Mr. Robert D. Ertsey Profile

Robert D. Ertsey

at Stanford Univ

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Author

Publications (5)

Proceedings Article | 4 March 2019 Presentation

Reversible blood-brain barrier modulation enhances in vivo delivery of panitumumab-IRDye800 to high-grade glioma in cranial window model (Conference Presentation)

Quan Zhou, Christy Wilson, Hannes Vogel, Nutte Teraphongphom, Robert Ertsey, Pauline Chu, Guolan Lu, Nynke van den Berg, Stan van Keulen, Naoki Nishio, Gerald Grant, Eben Rosenthal

Proceedings Volume 10864, 1086402 (2019) https://doi.org/10.1117/12.2511180

KEYWORDS: Modulation, Cranial windows, Tumors, Blood brain barrier, In vivo imaging, Brain, Near infrared, Surgery, Proteins, Animal model studies

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Background: Pediatric High-grade gliomas (pHGGs) are the No.1 cause of cancer-related deaths in children with median survival of less than a year. pHGGs tend to be infiltrative and appear irregularly shaped with ill-defined borders difficult to be distinguished from surrounding normal brain tissue. As the extent of surgical resection predicts survival, precise tumor removal with more accurate margin delineation means better treatment outcome and less loss of vital functions. While EGFR is one of the most commonly amplified genes in pHGGs, its protein-level expression is not as well characterized as in adult HGGs. Previously, near-infrared (NIR) dye labeled epidermal growth factor receptor (EGFR) antibody has served as contrast agent in fluorescence-guided surgery of head and neck cancer. However, it must overcome the blood-brain barrier (BBB) for effective intratumoral delivery in the case of brain cancer. Therefore, the latest advancement in reversible BBB opening with tight junction protein modulation has the potential to enable the molecular targeted imaging guidance of pHGG resection. Aims: The current study aimed to improve intratumoral delivery of NIR fluorescent EGFR antibody via reversible BBB permeability enhancement with siRNA modulation of tight junction protein in an orthotopic xenograft animal model of high-grade glioma with EGFR overexpression. Furthermore, resected pHGGs were examined for EGFR expression in order to stratify patient subpopulation most likely to benefit from intraoperative molecular imaging strategy that targets EGFR. Methods: An orthotopic high-grade glioma xenograft model was established in 6-15 week old mice (n=3) by intracranial injection of 10^6 EGFR-overexpressing high-grade glioma cells (D270, 10ul) 3mm below the surface of brain. Subsequently, the exposed brain was covered with a glass plate secured to the skull with cyanoacrylate glue. siRNA was selected from those targeting conserved regions of the mouse claudin-5 cDNA sequence. 20μg of claudin-5 siRNA was injected intravenously via the tail vein in an in vivo-Jet-PEI solution (Polyplus Transfection) at a rate of 0.2 ml/sec 10 days post tumor implant. 0.1mL tetramethylrhodamine (250kDa) and various sized FITC-dextran (4.4-150kDa) solutions were injected intravenously to visualize blood vessels and assess extravasation distance through cranial window via 2-photo microscopy. Enhanced permeability of BBB was characterized by increase in KTrans on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in the tumor region. Mean fluorescence intensity at 800nm was measured through cranial window with an in vivo NIR imager (Pearl Impulse, LI-COR Biosciences) 0-72 hours following tail vein injection of 200ug panitumumab-IRDye800 (pan800). Immunohistochemical analysis of EGFR expression was performed on surgically resected de novo primary pHGG tumors, from seven GBM and three anaplastic ependymoma patients respectively. Results: The siRNA has shown a reversible 80% suppression of claudin-5 at 48-hrs post-injection that returned to normal levels at 72 hours. More than three-fold increase in penetration distance of 70kDa enhancing agent was observed in extravascular space and a 74% increase in intratumoral permeability was observed on DCE-MRI. Intratumoral delivery of fluorescent EGFR antibody (panitumumab-IRDye800) occurred at 6 hours and peaked at 48 hours post systemic injection following BBB opening. Positive EGFR expression was found in 70% of all surgically removed high-grade pediatric brain tumor samples. The median age of patients with positive EGFR expression was 15 (IQR = 12.75 to 16.50), significantly higher (P = 0.018) than that of EGFR negative patients (median = 0.75, IQR = 0.47 to 5.38). Conclusions: We provided proof-of-concept evidence that the enabling technology of transient BBB modulation and fluorescence-guided imaging with EGFR targeting antibody has great potential for clinical translation to improve surgery outcome by providing tumor-specific precision resection to a significant subpopulation of young patients with pHGGs

Proceedings Article | 4 March 2019 Presentation

Predicting antibody penetration in a first-in-human clinical trial of head and neck cancers (Conference Presentation)

Guolan Lu, Shayan Fakurnejad, Brock Martin, Ashley Zhu, Nynke van den Berg, Stan van Keulen, Quan Zhou, Tarn Teraphongphom, Rebecca Gao, Nicholas Oberhelman, Stefania Chirita, Robert Erstey, Christina Kong, Dimitrios Colevas, Eben Rosenthal

Proceedings Volume 10859, 1085905 (2019) https://doi.org/10.1117/12.2513258

KEYWORDS: Tumors, Clinical trials, Head, Neck, Cancer, Image analysis, Tissues, Lymphatic system, Magnesium, Solids

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Proceedings Article | 14 March 2018 Presentation

MEMS based multi-spectral dual-axis confocal microendoscope for clinical applications (Conference Presentation)

Zhen Qiu, Nathan Loewke, Wibool Piyawattanametha, Il-woong Jung, Tarn Teraphongphom, Robert Ertsey, Frank Schonig, Stephan Rogalla, Shai Friedland, Michael Mandella, Daniel Lopez, Eben Rosenthal, Christopher Contag

Proceedings Volume 10545, 105450N (2018) https://doi.org/10.1117/12.2292262

KEYWORDS: Microelectromechanical systems, Confocal microscopy, Cancer, Scanners, Colorectal cancer, Microopto electromechanical systems, Tumors, Imaging systems, Molecular imaging, Algorithm development

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Proceedings Article | 14 March 2018 Presentation

Handheld dual-modality wide-field fluorescent imaging guided dual-axis confocal microscope for fluorescence molecular guidance of precise tumor resection in head and neck surgery (Conference Presentation)

Zhen Qiu, Tarn Teraphongphom, Nynke van den Berg, Nathan Loewke, Guolan Lu, Robert Ertsey, Frank Schonig, Stephan Rogalla, Shai Friedland, Michael Mandella, Eben Rosenthal, Christopher Contag

Proceedings Volume 10478, 104780E (2018) https://doi.org/10.1117/12.2291986

KEYWORDS: Luminescence, Tissues, Microscopes, Tissue optics, Confocal microscopy, Tumors, Head, Neck, Imaging systems, Surgery

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Proceedings Article | 14 March 2018 Presentation

Panitumumab-IRDye800 for fluorescence-guidance based metastatic lymph node identification in patients with head and neck cancer (Conference Presentation)

Nynke van den Berg, Nutte Teraphongphom, Willemieke S. F. Tummers, Steven Hong, Guolan Lu, Adam Gomez , Brock Martin, Robert Ertsey, Nicholas Oberhelman, Christina Kong, Dimitros Colevas, Eben Rosenthal

Proceedings Volume 10478, 104780T (2018) https://doi.org/10.1117/12.2291298

KEYWORDS: Tumors, Luminescence, Lymphatic system, Head, Neck, Cancer, Surgery, Imaging systems, Receptors

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