A Phase I Clinical Trial of Targeted Intraoperative Molecular Imaging for Pulmonary Adenocarcinomas

Predina, Jarrod D.; Newton, Andrew D.; Keating, Jane; Dunbar, Ashley; Connolly, Courtney; Baldassari, Michael P.; Mizelle, Jack; Xia, Leilei; Deshpande, Charuhas; Kucharczuk, John C.; Low, Philip S.; Singhal, Sunil

doi:10.1016/j.athoracsur.2017.08.062

Cited by 75 publications

(74 citation statements)

References 24 publications

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“…10 In our previous work, we have demonstrated that OTL38 binds the folate receptor with a high affinity, thus allowing for identification of synchronous disease in ∼10% of lung cancer patients and reproducible detection of subcentimeter nodules. 4,5 Based on our initial successes, we have hypothesized that this approach would be applicable to other pulmonary malignancies that express the FRα; however, the presented data herein are the first data to support this principle.…”

Section: Discussionmentioning

confidence: 97%

“…This expression pattern is similar to our observations involving molecular imaging with OTL38 for pulmonary adenocarcinomas, and we have previously noted that tumor fluorescence is present even when as little as 20% to 30% of tumor expresses FRα. 5,11 As we continue enrollment of patients with osteosarcoma metastases in clinical trials, we will better understand how this expression pattern impacts the reproducibility of in vivo tumor fluorescence during pulmonary metastasectomy.…”

Section: Discussionmentioning

confidence: 99%

“…For example, our group has recently reported phase I results involving a NIR folate receptor-α (FRα)-targeted probe, OTL38. 4,5 In these initial reports, we have found that >90% of primary lung cancers accumulate OTL38 and generate tumor fluorescence during minimally invasive pulmonary resection. In addition to reproducibly detecting nodules as small as 3 mm, this approach has allowed us to find occult cancers in 12% of patients enrolled.…”

Section: Introductionmentioning

confidence: 97%

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Utilization of targeted near-infrared molecular imaging to improve pulmonary metastasectomy of osteosarcomas

et al. 2018

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Pulmonary metastasectomy for osteosarcoma provides a select group of patients an opportunity for long-term survival and possible cure. Unfortunately, a complete metastasectomy is challenging due an inability to accurately identify lesions that lay below the threshold of preoperative imaging or intraoperative visual and tactile inspection. Growing evidence suggests that osteosarcomas express a number of unique molecular markers, including the folate receptor alpha. In this case report, we describe the application of a folate receptor-targeted, near-infrared optical contrast agent (OTL38) to improve osteosarcoma localization during minimally invasive pulmonary resection. In addition to localizing preoperatively identified lesions, this technology helped identify additional disease that was undetected on preoperative imaging or with traditional intraoperative techniques. This report marks the first successful utilization of a molecular imaging probe useful for osteosarcomas. This technology may provide a unique approach to improve pulmonary metastasectomy of osteosarcomas.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Utilization of targeted near-infrared molecular imaging to improve pulmonary metastasectomy of osteosarcomas

et al. 2018

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“…Given the use of numerous drug-device combinations in preclinical and clinical studies, a definitive TBR threshold that indicates a positive fluorescent signal is difficult to define. However, successful intraoperative visualization of tumors has been demonstrated with several targeted agents that produce TBRs > 2 (30,38,39) and suggests that contrast ratios for Ga-MMC(IR800)-TOC may be sufficient for tumor identification in a clinical setting.…”

Section: Discussionmentioning

confidence: 99%

Specific Targeting of Somatostatin Receptor Subtype-2 for Fluorescence-Guided Surgery

Vargas

Kossatz

Voss

et al. 2019

Clinical Cancer Research

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Purpose: Clinically available intraoperative imaging tools to assist surgeons in identifying occult lesions are limited and partially responsible for the high rate of disease recurrence in patients with neuroendocrine tumors (NET). Using the established clinical efficacy of radiolabeled somatostatin analogs as a model, we demonstrate the ability of a fluorescent somatostatin analog to selectively target tumors that overexpress somatostatin receptor subtype-2 (SSTR2) and demonstrate utility for fluorescence-guided surgery (FGS). Experimental Design: A multimodality chelator (MMC) was used as a "radioactive linker" to synthesize the fluorescently labeled somatostatin analog, 67/68 Ga-MMC(IR800)-TOC. In vivo studies were performed to determine the pharmacokinetic profile, optimal imaging time point, and specificity for SSTR2-expressing tissues. Meso-and microscopic imaging of resected tissues and frozen sections were also performed to further assess specific binding, and binding to human NETs was examined using surgical biospecimens from patients with pancreatic NETs. Results: Direct labeling with 67 Ga/ 68 Ga provided quantitative biodistribution analysis that was in agreement with fluorescence data. Receptor-mediated uptake was observed in vivo and ex vivo at the macro-, meso-, and microscopic scales. Surgical biospecimens from patients with pancreatic NETs also displayed receptor-specific agent binding, allowing clear delineation of tumor boundaries that matched pathology findings. Conclusions: The radioactive utility of the MMC allowed us to validate the binding properties of a novel FGS agent that could have a broad impact on cancer outcomes by equipping surgeons with real-time intraoperative imaging capabilities.

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“…EC-17 is a small-molecule FITC based probe that was originally developed for fluorescence guided surgery (FGS) and has been shown to have high-affinity for FR+ CTCs previously [48]. Moreover, EC-17 and its NIR analog OTL-38 have both been used in FGS clinical trials [39,50], leading to the exciting possibility of using DiFC in humans in the future. Cy5-PEG-FR is a larger molecular weight probe, but has the advantage of having red excitation and emission wavelengths, which in principle is favorable for DiFC because of reduced optical attenuation of red light in biological tissue [49].…”

Section: Introductionmentioning

confidence: 99%

Fluorescence Labeling of Circulating Tumor Cells with Folate Receptor Targeted Molecular Probes for DiffuseIn VivoFlow Cytometry

Patil¹,

Srinivasarao

Amiji

et al. 2020

Preprint

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Purpose: We recently developed a new instrument called 'diffuse in vivo flow cytometry' (DiFC) for enumeration of rare fluorescently-labeled circulating tumor cells (CTCs) in small animals without drawing blood samples. Until now, we have used cell lines that express fluorescent proteins, or were pre-labeled with a fluorescent dye ex-vivo. In this work, we investigated the use of two folate receptor (FR)-targeted fluorescence molecular probes for in vivo labeling of FR+ CTCs for DiFC.Methods: We used EC-17 and Cy5-PEG-FR fluorescent probes. We studied the affinity of these probes for L1210A and KB cancer cells, both of which over-express FR. We tested the labeling specificity in cells in culture in vitro, in whole blood, and in mice in vivo. We also studied detectability of labeled cells with DiFC.Results: Both EC-17 and Cy5-PEG-FR probes had high affinity for FR+ CTCs in cell culture in vitro.However, only EC-17 had sufficient specificity for CTCs in whole blood. EC-17 labeled CTCs were also readily detectable in circulation in mice with DiFC.Conclusions: This work demonstrates the feasibility of labeling CTCs for DiFC with a cell surface receptor targeted probe, greatly expanding the utility of the method for pre-clinical animal models. Because DiFC uses diffuse light, this method could be also used to enumerate CTCs in larger animal models and potentially even in humans.

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A Phase I Clinical Trial of Targeted Intraoperative Molecular Imaging for Pulmonary Adenocarcinomas

Cited by 75 publications

References 24 publications

Utilization of targeted near-infrared molecular imaging to improve pulmonary metastasectomy of osteosarcomas

Utilization of targeted near-infrared molecular imaging to improve pulmonary metastasectomy of osteosarcomas

Specific Targeting of Somatostatin Receptor Subtype-2 for Fluorescence-Guided Surgery

Fluorescence Labeling of Circulating Tumor Cells with Folate Receptor Targeted Molecular Probes for DiffuseIn VivoFlow Cytometry

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