A biomarker panel predicts progression of Barrett's esophagus to esophageal adenocarcinoma.

Progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) is uncommon but the consequences are serious. Predictors of progression are essential to optimize resource utilization. This study assessed the utility of a promising panel of biomarkers applicable to routine paraffin embedded biopsies (FFPE) to predict progression of BE to EAC in a large population-based, nested case-control study.We utilized the Amsterdam-based ReBus nested case-control cohort. BE patients who progressed to high-grade dysplasia (HGD)/EAC (n = 130) and BE patients who never progressed (n = 130) were matched on age, sex, length of the BE segment, and duration of endoscopic surveillance. All progressors had minimum 2 years of endoscopic surveillance without HGD/EAC to exclude prevalent neoplasia. We assessed abnormal DNA content, p53, Cyclin A, and Aspergillus oryzae lectin (AOL) in FFPE sections. We performed conditional logistic regression analysis to estimate odds ratio (OR) of progression based on biomarker status.Expert LGD (OR, 8.3; 95% CI, 1.7-41.0), AOL (3 vs. 0 epithelial compartments abnormal; OR, 3.6; 95% CI, 1.2-10.6) and p53 (OR, 2.3; 95% CI, 1.2-4.6) were independently associated with neoplastic progression. Cyclin A did not predict progression and DNA ploidy analysis by image cytometry was unsuccessful in the majority of cases, both were excluded from the multivariate analysis. The multivariable biomarker model had an area under the receiver operating characteristic curve of 0.73.Expert LGD, AOL, and p53 independently predict neoplastic progression in BE patients and are applicable to routine practice. These biomarkers can aid in selecting patients for endoscopic ablation or more intensive surveillance.

Association of sporadic and familial Barrett's esophagus with breast cancer.

Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC). Based on striking aggregation of breast cancer and BE/EAC within families as well as shared risk factors and molecular mechanisms of carcinogenesis, we hypothesized that BE may be associated with breast cancer. Pedigree analysis of families identified prospectively at multiple academic centers as part of the Familial Barrett's Esophagus Consortium (FBEC) was reviewed and families with aggregation of BE/EAC and breast cancer are reported. Additionally, using a matched case-control study design, we compared newly diagnosed BE cases in Caucasian females with breast cancer (cases) to Caucasian females without breast cancer (controls) who had undergone upper endoscopy (EGD). Two familial pedigrees, meeting a stringent inclusion criterion, manifested familial aggregation of BE/EAC and breast cancer in an autosomal dominant inheritance pattern with incomplete penetrance. From January 2008 to October 2016, 2812 breast cancer patient charts were identified, of which 213 were Caucasian females who underwent EGD. Six of 213 (2.82%) patients with breast cancer had pathology-confirmed BE, compared to 1 of 241 (0.41%) controls (P-value < 0.05). Selected families with BE/EAC show segregation of breast cancer. A breast cancer diagnosis is marginally associated with BE. We postulate a common susceptibility between BE/EAC and breast cancer.

Insulin/Insulin-Like Growth Factor-1 Pathway in Barrett's Carcinogenesis.

OBJECTIVES: Obesity-associated carcinogenesis is postulated to be mediated through the proliferative actions of insulin and the insulin-like growth factor (IGF) family. The aim of this study was to determine whether the insulin/IGF-1 pathway is involved in the sequential progression from metaplastic Barrett's esophagus (BE) to dysplasia to esophageal adenocarcinoma (EAC). METHODS: Fasting serum levels of insulin, glucose, IGF-1, insulin growth factor binding protein-1 (IGFBP1), and IGFBP3 were measured in 44 non-dysplastic, 9 low-grade dysplasia (LGD), 12 high-grade dysplasia (HGD), and 10 EAC subjects. Immunohistochemistry was performed on paraffin-embedded tissue derived from BE cases using rabbit monoclonal antibodies to p-mammalian target of rapamycin (mTOR) and p-AKT, mouse monoclonal antibody to Ki-67, and rabbit polyclonal antibody to p-insulin receptor substrate 1 (IRS1). RESULTS: Nineteen of 44 (43.2%) BE, 5/9 (55%) LGD, 8/12 (66.7%) HGD and EAC 7/10 (70%) cases showed strong staining for p-IRS1. A significantly higher proportion of HGD/EAC subjects showed p-IRS1 staining when compared with BE/LGD subjects, 63.6% vs. 41.5%, P<0.05. p-IRS1 immunostaining was moderately correlated with strong immunostaining of the downstream mediators p-AKT and p-mTOR (Spearman correlation coefficient=0.167 and 0.27 for p-IRS1/p-AKT and for p-IRS1/p-mTOR, respectively) and the proliferation marker Ki-67 (Spearman correlation coefficient=0.20, P=0.09). However, systemic levels of insulin, IGF-1, or IGF-2 were not associated with tissue immunostaining of p-IRS1. CONCLUSIONS: Activation of the insulin/IGF-1 pathway in BE may be associated with cellular proliferation and appears to have a role in the progression from metaplasia to cancer. The activation of the insulin/IGF-1 pathway at the tissue level is likely complex and does not have a simple association with systemic measures of insulin or IGF-1.

Lymph node characterization in vivo using endoscopic ultrasound spectrum analysis with electronic array echo endoscopes.

Our purpose was to demonstrate the use of radiofrequency spectral analysis to distinguish between benign and malignant lymph nodes with data obtained using electronic array echo endoscopes, as we have done previously using mechanical echo endoscopes. In a prospective study, images were obtained from eight patients with benign-appearing lymph nodes and 11 with malignant lymph nodes, as verified by fine-needle aspiration. Midband fit, slope, intercept, correlation coefficient, and root-mean-square (RMS) deviation from a linear regression of the calibrated power spectra were determined and compared between the groups. Significant differences were observable for mean midband fit, intercept, and RMS deviation (t test P < 0.05). For benign (n = 16) vs. malignant (n = 12) lymph nodes, midband fit and RMS deviation provided classification with 89 % accuracy and area under receiver operating characteristic (ROC) curve of 0.95 based on linear discriminant analysis. We concluded that the mean spectral parameters of the backscattered signals from electronic array echo endoscopy can provide a noninvasive method to quantitatively discriminate between benign and malignant lymph nodes.

[Impact of small molecules on intermolecular interactions underlying the ligand technologies in laboratory diagnosis].

Hydrogen peroxide has been found to have a distorting effect on the quality of determination of the serological markers of hepatitis B and C, transglutaminase antibodies: an increase in the percent of false higher (anti-HBsAg, HBeAg, anti-HCV) and false lower (anti-HBeAg) values, and on the results of PCR-based diagnosis (PCR inhibition that was more pronounced especially in low viremia). A possibility of interference of measurement results in the blood metabolite pool should be taken into account in the use of high-technology methods of laboratory analysis. In particular, there may be changes in the detection of immunological and molecular biological methods in hyperpyruvatemia and hyperoxaloacetatemia, with elevated peroxide concentrations during pathological processes.

Tissue apposition system: new technology to minimize surgery for endoscopically unresectable colonic polyps.

OBJECTIVE: This is the first clinical series using the Tissue Apposition System (TAS) device in a feasibility study of polypectomy as an alternative to laparoscopic colectomy (LC) for endoscopically unresectable polyps. TAS is a novel T-tag system for endoscopic placement of sutures, facilitating closure of larger defects from advanced endoluminal or transluminal endoscopic procedures. Such novel instrumentation may reduce risk and accelerate recovery. METHODS: After institutional review board approval, patients with endoscopically unresectable polyps who would otherwise require LC were enrolled. The polyp site was visualized by colonoscopy and resected with laparoscopic assistance, using endoscopic mucosal resection (EMR) or submucosal dissection. After confirming benign disease by frozen section, the polypectomy site was closed by TAS under laparoscopic observation to avoid injury to surrounding structures. Follow-up colonoscopy was performed at 3 months. RESULTS: Seven patients were recruited (5 men; mean age, 66 years). Polyps were from 20 to 50 (mean, 30) mm in diameter; six were in the right colon, and three were on the mesenteric border of the bowel. All final pathology was benign. Mean EMR time was 29 min, mean time taken for TAS was 37 min, and mean total operative time was 199 min. Two TAS procedures required conversion to LC (one unresectable polyp and one device failure). Five TAS procedures were completed, with a mean hospital stay of 1.2 days, and no complications. Follow-up colonoscopy revealed healing without polyp recurrence in any case. One patient (initial 5-cm sigmoid polyp) developed a very mild clinically asymptomatic stricture in the sigmoid colon. CONCLUSIONS: This initial human experience demonstrates that TAS can be used safely in the colon under laparoscopic control. TAS permits safe closure of defects after endoscopic polypectomy of selected and otherwise unresectable polyps. Such technology may potentially avoid the need for LC and permit rapid recovery with short hospital stay.

[AB0 blood group-associated biological variability in the content of metabolites].

The performed studies provided new evidence for biological variability in clinically important analytes, estimated a possible association of the metabolic features and the conservative genetic attribute--the ABO blood group. Certain features in the levels of protein, carbohydrate, lipid, and mineral metabolic parameters were revealed in relation to various blood groups.

Endoscopic full-thickness resection of gastric tumors using a novel grasp-and-snare technique: feasibility in ex vivo and in vivo porcine models.

BACKGROUND AND STUDY AIMS: Endoscopic full-thickness resection (EFTR) is a less-invasive method of en bloc removal of gastrointestinal tract tumors. The aim of this study was to evaluate the feasibility of a grasp-and-snare EFTR technique using a novel tissue-lifting device that provides more secure tissue anchoring and manipulation. METHODS: EFTR of normal gastric tissue and model stomach tumors was performed using a double-channel therapeutic endoscope with a prototype tissue-lifting device through one channel and a prototype hexagonal snare through the other. The lifting device was advanced through the open snare and anchored to the gastric wall immediately adjacent the model tumor. The tissue-lifting device was then partially retracted into the endoscope, causing the target tissue, including tumor, to evert into the gastric lumen. The open snare was then placed distal to the tumor around uninvolved gastric tissue. Resection was performed with a blended electrosurgical current through the snare. In the live pigs, EFTR was followed by laparotomy to asses for complications. RESULTS: 24 EFTRs were performed -- 14 in explanted stomachs and 10 in live pigs. In total, 23/24 resections resulted in full-thickness gastric defects. Resection specimens measured up to 5.0 cm when stretched and pinned on a histology stage. Gross margins were negative in 17/20 model tumor resections. Two resections were complicated by gastric mural bleeding. There was no evidence of adjacent organ injury. CONCLUSIONS: EFTR of gastric tumors using the grasp-and-snare technique is feasible in pigs. This technique is advantageous in that eversion of the gastric wall avoids injury to external organs, continuous luminal insufflation is not required, and the involved techniques are familiar to endoscopists. Additional research is necessary to further evaluate safety and reliable closure.

Complete endoscopic closure of gastrotomy after natural orifice translumenal endoscopic surgery using the NDO Plicator.

BACKGROUND: The NDO Plicator is a device developed for endoscopic treatment of gastroesophageal reflux disease (GERD) by approximation of tissues together with a double-pledgeted U-stitch. It was theorized that this device may facilitate transgastric natural orifice translumenal endoscopic surgery (NOTES) because closure of the transgastric defect remains a key component for advancement of this new technology. METHODS: A standardized 12-mm gastrotomy was created endoscopically in four pigs using a combination of needle-knife cautery and balloon dilation. As the endoscope was removed, a Savary soft-tipped wire was introduced into the stomach, and the NDO Plicator was subsequently advanced over the wire. Each defect was identified, and the device was positioned. If necessary, the Plicator's tissue grasper was used to hold the superior aspect of the gastrotomy and bring the opposed borders of the defect within the jaws of the device. The device was fired three times, leaving three pledgeted suture bundles to close the gastric defect. After closure, each animal was explored, and the integrity of the closure was assessed. The animals underwent in vivo contrast fluoroscopy and ex vivo burst pressure testing studies for assessment of leakage at the closure site. RESULTS: The first animal was used to test feasibility, refine techniques, and develop a standard procedure. All of the next three animals studied showed complete sealing of the gastrotomy site without evidence of contrast extravasation on multiplanar fluoroscopic imaging. Each stomach was excised, submerged in water, and subjected to a pressurized air leak test. No leaks were noted until pressures exceeded 55 mmHg. CONCLUSION: This study supports the use of the NDO Plicator for closure of standardized gastric defects in a porcine model. In addition to closing NOTES gastrotomies, the NDO Plicator may be a particularly useful tool for obtaining complete closure of gastric perforations and anastomotic leaks, and for performing stomal reduction after gastric bypass procedures. The mechanical properties of a closure are not the only factor determining whether a leak will develop. Tissue opposition, ischemia, and tension are important factors that are not easily or reliably measured. The physiologic relevance of gastric bursting pressure is not known. Therefore, corollary animal studies with longer-term evaluation are necessary before research proceeds to clinical trials.

A reliable method for monitoring intraabdominal pressure during natural orifice translumenal endoscopic surgery.

BACKGROUND: Natural orifice translumenal endoscopic surgery (NOTES) provides surgical access to the peritoneal cavity without skin incisions. The NOTES procedure requires pneumoperitoneum for visualization and manipulation of abdominal organs, similar to laparoscopy. Accurate measurement of the pneumoperitoneum pressure is essential to avoid potentially deleterious effects of intraabdominal compartment syndrome. A reliable method for monitoring pneumoperitoneum pressures during NOTES has not been identified. This study evaluated several methods of monitoring intraabdominal pressures with a standard gastroscope during NOTES. METHODS: Four female pigs (25 kg) were sedated, and a single-channel gastroscope was passed transgastrically into the peritoneal cavity. Pneumoperitoneum was achieved via a pressure insufflator through a percutaneous, intraperitoneal 14-gauge catheter. Three other pressures were recorded via separate catheters. First, a 14-gauge percutaneous catheter passed intraperitoneally measured true intraabdominal pressure. Second, a 14-gauge tube attached to the endoscope was used to measure endoscope tip pressure. The third pressure transducer was connected directly to the accessory channel of the endoscope. The abdomen was insufflated to a range of pressures (10-30 mmHg), and simultaneous pressures were recorded from all three pressure sensors. RESULTS: Pressure correlation curves were developed for all animals across all intraperitoneal pressures (mean error, -4.25 to -1 mmHg). Endoscope tip pressures correlated with biopsy channel pressures (R2 = 0.99). Biopsy channel and endoscope tip pressures fit a least-squares linear model to predict actual intraabdominal pressure (R = 0.99 for both). Both scope tip and biopsy channel port pressures were strongly correlative with true intraabdominal pressures (R2 = 0.98 and R2 = 0.99, respectively). CONCLUSION: This study demonstrates that monitoring pressure through an endoscope is reliable and predictive of true intraabdominal pressure. Gastroscope pressure monitoring is a useful adjunct to NOTES. Future NOTES procedures should incorporate continuous intraabdominal pressure monitoring to avoid the potentially deleterious effects of pneumoperitoneum during NOTES. This can be achieved by the integration of pressure-monitoring capabilities into gastroscopes.

Diaphragm pacing with natural orifice transluminal endoscopic surgery: potential for difficult-to-wean intensive care unit patients.

BACKGROUND: Up to 50% of the patients in the intensive care unit (ICU) require mechanical ventilation, with 20% requiring the use of a ventilator for more than 7 days. More than 40% of this time is spent weaning the patient from mechanical ventilation. Failure to wean from mechanical ventilation can in part be attributable to rapid onset of diaphragm atrophy, barotrauma, posterior lobe atelectasis, and impaired hemodynamics, which are normally improved by maintaining a more natural negative chest pressure. The authors have previously shown that laparoscopic implantation of a diaphragm pacing system benefits selected patients. They now propose that an acute ventilator assist with interventional neurostimulation of the diaphragm in the ICU is feasible and could facilitate the weaning of ICU patients from mechanical ventilation. Natural orifice transluminal endoscopic surgery (NOTES) has the potential to expand the benefits of the diaphragm pacing system to this acute patient population by allowing it to be performed at the bedside similarly to insertion of the common gastrostomy tube. This study evaluates the feasibility of this approach in a porcine model. METHODS: Pigs were anesthetized, and peritoneal access with the flexible endoscope was obtained using a guidewire, needle knife cautery, and balloon dilation. The diaphragm was mapped using a novel endoscopic electrostimulation catheter to locate the motor point (where stimulation provides complete contraction of the diaphragm). An intramuscular electrode then was placed at the motor point with a percutaneous needle. The gastrotomy was managed with a gastrostomy tube. RESULTS: Four pigs were studied, and the endoscopic mapping instrument was able to map the diaphragm to identify the motor point. In one animal, a percutaneous electrode was placed into the motor point under transgastric endoscopic visualization, and the diaphragm could be paced in conjunction with mechanical ventilation. CONCLUSIONS: These animal studies demonstrate the feasibility of transgastric mapping of the diaphragm and implantation of a percutaneous electrode for therapeutic diaphragmatic stimulation.

The No Endosonographic Detection of Tumor (NEST) Study: a case series of pancreatic cancers missed on endoscopic ultrasonography.

BACKGROUND AND STUDY AIMS: The purpose of this study was to identify possible associated factors that may have contributed to failure to detect a pancreatic neoplasm during endoscopic ultrasound (EUS) examinations by experienced endosonographers. PATIENTS AND METHODS: A multicenter retrospective study was organized, and 20 cases of pancreatic neoplasms missed by nine experienced endosonographers were identified. Careful analysis of each case was carried out to identify the factors that might have led to the missed diagnosis on EUS. RESULTS: Twelve patients with a missed pancreatic neoplasm had EUS features of chronic pancreatitis. Other factors that might have increased the likelihood of a false-negative EUS examination included a diffusely infiltrating carcinoma (n = 3), a prominent ventral/dorsal split (n = 2), and a recent episode (within the previous 4 weeks) of acute pancreatitis (n = 1). Five patients with a negative initial EUS underwent a follow-up EUS after 2-3 months, with a pancreatic mass being found in all cases. Three patients had a diffusely infiltrating pancreatic adenocarcinoma. CONCLUSIONS: EUS is not a foolproof method of detecting a pancreatic neoplasm. Possible associated factors that may increase the likelihood of a false-negative EUS examination include chronic pancreatitis, a diffusely infiltrating carcinoma, a prominent ventral/dorsal split and a recent episode (< 4 weeks) of acute pancreatitis. If there is a high clinical suspicion of pancreatic neoplasm, if EUS and other imaging methods are negative, and if the patient does not undergo surgery, this study suggests that a repeat EUS after 2-3 months may be useful for detecting an occult pancreatic neoplasm.

Endoscopic ultrasonography.

Increasing research related to endoscopic ultrasonography is published every year. A welcome trend towards outcomes-oriented research, evaluating the impact of endoscopic ultrasonography on patient management, is continuing. As experience regarding the safety and efficacy of endosonography-guided fine-needle aspiration in different clinical settings accumulates, this procedure is rapidly becoming a key component of endoscopic ultrasonography. Although promising developments in the fields of guided tissue sampling and image acquisition and analysis are being reported, innovative technical ideas need to be incorporated into the existing endoscopic ultrasound technology to take it to the next level of applications, such as endosurgery.