Development of CD44E/s dual-targeting DNA aptamer as nanoprobe to deliver treatment in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is the predominant subtype of liver cancer with an extraordinary high mortality. Resistance to systemic therapy is a major cause of inferior clinical outcome in most patients with HCC. CD44 is a transmembrane cell-surface glycoprotein that is characterized by its variants displaying differential overexpression in human cancers. Aptamers, also known as chemical antibodies, can target cell-surface molecules with high affinity and specificity via structural recognition. Aptamer-mediated drug delivery hence is of high potentials in guiding therapy to improve efficacy. Methods: Variants CD44E and CD44s were studied for HCC relevance by investigating their expressions in primary HCC tumors, adjacent cirrhotic/fibrotic livers and normal livers using junction specific primers in qPCR assay. CD44E/s dual-targeted aptamers were uncovered by integrating loss-gain cell-SELEX and next generation sequencing. Selected aptamers were characterized for binding affinity and specificity, biostability, in vivo and in vitro cytotoxicity, in vivo homing and biodistribution, and ability to deliver 5-FU into targeted cells in vitro. Results: Both CD44E and CD44s isoforms showed significant upregulations in HCC tumors with CD44E/s activities promoting cell proliferation and migration. Loss-gain cell-SELEX uncover a CD44E/s dual-targeting aptamer, termed CD44-Apt1. Strong binding of CD44-Apt1 to cell-surface CD44 positive cells but not CD44-negative cells was demonstrated by flow-cytometry. CD44-Apt1 displayed strong affinity to CD44E and CD44s with KD as low as 1 nM but not the hyaluronic acid binding domain of CD44. Confocal imaging of CD44-positive cells stained with fluorescent-labeled CD44-Apt1 showed profound cytoplasmic localization, suggesting efficient cell-penetrating ability. Meanwhile, no apparent staining was observed in CD44-negative cells. CD44-Apt1 when conjugated with inhibitor 5-FU showed efficient guidance of 5-FU into HCC cells that significantly enhanced drug toxicity by more than thousands-fold. Both in vitro cell treatment and in vivo animal biodistribution indicated that CD44-Apt1 is non-toxic. In HCC xenograft model, CD44-Apt1 efficiently homed to tumor xenografts in a CD44 expression-dependent manner. Conclusion: Novel discovery of aptamer CD44-Apt1 that can bind both CD44E and CD44s illustrates high potential as nanoprobe to deliver anti-cancer therapeutics.

Management of acute upper gastrointestinal bleeding: Urgent versus early endoscopy.

For decades, timing of endoscopy has been a controversy in the management of patients who present with upper gastrointestinal bleeding (GIB). The advent of endoscopic hemostatic therapy led to reduced further bleeding, surgery and mortality. Observational studies suggest that in patients at low risk of further bleeding, early endoscopy establishes diagnosis and allows their prompt hospital discharge. In the high-risk patients, early endoscopy with hemostatic treatment can stop bleeding and improve outcomes. Sample size in early randomized controlled trials (RCTs) was small. They included low-risk patients or patients with poorly defined risks. We designed a RCT to test the hypothesis that in high-risk patients (defined by those with an admission Glasgow Blatchford Score of 12 or greater), endoscopy within 6 h of gastrointestinal consultation, when compared to the standard of care i.e. endoscopy within 24 h, would improve outcomes. The primary outcomes, all-cause mortality at 30 days did not differ between groups; 23 of 258 (8.9%) in the urgent-endoscopy group and 17 of 258 (6.6%) in the early-endoscopy group died (difference 2.3%, 95% confidence interval -2.3 to 6.9%). Further bleeding was similar (10.9% vs. 7.8%) between groups. A higher rate in endoscopic hemostatic treatment was observed in the urgent-endoscopy group (60.1% vs. 48.4%). In patients with peptic ulcers, active bleeding or visible vessels were found on initial endoscopy in 105 of the 158 patients (66.4%) and in 76 of 159 (47.8%) in the respective group. In the majority of patients with GIB, endoscopy earlier than 24 h is not indicated.

Mesenchymal stem cells promote healing of nonsteroidal anti-inflammatory drug-related peptic ulcer through paracrine actions in pigs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most important causes of peptic ulcer disease in high-income countries. Proton pump inhibitors are the current standard treatment; however, safety and long-term adverse effects of using these drugs are attracting more and more concerns in recent years. Using a porcine model of NSAID-related gastric ulcer, we herein show that adipose-derived mesenchymal stem cells (ADMSCs) delivered by endoscopic submucosal injection promoted ulcer healing with less inflammatory infiltration and enhanced reepithelization and neovascularization at day 7 and day 21 when compared with the controls (saline injection). However, only few engrafted ADMSCs showed myofibroblast and epithelial cell phenotype in vivo, suggesting the ulcer healing process might be much less dependent on the stem cell transdifferentiation. Further experiment with submucosal injection of MSC-derived secretome revealed a therapeutic efficacy comparable to that of stem cell transplantation. Profiling analysis showed up-regulation of genes associated with inflammation, granulation formation, and extracellular matrix remodeling at day 7 after injection of MSC-derived secretome. In addition, the extracellular signal-regulated kinase/mitogen-activated protein kinase and the phosphoinositide-3-kinase/protein kinase B pathways were activated after injection of ADMSCs or MSC-derived secretome. Both signaling pathways were involved in mediating the major events critical to gastric ulcer healing, including cell survival, migration, and angiogenesis. Our data suggest that endoscopic submucosal injection of ADMSCs serves as a promising approach to promote healing of NSAID-related peptic ulcer, and the paracrine effectors released from stem cells play a crucial role in this process.

Machine learning model to predict recurrent ulcer bleeding in patients with history of idiopathic gastroduodenal ulcer bleeding.

BACKGROUND: Patients with a history of Helicobacter pylori-negative idiopathic bleeding ulcers have an increased risk of recurring ulcer complications. AIM: To build a machine learning model to identify patients at high risk for recurrent ulcer bleeding. METHODS: Data from a retrospective cohort of 22 854 patients (training cohort) diagnosed with peptic ulcer disease in 2007-2016 were analysed to build a model (IPU-ML) to predict recurrent ulcer bleeding. We tested the IPU-ML in all patients with a diagnosis of gastrointestinal bleeding (n = 1265) in 2008-2015 from a different catchment population (independent validation cohort). Any co-morbid conditions which had occurred in >1% of study population were eligible as predictors. RESULTS: Recurrent ulcer bleeding developed in 4772 patients (19.5%) in the training cohort, during a median follow-up period of 2.7 years. IPU-ML model built on six parameters (age, baseline haemoglobin, and presence of gastric ulcer, gastrointestinal diseases, malignancies, and infections) identified patients with bleeding recurrence within 1 year with an area under the receiver operating characteristic curve (AUROC) of 0.648. When we set the IPU-ML cutoff value at 0.20, 27.5% of patients were classified as high risk for rebleeding with a sensitivity of 41.4%, specificity of 74.6%, and a negative predictive value of 91.1%. In the validation cohort, the IPU-ML identified patients with a recurrence ulcer bleeding within 1 year with an AUROC of 0.775, and 84.3% of overall accuracy. CONCLUSION: We developed a machine-learning model to identify those patients with a history of idiopathic gastroduodenal ulcer bleeding who are not at high risk for recurrent ulcer bleeding.

Hydrogen sulfide mediates athero-protection against oxidative stress via S-sulfhydration.

S-sulfhydration is a signalling pathway of hydrogen sulfide (H2S), which is suggested as an anti-atherogenic molecule that may protect against atherosclerosis. The identification of S-sulfhydrated proteins by proteomic approach could be a major step towards understanding the mechanisms of H2S in response to atherosclerosis. The present study studied targeted S-sulfhydrated proteins using the modified biotin switch method followed by matrix-assisted laser desorption/ionisation time of flight tandem mass spectrometry identification. The results showed that H2S can protect against atherosclerosis by reducing body weight gain and alleviating aortic plaque formation. In addition, H2S treatment can increase aortic protein S-sulfhydration. Seventy targeted S-sulfhydrated aortic proteins were identified, mainly involved in metabolism, stimulus response and biological regulation, as determined by gene ontology database analysis. H2S also induced S-sulfhydration of glutathione peroxidase 1 and further reduced lipid peroxidation and increased antioxidant defence in the aorta by prompting glutathione synthesis. Our data suggest that H2S is a cardiovascular-protective molecule that S-sulfhydrates a subset of proteins that are mainly responsible for lipid metabolism and exerts its cytoprotective effects to clear free radicals and inhibit oxidative stress through cysteine S-sulfhydration.

Secretome from hypoxia-conditioned adipose-derived mesenchymal stem cells promotes the healing of gastric mucosal injury in a rodent model.

Studies have indicated that the definitive engraftment and transdifferentiation potential of stem cells do not seem crucial for its property of tissue repair. Our previous study showed that transplantation of adipose-derived mesenchymal stem cells (ADMSCs) enhanced the healing of sutured gastric perforation. This study aimed to investigate the paracrine role of ADMSCs in the experimental gastric mucosal injury. Normoxia-conditioned medium (Nor CM) and hypoxia (HPO) CM were obtained after culturing ADMSCs in 20% O2 and 5% O2 for 48h. Cell migration, proliferation, viability, and angiogenesis in vitro were significantly enhanced upon incubation with CM, especially the HPO CM. Experiments in vivo using a rodent model of gastric ulcer demonstrated that HPO CM treatment significantly accelerated wound healing by suppressing inflammation and promoting neovascularization and re-epithelization. Meanwhile, the infusion of HPO CM activated the COX2-PGE2 axis both in vitro and in vivo. And the upregulation of COX2 was further dependent on the activation of ErK1/2-MAPK pathway. In addition, vascular endothelial growth factor, tissue inhibitors of metalloproteinases-1, and chemokine (C-C motif) ligand 20 (CCL-20) were analyzed as being highly abundant factors secreted by ADMSCs under hypoxic condition. Notably, the blockade of CCL-20 abrogated the HPO CM-induced COX2 signaling in the primary gastric mucosal epithelial cells, while incubation with recombinant CCL-20 increased the expression of COX2. In conclusion, the secretome from hypoxia-conditioned ADMSCs facilitates the repair of gastric mucosal injury through the enhancement of angiogenesis and re-epithelization, as well as the activation of COX2-PGE2 axis with a paracrine activity involving CCL-20 factor.

Multicenter randomised controlled trial comparing the high definition white light endoscopy and the bright narrow band imaging for colon polyps.

AIM: To compare high definition white light endoscopy and bright narrow band imaging for colon polyps' detection rates. METHODS: Patients were randomised to high definition white light endoscopy (HD-WLE) or the bright narrow band imaging (bNBI) during withdrawal of the colonoscope. Polyps identified in either mode were characterised using bNBI with dual focus (bNBI-DF) according to the Sano's classification. The primary outcome was to compare adenoma detection rates (ADRs) between the two arms. The secondary outcome was to assess the negative predictive value (NPV) in differentiating adenomas from hyperplastic polyps for diminutive rectosigmoid lesions. RESULTS: A total of 1006 patients were randomised to HD-WLE (n = 511) or bNBI (n = 495). The mean of adenoma per patient was 1.62 and 1.84, respectively. The ADRs in bNBI and HD-WLE group were 37.4% and 39.3%, respectively. When adjusted for withdrawal time (OR = 1.19, 95%CI: 1.15-1.24, P < 0.001), the use of bNBI was associated with a reduced ADR (OR = 0.69, 95%CI: 0.52-0.92). Nine hundred and thirty three polyps (86%) in both arms were predicted with high confidence. The sensitivity (Sn), specificity (Sp), positive predictive value and NPV in differentiating adenomatous from non-adenomatous polyps of all sizes were 95.9%, 87.2%, 94.0% and 91.1% respectively. The NPV in differentiating an adenoma from hyperplastic polyp using bNBI-DF for diminutive rectal polyps was 91.0%. CONCLUSION: ADRs did not differ between bNBI and HD-WLE, however HD-WLE had higher ADR after adjustment of withdrawal time. bNBI surpassed the PIVI threshold for diminutive polyps.

Endoscopic ultrasound-guided gallbladder drainage reduces adverse events compared with percutaneous cholecystostomy in patients who are unfit for cholecystectomy.

Background and study aim There are no data comparing endoscopic ultrasound (EUS)-guided gallbladder drainage (EGBD) with percutaneous cholecystostomy as a treatment for patients with acute cholecystitis. Patients and methods This was a 1 : 1 matched cohort study of all patients who were unfit for cholecystectomy and underwent EGBD or percutaneous cholecystostomy instead for the treatment of acute cholecystitis. The outcomes were matched for age, sex, and American Society of Anesthesiologists grade. Outcome measures included the technical and clinical success rates, adverse events, hospital stay, the number of unplanned admissions, and mortality. Results Between November 2011 and August 2014, a total of 118 patients were included in the study (59 EGBD, 59 percutaneous cholecystostomy). Technical and clinical success rates were similar. In the EGBD group, significantly fewer patients suffered from overall adverse events (19 [32.2 %] vs. 44 [74.6 %]; P < 0.001) and serious adverse events (14 [23.7 %] vs. 44 [74.6 %]; P < 0.001) compared to the percutaneous cholecystostomy group. Patients in the EGBD group required fewer unplanned admissions (4 [6.8 %] vs. 42 [71.2 %]; P < 0.001), which were due to problems related to the cholecystostomy tube in 95.2 %. The 30-day adverse event rates were similar between the groups (17 [28.8 %] vs. 10 [16.9 %]; P = 0.13). For instance, recurrent acute cholecystitis occurred in 0 patients in the EGBD group and in 4 (6.8 %) patients in the percutaneous cholecystostomy group (P = 0.12). The 30-day mortality rates were non-significantly higher in the EGBD group (5 [8.5 %] vs. 1 [1.7 %]; P = 0.21). Conclusions EGBD and percutaneous cholecystostomy were both effective means of achieving gallbladder drainage. EGBD may be a promising alternative to percutaneous cholecystostomy for treatment of acute cholecystitis in patients who are unfit for surgery, provided that experienced endosonographers are available.

Comparison of early outcomes and quality of life after laparoscopic Heller's cardiomyotomy to peroral endoscopic myotomy for treatment of achalasia.

BACKGROUND AND AIM: This retrospective cohort study compared clinical outcomes and quality of life after peroral endoscopic myotomy (POEM) against laparoscopic Heller myotomy (LHM) for treatment of achalasia. METHODS: Patient demographics, operation time, intraoperative blood loss, hospital stay, time to resume diet and analgesic requirement were recorded. Clinical outcomes including recurrence of dysphagia, need for reintervention, and occurrence of gastroesophageal reflux disease (GERD) were recorded. RESULTS: From 2001 to 2014, 33 patients underwent POEM whereas 23 patients received LHM. Patients LHM had with longer mean operative time (P = 0.02), more blood loss (P = 0.001) and higher requirement for analgesics (P = 0.009) than those treated by POEM. Hospital stay and time to resume diet were similar. Both POEM and LHM achieved similar dysphagia scores at postoperative 4 weeks, 3 months and 6 months. Twenty-six percent of LHM patients and 15.2% of POEM patients sustained gastroesophageal reflux disease (GERD) after treatment (P = 0.311). Six patients required regular proton pump inhibitor three after POEM and three after LHM (P = 0.639). Thirteen percent of LHM patients sustained recurrent dysphagia and one required reintervention. There was no recurrence in the POEM group. Follow-up duration (mean [SD]) for the LHM group was significantly longer (60 [42] months vs 6 [4] months; P = 0.001). There was also no difference in all four aspects of GERD-related quality of life outcomes. CONCLUSION: Compared to LHM, POEM achieved shorter operative time, less blood loss and pain. POEM is comparable to LHM for treatment of achalasia with similar incidence of GERD after the procedure.

A multicenter randomized comparison between high-definition white light endoscopy and narrow band imaging for detection of gastric lesions.

OBJECTIVE: Narrow band imaging (NBI) is generally considered to be useful for lesion characterization, but not enhanced detection of gastric lesions, because of the dark endoscopic view. We tested whether the new generation of NBI (190-NBI or 290-NBI), which is twice as bright as the previous version, would improve detection of premalignant gastric lesions compared with high-definition white light endoscopy (HD-WLE). PATIENTS AND METHODS: This was a multicenter prospective randomized study involving five tertiary institutions in the Asia-Pacific region. A total of 579 patients aged older than 50 years who underwent diagnostic upper gastrointestinal endoscopy were randomized to either HD-WLE or NBI. The outcome measurements were detection of intestinal metaplasia (IM), focal gastric lesions, and gastric cancers. RESULTS: Focal gastric lesions were detected in 83/286 (29%) and 119/293 patients (40.6%) by HD-WLE and by NBI, respectively (P=0.003). IM was detected in 22/286 patients (7.7%) by HD-WLE and in 52/293 patients (17.7%) by NBI (P<0.001). Gastric cancer were found in 7/286 (2.4%) and 3/293 patients (1%) in HD-WLE and NBI groups, respectively (P=0.189). CONCLUSION: NBI increased the detection rate of IM compared with HD-WLE.

Tips in biliary stone removal using endoscopic papillary large balloon dilation.

The use of limited endoscopic sphincterotomy with large balloon dilation (ESLBD) has recently been shown to be useful for removal of large common bile duct stones in a dilated bile duct. The technique can reduce the need of mechanical lithotripsy, risk of adverse events and costs of the procedure. The aim of the review is to provide an overview in the current status of ESLBD with particular focus on the technical aspects of the technique for bile duct stone removal.

What if endoscopic hemostasis fails?: Alternative treatment strategies: surgery.

Management of bleeding peptic ulcers is increasingly challenging in an aging population. Endoscopic therapy reduces the need for emergency surgery in bleeding peptic ulcers. Initial endoscopic control offers an opportunity for selecting high-risk ulcers for potential early preemptive surgery. However, such an approach has not been supported by evidence in the literature. Endoscopic retreatment can be an option to control ulcer rebleeding and reduce complications. The success of endoscopic retreatment largely depends on the severity of rebleeding and ulcer characteristics. Large chronic ulcers with urgent bleeding are less likely to respond to endoscopic retreatment. Expeditious surgery is advised.

Anti-atherogenic effect of hydrogen sulfide by over-expression of cystathionine gamma-lyase (CSE) gene.

Hydrogen sulfide (H2S) is an important gaseous signaling molecule that functions in physiological and pathological conditions, such as atherosclerosis. H2S dilates vessels and therefore has been suggested as an anti-atherogenic molecule. Since cystathionine gamma-lyase (CSE) enzyme is responsible for producing H2S in the cardiovascular system, we hypothesized that up-regulation of CSE expression in vivo with preservation of H2S bioactivity can slow down plaque formation and, can serve as a therapeutic strategy against atherosclerosis. In this study, C57BL/6 wild type mice (WT), ApoE knockout mice (KO) and transgenic ApoE knockout mice overexpressing CSE (Tg/KO) at four weeks of age were weaned. They were then fed with either normal or atherogenic diet for 12 weeks. At week 16, serial plasma lipid levels, body weight, and blood pressure were measured prior to euthanization of the mice and the size of atherosclerotic plaques at their aortic roots was measured. Tg/KO mice showed an increase in endogenous H2S production in aortic tissue, reduced atherosclerotic plaque sizes and attenuation in plasma lipid profiles. We also showed an up-regulation in plasma glutathionine peroxidase that could indicate reduced oxidative stress. Furthermore, there was an increase in expression of p-p53 and down regulation of inflammatory nuclear factor-kappa B (NF-κB) in aorta. To conclude, alteration of endogenous H2S by CSE gene activation was associated with reduced atherosclerosis in ApoE-deficient mice. Up-regulation of CSE/H2S pathway attenuates atherosclerosis and this would be a potential target for therapeutic intervention against its formation.

Recognition of goblet cells upon endocytoscopy indicates the presence of gastric intestinal metaplasia.

BACKGROUND: Gastric intestinal metaplasia (IM) is considered precancerous and is difficult to differentiate upon endoscopy. Endocytoscopy enables observation at a cellular level for focused biopsy. The present study examined the use of endocytoscopy for recognition of gastric IM. PATIENTS AND METHODS: Patients with a history of gastric IM were recruited. We first carried out narrow band imaging (NBI) endoscopy to look for suspicious areas of gastric IM. A prototype endocytoscope with a magnification of 450× was used to re-examine these areas. Areas examined were biopsied for histological comparison. Presence of goblet cells was considered as representative of IM upon endocytoscopy. RESULTS: Twenty patients were recruited with NBI demonstrating 102 suspicious lesions of gastric IM. Mean age of patients was 53.9 ± 7.6 years. Upon histology, 72 biopsies were confirmed as gastric IM, 15 showed IM and low-grade dysplasia, whereas 15were diagnosed as chronic gastritis. Endocytoscopy image quality was significantly better for areas of IM as compared to gastritis (P < 0.05; OR 21.7 [95% CI 4.5-105.9]). The presence of goblet cells upon endocytoscopy achieved a diagnostic accuracy of 0.86 for gastric IM. Receiver operator characteristics curve achieved an area under curve of 0.8 with the presence of goblet cells under endocytoscopy as compared to 0.64 for NBI alone. CONCLUSIONS: Presence of goblet cells upon endocytoscopy indicates a diagnosis of gastric IM. Image quality of endocytoscopy, however, is suboptimal. Further developments in endocytoscopy should focus on image quality and staining methods to enhance differentiation between IM, dysplasia and early gastric cancer.

Endoscopic suturing is superior to endoclips for closure of gastrotomy after natural orifices translumenal endoscopic surgery (NOTES): an ex vivo study.

BACKGROUND: Closure of gastrotomy remains a major barrier to clinical application of NOTES. Full-thickness closure of gastrotomy using endoscopic suturing device is presumed to be safer than that by endoclips. We evaluated the safety and feasibility of closing gastrotomy by Eagle Claw VIII, endoclips, and surgical suturing. METHODS: Fifty-one ex vivo porcine stomach models were included with 17 closures per arm. A 2-cm linear incision was created at the gastric body using scalpel externally. The time for gastrotomy closure, pneumatic bursting pressure, site of air leakage and number of suturing, or clips used were recorded. In addition, the technical difficulties of closure using Eagle Claw VIII and endoclips were assessed by a quantitative scale. RESULTS: All gastrotomies were successfully closed without leakage upon full gaseous distension. Closure time of Eagle Claw VIII was significantly longer than that of endoclips and surgical suturing. The median pneumatic bursting pressures were 56 (range 35-110) mmHg for Eagle Claw VIII, 19 (range 9-65) mmHg for endoclips, and 78 (range 63-110) mmHg for surgical suturing. The bursting pressures for surgical suturing and Eagle Claw VIII were significantly higher than that of endoclips (P < 0.001 for both surgical suturing vs. endoclips and Eagle Claw VIII vs. endoclips). The median scores for technical difficulties was not significantly different between endoclips and Eagle Claw VIII [9.5 (range 7-10) vs. 10 (range 8.5-10); P = 0.073]. CONCLUSIONS: The results indicated that closure of gastrotomy by Eagle Claw VIII could withstand higher endoluminal pneumatic bursting pressure than endoclips. The performance of endoscopic suturing with Eagle Claw is still difficult, and further refinement of the endoscopic suturing device is necessary for clinical application.

Direct incision versus submucosal tunneling as a method of creating transgastric accesses for natural orifice transluminal endoscopic surgery (NOTES) peritoneoscopy: randomized controlled trial.

AIM: The optimal approach for creating accesses for transgastric peritoneoscopy is still uncertain. The present study aims to assess the feasibility of carrying out transgastric submucosal tunnel (SMT) peritoneoscopy and to determine whether this approach improves or restricts access to various sectors within the peritoneal cavity. METHODS: This was a randomized comparative study carried out in an in-vivo survival porcine model. Sixty-six beads in six swine were visualized and touched via gastrotomies created by either direct incision (DI) or SMT. The influence of the type of gastrotomy on improving or restricting access to particular sites within the peritoneal cavity for natural orifice transluminal endoscopic surgery (NOTES) peritoneoscopy was compared. The main outcome measurements were localization score of beads, overall procedural time, morbidities and mortalities. RESULTS: A significantly higher mean (SD) localization score was observed in peritoneoscopies carried out in the DI group (P < 0.001). Both the visualization and the touching scores were significantly better with the DI technique, and the overall yield of NOTES peritoneoscopy with DI and SMT were 72.73% and 60.6%, respectively (P = 0.043). Significantly more beads that were not touched in the SMT group were located in the sub-phrenic area (P = 0.013). The overall procedural time was significantly shorter in the DI group (P = 0.004). No major morbidities or mortalities occurred in any procedures. CONCLUSIONS: SMT resulted in lower visualization and touching scores for transgastric NOTES peritoneoscopy. Alternate methods to improve the diagnostic yield to the sub-phrenic area are required.

Peroral endoscopic myotomy for treatment of achalasia: from bench to bedside (with video).

BACKGROUND: Peroral endoscopic myotomy (POEM) is a novel approach to performing esophageal myotomy through a long submucosal tunnel. OBJECTIVE: This study aimed to investigate the feasibility and safety of POEM for treatment of achalasia. DESIGN: Preclinical animal study and prospective clinical study. PATIENTS: Consecutive patients diagnosed with achalasia with high-resolution manometry. INTERVENTIONS: POEM was standardized for preclinical and clinical studies. After submucosal injection, a mucosal incision was made 15 cm above the gastroesophageal junction (GEJ). A long submucosal tunnel was created to extend below the GEJ. The endoscopic myotomy started 10 cm above and extended 2 cm below the GEJ. We first conducted a preclinical animal study to confirm the safety of POEM. POEM was then performed for the treatment of achalasia in humans. MAIN OUTCOME MEASUREMENTS: Relief from dysphagia assessed by the dysphagia score and Eckhardt score. High-resolution manometry and pH monitoring were performed to evaluate the posttreatment effects and esophageal acid exposure. RESULTS: Seven 30-kg porcine models underwent POEM in the survival study. All of the pigs survived except 1, which sustained pneumomediastinum. POEM was performed for the treatment of achalasia in 16 patients. The mean operating time was 117.0 ± 34.1 minutes. All patients tolerated food on day 2, with a contrast study confirming no leakage. The median follow-up was 176.5 days (range 98-230 days). The postoperative basal lower esophageal sphincter pressure was significantly reduced (mean reduction, 13.9 ± 14.5 mm Hg; P = .005) and 4-second integrated relaxation pressure of the GEJ (mean reduction, 10.1 ± 7.4 mm Hg; P = .001). Of these patients, 58.3% had a normalized 4-second integrated relaxation pressure, whereas 20% had excessive esophageal acid exposure after the procedure. There was a significant improvement in quality of life 6 months after POEM measured by the Short Form-36 questionnaire. LIMITATION: Small sample size. CONCLUSIONS: POEM is a feasible, safe, and effective treatment for achalasia.