Miguel Ángel Gómez-Bravo

Point-of-care haemostasis monitoring during liver transplantation reduces transfusion requirements and improves patient outcome.

BACKGROUNDnOptimal haemostasis management can improve patient outcomes and reduce blood loss and transfusion volume in orthotopic-liver-transplant (OLT).nnnMETHODSnWe performed a prospective study including 200 consecutive OLTs. The first 100 patients were treated according to the clinics standards and the next 100 patients were treated using the new point-of-care (POC)-based haemostasis management strategy. Transfusion parameters and other outcomes were compared between groups.nnnRESULTSnTransfusion requirements were reduced in the POC group. The median and IQR of red-blood-cells (RBC) transfusion units were reduced from 5 [2-8] to 3 [0-5] (p < 0.001), plasma from 2 [0-4] to 0 (p < 0.001), and platelets from 1 [0-4] to 0 [0-1] (p < 0.001), into the POC group only four patients received tranexamic acid and fibrinogen transfusion rate was 1.13 ± 1.44 g (p = 0.001). We also improved the incidence of transfusion avoidance, 5% vs. 24% (p < 0.001) and reduced the incidence of massive transfusion (defined as the transfusion of more than 10 RBC units), 13% vs. 2% (p = 0.005). We also observed a relationship between RBC transfusion requirements and preoperative haemoglobin, and between platelet transfusion and preoperative fibrinogen levels. The incidence of postoperative complications, such as, reoperation for bleeding, acute-kidney-failure or haemodynamic instability was significantly lower (13.0% vs. 5%, p = 0.048, 17% vs. 2%, p < 0.001, and 29% vs. 16%, p = 0.028). Overall, blood product transfusion was associated with increased risk of postoperative complications.nnnCONCLUSIONSnA haemostatic therapy algorithm based on POC monitoring reduced transfusion and improved outcome in OLT.

Impact of donor and recipient CYP3A5 and ABCB1 genetic polymorphisms on tacrolimus dosage requirements and rejection in Caucasian Spanish liver transplant patients

Studies of liver transplant (LT) patients, mainly in Asians, have evaluated the influence of the CYP3A5*1 allele and P‐glycoprotein gene ABCB1 on tacrolimus pharmacokinetics or biopsy‐proven acute rejection (BPAR) incidence, with no conclusive results. To investigate these issues, 98 Caucasian Spanish LT patients with tacrolimus, mycophenolate mofetil and steroids and 88 cadaveric donors were genotyped for the SNPs CYP3A5 6986G>A, ABCB1 1236C>T, ABCB1 2677G>A/T and ABCB1 3435C>T;. On day 7 post‐LT, patients with a native CYP3A5*1 allele had significantly lower tacrolimus trough concentrations C0 (Pu2009=u2009.03) and dose‐adjusted concentrations C0/D (Pu2009=u2009.02) than CYP3A5 *3/*3 homozygotes. Three months post‐LT, patients carrying a liver with CYP3A5*1 had significantly lower C0/D (Pu2009=u2009.03) and took significantly higher tacrolimus doses (Pu2009=u2009.03) than the corresponding *3/*3 homozygotes. ABCB1 SNPs showed no significant association with tacrolimus variables. The 3‐month incidence of BPAR was 10.2%, with no statistically significant differences related to CYP3A5 (14.3% in expresser vs. 9.5% in non‐expresser) or ABCB1 genotype of either patient or donor. We conclude that in Caucasian Spanish LT patients, a native or graft‐borne CYP3A5*1 allele tends to lower tacrolimus concentrations and increase dosage needs, but has no significant impact on the incidence of BPAR.

Monitoring of Transplanted Liver Health by Quantification of Organ-Specific Genomic Marker in Circulating DNA from Receptor

Background Health assessment of the transplanted organ is very important due to the relationship of long-term survival of organ transplant recipients and health organ maintenance. Nowadays, the measurement of cell-free DNA from grafts in the circulation of transplant recipients has been considered a potential biomarker of organ rejection or transplant associated complications in an attempt to replace or reduce liver biopsy. However, methods developed to date are expensive and extremely time-consuming. Our approach was to measure the SRY gene, as a male organ biomarker, in a setting of sex-mismatched female recipients of male donor organs. Methods Cell-free DNA quantization of the SRY gene was performed by real-time quantitative PCR beforehand, at the moment of transplantation during reperfusion (day 0) and during the stay at the intensive care unit. Beta-globin cell-free DNA levels, a general cellular damage marker, were also quantified. Results Beta-globin mean values of patients, who accepted the graft without any complications during the first week after surgery, diminished from day 0 until patient stabilization. This decrease was not so evident in patients who suffered some kind of post-transplantation complications. All patients showed an increase in SRY levels at day 0, which decreased during hospitalization. Different complications that did not compromise donated organs showed increased beta-globin levels but no SRY gene levels. However, when a donated organ was damaged the patients exhibited high levels of both genes. Conclusion Determination of a SRY gene in a female recipients serum is a clear and specific biomarker of donated organs and may give us important information about graft health in a short period of time by a non-expensive technique. This approach may permit clinicians to maintain a close follow up of the transplanted patient.

Neumonitis asociada a everolimus en un receptor de trasplante hepático

la población general. Kanaji et al y Rosenthal et al describen una incidencia 2,1 y 1,5 veces superior a la de la población de referencia, respectivamente. El cáncer más frecuente es el de pulmón (sobre todo adenocarcinoma) seguido del de mama. En la serie de pacientes con ES de los autores de esta carta, se encontraron 8 casos de neoplasia entre un total de 168. En los diferentes estudios se mencionan, como factores de riesgo de neoplasia, las formas difusas de ES, los anticuerpos anti-Scl70, el tabaquismo, la fibrosis pulmonar asociada o los años de evolución de la enfermedad. Algunas citocinas implicadas en la ES (como factor de transformación y crecimiento beta) también lo están como factores mitóticos en la patogénesis de las neoplasias, y lo mismo ocurre con las alteraciones de la inmunidad celular y los tratamientos inmunosupresores. Tras una revisión extensa de la literatura médica (búsqueda en la base de datos Medline, con los descriptores ‘‘esclerosis sistémica’’, ‘‘coexistencia de autoanticuerpos’’ y ‘‘cáncer’’; con extensión temporal de 20 años), no se encontraron descritos otros casos de neoplasia en pacientes con ES y positividad de ambos autoanticuerpos.

Detection of p53 Mutations in Circulating DNA of Transplanted Hepatocellular Carcinoma Patients as a Biomarker of Tumor Recurrence

p53 is the most commonly mutated gene in malignant human cancers. To detect p53 mutations in circulating DNA (cirDNA) of transplanted hepatocellular carcinoma (HCC) patients could be an interesting approach to know of any tumor recurrence. In this study, our objective was to determine the utility of this method in the diagnosis and the prognosis of HCC tumor recurrence.Twenty four liver transplanted HCC patients were included in the study together with a group of healthy controls. Detection of the specific p53 mutation in cirDNA was performed by high-resolution melting PCR (HRM-PCR) and COLD-PCR immediately before the transplantation. Serum anti-p53 was also determined using a p53-autoantibody ELISA kit.The results of the HRM-PCR and COLD-PCR showed two well-differentiated groups of transplanted patients after normalization by healthy controls. These data allow us to distinguish between patients with p53 mutated cirDNA and those with wild type cirDNA. Moreover, we have found that most of p53 mutated patients also presented elevated anti-p53 antibodies. The present results indicate that it is possible to detect mutated p53 genes with the cirDNA and that this could be used as a biomarker of tumor recurrence during the clinical evolution of the transplanted patients.

Outcomes of Liver Transplantation During Adulthood After Kasai Portoenterostomy Due to Biliary Atresia

Biliary atresia (BA) is a neonatal progressive cholangiopathy of unknown etiology and one of the most common reasons for liver transplantation (LT) in children. Kasai portoenterostomy (KP) improves survival of the native liver, although LT remains the only ultimate treatment. In some cases KP makes it possible to defer the ultimate LT until adulthood. We report our experience regarding 5 cases of BA treated with LT during adulthood. KP was performed in all patients at an average age of 176 days (range, 60-280), which allowed an average survival of the native liver of 19.01 years (range, 14.06-22.32). Five-year survival rate was 100%. Ten-year survival rate did not reach 100% because of a death 9.55 years after LT due to chronic graft rejection, in a patient who was already prepared for a new LT. Our results corroborate that KP remains the first-line treatment of BA. Early performance of the KP provides children with the best chance of survival, allowing the delay of the LT to adulthood. LT during adulthood in these patients achieves good post-LT survival rate; we have not found any data regarding this group of patients in the literature.

Gallbladder leiomyoma in absence of immune system disorders: an unusual diagnosis

Mesenchymal neoplasms of the gallbladder are rare and in particular leiomyomas of the gallbladder have been rarely reported, all of them in patients with immune system disorders.This is the first report in Spanish of a 23-year-old female patient with a gallbladder leiomyoma without associated immunodeficiency. The patient lacks a previous history of uterine leiomyoma or any other form of neoplasm. She refers several episodes of epygastralgia. A hydatic cyst led to an initial diagnosis and the gallbladder was removed by means of simple cholecystectomy. The abnormal macroscopic aspect of the sample prompted intraoperative biopsy which revealed a benign gallbladder angiomyoma. Subsequent immunohistochemical analysis of the resected sample yielded the diagnosis of intramural endocavitary leiomyoma negative for EBV and C-kit / CD-117. The patient has good general condition and remains asymptomatic 15 months after surgery.

Ascaris lumbricoides as etiologic factor for pancreas inflammatory tumor

A 58 years old male consulted to his practitioner due to long evolution and continuous abdominal pain with non constantdiarrhea. His medical history includes chronic ischemic cardiopathy, atrial flutter, hypertension, bilateral hip prosthesis. Acolonoscopy was performed finding no abnormalities. The scanner showed an infiltrative mesenteric mass of 7 x 14 cmwith undefined margins which contacted with pancreatic cephalic portion and uncinate process (Fig. 1). A MRI dismissedlocal and linfovascular infiltration. The study was completed with a FNA cytology guided by EUS being positive for neoplasticcells, suggesting pancreatic adenocarcinoma moderately differentiated. After this diagnosis cephalic pancreaticoduodenectomywas performed.Postoperative evolution was good with a pancreatic leak solved with medical measures. Further anatomical pathologyanalysis demonstrated pancreatic ascariasis with fibrocaseous nodules and abscess affecting cephalic pancreas and transversemesocolon (Fig. 2). There were no tumor cells founded in the surgical specimen. The patient was treated with albendazole400 mg.

Influence of donor liver CYP3A4*20 loss-of-function genotype on tacrolimus pharmacokinetics in transplanted patients

Objective Cytochrome P450 3A4 (CYP3A4) metabolizes about half of all drugs on the market; however, the impact of CYP3A4 loss-of-function variants on drug exposures remains poorly characterized. Here, we report the effect of the CYP3A4*20 frameshift allele in two Spanish liver transplant patients treated with tacrolimus. Patients and methods A series of 90 transplanted patients (with DNA available for 89 of the recipients and 76 of the liver donors) treated with tacrolimus were included in the study. The genotypes of liver donors and of the recipients for CYP3A4*20 (rs67666821), CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746) were compared with weight-adjusted tacrolimus dose (D), tacrolimus trough concentration (C0), and dose-adjusted tacrolimus trough concentrations (C0/D) using the Mann–Whitney U-nonparametric test. Results The CYP3A4*20 allele was detected in two of the liver donors. This genotype yielded at all times higher C0/D (2.6-fold, average) than intermediate CYP3A metabolizers (CYP3A4*1/*1 and CYP3A5*3/*3) (P=0.045, 90 days after transplantation). CYP3A4*22 carriers showed a 1.9-fold average increase in C0/D (P=0.047, 0.025, and 0.053; at days 7, 14, and 30 after transplantation, respectively) compared with intermediate metabolizers. In terms of recipients’ genotype, CYP3A5*1 had reduced (P=0.025) and CYP3A4*22 increased C0/D (P=0.056) 7 days after transplantation. The incidence of biopsy-proven acute rejection was 0, 12, and 20% for livers with poor, intermediate, and extensive CYP3A-metabolizing capacity, respectively (P=0.0995). Conclusion This first description of CYP3A4*20 null genotype in liver-transplanted patients, supports the relevance of CYP3A genotyping in tacrolimus therapy.

Evaluation of the State of Transplanted Liver Health by Monitoring of Organ-Specific Genomic Marker in Circulating DNA from Receptor

The evaluation of the transplanted liver health by non-invasive approaches may offer an improvement in early clinical intervention. As transplanted organs have genomes that are distinct from the hosts genome, the quantification of the specific DNA of the donated liver in the patient serum will allow us to obtain information about its damage. We evaluated the state of transplanted liver health by monitoring the RH gene in serum circulating DNA (cirDNA) from 17 recipient and donor mismatched for this gene. cirDNA RH gene was quantified by RT- PCR before, at the moment of transplantation (day 0) and during the stay at the intensive care unit. Beta-globin cirDNA was quantified as a general cellular damage marker. Patients were grouped based on clinical outcomes: (A) patients with no complication; (B) patients that accepted the organ but suffered other complications; (C) patients that suffered organ rejection. All patients showed an increased cirDNA levels at day 0 that decreased until patient stabilization. Patients from groups A and B showed low levels of the RH gene cDNA during the follow-up, with an increase of beta-globin gene at the moment of any clinical complication. Patients from group C showed an increase in the RH gene during rejection.