Daniel Blero

Biliary stenting: indications, choice of stents and results: European Society of Gastrointestinal Endoscopy (ESGE) clinical guideline.

This article is part of a combined publication that expresses the current view of the European Society of Gastrointestinal Endoscopy about endoscopic biliary stenting. The present Clinical Guideline describes short-term and long-term results of biliary stenting depending on indications and stent models; it makes recommendations on when, how, and with which stent to perform biliary drainage in most common clinical settings, including in patients with a potentially resectable malignant biliary obstruction and in those who require palliative drainage of common bile duct or hilar strictures. Treatment of benign conditions (strictures related to chronic pancreatitis, liver transplantation, or cholecystectomy, and leaks and failed biliary stone extraction) and management of complications (including stent revision) are also discussed. A two-page executive summary of evidence statements and recommendations is provided. A separate Technology Review describes the models of biliary stents available and the stenting techniques, including advanced techniques such as insertion of multiple plastic stents, drainage of hilar strictures, retrieval of migrated stents and combined stenting in malignant biliary and duodenal obstructions.The target readership for the Clinical Guideline mostly includes digestive endoscopists, gastroenterologists, oncologists, radiologists, internists, and surgeons while the Technology Review should be most useful to endoscopists who perform biliary drainage.

Successful management of benign biliary strictures with fully covered self-expanding metal stents.

BACKGROUND & AIMS Fully covered self-expanding metal stents (FCSEMS) are gaining acceptance for the treatment of benign biliary strictures. We performed a large prospective multinational study to study the ability to remove these stents after extended indwell and the frequency and durability of stricture resolution. METHODS In a nonrandomized study at 13 centers in 11 countries, 187 patients with benign biliary strictures received FCSEMS. Removal was scheduled at 10-12 months for patients with chronic pancreatitis or cholecystectomy and at 4-6 months for patients who received liver transplants. The primary outcome measure was removal success, defined as either scheduled endoscopic removal of the stent with no removal-related serious adverse events or spontaneous stent passage without the need for immediate restenting. RESULTS Endoscopic removal of FCSEMS was not performed for 10 patients because of death (from unrelated causes), withdrawal of consent, or switch to palliative treatment. For the remaining 177 patients, removal success was accomplished in 74.6% (95% confidence interval [CI], 67.5%-80.8%). Removal success was more frequent in the chronic pancreatitis group (80.5%) than in the liver transplantation (63.4%) or cholecystectomy (61.1%) groups (P = .017). FCSEMS were removed by endoscopy from all patients in whom this procedure was attempted. Stricture resolution without restenting upon FCSEMS removal occurred in 76.3% of patients (95% CI, 69.3%-82.3%). The rate of resolution was lower in patients with FCSEMS migration (odds ratio, 0.22; 95% CI, 0.11-0.46). Over a median follow-up period of 20.3 months (interquartile range, 12.9-24.3 mo), the rate of stricture recurrence was 14.8% (95% CI, 8.2%-20.9%). Stent- or removal-related serious adverse events, most often cholangitis, occurred in 27.3% of patients. There was no stent- or removal-related mortality. CONCLUSIONS In a large prospective multinational study, removal success of FCSEMS after extended indwell and stricture resolution were achieved for approximately 75% of patients. ClincialTrials.gov number, NCT01014390.

Phosphoinositide phosphatases in a network of signalling reactions

Phosphoinositide phosphatases dephosphorylate the three positions (D-3, 4 and 5) of the inositol ring of the poly-phosphoinositides. They belong to different families of enzymes. The PtdIns(3,4)P2 4-phosphatase family, the tumour suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN), SAC1 domain phosphatases and myotubularins belong to the tyrosine protein phosphatases superfamily. They share the presence of a conserved cysteine residue in the consensus CX5RT/S. Another family consists of the inositol polyphosphate 5-phosphatase isoenzymes. The importance of these phosphoinositide phosphatases in cell regulation is illustrated by multiple examples of their implications in human diseases such as Lowe syndrome, X-linked myotubular myopathy, cancer, diabetes or bacterial infection.

SHIP2 interaction with the cytoskeletal protein Vinexin

The src homology 2 (SH2) domain‐containing inositol 5‐phosphatase 2 (SHIP2) catalyses the dephosphorylation of phosphatidylinositol 3,4,5‐trisphosphate [PtdIns(3,4,5)P3] to phosphatidylinositol 3,4‐bisphosphate [PtdIns(3,4)P2]. We report the identification of the cytoskeletal protein Vinexin as a protein interacting with SHIP2. This was achieved by yeast two‐hybrid screening using the C‐terminal region of SHIP2 as bait. Vinexin has previously been identified as a vinculin‐binding protein that plays a key role in cell spreading and cytoskeletal organization. The interaction between SHIP2 and Vinexin was confirmed in lysates of both COS‐7 cells and mouse embryonic fibroblasts (MEF). The C‐terminus was involved in the interaction, as shown by the transfection of a truncated C‐terminus mutant of SHIP2. In addition, we showed the colocalization between Vinexin α and SHIP2 at the periphery of transfected COS‐7 cells. When added in vitro to SHIP2, Vinexin did not affect the PtdIns(3,4,5)P3 5‐phosphatase activity of SHIP2. Enhanced cell adhesion to collagen‐I‐coated dishes was shown upon transfection of either SHIP2 or Vinexin to COS‐7 cells. This effect was no longer observed with either a catalytic mutant or the C‐terminus mutant of SHIP2. It also appears SHIP2 specific; this was not seen with SHIP1. Adhesion to the same matrix was decreased in SHIP2–/– MEF cells compared with MEF+/+ cells. Our data suggest that SHIP2 interaction with Vinexin promotes the localization of SHIP2 at the periphery of the cells leaving its catalytic site intact. The complex formation between Vinexin and SHIP2 may increase cellular adhesion. The data reinforce the concept that SHIP2 is active both as a PtdIns(3,4,5)P3 5‐phosphatase and as a modulator of focal contact formation.

Transoral gastroplasty for morbid obesity: a multicenter trial with a 1-year outcome

BACKGROUND Bariatric surgery is associated with specific complications and mortality. Transoral gastroplasty (TOGA) is a transoral restrictive bariatric procedure that might offer the benefits of surgery with a reduced complication rate. OBJECTIVE To evaluate the safety and efficacy of TOGA at 12-month follow-up. DESIGN Prospective, multicenter, single-arm trial. SETTING Two tertiary-care referral medical centers. PATIENTS This study involved 67 patients (average age 41.0 years, 47 women, baseline body mass index [BMI] 41.5 kg/m(2); 20 patients with BMI <40). INTERVENTION The TOGA procedures were performed by using 2 stapling devices that were used to create a small, restrictive pouch along the lesser gastric curvature. The pouch is designed to give the patient a sustained feeling of satiety after small meals. MAIN OUTCOME MEASUREMENTS Excess weight loss, excess BMI loss, safety, and improvements in quality of life, obesity-related comorbidities, and medication use. RESULTS Fifty-three patients were available at the 12-month follow-up. Excess BMI loss was 33.9%, 42.6%, and 44.8% at 3, 6, and 12 months, respectively. At 12 months, excess BMI loss was 52.2% for patients with a baseline BMI of <40.0 and 41.3% for patients with a baseline BMI of ≥ 40.0 (P < .05). At 12 months, hemoglobin A(1c) levels decreased from 7.0% at baseline to 5.7% (P = .01); triglyceride levels decreased from 142.9 mg/dL to 98 mg/dL (P < .0001); high-density lipoprotein levels increased from 47.0 mg/dL to 57.5 mg/dL (P < .0001). Two complications occurred: a case of respiratory insufficiency and an asymptomatic pneumoperitoneum treated conservatively. LIMITATIONS Small number of patients. Short-term follow-up. Twenty-one percent of patients were not available for the 12-month follow-up. CONCLUSION The TOGA procedure allowed a substantial weight loss 1 year after the operation without severe complications. A long-term evaluation is needed before definitive conclusions can be drawn.

Endoscopic removal of dysfunctioning bands or rings after restrictive bariatric procedures.

BACKGROUND Intragastric band migrations or dysfunctions are common long-term complications of both vertical banded gastroplasty (VBG) and laparoscopic adjustable gastric banding (Lap-Band) that classically require surgical treatment. OBJECTIVE In this series, we describe the endoscopic removal of partially eroded Lap-Bands or Silastic rings and noneroded dysfunctioning rings after VBG. DESIGN Case series. SETTING A European, tertiary-care academic center. PATIENTS This study involved 13 patients--3 with eroded Lap-Bands, 4 with eroded Silastic rings, and 6 with refractory outlet stoma stenosis after VBG. INTERVENTION Endoscopic removal was performed within 1 or 2 sessions, according to the presence and extent of band erosion at presentation, including optional placement of a self-expandable plastic stent across the band, followed about 6 to 8 weeks later by extraction with transsection, if needed, by using a wire-cutting system. MAIN OUTCOME MEASUREMENTS Technical success and safety. RESULTS One failure was caused by huge adhesion formation around a Lap-Band on the lesser curvature of the stomach and the left liver lobe. Twelve of 13 endoscopic removals were successful in 1 (n = 2) and 2 (n = 10) sessions. LIMITATIONS Highly selected patients (tertiary-case academic center). CONCLUSION Endoscopic removal of dysfunctioning bands or rings is safe and feasible by the use of a 1- or 2-step endoscopic procedure.

The two SH2-domain-containing inositol 5-phosphatases SHIP1 and SHIP2 are coexpressed in human T lymphocytes.

Abstract The activation of many hematopoietic cells via cytokine receptors, as well as B and T cell receptors, leads to the tyrosine phosphorylation of Shc and its association with both Grb2-Sos1 complexes and with a 145 kDa protein referred to as the SH2 containing inositol 5-phosphatase (SHIP1). In a search of putative 5-phosphatase isoenzymes, we have isolated a second SH2 domain containing inositol 5-phosphatase, referred to as (SHIP2). Both SHIP1 and SHIP2 are coexpressed in human T lymphocytes. This was shown at the protein level by Western blot analysis in transformed T cell lines and in peripheral blood T lymphocytes either unstimulated or after in vitro activation through TCR-CD3 complex. SHIP1 protein level was not modulated after activation of T lymphocytes, in contrast to SHIP2, which was increased after longterm stimulation. SHIP1 was tyrosine phosphorylated in resting naive T cells. This was not observed in the transformed T cell lines. T lymphocyte is therefore a model of coexpression of the two SH2-containing inositol 5-phosphatases SHIP1 and SHIP2.

Phosphatidylinositol 3,4,5-trisphosphate modulation in SHIP2-deficient mouse embryonic fibroblasts.

SHIP2, the ubiquitous SH2 domain containing inositol 5‐phosphatase, includes a series of protein interacting domains and has the ability to dephosphorylate phosphatidylinositol 3,4,5‐trisphosphate [PtdIns(3,4,5)P3]in vitro. The present study, which was undertaken to evaluate the impact of SHIP2 on PtdIns(3,4,5)P3 levels, was performed in a mouse embryonic fibroblast (MEF) model using SHIP2 deficient (–/–) MEF cells derived from knockout mice. PtdIns(3,4,5)P3 was upregulated in serum stimulated –/– MEF cells as compared to +/+ MEF cells. Although the absence of SHIP2 had no effect on basal PtdIns(3,4,5)P3 levels, we show here that this lipid was significantly upregulated in SHIP2 –/– cells but only after short‐term (i.e. 5–10 min) incubation with serum. The difference in PtdIns(3,4,5)P3 levels in heterozygous fibroblast cells was intermediate between the +/+ and the –/– cells. In our model, insulin‐like growth factor‐1 stimulation did not show this upregulation. Serum stimulated phosphoinositide 3‐kinase (PI 3‐kinase) activity appeared to be comparable between +/+ and –/– cells. Moreover, protein kinase B, but not mitogen activated protein kinase activity, was also potentiated in SHIP2 deficient cells stimulated by serum. The upregulation of protein kinase B activity in serum stimulated cells was totally reversed in the presence of the PI 3‐kinase inhibitor LY‐294002, in both +/+ and –/– cells. Altogether, these data establish a link between SHIP2 and the acute control of PtdIns(3,4,5)P3 levels in intact cells.

Extracellular Nucleotides and Interleukin-8 Production by ARPE Cells: Potential Role of Danger Signals in Blood–Retinal Barrier Activation

PURPOSE RPE cell activation is an important feature of autoimmune uveitis. This investigation focused on whether extracellular nucleotides could contribute to this activation, and the effects of ATPgammaS, UTP, and UDP on the production of IL-8 by RPE cells was studied in relation to their expression of functional P2Y receptors. METHODS ARPE-19 cells were cultured with ATPgammaS, UTP, UDP, and TNF. IL-8 gene transcription and protein production were measured by semiquantitative RT-PCR and ELISA. Western blot analysis and RT-PCR were used to investigate ERK 1/2 activation and P2Y expression. Changes in intracellular calcium and cAMP concentration were analyzed by spectrofluorometry and radioimmunoassay. RESULTS Stimulation of ARPE-19 cells with ATPgammaS, UTP, and UDP induced IL-8 gene transcription and protein secretion. TNFalpha induction of IL-8 secretion was also increased by ATPgammaS, UTP, and UDP. Nucleotide induction of IL-8 production was blocked by PD98059, and all nucleotides stimulated ERK 1/2 phosphorylation. P2Y(2) and P2Y(6) mRNAs were detected in ARPE-19 cells. All tested nucleotides induced a pulse of intracellular calcium. CONCLUSIONS ATPgammaS, UTP, and UDP stimulate both basal and TNFalpha-induced IL-8 secretion in RPE cells through an ERK 1/2-dependent pathway. The results suggest that those effects are mediated by P2Y(2) and P2Y(6) receptors.

Endoscopic complications--avoidance and management.

The frequency of endoscopic complications is likely to rise owing to the increased number of indications for therapeutic procedures and also to the increased complexity of endoscopic techniques. Informed patient consent should be obtained as part of the procedure. Prevention of endoscopic adverse events is based on knowledge of the relevant risk factors and their mechanisms of occurrence. Thus, suitable training of future gastroenterologists and endoscopists is required for these complex procedures. When facing a complication, appropriate management is generally provided by an early diagnosis followed by prompt therapeutic care tailored to the situation. The most common complications of diagnostic and therapeutic upper gastrointestinal endoscopy, retrograde cholangiopancreatography, small bowel endoscopy and colonoscopy are reviewed here. Different modalities of medical, endoscopic or surgical management are also considered.