Our analysis comprising the largest group of GIST patients treated with neoadjuvant imatinib in routine practice indicates excellent long-term results of combined therapy in locally advanced GISTs.
Vascular renal resistance (RR) during hypothermic machine perfusion (HMP) is frequently used in kidney graft quality assessment. However, the association between RR and outcome has never been prospectively validated. Prospectively collected RR values of 302 machine-perfused deceased donor kidneys of all types (standard and extended criteria donor kidneys and kidneys donated after cardiac death), transplanted without prior knowledge of these RR values, were studied. In this cohort, we determined the association between RR and delayed graft function (DGF) and 1-year graft survival. The RR (mmHg/mL/min) at the end of HMP was an independent risk factor for DGF (odds ratio 21.12 [1.03-435.0]; p = 0.048) but the predictive value of RR was low, reflected by a c-statistic of the receiver operator characteristic curve of 0.58. The RR was also found to be an independent risk factor for 1-year graft failure (hazard ratio 12.33 [1.11-136.85]; p = 0.004). Determinants of transplant outcome are multifactorial in nature and this study identifies RR as an additional parameter to take into account when evaluating graft quality and estimating the likelihood of successful outcome. However, RR as a stand-alone quality assessment tool cannot be used to predict outcome with sufficient precision.
BACKGROUND: Allogeneic blood products transfusion during liver transplantation (LT) can be associated with increased morbidity and mortality. Data on thromboelastometry (ROTEM)-guided coagulation management with coagulation factor concentrates (CFCs)-fibrinogen concentrate and/or prothrombin complex concentrate (PCC)-are sparse. We aimed to retrospectively evaluate the safety events observed with this approach in our clinic. STUDY DESIGN AND METHODS: LT patients from January 2009 to December 2010 (n = 266) were identified by chart review. A ROTEM-based algorithm with CFC guided the hemostatic therapy. Doppler ultrasound was used to evaluate thrombosis in the hepatic artery, portal vein, and hepatic veins. Stroke, myocardial isch-emia, pulmonary embolism, and transfusion variables were recorded. Patients receiving CFC were included in the CFC group (n = 156); those not receiving CFC were included in the non-CFC group (n = 110). Safety events were compared between these two groups. RESULTS: Allogeneic transfusion(s) in the 266 patients was low, with medians of 2 (interquartile range [IQR], 0-5), 0 (IQR 0-0), and 0 (IQR 0-1) units for red blood cells (RBCs), fresh-frozen plasma (FFP), and platelets (PLTs), respectively. Ninety-seven of 266 LTs (36.5%) were performed without RBCs transfusion, 227 (85.3%) without FFP, and 190 (71.4%) without PLTs. There were no significant differences in thrombotic, thrombo-embolic, and ischemic adverse events occurrence between the CFC group and the non-CFC group (11/ 156 patients vs. 5/110; p = 0.31). CONCLUSION: In LT, ROTEM-guided treatment with fibrinogen concentrate and/or PCC did not appear to increase the occurrence of thrombosis and ischemic events compared to patients who did not receive these concentrates. T he median model of end-stage liver disease (MELD) score in EUROTRANSPLANT has increased from 25 to 35 (match-MELD) in the past 6 years, attributable to the adoption of MELD score as the basis for organ allocation in liver trans-plantation (LT). 1 This increase is associated with an increased risk of bleeding. 2 However, chronic liver disease is associated with multiple changes in coagulation status. On the one hand, the activity and levels of vitamin K-dependent coagulation factors (II, VII, IX, and X) and coagulation inhibitors (protein C and S) are decreased, as well as platelet (PLT) count. 3 Levels of tissue factor-expressing cells, von Willebrand factor, and coagulation Factor (F)VIII are often increased. 4,5 The concomitant reduction of pro-and anticoagulants typically leads to rebalanced hemostasis, but the low levels of pro-and anti-coagulants mean that the balance can be easily disturbed, ABBREVIATIONS: ALI = acute lung injury; aPTT = activated partial thromboplastin time; CFC(s) = coagulation factor concentrate(s); HAT = hepatic artery thrombosis; ICU = intensive care unit; INR = international normalized ratio; IQR = interquartile range; LT(s) = liver transplantation(s); MELD = median model of end-stage liver disease; PCC(s) = prothrombin complex concentrate(...
Early allograft dysfunction correlates with early results of LT and can be predicted by donor data only. The newly introduced risk index potentially optimizes individual decisions to accept/decline high risk organs. Outcome of these organs might be improved by shortening CIT.
Although both postoperative standard laboratory tests and ROTEM ® assays could identify patients at risk for postoperative bleeding, ROTEM ® assays demonstrated a greater predictive value for impaired fibrinogen polymerization-related coagulopathy.
Cold preservation sensitizes organ grafts to exacerbation of tissue injury upon reperfusion. This reperfusion injury is not fully explained by the mere re‐introduction of oxygen but rather is pertinent to the immediate rise in metabolic turnover associated with the abrupt restoration of normothermia. Here we report the first clinical case of gradual resumption of graft temperature upon ex vivo machine perfusion from hypothermia up to normothermic conditions using cell‐free buffer as a perfusate. A kidney graft from an extended criteria donor was put on the machine after 12.5 hours of cold storage. During ex vivo perfusion, perfusion pressure and temperature were gradually elevated from 30 mm Hg and 8°C to 75 mm Hg and 35°C, respectively. Perfusate consisted of diluted Steen solution, oxygenated with 100% oxygen. Final flow rates at 35°C were 850 mL/min. The kidney was transplanted without complications and showed good immediate function. Serum creatinine fell from preoperative 720 µmol/L to 506 µmol/L during the first 24 hours after transplantation. Clearance after 1 week was 43.1 mL/min. Controlled oxygenated rewarming prior to transplantation can be performed up to normothermia without blood components or artificial oxygen carriers and may represent a promising tool to mitigate cold‐induced reperfusion injury or to evaluate graft performance.
Cholangiocarcinoma (CCA) cells paradoxically express the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and thus rely on potent survival signals to circumvent cell death by TRAIL. Hedgehog (Hh) signaling is an important survival pathway in CCA. Herein, we further examine the mechanisms whereby Hh signaling mediates apoptosis resistance in CCA, revealing a pivotal role for the cell division regulating serine/threonine kinase polo-like kinase 2 (PLK2). We employed 50 human CCA samples (25 intrahepatic and 25 extrahepatic CCA) as well as human KMCH-1, Mz-CHA-1, and HUCCT-1 CCA cells for these studies. In vivo experiments were conducted using a syngeneic rat orthotopic CCA model. In human samples, polo-like kinase (PLK)1/2/3-immunoreactive cancer cells were present in the preponderance of intra- and extrahepatic CCA specimens. Inhibition of Hh signaling by cyclopamine reduced PLK2, but not PLK1 or PLK3, messenger RNA and protein expression in vehicle-treated and sonic Hh–treated CCA cells, confirming our previous microarray study. PLK2 regulation by Hh signaling appears to be direct, because the Hh transcription factors, glioma-associated oncogene 1 and 2, bind to the PLK2 promotor. Moreover, inhibition of PLK2 by the PLK inhibitor, BI 6727 (volasertib), or PLK2 knockdown was proapoptotic in CCA cells. BI 6727 administration or PLK2 knockdown decreased cellular protein levels of antiapoptotic myeloid cell leukemia 1 (Mcl-1), an effect reversed by the proteasome inhibitor, MG-132. Finally, BI 6727 administration reduced Mcl-1 protein expression in CCA cells, resulting in CCA cell apoptosis and tumor suppression in vivo. Conclusion PLK2 appears to be an important mediator of Hh survival signaling. These results suggest PLK inhibitors to be of therapeutic value for treatment of human CCA.
Retrograde oxygen persufflation as a supplement of cold storage during the preservation period has the potential to better utilize ischemically damaged marginal livers in the experimental setting. Retrograde oxygen persufflation was applied in selected livers to demonstrate feasibility in the clinical setting and to investigate potential beneficial effects. Between 4/04 and 3/05 5 marginal otherwise discarded livers with warm ischemic damages from deceased donors (age 52 ) were accepted for transplantation. All organs were distantly procured and shipped to our center. Immediately after arrival, filtered humidified gaseous oxygen was given via the hepatic veins for at least 60 minutes with a pressure up to 18 mm mercury. Liver biopsies were analyzed for ATP content before and after persufflation. All patients (age 55 [46 -66]) survived without retransplantation, had good initial function and are alive and well after minimum follow-up of two years. Bleeding from pinpricks stopped spontaneously after 5-10 minutes after reperfusion but was prolonged in one patient with severe coagulopathy until correction. One patient developed arterial thrombosis at postop day 0. He fully recovered after thrombectomy. Another patient developed subcapsular hematoma, which was removed at postop day 10. On routine postoperative biopsies vascular structures appeared undamaged. ATP levels in pre-reperfusion biopsies revealed a more than twofold increase of ATP content compared to biopsies before persufflation. Retrograde oxygen persufflation preservation is feasible and save in the clinical setting, improves early aerobic metabolism and therefore potentially improves primary organ function after liver transplantation. Organ shortage is the main problem in liver transplantation leading to a high mortality rate on the waiting list. Possible mechanisms to alleviate this difficulty include extension of living donations, split liver transplantation, and, increasingly, the use of marginal organs. 1 The outcome of the use of potentially critical marginal organs could be enhanced by the improvement of preservation and revitalization techniques applied during the cold ischemia time period.Experimental studies investigating the effect of hypothermic liver perfusion pump systems with oxygenation reveal promising results. 2,3 However, these perfusion system machines are expensive, technically complex, and not yet fully developed for clinical application. 4 Machine perfusion, although analyzed in experimental studies up to now, does not have a clinical impact on the preservation of livers.In several ex vivo studies and recently in an in vivo study, we demonstrated successful extension of ischemic tolerance of porcine livers by cold preservation including postconditioning with gaseous oxygen [retrograde oxygen persufflation (ROP)]. 5,6 Also, the detrimental effects of 60 minutes of warm ischemia for kidneys were completely reversible with ROP. 7 On the basis of our experimental results, we applied ROP in Abbreviations: ALAT, alanine aminotransferase;...
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