Accuracy and interrater reliability for the diagnosis of Barrett's neoplasia among users of a novel, portable high-resolution microendoscope.

The high-resolution microendoscope (HRME) is a novel imaging modality that may be useful in the surveillance of Barrett's esophagus in low-resource or community-based settings. In order to assess accuracy and interrater reliability of microendoscopists in identifying Barrett's-associated neoplasia using HRME images, we recruited 20 gastroenterologists with no microendoscopic experience and three expert microendoscopists in a large academic hospital in New York City to interpret HRME images. They prospectively reviewed 40 HRME images from 28 consecutive patients undergoing surveillance for metaplasia and low-grade dysplasia and/or evaluation for high-grade dysplasia or cancer. Images were reviewed in a blinded fashion, after a 4-minute training with 11 representative images. All imaged sites were biopsied and interpreted by an expert pathologist. Sensitivity of all endoscopists for identification of high-grade dysplasia or cancer was 0.90 (95% confidence interval [CI]: 0.88-0.92) and specificity was 0.82 (95% CI: 0.79-0.85). Positive and negative predictive values were 0.72 (95% CI: 0.68-0.77) and 0.94 (95% CI: 0.92-0.96), respectively. No significant differences in accuracy were observed between experts and novices (0.90 vs. 0.84). The kappa statistic for all raters was 0.56 (95% CI: 0.54-0.58), and the difference between groups was not significant (0.64 vs. 0.55). These data suggest that gastroenterologists can diagnose Barrett's-related neoplasia on HRME images with high sensitivity and specificity, without the aid of prior microendoscopy experience.

High resolution microendoscopy for classification of colorectal polyps.

BACKGROUND AND STUDY AIMS: It can be difficult to distinguish adenomas from benign polyps during routine colonoscopy. High resolution microendoscopy (HRME) is a novel method for imaging colorectal mucosa with subcellular detail. HRME criteria for the classification of colorectal neoplasia have not been previously described. Study goals were to develop criteria to characterize HRME images of colorectal mucosa (normal, hyperplastic polyps, adenomas, cancer) and to determine the accuracy and interobserver variability for the discrimination of neoplastic from non-neoplastic polyps when these criteria were applied by novice and expert microendoscopists. METHODS: Two expert pathologists created consensus HRME image criteria using images from 68 patients with polyps who had undergone colonoscopy plus HRME. Using these criteria, HRME expert and novice microendoscopists were shown a set of training images and then tested to determine accuracy and interobserver variability. RESULTS: Expert microendoscopists identified neoplasia with sensitivity, specificity, and accuracy of 67 % (95 % confidence interval [CI] 58 % - 75 %), 97 % (94 % - 100 %), and 87 %, respectively. Nonexperts achieved sensitivity, specificity, and accuracy of 73 % (66 % - 80 %), 91 % (80 % - 100 %), and 85 %, respectively. Overall, neoplasia were identified with sensitivity 70 % (65 % - 76 %), specificity 94 % (87 % - 100 %), and accuracy 85 %. Kappa values were: experts 0.86; nonexperts 0.72; and overall 0.78. CONCLUSIONS: Using the new criteria, observers achieved high specificity and substantial interobserver agreement for distinguishing benign polyps from neoplasia. Increased expertise in HRME imaging improves accuracy. This low-cost microendoscopic platform may be an alternative to confocal microendoscopy in lower-resource or community-based settings.

Pre-clinical evaluation of fluorescent deoxyglucose as a topical contrast agent for the detection of Barrett's-associated neoplasia during confocal imaging.

The availability of confocal endomicroscopy motivates the development of optical contrast agents that can delineate the morphologic and metabolic features of gastrointestinal neoplasia. This study evaluates 2-NBDG, a fluorescent deoxyglucose, the uptake of which is associated with increased metabolic activity, in the identification of Barrett's-associated neoplasia. Surveillance biopsies from patients with varying pathologic grades of Barrett's esophagus were incubated ex vivo at 37°C with 2-NBDG and imaged with a fluorescence confocal microscope. Images were categorized as neoplastic (high grade dysplasia, esophageal adenocarcinoma) or metaplastic (intestinal metaplasia, low grade dysplasia) based on the degree of glandular 2-NBDG uptake. Classification accuracy was assessed using histopathology as the gold standard. Forty-four biopsies were obtained from twenty-six patients; 206 sites were imaged. The glandular mean fluorescence intensity of neoplastic sites was significantly higher than that of metaplastic sites (p<0.001). Chronic inflammation was associated with increased 2-NBDG uptake in the lamina propria but not in glandular epithelium. Sites could be classified as neoplastic or not with 96% sensitivity and 90% specificity based on glandular mean fluorescence intensity. Classification accuracy was not affected by the presence of inflammation. By delineating the metabolic and morphologic features of neoplasia, 2-NBDG shows promise as a topical contrast agent for confocal imaging. Further in vivo testing is needed to determine its performance in identifying neoplasia during confocal endomicroscopic imaging.

Emerging roles for multimodal optical imaging in early cancer detection: a global challenge.

Medical imaging technologies have become increasingly important in the clinical management of cancer, and now play key roles in cancer screening, diagnosis, staging, and monitoring response to treatment. Standard imaging modalities such as MRI, PET, and CT require significant financial resources and infrastructure, which limits access to these modalities to those patients in high-resource settings. In contrast, optical imaging strategies, with the potential for reduced cost and enhanced portability, are emerging as additional tools to facilitate the early detection and diagnosis of cancer. This article presents a vision for an expanding role for optical imaging in global cancer management, including screening, early detection at the point-of-care, biopsy guidance, and real-time histology. Multi-modal optical imaging - the combination of widefield and high resolution imaging - has the potential to aid in the detection and management of precancer and early cancer for traditionally underserved populations. Several recent widefield and high-resolution optical imaging technologies are described, along with requirements for implementing such devices into lower-resource - settings.

Novel endoscopic application of a new flexible-fiber CO2 laser for esophageal mucosal ablation in a porcine model.

BACKGROUND AND STUDY AIMS: The CO (2) laser is a surgical tool that is widely used because of its predictable penetration depth and minimal collateral damage due to efficient absorption of CO (2) laser energy by tissue water. Until recently, endoscopic use was limited by lack of an efficient, flexible delivery system. The aim of the current study was to evaluate the performance, efficacy, and safety of a novel, photonic band-gap CO (2) laser configured for esophageal mucosal ablation. MATERIALS AND METHODS: This was an endoscopic experimental study in a porcine survival model. Initial evaluation was done on ex vivo tissue followed by endoscopic studies at 7-, 10-, 15-, and 20-W power and at 0-, 1-, 2-, 5-, and 10-mm distances, using continuous and pulsed currents, to determine optimal performance settings. In an IACUC-approved protocol, six pigs underwent circumferential ablation of the distal 6 cm of the esophagus at 10W continuous current. The animals were monitored for 2 or 4 weeks to evaluate delayed effects. Prior to euthanasia, the proximal esophagus was ablated to evaluate the homogeneity of ablation and depth of injury immediately after single and repeat ablation. RESULTS: The animals resumed normal diets within 24 hours and experienced no dysphagia or weight loss. Pathology at 2 and 4 weeks revealed complete re-epithelialization with minimal histologic injury. A single application of the laser produced complete transepithelial ablation of a mean of 83.3 % of the surface area (range 55 % - 100 %); depth of injury was to the muscularis mucosa in five pigs and to the superficial submucosa in one pig. With ablation, sloughing, and re-ablation, a mean of 95 % transepithelial ablation was achieved (range 80 % -100 %) with similar depth of injury. CONCLUSIONS: Using a novel, flexible CO (2) laser, homogeneous ablation was achieved with predictable penetration and minimal deep tissue injury. These results warrant further evaluation of the laser in Barrett's esophagus, as it may overcome the limitations of current technologies including perforation, stricture, and inhomogeneity.

Adenocarcinoma of the lower esophagus with Barrett's esophagus or without Barrett's esophagus: differences in patients' survival after preoperative chemoradiation.

It remains unclear whether the overall survival (OS) of patients with localized esophageal adenocarcinoma (LEA) with Barrett's esophagus (BE) (Barrett's-positive) and those with LEA without BE (Barrett's-negative) following preoperative chemoradiation is different. Based on the published differences in the molecular biology of the two entities, we hypothesized that the two groups will have a different clinical biology (and OS). In this retrospective analysis, all patients with LEA had surgery following preoperative chemoradiation. Apart from age, gender, baseline clinical stage, location, class of cytotoxics, post-therapy stage, and OS, LEAs were divided up into Barrett's-positive and Barrett's-negative groups based on histologic documentation of BE. The Kaplan-Meier and Cox regression analytic methods were used. We analyzed 362 patients with LEA (137 Barrett's-positive and 225 Barrett's-negative). A higher proportion of Barrett's-positive patients had (EUS)T2 cancers (27%) than those with Barrett's-negative cancer (17%). More Barrett's-negative LEAs involved gastroesophageal junction than Barrett's-positive ones (P = 0.001). The OS was significantly shorter for Barrett's-positive patients than that for Barrett's-negative patients (32 months vs. 51 months; P = 0.04). In a multivariate analysis for OS, Barrett's-positive LEA (P = 0.006), old age (P = 0.016), baseline positive nodes (P = 0.005), more than 2 positive (yp)N (P = 0.0001), higher (yp)T (P = 0.003), and the use of a taxane (0.04) were the independent prognosticators. Our data demonstrate that the clinical biology (reflected in OS) is less favorable for patients with Barrett's-positive LEA than for patients with Barrett's-negative LEA. Our intriguing findings need confirmation followed by in-depth molecular study to explain these differences.

Molecular and idiotypic analyses of the antibody response to Cryptococcus neoformans glucuronoxylomannan-protein conjugate vaccine in autoimmune and nonautoimmune mice.

The antibody response to Cryptococcus neoformans capsular glucuronoxylomannan (GXM) in BALB/c mice frequently expresses the 2H1 idiotype (Id) and is restricted in variable gene usage. This study examined the immunogenicity of GXM-protein conjugates, V (variable)-region usage, and 2H1 Id expression in seven mouse strains: BALB/c, C57BL/6, A/J, C3H, NZB, NZW, and (NZB x NZW)F(1) (NZB/W). All mouse strains responded to vaccination with GXM conjugated to tetanus toxoid (TT), the relative magnitude of the antibody response being BALB/c approximately C3H > C57BL/6 approximately NZB approximately NZW approximately NZB/W > A/J. Analysis of serum antibody responses to GXM with polyclonal and monoclonal antibodies to the 2H1 Id revealed significant inter- and intrastrain differences in idiotype expression. Thirteen monoclonal antibodies (MAbs) (two immunoglobulin M [IgM], three IgG3, one IgG1, three IgG2a, two IgG2b, and two IgA) to GXM were generated from one NZB/W mouse and one C3H/He mouse. The MAbs from the NZB/W mouse were all 2H1 Id positive (Id(+)) and structurally similar to those previously generated in BALB/c mice, including the usage of a V(H) from the 7183 family and Vkappa5.1. Administration of both 2H1 Id(+) and Id(-) MAbs from NZB/W and C3H/H3 mice prolonged survival in a mouse model of cryptococcosis. Our results demonstrate (i) that V-region restriction as indicated by the 2H1 Id is a feature of both primary and secondary responses of several mouse strains; and (ii) that there is conservation of V-region usage and length of the third complementarity-determining region in antibodies from three mouse strains. The results suggest that V-region restriction is a result of antibody structural requirements necessary for binding an immunodominant antigen in GXM.

Innovative drug treatments for viral and autoimmune myocarditis.

Myocarditis has been shown to be a common cause of cardiomyopathy and is believed to account for 25% of all cases in human beings. Unfortunately, the disease is difficult to detect before a myopathic process ensues. Treatment of myocarditis-induced heart failure includes the standard regimen of diuretics, digoxin, angiotensin-converting enzyme inhibitors, and currently, beta-adrenergic blockers. Treatment of myocarditis itself is dependent on the etiology of the illness. Treatments under investigation include immunosuppressants, nonsteroidal antiinflammatory agents, immunoglobulins, immunomodulation, antiadrenergics, calcium-channel blockers, angiotensin-converting enzyme inhibitors, nitric oxide inhibition (e.g., aminoguanidine), and antiviral agents. Despite advances in treatment, more work needs to be done in the early detection of myocarditis. Additionally, better means need to be established for distinguishing between viral and autoimmune forms of the disease, so that appropriate treatment can be instituted.