C-Met targeted fluorescence molecular endoscopy in Barrett's esophagus patients and identification of outcome parameters for phase-I studies

Jongh, Steven J de; Voskuil, Floris; Schmidt, Iris; Karrenbeld, Arend; Kats-Ugurlu, Gürsah; Meersma, Gert Jan; Westerhof, Jessie; Witjes, Max J. H.; Dam, Gooitzen M. van; Robinson, Dominic J.; Nagengast, Wouter B.

doi:10.7150/thno.42224

Cited by 22 publications

(40 citation statements)

References 25 publications

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“…While for tissue incubation the maximum depth of tracer penetration is not yet well understood, there are studies that show that at least several cell layers (up to 300 µm) can be effectively stained and evaluated [ 28 , 29 ]. And while physics will dictate the superficial nature of fluorescence imaging, in vivo use of EMI-137 suggest that the issues behind tracer penetration in tissue are overcome when applying EMI-137 (or any other fluorescent tracer) in humans [ 8 , 9 , 25 ]. More specifically, in penile cancer patients, the presence of fluorescence was not limited to the rim of the tumor but could be detected throughout the tumor (tumor infiltration depth up to 24 mm [ 8 ]).…”

Section: Discussionmentioning

confidence: 99%

“…For example, in colorectal cancer patients, EMI-137 allowed for the identification of lesions that were missed using white-light endoscopy [ 9 ]. Additionally important, the clinical implementation of EMI-137 fluorescence guidance did not interfere with the standard clinical surgical and pathological workflow of Barret’s neoplasia and penile cancer [ 8 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

“…EMI-137 is a c-Met targeting fluorescent tracer that, following extensive tracer optimization and preclinical evaluations, has been translated to the clinic and comes with thoroughly documented pharmacokinetics [ 9 ]. This tracer also previously demonstrated its ability to apply c-Met targeted resection of colorectal polyps, Barret’s neoplasia and penile cancer, based on far-red related fluorescence after intravenous administration [ 8 , 9 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

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Translation of c-Met Targeted Image-Guided Surgery Solutions in Oral Cavity Cancer—Initial Proof of Concept Data

Buckle

Alphen

Oosterom

et al. 2021

Cancers

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Intraoperative tumor identification (extension/margins/metastases) via receptor-specific targeting is one of the ultimate promises of fluorescence-guided surgery. The translation of fluorescent tracers that enable tumor visualization forms a critical component in the realization of this approach. Ex vivo assessment of surgical specimens after topical tracer application could help provide an intermediate step between preclinical evaluation and first-in-human trials. Here, the suitability of the c-Met receptor as a potential surgical target in oral cavity cancer was explored via topical ex vivo application of the fluorescent tracer EMI-137. Freshly excised tumor specimens obtained from ten patients with squamous cell carcinoma of the tongue were incubated with EMI-137 and imaged with a clinical-grade Cy5 prototype fluorescence camera. In-house developed image processing software allowed video-rate assessment of the tumor-to-background ratio (TBR). Fluorescence imaging results were related to standard pathological evaluation and c-MET immunohistochemistry. After incubation with EMI-137, 9/10 tumors were fluorescently illuminated. Immunohistochemistry revealed c-Met expression in all ten specimens. Non-visualization could be linked to a more deeply situated lesion. Tumor assessment was improved via video representation of the TBR (median TBR: 2.5 (range 1.8–3.1)). Ex vivo evaluation of tumor specimens suggests that c-Met is a possible candidate for fluorescence-guided surgery in oral cavity cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Translation of c-Met Targeted Image-Guided Surgery Solutions in Oral Cavity Cancer—Initial Proof of Concept Data

Buckle

Alphen

Oosterom

et al. 2021

Cancers

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“…Moreover, the degree of correlation between CEA, EpCAM, αvβ6, and uPAR expression measured by IHC in FFPE material and in vivo expression as measured by fluorescence signal intensity has yet to be elucidated in clinical trials. However, clinical trials investigating c-Met-targeted fluorescence endoscopy have demonstrated an excellent correlation between the fluorescence signal intensity measured in vivo and the expression of the target measured with IHC [ 37 , 38 ], indicating the clinical relevance of IHC expression data of potential targets. Although the expression of CEA and EpCAM has already been demonstrated in patients without a pCR after neoadjuvant therapy [ 35 ], future studies should include these patients as a control group to directly compare marker expression between patients with and without a pCR.…”

Section: Discussionmentioning

confidence: 99%

CEA, EpCAM, αvβ6 and uPAR Expression in Rectal Cancer Patients with a Pathological Complete Response after Neoadjuvant Therapy

et al. 2021

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Rectal cancer patients with a complete response after neoadjuvant therapy can be monitored with a watch-and-wait strategy. However, regrowth rates indicate that identification of patients with a pathological complete response (pCR) remains challenging. Targeted near-infrared fluorescence endoscopy is a potential tool to improve response evaluation. Promising tumor targets include carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), integrin αvβ6, and urokinase-type plasminogen activator receptor (uPAR). To investigate the applicability of these targets, we analyzed protein expression by immunohistochemistry and quantified these by a total immunostaining score (TIS) in tissue of rectal cancer patients with a pCR. CEA, EpCAM, αvβ6, and uPAR expression in the diagnostic biopsy was high (TIS > 6) in, respectively, 100%, 100%, 33%, and 46% of cases. CEA and EpCAM expressions were significantly higher in the diagnostic biopsy compared with the corresponding tumor bed (p < 0.01). CEA, EpCAM, αvβ6, and uPAR expressions were low (TIS < 6) in the tumor bed in, respectively, 93%, 95%, 85%, and 62.5% of cases. Immunohistochemical evaluation shows that CEA and EpCAM could be suitable targets for response evaluation after neoadjuvant treatment, since expression of these targets in the primary tumor bed is low compared with the diagnostic biopsy and adjacent pre-existent rectal mucosa in more than 90% of patients with a pCR.

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“…Recently, discussion sessions and expert meetings were held within the field, resulting in the development of research guidelines and standards. [111][112][113] This will take research in the field of optical molecular imaging to a higher plan. Now the time has come to confirm the use of optical molecular imaging in larger patient populations, ideally as part of randomized controlled trials.…”

Section: Clinical Translation Beyond Proof-of-conceptmentioning

confidence: 99%

Molecular Fluorescence Endoscopy: clinical development and validation within the lower gastrointestinal tract

Tjalma¹

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Introduction: Small and flat adenomas are known to carry a high miss-rate during standard white-light endoscopy. Increased detection rate may be achieved by molecular fluorescence endoscopy with targeted near-infrared (NIR) fluorescent tracers. The aim of this study was to validate vascular endothelial growth factor A (VEGFA) and epidermal growth factor receptor (EGFR)-targeted fluorescent tracers during ex vivo colonoscopy with an NIR endoscopy platform. Methods: VEGFA and EGFR expression was determined by immunohistochemistry on a large subset of human colorectal tissue samples-48 sessile serrated adenomas/polyps, 70 sporadic high-grade dysplastic adenomas, 19 hyperplastic polyps-and tissue derived from patients with Lynch syndrome (LS)-78 low-grade dysplastic adenomas, 57 high-grade dysplastic adenomas and 31 colon cancer samples. To perform an ex vivo colonoscopy procedure, 14 mice with small intraperitoneal EGFR-positive HCT116 luc tumors received intravenous bevacizumab-800CW (anti-VEGFA), cetuximab-800CW (anti-EGFR), control tracer IgG-800CW, or sodium chloride. Three days later, 8 resected HCT116 luc tumors (2-5 mm) were stitched into 1 freshly resected human colon specimen and followed by an ex vivo molecular fluorescence colonoscopy procedure. Results: Immunohistochemistry showed high VEGFA expression in 79-96% and high EGFR expression in 51-69% of the colorectal lesions. Both targets were significantly overexpressed in the colorectal lesions, compared with the adjacent normal colon crypts. During ex vivo molecular fluorescence endoscopy, all tumors could clearly be delineated for both bevacizumab-800CW and cetuximab-800CW tracers. Specific tumor uptake was confirmed with fluorescent microscopy showing, respectively, stromal and cell membrane fluorescence. Conclusion: VEGFA is a promising target for molecular fluorescence endoscopy because it showed a high protein expression, especially in sessile serrated adenomas/polyps and LS. We demonstrated the feasibility to visualize small tumors in real time during colonoscopy using a NIR fluorescence endoscopy platform, providing the endoscopist a wide-field redflag technique for adenoma detection. Clinical studies are currently being performed in order to provide inhuman evaluation of our approach.

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C-Met targeted fluorescence molecular endoscopy in Barrett's esophagus patients and identification of outcome parameters for phase-I studies

Cited by 22 publications

References 25 publications

Translation of c-Met Targeted Image-Guided Surgery Solutions in Oral Cavity Cancer—Initial Proof of Concept Data

Translation of c-Met Targeted Image-Guided Surgery Solutions in Oral Cavity Cancer—Initial Proof of Concept Data

CEA, EpCAM, αvβ6 and uPAR Expression in Rectal Cancer Patients with a Pathological Complete Response after Neoadjuvant Therapy

Molecular Fluorescence Endoscopy: clinical development and validation within the lower gastrointestinal tract

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