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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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Representative intraoperative image of a canine lung cancer.(A) Signal-to-background ratio of tumor to surrounding normal lung tissue in situ and ex vivo in 8 canines. All values are reported in arbitrary units (a.u.). †Due to the large size of this tumor, no measurements of normal lung fluorescence could be obtained ex vivo. (B) After opening the chest, the tumor was visualized in the chest. The tumor was well-circumscribed and was highly fluorescent (signal-to-background ratio 11.3). The tumor lies in the caudad position and the hilum of the lung is cranial. (C) Ex vivo, the tumor was fluorescent (SBR 12.7) and the margins of the tumor were well-defined. (D) H&E confirmed a lung adenocarcinoma with 2+ CD31 staining. The signal-to-background ratio (SBR) was higher ex vivo than in situ because of superior control of the surrounding environment such as lighting conditions, exposure and lack of motion. Although the fluorescence from the tumors did not significantly change, the background fluorescence from the normal lung was reduced when the environment could be better controlled. Microscopically, the tumor microvascular density (MVD) did not seem to impact the degree of fluorescence.
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pone-0103342-g002: Representative intraoperative image of a canine lung cancer.(A) Signal-to-background ratio of tumor to surrounding normal lung tissue in situ and ex vivo in 8 canines. All values are reported in arbitrary units (a.u.). †Due to the large size of this tumor, no measurements of normal lung fluorescence could be obtained ex vivo. (B) After opening the chest, the tumor was visualized in the chest. The tumor was well-circumscribed and was highly fluorescent (signal-to-background ratio 11.3). The tumor lies in the caudad position and the hilum of the lung is cranial. (C) Ex vivo, the tumor was fluorescent (SBR 12.7) and the margins of the tumor were well-defined. (D) H&E confirmed a lung adenocarcinoma with 2+ CD31 staining. The signal-to-background ratio (SBR) was higher ex vivo than in situ because of superior control of the surrounding environment such as lighting conditions, exposure and lack of motion. Although the fluorescence from the tumors did not significantly change, the background fluorescence from the normal lung was reduced when the environment could be better controlled. Microscopically, the tumor microvascular density (MVD) did not seem to impact the degree of fluorescence.

Mentions: Small animal imaging is conducted in a controlled, artificial environment, so we evaluated NIR imaging for identification of solid tumors in a rigorous large animal model in the clinical setting. Eight outbred canines with naturally occurring tumors who presented to the University of Pennsylvania School of Veterinary Medicine surgery clinic with a primary lung tumor were enrolled in the study with informed consent from their owners and institutional approval (Figure 2a). Ages ranged from 4 to 14 years (median 10 years) and weights ranged from 6 to 60 kg (median 24 kg) (Table 1). Three dogs were spayed females and 5 dogs were castrated males. All dogs received ICG via the cephalic vein without any adverse reactions 24 hours before surgery.


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)

Representative intraoperative image of a canine lung cancer.(A) Signal-to-background ratio of tumor to surrounding normal lung tissue in situ and ex vivo in 8 canines. All values are reported in arbitrary units (a.u.). †Due to the large size of this tumor, no measurements of normal lung fluorescence could be obtained ex vivo. (B) After opening the chest, the tumor was visualized in the chest. The tumor was well-circumscribed and was highly fluorescent (signal-to-background ratio 11.3). The tumor lies in the caudad position and the hilum of the lung is cranial. (C) Ex vivo, the tumor was fluorescent (SBR 12.7) and the margins of the tumor were well-defined. (D) H&E confirmed a lung adenocarcinoma with 2+ CD31 staining. The signal-to-background ratio (SBR) was higher ex vivo than in situ because of superior control of the surrounding environment such as lighting conditions, exposure and lack of motion. Although the fluorescence from the tumors did not significantly change, the background fluorescence from the normal lung was reduced when the environment could be better controlled. Microscopically, the tumor microvascular density (MVD) did not seem to impact the degree of fluorescence.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0103342-g002: Representative intraoperative image of a canine lung cancer.(A) Signal-to-background ratio of tumor to surrounding normal lung tissue in situ and ex vivo in 8 canines. All values are reported in arbitrary units (a.u.). †Due to the large size of this tumor, no measurements of normal lung fluorescence could be obtained ex vivo. (B) After opening the chest, the tumor was visualized in the chest. The tumor was well-circumscribed and was highly fluorescent (signal-to-background ratio 11.3). The tumor lies in the caudad position and the hilum of the lung is cranial. (C) Ex vivo, the tumor was fluorescent (SBR 12.7) and the margins of the tumor were well-defined. (D) H&E confirmed a lung adenocarcinoma with 2+ CD31 staining. The signal-to-background ratio (SBR) was higher ex vivo than in situ because of superior control of the surrounding environment such as lighting conditions, exposure and lack of motion. Although the fluorescence from the tumors did not significantly change, the background fluorescence from the normal lung was reduced when the environment could be better controlled. Microscopically, the tumor microvascular density (MVD) did not seem to impact the degree of fluorescence.
Mentions: Small animal imaging is conducted in a controlled, artificial environment, so we evaluated NIR imaging for identification of solid tumors in a rigorous large animal model in the clinical setting. Eight outbred canines with naturally occurring tumors who presented to the University of Pennsylvania School of Veterinary Medicine surgery clinic with a primary lung tumor were enrolled in the study with informed consent from their owners and institutional approval (Figure 2a). Ages ranged from 4 to 14 years (median 10 years) and weights ranged from 6 to 60 kg (median 24 kg) (Table 1). Three dogs were spayed females and 5 dogs were castrated males. All dogs received ICG via the cephalic vein without any adverse reactions 24 hours before surgery.

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