Development of a drug–device combination for fluorescence-guided surgery in neuroendocrine tumors

Vargas, Servando Hernandez; Lin, Christie; Voss, Julie; Ghosh, Sukhen C.; Halperin, Daniel M.; AghaAmiri, Solmaz; Cao, Hop S. Tran; Ikoma, Naruhiko; Uselmann, Adam J.; Azhdarinia, Ali

doi:10.1117/1.jbo.25.12.126002

Cited by 8 publications

(9 citation statements)

References 48 publications

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“…Dose and time play an important role in determining tumor contrast and can be optimized to strengthen the predictive value of an FGS agent. − Since fluorescence emits low-energy photons that limit the measurement of absolute drug concentration, we radiolabeled MMC(FNIR-Tag)-TOC with the γ-emitting radionuclide 67 Ga to overcome attenuation and scattering phenomena. , We injected increasing doses (2, 5, and 10 nmol) of 67 Ga-MMC(FNIR-Tag)-TOC into nude mice with NCI-H69 xenografts, which endogenously express SSTR2, and imaged at 3 and 24 h p.i. Figure A qualitatively illustrates that tumor uptake increased as a function of dose while decreasing with time both at the macro- and mesoscopic scales; importantly, tumor signal was the highest among nonclearance organs regardless of dose or imaging time.…”

Section: Resultsmentioning

confidence: 99%

“…Dose and time play an important role in determining tumor contrast and can be optimized to strengthen the predictive value of an FGS agent. 28 − 30 Since fluorescence emits low-energy photons that limit the measurement of absolute drug concentration, 31 we radiolabeled MMC(FNIR-Tag)-TOC with the γ-emitting radionuclide 67 Ga to overcome attenuation and scattering phenomena. 32 , 33 We injected increasing doses (2, 5, and 10 nmol) of 67 Ga-MMC(FNIR-Tag)-TOC into nude mice with NCI-H69 xenografts, which endogenously express SSTR2, and imaged at 3 and 24 h p.i.…”

Section: Resultsmentioning

confidence: 99%

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High-Contrast Detection of Somatostatin Receptor Subtype-2 for Fluorescence-Guided Surgery

et al. 2022

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Dye design can influence the ability of fluorescently labeled imaging agents to generate tumor contrast and has become an area of significant interest in the field of fluorescence-guided surgery (FGS). Here, we show that the charge-balanced nearinfrared fluorescent (NIRF) dye FNIR-Tag enhances the imaging properties of a fluorescently labeled somatostatin analogue. In vitro studies showed that the optimized fluorescent conjugate MMC-(FNIR-Tag)-TOC bound primarily via somatostatin receptor subtype-2 (SSTR2), whereas its negatively charged counterpart with IRDye 800CW had higher off-target binding. NIRF imaging in cell line-and patient-derived xenograft models revealed markedly higher tumor contrast with MMC(FNIR-Tag)-TOC, which was attributed to increased tumor specificity. Ex vivo staining of surgical biospecimens from primary and metastatic tumors, as well as involved lymph nodes, demonstrated binding to human tumors. Finally, in an orthotopic tumor model, a simulated clinical workflow highlighted our unique ability to use standard preoperative nuclear imaging for selecting patients likely to benefit from SSTR2-targeted FGS. Our findings demonstrate the translational potential of MMC(FNIR-Tag)-TOC for intraoperative imaging and suggest broad utility for using FNIR-Tag in fluorescent probe development.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

High-Contrast Detection of Somatostatin Receptor Subtype-2 for Fluorescence-Guided Surgery

et al. 2022

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“…For instance, nuclear medicine is inherently quantitative, with well-established methods for determining in vivo drug distribution and concentration based on collected images or signals ( 89 ). By contrast, the underlying physics of fluorescence imaging in bulk tissue ( 90 ), compounded with the myriad of FGS devices ( 91 ), leads to uncertainty in the quantitative evaluation of drug performance ( 92 ). Particularly, tumor-specific FGS relies on fluorescent drugs that accumulate preferentially in tumors and a device to detect their distribution and concentration to reveal measurable outputs such as tumor contrast ( 93 , 94 ).…”

Section: Perspective On Emerging Tumor-selective Fgs Technologiesmentioning

confidence: 99%

“…Tumor contrast also depends largely on the differential drug uptake between tumor and normal tissue. This suggests that superior contrast may be achieved by (i) increasing tumor uptake, (ii) decreasing background uptake, or (iii) a combination of (i) and (ii) ( 92 ). Points (i-iii) are clinically significant because they could enable contrast detectability with higher certainty, which may directly increase the positive and negative predictive value ( 96 ) of tumor-specific FGS for real-time decision making ( 97 ).…”

Section: Perspective On Emerging Tumor-selective Fgs Technologiesmentioning

confidence: 99%

Receptor-Targeted Fluorescence-Guided Surgery With Low Molecular Weight Agents

et al. 2021

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Cancer surgery remains the primary treatment option for most solid tumors and can be curative if all malignant cells are removed. Surgeons have historically relied on visual and tactile cues to maximize tumor resection, but clinical data suggest that relapse occurs partially due to incomplete cancer removal. As a result, the introduction of technologies that enhance the ability to visualize tumors in the operating room represents a pressing need. Such technologies have the potential to revolutionize the surgical standard-of-care by enabling real-time detection of surgical margins, subclinical residual disease, lymph node metastases and synchronous/metachronous tumors. Fluorescence-guided surgery (FGS) in the near-infrared (NIRF) spectrum has shown tremendous promise as an intraoperative imaging modality. An increasing number of clinical studies have demonstrated that tumor-selective FGS agents can improve the predictive value of fluorescence over non-targeted dyes. Whereas NIRF-labeled macromolecules (i.e., antibodies) spearheaded the widespread clinical translation of tumor-selective FGS drugs, peptides and small-molecules are emerging as valuable alternatives. Here, we first review the state-of-the-art of promising low molecular weight agents that are in clinical development for FGS; we then discuss the significance, application and constraints of emerging tumor-selective FGS technologies.

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“…The LR model has been suggested for tissue class prediction 20 , given a certain fluorescence intensity value. This model has been thus far used in visualization of rat orthotopic glioma model 23 , 24 , rat cranial nerve ex-vivo 25 and mouse xenografts in-vivo 26 . We previously used the LR model with fluorescence texture metrics in freshly excised breast-specimens 21 which yielded 83% mean accuracy.…”

Section: Introductionmentioning

confidence: 99%

Indocyanine green fluorescence image processing techniques for breast cancer macroscopic demarcation

Leiloglou

Kedrzycki

Chalau

et al. 2022

Sci Rep

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Re-operation due to disease being inadvertently close to the resection margin is a major challenge in breast conserving surgery (BCS). Indocyanine green (ICG) fluorescence imaging could be used to visualize the tumor boundaries and help surgeons resect disease more efficiently. In this work, ICG fluorescence and color images were acquired with a custom-built camera system from 40 patients treated with BCS. Images were acquired from the tumor in-situ, surgical cavity post-excision, freshly excised tumor and histopathology tumour grossing. Fluorescence image intensity and texture were used as individual or combined predictors in both logistic regression (LR) and support vector machine models to predict the tumor extent. ICG fluorescence spectra in formalin-fixed histopathology grossing tumor were acquired and analyzed. Our results showed that ICG remains in the tissue after formalin fixation. Therefore, tissue imaging could be validated in freshly excised and in formalin-fixed grossing tumor. The trained LR model with combined fluorescence intensity (pixel values) and texture (slope of power spectral density curve) identified the tumor’s extent in the grossing images with pixel-level resolution and sensitivity, specificity of 0.75 ± 0.3, 0.89 ± 0.2.This model was applied on tumor in-situ and surgical cavity (post-excision) images to predict tumor presence.

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Development of a drug–device combination for fluorescence-guided surgery in neuroendocrine tumors

Cited by 8 publications

References 48 publications

High-Contrast Detection of Somatostatin Receptor Subtype-2 for Fluorescence-Guided Surgery

High-Contrast Detection of Somatostatin Receptor Subtype-2 for Fluorescence-Guided Surgery

Receptor-Targeted Fluorescence-Guided Surgery With Low Molecular Weight Agents

Indocyanine green fluorescence image processing techniques for breast cancer macroscopic demarcation

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