Today's Mistakes and Tomorrow's Wisdom in Endoscopic Imaging of Barrett's Esophagus

Background: Esophageal adenocarcinoma (EAC) is one of the main causes of cancer-related deaths worldwide and its incidence is rising. Barrett's esophagus (BE) can develop low- and high-grade dysplasia which can progress to EAC overtime. The golden standard to detect dysplastic BE (DBE) or EAC is surveillance with high-definition white-light endoscopy (HD-WLE) and random biopsies according to the Seattle protocol. However, this method is time-consuming and associated with a remarkable miss rate. Therefore, there is great need for the development of novel reliable techniques to optimize surveillance strategies and improve detection rates.Summary: Optical chromoendoscopy (OC) techniques like narrow-band imaging have shown improved detection of DBE and EAC compared to HD-WLE and random biopsies. Most recent OC techniques, including the iSCAN optical enhancement system and linked color imaging, showed improved characterization of DBE and EAC retrospectively. Fluorescence molecular endoscopy (FME) presented promising results to highlight DBE and EAC. Moreover, with the establishment of well-performing delineation computer-aided detection (CAD) algorithms and the first real-time CAD system for EAC, we expect clinical application of CAD in the near future.Key Messages: Despite impressive progress made in the development of advanced endoscopic techniques, combined HD-WLE/OC followed by random biopsies remains the golden standard for BE surveillance. Surveillance depends on appropriate mucosal cleansing, sufficient inspection time, and competence of the performing gastroenterologist to improve detection of EAC. In addition, to facilitate the clinical implementation of advanced endoscopic techniques, multicenter prospective clinical studies are demanded for OC and FME. Meanwhile, further optimization of CAD algorithms, the education of gastroenterologists, and analysis of the interaction between the clinician and the computer should be performed.</p

Validation of Novel Molecular Imaging Targets Identified by Functional Genomic mRNA Profiling to Detect Dysplasia in Barrett’s Esophagus

SIMPLE SUMMARY: Barrett’s esophagus (BE) is the precursor of esophageal adenocarcinoma (EAC). Dysplastic BE (DBE), including low-grade dysplasia (LGD) and high-grade dysplasia (HGD), shows a higher progression risk to EAC compared to non-dysplastic BE (NDBE). If LGD or HGD is detected, more intensive endoscopic surveillance or endoscopic treatment is recommended. This results in a significantly improved prognosis compared to EACs treated by surgery and/or chemoradiotherapy. However, the miss rates for detecting DBE by endoscopy remain high. Fluorescence molecular endoscopy (FME) can fill this gap by targeting the tumor-specific expression of proteins. This study aimed to identify target proteins suitable for FME. We identified SPARC, SULF1, PKCι, and DDR1 as promising imaging targets for FME to differentiate DBE from NDBE tissue. We are also the first to develop near-infrared fluorescent tracers, SULF1-800CW and SPARC-800CW, for the endoscopic imaging of DBE tissue. ABSTRACT: Barrett’s esophagus (BE) is the precursor of esophageal adenocarcinoma (EAC). Dysplastic BE (DBE) has a higher progression risk to EAC compared to non-dysplastic BE (NDBE). However, the miss rates for the endoscopic detection of DBE remain high. Fluorescence molecular endoscopy (FME) can detect DBE and mucosal EAC by highlighting the tumor-specific expression of proteins. This study aimed to identify target proteins suitable for FME. Publicly available RNA expression profiles of EAC and NDBE were corrected by functional genomic mRNA (FGmRNA) profiling. Following a class comparison between FGmRNA profiles of EAC and NDBE, predicted, significantly upregulated genes in EAC were prioritized by a literature search. Protein expression of prioritized genes was validated by immunohistochemistry (IHC) on DBE and NDBE tissues. Near-infrared fluorescent tracers targeting the proteins were developed and evaluated ex vivo on fresh human specimens. In total, 1976 overexpressed genes were identified in EAC (n = 64) compared to NDBE (n = 66) at RNA level. Prioritization and IHC validation revealed SPARC, SULF1, PKCι, and DDR1 (all p < 0.0001) as the most attractive imaging protein targets for DBE detection. Newly developed tracers SULF1-800CW and SPARC-800CW both showed higher fluorescence intensity in DBE tissue compared to paired non-dysplastic tissue. This study identified SPARC, SULF1, PKCι, and DDR1 as promising targets for FME to differentiate DBE from NDBE tissue, for which SULF1-800CW and SPARC-800CW were successfully ex vivo evaluated. Clinical studies should further validate these findings

Fitz-Hugh-Curtis syndrome resulting in nutmeg liver on computed tomography.

A 34-year-old woman entered the emergency room with abdominal pain in the right upper quadrant. Computed tomography scan showed a nutmeg liver suspected for increased venous pressure by thrombosis of the liver veins, Budd-Chiari malformation, or right-sided heart failure. Interestingly, the diagnosis was pelvic inflammatory disease complicated by the Fitz-Hugh-Curtis syndrome (FHCS). Pelvic inflammatory disease resulted from an ascended infection by Chlamydia trachomatis. FHCS was caused by perihepatitis defined as inflammation of the peritoneal capsule of the liver. Fast diagnosis and treatment is crucial. Therefore, we report a case of FHCS characterized by a nutmeg liver on computed tomography

NEAR-INFRARED FLUORESCENCE MOLECULAR ENDOSCOPY SHOWS PROMISING RESULTS IN DETECTING DYSPLASTIC ESOPHAGEAL LESIONS USING TOPICALLY ADMINISTERED BEVACIZUMAB-800CW: THE PRELIMINARY RESULTS OF A PHASE 2 STUDY

Esophageal cancer (EC) is affecting more than 450,000 people worldwide and is the 6th leading cause of cancer-related deaths. The poor EC survival is attributed to the insufficient methods for premalignant lesion detection and therefore there is a great need for new endoscopic techniques that can visualize early stage lesions. In this phase II study we aim to evaluate the sensitivity and specificity of the tracer bevacizumab-800CW in combination with near infrared fluorescent molecular endoscopy (NIR-FME) for detecting (pre)malignant lesions in patients with Barrett’s esophagus (BE).The tracer, Bevacizumab-800CW, was topically administered to the patients and after 5 minutes of incubation NIR-FME was performed. To quantify the intrinsic fluorescent signal, we used multi-diameter single fiber spectroscopy/single fiber fluorescence (MDSFR/SFF) spectroscopy measurements both in vivo and ex vivo. In case of additional fluorescent lesions biopsies were taken to analyze if dysplasia was present. The day after the endoscopic procedure the endoscopic mucosal resection (EMR) specimen was analyzed with widefield back-table imaging.In our preliminary results topical-based NIR-FME detected all 4 adenocarcinoma lesions and all 8 high grade dysplasia lesions. Additionally, in one patient, this novel endoscopic technique identified another dysplastic lesion which was not visualized by high definition white light endoscopy (HD-WLE) and narrow band imaging (NBI) inspection. In our cohort no (serious) adverse events related to the tracer were observed. In the upcoming months we will include 52 more patients, add MDSFR/SFF spectroscopy data and determine tumor to background ratios.Based on the preliminary results combined with the results of the Phase I study we can conclude that VEGF-A guided NIR-FME is able to reliably detect (pre)malignant dysplastic lesions in patients with BE and improves early lesion detection compared with HD-WL/NBI endoscopy. Moreover, the topically administered tracer Bevacizumab-800CW is safe and well tolerated

Validation of Novel Molecular Imaging Targets Identified by Functional Genomic mRNA Profiling to Detect Dysplasia in Barrett’s Esophagus

Simple Summary: Barrett's esophagus (BE) is the precursor of esophageal adenocarcinoma (EAC). Dysplastic BE (DBE), including low-grade dysplasia (LGD) and high-grade dysplasia (HGD), shows a higher progression risk to EAC compared to non-dysplastic BE (NDBE). If LGD or HGD is detected, more intensive endoscopic surveillance or endoscopic treatment is recommended. This results in a significantly improved prognosis compared to EACs treated by surgery and/or chemoradiotherapy. However, the miss rates for detecting DBE by endoscopy remain high. Fluorescence molecular endoscopy (FME) can fill this gap by targeting the tumor-specific expression of proteins. This study aimed to identify target proteins suitable for FME. We identified SPARC, SULF1, PKC iota, and DDR1 as promising imaging targets for FME to differentiate DBE from NDBE tissue. We are also the first to develop near-infrared fluorescent tracers, SULF1-800CW and SPARC-800CW, for the endoscopic imaging of DBE tissue. Abstract: Barrett's esophagus (BE) is the precursor of esophageal adenocarcinoma (EAC). Dysplastic BE (DBE) has a higher progression risk to EAC compared to non-dysplastic BE (NDBE). However, the miss rates for the endoscopic detection of DBE remain high. Fluorescence molecular endoscopy (FME) can detect DBE and mucosal EAC by highlighting the tumor-specific expression of proteins. This study aimed to identify target proteins suitable for FME. Publicly available RNA expression profiles of EAC and NDBE were corrected by functional genomic mRNA (FGmRNA) profiling. Following a class comparison between FGmRNA profiles of EAC and NDBE, predicted, significantly upregulated genes in EAC were prioritized by a literature search. Protein expression of prioritized genes was validated by immunohistochemistry (IHC) on DBE and NDBE tissues. Near-infrared fluorescent tracers targeting the proteins were developed and evaluated ex vivo on fresh human specimens. In total, 1976 overexpressed genes were identified in EAC (n = 64) compared to NDBE (n = 66) at RNA level. Prioritization and IHC validation revealed SPARC, SULF1, PKC iota, and DDR1 (all p < 0.0001) as the most attractive imaging protein targets for DBE detection. Newly developed tracers SULF1-800CW and SPARC-800CW both showed higher fluorescence intensity in DBE tissue compared to paired non-dysplastic tissue. This study identified SPARC, SULF1, PKC iota, and DDR1 as promising targets for FME to differentiate DBE from NDBE tissue, for which SULF1-800CW and SPARC-800CW were successfully ex vivo evaluated. Clinical studies should further validate these findings