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// Leonardo Lorente 1 , Sergio T. Rodriguez 2 , Pablo Sanz 3 , Antonia Perez-Cejas 4 , Javier Padilla 3 , Dacil Diaz 5 , Antonio Gonzalez 5 , Maria M. Martin 2 , Alejandro Jimenez 6 , Purificacion Cerro 7 and Manuel A. Barrera 3 1 Intensive Care Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife, 38320, Spain 2 Intensive Care Unit, Hospital Universitario Nuestra Senora Candelaria, Santa Cruz de Tenerife, 38010, Spain 3 Department of Surgery, Hospital Universitario Nuestra Senora de Candelaria, Santa Cruz de Tenerife, 38010, Spain 4 Laboratory Department, Hospital Universitario de Canarias, San Cristobal de La Laguna, 38320, Spain 5 Department of Digestive, Hospital Universitario Nuestra Senora de Candelaria, Santa Cruz de Tenerife, 38010, Spain 6 Research Unit, Hospital Universitario de Canarias, San Cristobal de La Laguna, 38320, Spain 7 Transplant Unit, Hospital Universitario Nuestra Senora Candelaria, Santa Cruz de Tenerife, 38010, Spain Correspondence to: Leonardo Lorente, email: lorentemartin@msn.com Keywords: substance P; hepatocellular carcinoma; liver transplantation; mortality; outcome Abbreviations: AFP: alpha-fetoprotein; AUC: area under curve; HCC: hepatocellular carcinoma; LT: liver transplantation; MELD: model for end-stage liver disease Received: December 12, 2017 Accepted: March 23, 2018 Published: April 20, 2018 ABSTRACT Purpose: Substance P is a tachykinins family member with inflammatory effects. Higher circulating levels of substance P have been found in patients with liver diseases and in patients with higher severity of liver diseases. The objective of this study was to determine whether serum levels of substance P levels, prior to liver transplantation (LT) for hepatocellular carcinoma (HCC) are associated with one-year LT mortality. Material and Methods: In this observational retrospective unicenter study were included patients with LT for HCC. Serum levels of substance P were measured before LT. The end-point of the study was one-year mortality after LT. Results: We found that one-year survivor patients ( n = 127) showed a lower age in liver donors ( p = 0.03) and lower levels of serum substance P levels ( p = 0.003) than non-survivor patients ( n = 15). Logistic regression analysis showed that serum levels of substance P (levels) were associated with one-year mortality (Odds Ratio = 1.011; 95% CI = 1.004–1.018; p = 0.002) controlling for the age of the LT donor. Conclusions: We believe that our study is the first study reporting data on circulating levels of substance P previously to LT for HCC, and an association between elevated levels of serum substance P before LT and mortality during the first year of LT.

Background: Higher liver caspase-3 activity has been found in patients with different liver diseases. However, there is no published data about circulating caspase-3 levels in patients with hepatocellular carcinoma (HCC) who underwent liver transplantation (LT). Therefore, our objective in this study was to determine whether an association between circulating caspase-3 levels in HCC patients prior to LT and one-year mortality after LT exists. Methods: In this observational and retrospective study, we included HCC patients who underwent LT. We measured serum levels of caspase-3 (as the main executor of apoptosis) and caspase-cleaved cytokeratin (CCCK)-18 (to estimate apoptosis degree) before LT. Results: One-year surviving LT patients (n = 129) showed lower serum levels of caspase-3 (p = 0.004) and CCCK-18 (p = 0.001) than non-surviving LT patients (n = 16). Logistic regression analysis showed that serum caspase-3 levels prior to LT were associated with one-year after LT mortality (Odds Ratio = 2.612; 95% CI = 1.519-4.493; p = 0.001). We found a positive association between serum levels of caspase-3 and CCCK-18 (rho = 0.26; p = 0.002). Conclusions: Our study is the first one reporting data of circulating caspase-3 levels prior to LT for HCC, and an association between high serum caspase-3 levels previously to LT and survival at first year after LT.

Melatonin administration has been associated with different benefits in animals and patients suffering from liver diseases. However, there is no published data about circulating melatonin levels in patients with hepatocellular carcinoma (HCC) who underwent liver transplantation (LT). Thus, the objective of this observational and retrospective study was to determine whether patients with HCC with lower serum melatonin levels prior to LT have a higher risk of one-year mortality after LT. We measured serum levels of melatonin, malondialdehyde (to assess lipid peroxidation), and total antioxidant capacity (to assess antioxidant state) before LT. One-year surviving LT patients (n = 129) showed higher serum levels of melatonin (p = 0.001) and total antioxidant capacity (p = 0.001) and lower serum levels of malondialheyde (p = 0.01) than non-surviving LT patients (n = 16). Logistic regression analysis showed that high serum melatonin levels prior to LT were associated with lower one-year LT mortality (odds ratio = 0.525, 95% confidence interval (CI) = 0.331&ndash, 0.834, p = 0.006). We found an association between serum levels of melatonin with serum levels of malondialheyde (rho = &minus, 0.22, p = 0.01) and total antioxidant capacity (rho = 0.21, p = 0.01). Thus, the novel findings of our study were the association between high serum melatonin levels prior to LT and survival at first year after LT and the association between serum levels of melatonin with malondialheyde and total antioxidant capacity.

Objective To determine whether there was an association between serum total antioxidant capacity (TAC) levels prior to in liver transplantation (LT) for hepatocellular carcinoma (HCC) and 1-year LT mortality. Methods This observational retrospective single-centre study of patients with LT for HCC measured serum levels of TAC and malondialdehyde (as a biomarker of lipid peroxidation) before LT. The study endpoint was 1-year LT mortality. Results This study included 142 patients who underwent LT for HCC. Patients who survived the first year ( n = 127) had significantly lower aged liver donors, significantly higher serum TAC levels, and significantly lower serum malondialdehyde levels compared with the non-survivors ( n = 15). Logistic regression analysis found that serum TAC levels (odds ratio [OR] 0.275; 95% confidence interval [CI] 0.135, 0.562) and the age of the LT donor (OR 1.050; 95% CI 1.009, 1.094) were associated with 1-year LT mortality. There was an inverse association between serum levels of TAC and malondialdehyde levels (rho = –0.22). Conclusions There was an association between low serum TAC levels prior to LT for HCC and mortality during the first year after LT. There was an inverse association between serum TAC levels and lipid peroxidation as measured by malondialdehyde levels.

Purpose CD40L and its soluble form (sCD40L) are proteins of the tumor necrosis factor superfamily (TNFSF) that exhibit prothrombotic and proinflammatory properties when binding to CD40, which is a cell surface receptor of the tumor necrosis factor receptor superfamily (TNFRSF). High circulating levels of sCD40L have been associated with poor prognosis in patients with hepatocellular carcinoma (HCC). However, it is unknown whether there is an association between circulating sCD40L levels and survival in patients with HCC underwent to liver transplantation (LT), and this was the objective of that study. Methods Serum sCD40L levels were measured in a total of 139 patients before LT (124 survivors at 1 year of LT and 15 non-survivors). The end-point study was 1 year survival after liver LT. Results We found that 1-year non-surviving patients showed higher serum sCD40L levels than survivor patients (p = 0.02). We found in logistic regression analysis that serum sCD40L levels higher than 321 pg/mL (Odds Ratio = 6.86; 95% confidence interval = 2.06–22.76; p = 0.002) and age of LT deceased donor were associated with death at 1 year. Conclusions The new finding of our study was that high serum sCD40L levels previously to LT in patients with HCC are associated with higher mortality at one year.

Serum soluble CD40 Ligand (sCD40L) levels, which exhibit prothrombotic and proinflammatory properties, have not been studied in patients with traumatic brain injury (TBI). Thus, the objective of this study was to determine whether serum sCD40L levels are associated with severity and mortality in patients with severe TBI.This was a prospective, observational and multicenter study carried out in six Spanish Intensive Care Units. Patients with severe TBI defined as Glasgow Coma Scale (GCS) lower than 9 were included, while those with Injury Severity Score (ISS) in non-cranial aspects higher than 9 were excluded. Serum levels of sCD40L were measured on the day of TBI. Endpoint was established in 30-day mortality.We found higher serum sCD40L levels (P0.001) in non-surviving TBI patients (N=27) than in survivor ones (N=73). Logistic regression analysis showed that serum sCD40L levels were associated with 30-day mortality (OR=1.58; 95% CI=1.12-2.21; P=0.008) controlling for APACHE-II score and computer tomography findings. The area under the curve (AUC) for serum sCD40L levels as predictor of 30-day mortality was 0.79 (95% CI=0.70-0.86; P0.001). Survival analysis showed that patients with serum sCD40L levels higher than 2.11 ng/mL presented increased 30-day mortality than patients with lower levels (Hazard ratio=9.0; 95% CI=4.25-19.27; P0.001). We found an association between serum sCD40L levels and APACHE-II (rho=0.33; P=0.001), and GCS score (rho=-0.21; P=0.04).To our knowledge, this is the first study reporting data on serum sCD40L levels in patients with severe TBI. The most relevant and newer findings of our study are that serum sCD40L levels in non-surviving patients with severe TBI are higher than in surviving ones, and that there are an association between serum sCD40L levels and TBI severity and mortality.

Cytokeratin (CK)-18 is the major intermediate filament protein in the liver and during hepatocyte apoptosis is cleaved by the action of caspases; the resulting fragments are released into the blood as caspase-cleaved cytokeratin (CCCK)-18. Higher circulating levels of CCCK-18 have been found in patients with hepatocellular carcinoma (HCC) than in healthy controls and than in cirrhotic patients. However, it is unknown whether serum CCCK-18 levels before liver transplantation (LT) in patients with HCC could be used as a prognostic biomarker of one-year survival, and this was the objective of our study with 135 patients. At one year after LT, non-survivors showed higher serum CCCK-18 levels than survivors (p = 0.001). On binary logistic regression analysis, serum CCCK-18 levels >384 U/L were associated with death at one year (odds ratio = 19.801; 95% confidence interval = 5.301–73.972; p < 0.001) after controlling for deceased donor age. The area under the receiver operating characteristic (ROC) curve of serum CCCK-18 levels to predict death at one year was 77% (95% CI = 69%–84%; p < 0.001). The new finding of our study was that serum levels of CCCK-18 before LT in patients with HCC could be used as prognostic biomarker of survival.

Previous studies have found higher levels of serum malondialdehyde (MDA) in hepatocellular carcinoma (HCC) patients compared to healthy controls and higher MDA concentrations in tumoral tissue of HCC patients than in non-tumoral tissue. However, the association between pre-transplant serum levels of MDA and survival in HCC patients after liver transplantation (LT) has not been described, and the aim of the present study was to determine whether such an association exists. In this observational study we measured serum MDA levels in 127 patients before LT. We found higher pre-LT serum MDA levels in 15 non-surviving than in 112 surviving patients one year after LT (p = 0.02). Exact binary logistic regression analysis revealed that pre-LT serum levels of MDA over 3.37 nmol/mL were associated with mortality after one year of LT (Odds ratio = 5.38; 95% confidence interval (CI) = from 1.580 to infinite; p = 0.007) adjusting for age of the deceased donor. The main finding of our study was that there is an association between serum MDA levels before LT for HCC and 1-year survival after LT.