Hiroshi Mashimo

Radiofrequency Ablation in Barrett's Esophagus with Dysplasia

BACKGROUND Barretts esophagus, a condition of intestinal metaplasia of the esophagus, is associated with an increased risk of esophageal adenocarcinoma. We assessed whether endoscopic radiofrequency ablation could eradicate dysplastic Barretts esophagus and decrease the rate of neoplastic progression. METHODS In a multicenter, sham-controlled trial, we randomly assigned 127 patients with dysplastic Barretts esophagus in a 2:1 ratio to receive either radiofrequency ablation (ablation group) or a sham procedure (control group). Randomization was stratified according to the grade of dysplasia and the length of Barretts esophagus. Primary outcomes at 12 months included the complete eradication of dysplasia and intestinal metaplasia. RESULTS In the intention-to-treat analyses, among patients with low-grade dysplasia, complete eradication of dysplasia occurred in 90.5% of those in the ablation group, as compared with 22.7% of those in the control group (P<0.001). Among patients with high-grade dysplasia, complete eradication occurred in 81.0% of those in the ablation group, as compared with 19.0% of those in the control group (P<0.001). Overall, 77.4% of patients in the ablation group had complete eradication of intestinal metaplasia, as compared with 2.3% of those in the control group (P<0.001). Patients in the ablation group had less disease progression (3.6% vs. 16.3%, P=0.03) and fewer cancers (1.2% vs. 9.3%, P=0.045). Patients reported having more chest pain after the ablation procedure than after the sham procedure. In the ablation group, one patient had upper gastrointestinal hemorrhage, and five patients (6.0%) had esophageal stricture. CONCLUSIONS In patients with dysplastic Barretts esophagus, radiofrequency ablation was associated with a high rate of complete eradication of both dysplasia and intestinal metaplasia and a reduced risk of disease progression. (ClinicalTrials.gov number, NCT00282672.)

Impaired Defense of Intestinal Mucosa in Mice Lacking Intestinal Trefoil Factor

The mechanisms that maintain the epithelial integrity of the gastrointestinal tract remain largely undefined. The gene encoding intestinal trefoil factor (ITF), a protein secreted throughout the small intestine and colon, was rendered nonfunctional in mice by targeted disruption. Mice lacking ITF had impaired mucosal healing and died from extensive colitis after oral administration of dextran sulfate sodium, an agent that causes mild epithelial injury in wild-type mice. ITF-deficient mice manifested poor epithelial regeneration after injury. These findings reveal a central role for ITF in the maintenance and repair of the intestinal mucosa.

Durability of Radiofrequency Ablation in Barrett's Esophagus With Dysplasia

BACKGROUND & AIMS Radiofrequency ablation (RFA) can eradicate dysplasia and intestinal metaplasia in patients with dysplastic Barretts esophagus (BE), and reduce rates of esophageal adenocarcinoma. We assessed long-term rates of eradication, durability of neosquamous epithelium, disease progression, and safety of RFA in patients with dysplastic BE. METHODS We performed a randomized trial of 127 subjects with dysplastic BE; after cross-over subjects were included, 119 received RFA. Subjects were followed for a mean time of 3.05 years; the study was extended to 5 years for patients with eradication of intestinal metaplasia at 2 years. Outcomes included eradication of dysplasia or intestinal metaplasia after 2 and 3 years, durability of response, disease progression, and adverse events. RESULTS After 2 years, 101 of 106 patients had complete eradication of all dysplasia (95%) and 99 of 106 had eradication of intestinal metaplasia (93%). After 2 years, among subjects with initial low-grade dysplasia, all dysplasia was eradicated in 51 of 52 (98%) and intestinal metaplasia was eradicated in 51 of 52 (98%); among subjects with initial high-grade dysplasia, all dysplasia was eradicated in 50 of 54 (93%) and intestinal metaplasia was eradicated in 48 of 54 (89%). After 3 years, dysplasia was eradicated in 55 of 56 of subjects (98%) and intestinal metaplasia was eradicated in 51 of 56 (91%). Kaplan-Meier analysis showed that dysplasia remained eradicated in >85% of patients and intestinal metaplasia in >75%, without maintenance RFA. Serious adverse events occurred in 4 of 119 subjects (3.4%); the rate of stricture was 7.6%. The rate of esophageal adenocarcinoma was 1 per 181 patient-years (0.55%/patient-years); there was no cancer-related morbidity or mortality. The annual rate of any neoplastic progression was 1 per 73 patient-years (1.37%/patient-years). CONCLUSIONS In subjects with dysplastic BE, RFA therapy has an acceptable safety profile, is durable, and is associated with a low rate of disease progression, for up to 3 years.

Neuronal constitutive nitric oxide synthase is involved in murine enteric inhibitory neurotransmission.

UNLABELLED Mice lacking neuronal nitric oxide synthase gene (ncNOS) were used to determine the enzymatic source of nitric oxide (NO) and its relationship with other putative inhibitory neurotransmitters. Inhibitory junction potentials (IJP) of circular smooth muscle of gastric fundus were studied. The IJP in the wild-type mice consists of overlapping components, the fast and slow IJPs. NOS inhibitor L-NA or VIP receptor antagonist VIP(10-28), blocks the slow IJP but not the fast IJP. The fast UP is blocked by alpha-beta methylene ATP tachyphylaxis, by reactive blue 2, and by apamin. The IJP in the ncNOS-deficient [ncNOS(-)] mutant is of short duration and is abolished by blockers of the fast IJP, but is unaffected by blockers of the slow UP. Exogenous VIP produces membrane hyperpolarization in strips from wild-type but not ncNOS(-) mice. The hyperpolarizing action of VIP is resistant to nifedipine but is sensitive to omega-conotoxin GVIA. IN CONCLUSION (a) NO derived from ncNOS is an inhibitory neurotransmitter rather than a postjunctional mediator; (b) VIP is a prejunctional neurotransmitter that causes release of evanescent NO; and (c) ATP acts in parallel with the VIP/NO pathway.

Immunostaining of Lgr5, an intestinal stem cell marker, in normal and premalignant human gastrointestinal tissue.

Lgr5 has recently been identified as a murine marker of intestinal stem cells. Its expression has not been well characterized in human gastrointestinal tissues, but has been reported in certain cancers. With the increasing appreciation for the role of cancer stem cells or tumor-initiating cells in certain tumors, we sought to explore the expression of Lgr5 in normal and premalignant human gastrointestinal tissues. Using standard immunostaining, we compared expression of Lgr5 in normal colon and small intestine vs. small intestinal and colonic adenomas and Barretts esophagus. In the normal tissue, Lgr5 was expressed in the expected stem cell niche, at the base of crypts, as seen in mice. However, in premalignant lesions, Lgr5+ cells were not restricted to the crypt base. Additionally, their overall numbers were increased. In colonic adenomas, Lgr5+ cells were commonly found clustered at the luminal surface and rarely at the crypt base. Finally, we compared immunostaining of Lgr5 with that of CD133, a previously characterized marker for tumor-initiating cells in colon cancer, and found that they identified distinct subpopulations of cells that were in close proximity, but did not costain. Our findings suggest that (1) Lgr5 is a potential marker of intestinal stem cells in humans and (2) loss of restriction to the stem cell niche is an early event in the premalignant transformation of stem cells and may play a role in carcinogenesis.

Three-dimensional endomicroscopy of the human colon using optical coherence tomography

Three-dimensional (3D) endomicroscopy imaging of the human gastrointestinal tract is demonstrated in vivo using a swept source optical coherence tomography (OCT) system. 3D datasets of normal and pathologic regions of the colon, rectum, and anal verge were obtained from seven volunteers undergoing diagnostic or therapeutic colonoscopy. 3D-OCT enables high resolution endomicroscopy examination through visualization of tissue architectural morphology using virtual cross-sectional images with arbitrary orientations as well as en face projection images. Axial image resolutions of 6 mum in tissue are obtained over a approximately 180 mm2 field with an imaging range of 1.6 mm. A Fourier domain mode locked (FDML) laser providing a tuning range of 180 nm at a sweep rate of 62 kHz is used as the system light source. This clinical pilot study demonstrates the potential of 3D-OCT for distinguishing normal from pathologic colorectal tissue, assessing endoscopic therapies and healing progression.

Characterization of buried glands before and after radiofrequency ablation by using 3-dimensional optical coherence tomography (with videos)

BACKGROUND Radiofrequency ablation (RFA) is an endoscopic technique used to eradicate Barretts esophagus (BE). However, such ablation can commonly lead to neosquamous epithelium overlying residual BE glands not visible by conventional endoscopy and may evade detection on random biopsy samples. OBJECTIVE To demonstrate the capability of endoscopic 3-dimensional optical coherence tomography (3D-OCT) for the identification and characterization of buried glands before and after RFA therapy. DESIGN Cross-sectional study. SETTING Single teaching hospital. PATIENTS Twenty-six male and 1 female white patients with BE undergoing RFA treatment. INTERVENTIONS 3D-OCT was performed at the gastroesophageal junction in 18 patients before attaining complete eradication of intestinal metaplasia (pre-CE-IM group) and in 16 patients after CE-IM (post-CE-IM group). MAIN OUTCOME MEASUREMENTS Prevalence, size, and location of buried glands relative to the squamocolumnar junction. RESULTS 3D-OCT provided an approximately 30 to 60 times larger field of view compared with jumbo and standard biopsy and sufficient imaging depth for detecting buried glands. Based on 3D-OCT results, buried glands were found in 72% of patients (13/18) in the pre-CE-IM group and 63% of patients (10/16) in the post-CE-IM group. The number (mean [standard deviation]) of buried glands per patient in the post-CE-IM group (7.1 [9.3]) was significantly lower compared with the pre-CE-IM group (34.4 [44.6]; P = .02). The buried gland size (P = .69) and distribution (P = .54) were not significantly different before and after CE-IM. LIMITATIONS A single-center, cross-sectional study comparing patients at different time points in treatment. Lack of 1-to-1 coregistered histology for all OCT data sets obtained in vivo. CONCLUSION Buried glands were frequently detected with 3D-OCT near the gastroesophageal junction before and after radiofrequency ablation.

Ultrahigh resolution optical biopsy with endoscopic optical coherence tomography

Optical coherence tomography (OCT) is an emerging medical imaging technology that can generate high resolution, cross-sectional images of tissue in situ and in real time. Although endoscopic OCT has been used successfully to identify certain pathologies in the gastrointestinal tract, the resolution of current endoscopic OCT systems has been limited to 10-15 microm for in vivo studies. In this study, in vivo imaging of the rabbit gastrointestinal tract is demonstrated at a three-fold higher resolution (< 5 microm), using a broadband Cr(4+):Forsterite laser as the optical light source. Images acquired from the esophagus, trachea, and colon reveal high resolution details of tissue architecture. Definitive correlation of architectural features in OCT images and histological sections is shown. The ability of ultrahigh resolution endoscopic OCT to image tissue morphology at an unprecedented resolution in vivo advances the development of OCT as a potential imaging tool for the early detection of neoplastic changes in biological tissue.

Ultrahigh speed endoscopic optical coherence tomography using micromotor imaging catheter and VCSEL technology

We developed a micromotor based miniature catheter with an outer diameter of 3.2 mm for ultrahigh speed endoscopic swept source optical coherence tomography (OCT) using a vertical cavity surface-emitting laser (VCSEL) at a 1 MHz axial scan rate. The micromotor can rotate a micro-prism at several hundred frames per second with less than 5 V drive voltage to provide fast and stable scanning, which is not sensitive to the bending of the catheter. The side-viewing probe can be pulled back to acquire a three-dimensional (3D) data set covering a large area on the specimen. The VCSEL provides a high axial scan rate to support dense sampling under high frame rate operation. Using a high speed data acquisition system, in vivo 3D-OCT imaging in the rabbit GI tract and ex vivo imaging of a human colon specimen with 8 μm axial resolution, 8 μm lateral resolution and 1.2 mm depth range in tissue at a frame rate of 400 fps was demonstrated.

Effective treatment of chronic radiation proctitis using radiofrequency ablation

Endoscopic argon plasma coagulation and bipolar electrocautery are currently preferred treatments for chronic radiation proctitis, but ulcerations and strictures frequently occur. Radiofrequency ablation (RFA) has been successful for mucosal ablation in the esophagus. Here we report the efficacy of RFA with the BarRx Halo90 system in three patients with bleeding from chronic radiation proctitis. In all cases, the procedure was well tolerated and hemostasis was achieved after 1 or 2 RFA sessions. Re-epithelialization of squamous mucosa was observed over areas of prior hemorrhage. No stricturing or ulceration was seen on follow-up up to 19 months after RFA treatment. Real-time endoscopic optical coherence tomography (EOCT) visualized epithelialization and subsurface tissue microvasculature pre- and post-treatment, demonstrating its potential for follow-up assessment of endoscopic therapies.