Selective Indication of T-Tube in Liver Transplantation: Prospective Validation of the Results of a Randomized Controlled Trial.

BACKGROUND AND AIMS: T-tube placement during choledochocholedochostomy (CCS) associated with liver transplantation (LT) remains controversial. This study was designed to validate the results of an earlier prospective randomized controlled trial (RCT) on use versus nonuse of the T-tube during CCS associated with LT. METHODS: Prospective cohort study. The primary outcome was the overall incidence of biliary complications (BCs). RESULTS: In total, 405 patients were included, and the median overall monitoring period was 29 months (interquartile range: 13-47 months). Selective use of the T-tube reduced BCs (23% vs 13%; P = .003), of which 75% were type IIIa or less in the Clavien-Dindo classification. The overall BC rate did not differ between patients with versus without T-tube placement. CONCLUSIONS: We confirmed that selective use of a rubber T-tube during CCS associated with LT, following the principles established in our prospective RCT, reduced the rate of BC by 10% without detriment, even after enrolling patients at an a priori greater risk of BCs than were the RCT patients.

Assessing standardization of molecular testing for non-small-cell lung cancer: results of a worldwide external quality assessment (EQA) scheme for EGFR mutation testing.

BACKGROUND: The external quality assurance (EQA) process aims at establishing laboratory performance levels. Leading European groups in the fields of EQA, Pathology, and Medical and Thoracic Oncology collaborated in a pilot EQA scheme for somatic epidermal growth factor receptor (EGFR) gene mutational analysis in non-small-cell lung cancer (NSCLC). METHODS: EQA samples generated from cell lines mimicking clinical samples were provided to participating laboratories, each with a mock clinical case. Participating laboratories performed the analysis using their usual method(s). Anonymous results were assessed and made available to all participants. Two subsequent EQA rounds followed the pilot scheme. RESULTS: One hundred and seventeen labs from 30 countries registered and 91 returned results. Sanger sequencing and a commercial kit were the main methodologies used. The standard of genotyping was suboptimal, with a significant number of genotyping errors made. Only 72 out of 91 (72%) participants passed the EQA. False-negative and -positive results were the main sources of error. The quality of reports submitted was acceptable; most were clear, concise and easy to read. However, some participants reported the genotyping result in the absence of any interpretation and many obscured the interpretation required for clinical care. CONCLUSIONS: Even in clinical laboratories, the technical performance of genotyping in EGFR mutation testing for NSCLC can be improved, evident from a high level of diagnostic errors. Robust EQA can contribute to global optimisation of EGFR testing for NSCLC patients.

Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript.

Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P = 3.9 × 10(-22)). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P = 1.9 × 10(-34)). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk.

BRCA1 mRNA expression and outcome to neoadjuvant cisplatin-based chemotherapy in bladder cancer.

BACKGROUND: neoadjuvant chemotherapy has shown a modest benefit in muscle-invasive bladder cancer patients; however, the subset of patients most likely to benefit has not been identified. BRCA1 plays a central role in DNA repair pathways and low BRCA1 expression has been associated with sensitivity to cisplatin and longer survival in lung and ovarian cancer patients. PATIENTS AND METHODS: we assessed BRCA1 messenger RNA expression levels in paraffin-embedded pre-treatment tumor samples obtained by transurethral resection from 57 patients with locally advanced bladder cancer subsequently treated with neoadjuvant cisplatin-based chemotherapy. BRCA1 levels were divided into terciles and correlated with pathological response and survival. RESULTS: a significant pathological response (pT0-1) was attained in 66% (24 of 39) of patients with low/intermediate BRCA1 levels compared with 22% (4 of 18) of patients with high BRCA1 levels (P = 0.01). Median survival was 168 months in patients with low/intermediate levels and 34 months in patients with high BRCA1 levels (P = 0.002). In the multivariate analysis for survival, only BRCA1 expression levels and lymphovascular invasion emerged as independent prognostic factors. CONCLUSIONS: our data suggest that BRCA1 expression may predict the efficacy of cisplatin-based neoadjuvant chemotherapy and may help to customize therapy in bladder cancer patients.

Valor pronóstico de la concentración del inhibidor de la fibrinolisis activable por trombina y del polimorfismo C1040T en el infarto agudo de miocardio tratado con fibrinolisis / Prognosis value of thrombin activatable fibrinolysis inhibitor concentration and C1040T polymorphism in acute myocardial infarction treated with fibrinolysis

Objetivos: Analizar el valor pronóstico del inhibidor de la fibrinolisis activable por trombina (TAFI) y del polimorfismo C1040T en el infarto agudo de miocardio (IAM) fibrinolisado. Analizar la influencia del polimorfismo C1040T en la concentración plasmática del TAFI. Diseño: Estudio observacional prospectivo, desde noviembre 2003 hasta noviembre 2005. Seguimiento 3 meses. Ámbito: Servicio de medicina intensiva de hospital universitario. Pacientes: Cincuenta y tres pacientes con infarto agudo de miocardio con elevación persistente del ST fibrinolisado. Grupo control de 53 sujetos biológicamente similares. Intervenciones: Ninguna. Variables de interés: Características basales; frecuencia del genotipo salvaje (Thr325Thr) y de los correspondientes a la mutación (Thr325Ile y Ile325Ile); concentración de TAFI a las 6h, 34h, 48h y 3meses; fracción eyección ventricular; Killip-Kimball; reperfusión; recurrencia isquémica; muerte. Resultados: Las características biológicas no se relacionaron con la concentración de TAFI, que fue significativamente superior en el infarto (p<0,01) y en la mutación (p<0,01). Esta en homocigosis (Ile325Ile) fue significativamente más frecuente en el infarto (p<0,01). La reperfusión asoció significativamente menores: índice de masa corporal (p=0,02. OR 0,22. IC95%), fracción de eyección (p=0,004. OR 0,91. IC95%), trigliceridemia (p=0,01. OR 1,02. IC95%) y colesterolemia (p=0,001. OR 0,84. IC95%). La mutación se asoció a un descenso significativo del TAFI antigénico y TAFI funcional post-fibrinolisis (p=0,01) y (p=0,02), y a menor frecuencia de reperfusión. La reperfusión asoció un descenso significativo del TAFI antigénico post-fibrinolisis (p=0,02). La recurrencia asoció un TAFI antigénico post-fibrinolisis significativamente superior (p=0,05. OR 0,84. IC95%). Ésta fue más frecuente en la mutación. Conclusiones: Un nivel elevado de TAFI asocia peor pronóstico en cuanto a reperfusión y recurrencia en el IAM fibrinolisado. La mutación en homocigosis presenta mayor frecuencia en el infarto. El genotipo salvaje se asocia a un mejor pronóstico. Los portadores de mutación se asocian a una mayor expresión de TAFI (AU)

Objective: To analyze the prognostic value of thrombin activatable fibrinolysis inhibitor (TAFI) and C1040T polymorphism in acute myocardial infarction treated with fibrinolysis. To analyze C1040T polymorphism influence on its plasma level. Design: An observational, prospective study performed from November 2003 to November 2005 and with a 3 month follow-up. Setting: Intensive Medicine Service from a university-affiliated teaching hospital. Patients: A total of 53 patients with acute myocardial infarction with persistent ST segment elevation treated with the same fibrinolytic therapy. A control group of 53 biologically similar subjects was included. Interventions: None. Main measurements: Baseline characteristics; frequency of wild-type genotype (Thr325Thr) and of those corresponding to the mutation (Thr325LLe and LLe325lle), TAFI levels at 6h, 34h and 3 months post-fibrinolysis; ejection fraction; Killip-Kimball; reperfusion; ischemic recurrence; death. Results: No relationship was found between biological features and TAFI concentration. The latter was significantly higher in infarct patients (p<0.01) and in the mutation group (p<0.01). The homozygotic mutation (Ile325Ile) was significantly higher in infarct patients (p<0.01). Reperfusion was significantly associated with lower body mass index (p=0.02. OR 0.22. 95% CI), ejection fraction (p=0.004. OR 0.91. 95% CI), triglyceride level (p=0.01. OR 1.02. 95% CI) and cholesterol levels (p=0.001. OR=0.84. 95% CI). Mutation was associated to a significant fall in post-fibrinolysis concentration TAFI antigen and functional TAFI (p=0.01) and (p=0.02), and lower frequency of reperfusion. Reperfusion was associated with a significant post-fibrinolysis reduction in the level of TAFI antigen (p=0.02). Recurrence was associated to a significantly higher post-fibrinolysis level (p=0.05. OR=0.84. 95% CI). This was more frequent in mutation. Post-fibrinolysis TAFI antigen concentration was significantly lower in non-recurrence patients (p=0.028. OR=1.03. 95% CI). Conclusions: A higher concentration of TAFI is associated to a worse prognosis in reperfusion and recurrence in acute myocardial infarction treated with fibrinolysis. Homozygotic mutation was more frequent in myocardial infarction patients. Wild genotype is associated to a better prognosis. Mutation is associated to a higher expression of TAFI (AU)

[Prognosis value of thrombin activatable fibrinolysis inhibitor concentration and C1040T polymorphism in acute myocardial infarction treated with fibrinolysis]. / Valor pronóstico de la concentración del inhibidor de la fibrinolisis activable por trombina y del polimorfismo C1040T en el infarto agudo de miocardio tratado con fibrinolisis.

OBJECTIVE: To analyze the prognostic value of thrombin activatable fibrinolysis inhibitor (TAFI) and C1040T polymorphism in acute myocardial infarction treated with fibrinolysis. To analyze C1040T polymorphism influence on its plasma level. DESIGN: An observational, prospective study performed from November 2003 to November 2005 and with a 3 month follow-up. SETTING: Intensive Medicine Service from a university-affiliated teaching hospital. PATIENTS: A total of 53 patients with acute myocardial infarction with persistent ST segment elevation treated with the same fibrinolytic therapy. A control group of 53 biologically similar subjects was included. INTERVENTIONS: None. MAIN MEASUREMENTS: Baseline characteristics; frequency of wild-type genotype (Thr325Thr) and of those corresponding to the mutation (Thr325LLe and LLe325lle), TAFI levels at 6 h, 34 h and 3 months post-fibrinolysis; ejection fraction; Killip-Kimball; reperfusion; ischemic recurrence; death. RESULTS: No relationship was found between biological features and TAFI concentration. The latter was significantly higher in infarct patients (p<0.01) and in the mutation group (p<0.01). The homozygotic mutation (Ile325Ile) was significantly higher in infarct patients (p<0.01). Reperfusion was significantly associated with lower body mass index (p=0.02. OR 0.22. 95% CI), ejection fraction (p=0.004. OR 0.91. 95% CI), triglyceride level (p=0.01. OR 1.02. 95% CI) and cholesterol levels (p=0.001. OR=0.84. 95% CI). Mutation was associated to a significant fall in post-fibrinolysis concentration TAFI antigen and functional TAFI (p=0.01) and (p=0.02), and lower frequency of reperfusion. Reperfusion was associated with a significant post-fibrinolysis reduction in the level of TAFI antigen (p=0.02). Recurrence was associated to a significantly higher post-fibrinolysis level (p=0.05. OR=0.84. 95% CI). This was more frequent in mutation. Post-fibrinolysis TAFI antigen concentration was significantly lower in non-recurrence patients (p=0.028. OR=1.03. 95% CI). CONCLUSIONS: A higher concentration of TAFI is associated to a worse prognosis in reperfusion and recurrence in acute myocardial infarction treated with fibrinolysis. Homozygotic mutation was more frequent in myocardial infarction patients. Wild genotype is associated to a better prognosis. Mutation is associated to a higher expression of TAFI.

Non-small-cell lung cancer harbouring mutations in the EGFR kinase domain

Key "driver" mutations have been discovered in specific subgroups of non-small-cell lung cancer (NSCLC) patients. Activating mutations in the form of deletions in exon 19 (del 19) or the missense mutation L858R in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) predict outcome to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. Pooled data from several phase II studies show that gefitinib and erlotinib induce responses in over 70% of NSCLC patients harbouring EGFR mutations, with progression-free survival (PFS) ranging from 9 to 13 months and median survival of around 23 months. Two studies in Caucasian and Asian patients have confirmed that these subgroups of patients attain response rates of 70% with erlotinib and ge- fitinib, including complete responses, PFS up to 14 months and median survival up to 27 months. These landmark outcomes have been accompanied by new challenges: the additional role of chemotherapy and the management of tumours with the secondary T790M mutation that confers resistance to EGFR TKIs. Mechanisms of resistance to reversible EGFR TKIs should be further clarified and could be related to modifications in DNA repair. The presence of double mutations (T790M plus either L858R or del 19) at the time of diagnosis could be much more frequent than originally thought. The sensitivity to EGFR TKIs could be greatly influenced by the expression of genes involved in the repair of DNA double-strand breaks by homologous recombination and non-homologous end joining (AU)

Expression of molecular markers in mediastinal nodes from resected stage I non-small-cell lung cancer (NSCLC): prognostic impact and potential role as markers of occult micrometastases.

BACKGROUND: Occult lymph node (LN) metastases are clinically relevant and confer a worse prognosis in non-small-cell lung cancer (NSCLC) patients. Current staging methods are unable to identify patients with poor outcome. Their detection requires both a more sensitive and specific technique. We aimed to assess the role of messenger RNA expression in pathologically negative LNs (pN0) of stage I NSCLC patients as markers of occult micrometastases and to correlate the results with local or distant tumor recurrence and survival. PATIENTS AND METHODS: Potential molecular markers were evaluated in 344 LNs and 38 tumors by quantitative real-time RT-PCR. Only CEACAM5 and PLUNC showed high expression in lung tumor tissue and null expression in RNA from benign LNs. RESULTS: Thirteen per cent of the LNs were positive for CEACAM5 and 16% for PLUNC. Eight of 38 NSCLC patients had positive expression in pN2 nodes by CEACAM5 and/or PLUNC and disease-free survival (P=0.028) and overall survival time was significantly worse in these patients compared with those with negative expression (P=0.0083). CONCLUSIONS: Quantitative real-time RT-PCR of CEACAM5 and PLUNC can estimate the presence of micrometastatic cells in LNs with greater precision than current staging method used for assessing tumor recurrence risk.

Tratamiento del paciente con cirrosis hepática descompensada por el virus de la hepatitis B / No disponible

No disponible

Intragenomic 16S rDNA divergence in Haloarcula marismortui is an adaptation to different temperatures.

The halophilic archaeon Haloarcula marismortui contains three ribosomal RNA operons, designated rrnA, rrnB, and rrnC. Operons A and C are virtually identical, whereas operon B presents a high divergence in nucleotide sequence, having up to 135 nucleotide polymorphisms among the three 16S, 23S, and 5S ribosomal RNA genes. Quantitative PCR and structural analyses have been performed to elucidate whether the presence of this intragenomic heterogeneity could be an adaptation to the variable environmental conditions in the natural habitat of H. marismortui. Variation in salt concentration did not affect expression but variation in incubation temperature did produce significant changes, with operon B displaying an expression level four times higher than the other two together at 50 degrees C and three times lower at 15 degrees C. We show that the putative promoter region of operon B is also different. In addition, the predicted secondary structure of these genes indicated that they have distinct stabilities at different temperatures and a mutant strain lacking operon B grew slower at high temperatures. This study supports the idea that divergent rRNA genes can be adaptive, with different variants being functional under different environmental conditions (e.g., temperature). The same phenomenon could take place in other halophiles or thermophiles with intragenomic rDNA heterogeneity, where the use of 16S rDNA as a phylogenetic marker and indicator of biodiversity should be used with caution.

Gastrointestinal complications in liver transplant recipients: MITOS study.

INTRODUCTION: Liver transplant recipients frequently suffer gastrointestinal (GI) complications but their prevalence and their influence on quality of life remain unknown. OBJECTIVE: The objective of this study was to asses the prevalence, impact on quality of life, and management of GI complications in liver transplant recipients. PATIENTS AND METHODS: This was an epidemiologic, cross-sectional, multicenter study. Four hundred seventeen liver recipients were recruited in 14 centers. A questionnaire was filled for every patient. RESULTS: The median age of the patients was 55 years. The median time since transplantation was 4.1 +/- 4 years. Whereas 19.2% presented some GI disease before transplantation, 49.4% showed this type of complication after transplantation. Diarrhea was the most prevalent GI complication, and anorexia was the GI disorder that affected patients daily activities the most frequently. GI complications were more frequent among female patients, subjects with pretransplantation hiatal hernia, and those readmitted after transplantation. Of the patients with GI complications, 70.9% received pharmacological treatment (89.7% with gastric protectors). Immunosuppressive therapy was also modified because of GI complications. Immunosuppressive drug dose was reduced in 18.1%, transiently stopped in 3.4%, and definitively stopped in 3.4% of cases. The drug most frequently changed was mycophenolate mofetil: dose reduction, 23.6%; transient withdrawal, 5.7%; and definitive withdrawal, 6.6%. CONCLUSIONS: The prevalence of GI complications in the liver transplant population was approximately 50%. GI complications showed a significant impact on the quality of life of the patients. They were related to female gender, to pretransplantation GI pathology, and posttransplantation hospital admission. These complications were frequently managed with pharmacological therapy or with changes in immunosuppressive therapy.

Actualización del trasplante hepático en la hepatitis C crónica / No disponible

No disponible

Colestasis inducida por consumo de estanozolol / Cholestatic injury by stanozolol intake

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[Taxonomical study of bacteria from genera Alteromonas and Pseudoalteromonas isolated from Black Sea water and invertebrates].

Nineteen (19) strains of bacteria have been isolated from the Black Sea water and invertebrates (mollusks and actinia). Most of them have been identified as Alteromonas macleodii, Pseudoalteromonas citrea and P. haloplanktis on the basis of polyphasic taxonomical analysis. Six strains showed 96-97 % similarity to 16S rRNA sequence of the known species of Pseudoalteromonas and obviously belonged to new species. The studied strains have been characterized by a wide spectrum of phenotypic features (morphology, enzyme activity, spectra of carbon nutrition, antibiotic sensitivity); high sensitivity of P. haloplanktis strains to cephalotin and resistance of A. macleodii strains to furadonin made them different than other studied strains of Alteromonas and Pseudoalteromonas.

Detection and identification of bacterial DNA in serum from patients with acute pancreatitis.

BACKGROUND AND AIMS: Bacterial infections are common complications in patients with acute pancreatitis, and translocation of bacteria from the intestinal lumen is probably the first step in the pathogenesis of these infections. As blood cultures in afebrile patients are usually negative, more sensitive methods to investigate this hypothesis in patients are needed. Our group has recently developed a method to detect the presence of bacterial DNA in biological fluids, and we aimed to detect bacterial DNA in patients with acute pancreatitis, as molecular evidences of bacterial translocation. METHODS: Samples of blood were obtained on three consecutive days within the first six days after admission. Bacterial DNA was detected using a polymerase chain reaction based method, and an automated DNA nucleotide sequencing process allowed identification of bacteria species. RESULTS: Thirty one consecutively admitted patients with acute pancreatitis were studied. Bacterial DNA was detected in six patients (19.3%), and the sequencing process allowed identification of Citrobacter freundii and Pseudomonas aeruginosa. In two patients the same bacteria detected at admission was detected 24 hours later (above 99.9% homology of nucleotide sequence). Basic clinical and biochemical characteristics were similar among patients with or without the presence of bacterial DNA. CONCLUSION: Detection of gram negative bacteria derived bacterial DNA in our series supports the contention that bacterial translocation is a systemic process in approximately 20% of patients with acute pancreatitis that does not seem to be related to the severity of the episode or immediate development of infection.

Status no convulsivo en paciente trasplantado tratado con ciclosporina. Papel del EEG / No disponible

No disponible

[Study of patients referred for elevated ferritin levels and/or transferrin saturation: significance of non-alcoholic fatty liver disease]. / Estudio de pacientes remitidos por elevación de la ferritina y/o saturación de la transferrina: importancia del hígado graso no alcohólico.

OBJECTIVE: To determine the etiology of increased ferritin concentrations and/or transferrin saturation in patients in whom classical causes were ruled out. PATIENTS AND METHOD: We studied 43 patients (35 males and 8 females) who were referred for ferritinemia greater than 300 ng/ml and or a transferrin saturation index (TSI) greater than 40%. In all patients, glycemia, cholesterol, triglycerides, uric acid, total and fractionated bilirubin, transaminase, gammaglutamyltranspeptidase, sideremia, TSI, ferritin, HFE gene mutations, ceruloplasmin and total 24-hour urine porphyrin were evaluated and abdominal ultrasonography was performed. In 14 patients liver biopsy was performed. RESULTS: Fifty-three percent was overweight and 19% was obese. Alterations in carbohydrate metabolism were detected in 33%, hypercholesterolemia was found in 14%, hypertriglyceridemia in 35%, and hyperlipemia type IIb in 16%. Thirty-two percent showed isolated elevated ferritin, 12% had elevated TSI and 56% showed elevation of both. Transaminase levels were normal in 61%. No mutation in the HFE gene was found in 10 patients, the H63D/wt mutation was found in 18, C262Y/wt in 1, C282Y/H63D in 5, C282Y/C282Y in 4, H63D/H63D in 3 and Ser65cys/wt in 1. Ultrasonography revealed steatosis in 19 patients (44%). Definitive diagnoses were HFE-linked hemochromatosis (4 patients), juvenile hemochromatosis (1 patient), hepaticocutaneous porphyria (1 patient), and non-alcoholic fatty liver disease (22 patients; 51%). Most of the remaining patients could be included under insulin resistance syndrome. Phlebotomy was performed in 25 patients, with improvement in clinical and laboratory parameters. CONCLUSIONS: Non-alcoholic fatty acid disease is frequently detected in patients with iron metabolism disorders. These patients should undergo investigations for metabolic alterations and liver ultrasonography and, if necessary, biopsy. Phlebotomy can be useful in the treatment of these patients.

Diagnostic value of symptoms in patients with suspected upper digestive tract disease.

OBJECTIVE: to develop a predictive model based on clinical data for patients with suspected upper digestive tract disease. PATIENTS AND METHODS: forty-seven clinical data were obtained before endoscopy from 283 patients with suspected upper digestive disease (153 men; mean age 55 years, limits 17-92 years). A clinical prediction of diagnosis was made before endoscopy. On the basis of the endoscopic findings, the patients were divided into three diagnostic groups: absence of significant disease (group I), significant benign disease (group II) and malignant disease (group III). The probability rate of belonging to each one of the three groups was obtained for each patient by using Bayes' theorem. RESULTS: the endoscopic findings were classified according to their clinical importance: 121 patients (43%) belonged to group I, 137 (48%) were included in group II; and 25 (9%) in group III. The clinical prediction correctly classified 61% of the patients (group I: 56%, group II: 62% and group III: 76%) The coincidence between prediction obtained using Bayes' theorem and the actual diagnosis was 61% (group I: 65%, group II: 51%, group III: 92%). The predictive model was useful to confirm or not the clinical prediction. CONCLUSION: objective analysis of clinical data can be useful to support clinical judgment, mainly in patients with neoplasia. However, the model is not adequate to improve indication of upper endoscopy since many patients are misclassified.