Metastasis Models: Thermodynamics and Complexity.

The thermodynamic formalism of nonequilibrium systems together with the theory of complex systems and systems biology offer an appropriate theoretical framework to explain the complexity observed at the macroscopic level in physiological phenomena. In turn, they allow the establishment of an appropriate conceptual and operational framework to address the study of phenomena such as the emergence and evolution of cancer.This chapter is organized as follows: In Subheading 1, an integrated vision of these disciplines is offered for the characterization of the emergence and evolution of cancer, seen as a nonlinear dynamic system, temporally and spatially self-organized out of thermodynamic equilibrium. The development of the various mathematical models and different techniques and approaches used in the characterization of cancer metastasis is presented in Subheading 2. Subheading 3 is devoted to the time course of cancer metastasis, with particular emphasis on the epithelial-mesenchymal transition (EMT henceforth) as well as chronotherapeutic treatments. In Subheading 4, models of the spatial evolution of cancer metastasis are presented. Finally, in Subheading 5, some conclusions and remarks are presented.

Tratamiento quirúrgico de los leiomiosarcomas de vena cava. Serie de casos en un hospital de tercer nivel y revisión de la literatura / Surgical treatment of vena cava leiomyosarcomas: Series of cases in a referral center and literature review

Introducción Los tumores primarios de vena cava inferior son tumores raros de origen mesenquimal que surgen de la musculatura lisa de la pared. Debido a su escasa prevalencia, existen pocos datos definitivos sobre su tratamiento y pronóstico. Su tratamiento se basa en principios oncológicos generales. Métodos Se ha analizado una serie de 6 casos intervenidos desde 2010 a 2020, evaluando distintos parámetros relacionados con las características demográficas del tumor, del tratamiento recibido y de los resultados obtenidos en supervivencia y morbilidad. Además, se ha llevado a cabo una revisión bibliográfica de la evidencia disponible actualmente. Resultados En todos los pacientes se llevó a cabo una resección quirúrgica óptima con R0 en 4/6 y R1 en 2/6. La mayor morbilidad sucedió en un paciente fallecido en periodo intraoperatorio. Se realizó cavorrafia en un paciente y cavoplastia en 5/6 utilizando injerto criopreservado en 3/6 y prótesis en 2/6. Al final del seguimiento de nuestra serie (con una media de seguimiento de 10,7 meses), el 50% de los pacientes continúan vivos. La media de supervivencia fue de 11,3±9,07 meses. De los 6 pacientes, 3 presentaron recidivas hematógenas con un intervalo libre de enfermedad de 9±2 meses. Conclusión El diagnóstico y tratamiento del leiomiosarcoma de vena cava inferior continúa siendo un reto. Debido a su baja prevalencia, resultará difícil establecer un tratamiento totalmente estandarizado, y se recomienda su abordaje en centros especializados. Por otra parte, se deberían intentar aunar los casos intervenidos de cara a avanzar en el conocimiento del abordaje de esta enfermedad (AU)

Introduction Primary tumors of the inferior vena cava are rare tumors of mesenchymal origin. They arise from the smooth muscles of the vena cava wall. Due to its low prevalence, there are few definitive data on its treatment and prognosis. Its treatment is based on general oncological principles. Methods A series of six cases operated from 2010 to 2020 were analyzed. Different parameters related to the demographic characteristics, the tumor, the treatment received, and the results obtained in survival and morbidity were analyzed. In addition, a bibliographical review of the currently available evidence was carried out. Results Optimal surgical resection was accomplished in all patients with R0 in 4/6 and R1 in 2/6. The greatest morbidity occurred in a patient who died in the intraoperative period. Cavography was performed in one patient and cavoplasty in 5/6 using cryopreserved graft in 3/6 and prothesis in 2/6. The 50% were still alive at the end of the follow-up (with a mean follow-up of 10.7 months). The mean survival was 11.3±9.07 months. 3/6 patients presented hematogenous recurrences with a disease-free interval of 9±2 months. Conclusion The diagnosis and treatment of inferior vena cava leiomyosarcoma is still a challenge. Due to its low prevalence, it will be difficult to establish a totally standardized treatment and its approach is recommended in specialized centers. On the other hand, a multicentric study should be made to collect the most cases as possible in order to advance in the understanding of the approach to this disease (AU)

Ammonia volatilisation from pig slurry and ANS with DMPP applied to Westerwold ryegrass (Lolium multiflorum Lam., cv. Trinova) under Mediterranean conditions.

Ammonia volatilisation from agriculture represents an important nitrogen (N) loss which has both environmental and economic impacts. In regions where large amounts of manures are available, there is a need to find appropriate management strategies that help to reuse them without increasing ammonia volatilisation. A study was made of the effect on ammonia volatilisation and yield of fertilising ryegrass with pig slurry (PS) and ammonium nitrosulphate (ANS-26) alone and with the 3,4-dimethylpyrazol phosphate (DMPP) nitrification inhibitor added to them. The study was conducted under Mediterranean conditions at two different sites. The treatments (control, PS, PS + DMPP, ANS-26 and ENTEC®) were established in a randomised block design with three replicates. Ammonia was sampled daily after each fertilisation using semi-static volatilisation chambers. We hypothesised that PS could replace mineral fertiliser without substantially increasing ammonia volatilisation in the studied systems. Temperature positively correlated with ammonia emissions. On the whole, during the two years of the study, the PS treatments presented higher average cumulative ammonia volatilisation (25% of total ammonium nitrogen (TAN) applied at Site 1; 21% of TAN applied at Site 2) than the mineral ones (11% of TAN applied at Site 1; 10% of TAN applied at Site 2). At pre-sowing, ammonia volatilisation was significantly (p < .05) lower (51% at Site 1; 55% at Site 2) than after ryegrass cuts due to burying PS immediately after application. Overall, applying DMPP had no effect on ammonia volatilisation. There were no significant differences in average yield (from 13.7 to 15.8 kg ha-1 at Site 1; from 11.6 to 13.5 kg ha-1 at Site 2) between the fertilised treatments, though ENTEC® tended to increase it. Applying PS (pre-sowing fertilisation) in combination with mineral N or processed PS fractions after ryegrass cuts could be an interesting option for the recycling of this livestock by-product without increasing ammonia volatilisation while maintaining yields.

Effect of N dose, fertilisation duration and application of a nitrification inhibitor on GHG emissions from a peach orchard.

Despite only occupying 5% of the worldwide arable area, fruit tree crops are of vital economic importance in many regions. Intensive cropping practices can lead to greenhouse gas (GHG) emissions. In order to reduce these emissions, numerous studies have been made on lowering N inputs or applying nitrification inhibitors (NIs) which tend to maintain or even increase yield while reducing N leaching and nitrogenous emissions to the atmosphere. However, very few studies have been conducted on potential GHG emissions from the peach crop. In this work, a three-year study was carried out in a commercial peach orchard with a split-plot design with three replicates, in which the main factor was N dose (25, 50 and 100 kg N ha-1 year-1, and 50 kg N ha-1 year-1 applied during a shorter period of time in 2015 and 2016; and only 70 kg N ha-1 year-1 in 2017). Subplots in the study were used to analyse the effect of the application of a NI (3,4-dimethylpyrazole phosphate; DMPP). The aim was to qualitatively compare the effect of these factors on N2O, N2O + N2, CH4 and CO2 emissions from a peach orchard soil in order to recommend agricultural practices that minimise emissions without concurrent yield reductions. We show that N2O and N2O + N2 emissions were linked to fertilisation and increased with N dose. The N2O emissions were mitigated (up to 49%) by DMPP up to the 50 kg N ha-1 dose (not significantly). It seems that between 70 and 100 kg N ha-1 the application of DMPP loses effectiveness. Methane oxidation increased with N dose and decreased with DMPP application; CO2 emissions increased with DMPP and were unaffected by N dose. The intermediate N dose (50 kg N ha-1) applied during a shorter period of time increased yield (not significantly) and NUE without increasing GHG emissions.

Effect of N dose on soil GHG emissions from a drip-fertigated olive (Olea europaea L.) orchard.

Agronomic practices may mitigate greenhouse gas emissions (GHG) from crops. Appropriate nitrogen (N) and irrigation management provide the potential to reduce nitrous oxide (N2O) and methane (CH4) emissions. However, there is little information about the combination of both practices on the GHG emissions from olive orchards. This four-year study was conducted to qualitatively compare the effect of N doses applied through two drip irrigation strategies on N2O and CH4 emissions in a super-intensive (1010 trees ha-1) olive orchard. The design (randomised blocks) was asymmetric: 0, 50 and 100 kg N ha-1 yr-1 were tested with full irrigation (FI; 2013 to 2016), but only 0 and 50 kg N ha-1 yr-1 were tested with regulated deficit irrigation (RDI; 2014 to 2016). The study shows that the soil acted as a main sink of N2O and CH4, regardless of the soil water content. Methane oxidation increased with N dose in the FI strategy (significant in 2013 and 2015). Overall, there was a tendency of yield to increase with the N dose without increasing emissions and without depending of the irrigation strategy. However, these results were not significant. Further confirmation of this tendency is necessary; particularly comparing FI + N100 (most promising treatment in terms of profitability) with the RDI + N100 (not available in this study) water-saving strategy.

Protein surface roughness accounts for binding free energy of Plasmepsin II-ligand complexes.

The calculation of absolute binding affinities for protein-inhibitor complexes remains as one of the main challenges in computational structure-based ligand design. The present work explored the calculations of surface fractal dimension (as a measure of surface roughness) and the relationship with experimental binding free energies of Plasmepsin II complexes. Plasmepsin II is an attractive target for novel therapeutic compounds to treat malaria. However, the structural flexibility of this enzyme is a drawback when searching for specific inhibitors. Concerning that, we performed separate explicitly solvated molecular dynamics simulations using the available high-resolution crystal structures of different Plasmepsin II complexes. Molecular dynamics simulations allowed a better approximation to systems dynamics and, therefore, a more reliable estimation of surface roughness. This constitutes a novel approximation in order to obtain more realistic values of fractal dimension, because previous works considered only x-ray structures. Binding site fractal dimension was calculated considering the ensemble of structures generated at different simulation times. A linear relationship between binding site fractal dimension and experimental binding free energies of the complexes was observed within 20 ns. Previous studies of the subject did not uncover this relationship. Regression model, coined FD model, was built to estimate binding free energies from binding site fractal dimension values. Leave-one-out cross-validation showed that our model reproduced accurately the absolute binding free energies for our training set (R2  = 0.76; <|error|> =0.55 kcal/mol; SDerror  = 0.19 kcal/mol). The fact that such a simple model may be applied raises some questions that are addressed in the article.

Unravelling the relationship between protein sequence and low-complexity regions entropies: Interactome implications.

Low-complexity regions are sub-sequences of biased composition in a protein sequence. The influence of these regions over protein evolution, specific functions and highly interactive capacities is well known. Although protein sequence entropy has been largely studied, its relationship with low-complexity regions and the subsequent effects on protein function remains unclear. In this work we propose a theoretical and empirical model integrating the sequence entropy with local complexity parameters. Our results indicate that the protein sequence entropy is related with the protein length, the entropies inside and outside the low-complexity regions as well as their number and average size. We found a small but significant increment in the sequence entropy of hubs proteins. In agreement with our theoretical model, this increment is highly dependent of the balance between the increment of protein length and average size of the low-complexity regions. Finally, our models and proteins analysis provide evidence supporting that modifications in the average size is more relevant in hubs proteins than changes in the number of low-complexity regions.

La cirugía del síndrome del túnel carpiano en pacientes de edad avanzada / The surgery of carpal tunnel syndrome in elderly patients

Objetivo: Presentamos los resultados a largo plazo de la cirugía de descompresión del nervio mediano en la muñeca en pacientes de edad avanzada. Métodos: Estudio prospectivo histórico, de larga evolución, en 98 pacientes intervenidos de síndrome del túnel carpiano, considerados por grupos de edad, con un tiempo postoperatorio medio de diez años. Se realizó la valoración con el cuestionario clínico-funcional de Levine, electromiografía y dinamometría de los pacientes estudiados. Resultados: Para la mayor parte de las preguntas del cuestionario de Levine, así como para los valores de velocidad sensitiva y latencia motora del nervio mediano, encontramos diferencias favorables con respecto a la valoración preoperatoria. Sin embargo, los datos de fuerza de presión manual fueron desfavorables. Conclusiones: En pacientes de edad avanzada, la sección completa del ligamento transverso del carpo permite mantener diferencias favorables en la mayoría de los parámetros estudiados tras diez años desde la cirugía, siendo el tratamiento quirúrgico una opción recomendable(AU)

Purpose: We present in this article the long term outcomes of median nerve release at the wrist in elderly patients. Methods: Historical prospective long term study over 98 patients that received surgical treatment of carpal tunnel syndrome considered by aging and with a mean follow-up of ten years. A clinical-functional (with the Levine Questionnaire), electromyographic and dynamometric evaluation of the patients studied have been carried out. Results: For most of the items of the Questionnaire of Levine, as well as for the values of sensitive velocity and motor latency of the median nerve, we have found favourable differences with respect to the preoperative evaluation. The data of grip strength are unfavourable. Conclusions: In elderly patients, complete section of the carpal transverse ligament, allows maintaining favourable differences in most of the parameters studied, after ten years from the surgery, being the surgical treatment a recommendable option(AU)

Perioperative values of glutathione peroxidase activity and malondialdehyde levels in enolic cirrhotic recipients of a liver transplant.

Reactive oxygen species play a central role in ischemia-reperfusion injury after organ transplantation. They are degraded by endogenous radical scavengers such as antioxidant enzymes. The purpose of this study was to evaluate the temporal variation in glutathione peroxidase (GPX) activity and malondialdehyde (MDA) levels among alcoholic cirrhotic recipients of liver transplantations. The study included 30 recipients: 26 males and 4 females in the provided blood samples before and after transplantation. The results showed significant enhancement of MDA levels at 1 and 6 hours after transplantation: 4.458 ± 2.273 µmol/L and 4.4628 ± 2.405 µmol/L respectively (P < .001). In contrast, GPX activity showed a maximum at 3 days there after 3.541 ± 2,315 nmol/mg protein. In conclusion, although MDA levels show an enormous increase at 1 hour after transplantation suggesting lipid peroxidation, they were compensated by GPX activity thereafter, indicating control of the oxidative stress generated by liver transplantation.

Gene network profiling before and after transplantation in alcoholic cirrhosis liver transplant recipients.

The main objective of this study was to define a gene network profile network in liver transplant recipients with alcoholic cirrhosis before and after liver transplantation. Genes were selected from data obtained in a previous study of liver transplant recipients with alcoholic cirrhosis. Selected up-regulated genes were further validated by quantitative real-time polymerase chain reaction in different groups of liver transplant recipients with alcoholic cirrhosis (n=5). Selected genes up-regulated before transplantation were: TNFRSF9 (tumor necrosis factor [TNF] receptor superfamily, member 9); IL2RB (interleukin-2 receptor beta); BCL2L2 (BCL2-like 2); NOX5 (NADPH) oxidase, EF-hand calcium binding domain 5); PEX5 (peroxisomal biogenesis factor 5); PPARG (peroxisome proliferator-activated receptor gamma); NIBP (IKK2 binding protein); NKIRAS2 (NFKappaBeta inhibitor interacting Ras-like 2); IL4 (interleukin-4); IL-4R (interleukin 4 receptor); ADH1A (alcohol dehydrogenase 1A, class 1); ALDH1L1 (aldehyde dehydrogenase 1 family, member L1); MPO (myeloperoxidase); NPPA (natriuretic peptide precursor A); BCL2A1 (BCL2-related protein A1); GADD45A (growth arrest and DNA-damage-inducible alpha); TEGT (Bax inhibitor 1); PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide); IFNGR2 (interferon gamma receptor 2); JAK2 (Janus Kinase 2); FAS (Fas, TNF receptor superfamily, member 6); TANK (TRAF family member-associated NFKB activator); TTRAP (TRAF and TNF receptor-associated protein); and ANXA5 (annexin A5).

Intraoperative pH values after N-acetylcysteine administration during liver transplantation.

We investigated whether intraoperative administration of N-acetylcysteine (NAC) to liver transplant recipients affected pH values. This prospective, randomized, double-blind clinical trial included liver transplant recipients who were randomly assigned to NAC-treated (n=25) or placebo (n=25) groups. The NAC-treated group received 100 mg/kg dissolved in 5% dextrose over 15 minutes during the anhepatic phase, followed by a continuous infusion of 50 mg/kg in 5% dextrose during the next 24 hours. The placebo group received equal amounts of 5% dextrose solution during the same times. Peripheral blood samples were drawn in Ca2+-80 IU-containing syringes after induction of anesthesia (I-1), at 15 minutes into the anhepatic phase (I-2) prior to the administration of NAC or placebo, at 5 minutes before reperfusion (I-3), at 5 minutes after reperfusion (I-4), at 20 minutes after reperfusion (I-5), at 60 minutes after reperfusion (I-6), and at 1 hour after completion of the procedure (I-7). pH levels, which were determined using a radiometer ABL77 (Copenhagen, Denmark), were significantly lower among the NAC than the placebo group at I-4 (P=.027) and I-5 (P=.031). An early decrease in pH values was detected in the NAC-treated group at 5 minutes before reperfusion (I-3; P=.051). We concluded that intraoperative NAC administration during the anhepatic phase of liver transplantation significantly decreased recipient pH values at 5 and 20 minutes after reperfusion, a decrease that was detected at 5 minutes before reperfusion (I-3). The decrease seemed to be associated with NAC metabolism.

Clinical and pathological factors related to 18F-FDG-PET positivity in the diagnosis of recurrence and/or metastasis in patients with differentiated thyroid cancer.

BACKGROUND: Objectives were to analyze the relationship between a positive (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) result and clinical and tumor factors in patients treated for differentiated thyroid cancer (DTC) and under suspicion of recurrence or metastasis, and to determine the diagnostic validity of PET in DTC patients with elevated serum thyroglobulin (Tg) and negative (131)I whole-body scan ((131)I-WBS). METHODS: We studied 50 DTC patients with elevated serum Tg and negative WBS treated with total thyroidectomy and (131)I ablation. Thyroxin treatment was withdrawn and patients were on iodine-free diet before WBS. Tg, anti-Tg antibodies, and thyroid-stimulating hormone (TSH) were determined. Patients with negative WBS and elevated Tg underwent PET study 1 week later. PET findings were verified by pathology findings or other imaging techniques [computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US)] and/or 12-month follow-up. The relationship between PET findings and tumor (histological type, size, multifocality, thyroid capsular invasion, lymph-node and/or metastatic involvement) and clinical (age at diagnosis, sex, Tg, accumulated iodine dose, and recurrence time) variables was analyzed. RESULTS: PET was positive in 32/39 patients with confirmed disease (82% sensitivity) and negative in 7/11 of disease-free cases (64% specificity), a positive predictive value (PPV) of 89%. Tumor size (P < 0.05) and thyroid capsular invasion (P < 0.05) were significantly associated with positive PET study. The relationship of PET findings with Tg levels and age at diagnosis was close to significance. CONCLUSION: (18)F-FDG-PET study offers a high sensitivity and positive predictive value (PPV) in patients with negative WBS and Tg positive. The use of FDG-PET is strongly recommended in DTC patients with large tumors, thyroid capsule invasion or poor-prognosis variants.

Gene expression profiling in liver transplant recipients with alcoholic cirrhosis.

The main objective of this study was to identify differences in gene expression profile using microarray technology in liver transplant recipients with alcoholic cirrhosis before and after liver transplantation. The study was performed in liver transplant recipients with alcoholic cirrhosis (n = 10) and in healthy volunteers (n = 10), as a reference group. Peripheral blood samples were obtained before (T0) and 7 days after liver transplantation (T7d) using tubes with an RNA stabilizer. RNA was purified and quality tested. From each participant in the study, microarrays were done in duplicate using 10 mug of cRNA. After reverse transcription, complementary RNAs were labeled with Cy5 Streptavidine and used for hybridization of 20,000 human genes CodeLink bioarrays (Applied Microarrays, United States) overnight at 37 degrees C. Arrays were read with a laser scanner and quantified and normalized with CodeLink Software 4.2. Liver transplant recipients showed a gene expression profile before transplantation (T0) of 4310 overexpressed genes compared with healthy volunteers, with 407 of these genes increased more than 2-fold (P < .05). After transplantation (T7d), the same group of patients showed a profile of 1011 overexpressed genes compared with T0, with 109 of these genes increased more than 2-fold (P < .05). We determined gene expression profiles in peripheral blood samples obtained before and after liver transplantation, giving a report of array gene expression profiles of peripheral blood samples from each of these patients. One implication of these results is that gene profiling of peripheral blood samples using microarray technology could be used to dynamically monitor the impact and adequacy of immunosuppression in individual patients.

Study of gene expression profile in liver transplant recipients with hepatitis C virus.

The main objective of this study was to identify differences in gene expression profiles by liver transplant recipients with hepatitis C virus (HCV) using microarray technology before versus after liver transplantation. The study was performed in liver transplant recipients with HCV (n = 6) versus a group of healthy volunteers (n = 6). Peripheral blood samples were obtained before (T0) and 7 days after liver transplantation (T7d) using tubes with an RNA stabilizer. The quality of purified RNA was tested (28S/18S ratio >1.5) in a bioanalyzer. Each participant in the study underwent microarrays in duplicate using 10 mug of complementary RNA. After reverse transcription, cRNAs were labeled with Cy5 Streptavidine. Hybridization of 20000 human genes CodeLink bioarrays (Applied Microarrays, United States) was performed overnight at 37 degrees C. Arrays read with a laser scanner were normalized with CodeLink Software 4.2. At T0, liver transplant recipients showed 116 over-expressed genes when compared with healthy volunteers, who had 33 genes increased >2-fold (P < .05). At T7d after transplantation, the same group of patients showed 613 over-expressed genes compared with T0, of which 97 genes were increased >2-fold (P < .05). We determined gene expression profiles in peripheral blood samples obtained before and after liver transplantation, reporting the array of gene expression profiles in peripheral blood samples from each of these patients classes. One implication of these results is that gene profiling of peripheral blood samples could be used to dynamically monitor the impact and adequacy of immunosuppression in individual patients using microarray technology.

Effect of N-acetylcysteine administration on intraoperative plasma levels of interleukin-4 and interleukin-10 in liver transplant recipients.

We investigated whether intraoperative administration of N-acetylcysteine (NAC) in liver transplant recipients ameliorated their inflammatory responses by increasing intraoperative plasma levels of interleukin (IL)-4 and IL-10. This prospective, randomized, double-blind clinical trial included liver transplant recipients randomly assigned to the NAC-treated (n = 25) or the placebo (n = 25) group. The NAC-treated group received 100 mg/kg dissolved in 5% dextrose over 15 minutes during the anhepatic phase, followed by a continuous infusion of 50 mg/kg in 5% dextrose over the next 24 hours, whereas the placebo group received equal amounts of 5% dextrose solution during the same time. Peripheral blood samples were drawn in EDTA-containing tubes after induction of anesthesia (I-1); at 15 minutes into the anhepatic phase (I-2) prior to the administration of NAC or placebo; at 5 minutes before reperfusion (I-3); at 10 minutes after reperfusion (I-4); at 20 minutes after reperfusion (I-5); at 60 minutes after reperfusion (I-6); and at 1 hour after completion of the liver transplantation (I-7). Cytokine levels were determined using a technique which combined enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Plasma IL-4 levels were significantly higher among the NAC-treated group than the placebo group at I-3 (P = .046) and I-4 (P = .041). Plasma IL-10 levels showed significant enhancement in the NAC-treated group at 5 minutes before reperfusion (I-3; P = .007). We concluded that intraoperative NAC administration during the anhepatic phase of liver transplantation significantly increased recipient IL-4 plasma levels before and after reperfusion, and IL-10 plasma values before reperfusion (I-3). These enhancements seemed to be associated with a protective effect against reperfusion injury.

Early postoperative response of cytokines in liver transplant recipients.

We evaluated the early postoperative response of several cytokines (IL-2, IL-4, IL-6, IL-10, TNF-alpha, IFN-gamma) prior to liver transplantation (T(0)) as well as 1, 6, and 12 hours and 1, 2, 3, 5, and 7 days afterward. Cytokine concentrations were correlated with serum levels of bilirubin as a predictor of postoperative complications. Cytokine levels were determined in plasma samples from 16 liver transplant recipients (13 men, 3 women) aged 43 to 61 years. IL-6 and IL-10 reached their maximum concentrations 1 hour after transplantation. Each increase in IL-6 correlated to a rise in IL-10. IL-2, IL-4, TNF-alpha, and IFN-gamma had a particular time-course for each patient studied. Bilirubin fell to almost normal values but not in cases of postoperative complications, where IL-6 showed values four times higher compared to those of liver transplant recipients who did not show postoperative complications. IL-6 and IL-10 plasma concentrations and serum bilirubin level might be useful as a predictive factor of postoperative complications in liver transplant recipients.

Time course of intraoperative cytokine levels in liver transplant recipients.

We evaluated the levels of several cytokines (interleukin [IL]-2, IL-4, IL-6, IL-10, tumor necrosis factor [TNF]-alpha, and interferon [IFN]-gamma) in plasma samples obtained before surgical intervention (T0) and during intraoperative liver transplantation: after induction of anesthesia (I-1), 15 minutes of anhepatic phase (I-2), 5 minutes before reperfusion (I-3), 10 minutes after reperfusion (I-4), 20 minutes after reperfusion (I-5), 60 minutes after reperfusion (I-6), and 1 hour after liver transplantation (I-7). Cytokine levels were determined using a technique which combines ELISA technique and flow cytometry. The study was approved by the local clinical research (ethics) committee. Written informed consent was obtained from patients' relatives. Twenty patients (14 men, 6 women) aged 23 to 61 years, recipients of a liver transplantation were studied. The cytokine IL-2 plasma values were maintained during the whole study period, with a slight increase at 15 minutes of anhepatic phase (I-2). IL-4 showed a peak value 20 minutes after reperfusion (I-5). IL-6 increased its plasma value starting at 15 minutes of anhepatic phase (I-2), maintaining high concentrations during the whole intraoperative period. IL-10 increased progressively, reaching a maximum 1 hour after transplantation (I-7). TNF-alpha reached maximum plasma levels 20 minutes after reperfusion (I-5), whereas IFN-gamma showed a peak at 15 minutes of anhepatic phase (I-2). Our results indicate that the anhepatic phase (I-2) is the earliest phase during which proinflammatory and anti-inflammatory cytokines, such as IL-6 and IL-10, respectively, are involved during liver transplantation. We conclude that IL-6 is the first cytokine involved in the inflammatory response during liver transplantation.