Potential red-flag identification of colorectal adenomas with wide-field fluorescence molecular endoscopy

Adenoma miss rates in colonoscopy are unacceptably high, especially for sessile serrated adenomas / polyps (SSA/Ps) and in high-risk populations, such as patients with Lynch syndrome. Detection rates may be improved by fluorescence molecular endoscopy (FME), which allows morphological visualization of lesions with high-definition white-light imaging as well as fluorescence-guided identification of lesions with a specific molecular marker. In a clinical proof-of-principal study, we investigated FME for colorectal adenoma detection, using a fluorescently labelled antibody (bevacizumab-800CW) against vascular endothelial growth factor A (VEGFA), which is highly upregulated in colorectal adenomas. Methods: Patients with familial adenomatous polyposis (n = 17), received an intravenous injection with 4.5, 10 or 25 mg of bevacizumab-800CW. Three days later, they received NIR-FME. Results: VEGFA-targeted NIR-FME detected colorectal adenomas at all doses. Best results were achieved in the highest (25 mg) cohort, which even detected small adenomas ( < 3 mm). Spectroscopy analyses of freshly excised specimen demonstrated the highest adenoma-to-normal ratio of 1.84 for the 25 mg cohort, with a calculated median tracer concentration in adenomas of 6.43 nmol/mL. Ex vivo signal analyses demonstrated NIR fluorescence within the dysplastic areas of the adenomas. Conclusion: These results suggest that NIR-FME is clinically feasible as a real-time, red-flag technique for detection of colorectal adenomas

Potential Red-Flag Identification of Colorectal Adenomas with Wide-Field Fluorescence Molecular Endoscopy

Adenoma miss rates in colonoscopy are unacceptably high, especially for sessile serrated adenomas/polyps (SSA/Ps) and in high-risk populations, such as patients with Lynch syndrome. Detection rates may be improved by fluorescence molecular endoscopy (FME), which allows morphological visualization of lesions with high-definition white-light imaging as well as fluorescence-guided identification of lesions with a specific molecular marker. In a clinical proof-of-principal study, we investigated FME for colorectal adenoma detection, using a fluorescently labelled antibody (bevacizumab-800CW) against vascular endothelial growth factor A (VEGFA), which is highly upregulated in colorectal adenomas. Methods: Patients with familial adenomatous polyposis (n = 17), received an intravenous injection with 4.5, 10 or 25 mg of bevacizumab-800CW. Three days later, they received NIR-FME. Results: VEGFA-targeted NIR-FME detected colorectal adenomas at all doses. Best results were achieved in the highest (25 mg) cohort, which even detected small adenomas ( Conclusion: These results suggest that NIR-FME is clinically feasible as a real-time, red-flag technique for detection of colorectal adenomas

EGFR & CD44 as potential targets for detection of (pre)malignant lesions with the use offluorescent Near Infrared (NIR) endoscopy

Background Colorectal carcinoma (CRC) represents one of the leading causes of cancer related deaths worldwide. Early diagnosis of (pre)malignant colorectal lesions is the key factor in reducing CRC related morbidity and mortality. Unfortunately, conventional white-light endoscopy appears to be insufficient. For this reason a progressive dual technique is being developed, combining white-light endoscopy with a targeted fluorescent Near Infrared (NIR) modality. With this, a red-flagged imaging method based on a wide-field overview will be accomplished, which enables immediate tissue differentiation and proper small lesion detection. To carry out this fluorescent NIR-technique, cancer-specific NIR-targets need to be identified first. Based on literature, membrane receptors EGFR and CD44 potentially fulfill such a role, but their successful application for identifying (pre)malignant lesions by using the NIR-modality has yet to be investigated. Methods Polyps from Lynch patients (LS), a hereditary colon cancer syndrome hallmarked by small sized colorectal lesions, were included and immunohistochemically (IHC) stained for the presence of EGFR and CD44. Polyps of different dysplasia stages, namely low grade dysplasia (LGD), high grade dysplasia (HGD), carcinoma (CA) tissue and surrounding normal crypts were separately scored on a 4-point scale (0-3) for staining intensity and percentage of positively stained dysplastic cells per tissue sample. In addition, non-hereditary rectal cancer (RC) material was stained and scored for EGFR to serve as a comparison. Results For EGFR we found high receptor expression; respectively 85% for LGD (n=64), 74% for HGD (n=65) and 85% for CA (n=34). The surrounding normal crypts showed significantly less EGFR-expression (all P<0.05; overall sensitivity 80%/specificity 71%). Furthermore, our data suggest a significant trend of increasing EGFR-intensity following progression within the adenoma-carcinoma sequence (P=0.001). Moreover, we did not find measurable difference between the hereditary lynch carcinoma tissue and the non-hereditary rectal carcinoma material (P=0.71). For CD44 we also found high receptor expression; respectively 88% for LGD (n=74), 73% for HGD (n=60) and 85% for CA (n=33). Interestingly, we found hardly any CD44 expression within the normal crypts (all P<0.001), which makes this an extremely specific target in identifying (pre)malignant lesions (overall sensitivity 82%/specificity 99%). Additionally, throughout the tissue of all three dysplasia stages, we established an overall heterogeneous distribution pattern of both receptors. This emphasizes the need for a wide-field overview and real-time tissue differentiation. Conclusion Our data suggest that both EGFR and CD44 could serve as potential NIR-targets for future diagnostic purposes in identifying (pre)malignant lesions using the fluorescent targeted NIR-endoscopic technique.