Mechanisms of tumor necrosis factor-α and interleukin-6 induction during human liver transplantation

In human orthotopic liver transplantation (LTX) intraoperative elevations of TNF-α (> 100 pg/ml) and IL-6 (>800 pg/ml) have been found to correlate with early post-operative rejections and infections respectively. In this study the possible mechanism responsible for the induction of these cytokines has been investigated during liver allografting in 38 recipients. Intraoperative elevations of TNF-α (> 100 pg/ml) were detected in the majority of pre-transplant endotoxin positive recipients (8/12, > 10 endotoxin units/ml), the patients turning endotoxin positive until the end of grafting (3/5), and in a subgroup (6/21 patients), apparently endotoxin negative for the whole operation. Therefore endotoxin (ET) seems to stimulate release of TNF-α in approximately 50% of the patients, whereas sensitized Kupffer graft cells or immediate allograft reactivity of the host are likely to account for the remaining TNF-α positive cases. Elevations of IL-6 > 800 pg/ml) were found in approximately 50% of the TNF-α positive cases, indicating partially independent regulatory pathways for IL-6 induction in the TNF-α negative patients. In agreement with a previous study, 11/13 (85%) of the intraoperative TNF-α positive recipients rejected their grafts within the first 10 days post-operatively. These data demonstrate that ET/infection associated as well as ET independent/reperfusion associated intraoperative TNF-α elevations, promote the initiation of allograft rejection in human liver transplantation. The transient and low endotoxaemia caused by the liver grafting procedure performed without veno-venous bypass seems to be of minor importance in the intraoperative induction of TNF-α

A Preoperative Clinical Risk Score Including C-Reactive Protein Predicts Histological Tumor Characteristics and Patient Survival after Surgery for Sporadic Non-Functional Pancreatic Neuroendocrine Neoplasms:An International Multicenter Cohort Study

Background: Oncological survival after resection of pancreatic neuroendocrine neoplasms (panNEN) is highly variable depending on various factors. Risk stratification with preoperatively available parameters could guide decision-making in multidisciplinary treatment concepts. C-reactive Protein (CRP) is linked to inferior survival in several malignancies. This study assesses CRP within a novel risk score predicting histology and outcome after surgery for sporadic non-functional panNENs. Methods: A retrospective multicenter study with national exploration and international validation. CRP and other factors associated with overall survival (OS) were evaluated by multivariable cox-regression to create a clinical risk score (CRS). Predictive values regarding OS, disease-specific survival (DSS), and recurrence-free survival (RFS) were assessed by time-dependent receiver-operating characteristics. Results: Overall, 364 patients were included. Median CRP was significantly higher in patients >60 years, G3, and large tumors. In multivariable analysis, CRP was the strongest preoperative factor for OS in both cohorts. In the combined cohort, CRP (cut-off >= 0.2 mg/dL; hazard-ratio (HR):3.87), metastases (HR:2.80), and primary tumor size >= 3.0 cm (HR:1.83) showed a significant association with OS. A CRS incorporating these variables was associated with postoperative histological grading, T category, nodal positivity, and 90-day morbidity/mortality. Time-dependent area-under-the-curve at 60 months for OS, DSS, and RFS was 69%, 77%, and 67%, respectively (all p <0.001), and the inclusion of grading further improved the predictive potential (75%, 84%, and 78%, respectively). Conclusions: CRP is a significant marker of unfavorable oncological characteristics in panNENs. The proposed internationally validated CRS predicts histological features and patient survival

Kidney Transplantation After Rescue Allocation-the Eurotransplant Experience:A Retrospective Multicenter Outcome Analysis

BACKGROUND: At Eurotransplant (ET), kidneys are transferred to 'rescue allocation' (RA), whenever the standard allocation (SA) algorithms Eurotransplant kidney allocation system (ETKAS) and Eurotransplant senior program (ESP) fail. We analyzed the outcome of RA. METHODS: Retrospective patient clinical and demographic characteristics association analyses with graft outcomes for 2,421 recipients of a deceased donor renal transplantation (DDRT) after RA versus 25,475 after SA from 71 centers across all ET countries from 2006 to 2018. RESULTS: Numbers of DDRTs after RA increased over the time, especially in Germany. RA played a minor role in ESP vs. ETKAS (2.7% vs. 10.4%). RA recipients and donors were older compared to SA recipients and donors, cold ischemia times were longer, waiting times were shorter, and the incidence of primary non-function was comparable. Among ETKAS-recipients, HLA matching was more favorable in SA (mean 3.7 vs. 2.5). In multivariate modeling, the incidence of death with a functioning graft (DwFG) in ETKAS was reduced in RA compared to SA (subdistribution hazard ratio 0.70, 95% confidence interval [0.60-0.81], p<0.001) whereas other outcomes (mortality, graft loss) were not significantly different. None of the three outcomes were significantly different when comparing RA with SA within the ESP program. CONCLUSIONS: Facing increased waiting times and mortality on dialysis due to donor shortage, this study reveals encouragingly positive DDRT outcomes following RA. This supports the extension of RA to more patients and as an alternative tool to enable transplantation in patients in countries with prohibitively long waiting times or at risk of deterioration.Supplemental Visual Abstract; http://links.lww.com/TP/C297