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.

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.

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.

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.

[Intestinal leishmaniasis and Sézary syndrome: endoscopic diagnosis]. / Leishmaniasis intestinal y síndrome de Sézary: diagnóstico endoscópico.

Sézary syndrome is a non-Hodgkin's lymphoma of cutaneous origin that provokes severe cellular immunosuppression leading to greater susceptibility to opportunistic infections. We present the case of a male patient with a diagnosis of Sézary syndrome complicated by visceral leishmaniasis and Mycobacterium avium complex coinfection, with intestinal involvement of both pathogens -an exceptional finding in the absence of HIV infection. The diagnosis was confirmed by bone marrow biopsy and oral endoscopy with intestinal biopsy. Because of the severity of the infection and the failure of conventional treatment, miltefosine, a new antiparasitic agent still under investigation, was administered with favorable response. However the patient developed fatal pneumonia.

Factors associated with the presence of nonalcoholic steatohepatitis in patients with chronic hepatitis C.

OBJECTIVES: The aim of this study was to identify factors associated with the presence of nonalcoholic steatohepatitis (NASH) in patients with chronic hepatitis C (CHC). METHODS: We studied 98 patients with CHC [47 with NASH (group HCV/NASH), 51 without NASH (group HCV)] and 85 with NASH not infected with hepatitis C virus (HCV) (group NASH). We determined factors associated with the presence of NASH in patients with hepatitis C. RESULTS: Group HCV/NASH patients resembled those with NASH. Body mass index (BMI) was higher in group HCV/NASH than in group HCV, but was similar to group NASH. Most HCV/NASH patients had risk factors for NASH. In patients infected with HCV, NASH and NASH-related lesions were independently associated with BMI, while steatosis score was associated with HCV genotype 3 and BMI. Fibrosis stage was independently associated with steatosis, necroinflammatory activity index, and NASH lesions. CONCLUSION: While HCV genotype 3 infection and BMI are associated with the presence of steatosis in CHC, BMI is the only factor independently associated with the presence of NASH in these patients. We suggest that overweight-related factors might induce NASH in CHC patients.

Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis.

Mitochondrial dysfunction might play a central role in the pathogenesis of nonalcoholic steatohepatitis (NASH). The aims of this study were to evaluate whether free fatty acid (FFA) transport into the mitochondria or the activity of mitochondria respiratory chain (MRC) complexes are impaired in NASH. In patients with NASH and control subjects, we measured free carnitine, short-chain acylcarnitine (SCAC) and long-chain acylcarnitine (LCAC) esters, carnitine palmitoyltransferase (CPT) activity, and MRC enzyme activity in liver tissue as well as serum concentration of tumor necrosis factor alpha (TNF-alpha), homeostatic metabolic assessment of insulin resistance (HOMA(IR)), and body mass index (BMI). In patients with NASH, the LCAC/free carnitine ratio was significantly increased and the SCAC/free carnitine ratio was decreased. In patients with NASH, the activity of the MRC complexes was decreased to 63% +/- 20% (complex I), 58.5% +/- 16.7% (complex II), 70.6% +/- 10.3% (complex III), 62.5% +/- 13% (complex IV), and 42.4% +/- 9.1% (adenosine triphosphate synthase) of the corresponding control values. Activity of these complexes correlated significantly with serum TNF-alpha and HOMA(IR). Serum TNF-alpha (36.3 +/- 23.1 pg/mL), HOMA(IR) (4.5 +/- 2.38), and BMI (29.9 +/- 3.5 kg/m(2)) values were significantly increased in patients with NASH. In conclusion, activities of MRC complexes were decreased in liver tissue of patients with NASH. This dysfunction correlated with serum TNF-alpha, insulin resistance, and BMI values.