The FLARE™ Intraoperative Near-Infrared Fluorescence Imaging System: A First-in-Human Clinical Trial in Breast Cancer Sentinel Lymph Node Mapping
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
Invisible NIR fluorescent light can provide high sensitivity, high-resolution, and real-time image-guidance during oncologic surgery, but imaging systems that are presently available do not display this invisible light in the context of surgical anatomy. The FLARE™ imaging system overcomes this major obstacle.
Color video was acquired simultaneously, and in real-time, along with two independent channels of NIR fluorescence. Grayscale NIR fluorescence images were converted to visible “pseudo-colors” and overlaid onto the color video image. Yorkshire pigs weighing 35 kg (n = 5) were used for final preclinical validation of the imaging system. A six-patient pilot study was conducted in women undergoing sentinel lymph node (SLN) mapping for breast cancer. Subjects received 99mTc-sulfur colloid lymphoscintigraphy. In addition, 12.5 μg of indocyanine green (ICG) diluted in human serum albumin (HSA) was used as an NIR fluorescent lymphatic tracer.
The FLARE™ system permitted facile positioning in the operating room. NIR light did not change the look of the surgical field. Simultaneous pan-lymphatic and SLN mapping was demonstrated in swine using clinically available NIR fluorophores and the dual NIR capabilities of the system. In the pilot clinical trial, a total of nine SLNs were identified by 99mTc- lymphoscintigraphy and nine SLNs were identified by NIR fluorescence, although results differed in two patients. No adverse events were encountered.
We describe the successful clinical translation of a new NIR fluorescence imaging system for image-guided oncologic surgery.
- Frangioni, JV (2008) New technologies for human cancer imaging. J Clin Oncol. 26: pp. 4012-4021 CrossRef
- Frangioni, JV (2003) In vivo near-infrared fluorescence imaging. Curr Opin Chem Biol. 7: pp. 626-634 CrossRef
- Fujiwara M, Mizukami T, Suzuki A, Fukamizu H. Sentinel lymph node detection in skin cancer patients using real-time fluorescence navigation with indocyanine green: preliminary experience. J Plast Reconstr Aesthet Surg. 2008 [Epub ahead of print].
- Kitai, T, Inomoto, T, Miwa, M, Shikayama, T (2005) Fluorescence navigation with indocyanine green for detecting sentinel lymph nodes in breast cancer. Breast Cancer. 12: pp. 211-215 CrossRef
- Ogasawara, Y, Ikeda, H, Takahashi, M, Kawasaki, K, Doihara, H (2008) Evaluation of breast lymphatic pathways with indocyanine green fluorescence imaging in patients with breast cancer. World J Surg. 32: pp. 1924-1929 CrossRef
- Sevick-Muraca, EM, Sharma, R, Rasmussen, JC (2008) Imaging of lymph flow in breast cancer patients after microdose administration of a near-infrared fluorophore: feasibility study. Radiology. 246: pp. 734-741 CrossRef
- Kusano, M, Tajima, Y, Yamazaki, K, Kato, M, Watanabe, M, Miwa, M (2008) Sentinel node mapping guided by indocyanine green fluorescence imaging: a new method for sentinel node navigation surgery in gastrointestinal cancer. Dig Surg. 25: pp. 103-108 CrossRef
- Miyashiro, I, Miyoshi, N, Hiratsuka, M (2008) Detection of sentinel node in gastric cancer surgery by indocyanine green fluorescence imaging: comparison with infrared imaging. Ann Surg Oncol. 15: pp. 1640-1643 CrossRef
- Nakayama, A, del Monte, F, Hajjar, RJ, Frangioni, JV (2002) Functional near-infrared fluorescence imaging for cardiac surgery and targeted gene therapy. Mol Imaging. 1: pp. 365-377 CrossRef
- Grand, AM, Frangioni, JV (2003) An operational near-infrared fluorescence imaging system prototype for large animal surgery. Technol Cancer Res Treat. 2: pp. 553-562
- Gioux, S, Grand, AM, Lee, DS, Yazdanfar, S, Idoine, JD, Lomnes, SJ, Frangioni, JV (2005) Improved optical sub-systems for intraoperative near-infrared fluorescence imaging. SPIE Proc. 6009: pp. 39-48
- Tanaka, E, Choi, HS, Fujii, H, Bawendi, MG, Frangioni, JV (2006) Image-guided oncologic surgery using invisible light: completed pre-clinical development for sentinel lymph node mapping. Ann Surg Oncol. 13: pp. 1671-1681 CrossRef
- Gioux S, Kianzad V, Ciocan R, Gupta S, Oketokoun R, Frangioni JV. High power, computer-controlled, LED-based light sources for fluorescence imaging and image-guided surgery. Mol Imaging. 2009 (in press).
- Bhushan, KR, Misra, P, Liu, F, Mathur, S, Lenkinski, RE, Frangioni, JV (2008) Detection of breast cancer microcalcifications using a dual-modality SPECT/NIR fluorescent probe. J Am Chem Soc. 130: pp. 17648-17649 CrossRef
- Choi, HS, Liu, W, Misra, P (2007) Renal clearance of quantum dots. Nat Biotechnol. 25: pp. 1165-1170 CrossRef
- Frangioni, JV, Kim, SW, Ohnishi, S, Kim, S, Bawendi, MG (2007) Sentinel lymph node mapping with type-II quantum dots. Methods Mol Biol. 374: pp. 147-159
- Humblet, V, Lapidus, R, Williams, LR (2005) High-affinity near-infrared fluorescent small-molecule contrast agents for in vivo imaging of prostate-specific membrane antigen. Mol Imaging. 4: pp. 448-462
- Kim, S, Lim, YT, Soltesz, EG (2004) Near-infrared fluorescent type II quantum dots for sentinel lymph node mapping. Nat Biotechnol. 22: pp. 93-97 CrossRef
- Kim, SW, Zimmer, JP, Ohnishi, S, Tracy, JB, Frangioni, JV, Bawendi, MG (2005) Engineering InAs(x)P(1-x)/InP/ZnSe III-V alloyed core/shell quantum dots for the near-infrared. J Am Chem Soc. 127: pp. 10526-10532 CrossRef
- Lenkinski, RE, Ahmed, M, Zaheer, A, Frangioni, JV, Goldberg, SN (2003) Near-infrared fluorescence imaging of microcalcification in an animal model of breast cancer. Acad Radiol. 10: pp. 1159-1164 CrossRef
- Liu, F, Bloch, N, Bhushan, KR (2008) Humoral bone morphogenetic protein 2 is sufficient for inducing breast cancer microcalcification. Mol Imaging. 7: pp. 175-186
- Liu, W, Choi, HS, Zimmer, JP, Tanaka, E, Frangioni, JV, Bawendi, M (2007) Compact cysteine-coated CdSe(ZnCdS) quantum dots for in vivo applications. J Am Chem Soc. 129: pp. 14530-14531 CrossRef
- Nakayama, A, Bianco, AC, Zhang, CY, Lowell, BB, Frangioni, JV (2003) Quantitation of brown adipose tissue perfusion in transgenic mice using near-infrared fluorescence imaging. Mol Imaging. 2: pp. 37-49 CrossRef
- Ohnishi, S, Vanderheyden, JL, Tanaka, E (2006) Intraoperative detection of cell injury and cell death with an 800 nm near-infrared fluorescent Annexin V derivative. Am J Transplant. 6: pp. 2321-2331 CrossRef
- Parungo, CP, Colson, YL, Kim, SW, Kim, S, Cohn, LH, Bawendi, MG, Frangioni, JV (2005) Sentinel lymph node mapping of the pleural space. Chest. 127: pp. 1799-1804 CrossRef
- Parungo, CP, Ohnishi, S, Grand, AM (2004) In vivo optical imaging of pleural space drainage to lymph nodes of prognostic significance. Ann Surg Oncol. 11: pp. 1085-1092 CrossRef
- Parungo, CP, Soybel, DI, Colson, YL (2007) Lymphatic drainage of the peritoneal space: a pattern dependent on bowel lymphatics. Ann Surg Oncol. 14: pp. 286-298 CrossRef
- Tanaka, E, Ohnishi, S, Laurence, RG, Choi, HS, Humblet, V, Frangioni, JV (2007) Real-time intraoperative ureteral guidance using invisible near-infrared fluorescence. J Urol. 178: pp. 2197-2202 CrossRef
- Zaheer, A, Lenkinski, RE, Mahmood, A, Jones, AG, Cantley, LC, Frangioni, JV (2001) In vivo near-infrared fluorescence imaging of osteoblastic activity. Nat Biotechnol. 19: pp. 1148-1154 CrossRef
- Zaheer, A, Murshed, M, Grand, AM, Morgan, TG, Karsenty, G, Frangioni, JV (2006) Optical imaging of hydroxyapatite in the calcified vasculature of transgenic animals. Arterioscler Thromb Vasc Biol. 26: pp. 1132-1136 CrossRef
- Zimmer, JP, Kim, SW, Ohnishi, S, Tanaka, E, Frangioni, JV, Bawendi, MG (2006) Size series of small indium arsenide-zinc selenide core-shell nanocrystals and their application to in vivo imaging. J Am Chem Soc. 128: pp. 2526-2527 CrossRef
- Soltesz, EG, Kim, S, Kim, SW (2006) Sentinel lymph node mapping of the gastrointestinal tract by using invisible light. Ann Surg Oncol. 13: pp. 386-396 CrossRef
- Parungo, CP, Ohnishi, S, Kim, SW (2005) Intraoperative identification of esophageal sentinel lymph nodes with near-infrared fluorescence imaging. J Thorac Cardiovasc Surg. 129: pp. 844-850 CrossRef
- Soltesz, EG, Kim, S, Laurence, RG (2005) Intraoperative sentinel lymph node mapping of the lung using near-infrared fluorescent quantum dots. Ann Thorac Surg. 79: pp. 269-277 CrossRef
- Ohnishi, S, Garfein, ES, Karp, SJ, Frangioni, JV (2006) Radiolabeled and near-infrared fluorescent fibrinogen derivatives create a system for the identification and repair of obscure gastrointestinal bleeding. Surgery. 140: pp. 785-792 CrossRef
- Ohnishi, S, Lomnes, SJ, Laurence, RG, Gogbashian, A, Mariani, G, Frangioni, JV (2005) Organic alternatives to quantum dots for intraoperative near-infrared fluorescent sentinel lymph node mapping. Mol Imaging. 4: pp. 172-181
- Bhushan, KR, Tanaka, E, Frangioni, JV (2007) Synthesis of conjugatable bisphosphonates for molecular imaging of large animals. Angew Chem Int Ed Engl. 46: pp. 7969-7971 CrossRef
- Soltesz, EG, Laurence, RG, Grand, AM, Cohn, LH, Mihaljevic, T, Frangioni, JV (2007) Image-guided quantification of cardioplegia delivery during cardiac surgery. Heart Surg Forum. 10: pp. E381-E386 CrossRef
- Tanaka, E, Choi, HS, Humblet, V, Ohnishi, S, Laurence, RG, Frangioni, JV (2008) Real-time intraoperative assessment of the extrahepatic bile ducts in rats and pigs using invisible near-infrared fluorescent light. Surgery. 144: pp. 39-48 CrossRef
- Knapp, DW, Adams, LG, Degrand, AM (2007) Sentinel lymph node mapping of invasive urinary bladder cancer in animal models using invisible light. Eur Urol. 52: pp. 1700-1708 CrossRef
- Flaumenhaft, R, Tanaka, E, Graham, GJ (2007) Localization and quantification of platelet-rich thrombi in large blood vessels with near-infrared fluorescence imaging. Circulation. 115: pp. 84-93 CrossRef
- Tanaka E, Chen FY, Flaumenhaft R, Graham GJ, Laurence RG, Frangioni JV. Real-time assessment of cardiac perfusion, coronary angiography, and acute intravascular thrombi using dual-channel near-infrared fluorescence imaging. J Thorac Cardiovasc Surg. 2009 (in press).
- Paladini G, Azar FS. An extensible imaging platform for optical imaging applications. SPIE Photonics West - Multimodal Biomedical Imaging IV (Session 2), Proceedings of SPIE 2009;7171.
- Zakaria, S, Hoskin, TL, Degnim, AC (2008) Safety and technical success of methylene blue dye for lymphatic mapping in breast cancer. Am J Surg. 196: pp. 228-233 CrossRef
- The FLARE™ Intraoperative Near-Infrared Fluorescence Imaging System: A First-in-Human Clinical Trial in Breast Cancer Sentinel Lymph Node Mapping
Annals of Surgical Oncology
Volume 16, Issue 10 , pp 2943-2952
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Industry Sectors
- Author Affiliations
- 1. Breast Care Center, Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
- 2. Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- 3. Siemens Corporate Research, Princeton, NJ, USA
- 4. Division of General Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- 5. Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA, USA