Near-Infrared Intraoperative Molecular Imaging Can Locate Metastases to the Lung

Keating, Jane; Newton, Andrew D.; Venegas, Ollin; Nims, Sarah; Zeh, Ryan; Predina, Jarrod D.; Deshpande, Charuhas; Kucharczuk, John C.; Nie, Shuming; Delikatny, Edward J.; Singhal, Sunil

doi:10.1016/j.athoracsur.2016.08.079

Cited by 61 publications

(91 citation statements)

References 32 publications

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“…First, delivery of this dosage of ICG was well tolerated, which is consistent with our previous experiences with ICG (3). Second, we found that the addition of intraoperative imaging was efficient and addended only several minutes to the case duration.…”

Section: Discussionsupporting

confidence: 88%

“…Our group has previously reported successful utilization of near-infrared (NIR) fluorescent, real-time intraoperative imaging to improve pulmonary metastasectomy (3). In this report, we detail successful utilization of this approach to enhance accurate identification of malignancy during resection of a thymic carcinosarcoma in a patient that previously underwent neoadjuvant chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

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Near‑infrared intraoperative imaging during resection of an anterior mediastinal soft tissue sarcoma

et al. 2017

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Abstract. Sarcomas are rare malignancies that are generally treated with multimodal therapy protocols incorporating complete local resection, chemotherapy and radiation. Unfortunately, even with this aggressive approach, local recurrences are common. Near-infrared intraoperative imaging is a novel technology that provides real-time visual feedback that can improve identification of disease during resection. The presented study describes utilization of a near-infrared agent (indocyanine green) during resection of an anterior mediastinal sarcoma. Real-time fluorescent feedback provided visual information that helped the surgeon during tumor localization, margin assessment and dissection from mediastinal structures. This rapidly evolving technology may prove useful in patients with primary sarcomas arising from other locations or with other mediastinal neoplasms. IntroductionPrimary mediastinal sarcomas are rare (1). Similar to other primary sarcomas, achieving long-term survival often requires multimodal therapy including complete local resection, chemotherapy, and radiation (2). Accomplishing complete resection of anterior mediastinal sarcomas poses challenges given proximity to critical mediastinal structures such as the phrenic nerve, heart, and great vessels. Accurate tumor identification and margin assessment during mediastinal dissection is further complicated when occurring after neoadjvant chemotherapy, an approach commonly implemented for sarcomas.Our group has previously reported successful utilization of near-infrared (NIR) fluorescent, real-time intraoperative imaging to improve pulmonary metastasectomy (3). In this report, we detail successful utilization of this approach to enhance accurate identification of malignancy during resection of a thymic carcinosarcoma in a patient that previously underwent neoadjuvant chemotherapy. This report highlights how this approach can improve a surgeon's ability to identify disease and safely obtain adequate margins during resection of primary mediastinal sarcomas and, perhaps more broadly, other solid tumors located near critical structures. Case reportA 59-year-old male was seen in our multi-disciplinary thoracic oncology institute for management of an incidentally identified 5.7x7.5x8.4 cm anterior mediastinal mass (Fig. 1A). This mass was abutting the left pulmonary artery without obvious vascular invasion. Metastatic work-up revealed no suspicious metastases. A transthoracic needle biopsy was suspicious for a thymic carcinosarcoma with rhabdomyosarcomatous elements. Six rounds of neoadjuvant chemotherapy with Adriamycin, Ifosfosfamide and Vinicristine. After completing neoadjuvant treatment, the patient was consented for resection via left thoracosternotomy with NIR intraoperative imaging.Twenty-four hours before resection, intravenous indocyanine-green (ICG) was delivered (5 mg/kg). During resection, the tumor displayed high levels of fluorescence (tumor-to-background signal ratio of 3.6) ( Fig. 1B and C). Real-time fluorescent feedback aided the surgeon when...

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Near‑infrared intraoperative imaging during resection of an anterior mediastinal soft tissue sarcoma

et al. 2017

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“…Despite these advantages, 5-ALA is not FDA-approved. Indocyanine green, however, is a readily available, FDA-approved NIR fluorescent drug which has promise as a tumor optical contrast agent [11–16]. Although the Second Window ICG technique has been studied in a rodent model of lung cancer, we hypothesized that Second Window ICG could also provide optical contrast of brain tumors.…”

Section: Discussionmentioning

confidence: 99%

“…By exploiting this delivery method, NIR cameras can be used in the operating room environment to visualize ICG accumulation within tumors. Our lab has used this technique in a variety of tumor types, including lung, ovarian, colorectal, breast, and metastases [9, 11–17]. …”

Section: Introductionmentioning

confidence: 99%

The second window ICG technique demonstrates a broad plateau period for near infrared fluorescence tumor contrast in glioblastoma

et al. 2017

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IntroductionFluorescence-guided surgery has emerged as a powerful tool to detect, localize and resect tumors in the operative setting. Our laboratory has pioneered a novel way to administer an FDA-approved near-infrared (NIR) contrast agent to help surgeons with this task. This technique, coined Second Window ICG, exploits the natural permeability of tumor vasculature and its poor clearance to deliver high doses of indocyanine green (ICG) to tumors. This technique differs substantially from established ICG video angiography techniques that visualize ICG within minutes of injection. We hypothesized that Second Window ICG can provide NIR optical contrast with good signal characteristics in intracranial brain tumors over a longer period of time than previously appreciated with ICG video angiography alone. We tested this hypothesis in an intracranial mouse glioblastoma model, and corroborated this in a human clinical trial.MethodsIntracranial tumors were established in 20 mice using the U251-Luc-GFP cell line. Successful grafts were confirmed with bioluminescence. Intravenous tail vein injections of 5.0 mg/kg (high dose) or 2.5 mg/kg (low dose) ICG were performed. The Perkin Elmer IVIS Spectrum (closed field) was used to visualize NIR fluorescence signal at seven delayed time points following ICG injection. NIR signals were quantified using LivingImage software. Based on the success of our results, human subjects were recruited to a clinical trial and intravenously injected with high dose 5.0 mg/kg. Imaging was performed with the VisionSense Iridium (open field) during surgery one day after ICG injection.ResultsIn the murine model, the NIR signal-to-background ratio (SBR) in gliomas peaks at one hour after infusion, then plateaus and remains strong and stable for at least 48 hours. Higher dose 5.0 mg/kg improves NIR signal as compared to lower dose at 2.5 mg/kg (SBR = 3.5 vs. 2.8; P = 0.0624). Although early (≤ 6 hrs) visualization of the Second Window ICG accumulation in gliomas is stronger than late (≥24 hrs) visualization (SBR = 3.94 vs. 2.32; p<0.05) there appears to be a long plateau period of stable ICG NIR signal accumulation within tumors in the murine model. We call this long plateau period the “Second Window” of ICG. In glioblastoma patients, the delayed visualization of intratumoral NIR signal was strong (SBR 7.50 ± 0.74), without any significant difference within the 19 to 30 hour visualization window (R2 = 0.019).ConclusionThe Second Window ICG technique allows neurosurgeons to deliver NIR optical contrast agent to human glioblastoma patients, thus providing real-time tumor identification in the operating room. This nonspecific tumor accumulation of ICG within the tumor provides strong signal to background contrast, and is not significantly time dependent between 6 hours to 48 hours, providing a broad plateau for stable visualization. This finding suggests that optimal imaging of the “Second Window of ICG” may be within this plateau period, thus providing signal uniformity across subjects.

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“…Several groups have demonstrated the efficacy of IMI for the detection of intrathoracic and extrathoracic malignancies (7,(12)(13)(14)(15)(16)(17)(18)(19). Our group has investigated two different tracers for the intraoperative detection of pulmonary nodules and occult metastases-indocyanine green (ICG) and a folate receptor alpha (FRα) targeted fluorophore.…”

Section: Preclinical Studiesmentioning

confidence: 99%

Intraoperative near-infrared imaging of mesothelioma

Kennedy

Newton

Predina

et al. 2017

Transl. Lung Cancer Res.

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Near-Infrared Intraoperative Molecular Imaging Can Locate Metastases to the Lung

Abstract: Systemic ICG identifies subcentimeter tumor metastases to the lung in murine models, and this work provides proof of principle in humans. Future research is focused on improving depth of penetration into the lung parenchyma.

Cited by 61 publications

References 32 publications

Near‑infrared intraoperative imaging during resection of an anterior mediastinal soft tissue sarcoma

Near‑infrared intraoperative imaging during resection of an anterior mediastinal soft tissue sarcoma

The second window ICG technique demonstrates a broad plateau period for near infrared fluorescence tumor contrast in glioblastoma

Intraoperative near-infrared imaging of mesothelioma

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