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.

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.

Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver.

Obesity is a major risk factor for cancers including hepatocellular carcinoma (HCC) that develops from a background of non-alcoholic fatty liver disease (NAFLD). Hypercholesterolemia is a common comorbidity of obesity. Although cholesterol biosynthesis mainly occurs in the liver, its role in HCC development of obese people remains obscure. Using high-fat high-carbohydrate diet-associated orthotopic and spontaneous NAFLD-HCC mouse models, we found that hepatic cholesterol accumulation in obesity selectively suppressed natural killer T (NKT) cell-mediated antitumor immunosurveillance. Transcriptome analysis of human liver revealed aberrant cholesterol metabolism and NKT cell dysfunction in NAFLD patients. Notably, cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to prevent obesogenic diet-promoted HCC development. Moreover, suppression of hepatic cholesterol biosynthesis by a mammalian target of rapamycin (mTOR) inhibitor vistusertib preceded tumor regression, which was abolished by NKT inactivation but not CD8+ T cell depletion. Mechanistically, sterol regulatory element-binding protein 2 (SREBP2)-driven excessive cholesterol production from hepatocytes induced lipid peroxide accumulation and deficient cytotoxicity in NKT cells, which were supported by findings in people with obesity, NAFLD and NAFLD-HCC. This study highlights mTORC1/SREBP2/cholesterol-mediated NKT dysfunction in the tumor-promoting NAFLD liver microenvironment, providing intervention strategies that invigorating NKT cells to control HCC in the obesity epidemic.

Effects of long-term rofecoxib on gastric intestinal metaplasia: results of a randomized controlled trial.

PURPOSE: Gastric cancer and its premalignant gastric lesion, intestinal metaplasia (IM), frequently express cyclooxygenase-2 (COX-2) at high levels. We tested whether long-term use of specific COX-2 inhibitors regress gastric IM. EXPERIMENTAL DESIGN: This is a double-blind, randomized, placebo-controlled trial. Individuals with confirmed IM and Helicobacter pylori clearance were randomized to receive rofecoxib 25 mg daily or placebo. Endoscopy was done at baseline, at the end of year 1, and at the end of year 2, with multiple biopsies taken from the antrum and corpus. The primary end point was the proportion of subjects with regression of IM. Secondary end points were the severity of other histologic variables and the proportion of subjects with complete regression of IM. RESULTS: Two-hundred and thirteen subjects with confirmed IM were randomized. The proportion of subjects with the regression of IM did not differ significantly between rofecoxib and placebo groups (antrum, 24.5% versus 26.9%; P = 0.74; corpus, 4.3% versus 2.2%; P = 0.68). Patients on rofecoxib (19.1%) and on placebo (16.1%) had no IM detected in the stomach (P = 0.59). There was also no significant difference in the severity of IM between the two treatment groups (P >or= 0.3). CONCLUSIONS: There was no trend to suggest that treatment with rofecoxib for 2 years resulted in the regression of gastric IM. Although our findings cast doubt on the reversibility of gastric IM by COX-2 inhibitor, further studies are needed to establish the role of COX-2 inhibitors in different stages of gastric carcinogenesis.

Risk factors associated with the development of intestinal metaplasia in first-degree relatives of gastric cancer patients.

Family relatives of gastric cancer patients have a higher risk of gastric cancer and premalignant gastric lesions. We sought to determine the risk factors associated with the presence of intestinal metaplasia in a large cohort of gastric cancer relatives. First-degree relatives of gastric cancer patients were invited for screening gastroscopy. Endoscopic gastric biopsies were obtained from the antrum and corpus. Gastric biopsies were analyzed for Helicobacter pylori infection, severity of inflammation, and presence of intestinal metaplasia. Stepwise logistic regressions were used to identify for risk factors associated with presence of intestinal metaplasia in cancer relatives. Two hundred seventy cancer relatives underwent screening endoscopy (median age, 42; 47% male and 48% siblings). Among them, 161 (59.6%) were H. pylori positive and 81 (30%) had confirmed intestinal metaplasia. The following factors were found to be associated with the presence of intestinal metaplasia: age, male sex, H. pylori infection, birth order, alcohol use, siblings with stomach cancer, childhood living conditions, and water supply. Individuals with intestinal metaplasia had more severe acute and chronic inflammation in the antrum and corpus (P < 0.003). With multiple logistic regression, H. pylori infection [odds ratio (OR), 3.23], male gender (OR, 2.09), age (OR, 1.07), and a history of gastric cancer in siblings (OR, 1.91) were independent factors associated with the development of intestinal metaplasia in cancer relatives. In conclusion, we have identified risk factors associated with gastric intestinal metaplasia in stomach cancer relatives, which may be useful in the understanding of gastric carcinogenesis in these high-risk individuals.

Ghrelin level and weight loss after laparoscopic sleeve gastrectomy and gastric mini-bypass for Prader-Willi syndrome in Chinese.

Prader-Willi syndrome (PWS) is a chromosomal disorder characterized by the presence of hyperghrelinemia, hyperphagia, and obesity. The optimal treatment for PWS patient remains controversial. Here, we present our experience of treating PWS with laparoscopic mini-gastric bypass (LMGBP) and laparoscopic sleeve gastrectomy (LSG). Three patients with genetic diagnosis of PWS and body mass index (BMI) greater than 40 kg/m(2) were referred for bariatric surgery. All of them had completed 2-year postoperative follow-up. Body weight, BMI, and ghrelin levels were recorded before and after surgery. They were two females and one male. Their age ranged from 15 to 23 years old, and the mean BMI was 46.7 kg/m(2) (range 44-50). Two patients underwent LSG and one patient underwent LMGBP. After a median follow-up of 33 months (range 24-36 months), mean weight loss and percentage of excessive weight loss at 2 years were 32.5 kg (24.9-38.3 kg) and 63.2 % (range 50.5-86.2 %), respectively. The mean fasting active ghrelin level decreased from 1,134.2 pg/ml preoperatively to 519.8 pg/ml 1 year after surgery. No major complication was observed. Iron deficiency anemia was observed in the patient who underwent LMGBP. Significant reduction of body weight and level of serum ghrelin can be achieved with minimal morbidity by LSG or LMGBP in patients with PWS.

Helicobacter pylori infection in 1st degree relatives of Chinese gastric cancer patients.

OBJECTIVE: Familial aggregation of gastric cancer has been linked to familial clustering of Helicobacter pylori infection. Patterns and risk factors associated with H. pylori infection were investigated in 1st degree relatives of Chinese gastric cancer patients. MATERIAL AND METHODS: Gastric cancer relatives were invited for screening endoscopy. H. pylori infection was diagnosed by endoscopic and serological methods. RESULTS: Among the 270 cancer relatives examined, 161 (59.6%) were found to be infected with H. pylori. The prevalence of infection in cancer relatives was significantly higher than age- and gender-matched dyspeptic control (45.5%, p=0.0006). The mean age of H. pylori-infected relatives was significantly older than that of non-infected relatives (43.9 versus 38.3 years; p<0.001). The prevalence of H. pylori infection was higher in those with more siblings (p=0.013, chi(2) test for trend). Moreover, individuals whose siblings had stomach cancer were more likely to have H. pylori infection than those with a parental history of cancer (68.2% versus 51.8%, p=0.007). In contrast, the youngest sibling had a significantly lower H. pylori infection rate than other siblings (39.2% versus 64.2%, p=0.001). Using multiple logistic regression, it was found that age >45 years (OR=1.8; 95% CI, 1.02-3.3) and a history of gastric cancer in siblings (OR=1.9; 95% CI, 1.06-3.3) were independent risk factors for H. pylori infection, and that the youngest sibling in the family had a reduced risk (OR=0.45; 95% CI, 0.24-0.84). CONCLUSIONS: This study identifies the patterns and risk factors for H. pylori in gastric cancer relatives, which may shed light on the evolving epidemiology of H. pylori infection in Chinese patients.