Dr. Stan van Keulen Profile

Dr. Stan van Keulen

at Stanford Univ

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Publications (3)

Proceedings Article | 4 March 2019 Presentation

fluorescence-guided surgery with panitumumab-IRDye800 and cetuximab-IRDye800 in glioblastoma patients (Conference Presentation)

Quan Zhou, Sarah Miller, Nynke van den Berg, Guolan Lu, Hannes Vogel, Romain Cayrol, Nicholas Oberhelman, Stefania Chirita, Stan van Keulen, Gerald Grant, Gordon Li, Eben Rosenthal

Proceedings Volume 10862, 108620Y (2019) https://doi.org/10.1117/12.2510366

KEYWORDS: Tumors, Luminescence, Tissues, Surgery, Brain, Magnesium, Near infrared, Receptors, Monoclonal antibodies, Tissue optics

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Introduction: Glioblastoma (GBM) is the most common and devastating primary brain tumor. The recurrence rate remains high with a median survival of 15 months. GBM’s infiltrative nature results in ill-defined margins that makes maximal tumor resection with minimal morbidity a challenge. Epidermal growth factor receptor (EGFR) is the most frequently amplified gene in GBM (35-45% of tumors) and is associated with overexpression in about 40-98% of cases, a characteristic of more aggressive phenotypes. We hypothesize that fluorescence labeled anti-EGFR monoclonal antibodies (mAb), panitumumab-IRDye800 (pan800) and cetuximab-IRDye800 (cet800), could be leveraged to enhance tumor contrast during surgical resection and improve patient outcome. Methods: 50mg fluorescently labeled corresponding study drugs, pan800 and cet800 respectively, were administered 1-2 days in glioblastoma patients with contrast enhancing (CE) tumors prior to surgery following 100 mg loading dose of unlabeled cetuximab or panitumumab. Near-infrared fluorescence imaging of tumor and histologically negative peri-tumoral tissue was performed intraoperatively and ex vivo. Fluorescence was measured as mean fluorescence intensity (MFI), and tumor-to-background ratios (TBRs) were calculated by comparing MFIs of tumor and histologically uninvolved tissue. Results: Despite heterogeneous drug uptake across all resected brain tissues, mean fluorescence intensity (MFI) correlated strongly (R^2=0.97) with tumor volume among histologically confirmed tumor tissues. The smallest detectable tumor size in a closed-field setting was 4.2 x 2.7 mm^2 (8.2 mg) for pan800 and 8.5 x 6.6 mm^2 (70mg) for cet800. Tumor tissues from pan800 infusion had significantly higher mean TBR (8.1 ± 4.6) than cet800 infused ones in intraoperative imaging (3.3 ± 2.7; P = 0.004). NIR fluorescence from both test drugs provided high contrast to identify as few as a cluster of (5 ± 1) tumor cells in macroscopic imaging of whole sections of paraffin embedded tissues. Sensitivity and specificity of MFI for viable tumor detection was calculated and fluorescence was found to be highly sensitive (64.4% for pan800, 73.0% for cet800) and specific (98.0% for pan800, 66.3% for cet800) for viable tumor tissue while normal peri-tumoral tissue showed minimal fluorescence. No related grade-2 adverse events were observed 30 days beyond the infusion of either study drugs. Conclusion: EGFR antibody based imaging for contrast-enhanced glioblastomas proved safe in human patients and specific intratumoral delivery of NIR fluorescence provided high optical contrast and resolution for intraoperative image-guided resection. Fully humanized panitumumab-IRDye800 demonstrated superior detection sensitivity and tumor specificity over the chimeric cetuximab-IRDye800.

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 | 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

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