Volumetric laser endomicroscopy and its application to Barrett's esophagus: results from a 1,000 patient registry.

Volumetric laser endomicroscopy (VLE) uses optical coherence tomography (OCT) for real-time, microscopic cross-sectional imaging. A US-based multi-center registry was constructed to prospectively collect data on patients undergoing upper endoscopy during which a VLE scan was performed. The objective of this registry was to determine usage patterns of VLE in clinical practice and to estimate quantitative and qualitative performance metrics as they are applied to Barrett's esophagus (BE) management. All procedures utilized the NvisionVLE Imaging System (NinePoint Medical, Bedford, MA) which was used by investigators to identify the tissue types present, along with focal areas of concern. Following the VLE procedure, investigators were asked to answer six key questions regarding how VLE impacted each case. Statistical analyses including neoplasia diagnostic yield improvement using VLE was performed. One thousand patients were enrolled across 18 US trial sites from August 2014 through April 2016. In patients with previously diagnosed or suspected BE (894/1000), investigators used VLE and identified areas of concern not seen on white light endoscopy (WLE) in 59% of the procedures. VLE imaging also guided tissue acquisition and treatment in 71% and 54% of procedures, respectively. VLE as an adjunct modality improved the neoplasia diagnostic yield by 55% beyond the standard of care practice. In patients with no prior history of therapy, and without visual findings from other technologies, VLE-guided tissue acquisition increased neoplasia detection over random biopsies by 700%. Registry investigators reported that VLE improved the BE management process when used as an adjunct tissue acquisition and treatment guidance tool. The ability of VLE to image large segments of the esophagus with microscopic cross-sectional detail may provide additional benefits including higher yield biopsies and more efficient tissue acquisition. Clinicaltrials.gov NCT02215291.

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma.

BACKGROUND: Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma. METHODS: We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score. RESULTS: In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. CONCLUSIONS: Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).

Ablation therapies for pancreatic cancer: an updated review.

While impressive strides have been made in the detection and management of numerous somatic malignancies over the past two decades, safe and effective treatments for pancreatic cancer have remained elusive. However, a number of emerging new therapies hold the promise of improving survival and quality of life for those stricken with the disease. Ablative therapies in particular, including those utilizing radiofrequency waves, microwaves, thermal energy, photodynamic energy and focused ultrasound waves provide an opportunity to target neoplasms while sparing healthy surrounding tissue. Paired with endoscopic ultrasound, these therapies offer a safe, effective and minimally invasive means to care of patients with otherwise inoperable tumors.

Endoscopic resolution of secondary complications in bariatric surgery.

Morbid obesity has become an epidemic in past few decades. It has become an important aspect of public health-focused issues due its impact on several chronic diseases, including diabetes and cardiovascular diseases. Consequently the number of bariatric surgeries have increased in the past few years due to improved techniques and devices. A multidisciplinary approach such as surgical intervention and diet modification has yielded effective and sustainable weight loss in morbidly obese patients. However, as with as surgical procedure, immediate and long term complications may occur after bariatric surgery. Approximately 5% to 10% of patients who undergo bariatric surgery develop early complications (also known as perioperative complications), those that appear within the first 30 days of surgery, and 9% to 25% show sign of problems after the initial 30 days (late complications). Complications of bariatric surgery are related to the type of procedure performed and this review will describe the most common complication and their endoscopic management.

FcγRIIa ligation induces platelet hypersensitivity to thrombotic stimuli.

Platelets are known for their important role in hemostasis, however their significance in other functions, including inflammation and infection, are becoming more apparent. Patients with systemic lupus erythematosus (SLE) are known to have circulating IgG complexes in their blood and are highly susceptible to thrombotic events. Because platelets express a single receptor for IgG, we tested the hypothesis that ligation of this receptor (FcγRIIa) induces platelet hypersensitivity to thrombotic stimuli. Platelets from SLE patients were considerably more sensitive to thrombin compared to healthy volunteers, and this correlated with elevated levels of surface IgG on SLE platelets. To test whether FcγRIIa ligation stimulated thrombin hypersensitivity, platelets from healthy volunteers were incubated with buffer or heat-aggregated IgG, then stimulated with increasing concentrations of thrombin. Interestingly, heat-aggregated IgG-stimulated platelets, but not buffer-treated platelets, were hypersensitive to thrombin, and hypersensitivity was blocked by an anti-FcγRIIa monoclonal antibody (mAb). Thrombin hypersensitivity was not due to changes in thrombin receptor expression (GPIbα or PAR1) but is dependent on activation of shared signaling molecules. These observations suggest that ligation of platelet FcγRIIa by IgG complexes induces a hypersensitive state whereby small changes in thrombotic stimuli may result in platelet activation and subsequent vascular complications such as transient ischemic attacks or stroke.

Elevated stricture rate following the use of fully covered self-expandable metal biliary stents for biliary leaks following liver transplantation.

BACKGROUND: Biliary leaks and strictures are common complications after liver transplantation and can be managed surgically or endoscopically. Endoscopic management using fully covered self-expandable metal stents (FCSEMS) might provide some advantages over the commonly used plastic stents in the management of bile leaks after liver transplantation. METHODS: Between December 2006 and January 2009, 17 liver transplant recipients underwent placement of a FCSEMS for treatment of biliary leaks. RESULTS: FCSEMS were deployed at median of 18 days (range: 6 - 160) after liver transplantation and left in place for a median of 102 days (range: 35 - 427), with a median follow-up after FCSEMS removal of 407 days (range: 27 - 972). Long-term leak control was obtained in all but one patient. Complications included 6 clinically significant biliary strictures (35 %), which were treated with repeat stent placement, and two clinically insignificant strictures (12 %) which required no intervention. Additionally, three patients (18 %) had biliary ulcerations after stent removal, confirmed by choledochoscopy, and were managed conservatively. Two patients required repeat liver transplantation due to hepatic artery thrombosis, and one patient died from sepsis unrelated to FCSEMS stenting. CONCLUSIONS: FCSEMS treat biliary leaks effectively, but carry a relatively high stricture risk in patients who have received liver transplants. FCSEMS cannot be recommended for management of biliary leaks following liver transplantation at this point.

Fully covered self-expandable metallic stents in the management of complex biliary leaks: preliminary data - a case series.

Techniques for management of bile leaks include biliary sphincterotomy and stenting. Partially covered self-expandable metallic stents have been used in complex bile leaks, but they are associated with migration and hyperplasia. A fully covered self-expandable metallic stent (CSEMS) with anchoring fins might be effective in treating bile leaks without these complications. The aim of this study was to investigate the safety and efficacy of temporary placement of a CSEMS for resolving complex bile leaks. Thirteen patients with complex bile leaks underwent endoscopic retrograde cholangiopancreatography (ERCP) with temporary placement of a CSEMS following cholecystectomy (n = 8) or liver transplantation (n = 5). All patients had resolution of their bile leaks. Two patients developed a stricture below the confluence. Three patients died from unrelated causes. Two deaths occurred prior to CSEMS removal. Ten of 11 patients had evidence of biliary debris at the time of CSEMS removal. Overall, temporary placement of CSEMS is efficacious atresolving bile leaks. CSEMS are less prone to migration, but are associated with ulcerations, de novo choledocholithiasis, and strictures.

Interventional endoscopic ultrasound-guided cholangiography: long-term experience of an emerging alternative to percutaneous transhepatic cholangiography.

BACKGROUND AND STUDY AIMS: Endoscopic retrograde cholangiography (ERC) with stenting is the procedure of choice for biliary decompression in patients with obstructive jaundice. In cases where biliary access cannot be achieved, interventional endoscopic ultrasound-guided cholangiography (IEUC) has become an alternative to percutaneous transhepatic cholangiography (PTC). PATIENTS AND METHODS: We report on 5 years of experience in patients who underwent IEUC after failed endoscopic retrograde cholangiopancreatography (ERCP). Endoscopic ultrasound-guided access to the targeted biliary duct was attempted with one of two approaches: transgastric-transhepatic (intrahepatic) or transenteric-transcholedochal (extrahepatic). A stent was then advanced over the wire and into the biliary tree. RESULTS: A total of 49 patients underwent IEUC: 35 had biliary obstruction due to malignancy and 14 had a benign etiology. The overall success rate of IEUC was 84% (41/49), with an overall complication rate of 16%. Of the 35 patients who underwent the intrahepatic approach, 23 had a stent placed across the major papilla, one had a stent placed intraductally in the common bile duct, and three patients underwent placement of a gastrohepatic stent. Resolution of obstruction was achieved in 29 patients, with a success rate of 83%. In all, 14 patients underwent an extrahepatic approach. In 8/14 (57%), stent placement across the major papilla was achieved. A transenteric stent was placed in four patients. Biliary decompression was achieved in 12/14 cases (86%). Based on intention-to-treat analysis, the intrahepatic approach achieved success in 29 of 40 cases (73%), and the extrahepatic approach was successful in seven of nine cases (78%). There were no procedure-related deaths. CONCLUSION: IEUC offers a feasible alternative to PTC in patients with obstructive jaundice in whom ERC has failed.

Partially covered self-expandable metallic stents for benign biliary strictures due to chronic pancreatitis.

BACKGROUND AND STUDY AIMS: Benign biliary strictures (BBS) may occur in patients with chronic pancreatitis and may lead to secondary biliary cirrhosis or recurrent cholangitis. Although surgical diversion may provide definitive therapy, it can be associated with significant morbidity. Endoscopic therapy with plastic stents has been used as an alternative to surgery but has resulted in unsatisfactory long-term outcomes. We evaluated the temporary placement of partially covered self-expandable metallic stents (PCMS) in patients with BBS due to chronic pancreatitis. PATIENTS AND METHODS: A total of 20 patients with BBS due to chronic pancreatitis underwent temporary placement of PCMS over a 6-year period. The primary outcome of interest was the proportion of patients with stricture resolution persisting 6 months after stent removal. Secondary outcomes included the stent failure rate, number of endoscopic sessions required to achieve biliary drainage, total duration of stenting, and complication rate. RESULTS: Adequate biliary drainage was achieved in 19 patients with PCMS (95%). Eighteen of the 20 patients (90%) had persistent stricture resolution 6 months after PCMS removal. In two of the 20 patients (10%), PCMS stenting failed and these patients underwent alternative therapies. Complications occurred in four patients (20%). Median duration of PCMS placement was 5 months, requiring a median of two endoscopic procedures. CONCLUSION: In this series of patients with BBS due to chronic pancreatitis, temporary PCMS placement achieved persistent stricture resolution in the majority of patients with acceptable complication rates. Comparative trials evaluating temporary PCMS placement and plastic stenting in patients with BBS due to chronic pancreatitis are needed.

Marinobufagenin induces increases in procollagen expression in a process involving protein kinase C and Fli-1: implications for uremic cardiomyopathy.

The cardiotonic steroid marinobufagenin (MBG) has been implicated in the pathogenesis of experimental uremic cardiomyopathy, which is characterized by progressive cardiac fibrosis. We examined whether the transcription factor Friend leukemia integration-1 (Fli-1) might be involved in this process. Fli-1-knockdown mice demonstrated greater cardiac collagen-1 expression and fibrosis compared with wild-type mice; both developed increased cardiac collagen expression and fibrosis after 5/6 nephrectomy. There was a strong inverse relationship between the expressions of Fli-1 and procollagen in primary culture of rat cardiac and human dermal fibroblasts as well as a cell line derived from renal fibroblasts and MBG-induced decreases in nuclear Fli-1 as well as increases in procollagen-1 expression in these cells. Transfection of a Fli-1 expression vector prevented increased procollagen-1 expression from MBG. MBG exposure induced a rapid translocation of the delta-isoform of protein kinase C (PKCdelta) to the nucleus. This translocation was prevented by pharmacological inhibition of phospholipase C, and MBG-induced increases in procollagen-1 expression were prevented with a PKCdelta- but not a PKCalpha-specific inhibitor. Finally, immunoprecipitation studies strongly suggest that MBG induced phosphorylation of Fli-1. We feel these data support a causal relationship with MBG-induced translocation of PKCdelta, which results in phosphorylation of as well as decreases in nuclear Fli-1 expression, which, in turn, leads to increases in collagen production. Should these findings be confirmed, we speculate that this pathway may represent a therapeutic target for uremic cardiomyopathy as well as other conditions associated with excessive fibrosis.

Effects of cardiotonic steroids on dermal collagen synthesis and wound healing.

We previously reported that cardiotonic steroids stimulate collagen synthesis by cardiac fibroblasts in a process that involves signaling through the Na-K-ATPase pathway (Elkareh et al. Hypertension 49: 215-224, 2007). In this study, we examined the effect of cardiotonic steroids on dermal fibroblasts collagen synthesis and on wound healing. Increased collagen expression by human dermal fibroblasts was noted in response to the cardiotonic steroid marinobufagenin in a dose- and time-dependent fashion. An eightfold increase in collagen synthesis was noted when cells were exposed to 10 nM marinobufagenin for 24 h (P < 0.01). Similar increases in proline incorporation were seen following treatment with digoxin, ouabain, and marinobufagenin (10 nM x 24 h, all results P < 0.01 vs. control). The coadministration of the Src inhibitor PP2 or N-acetylcysteine completely prevented collagen stimulation by marinobufagenin. Next, we examined the effect of digoxin, ouabain, and marinobufagenin on the rate of wound closure in an in vitro model where human dermal fibroblasts cultures were wounded with a pipette tip and monitored by digital microscopy. Finally, we administered digoxin in an in vivo wound healing model. Olive oil was chosen as the digoxin carrier because of a favorable partition coefficient observed for labeled digoxin with saline. This application significantly accelerated in vivo wound healing in rats wounded with an 8-mm biopsy cut. Increased collagen accumulation was noted 9 days after wounding (both P < 0.01). The data suggest that cardiotonic steroids induce increases in collagen synthesis by dermal fibroblasts, as could potentially be exploited to accelerate wound healing.

Transnasal OGD: practice survey and impact of a live video retransmission.

BACKGROUND: Unsedated transnasal oesogastroduodenoscopy significantly improves patient tolerance compared to unsedated conventional peroral oesogastroduodenoscopy. AIMS: To assess the adoption of transnasal oesogastroduodenoscopy among endoscopists from various European countries and its determinants. METHODS: A survey was distributed to 624 endoscopists attending a live course on digestive endoscopy; a poll was also performed immediately before and after live video retransmission of a transnasal oesogastroduodenoscopy. RESULTS: Answer rate was 48%; transnasal oesogastroduodenoscopy was practised by 31% of respondents. In multivariate analysis, practice of transnasal oesogastroduodenoscopy was associated with location in France and Netherlands (P<0.0001), availability of many gastroscopes (P<0.0001) and less frequent use of sedation (P=0.006). Endoscopists who did not practise transnasal oesogastroduodenoscopy cited doubts about its advantages over conventional oesogastroduodenoscopy and lack of training (34% each) as barriers to adoption. Seventy-four percent of endoscopists practicing transnasal oesogastroduodenoscopy did actually use it in <20% of eligible cases. Live video retransmission of a transnasal oesogastroduodenoscopy increased the proportion of endoscopists interested in this technique (P=0.006). CONCLUSIONS: Adoption of transnasal oesogastroduodenoscopy largely varies between European countries; endoscopists practicing this technique use it in a minority of eligible cases. Live case demonstration may decrease barriers to the adoption of this technique.

Covered self-expandable metal stents in pancreatic malignancy regardless of resectability: a new concept validated by a decision analysis.

BACKGROUND AND STUDY AIMS: The current treatment model for the management of malignant biliary obstruction is to place a plastic stent for unstaged pancreatic cancer. In patients with unresectable disease but a life expectancy of more than 6 months, self-expandable metal stents (SEMS) are favored because of their more prolonged patency. We analyzed the efficacy and cost-effectiveness of covered SEMS (CSEMS) in patients with pancreatic cancer and distal biliary obstruction without regard to surgical resectability. PATIENTS AND METHODS: Between March 2001 and March 2005, 101 consecutive patients with obstructive jaundice secondary to pancreatic cancer underwent placement of a CSEMS. Patients with resectable tumor were offered pancreaticoduodenectomy. A model was developed to compare the costs of CSEMS and polyethylene and DoubleLayer stents. RESULTS: A total of 21 patients underwent staging laparoscopy, of whom 16 had a resection (76%). The 85 patients who did not have a resection had a mean survival of 5.9 months (range 1-25 months) and a mean CSEMS patency duration of 5.5 months (range 1-16 months). Life-table analysis demonstrated CSEMS patency rates of 97% at 3 months, 85% at 6 months, and 68% at 12 months. In a cost model that accounted for polyethylene and DoubleLayer stent malfunction and surgical resections, initial CSEMS placement (3177 euros per patient) was a less costly intervention than either DoubleLayer stent placement (3224 euros per patient) or polyethylene stent placement with revision (3570 euros per patient). CONCLUSIONS: Covered SEMS are an effective treatment for distal biliary obstructions caused by pancreatic carcinoma. Their prolonged patency and removability makes them an attractive option for biliary decompression, regardless of resectability. The strategy of initial covered SEMS placement might be the most cost-effective strategy in these patients.

Marinobufagenin stimulates fibroblast collagen production and causes fibrosis in experimental uremic cardiomyopathy.

We have observed recently that experimental renal failure in the rat is accompanied by increases in circulating concentrations of the cardiotonic steroid, marinobufagenin (MBG), and substantial cardiac fibrosis. We performed the following studies to examine whether MBG might directly stimulate cardiac fibroblast collagen production. In vivo studies were performed using the 5/6th nephrectomy model of experimental renal failure (PNx), MBG infusion (MBG), PNx after immunization against MBG, and concomitant PNx and adrenalectomy. Physiological measurements with a Millar catheter and immunohistochemistry were performed. In vitro studies were then pursued with cultured isolated cardiac fibroblasts. We observed that PNx and MBG increased MBG levels, blood pressure, heart size, impaired diastolic function, and caused cardiac fibrosis. PNx after immunization against MBG and concomitant PNx and adrenalectomy had similar blood pressure as PNx but less cardiac hypertrophy, diastolic dysfunction, and cardiac fibrosis. MBG induced increases in procollagen-1 expression by cultured cardiac fibroblasts at 1 nM concentration. These increases in procollagen expression were accompanied by increases in collagen translation and increases in procollagen-1 mRNA without any demonstrable increase in procollagen-1 protein stability. The stimulation of fibroblasts with MBG could be prevented by administration of inhibitors of tyrosine phosphorylation, Src activation, epidermal growth factor receptor transactivation, and N-acetyl cysteine. Based on these findings, we propose that MBG directly induces increases in collagen expression by fibroblasts, and we suggest that this may be important in the cardiac fibrosis seen with experimental renal failure.

Endoscopic ultrasound drainage of pancreatic pseudocyst: a prospective comparison with conventional endoscopic drainage.

BACKGROUND AND STUDY AIMS: Pancreatic pseudocysts are a complication in up to 20% of patients with pancreatitis. Endoscopic management of pseudocysts by a conventional transenteric technique, i. e. conventional transmural drainage (CTD), or by endoscopic ultrasound-guided drainage (EUD), is well described. Our aim was to prospectively compare the short-term and long-term results of CTD and EUD in the management of pseudocysts. PATIENTS AND METHODS: A total of 99 consecutive patients underwent endoscopic management of pancreatic pseudocysts according to this predetermined treatment algorithm: patients with bulging lesions without obvious portal hypertension underwent CTD; all remaining patients underwent EUD. Patients were followed prospectively, with cross-sectional imaging during clinic visits. We compared short-term and long-term results (effectiveness and complications) at 1 and 6 months post procedure. RESULTS: 46 patients (37 men) underwent EUD and 53 patients (39 men) had CTD. The mean age of the entire group was 50 +/- 13 years. There were no significant differences between the two groups regarding short-term success (93% vs. 94%) or long-term success (84% vs. 91%); 68 of the 99 patients completed 6 months of follow-up. Complications occurred in 19% of EUD vs. 18% of CTD patients, and consisted of bleeding in three, infection of the collection in eight, stent migration into the pseudocyst in three, and pneumoperitoneum in five. All complications but one could be managed conservatively. CONCLUSIONS: No clear differences in efficacy or safety were observed between conventional and EUS-guided cystenterostomy. The choice of technique is likely best predicated by individual patient presentation and local expertise.

Central role for the cardiotonic steroid marinobufagenin in the pathogenesis of experimental uremic cardiomyopathy.

Patients with chronic renal failure develop a "uremic" cardiomyopathy characterized by diastolic dysfunction, cardiac hypertrophy, and systemic oxidant stress. Patients with chronic renal failure are also known to have increases in the circulating concentrations of the cardiotonic steroid marinobufagenin (MBG). On this background, we hypothesized that elevations in circulating MBG may be involved in the cardiomyopathy. First, we observed that administration of MBG (10 microg/kg per day) for 4 weeks caused comparable increases in plasma MBG as partial nephrectomy at 4 weeks. MBG infusion caused increases in conscious blood pressure, cardiac weight, and the time constant for left ventricular relaxation similar to partial nephrectomy. Decreases in the expression of the cardiac sarcoplasmic reticulum ATPase, cardiac fibrosis, and systemic oxidant stress were observed with both MBG infusion and partial nephrectomy. Next, rats were actively immunized against a MBG-BSA conjugate or BSA control, and partial nephrectomy was subsequently performed. Immunization against MBG attenuated the cardiac hypertrophy, impairment of diastolic function, cardiac fibrosis, and systemic oxidant stress seen with partial nephrectomy without a significant effect on conscious blood pressure. These data suggest that the increased concentrations of MBG are important in the cardiac disease and oxidant stress state seen with renal failure.

Drainage of gallbladder fossa fluid collections with endoprosthesis placement under endoscopic ultrasound guidance: a preliminary report of two cases.

Collections of fluid in the gallbladder fossa can be detected by ultrasound in as many as 29% of patients following cholecystectomy. Traditionally, persistent collections are treated by percutaneous drainage and bile duct decompression. We present two cases of persistent gallbladder fossa fluid collections which were refractory to bile duct decompression but which were successfully drained by endoscopic ultrasound-guided endoprosthesis placement. Under endoscopic ultrasound (EUS) control, a 19-gauge needle was inserted through the duodenal wall into the gallbladder fossa fluid collection. A guide wire was coiled within the collection, and an endoprosthesis was placed over the wire. Endoprosthesis insertion was successful in both cases, resulting in rapid symptomatic and radiographic improvement. EUS-guided drainage offers a minimally invasive alternative to percutaneous treatment of persistent gallbladder fossa fluid collections following cholecystectomy.