Manuel García de los Ríos Alvarez

Non‐alcoholic fatty liver disease and its association with obesity, insulin resistance and increased serum levels of C‐reactive protein in Hispanics

Background: Non‐alcoholic fatty liver disease (NAFLD) is a metabolic disorder of the liver, which may progress to fibrosis or cirrhosis. Recent studies have shown a significant impact of ethnicity on susceptibility to steatosis‐related liver disease.

Use of methylene blue in patients with refractory septic shock: Impact on hemodynamics and gas exchange

PURPOSE The purpose of this study was to assess the acute effects of methylene blue, an inhibitor of nitric oxide synthesis, on hemodynamics and gas exchange in patients with refractory septic shock in a prospective clinical trial at medical and surgical intensive care units in a tertiary university hospital. PATIENTS AND METHODS Prospective, sequential study of 10 consecutive patients admitted with severe septic shock of diverse causes and unable to achieve an adequate arterial pressure despite the use of at least two vasoactive drugs. Six of them also developed acute lung injury. All received 1 mg/kg intravenous bolus of methylene blue. Hemodynamic and respiratory parameters were measured at baseline and at 30, 60, 120, and 180 minutes after the bolus injection. RESULTS Systolic, diastolic, mean arterial blood pressure, and systemic vascular resistance increased significantly in all patients, whereas no significant changes were observed in cardiac output, oxygen consumption, or oxygen extraction ratio. Gas exchange remained unaffected in patients with acute lung injury. CONCLUSIONS Methylene blue had an acute vasopressor effect in patients with refractory septic shock, and it was not deleterious on respiratory function.

Promoter hypermethylation of BRCA1 correlates with absence of expression in hereditary breast cancer tumors.

Germline mutations in BRCA1 account for a low proportion of hereditary cases in diverse populations. Several efforts have been made to find new genes involved in the inheritance of breast cancer with no success until today. The participation of BRCA1 in the development of breast cancer has been proposed in several studies where hypermethylation of its promoter and a decrease in expression has been reported for sporadic cases and one study on familial cases. To explore the participation of BRCA1 in hereditary carcinogenesis through a different mechanism than the inheritance of germline mutations, we studied the methylation status of its promoter in breast tumors, from patients previously screened for BRCA1/BRCA2 germline mutations. We also determined the presence of the BRCA1 protein in these tumors and correlated both events with tumor grade, hormone receptors and ERBB2 presence. Promoter hypermethylation of the BRCA1 gene was detected in 51% of our biopsies, among which 67% did not express the respective protein. This result leads us to suggest that hypermethylation could be considered as an inactivating mechanism for BRCA1 expression, either as a first or second hit. Moreover, a number of biopsies with absence of expression on BRCA1 showed negative detection of estrogen and progesterone receptors, a similar phenotype to BRCA1 mutated breast tumors.

Increased orocecal transit time in patients with nonalcoholic fatty liver disease.

Intestinal bacterial overgrowth (IBO) has been suggested to play a pathogenic role in patients with nonalcoholic fatty liver disease (NAFLD). Delayed intestinal transit may contribute to IBO development. Ten nondiabetic patients with NAFLD and abnormal liver enzymes were recruited. Ten healthy individuals, matched by sex, age, and body mass index, were used as controls. Orocecal transit time (OCTT) was measured by the lactulose breath test. Anti-endotoxin core antibodies (EndoCAb) were determined. The effect of oral norfloxacin (400 mg BID during 2 weeks) on liver enzymes, lactulose breath test, and EndoCAb was also studied. NAFLD patients had higher basal breathed H2 and prolonged OCTT compared to controls (127 ± 61 vs. 57 ± 23 min, respectively; P = 0.0037). EndoCAb titers were similar in NAFLD patients and controls. Norfloxacin administration had no effect on ALT levels, lactulose breath test, or EndoCAb titers in patients with NAFLD. The present data show evidence of deranged intestinal motility in nondiabetic patients with NAFLD and support the hypothesis that NAFLD could be linked to endotoxin-induced liver damage of intestinal origin.

Silencing of tumor suppressor genes RASSF1A, SLIT2, and WIF1 by promoter hypermethylation in hereditary breast cancer

Promoter hypermethylation is gaining strength as one of the main mechanisms through which tumor suppressor genes are silenced during tumor progression. Three tumor suppressor genes are frequently found methylated in their promoter, in concordance with absence of expression, RASSF1A, SLIT2, and WIF1. In addition, a previous array‐CGH analysis from our group showed that these genes are found in deleted genomic regions observed in hereditary breast cancer tumors. In the present work we analyzed the methylation status of these three tumor suppressor gene promoters in 47 hereditary breast cancer tumors. Promoter methylation status analysis of hereditary breast tumors revealed high methylation frequencies for the three genes (67% RASSF1A, 80% SLIT2, and 72% WIF1). Additionally, the presence of methylated PCR products was associated with absence of protein expression for the three genes and statistically significant for RASSF1A and WIF1. Interestingly, methylation of all the three genes was found in 4 out of 6 grade I invasive ductal carcinoma tumors. Association between RASSF1A methylation and DCIS tumors was found. These results suggest that silencing of these tumor suppressor genes is an early event in hereditary breast cancer, and could be a marker for pre‐malignant phenotypes.

MOLECULAR BASIS OF CANCER AND CLINICAL APPLICATIONS

This article attempts to show the vertiginous advances that exist today in the concept of what cancer is. The authors chose some multiple biologic concepts that have enabled the progress in the knowledge of this disease to occur at a speed no one could imagine until recently. Although the areas and biologic problems that remain to be solved are more numerous and complex than they expected, the basic fundamentals already partially understood and the multidisciplinary integration of the various medical specialties with biomolecular research enable physicians to face the next millennium with great optimism about the possibilities of therapeutic success, prevention, and effective early diagnosis.

Avances en radiología del intestino delgado: enteroclisis por tomografía computarizada

Resumen La enteroclisis por tomografia computarizada (TC) es una nueva tecnica que consiste en una TC helicoidal con multiples detectores realizada tras la administracion de agua a traves de una sonda nasoyeyunal y medio de contraste intravenoso, lo que permite una adecuada distension y visualizacion del intestino delgado. El uso de esta tecnica esta especialmente indicado en pacientes con enfermedad inflamatoria intestinal, hemorragia digestiva de causa no precisada, obstruccion parcial de intestino delgado y sospecha de neoplasia intestinal. Un total de 100 pacientes consecutivos se sometieron a una enteroclisis por TC (multiples detectores: 8, 16 o 64) debido a la sospecha de lesion en el intestino delgado. De ellos, 31 presentaron lesiones en esa localizacion: enfermedad de Crohn (n = 17), tumores (n = 8), obstruccion intestinal (n = 2), enteritis actinica (n = 1), enfermedad celiaca (n = 1), neumatosis cistoide (n = 1) y dilatacion de asas (n = 1); 28 de los 31 casos fueron confirmados por anatomia patologica, hallazgos endoscopicos o seguimiento clinico.

Nuevas alternativas en el tratamiento del cancer gástrico avanzado

Patients with stage IV gastric cancer, according to the American JointCommittee on Cancer or with relapsed disease and functional capacity 0-2 of the South WestOncology Group, were included. FOLFOX-4 chemotherapy was used as first or second linetreatment. The response to treatment and survival were assessed.

Different Array CGH profiles within hereditary breast cancer tumors associated to BRCA1 expression and overall survival

BackgroundArray CGH analysis of breast tumors has contributed to the identification of different genomic profiles in these tumors. Loss of DNA repair by BRCA1 functional deficiency in breast cancer has been proposed as a relevant contribution to breast cancer progression for tumors with no germline mutation. Identifying the genomic alterations taking place in BRCA1 not expressing tumors will lead us to a better understanding of the cellular functions affected in this heterogeneous disease. Moreover, specific genomic alterations may contribute to the identification of potential therapeutic targets and offer a more personalized treatment to breast cancer patients.MethodsForty seven tumors from hereditary breast cancer cases, previously analyzed for BRCA1 expression, and screened for germline BRCA1 and 2 mutations, were analyzed by Array based Comparative Genomic Hybridization (aCGH) using Agilent 4x44K arrays. Overall survival was established for tumors in different clusters using Log-rank (Mantel-Cox) Test. Gene lists obtained from aCGH analysis were analyzed for Gene Ontology enrichment using GOrilla and DAVID tools.ResultsGenomic profiling of the tumors showed specific alterations associated to BRCA1 or 2 mutation status, and BRCA1 expression in the tumors, affecting relevant cellular processes. Similar cellular functions were found affected in BRCA1 not expressing and BRCA1 or 2 mutated tumors. Hierarchical clustering classified hereditary breast tumors in four major, groups according to the type and amount of genomic alterations, showing one group with a significantly poor overall survival (p = 0.0221). Within this cluster, deletion of PLEKHO1, GDF11, DARC, DAG1 and CD63 may be associated to the worse outcome of the patients.ConclusionsThese results support the fact that BRCA1 lack of expression in tumors should be used as a marker for BRCAness and to select these patients for synthetic lethality approaches such as treatment with PARP inhibitors. In addition, the identification of specific alterations in breast tumors associated with poor survival, immune response or with a BRCAness phenotype will allow the use of a more personalized treatment in these patients.

Radio-quimioterapia postoperatoria en cáncer gástrico localmente avanzado

BACKGROUND Overall 5 years survival for surgically excised gastric cancer is 30%. Adjuvant treatment may improve the surgical results. AIM To assess treatment results and toxicity in patients with surgically excised gastric cancer, treated with adjuvant radiotherapy and concomitant continuous 5-Fluorouracil (5-FU). MATERIAL AND METHODS Forty one patients aged 32 to 73 years (29 males) with stage II-IVA gastric cancer, subjected to a total or subtotal gastrectomy and D2 nodal dissection between 1997 to 2006, were studied. They received adjuvant radiotherapy to the gastric bed and draining nodes in a total dose of 50.4 Gy in 28 fractions and chemotherapy with continuous infusion 5-FU, 200 mg/m(2)/day. Results were compared to historical controls matched according to demographic parameters and tumor characteristics. RESULTS Eighteen patients were in stage II, 10 in stage IIIA, nine in stage IIIB and four in stage IVA. Twelve patients had an NO nodal status, 15 were NI, nine were N2 and five were N3. After a mean follow up of 32 months, 26 patients (63%) were alive. Five year overall survival was 49.6% for surgery plus radiochemotherapy compared to 30.7% for the historical group subjected only to surgery (p =0.002). Radiotherapy was associated with grade 1-2 toxicity and treatment was completed without interruptions in all patients. Chemotherapy was delayed temporarily in 3 patients. CONCLUSIONS Adjuvant radio-chemotherapy improved overall survival in gastric cancer, compared to historical controls subjected only to surgical treatment.