the effects of omalizumab.
Biologics for chronic rhinosinusitis
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:. Main objective. To assess the effects of biologics for the treatment of chronic rhinosinusitis. Secondary objective. To maintain the currency of the evidence, using a living systematic review approach.
B cell repopulation after alemtuzumab induction - Transient increase in transitional B cells and long-term dominance of naïve B cells
In organ transplantation, the composition of the B-cell compartment is increasingly identified as an important determinant for graft outcome. Whereas naïve and transitional B cells have been associated with long-term allograft survival and operational tolerance, memory B cells have been linked to decreased allograft survival. Alemtuzumab induction therapy effectively depletes B cells, but is followed by rapid repopulation up to levels exceeding base line. The characteristics of the repopulating B cells are currently unknown. We studied the phenotypic and functional characteristics of B cells longitudinally in 19 kidney transplant recipients, before and at 6, 9 and 12 months after alemtuzumab induction therapy. A transient increase in transitional B cells and cells with phenotypic characteristics of regulatory B cells, as well as a long-term dominance in naïve B cellswas found in alemtuzumab-treated kidney transplant recipients, which was not influenced by conversion from tacrolimus to sirolimus. At all time-points after treatment, B cells showed unaltered proliferative and IgM-producing capacity as compared to pretransplant samples, whereas the ability to produce IgG was inhibited long-term. In conclusion, induction therapy with alemtuzumab results in a long-term shift toward naïve B cells with altered phenotypic and functional characteristics. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.