Fluorescence-guided tumor detection with a novel anti-EpCAM targeted antibody fragment: Preclinical validation

Boogerd, Leonora S. F.; Boonstra, Martin C.; Prevoo, H.A.J.M.; Handgraaf, Henricus J.M.; Kuppen, Peter J.K.; Velde, Cornelis J.H. van de; Fish, Alexander; Cordfunke, Robert A.; Valentijn, A. Rob P. M.; Scheltinga, Anton Gt Terwisscha van; MacDonald, Glen C.; Cizeau, Jeannick; Premsukh, Arjune; Slooten, Maaike L. Vinkenburg van; Burggraaf, Jacobus; Sier, Cornelis F.M.; Vahrmeijer, Alexander L.

doi:10.1016/j.suronc.2018.10.004

Cited by 27 publications

(23 citation statements)

References 41 publications

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“…Therefore, the primary objective of this study was to determine suitable biomarkers for targeted molecular imaging in myxofibrosarcoma using immunohistochemical analyses of surgically obtained tumor specimens. Ten biomarker candidates were selected based on the literature and availability of imaging agents that specifically target these biomarkers [21][22][23][24][25][26][27][28][29] . The biomarker with the highest expression rate was subsequently evaluated on a selection of whole slides to evaluate the contrast between tumor tissue and adjacent benign regions.…”

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confidence: 99%

Immunohistochemical selection of biomarkers for tumor-targeted image-guided surgery of myxofibrosarcoma

Gooyer

Versleijen-Jonkers²,

Hillebrandt-Roeffen³

et al. 2020

Sci Rep

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Myxofibrosarcoma(MFS) is the most common soft tissue sarcoma(STS) in elderly patients. Surgical resection remains the main treatment modality but tumor borders can be difficult to delineate with conventional clinical methods. Incomplete resections are a common problem and local recurrence remains a clinical issue. A technique that has shown great potential in improving surgical treatment of solid tumors is tumor targeted imaging and image-guided surgery with near-infrared fluorescence. To facilitate this technique, it is essential to identify a biomarker that is highly and homogenously expressed on tumor cells, while being absent on healthy non-malignant tissue. The purpose of this study was to identify suitable molecular targets for tumor-targeted imaging of myxofibrosarcoma. Ten potential molecular targets for tumor targeted imaging were investigated with immunohistochemical analysis in myxofibrosarcoma tissue (n = 34). Results were quantified according to the immunoreactive score(IRS). Moderate expression rates were found for uPAR, PDGFRa and EMA/MUC1. High expression rates of VEGF and TEM1 were seen. Strong expression was most common for TEM1 (88.2%). These results confirms that TEM1 is a suitable target for tumor-targeted imaging of myxofibrosarcoma. Keywords Image-guided surgery; Immunohistochemistry; Molecular imaging; Myxofibrosarcoma; Soft tissue sarcoma; Tumor endothelial marker 1(TEM1), Vascular endothelial growth factor (VEGF).Myxofibrosarcoma (MFS) is a histological subtype of soft tissue sarcoma (STS) formerly classified as a myxoidtype malignant fibrous histiocytoma. It has been reclassified and defined as a distinct pathological entity in the World Health Organization (WHO) criteria set in 2002 1,2 . Myxofibrosarcoma is a relatively common sarcoma in the elderly that mainly arises in the extremities 3 . Primary MFS most often presents as a subcutaneous painless, slow growing nodule, but completely infiltrative growth patterns along fascial planes without formation of an evident tumor mass have also been described 4 . The low-grade lesions have a relatively low metastatic potential but show a significant propensity for local recurrences 5-8 . These recurrences show higher-grade histology in up to 50% of all cases compared to the primary tumor 3 . Subsequently, high and intermediate grade disease exhibits a greater metastatic potential, mainly metastasizing to the lungs and lymph nodes 7,9 . Current guidelines recommend wide surgical resection combined with pre or post-operative radiotherapy as the preferred treatment 10 . Despite this strategy, positive margins after surgery occur in up to 20% of cases and reported local relapse rates range from 15 to 65% [5][6][7][8]11 .Currently clinicians rely on conventional imaging modalities such as CT and MRI to determine the location and extent of tumor burden prior to surgery. Translating these conventional imaging modalities to the surgical theatre remains challenging, forcing the surgeon to depend mainly on tactile and visual cues during the procedure. P...

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mentioning

confidence: 99%

Immunohistochemical selection of biomarkers for tumor-targeted image-guided surgery of myxofibrosarcoma

Gooyer

Versleijen-Jonkers²,

Hillebrandt-Roeffen³

et al. 2020

Sci Rep

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“…A fluorescent tracer targeting EpCAM has not yet been used in human clinical trials. However, Boogerd et al [29] reported on a fluorescent anti-EpCAM tracer that was tested preclinically. Further work should focus on the clinical validation of EpCAM and CEA targets for intraoperative tumor-targeted imaging in EAC to personalize esophageal surgery.…”

Section: Discussionmentioning

confidence: 99%

Identifying Biomarkers in Lymph Node Metastases of Esophageal Adenocarcinoma for Tumor-Targeted Imaging

et al. 2020

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Introduction Tumor-targeted imaging is a promising technique for the detection of lymph node metastases (LNM) and primary tumors. It remains unclear which biomarker is the most suitable target to distinguish malignant from healthy tissue in esophageal adenocarcinoma (EAC).Objective We performed an immunohistochemistry study to identify viable tumor markers for tumor-targeted imaging of EAC. Methods We used samples from 72 patients with EAC to determine the immunohistochemical expression of ten potential tumor biomarkers for EAC (carbonic anhydrase IX [CA-IX], carcinoembryonic antigen [CEA], hepatic growth factor receptor, epidermal growth factor receptor, epithelial membrane antigen [EMA], epithelial cell adhesion molecule [EpCAM], human epidermal growth factor receptor 2 [HER-2], urokinase plasminogen activator receptor, vascular endothelial growth factor-A [VEGF-A], and VEGF receptor 2). Immunohistochemistry was performed on tissue microarrays of LNM (n = 48), primary EACs (n = 62), fibrotic tissues (n = 11), nonmalignant lymph nodes (n = 24), and normal esophageal and gastric tissues (n = 40). Tumor marker staining was scored on intensity and percentage of positive cells. Results EMA and EpCAM showed strong expression in LNM (> 95%) and primary EACs (> 95%). Significant expression was also observed for LNM and EAC using VEGF-A (85 and 92%), CEA (68 and 54%), and CA-IX (4 and 34%). The other tumor biomarkers showed expression of 0-15% for LNM and primary EAC. Except for VEGF-A, nonmalignant lymph node staining was scored as slight or absent. Conclusions High expression rates and correlation between LNM in EAC combined with low expression rates in healthy lymph nodes and esophagus tissues were observed for EpCAM and CEA, meaning these are promising targets for tumortargeted imaging approaches for lymph nodes in patients with EAC. Key PointsThe use of intraoperative targeted imaging to detect lymph node metastases is promising and will be an important step forward in personalizing the surgical treatment of patients with esophageal cancer.The most suitable biomarker for targeted imaging techniques in lymph node metastases of esophageal adenocarcinoma remains unclear.Histological evaluation shows that epithelial cell adhesion molecule and carcinoembryonic antigen are suitable targets for image-guided esophageal surgery, both before and after neoadjuvant chemoradiotherapy.

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“…To be able to recognize malignancy during an operation, the expression in normal tissue should preferably be absent. But recent (pre)clinical studies indicate that a ratio of at least 2 in favor of the tumor might suffice for other tumor targets like EpCAM [ 23 ]. Presence in cytoplasm will not interfere with targeted imaging; it could even be an advantage if EphB4 would be internalized after being targeted by a tracer.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of EphB4 as Target for Image-Guided Surgery of Breast Cancer

et al. 2020

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Background: Targeted image-guided surgery is based on the detection of tumor cells after administration of a radio-active or fluorescent tracer. Hence, enhanced binding of a tracer to tumor tissue compared to healthy tissue is crucial. Various tumor antigens have been evaluated as possible targets for image-guided surgery of breast cancer, with mixed results. Methods: In this study we have evaluated tyrosine kinase receptor EphB4, a member from the Eph tyrosine kinase receptor family, as a possible target for image-guided surgery of breast cancers. Two independent tissue micro arrays, consisting of matched sets of tumor and normal breast tissue, were stained for EphB4 by immunohistochemistry. The intensity of staining and the percentage of stained cells were scored by two independent investigators. Results: Immunohistochemical staining for EphB4 shows that breast cancer cells display enhanced membranous expression compared to adjacent normal breast tissue. The enhanced tumor staining is not associated with clinical variables like age of the patient or stage or subtype of the tumor, including Her2-status. Conclusion: These data suggest that EphB4 is a promising candidate for targeted image-guided surgery of breast cancer, especially for Her2 negative cases.

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Fluorescence-guided tumor detection with a novel anti-EpCAM targeted antibody fragment: Preclinical validation

Cited by 27 publications

References 41 publications

Immunohistochemical selection of biomarkers for tumor-targeted image-guided surgery of myxofibrosarcoma

Immunohistochemical selection of biomarkers for tumor-targeted image-guided surgery of myxofibrosarcoma

Identifying Biomarkers in Lymph Node Metastases of Esophageal Adenocarcinoma for Tumor-Targeted Imaging

Evaluation of EphB4 as Target for Image-Guided Surgery of Breast Cancer

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