Exogenous aralar/slc25a12 can replace citrin/slc25a13 as malate aspartate shuttle component in liver.

The deficiency of CITRIN, the liver mitochondrial aspartate-glutamate carrier (AGC), is the cause of four human clinical phenotypes, neonatal intrahepatic cholestasis caused by CITRIN deficiency (NICCD), silent period, failure to thrive and dyslipidemia caused by CITRIN deficiency (FTTDCD), and citrullinemia type II (CTLN2). Clinical symptoms can be traced back to disruption of the malate-aspartate shuttle due to the lack of citrin. A potential therapy for this condition is the expression of aralar, the AGC present in brain, to replace citrin. To explore this possibility we have first verified that the NADH/NAD+ ratio increases in hepatocytes from citrin(-/-) mice, and then found that exogenous aralar expression reversed the increase in NADH/NAD+ observed in these cells. Liver mitochondria from citrin (-/-) mice expressing liver specific transgenic aralar had a small (~ 4-6 nmoles x mg prot-1 x min-1) but consistent increase in malate aspartate shuttle (MAS) activity over that of citrin(-/-) mice. These results support the functional replacement between AGCs in the liver. To explore the significance of AGC replacement in human therapy we studied the relative levels of citrin and aralar in mouse and human liver through absolute quantification proteomics. We report that mouse liver has relatively high aralar levels (citrin/aralar molar ratio of 7.8), whereas human liver is virtually devoid of aralar (CITRIN/ARALAR ratio of 397). This large difference in endogenous aralar levels partly explains the high residual MAS activity in liver of citrin(-/-) mice and why they fail to recapitulate the human disease, but supports the benefit of increasing aralar expression to improve the redox balance capacity of human liver, as an effective therapy for CITRIN deficiency.

Non-alcoholic fatty liver disease in patients with intestinal, pulmonary or skin diseases: Inflammatory cross-talk that needs a multidisciplinary approach.

Non-alcoholic fatty liver disease (NAFLD) is currently considered the most common cause of liver disease. Its prevalence is increasing in parallel with the obesity and type 2 diabetes mellitus (DM2) epidemics in developed countries. Several recent studies have suggested that NAFLD may be the hepatic manifestation of a systemic inflammatory metabolic disease that also affects other organs, such as intestine, lungs, skin and vascular endothelium. It appears that local and systemic proinflammatory/anti-inflammatory cytokine imbalance, together with insulin resistance and changes in the intestinal microbiota, are pathogenic mechanisms shared by NAFLD and other comorbidities. NAFLD is more common in patients with extrahepatic diseases such as inflammatory bowel disease (IBD), obstructive syndrome apnea (OSA) and psoriasis than in the general population. Furthermore, there is evidence that this association has a negative impact on the severity of liver lesions. Specific risk characteristics for NAFLD have been identified in populations with IBD (i.e. age, obesity, DM2, previous bowel surgery, IBD evolution time, methotrexate treatment), OSA (i.e. obesity, DM2, OSA severity, increased transaminases) and psoriasis (i.e. age, metabolic factors, severe psoriasis, arthropathy, elevated transaminases, methotrexate treatment). These specific phenotypes might be used by gastroenterologists, pneumologists and dermatologists to create screening algorithms for NAFLD. Such algorithms should include non-invasive markers of fibrosis used in NAFLD to select subjects for referral to the hepatologist. Prospective, controlled studies in NAFLD patients with extrahepatic comorbidities are required to demonstrate a causal relationship and also that appropriate multidisciplinary management improves these patients' prognosis and survival.

VCN-01 disrupts pancreatic cancer stroma and exerts antitumor effects.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense desmoplastic stroma that limits the delivery of anticancer agents. VCN-01 is an oncolytic adenovirus designed to replicate in cancer cells with a dysfunctional RB1 pathway and express hyaluronidase. Here, we evaluated the mechanism of action of VCN-01 in preclinical models and in patients with pancreatic cancer. METHODS: VCN-01 replication and antitumor efficacy were evaluated alone and in combination with standard chemotherapy in immunodeficient and immunocompetent preclinical models using intravenous or intratumoral administration. Hyaluronidase activity was evaluated by histochemical staining and by measuring drug delivery into tumors. In a proof-of-concept clinical trial, VCN-01 was administered intratumorally to patients with PDAC at doses up to 1×1011 viral particles in combination with chemotherapy. Hyaluronidase expression was measured in serum by an ELISA and its activity within tumors by endoscopic ultrasound elastography. RESULTS: VCN-01 replicated in PDAC models and exerted antitumor effects which were improved when combined with chemotherapy. Hyaluronidase expression by VCN-01 degraded tumor stroma and facilitated delivery of a variety of therapeutic agents such as chemotherapy and therapeutic antibodies. Clinically, treatment was generally well-tolerated and resulted in disease stabilization of injected lesions. VCN-01 was detected in blood as secondary peaks and in post-treatment tumor biopsies, indicating virus replication. Patients had increasing levels of hyaluronidase in sera over time and decreased tumor stiffness, suggesting stromal disruption. CONCLUSIONS: VCN-01 is an oncolytic adenovirus with direct antitumor effects and stromal disruption capabilities, representing a new therapeutic agent for cancers with dense stroma. TRIAL REGISTRATION NUMBER: EudraCT number: 2012-005556-42 and NCT02045589.

Esteatohepatitis no alcohólica y adenomatosis hepática: ¿asociación casual o causal? / Nonalcoholic steatohepatitis and hepatic adenomatosis: casual or causal relationship?

La adenomatosis hepática es una enfermedad benigna definida por la aparición de múltiples adenomas en un hígado normal. Se trata de una entidad poco frecuente y de causa no conocida, de la que existen menos de un centenar de casos publicados en la literatura médica y que se ha relacionado con la toma de anticonceptivos orales o esteroides anabolizantes, con enfermedades por depósito y con mutaciones genéticas asociadas a la diabetes mellitus tipo MODY (maturity onset diabetes of the young). En los últimos años se ha comunicado la coexistencia de adenomatosis hepática con lesiones de esteatohepatitis no alcohólica en dos pacientes con síndrome metabólico, una asociación de interés por la creciente prevalencia de la enfermedad hepática grasa no alcohólica en los países desarrollados y por la posibilidad de que compartan un mecanismo causal. Comunicamos el caso de una mujer joven con fructosemia familiar y esteatosis hepática durante cuyo seguimiento aparecieron múltiples adenomas hepáticos asociados a lesiones de esteatohepatitis y discutimos el posible significado de dicha asociación (AU)

Hepatic adenomatosis is a benign disease defined as the presence of multiple adenomas in a normal liver. It is an uncommon condition and there are less than a hundred reported cases in the literature. The etiology is unknown, although it has been associated with the use of oral contraceptives, anabolic steroids, certain storage diseases and some genetic mutations linked to maturity onset diabetes of the young. The coexistence of hepatic adenomatosis and nonalcoholic steatohepatitis has been recently described in two patients suffering from metabolic syndrome. This association is particularly interesting due to the growing prevalence of nonalcoholic fatty liver disease in developed countries and the possibility of a common causal pathway. We report the case of a young woman with fructosemia and hepatic steatosis; multiple hepatic adenomas associated to steatohepatitis lesions were also found during clinical follow-up. The possible implications are discussed (AU)

Nonalcoholic steatohepatitis and hepatic adenomatosis: casual or causal relationship?

Hepatic adenomatosis is a benign disease defined as the presence of multiple adenomas in a normal liver. It is an uncommon condition and there are less than a hundred reported cases in the literature. The etiology is unknown, although it has been associated with the use of oral contraceptives, anabolic steroids, certain storage diseases and some genetic mutations linked to maturity onset diabetes of the young. The coexistence of hepatic adenomatosis and nonalcoholic steatohepatitis has been recently described in two patients suffering from metabolic syndrome. This association is particularly interesting due to the growing prevalence of nonalcoholic fatty liver disease in developed countries and the possibility of a common causal pathway. We report the case of a young woman with fructosemia and hepatic steatosis; multiple hepatic adenomas associated to steatohepatitis lesions were also found during clinical follow-up. The possible implications are discussed.

Extrinsic esophageal compression by the vertebral body.

A 78-year-old woman with hypertension, diabetes, dyslipidemia, and revascularized ischemic heart disease was diagnosed with gastric adenocarcinoma in 2011, with suspected bilateral adrenal metastatic disease, and was treated with subtotal gastrectomy and palliative chemotherapy. A follow-up gastroscopy in 2015 identified a protruding, erosive mid-esophageal lesion suggestive of extrinsic compression or ulcerated submucosal lesion, which had not been described previously. Follow-up was advised, and the lesion persisted after three months. The patient had no esophageal symptoms, and subsequent thoracoabdominal CT scans found no bony abnormalities in the cervicothoracic spine or mediastinal changes. Endoscopic ultrasound was recommended given the patient's cancer history.

Compresión esofágica extrínseca por cuerpo vertebral / Extrinsic esophageal compression by the vertebral body

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Tumor neuroendocrino de recto de comportamiento excepcional / Rectal neuroendocrine tumor with an exceptional behaviour

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Evaluation of the short- and long-term effectiveness and safety of fully covered self-expandable metal stents for drainage of pancreatic fluid collections: results of a Spanish nationwide registry.

BACKGROUND AND AIMS: Initial reports suggest that fully covered self-expandable metal stents (FCSEMSs) may be better suited for drainage of dense pancreatic fluid collections (PFCs), such as walled-off pancreatic necrosis. The primary aim was to analyze the effectiveness and safety of FCSEMSs for drainage of different types of PFCs in a large cohort. The secondary aim was to investigate which type of FCSEMS is superior. METHODS: This was a retrospective, noncomparative review of a nationwide database involving all hospitals in Spain performing EUS-guided PFC drainage. From April 2008 to August 2013, all patients undergoing PFC drainage with an FCSEMS were included in a database. The main outcome measurements were technical success, short-term (2 weeks) and long-term (6 months) effectiveness, adverse events, and need for surgery. RESULTS: The study included 211 patients (pseudocyst/walled-off pancreatic necrosis, 53%/47%). The FCSEMSs used were straight biliary (66%) or lumen-apposing (34%). Technical success was achieved in 97% of patients (95% confidence interval [CI], 93%-99%). Short-term- and long-term clinical success was obtained in 94% (95% CI, 89%-97%) and 85% (95% CI, 79%-89%) of patients, respectively. Adverse events occurred in 21% of patients (95% CI, 16%-27%): infection (11%), bleeding (7%), and stent migration and/or perforation (3%). By multivariate analysis, patient age (>58 years) and previous failed drainage were the most important factors associated with negative outcome. CONCLUSIONS: An FCSEMS is effective and safe for PFC drainage. Older patients with a history of unsuccessful drainage are more likely to fail EUS-guided drainage. The type of FCSEMS does not seem to influence patient outcome.

Metástasis esplénica solitaria en una paciente con adenocarcinoma colorrectal / Splenic metastases secondary to colorrectal carcinoma

Introduction: Splenic metastases are unusual, arising in less than 1 percent of all metastases. Splenic metastases from colorrectal carcinoma is considered excepcional. If present, they generally occur in concert with disseminated disease. Case report: We present a case of 78 year old man operated of colon tumor by right hemicolectomy. Nine months after first surgical, CT scan showed metastases in spleen, splenectomy was performed.

Introducción: Las metástasis esplénicas son inusuales, representando menos del 1 por ciento de todas las metástasis. Que este tipo de localización secundaria sea ocasionado por carcinomas colorrectales puede considerarse como algo excepcional. Cuando se presentan generalmente lo hacen en el contexto de una enfermedad diseminada. Caso clínico: Presentamos el caso de un varón de 78 años de edad que fue intervenido de un carcinoma colorrectal mediante hemicolectomía derecha. nueve meses después de la primera cirugía el escáner muestra metástasis en el bazo, por lo que se realizó una esplenectomía.

Endoscopic submucosal dissection (ESD) of antral subepithelial lesion suspected of malignancy.

Subepithelial gastric tumours comprise a heterogeneous group of lesions. Endoscopic ultrasonography with fine-needle aspiration (EUS-FNA) is a useful approach but cannot always offer a definitive diagnosis to guide future therapeutic decisions. In the case we describe, biopsy samples of an antral subepithelial lesion and cytological analysis obtained with an EUS-FNA suggested the diagnosis of an adenocarcinoma. Endoscopic submucosal dissection (ESD) allowed en bloc resection of the tumour ensuring diagnosis and providing a definitive treatment.

Endoscopic submucosal dissection (ESD) of antral subepithelial lesion suspected of malignancy

Subepithelial gastric tumours comprise a heterogeneous group of lesions. Endoscopic ultrasonography with fine-needle aspiration (EUS-FNA) is a useful approach but cannot always offer a definitive diagnosis to guide future therapeutic decisions. In the case we describe, biopsy samples of an antral subepithelial lesion and cytological analysis obtained with an EUS-FNA suggested the diagnosis of an adenocarcinoma. Endoscopic submucosal dissection (ESD) allowed en bloc resection of the tumour ensuring diagnosis and providing a definitive treatment (AU)

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The role of endoscopic ultrasound guided fine needle aspiration (EUS-FNA) in non small cell lung cancer (NSCLC) patients: SEED-SEPD-AEG Joint Guideline.

Lung cancer is one of the most frequent neoplasms in our environment, and represents the first cause of cancer related death in western countries. Diagnostic and therapeutic approach to these patients may be complicated, with endoscopic ultrasound guided fine needle aspiration (EUS-FNA), classically performed by gastroenterologists, playing a very important role. As this disease is not closely related to the "digestive tract", gastroenterologists have been forced to update their knowledge on this field o adequately diagnose this significant group of patients. The recent advent of modern and promising techniques like endobronchial ultrasound guided fine needle aspiration (EBUS-FNA) have prompted new approaches for diagnosis and staging of this type of patients. In this clinical guideline, the "Sociedad Española de Endoscopia Digestiva" (SEED), "Sociedad Española de Patología Digestiva" (SEPD) and the "AsociaciónEspañola de Gastroenterología", have jointed efforts to update the existing knowledge on the field and provide their members with evidence based recommendations.

Papel de la punción guiada por ecoendoscopia en pacientes con carcinoma de pulmón de células no pequeñas (CPNM): guía clínica de consenso Sociedad Española de Endoscopia Digestiva (SEED) - Sociedad Española de Patología Digestiva (SEPD) - Asociación Española de Gastroenterología (AEG) / The role of endoscopic ultrasound guided fine needle aspiration EUS-FNA) in non small cell lung cancer (NSCLC) patients: SEED-SEPD-AEG Joint Guideline

El cáncer de pulmón es una de las neoplasias más frecuentes en nuestro medio y la principal causa de muerte por cáncer en países occidentales. El manejo diagnóstico y terapéutico de estos pacientes es complejo, desempeñando en el mismo un papel muy relevante la punción guiada por ultrasonografía endoscópica (USE-PAAF), que clásicamente realizan los gastroenterólogos. Al tratarse de una enfermedad no relacionada con el “aparato digestivo”, los gastroenterólogos han tenido que actualizar sus conocimientos en este campo, para diagnosticar de forma adecuada a este nutrido grupo de pacientes. La incorporación en estos últimos años de nuevas y prometedoras técnicas, como la punción aspirativa transbronquial guiada por ecobroncoscopia (USEB-PAAF), han modificado el acercamiento al diagnóstico y estadificación de estos pacientes. En la presente guía clínica, la Sociedad Española de Endoscopia Digestiva (SEED), la Sociedad Española de Patología Digestiva (SEPD) y la Asociación Española de Gastroenterología (AEG), han aunado esfuerzos para actualizar el grado de conocimiento existente sobre este tema y dar recomendaciones basadas en la evidencia a sus miembros (AU)

Lung cancer is one of the most frequent neoplasms in our environment, and represents the first cause of cancer related death in western countries. Diagnostic and therapeutic approach to these patients may be complicated, with endoscopic ultrasound guided fine needle aspiration (EUS-FNA), classically performed by gastroenterologists, playing a very important role. As this disease is not closely related to the “digestive tract”, gastroenterologists have been forced to update their knowledge on this field o adequately diagnose this significant group of patients. The recent advent of modern and promising techniques like endobronchial ultrasound guided fine needle aspiration (EBUS-FNA) have prompted new approaches for diagnosis and staging of this type of patients. In this clinical guideline, the “Sociedad Española de Endoscopia Digestiva” (SEED), “Sociedad Española de Patología Digestiva” (SEPD) and the “Asociación Española de Gastroenterología”, have jointed efforts to update the existing knowledge on the field and provide their members with evidence based recommendations (AU)

Trombosis venosa portal y mesentérica asociadas a hiperhomocisteinemia y anemia perniciosa en un paciente heterocigoto para la mutación C677T del gen de la MTHFR / Portal and mesenteric vein thrombosis associated with hyperhomocysteinemia and pernicious anemia in a patient heterozygous for the MTHFR C677T mutation

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Colestasis aguda en un varón con trasplante renal y hepatitis C crónica / No disponible

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