Liquid nitrogen spray cryotherapy for eradication of dysplastic Barrett's esophagus: results from a multicenter prospective registry.

BACKGROUND AND AIMS: Liquid nitrogen spray cryotherapy (SCT) is an alternative to radiofrequency ablation (RFA) for eradication of dysplastic Barrett's esophagus (BE). We aimed to assess the safety, efficacy, and durability of SCT in a multicenter U.S. registry. METHODS: This is a multicenter prospective registry of adults with BE treated with truFreeze Spray Cryotherapy (Steris, Mentor, Ohio, USA) (4 community and 11 academic sites, 2013-2022). Complete eradication of intestinal metaplasia (CEIM) and dysplasia (CED) were assessed in BE with dysplasia or intramucosal adenocarcinoma. Kaplan-Meier analysis of CEIM and CED was performed. Hazard ratios for CEIM stratified by baseline risk factors were calculated. RESULTS: Among 138 subjects with low-grade dysplasia (24%), high-grade dysplasia (49%), and intramucosal adenocarcinoma (27%), 34% received prior RFA therapy. Subjects received a median of 2 SCT sessions. Adverse events were uncommon, with 5.5% reporting strictures and 0.7% a perforation. Rates of CEIM and CED, respectively, were 66% and 84% after 2 years and 67% and 92% after 3 years. In RFA-naïve patients, CEIM was 77% and CED was 96% at 3 years. Increasing BE length (per centimeter: adjusted hazard ratio, 0.90; 95% confidence interval, 0.83-0.96) and prior treatment with RFA (adjusted hazard ratio, 0.39; 95% confidence interval, 0.22-0.69) were associated with a lower rate of CEIM. Recurrence occurred in 8.8% (n = 6) at a mean follow-up of 2.5 years after CEIM. CONCLUSION: In this largest reported prospective cohort, liquid nitrogen SCT was safe and effective for the treatment of dysplastic and neoplastic BE. Response was lower in those with prior failed RFA; in that cohort, approximately 50% attained CEIM at 3 years.

Probe-based confocal laser endomicroscopy in the evaluation of dominant strictures in patients with primary sclerosing cholangitis: results of a U.S. multicenter prospective trial.

BACKGROUND AND AIMS: Patients with primary sclerosing cholangitis (PSC) and dominant biliary strictures carry increased risk for the development of cholangiocarcinoma. Although ERCP-based techniques including brush cytology and intraductal biopsy sampling represent first-line tissue sampling methods for dominant strictures, sensitivity is low. Probe-based confocal laser endomicroscopy (pCLE) offers microscopic-level imaging of subepithelial biliary mucosa. Because data regarding the use of pCLE in PSC are limited, we aimed to investigate its diagnostic performance in dominant strictures. METHODS: This was a multicenter prospective study involving PSC patients with dominant strictures. ERCP with pCLE was performed with use of the Miami classification (2+ criteria for malignant diagnosis) and Paris classification. Final malignant diagnoses required histopathologic confirmation, and benign diagnoses required a minimum of 1 year of follow-up without development of cancer. RESULTS: Fifty-nine patients (mean age, 49 years; 59% men) with 63 strictures were included in the study. Stricture locations included the common bile duct (31.7%), bifurcation (22.2%), and common hepatic duct (19%). Seven patients (11.9%) were found to have cholangiocarcinoma. The sensitivity and specificity of pCLE was 85.7% (95% confidence interval [CI], 42.1-99.6) and 73.1% (95% CI, 58.9-84.4), respectively. Within specific stricture locations, the highest sensitivity was seen at the bifurcation (100%; 95% CI, 2.5-100) and the right hepatic duct (100%; 95% CI, 29.2-100). The lowest sensitivities were seen at the common bile duct (25%; 95% CI, 5.5-57.2) and the left hepatic duct (28.6%; 95% CI, 3.7-70.9). CONCLUSIONS: In this prospective multicenter study, pCLE had a high sensitivity in detecting cholangiocarcinoma, but technical aspects of the probe may limit evaluation in the common bile duct and left hepatic duct. Further evaluation is needed to elucidate the role of pCLE in the algorithm of excluding neoplasia in biliary strictures associated with PSC. (Clinical trial registration number: NCT02736708.).

Evaluation of Serum Glycoprotein Biomarker Candidates for Detection of Esophageal Adenocarcinoma and Surveillance of Barrett's Esophagus.

Esophageal adenocarcinoma (EAC) is thought to develop from asymptomatic Barrett's esophagus (BE) with a low annual rate of conversion. Current endoscopy surveillance of BE patients is probably not cost-effective. Previously, we discovered serum glycoprotein biomarker candidates which could discriminate BE patients from EAC. Here, we aimed to validate candidate serum glycoprotein biomarkers in independent cohorts, and to develop a biomarker candidate panel for BE surveillance. Serum glycoprotein biomarker candidates were measured in 301 serum samples collected from Australia (4 states) and the United States (1 clinic) using previously established lectin magnetic bead array (LeMBA) coupled multiple reaction monitoring mass spectrometry (MRM-MS) tier 3 assay. The area under receiver operating characteristic curve (AUROC) was calculated as a measure of discrimination, and multivariate recursive partitioning was used to formulate a multi-marker panel for BE surveillance. Complement C9 (C9), gelsolin (GSN), serum paraoxonase/arylesterase 1 (PON1) and serum paraoxonase/lactonase 3 (PON3) were validated as diagnostic glycoprotein biomarkers in lectin pull-down samples for EAC across both cohorts. A panel of 10 serum glycoprotein biomarker candidates discriminated BE patients not requiring intervention (BE± low grade dysplasia) from those requiring intervention (BE with high grade dysplasia (BE-HGD) or EAC) with an AUROC value of 0.93. Tissue expression of C9 was found to be induced in BE, dysplastic BE and EAC. In longitudinal samples from subjects that have progressed toward EAC, levels of serum C9 were significantly (p < 0.05) increased with disease progression in EPHA (erythroagglutinin from Phaseolus vulgaris) and NPL (Narcissus pseudonarcissus lectin) pull-down samples. The results confirm alteration of complement pathway glycoproteins during BE-EAC pathogenesis. Further prospective clinical validation of the confirmed biomarker candidates in a large cohort is warranted, prior to development of a first-line BE surveillance blood test.

Improved classification of indeterminate biliary strictures by probe-based confocal laser endomicroscopy using the Paris Criteria following biliary stenting.

BACKGROUND AND AIMS: Probe-based confocal laser endomicroscopy (pCLE) using the Miami Criteria has improved classification of indeterminate biliary strictures. However, previous biliary stenting may result in their misclassification as malignant strictures. Inflammatory criteria were added to form the Paris Classification to prevent this misclassification and reduce false positives. The aim of this study was to assess if the Paris Classification was more accurate than the Miami Classification in classifying indeterminate biliary strictures after biliary stenting. METHODS: This was a retrospective observational study involving 21 patients with indeterminate biliary strictures from whom 27 pCLE video sequences were obtained (20 benign and seven malignant). Patients with and without prior biliary stenting underwent pCLE. Two investigators classified the strictures as malignant or benign using the Miami and Paris Classifications. Diagnostic accuracy, sensitivity (Se), and specificity (Sp) of endoscopic retrograde-guided pCLE were compared with final histopathology. RESULTS: In those without biliary stenting, the Miami Criteria resulted in Se 88%, Sp 75%, positive predictive value (PPV) 64%, negative predictive value (NPV) 92%, and accuracy 79%, while the Paris Classification resulted in Se 63%, Sp 88%, PPV 71%, NPV 82%, and accuracy 79%. In those with prior biliary stenting, the Miami Criteria resulted in Se 88%, Sp 36%, PPV 23%, NPV 93%, and accuracy 45%, while the Paris Classification resulted in Se 63%, Sp 73%, PPV 31%, NPV 91%, and accuracy 71%. The kappa statistic was 0.56. CONCLUSION: The Paris Classification improved specificity and accuracy of biliary stricture classification in those who had been previously stented and decreased the rate of misclassification of benign strictures as malignant.

Serum Glycoprotein Biomarker Discovery and Qualification Pipeline Reveals Novel Diagnostic Biomarker Candidates for Esophageal Adenocarcinoma.

We report an integrated pipeline for efficient serum glycoprotein biomarker candidate discovery and qualification that may be used to facilitate cancer diagnosis and management. The discovery phase used semi-automated lectin magnetic bead array (LeMBA)-coupled tandem mass spectrometry with a dedicated data-housing and analysis pipeline; GlycoSelector (http://glycoselector.di.uq.edu.au). The qualification phase used lectin magnetic bead array-multiple reaction monitoring-mass spectrometry incorporating an interactive web-interface, Shiny mixOmics (http://mixomics-projects.di.uq.edu.au/Shiny), for univariate and multivariate statistical analysis. Relative quantitation was performed by referencing to a spiked-in glycoprotein, chicken ovalbumin. We applied this workflow to identify diagnostic biomarkers for esophageal adenocarcinoma (EAC), a life threatening malignancy with poor prognosis in the advanced setting. EAC develops from metaplastic condition Barrett's esophagus (BE). Currently diagnosis and monitoring of at-risk patients is through endoscopy and biopsy, which is expensive and requires hospital admission. Hence there is a clinical need for a noninvasive diagnostic biomarker of EAC. In total 89 patient samples from healthy controls, and patients with BE or EAC were screened in discovery and qualification stages. Of the 246 glycoforms measured in the qualification stage, 40 glycoforms (as measured by lectin affinity) qualified as candidate serum markers. The top candidate for distinguishing healthy from BE patients' group was Narcissus pseudonarcissus lectin (NPL)-reactive Apolipoprotein B-100 (p value = 0.0231; AUROC = 0.71); BE versus EAC, Aleuria aurantia lectin (AAL)-reactive complement component C9 (p value = 0.0001; AUROC = 0.85); healthy versus EAC, Erythroagglutinin Phaseolus vulgaris (EPHA)-reactive gelsolin (p value = 0.0014; AUROC = 0.80). A panel of 8 glycoforms showed an improved AUROC of 0.94 to discriminate EAC from BE. Two biomarker candidates were independently verified by lectin magnetic bead array-immunoblotting, confirming the validity of the relative quantitation approach. Thus, we have identified candidate biomarkers, which, following large-scale clinical evaluation, can be developed into diagnostic blood tests. A key feature of the pipeline is the potential for rapid translation of the candidate biomarkers to lectin-immunoassays.

Endoscopic Therapy With Lumen-apposing Metal Stents Is Safe and Effective for Patients With Pancreatic Walled-off Necrosis.

BACKGROUND & AIMS: Endoscopic ultrasound-guided transmural drainage and necrosectomy have become the standard treatment for patients with pancreatic walled-off necrosis (WON). Lumen-apposing metal stents (LAMS) have shown success in the management of pancreatic fluid collections. However, there are few data on their specific roles in management of WON. We investigated the efficacy and safety of LAMS in treatment of WON. METHODS: We performed a retrospective multicenter case series of 124 patients with WON who underwent endoscopic transmural drainage by using LAMS at 17 tertiary care centers from January 2014 through May 2015. Patients underwent endoscopic ultrasound-guided cystogastrostomy or cystoenterostomy with placement of an LAMS into the WON collection. At the discretion of the endoscopist, we performed direct endoscopic necrosectomy, irrigation with hydrogen peroxide, and/or nasocystic drain placement. We performed endoscopic retrograde cholangiopancreatography with pancreatic duct stent placement when indicated. Concomitant therapies included direct endoscopic debridement (n = 78), pancreatic duct stent placement for leak (n = 19), hydrogen peroxide-assisted necrosectomy (n = 38), and nasocystic irrigation (n = 22). We collected data for a median time of 4 months (range, 1-34 months) after the LAMS placement. The primary outcomes were rates of technical success (successful placement of the LAMS), clinical success (resolution of WON, on the basis of image analysis, without need for further intervention via surgery or interventional radiology), and adverse events. RESULTS: The median size of the WON was 9.5 cm (range, 4-30 cm). Eight patients had 2 LAMS placed for multiport access, all with technical success (100%). Clinical success was achieved in 107 patients (86.3%) after 3 months of follow-up. Thirteen patients required a percutaneous drain, and 3 required a surgical intervention to manage their WON. The stents remained patent in 94% of patients (117 of 124) and migrated in 5.6% of patients (7 of 124). The median number of endoscopic interventions was 2 (range, 1-9 interventions). CONCLUSIONS: On the basis of a retrospective analysis of 124 patients, endoscopic therapy of WON by using LAMS is safe and effective. Creation of a large and sustained cystogastrostomy or cystoenterostomy tract is effective in the drainage and treatment of WON.

Endoscopic Management of Necrotizing Pancreatitis: A Case Report and Review of the Literature.

Severe acute pancreatitis has two predominant phases. The first, "early" phase (1-2 weeks) is characterized by a severe pro-inflammatory state and is best ameliorated with conservative management. The second, "late" phase is a more complex immune-compromised state, during which pancreatic fluid collections become demarcated and walled-off. During this phase, patients are at an increased risk of infection and necrosis secondary to break in the gut barrier. Therefore, treatment becomes more complicated. Though open surgical necrosectomy has historically been the treatment of choice for infected pancreatic necrosis, it carries a mortality rate up to 40 percent, likely due to additional physiologic stress in an already pro-inflammatory state. A growing body of evidence suggests that primary minimally invasive approaches, including endoscopy, can be used with equivalent or increased efficacy and lower morbidity and mortality rates than the traditional methods.

A case report of intraoperative endoscopic ultrasound during robotic assisted Heller myotomy for severe esophageal achalasia.

Esophageal achalasia is the best described primary esophageal motility disorder. Endoscopic ultrasound (EUS) is considered a useful adjunct for grading and establishing the prognosis of these patients. Recent experience using Da Vinci robotic assisted myotomy has demonstrated that this is a safe and effective approach of treatment. The benefit of magnification and three dimensional imaging helps prevent esophageal perforation and identify residual circular muscle fibers. This paper reports the relative efficacy and safety of intraoperative ultrasound during robotic assisted myotomy in a patient with severe achalasia. Intraoperative esophageal endoscopic ultrasound is a safe technique that may improve the success rate of surgery by confirming the adequacy of myotomy, thereby decreasing the likelihood of recurrent symptoms.

Robotic-assisted laparoscopic wedge resection of a gastric leiomyoma with intraoperative ultrasound localization.

Gastric leiomyoma is a rare gastric neoplasm that traditionally has been resected for negative margins using an open approach. The laparoscopic approach may also treat various gastric tumors without opening the gastric cavity. Robotic surgery was developed in response to the limitations and drawbacks of laparoscopic surgery. Herein, we describe a case of robotic-assisted laparoscopic wedge resection of a gastric leiomyoma. A 63-year-old male complaining of abdominal pain was found to have an incidental 3 cm antral mass on an abdominal CT. Endoscopy with endoscopic ultrasound (EUS) confirmed a submucosal mass. Biopsy of the lesion was consistent with a leiomyoma. The DaVinci robotic system was used for partial gastrectomy and reconstruction, with the addition of intraoperative ultrasound to localize the lesion intraoperatively. Pathological examination of the resected mass confirmed a diagnosis of leiomyoma with negative margins. There were no intraoperative or postoperative complications. The patient was discharged home on the second postoperative day. Intraoperative endoscopic ultrasound is a safe technique that may improve the success rate of surgery by confirming the location of the lesion. Robotic assistance in gastric resection offers an easy minimally invasive approach to such tumors. This approach can achieve adequate surgical margins and lead to short hospital stays.

An international study of interobserver variability of "string sign" of pancreatic cysts among experienced endosonographers.

BACKGROUND AND OBJECTIVES: No single optimal test reliably determines the pancreatic cyst subtype. Following EUS-FNA, the "string sign" test can differentiate mucinous from nonmucinous cysts. However, the interobserver variability of string sign results has not been studied. METHODS: An experienced endosonographer performed EUS-FNA of pancreatic cysts on different patients and was recorded on video performing the string sign test for each. The videos were shared internationally with 14 experienced endosonographers, with a survey for each video: "Is the string sign positive?" and "If the string sign is positive, what is the length of the formed string?" Also asked "What is the cutoff length for string sign to be considered positive?" Interobserver variability was assessed using the kappa statistic (κ). RESULTS: A total of 112 observations were collected from 14 endosonographers. Regarding string sign test positivity, κ was 0.6 among 14 observers indicating good interrater agreement (P < 0.001) while κ was 0.38 when observers were compared to the index endosonographer demonstrating marginal agreement (P < 0.001). Among observations of the length of the string in positive samples, 89.8% showed >5 mm of variability (P < 0.001), indicating marked variability. There was poor agreement on the cutoff length for a string to be considered positive. CONCLUSION: String sign of pancreatic cysts has a good interobserver agreement regarding its positivity that can help in differentiating mucinous from nonmucinous pancreatic cysts. However, the agreement is poor on the measured length of the string and the cutoff length of the formed string to be considered a positive string sign.

Natural orifice translumenal endoscopic surgery (NOTES) partial nephrectomy in a porcine model.

BACKGROUND: This study aimed to evaluate the feasibility of natural orifice translumenal endoscopic surgery (NOTES) transgastric partial nephrectomy without hilar clamping in a porcine model. METHODS: A 45-kg male pig was placed in the supine position after endotracheal general anesthesia. A therapeutic gastroscope was introduced through the esophagus, and a 2-cm gastrotomy was performed using a diathermy electrocautery needle at the junction of the fundus and the proximal body. After incision of Gerota's fascia, the left kidney's upper pole was excised using the thulium laser without hilar dissection or clamping. An endoscopic wire loop was used to entrap and extract the specimen into the stomach. The gastroscope was subsequently withdrawn with the intact specimen. After hemostasis via reinsertion of the endoscope was ensured, metal clips were applied endoscopically to close the gastrotomy. RESULTS: The total operative time for the NOTES transgastric partial nephrectomy was 240 min. Use of the therapeutic double-channel gastroscope allowed for scarless NOTES. The available 3.7- and 2.8-mm gastroscope ports were used for gastrotomy, excision, removal of the specimen, and endoscopic clip application. The procedure was performed in a nonischemic fashion with application of the thulium laser, which provided adequate hemostasis. No further interventions such as suturing of the renal capsule or use of hemostatic agents were required. The final specimen was 3 cm in size, and the estimated blood loss was 200 ml. A major drawback of the thulium laser was excessive smoke produced by vaporization of the tissue, which was minimized with the use of external irrigation. CONCLUSION: The findings show that NOTES transgastric partial nephrectomy with thulium laser is feasible. Further studies are needed to demonstrate long-term efficacy and provide additional data regarding practical applications of this novel approach and technique.

A simple and safe minimally invasive technique for laparoscopic gastrostomy.

INTRODUCTION: Percutaneous endoscopic gastrostomy (PEG) is the procedure of choice in the nutritional management of patients requiring gastrostomies. However, PEG tubes are not always feasible. The aim of the present study was to determine the feasibility, complications, and adequacy of feeding support of a novel laparoscopic gastrostomy technique in adults where PEG tubes were neither feasible nor safe. METHODS: A retrospective chart review of patients who underwent a laparoscopic gastrostomy from August 2007 to July 2008 was performed. Demographic and outcome data were abstracted. RESULTS: Fourteen patients underwent laparoscopic gastrostomy. Nine had obstructing head/neck cancer, 2 had severe head trauma, and one was morbidly obese. Nine patients had previous abdominal surgery. The mean operative time was 29.8 minutes (+/-7.2). There were no conversions to open gastrostomy. Two ports (5mm and 10mm) were used in the majority of patients (78.5%). No major complications were observed. The mean follow-up was 3.1 months (range, 2 to 8). CONCLUSION: This innovative 2-port laparoscopic technique for gastrostomy tube placement is safe and effective. It allows for the quick, accurate, and safe insertion of the feeding tube under direct visualization and avoids open techniques in patients where PEG tubes are not feasible.

Optical coherence tomography of the pancreatic and bile ducts: are we ready for prime time?

Background and study aims First-generation optical coherence tomography (OCT) has been shown to increase diagnostic sensitivity for malignant biliary and pancreatic-duct strictures. A newer OCT imaging system, NVision Volumetric Laser Endomicroscopy (VLE), allows for in vivo cross-sectional imaging of the ductal wall at the microstructure level during endoscopic retrograde cholangiopancreatography (ERCP). The aim of this study was to identify and evaluate characteristics on OCT that are predictive of benign and malignant strictures. Patients and methods Consecutive patients from six centers who underwent OCT between September 2016 and September 2017 were included in a dedicated registry. OCT images were analyzed, and nine recurring characteristics were further assessed. Final diagnosis was based on histology and/or surgical pathology. Results 86 patients were included (49 % male, mean age 64.7). OCT was performed in the bile duct in 79 patients and the pancreatic duct in seven. Nine OCT characteristics were identified: dilated hypo-reflective structures (n = 7), onion-skin layering (n = 8), intact layering (n = 17), layering effacement (n = 25), scalloping (n = 20), thickened epithelium (n = 42), hyper-glandular mucosa (n = 13), prominent blood vessels (n = 6), and a hyper-reflective surface (n = 20). Presence of hyper-glandular mucosa, hyper-reflective surface and scalloping significantly increased the odds of malignancy diagnosis by 6 times more ( P  = 0.0203; 95 % CI 1.3 to 26.5), 4.7 times more ( P  = 0.0255; 95 % CI 1.2 to 18.0) and 7.9 times more ( P  = 0.0035; 95 % CI 1.97 to 31.8) respectively. Conclusion By providing in-vivo cross-sectional imaging of the pancreatic and biliary duct wall, OCT technology may improve sensitivity in diagnosing malignant strictures and provide standardizable criteria predictive of malignancy.

Crohn disease of the esophagus: a review of the literature.

Esophageal Crohn disease is a difficult disease both to diagnose and treat. The diagnosis is made in patients with other extraintestinal manifestations of Crohn disease in whom other esophageal pathology has been ruled out. This often requires integration of clinical, endoscopic, radiographic, and histologic findings. Despite its relative rarity, it does cause severe symptoms that are difficult to treat. Treatment requires careful integration of medical, endoscopic, and surgical techniques. This review aims to discuss the significant literature regarding diagnosis and treatment of this important manifestation of inflammatory bowel disease. There is additional discussion of the literature regarding the efficacy of newer medical and endoscopic therapies, including biologic agents and removable polymer stents.

Castleman Disease Presenting as an Abdominal Mass.

Unicentric Castleman disease is a rare condition of lymphoid hyperplasia, of which only 15% of cases occur in the abdomen. We report a 66-year-old man who presented with complaints of abdominal pain. Computed tomography scans revealed nephrolithiasis and a homogeneous calcified mass between the pancreas and stomach and several para-pancreatic nodes. Direct visualization during exploratory laparotomy revealed a mass on the lesser curvature of the stomach. Pyloromyotomy and mass resection were performed. Biopsy showed reactive lymphoid hyperplasia consistent with the hyaline vascular variant of Castleman disease.

Tumour-derived exosomes as a signature of pancreatic cancer - liquid biopsies as indicators of tumour progression.

Pancreatic cancer is the fourth most common cause of death due to cancer in the world. It is known to have a poor prognosis, mostly because early stages of the disease are generally asymptomatic. Progress in pancreatic cancer research has been slow, leaving several fundamental questions pertaining to diagnosis and treatment unanswered. Recent studies highlight the putative utility of tissue-specific vesicles (i.e. extracellular vesicles) in the diagnosis of disease onset and treatment monitoring in pancreatic cancer. Extracellular vesicles are membrane-limited structures derived from the cell membrane. They contain specific molecules including proteins, mRNA, microRNAs and non-coding RNAs that are secreted in the extracellular space. Extracellular vesicles can be classified according to their size and/or origin into microvesicles (~150-1000 nm) and exosomes (~40-120 nm). Microvesicles are released by budding from the plasmatic membrane, whereas exosomes are released via the endocytic pathway by fusion of multivesicular bodies with the plasmatic membrane. This endosomal origin means that exosomes contain an abundance of cell-specific biomolecules which may act as a 'fingerprint' of the cell of origin. In this review, we discuss our current knowledge in the diagnosis and treatment of pancreatic cancer, particularly the potential role of EVs in these facets of disease management. In particular, we suggest that as exosomes contain cellular protein and RNA molecules in a cell type-specific manner, they may provide extensive information about the signature of the tumour and pancreatic cancer progression.

Optical coherence tomography in gastroenterology: a review and future outlook.

Optical coherence tomography (OCT) is an imaging technique optically analogous to ultrasound that can generate depth-resolved images with micrometer-scale resolution. Advances in fiber optics and miniaturized actuation technologies allow OCT imaging of the human body and further expand OCT utilization in applications including but not limited to cardiology and gastroenterology. This review article provides an overview of current OCT development and its clinical utility in the gastrointestinal tract, including disease detection/differentiation and endoscopic therapy guidance, as well as a discussion of its future applications.