Detection of early neoplasia in Barrett's esophagus using lectin-based near-infrared imaging: an ex vivo study on human tissue.
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ABSTRACT:
SUBMITTER: Neves AA
PROVIDER: S-EPMC6193410 | biostudies-other | 2018 Jun
REPOSITORIES: biostudies-other
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Project description:Confocal laser endomicroscopy (CLE) enables in vivo microscopic imaging of the GI tract mucosa. However, there are limited data on endoscope-based CLE (eCLE) for imaging Barrett's esophagus (BE).To compare high-definition white-light endoscopy (HDWLE) alone with random biopsy (RB) and HDWLE + eCLE and targeted biopsy (TB) for diagnosis of BE neoplasia.Multicenter, randomized, controlled trial.Academic medical centers.Adult patients with BE undergoing routine surveillance or referred for early neoplasia.Patients were randomized to HDWLE + RB (group 1) or HDWLE + eCLE + TB (group 2). Real-time diagnoses and management plans were recorded after HDWLE in both groups and after eCLE in group 2. Blinded expert pathology diagnosis was the reference standard.Diagnostic yield, performance characteristics, clinical impact.A total of 192 patients with BE were studied. HDWLE + eCLE + TB led to a lower number of mucosal biopsies and higher diagnostic yield for neoplasia (34% vs 7%; P < .0001), compared with HDWLE + RB but with comparable accuracy. HDWLE + eCLE + TB tripled the diagnostic yield for neoplasia (22% vs 6%; P = .002) and would have obviated the need for any biopsy in 65% of patients. The addition of eCLE to HDWLE increased the sensitivity for neoplasia detection to 96% from 40% (P < .0001) without significant reduction in specificity. In vivo CLE changed the treatment plan in 36% of patients.Tertiary-care referral centers and expert endoscopists limit generalizability.Real-time eCLE and TB after HDWLE can improve the diagnostic yield and accuracy for neoplasia and significantly impact in vivo decision making by altering the diagnosis and guiding therapy. (NCT01124214.).
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Project description:Fourier transform infrared (FTIR) spectroscopy provides a unique molecular fingerprint of tissue from endogenous sources of light absorption; however, specific molecular components of the overall FTIR signature of precancer have not been characterized. In attenuated total reflectance mode, infrared light penetrates only a few microns of the tissue surface, and the influence of water on the spectra can be minimized, allowing for the analyses of the molecular composition of tissues. Here, spectra were collected from 98 excised specimens of the distal esophagus, including 38 squamous, 38 intestinal metaplasia (Barrett's), and 22 gastric, obtained endoscopically from 32 patients. We show that DNA, protein, glycogen, and glycoprotein comprise the principal sources of infrared absorption in the 950- to 1,800-cm(-1) regime. The concentrations of these biomolecules can be quantified by using a partial least-squares fit and used to classify disease states with high sensitivity, specificity, and accuracy. Moreover, use of FTIR to detect premalignant (dysplastic) mucosa results in a sensitivity, specificity, positive predictive value, and total accuracy of 92%, 80%, 92%, and 89%, respectively, and leads to a better interobserver agreement between two gastrointestinal pathologists for dysplasia (kappa = 0.72) versus histology alone (kappa = 0.52). Here, we demonstrate that the concentration of specific biomolecules can be determined from the FTIR spectra collected in attenuated total reflectance mode and can be used for predicting the underlying histopathology, which will contribute to the early detection and rapid staging of many diseases.
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Project description:BACKGROUND: Dysplasia arising from Barrett's esophagus precedes esophageal adenocarcinoma (EAC). Cases that are difficult to diagnose as dysplastic, especially in the setting of inflammation, may be designated "indefinite for dysplasia (IND)." Although flow cytometric analysis of DNA content has shown some promise in detecting EAC, there are few reports that have specifically evaluated the outcome of IND. AIMS AND METHODS: We analyzed a series of 96 IND patients seen at the University of Washington between 2005 and 2013 to determine the outcome of IND and to identify factors (including histologic features and DNA flow cytometric data) associated with subsequent detection of neoplasia. RESULTS: Twenty-five percent of IND cases were found to have low-grade dysplasia, high-grade dysplasia (HGD), or EAC within 1 year, with 37% and 47% detected within 2 and 3 years, respectively. The 1-, 2-, and 3-year detection rates of HGD or EAC were 10%, 13%, and 20%, respectively. Active inflammation (hazard ratio (HR)=3.4, P=0.0005) and abnormal DNA content (HR=5.7, P=0.003) were significant risk factors of neoplasia. When active inflammation and DNA flow cytometric results were considered together, the HR for the combined markers was 18.8 (P<0.0001). The sensitivity and specificity of the combined markers for predicting detection of subsequent neoplasia within 3 years were 100% and 60%, respectively, with 100% negative and 89% positive predictive values. CONCLUSIONS: Histology with the support of DNA flow cytometry can identify a subset of IND patients who may have a higher risk for subsequent detection of neoplasia.
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Project description:Multiple endoscopic sessions may be necessary for treatment and surveillance of Barrett's esophagus (BE)-associated neoplasia. Adherence to an endoscopic therapeutic regimen is important for longitudinal management of BE. The objective of this study was to identify the factors associated with adherence to therapy for BE-associated neoplasia.We retrospectively identified patients with BE whom were referred to a tertiary center for endoscopic mucosal resection (EMR) or radiofrequency ablation (RFA) between 2009 and 2012. Demographic and clinical data were extracted from the medical record.We had 69 subjects meet our inclusion criteria. Referral diagnosis was low-grade dysplasia in 9 (13%) subjects, high-grade dysplasia in 33 (48%) subjects and adenocarcinoma in 26 (38%) subjects. The majority (55%) lived more than 100 miles from the treatment center. The primary third-party payer was US Medicare for 54% of the subjects and private insurance for 36% of them; 45% of the subjects were seen in the clinic by the treating endoscopist, prior to endoscopic therapy and 71% underwent EMR as the initial treatment, while 29% underwent RFA without prior EMR. We found that 72% of subjects were adherent to therapy, including: 23 (33%) completing endoscopic therapy with documented post-treatment surveillance, 18 (26%) with ongoing endoscopic therapy, and 9 (13%) whom underwent esophagectomy. Subjects seen in gastroenterology clinical consultation were significantly more likely to demonstrate adherence than those referred for open access endoscopy (Lasso OR 2.31).Patients seen in a clinical consultation prior to endoscopic therapy for BE-associated neoplasia were more likely to demonstrate treatment adherence, compared to patients referred for open-access endoscopy. A clinic visit prior to therapy may define expectations regarding treatment course and increase the likelihood of patient adherence.
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Project description:Barrett's esophagus (BE) patients are routinely screened for high grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) through endoscopic screening, during which multiple esophageal tissue samples are removed for histological analysis. We propose a computational method called the multistage clonal expansion for EAC (MSCE-EAC) screening model that is used for screening BE patients in silico to evaluate the effects of biopsy sampling, diagnostic sensitivity, and treatment on disease burden. Our framework seamlessly integrates relevant cell-level processes during EAC development with a spatial screening process to provide a clinically relevant model for detecting dysplastic and malignant clones within the crypt-structured BE tissue. With this computational approach, we retain spatio-temporal information about small, unobserved tissue lesions in BE that may remain undetected during biopsy-based screening but could be detected with high-resolution imaging. This allows evaluation of the efficacy and sensitivity of current screening protocols to detect neoplasia (dysplasia and early preclinical EAC) in the esophageal lining. We demonstrate the clinical utility of this model by predicting three important clinical outcomes: (1) the probability that small cancers are missed during biopsy-based screening, (2) the potential gains in neoplasia detection probabilities if screening occurred via high-resolution tomographic imaging, and (3) the efficacy of ablative treatments that result in the curative depletion of metaplastic and neoplastic cell populations in BE in terms of the long-term impact on reducing EAC incidence.
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Project description:Background & aimsGuidelines suggest endoscopic screening of individuals who are at increased risk for Barrett's esophagus (BE) and esophageal adenocarcinoma. Tools based on clinical factors are available for identifying patients at risk, but only some have been validated. We aimed to compare and validate available tools.MethodsWe performed a prospective study of 1241 patients, ages 40 to 79 years, presenting either for their first esophagogastroduodenoscopy (EGD) or their first endoscopic therapy of early neoplastic BE, from April 2015 through June 2018. We calculated risk scores for 6 previously published tools (the Gerson, Locke, Thrift, Michigan BE pREdiction Tool [M-BERET], Nord-Trøndelag Health Study [HUNT], and Kunzmann tools). We also investigated the accuracy of frequency and duration of gastroesophageal reflux disease (GERD), using data from a randomly selected 50% of patients undergoing their first EGD. We compared the ability of all these tools to discriminate patients with BE and early neoplasia from patients without BE, using findings from endoscopy as the reference standard.ResultsBE was detected in 81 of 1152 patients during their first EGD (7.0%). GERD symptoms alone identified patients with BE with an area under the receiver operating characteristic curve (AuROC) of 0.579. All of the tools were more accurate in identifying patients with BE than the frequency and duration of GERD (AuROC for GERD, 0.579 vs range for other tools, 0.660-0.695), and predicted risk correlated well with observed risk (calibration). The AUROCs of the HUNT tool (0.796), the M-BERET (0.773), and the Kunzmann tool (0.763) were comparable in discriminating between patients with early neoplasia (n = 94) vs no BE. Each tool was more accurate in discriminating BE with early neoplasia than GERD frequency and duration alone (AuROC, 0.667; P < .01).ConclusionsThe HUNT, M-BERET, and Kunzmann tools identify patients with BE with AuROC values ranging from 0.665 to 0.695, and discriminate patients with early neoplasia from patients without BE with AuROC values ranging from 0.763 to 0.796. These tools are more accurate than frequency and duration of GERD in identifying individuals at risk for neoplastic BE.
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Project description:Early detection of esophageal neoplasia enables curative endoscopic therapy, but the current diagnostic standard of care has low sensitivity because early neoplasia is often inconspicuous with conventional white-light endoscopy. Here, we hypothesized that spectral endoscopy could enhance contrast for neoplasia in surveillance of patients with Barrett's esophagus. A custom spectral endoscope was deployed in a pilot clinical study of 20 patients to capture 715 in vivo tissue spectra matched with gold standard diagnosis from histopathology. Spectral endoscopy was sensitive to changes in neovascularization during the progression of disease; both non-dysplastic and neoplastic Barrett's esophagus showed higher blood volume relative to healthy squamous tissue (P = 0.001 and 0.02, respectively), and vessel radius appeared larger in neoplasia relative to non-dysplastic Barrett's esophagus (P = 0.06). We further developed a deep learning algorithm capable of classifying spectra of neoplasia versus non-dysplastic Barrett's esophagus with high accuracy (84.8% accuracy, 83.7% sensitivity, 85.5% specificity, 78.3% positive predictive value, and 89.4% negative predictive value). Exploiting the newly acquired library of labeled spectra to model custom color filter sets identified a potential 12-fold enhancement in contrast between neoplasia and non-dysplastic Barrett's esophagus using application-specific color filters compared with standard-of-care white-light imaging (perceptible color difference = 32.4 and 2.7, respectively). This work demonstrates the potential of endoscopic spectral imaging to extract vascular properties in Barrett's esophagus, to classify disease stages using deep learning, and to enable high-contrast endoscopy. SIGNIFICANCE: The results of this pilot first-in-human clinical trial demonstrate the potential of spectral endoscopy to reveal disease-associated vascular changes and to provide high-contrast delineation of neoplasia in the esophagus. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3415/F1.large.jpg.
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Project description:BACKGROUND: Cryotherapy is a relatively novel ablation modality for the endoscopic ablation of Barrett's esophagus (BE). Data on the use of pressurized carbon dioxide (CO2) gas for cryoablation are scarce. STUDY AIM: To determine the efficacy and safety of cryospray ablation using pressurized CO2 gas in the treatment of BE with early neoplasia. METHODS: In this prospective single center case series, we aimed to include 30 patients with BE and early neoplasia. Nodular neoplastic lesions were treated with endoscopic mucosal resection (EMR). Residual BE mucosa was treated with cryospray ablation every 4 weeks until the complete BE segment was eliminated or up to seven treatment sessions. If no reduction of the BE segment was observed after two subsequent treatment sessions, cryoablation was terminated. Patients were contacted at days 1 and 4 post-treatment to evaluate the level of discomfort. Endoscopic and histologic follow-up evaluations were performed up to 24 months post-treatment. RESULTS: After the inclusion of 10 patients, insufficient effect of cryoablation was observed, resulting in early termination of the study. In total, seven patients with intramucosal carcinoma (IMC) and three with high grade dysplasia (HGD) were included. Prior EMR was performed in nine patients. A median of 2.5 (IQR 2.0 - 4.0) cryoablation sessions were performed. At 6 months of follow-up, complete eradication of intestinal metaplasia was observed in 11 % (1 /9; one patient died, not treatment or disease related) of the patients and complete eradication of dysplasia in 44 % (4 /9). In three patients, HGD or IMC was detected during follow-up, and was endoscopically treated. Apart from a gastric perforation as a result of gastric distension caused by CO2 gas during the first treatment, cryospray treatments were well tolerated. CONCLUSION: After a short learning curve, cryoablation using CO2 gas was found to be a safe and well tolerated treatment modality. However, in our experience, the efficacy of CO2 cryoablation combined with EMR for nodular lesions is disappointing for the treatment of BE associated neoplasia.
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Project description:The incidence of esophageal adenocarcinoma (EAC) is rising rapidly, and early detection within the precursor state of Barrett's esophagus (BE) is challenged by flat premalignant lesions that are difficult detect with conventional endoscopic surveillance. Overexpression of cell surface fibroblast growth factor receptor 2 (FGFR2) is an early event in progression of BE to EAC, and is a promising imaging target. We used phage display to identify the peptide SRRPASFRTARE that binds specifically to the extracellular domain of FGFR2. We labeled this peptide with a near-infrared fluorophore Cy5.5, and validated the specific binding to FGFR2 overexpressed in cells in vitro. We found high affinity kd = 68 nM and rapid binding k = 0.16 min-1 (6.2 min). In human esophageal specimens, we found significantly greater peptide binding to high-grade dysplasia (HGD) versus either BE or normal squamous epithelium, and good correlation with anti-FGFR2 antibody. We also observed significantly greater peptide binding to excised specimens of esophageal squamous cell carcinoma and gastric cancer compared to normal mucosa. These results demonstrate potential for this FGFR2 peptide to be used as a clinical imaging agent to guide tissue biopsy and improve methods for early detection of EAC and potentially other epithelial-derived cancers.
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