Anthony N. Kalloo

Flexible transgastric peritoneoscopy: a novel approach to diagnostic and therapeutic interventions in the peritoneal cavity

BACKGROUND A novel endoscopic peroral transgastric approach to the peritoneal cavity was tested in a porcine model in acute and long-term survival experiments. METHODS Transgastric peritoneoscopy was evaluated in 50-kg pigs. After upper endoscopy, the peritoneal cavity was accessed by needle-knife puncture of the gastric wall, followed by extension of the incision either with a pull-type sphincterotome or by balloon dilation. The peritoneal cavity was examined, and a liver biopsy specimen was obtained. The gastric wall incision was closed with clips. OBSERVATIONS Twelve acute and 5 survival experiments were performed. Both techniques of gastric wall incision were without complication. The acute experiments demonstrated the technical feasibility of the approach. In the survival experiments, all pigs recovered and gained weight. CONCLUSIONS The peroral transgastric approach to peritoneal cavity technically is feasible and has the potential to be an alternative to laparoscopy and laparotomy.

ASGE/SAGES Working Group on Natural Orifice Translumenal Endoscopic Surgery

The growing capabilities of therapeutic flexible endoscopy have ushered in a new era in the treatment of gastrointestinal conditions. Refinements in laparoscopic surgery have progressed to the point that complex surgical procedures, such as gastric bypass, can now be performed in a minimally invasive fashion. These trends have set the stage for the development of even less invasive methods to treat conditions in both the gut lumen and in the peritoneal cavity. It seems feasible that major intraperitoneal surgery may one day be performed without skin incisions. The natural orifices may provide the entry point for surgical interventions in the peritoneal cavity, thereby avoiding abdominal wall incisions. In the first published description, Kalloo et al. [1] demonstrated the feasibility and safety of a per-oral transgastric endoscopic approach to the peritoneal cavity with long-term survival in a porcine model. This was soon followed by other transgastric peritoneal procedures in the porcine model, including tubal ligation, [2] cholecystectomy, [3] gastrojejunostomy, [4] splenectomy, [5] and oophorectomy with tubectomy [6, 7]. Although there are no publications, Rao et al. have described transgastric appendectomy in humans (personal communication). There have been two excellent editorials on this potentially emerging field. [8, 9] To discuss this vision, 14 leaders from the American Society of Gastrointestinal Endoscopy (ASGE) and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) met in New York City on July 22 and 23, 2005. The participants are listed in Table 1. All agreed that Translumenal Endoscopic Surgery could offer significant benefits to patients such as less pain, faster recovery, and better cosmesis than current laparoscopic techniques. The group identified the barriers that needed to be surmounted for the development of translumenal endoscopic intraperitoneal surgery and developed a list of next steps and guidelines to move this concept ahead.

Diagnosis and management of primary sclerosing cholangitis

Preamble This guideline has been approved by the American Association for the Study of Liver Diseases and represents the position of the Association. These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of the recentlypublished world literature on the topic (Medline search); (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines1; (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association Policy Statement on Guidelines2; and (4) the experience of the authors in the specified topic. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventative aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the available evidence supporting the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1).3 The strength of recommendations in the GRADE system are classified as strong (class 1) or weak (class 2). The quality of evidence supporting strong or weak recommendations is designated by one of three levels: high (level A), moderate (level B), or low-quality (level C).

Intrasphincteric Botulinum Toxin for the Treatment of Achalasia

BACKGROUND Achalasia is a disorder of swallowing in which the lower esophageal sphincter fails to relax. We report the use of botulinum toxin, a paralytic agent, for the treatment of this condition. METHODS In a double-blind trial, 21 patients with achalasia received either 80 units of botulinum toxin or placebo, injected endoscopically into the lower esophageal sphincter. One week later, the response to treatment was assessed on the basis of changes in the symptom scores (measured on a scale from 0 to 9), pharyngoesophagograms, and results of esophageal manometric and scintigraphic studies. Patients who received placebo initially were subsequently treated with botulinum toxin. After six months, esophageal scintigraphy was repeated. RESULTS One week after treatment, the mean decrease in the symptom score was 5.4 points for the patients treated with botulinum toxin and 0.5 point for the placebo group (P = 0.001). The mean decrease in the pressure of the lower esophageal sphincter was 33 percent in the treatment group, as compared with a mean increase of 12 percent in the placebo group (P = 0.02), and the mean increase in the width of the opening of the lower esophageal sphincter was 204 percent in the treatment group, as compared with a mean decrease of 14 percent in the placebo group (P = 0.02). Nineteen of the 21 patients treated with botulinum toxin had symptomatic improvement initially; after six months 14 patients were still in remission. This improvement was accompanied by a decrease in esophageal retention that was sustained at six months (46 percent, as compared with a pretreatment value of 77 percent; P = 0.04). There were no serious adverse effects. CONCLUSIONS Injection of botulinum toxin into the lower esophageal sphincter is an effective, safe, and simple method of treatment for achalasia, with results that are sustained for several months.

Endoscopic gastrojejunostomy with survival in a porcine model

BACKGROUND We have previously reported the feasibility and the safety of an endoscopic transgastric approach to the peritoneal cavity in a porcine model. We now report successful performance of endoscopic gastrojejunostomy with survival. METHODS All procedures were performed on 50-kg pigs, with the pigs under general anesthesia, in aseptic conditions with sterilized endoscopes and accessories. The stomach was irrigated with antibiotic solution, and a gastric incision was performed with a needle-knife and a sphincterotome. A standard upper endoscope was advanced through a sterile overtube into the peritoneal cavity. A loop of jejunum was identified, was retracted into the stomach, and was secured with sutures while using a prototype endoscopic suturing device. An incision was made into the jejunal loop with a needle-knife, and the filet-opened ends of the jejunal wall were secured to the gastric wall with a second line of sutures, completing the gastrojejunostomy. OBSERVATIONS Two pigs survived for 2 weeks. Endoscopy and a radiographic contrast study performed after gastrojejunostomy revealed a patent anastomosis with normal-appearing gastric and jejunal mucosa. Postmortem examination demonstrated a well-healed anastomosis without infection or adhesions. CONCLUSIONS The endoscopic transgastric approach to create a gastrojejunostomy is technically feasible and can be performed, with survival, in a porcine model.

Peroral transgastric endoscopic ligation of fallopian tubes with long-term survival in a porcine model.

BACKGROUND We have previously reported the feasibility and safety of the peroral transgastric endoscopic approach for diagnostic peritoneoscopy, liver biopsy, and gastrojejunostomy with long-term survival in a porcine model. This approach eliminates incisions of the abdominal wall, providing a less invasive alternative to diagnostic and therapeutic laparoscopy. We now report successful performance of peroral endoscopic transgastric ligation of Fallopian tubes with long-term survival in a porcine model. METHODS Six female 50-kg pigs had general anesthesia and irrigation of the stomach with an antibiotic solution. Gastric puncture was performed with needleknife electrocautery followed by balloon dilatation of the tract with 20-mm TTS dilating balloon (Microvasive). A standard upper endoscope that underwent high-level disinfection and gas sterilzation was advanced into the peritoneal cavity through a sterile overtube. Both Fallopian tubes were identified and one was ligated using Olympus Endoloops. The other patent tube served as a control. Tubal patency was evaluated by hysterosalpingogram before and after ligation. After a follow-up period of 2-3 weeks, the pigs were sacrificed for postmortem examination. RESULTS The Fallopian tubes were easily accessed, identified and ligated in all 6 pigs. In each pig, fluoroscopy confirmed complete obstruction of the ligated tube with preserved patency of the other tube. All pigs survived well and ate heartily without any ill-effects. Postmortem examination did not reveal any peritonitis or intra-abdominal adhesions. The Endoloops were in place with complete obstruction of the ligated tubes and patency of the controls. Histopathologic examination of the tubes showed chronic inflammatory infiltrates without abscesses. CONCLUSIONS The peroral endoscopic transgastric approach to ligation of the Fallopian tubes with long-term survival is technically feasible and safe in a porcine model. The endoscopic transgastric approach to the peritoneal cavity has potential for a wide array of diagnostic and therapeutic procedures.

Transgastric endoscopic splenectomy: is it possible?

BackgroundWe have previously reported the feasibility of diagnostic and therapeutic peritoneoscopy including liver biopsy, gastrojejunostomy, and tubal ligation by an oral transgastric approach. We present results of per-oral transgastric splenectomy in a porcine model. The goal of this study was to determine the technical feasibility of per-oral transgastric splenectomy using a flexible endoscope.MethodsWe performed acute experiments on 50-kg pigs. All animals were fed liquids for 3 days prior to procedure. The procedures were performed under general anesthesia with endotracheal intubation. The flexible endoscope was passed per orally into the stomach and puncture of the gastric wall was performed with a needle knife. The puncture was extended to create a 1.5-cm incision using a pull-type sphincterotome, and a double-channel endoscope was advanced into the peritoneal cavity. The peritoneal cavity was insufflated with air through the endoscope. The spleen was visualized. The splenic vessels were ligated with endoscopic loops and clips, and then mesentery was dissected using electrocautery.ResultsEndoscopic splenectomy was performed on six pigs. There were no complications during gastric incision and entrance into the peritoneal cavity. Visualization of the spleen and other intraperitoneal organs was very good. Ligation of the splenic vessels and mobilization of the spleen were achieved using commercially available devices and endoscopic accessories.ConclusionsTransgastric endoscopic splenectomy in a porcine model appears technically feasible. Additional long-term survival experiments are planned.

DNA methylation alterations in the pancreatic juice of patients with suspected pancreatic disease

Molecular markers of pancreatic neoplasia could aid in the evaluation of visible pancreatic lesions and indicate neoplasia invisible to imaging. We evaluated methylation-specific PCR (MSP) assays that detect aberrantly methylated DNA for their use as markers of pancreatic neoplasia. Methylation analysis was done on pancreatic juice collected endoscopically or surgically from 155 individuals with suspected pancreatic disease: 56 patients had pancreatic ductal adenocarcinoma, 17 had intraductal papillary mucinous neoplasms, 26 had symptomatic chronic pancreatitis, 12 controls lacked evidence of pancreatic disease, and 44 were asymptomatic individuals at increased risk of developing familial pancreatic cancer undergoing screening for pancreatic neoplasia. Pancreatic juice DNA was analyzed for promoter methylation using conventional MSP assays for 17 genes. For six genes, pancreatic juice methylation was quantified using real-time quantitative MSP (QMSP; Cyclin D2, FOXE1, NPTX2, ppENK, p16, and TFPI2). Quantifying pancreatic juice methylation using QMSP with a cutoff of >1% methylated DNA could better predict pancreatic cancer than detecting methylation using conventional MSP. In the endoscopic group, 9 of 11 patients with pancreatic cancer, but none of 64 individuals without neoplasia had > or =1% methylation for two or more of the best five QMSP assays (82% sensitivity and 100% specificity; P < 0.0001). The prevalence of pancreatic juice methylation in patients with chronic pancreatitis was less than in patients with pancreatic cancer but higher than in controls and similar to high-risk individuals. The detection and quantification of aberrantly methylated DNA in pancreatic juice is a promising approach to the diagnosis of pancreatic cancer.

Effect of a retrograde-viewing device on adenoma detection rate during colonoscopy: the TERRACE study

BACKGROUND Although colonoscopy is currently the optimal method for detecting colorectal polyps, some are missed. The Third Eye Retroscope provides an additional retrograde view that may detect polyps behind folds. OBJECTIVE To determine whether the addition of the Third Eye Retroscope to colonoscopy improves the adenoma detection rate. DESIGN Prospective, multicenter, randomized, controlled trial. SETTING Nine European and U.S. centers. PATIENTS Of 448 enrolled subjects, 395 had data for 2 procedures. INTERVENTIONS Subjects underwent same-day tandem examinations with standard colonoscopy (SC) and Third Eye colonoscopy (TEC). Subjects were randomized to SC followed by TEC or TEC followed by SC. MAIN OUTCOME MEASUREMENTS Detection rates for all polyps and adenomas with each method. RESULTS In the per-protocol population, 173 subjects underwent SC and then TEC, and TEC yielded 78 additional polyps (48.8%), including 49 adenomas (45.8%). In 176 subjects undergoing TEC and then SC, SC yielded 31 additional polyps (19.0%), including 26 adenomas (22.6%). Net additional detection rates with TEC were 29.8% for polyps and 23.2% for adenomas. The relative risk of missing with SC compared with TEC was 2.56 for polyps (P < .001) and 1.92 for adenomas (P = .029). Mean withdrawal times for SC and TEC were 7.58 and 9.52 minutes, respectively (P < .001). The median difference in withdrawal times was 1 minute (P < .001). The mean total procedure times for SC and TEC were 16.97 and 20.87 minutes, respectively (P < .001). LIMITATIONS Despite randomization and a large cohort, there was disparity in polyp prevalence between the 2 groups of subjects. CONCLUSION The Third Eye Retroscope increases adenoma detection rate by visualizing areas behind folds. ( CLINICAL TRIAL REGISTRATION NUMBER NCT01044732.).

Treatment of achalasia with intrasphincteric injection of botulinum toxin. A pilot trial.

Achalasia is a disorder characterized by a failure of the lower esophageal sphincter to relax with swallowing and by a lack of esophageal peristalsis. The sphincteric abnormalities in achalasia are thought to be caused by a selective loss of inhibitory neurons in the myenteric plexus, resulting in the relatively unopposed excitation of the smooth muscle by acetylcholine and other mediators. Our previous studies in animals [1] have shown that locally injected botulinum toxin, a potent inhibitor of acetylcholine release, can reduce lower esophageal sphincter tone. We report our initial experience with this agent for the treatment of achalasia in humans. Methods Ten symptomatic adult patients with achalasia were prospectively evaluated by barium video-esophagograms, esophageal scintigraphy, and manometry. Clinical response was evaluated by scoring three symptoms (dysphagia, regurgitation, and chest pain) on a scale ranging from 0 to 3 (0 = none, 1 = occasional, 2 = daily, and 3 = with each meal) [2]. At the time of upper endoscopy, 80 units of botulinum toxin was injected through a 5-mm sclerotherapy needle into the lower esophageal sphincter as estimated by endoscopy (1 mL of a 20 U/mL solution in each of the four quadrants). Patients were re-evaluated 1 week later. The study was approved by the Johns Hopkins Hospital Institutional Review Board. Statistical analysis was done using the student t-test. Unless otherwise stated, results are expressed as the mean SE. Results The study group consisted of 4 men and 6 women whose mean age was 51 years (range, 24 to 80 years). Patients had been symptomatic for an average of 4.7 years, during which time most patients had had esophageal dilatation at least once. One week after treatment, clinical scores for the 10 patients decreased from 5.3 0.4 to 0.7 0.3 (P < 0.001), and all three symptoms improved significantly. Seven patients became asymptomatic after one injection. Two patients with initially modest improvement required a second injection for a satisfactory response. One patient remained unsatisfied with the clinical response despite three injections; this treatment was thus considered a failure. All objective measurements of esophageal function improved. In 7 patients for whom results were available, lower esophageal sphincter pressure decreased from 46.0 5.5 mm Hg to 26.0 3.7 mm Hg (P = 0.007); in 9 patients, esophageal diameter decreased from 5.2 0.7 cm to 4.3 0.7 cm (P = 0.002); and in 9 patients, 5-minute esophageal retention decreased from 75% 8.9% to 56% 13% (P = 0.02). Of the nine initial responders, three relapsed approximately 2 months later. The other six patients remained asymptomatic after a single injection of botulinum toxin for a median duration of about 12 months (range, 11 to 14 months). Most patients gained weightin one case, as much as 16 kg. Clinical remission was accompanied by a sustained improvement in esophageal retention, as measured in two patients (the mean 5-minute retention at an average of 6 months after treatment was 26.3% compared with 38.5% before treatment; P = 0.01). The symptoms of three patients recurred approximately 1 year after treatment. Two of these patients have since been re-treated with botulinum toxin, and their symptoms completely resolved once again (Figure 1). No adverse effects were seen in any patient. No esophagitis was seen at follow-up endoscopy 1 week after injection. Figure 1. The change in esophageal clearance in one patient in response to injections of botulinum toxin. Discussion Traditional treatment of achalasia consists of balloon dilatation or myotomy. Although these procedures may relieve symptoms, they carry a significant risk for complications, notably perforation and gastroesophageal reflux [3-5]. A need therefore exists for alternative ways to treat this condition. Our preliminary open-label trial of botulinum toxin in patients with achalasia did not use control injections. Nevertheless, our results are encouraging and suggest that this treatment is potentially safe and relatively simple. An initial response was seen in 9 of the 10 patients (90%); 60% had a satisfactory long-term response (defined arbitrarily as >6 months). This compares favorably to the response rates after a single pneumatic dilatation (approximately 60%) and surgery (64% to 95%) [2, 6, 7]. The response of symptoms in our patients was accompanied by significant improvement in all objective esophageal test results. Most importantly, lower esophageal sphincter pressure decreased by about 50%, a change equivalent to that reported after balloon dilatation (41% to 50%) [2, 8, 9]. Symptoms seem to recur in the long-term responders about 1 year after the initial injection. However, it appears that in these patients, further injections at this stage retain their efficacy. Pneumatic dilatation also has a high rate of relapse after the first dilatation [2]. This necessitates further dilatations, each with its own risk for perforation. Botulinum toxin therapy is therefore an attractive alternative to dilatation, even if repeated injections are required. Although locally injected botulinum toxin has been used in several disorders of skeletal muscle spasm [10], this is the first report of its use in a disorder of gastrointestinal smooth muscle. Further studies are needed to confirm the initial promise of this new approach to treating achalasia.