A sub-10-nm, folic acid-conjugated gold nanoparticle as self-therapeutic treatment of tubulointerstitial fibrosis.

Nanomedicines for treating chronic kidney disease (CKD) are on the horizon, yet their delivery to renal tubules where tubulointerstitial fibrosis occurs remains inefficient. We report a folic acid-conjugated gold nanoparticle that can transport into renal tubules and treat tubulointerstitial fibrosis in mice with unilateral ureteral obstruction. The 3-nm gold core allows for the dissection of bio-nano interactions in the fibrotic kidney, ensures the overall nanoparticle (~7 nm) to be small enough for glomerular filtration, and naturally inhibits the p38α mitogen-activated protein kinase in the absence of chemical or biological drugs. The folic acids support binding to selected tubule cells with overexpression of folate receptors and promote retention in the fibrotic kidney. Upon intravenous injection, this nanoparticle can selectively accumulate in the fibrotic kidney over the nonfibrotic contralateral kidney at ~3.6% of the injected dose. Delivery to the fibrotic kidney depends on nanoparticle size and disease stage. Notably, a single injection of this self-therapeutic nanoparticle reduces tissue degeneration, inhibits genes related to the extracellular matrix, and treats fibrosis more effectively than standard Captopril therapy. Our data underscore the importance of constructing CKD nanomedicines based on renal pathophysiology.

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.

Endosonography-guided gallbladder drainage versus percutaneous cholecystostomy in very high-risk surgical patients with acute cholecystitis: an international randomised multicentre controlled superiority trial (DRAC 1).

OBJECTIVE: The optimal management of acute cholecystitis in patients at very high risk for cholecystectomy is uncertain. The aim of the current study was to compare endoscopic ultrasound (EUS)-guided gallbladder drainage (EUS-GBD) to percutaneous cholecystostomy (PT-GBD) as a definitive treatment in these patients under a randomised controlled trial. DESIGN: Consecutive patients suffering from acute calculous cholecystitis but were at very high-risk for cholecystectomy were recruited. The primary outcome was the 1-year adverse events rate. Secondary outcomes include technical and clinical success, 30-day adverse events, pain scores, unplanned readmissions, re-interventions and mortalities. RESULTS: Between August 2014 to February 2018, 80 patients were recruited. EUS-GBD significantly reduced 1 year adverse events (10 (25.6%) vs 31 (77.5%), p<0.001), 30-day adverse events (5 (12.8%) vs 19 (47.5%), p=0.010), re-interventions after 30 days (1/39 (2.6%) vs 12/40 (30%), p=0.001), number of unplanned readmissions (6/39 (15.4%) vs 20/40 (50%), p=0.002) and recurrent cholecystitis (1/39 (2.6%) vs 8/40 (20%), p=0.029). Postprocedural pain scores and analgesic requirements were also less (p=0.034). The technical success (97.4% vs 100%, p=0.494), clinical success (92.3% vs 92.5%, p=1) and 30-day mortality (7.7% vs 10%, p=1) were statistically similar. The predictor to recurrent acute cholecystitis was the performance of PT-GBD (OR (95% CI)=5.63 (1.20-53.90), p=0.027). CONCLUSION: EUS-GBD improved outcomes as compared to PT-GBD in those patients that not candidates for cholecystectomy. EUS-GBD should be the procedure of choice provided that the expertise is available after a multi-disciplinary meeting. Further studies are required to determine the long-term efficacy. TRIAL REGISTRATION NUMBER: NCT02212717.

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.

Electroacupuncture-reduced sedative and analgesic requirements for diagnostic EUS: a prospective, randomized, double-blinded, sham-controlled study.

BACKGROUND AND AIMS: The role of electroacupuncture (EA) in reducing sedative and analgesic requirements during EUS is uncertain. The aim of this study was to investigate the efficacy of EA in reducing procedure-related pain and discomfort during EUS. METHODS: This was a double-blinded randomized controlled study conducted between March 2014 and July 2016. Consecutive patients who were scheduled for diagnostic EUS were recruited and randomized to receive EA or sham-electroacupuncture (SA). The primary outcome was the dosage of propofol used. Other outcome measurements included pain scores, anxiety scores, satisfaction scores, patients' willingness to repeat the procedure, total procedure time, and adverse events. RESULTS: A total of 128 patients were recruited to the study. The patients who received EA had significantly fewer requirements for patient-controlled sedation and analgesia (PCA). The median (interquartile range) number of demands for PCA (2 [1-5] vs 16.5 [8.5-33.8]; P < .001), the number of successful demands (2 [1-4] vs 9 [5.3-13]; P < .001), and the total dose of propofol (0.15 [0.08-0.34] vs 0.77 [0.38-1.09]; P < .001) and alfentanil (0.38 [0.20-0.86] vs 1.92 [0.94-2.72]; P < .001) were all significantly less. Patients who received EA also had significantly lower procedural pain scores and anxiety scores (P < .001), and higher satisfaction scores (P < .001), and they were more willing to repeat the procedure (P < .001). Being in the SA group and the procedure time were significant predictors of increased PCA demands (P < .001 and P = .009, respectively). CONCLUSIONS: In conclusion, the use of EA reduced sedative and analgesia demands, improved patient experience, and was associated with a low risk of adverse events during diagnostic EUS. (Clinical trial registration number: NCT02066194.).

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.

Randomized trial of endoscopic sphincterotomy with balloon dilation versus endoscopic sphincterotomy alone for removal of bile duct stones.

BACKGROUND & AIMS: Limited endoscopic sphincterotomy with large balloon dilation (ESBD) is an alternative to endoscopic sphincterotomy (ES) for removing bile duct stones, but it is not clear which procedure is most effective. We compared the 2 techniques in removal of bile duct stones. METHODS: Between September 2005 and September 2011, 156 consecutive patients with suspected of having, or known to have, common bile duct stones were randomly assigned to groups that underwent ES or ESBD. Patients in the ESBD group underwent limited sphincterotomy (up to half of the sphincter) followed by balloon dilation to the size of the common bile duct or 15 mm, and patients in the ES group underwent complete sphincterotomy alone. Stones were then removed using standard techniques. The primary outcome was percentage of stones cleared, and secondary outcomes included procedural time, method of stone extraction, number of procedures required for stone clearance, morbidities and mortality within 30 days, and direct cost. RESULTS: There was no significant difference between groups in percentage of stones cleared (ES vs ESBD: 88.5% vs 89.0%). More patients in the ES group (46.2%) than the ESBD group (28.8%) required mechanical lithotripsy (P = .028), particularly for stones ≥15 mm (90.9% vs 58.1%; P = .002). Morbidities developed in 10.3% of patients in the ES group and 6.8% of patients in the ESBD group (P = .46). The cost of the hospitalization was also significantly lower in the ESBD group (P = .034). CONCLUSIONS: ESBD and ES clear bile stones with equal efficacy. However, ESBD reduces the need for mechanical lithotripsy and is less expensive; ClinicalTrials.gov number, NCT00164853.

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.

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.

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.

Ex vivo comparative study using the Endolifter® as a traction device for enhancing submucosal visualization during endoscopic submucosal dissection.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a technically demanding procedure, and exposure of the submucosa depends on the action of gravity and submucosal injection. The aim of the study was to investigate the effectiveness of the Endolifter(®) as a traction device for enhancing submucosal visualization during ESD. METHODS: This was a prospective ex vivo comparative study conducted between September 2010 and March 2011 in the Prince of Wales Hospital. Consecutive ESDs were performed by four experienced endoscopists in an ex vivo ESD model with or without the Endolifter(®). The Endolifter(®) allows simultaneous grasping, retracting and lifting of the mucosa during ESD, resulting in exposure of the submucosa. Each of the procedures were recorded and reviewed later by two independent assessors. The outcome measures included the proportion of time that the submucosa was visualized during the procedures (SM ratio), procedural times, perforation rates, amount of submucosal injections, and the difficulty of the procedure. RESULTS: Forty-eight gastric ESD procedures were performed on the model. The SM ratio was higher in the Endolifter(®) group (P = 0.007), particularly for lesions located at the antrum (P < 0.001). The time required for submucosal dissection and the total procedural time were also less in the Endolifter(®) group. The endoscopists rated the ESD procedures in the Endolifter(®) group as less difficult (P = 0.033). CONCLUSIONS: The Endolifter(®) improved submucosal visualization during gastric ESD and reduces the difficulty of performing the procedures. The device may improve the ease of performing ESD in low-volume centers or large mucosal lesions.

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.

Endoscopic submucosal dissection (ESD) compared with gastrectomy for treatment of early gastric neoplasia: a retrospective cohort study.

INTRODUCTION: This study aims to compare perioperative outcomes and oncological clearance of endoscopic submucosal dissection (ESD) versus gastrectomy for treatment of early gastric cancer (EGC). METHODS: This is a retrospective cohort study including all cases of EGC or severe dysplasia treated at a university-affiliated hospital from 1993 to 2010. Preoperative endoscopic ultrasound and image-enhanced endoscopy were employed to determine depth of invasion. Clinical outcomes including baseline demographics, pathology, postoperative complication, and hospital stay, as well as 3-year survival were compared. RESULTS: From 1993 to 2010, 114 patients with severe dysplasia or EGC were treated: 40 of them received gastrectomy, while 74 received ESD. There was no difference in age, gender, comorbidity or American Society of Anesthesiologists grade between the two groups. Of patients in the gastrectomy group, 92.5% presented with symptoms as compared with 27.0% of those treated by ESD (p < 0.001). More patients in the ESD group had atrophic gastritis (31.1 vs 10%; p = 0.009) and intestinal metaplasia (68.9 vs 55.0%; p = 0.04). Patients treated by gastrectomy sustained longer operative time [265 (150-360) min] when compared with ESD [89.6 (45-360) min; p < 0.001]. They also had longer median hospital stay [9.9 (6-26) days vs 3.0 (2-10) days; p < 0.001]. There was no perioperative mortality, but the overall complication rate was significantly higher in the gastrectomy group. The 3-year survival rate was 94.6% for ESD and 89.7% for gastrectomy group (log-rank test, p = 0.44). CONCLUSIONS: ESD achieved similar oncological outcomes when compared with radical gastrectomy for treatment of EGC. Patients receiving ESD had better perioperative outcomes in terms of operative time, complication rate, and hospital stay.

High prevalence of colorectal neoplasm in patients with non-alcoholic steatohepatitis.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) affects 20-40% of the general adult population. Due to shared risk factors, it is postulated that NAFLD patients have an increased risk of colorectal neoplasm and should be a target group for screening. The aim of this study was to examine the prevalence of colorectal neoplasm in NAFLD patients and the risk of colorectal neoplasm in relation to the severity of NAFLD histology. Design Cross-sectional study. SETTING: University hospital with case recruitment from the community and clinics. PATIENTS: Subjects aged 40-70 years were recruited for colonoscopic screening from two study cohorts: (1) community subjects; and (2) consecutive patients with biopsy proven NAFLD. In the community cohort, hepatic fat was measured by proton-magnetic resonance spectroscopy. MAIN OUTCOME MEASURES: Prevalence of colorectal adenomas. Advanced colorectal neoplasm was defined as cancer or adenomas with villous architecture or high grade dysplasia. RESULTS: NAFLD patients (N=199) had a higher prevalence of colorectal adenomas (34.7% vs 21.5%; p=0.043) and advanced neoplasms (18.6% vs 5.5%; p=0.002) than healthy controls (N=181). Thirteen of 29 (45%) NAFLD patients with advanced neoplasms had isolated lesions in the right sided colon. Among patients with biopsy proven NAFLD, patients with non-alcoholic steatohepatitis (N=49) had a higher prevalence of adenomas (51.0% vs 25.6%; p=0.005) and advanced neoplasms (34.7% vs 14.0%; p=0.011) than those with simple steatosis (N=86). After adjusting for demographic and metabolic factors, non-alcoholic steatohepatitis remained associated with adenomas (adjusted OR 4.89, 95% CI 2.04 to 11.70) and advanced neoplasms (OR 5.34, 95% CI 1.92 to 14.84). In contrast, the prevalence of adenomas and advanced neoplasms was similar between patients with simple steatosis and control subjects. CONCLUSIONS: Non-alcoholic steatohepatitis is associated with a high prevalence of colorectal adenomas and advanced neoplasms. The adenomas are found more commonly in the right sided colon. Colorectal cancer screening is strongly indicated in this high risk group.

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.

Randomized comparative trial of a novel one-step needle sphincterotome versus direct incision and balloon dilation used to create gastrotomies for natural orifice translumenal endoscopic surgery (NOTES) in the porcine model.

BACKGROUND: This study aimed to assess the feasibility, safety, and efficacy of a prototype device (the one-step needle sphincterotome) versus direct incision and balloon dilation for creating transgastric access to the peritoneal cavity in a porcine model. METHODS: In five swine, 24 gastrotomies were created using direct incision followed by balloon dilation (group A) or by the one-step needle sphincterotome (group B) in an in vivo nonsurvival model. The one-step needle sphincterotome is a novel instrument comprising two components including a retractable needleknife and a pull-type sphincterotome on the same instrument shaft, reducing the need to exchange instruments. RESULTS: The 24 gastrotomies created in the five swine all were successful. The mean time required for creation of a gastrotomy was 613.08 ± 289.64 s in group A and 310.58 ± 137.39 s in group B. The total procedural time was 830.42 ± 296.17 s in group A and 529 ± 143.97 s in group B. Both were significantly shorter in the prototype device group (P = 0.002). The mean length of gastrotomy, mean number of clips required for closure, and mean overall closure time were not significantly different. One swine from each group suffered morbidities and another experienced mortality. CONCLUSIONS: The one-step needle sphincterotome hastened the creation of gastrotomies for natural orifice translumenal endoscopic surgery (NOTES). The gastrotomies created by both procedures were effective means of gaining peritoneal access, and neither method demonstrated superiority in expediting closure. However, the initial blind transgastric incision by a needleknife may be associated with a risk of injuring surrounding structures.