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Intraoperative near-infrared imaging can distinguish cancer from normal tissue but not inflammation.

Holt D, Okusanya O, Judy R, Venegas O, Jiang J, DeJesus E, Eruslanov E, Quatromoni J, Bhojnagarwala P, Deshpande C, Albelda S, Nie S, Singhal S - PLoS ONE (2014)

Bottom Line: Surgeons depend on visual and tactile clues to select which tissues should be removed from a patient.However, in situations where there is significant peritumoral inflammation, NIR imaging with ICG is not helpful.This suggests that non-targeted NIR dyes that accumulate in hyperpermeable tissues will have significant limitations in the future, and receptor-specific NIR dyes may be necessary to overcome this problem.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Studies, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of America.

ABSTRACT

Introduction: Defining tumor from non-tumor tissue is one of the major challenges of cancer surgery. Surgeons depend on visual and tactile clues to select which tissues should be removed from a patient. Recently, we and others have hypothesized near-infrared (NIR) imaging can be used during surgery to differentiate tumors from normal tissue.

Methods: We enrolled 8 canines and 5 humans undergoing cancer surgery for NIR imaging. The patients were injected with indocyanine green (ICG), an FDA approved non-receptor specific NIR dye that accumulates in hyperpermeable tissues, 16-24 hours prior to surgery. During surgery, NIR imaging was used to discriminate the tumor from non-tumor tissue.

Results: NIR imaging identified all tumors with a mean signal-to-background ratio of 6.7. Optical images were useful during surgery in discriminating normal tissue from cancer. In 3 canine cases and 1 human case, the tissue surrounding the tumor was inflamed due to obstruction of the vascular supply due to mass effect. In these instances, NIR imaging could not distinguish tumor tissue from tissue that was congested, edematous and did not contain cancer.

Conclusions: This study shows that NIR imaging can identify tumors from normal tissues, provides excellent tissue contrast, and it facilitates the resection of tumors. However, in situations where there is significant peritumoral inflammation, NIR imaging with ICG is not helpful. This suggests that non-targeted NIR dyes that accumulate in hyperpermeable tissues will have significant limitations in the future, and receptor-specific NIR dyes may be necessary to overcome this problem.

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Preclinical evidence for NIR tumor labeling to detect primary and metastatic tumor deposits.(A) Five cancer cell types were injected into the flank of syngeneic mice. Once established (200 mm3), animals were dosed with 7.5 mg/kg of ICG and imaged. Tumors were harvested, imaged and stained for CD31 (Marked with black arrows). Histology images taken at 200x magnification. (B) C57bl/6 mice (n = 21) were injected with LLC cells in their flanks on Day 0. Starting on Day 12, the animals were euthanized, dosed with 7.5 mg/kg ICG 24 hours earlier and their thoracic cavities opened. Observers determined if the metastatic tumor nodules were visible in the lung. NIR imaging was then used to detect disease that was not visible to the un-assisted human eye. Histology images taken at 100x.
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pone-0103342-g001: Preclinical evidence for NIR tumor labeling to detect primary and metastatic tumor deposits.(A) Five cancer cell types were injected into the flank of syngeneic mice. Once established (200 mm3), animals were dosed with 7.5 mg/kg of ICG and imaged. Tumors were harvested, imaged and stained for CD31 (Marked with black arrows). Histology images taken at 200x magnification. (B) C57bl/6 mice (n = 21) were injected with LLC cells in their flanks on Day 0. Starting on Day 12, the animals were euthanized, dosed with 7.5 mg/kg ICG 24 hours earlier and their thoracic cavities opened. Observers determined if the metastatic tumor nodules were visible in the lung. NIR imaging was then used to detect disease that was not visible to the un-assisted human eye. Histology images taken at 100x.

Mentions: The mean fluorescence from the flank tumors was 52,710 arbitrary units (au) (range 46,283-60,000), and the mean fluorescence from surrounding normal tissues and organs averaged 6173 ± 3300 au. Thus, the mean signal-to-background ratio (SBR) was 8.5 (Figure 1a). We noticed that the fluorescence from different histological tumor subtypes was not markedly different. In the past, we and others have hypothesized that uptake of NIR dyes is variable and dependent on tumor vascularity.[5], [6] Thus, tumors of different histology should have different fluorescence. Tumors were harvested, sectioned, and assayed for microvessel density by CD31 staining. Although there was as wide range of microvessel density, we did not find a significant difference in the SBR of the tumor in different histological tumor types (p>0.1). In addition, we did not find that tumor fluorescence correlated with tumor vascularity (Figure 1a).


Intraoperative near-infrared imaging can distinguish cancer from normal tissue but not inflammation.

Holt D, Okusanya O, Judy R, Venegas O, Jiang J, DeJesus E, Eruslanov E, Quatromoni J, Bhojnagarwala P, Deshpande C, Albelda S, Nie S, Singhal S - PLoS ONE (2014)

Preclinical evidence for NIR tumor labeling to detect primary and metastatic tumor deposits.(A) Five cancer cell types were injected into the flank of syngeneic mice. Once established (200 mm3), animals were dosed with 7.5 mg/kg of ICG and imaged. Tumors were harvested, imaged and stained for CD31 (Marked with black arrows). Histology images taken at 200x magnification. (B) C57bl/6 mice (n = 21) were injected with LLC cells in their flanks on Day 0. Starting on Day 12, the animals were euthanized, dosed with 7.5 mg/kg ICG 24 hours earlier and their thoracic cavities opened. Observers determined if the metastatic tumor nodules were visible in the lung. NIR imaging was then used to detect disease that was not visible to the un-assisted human eye. Histology images taken at 100x.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4114746&req=5

pone-0103342-g001: Preclinical evidence for NIR tumor labeling to detect primary and metastatic tumor deposits.(A) Five cancer cell types were injected into the flank of syngeneic mice. Once established (200 mm3), animals were dosed with 7.5 mg/kg of ICG and imaged. Tumors were harvested, imaged and stained for CD31 (Marked with black arrows). Histology images taken at 200x magnification. (B) C57bl/6 mice (n = 21) were injected with LLC cells in their flanks on Day 0. Starting on Day 12, the animals were euthanized, dosed with 7.5 mg/kg ICG 24 hours earlier and their thoracic cavities opened. Observers determined if the metastatic tumor nodules were visible in the lung. NIR imaging was then used to detect disease that was not visible to the un-assisted human eye. Histology images taken at 100x.
Mentions: The mean fluorescence from the flank tumors was 52,710 arbitrary units (au) (range 46,283-60,000), and the mean fluorescence from surrounding normal tissues and organs averaged 6173 ± 3300 au. Thus, the mean signal-to-background ratio (SBR) was 8.5 (Figure 1a). We noticed that the fluorescence from different histological tumor subtypes was not markedly different. In the past, we and others have hypothesized that uptake of NIR dyes is variable and dependent on tumor vascularity.[5], [6] Thus, tumors of different histology should have different fluorescence. Tumors were harvested, sectioned, and assayed for microvessel density by CD31 staining. Although there was as wide range of microvessel density, we did not find a significant difference in the SBR of the tumor in different histological tumor types (p>0.1). In addition, we did not find that tumor fluorescence correlated with tumor vascularity (Figure 1a).

Bottom Line: Surgeons depend on visual and tactile clues to select which tissues should be removed from a patient.However, in situations where there is significant peritumoral inflammation, NIR imaging with ICG is not helpful.This suggests that non-targeted NIR dyes that accumulate in hyperpermeable tissues will have significant limitations in the future, and receptor-specific NIR dyes may be necessary to overcome this problem.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Studies, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of America.

ABSTRACT

Introduction: Defining tumor from non-tumor tissue is one of the major challenges of cancer surgery. Surgeons depend on visual and tactile clues to select which tissues should be removed from a patient. Recently, we and others have hypothesized near-infrared (NIR) imaging can be used during surgery to differentiate tumors from normal tissue.

Methods: We enrolled 8 canines and 5 humans undergoing cancer surgery for NIR imaging. The patients were injected with indocyanine green (ICG), an FDA approved non-receptor specific NIR dye that accumulates in hyperpermeable tissues, 16-24 hours prior to surgery. During surgery, NIR imaging was used to discriminate the tumor from non-tumor tissue.

Results: NIR imaging identified all tumors with a mean signal-to-background ratio of 6.7. Optical images were useful during surgery in discriminating normal tissue from cancer. In 3 canine cases and 1 human case, the tissue surrounding the tumor was inflamed due to obstruction of the vascular supply due to mass effect. In these instances, NIR imaging could not distinguish tumor tissue from tissue that was congested, edematous and did not contain cancer.

Conclusions: This study shows that NIR imaging can identify tumors from normal tissues, provides excellent tissue contrast, and it facilitates the resection of tumors. However, in situations where there is significant peritumoral inflammation, NIR imaging with ICG is not helpful. This suggests that non-targeted NIR dyes that accumulate in hyperpermeable tissues will have significant limitations in the future, and receptor-specific NIR dyes may be necessary to overcome this problem.

Show MeSH
Related in: MedlinePlus