Dr. Eben L. Rosenthal Profile

Dr. Eben L. Rosenthal

Chair at Vanderbilt University Medical Center

SPIE Involvement:

Conference Program Committee | Author

Publications (23)

Proceedings Article | 13 March 2024 Presentation

Direct measurement trials: use of optically labeled therapeutic antibodies in human trials identifies novel barriers to delivery in intact human tumors

Eben Rosenthal, Guolan Lu, Gary Nolan

Proceedings Volume PC12821, PC1282103 (2024) https://doi.org/10.1117/12.3009461

KEYWORDS: Tumors, Therapeutic antibodies, Pharmacology, Tissues, Therapeutics, Testing and analysis, Resection, Proteins, Matrices, In vivo imaging

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SPIE Journal Paper | 13 May 2023 Open Access

Intraoperative molecular imaging: 3rd biennial clinical trials update

Patrick Bou-Samra, Najib Muhammad, Austin Chang, Ritesh Karsalia, Feredun Azari, Gregory Kennedy, Walter Stummer, Janos Tanyi, Linda Martin, Alexander Vahrmeijer, Barbara Smith, Eben Rosenthal, Patrick Wagner, David Rice, Amy Lee, Hafeez Abdelhafeez, Marcus M. Malek, Gary Kohanbash, Wilson Barry Edwards, Eric Henderson, Jane Skjøth-Rasmussen, Ryan Orosco, Summer Gibbs, Richard W. Farnam, Lalitha Shankar, Baran Sumer, Anand T. N. Kumar, Laura Marcu, Lei Li, Viktor Greuv, Edward J. Delikatny, John Y. K. Lee, Sunil Singhal

JBO, Vol. 28, Issue 05, 050901, (May 2023) https://doi.org/10.1117/12.10.1117/1.JBO.28.5.050901

KEYWORDS: Tumors, Surgery, Dyes, Clinical trials, Cancer, Resection, Fluorescence, Cancer detection, Near infrared, Tissues

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Proceedings Article | 28 March 2023 Open Access

First clinical results of fluorescence lifetime enhanced tumor imaging using exogenous agents (Conference Presentation) (Withdrawal Notice)

Rahul Pal, Thinzar Lwin, Murali Krishnamoorthy, Stefan Carp, Corey Chan, Maclean Nasrallah, John Y. Lee, Yin Hung, Allen Feng, Kenneth Tanabe, Eben Rosenthal, Brian Nahed, Kevin Emerick, Kenneth Rankin, Santiago Lozano-Calderon, Mark Varvares, Anand T. Kumar

Proceedings Volume PC12361, PC123610H (2023) https://doi.org/10.1117/12.2649241

KEYWORDS: Tumors, Fluorescence imaging, Fluorescence, Surgery, Molecules, Molecular photonics, Biomedical applications

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Proceedings Article | 17 March 2023 Presentation

Fluorescence lifetime-enhanced tumor margin assessment in head and neck cancers using receptor targeted probes

Rahul Pal, Thinzar Lwin, Marisa Hom, Mark Varvares, Eben Rosenthal, Anand Kumar

Proceedings Volume 12354, 123540E (2023) https://doi.org/10.1117/12.2649378

KEYWORDS: Receptors, Tumors, Luminescence, Neck, Head, Cancer, Tissues, Surgery, Near infrared, Continuous wave operation

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Proceedings Article | 7 March 2022 Presentation

Between two tissues: fluorescent guided surgery to improve clinical outcomes

Eben Rosenthal

Proceedings Volume PC11943, PC119430B (2022) https://doi.org/10.1117/12.2619279

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Proceedings Article | 4 March 2022 Presentation + Paper

Epidermal growth factor-targeted fluorescence is unaffected by standard neoadjuvant therapies in human sarcomas

Eric Henderson, Paul Werth, Xiaochun Xu, Lesley Jarvis, Keith Paulsen, P. Jack Hoopes, Eben Rosenthal, Brian Pogue, Kimberley Samkoe

Proceedings Volume 11943, 119430B (2022) https://doi.org/10.1117/12.2610226

KEYWORDS: Surgery, Receptors, Tumors, Therapeutics, Luminescence, Tissues, Cancer, Radiotherapy, Medicine, Bone

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SPIE Journal Paper | 17 May 2021 Open Access

Intraoperative molecular imaging clinical trials: a review of 2020 conference proceedings

Feredun Azari, Gregory Kennedy, Elizabeth Bernstein, Constantinos Hadjipanayis, Alexander Vahrmeijer, Barbara Smith, Eben Rosenthal, Baran Sumer, Jie Tian, Eric Henderson, Amy Lee, Quyen Nguyen, Summer Gibbs, Brian Pogue, Daniel Orringer, Cleopatra Charalampaki, Linda Martin, Janos Tanyi, Major Lee, John Y. Lee, Sunil Singhal

JBO, Vol. 26, Issue 05, 050901, (May 2021) https://doi.org/10.1117/12.10.1117/1.JBO.26.5.050901

KEYWORDS: Tumors, Surgery, Cancer, Tissues, Clinical trials, Imaging systems, Luminescence, Molecular imaging, Medicine, Near infrared

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Significance: Surgery is often paramount in the management of many solid organ malignancies because optimal resection is a major factor in disease-specific survival. Cancer surgery has multiple challenges including localizing small lesions, ensuring negative surgical margins around a tumor, adequately staging patients by discriminating positive lymph nodes, and identifying potential synchronous cancers. Intraoperative molecular imaging (IMI) is an emerging potential tool proposed to address these issues. IMI is the process of injecting patients with fluorescent-targeted contrast agents that highlight cancer cells prior to surgery. Over the last 5 to 7 years, enormous progress has been achieved in tracer development, near-infrared camera approvals, and clinical trials. Therefore, a second biennial conference was organized at the University of Pennsylvania to gather surgical oncologists, scientists, and experts to discuss new investigative findings in the field. Our review summarizes the discussions from the conference and highlights findings in various clinical and scientific trials. Aim: Recent advances in IMI were presented, and the importance of each clinical trial for surgical oncology was critically assessed. A major focus was to elaborate on the clinical endpoints that were being utilized in IMI trials to advance the respective surgical subspecialties. Approach: Principal investigators presenting at the Perelman School of Medicine Abramson Cancer Center’s second clinical trials update on IMI were selected to discuss their clinical trials and endpoints. Results: Multiple phase III, II, and I trials were discussed during the conference. Since the approval of 5-ALA for commercial use in neurosurgical malignancies, multiple tracers and devices have been developed to address common challenges faced by cancer surgeons across numerous specialties. Discussants also presented tracers that are being developed for delineation of normal anatomic structures that can serve as an adjunct during surgical procedures. Conclusions: IMI is increasingly being recognized as an improvement to standard oncologic surgical resections and will likely advance the art of cancer surgery in the coming years. The endpoints in each individual surgical subspecialty are varied depending on how IMI helps each specialty solve their clinical challenges.

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SPIE Journal Paper | 13 March 2021 Open Access

Review of successful pathways for regulatory approvals in open-field fluorescence-guided surgery

Brian Pogue, Eben Rosenthal

JBO, Vol. 26, Issue 03, 030901, (March 2021) https://doi.org/10.1117/12.10.1117/1.JBO.26.3.030901

KEYWORDS: Imaging systems, Surgery, Luminescence, Imaging devices, Angiography, Tissues, Visualization, Lymphatic system, X-ray imaging, Endoscopy

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Significance: The modern use of fluorescence in surgery came iteratively through new devices and pre-existing imaging agents, with indications that were paved via regulatory approvals and device clearances. These events led to a growing set of surgery subspecialty uses. Aim: This article outlines the key milestones that initiated commercially marketed systems and agents by highlighting temporal sequences and strategic decisions between them, with the goal of helping to inform future successes. Approach: A review of successful regulatory approvals and the sequences between them was completed for companies that achieved US Food and Drug Administration (FDA) premarket approval or new drug approvals (NDAs) or device clearances in the fields of fluorescent imaging agents, open surgery imaging devices, and their approved medical indications. Results: Angiography agents, indocyanine green and fluorescein, were approved for human use as absorbing dyes, and this use in retinal imaging was the precursor to lateral translation into tissue perfusion imaging in the last two decades with a growing number of devices. Many FDA cleared devices for open fluorescence-guided surgery used the predicate created by the SPY SP2000 system. This first system was 510(k) cleared for angiography imaging with a unique split predicate from x-ray imaging of vasculature and retinal fluorescence angiography. Since that time, the lateral spread of open surgery devices being cleared for new indications has been occurring with a growth of adoption in surgical subspecialties. Growth into new surgical subspecialties has been achieved by leveraging different NDAs and clearances between indications, such that medical uses have broadened over time. Conclusions: Key decisions made by developers to advance specific device clearances and NDAs have been based upon existing optical fluorescent agents. The historical lessons and regulatory trends in newer indications and contrast agents can help the field evolve via successful investment in new systems and applications.

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Proceedings Article | 10 March 2020 Presentation

Clinical application of fluorescence in the operating room (Conference Presentation)

Eben Rosenthal

Proceedings Volume 11222, 112220V (2020) https://doi.org/10.1117/12.2548747

KEYWORDS: Luminescence, Surgery, Visualization, Head, Neck, Tumors, Medicine, Cancer

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SPIE Journal Paper | 5 December 2019 Open Access

Review of clinical trials in intraoperative molecular imaging during cancer surgery

John Y. Lee, Steve Cho, Walter Stummer, Janos Tanyi, Alexander Vahrmeijer, Eben Rosenthal, Barbara Smith, Eric Henderson, David Roberts, Amy Lee, Constantinos Hadjipanayis, Jeffrey Bruce, Jason G. Newman, Sunil Singhal

JBO, Vol. 24, Issue 12, 120901, (December 2019) https://doi.org/10.1117/12.10.1117/1.JBO.24.12.120901

KEYWORDS: Surgery, Tumors, Cancer, Clinical trials, Molecular imaging, Tissues, Head, Neck, Ovarian cancer, Colorectal cancer

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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

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

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.

SPIE Journal Paper | 5 October 2018 Open Access

Perspective review of what is needed for molecular-specific fluorescence-guided surgery

Brian Pogue, Eben Rosenthal, Samuel Achilefu, Gooitzen van Dam

JBO, Vol. 23, Issue 10, 100601, (October 2018) https://doi.org/10.1117/12.10.1117/1.JBO.23.10.100601

KEYWORDS: Surgery, Tumors, Cancer, Imaging systems, In vivo imaging, Luminescence, Tissues, Colorectal cancer, Pancreatic cancer, Pathology

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Molecular image-guided surgery has the potential for translating the tools of molecular pathology to real-time guidance in surgery. As a whole, there are incredibly positive indicators of growth, including the first United States Food and Drug Administration clearance of an enzyme-biosynthetic-activated probe for surgery guidance, and a growing number of companies producing agents and imaging systems. The strengths and opportunities must be continued but are hampered by important weaknesses and threats within the field. A key issue to solve is the inability of macroscopic imaging tools to resolve microscopic biological disease heterogeneity and the limitations in microscopic systems matching surgery workflow. A related issue is that parsing out true molecular-specific uptake from simple-enhanced permeability and retention is hard and requires extensive pathologic analysis or multiple in vivo tests, comparing fluorescence accumulation with standard histopathology and immunohistochemistry. A related concern in the field is the over-reliance on a finite number of chosen preclinical models, leading to early clinical translation when the probe might not be optimized for high intertumor variation or intratumor heterogeneity. The ultimate potential may require multiple probes, as are used in molecular pathology, and a combination with ultrahigh-resolution imaging and image recognition systems, which capture the data at a finer granularity than is possible by the surgeon. Alternatively, one might choose a more generalized approach by developing the tracer based on generic hallmarks of cancer to create a more “one-size-fits-all” concept, similar to metabolic aberrations as exploited in fluorodeoxyglucose - positron emission tomography (FDG-PET) (i.e., Warburg effect) or tumor acidity. Finally, methods to approach the problem of production cost minimization and regulatory approvals in a manner consistent with the potential revenue of the field will be important. In this area, some solid steps have been demonstrated in the use of fluorescent labeling commercial antibodies and separately in microdosing studies with small molecules.

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