Annals of Surgical Oncology

, Volume 16, Issue 10, pp 2943–2952 | Cite as

The FLARE Intraoperative Near-Infrared Fluorescence Imaging System: A First-in-Human Clinical Trial in Breast Cancer Sentinel Lymph Node Mapping

  • Susan L. Troyan
  • Vida Kianzad
  • Summer L. Gibbs-Strauss
  • Sylvain Gioux
  • Aya Matsui
  • Rafiou Oketokoun
  • Long Ngo
  • Ali Khamene
  • Fred Azar
  • John V. Frangioni
Translational Research and Biomarkers



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.


Flare Sentinel Lymph Node Methylene Blue Human Serum Albumin Sentinel Lymph Node Mapping 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank Barbara L. Clough and Mireille Rosenberg for clinical trial preparation, Judith Hirshfield-Bartek for assistance with patient medical histories, Eiichi Tanaka, M.D. for preliminary swine studies, and Sunil Gupta and Razvan Ciocan for technical assistance with the imaging system. This study was supported by the following grants from the National Institutes of Health (National Cancer Institute) to JVF: Bioengineering Research Partnership grant #R01-CA-115296 and Quick Trials for Imaging grant #R21-CA-130297. We thank the following individuals and companies for their contributions to this project: Gordon Row (Yankee Modern Engineering), Kelly Stockwell and Paul Millman (Chroma Technology), David Comeau and Robert Waitt (Albright Technologies), Gary Avery, Phil Dillon, and Ed Schultz (Qioptiq Imaging Solutions), Jeffrey Thumm (Duke River Engineering), Michael Paszak and Victor Laronga (Microvideo Instruments), Colin Johnson (LAE Technologies), Robert Eastlund (Graftek Imaging), John Fortini (Lauzon Manufacturing), Steve Huchro (Solid State Cooling), Clay Sakewitz and Will Richards (Design and Assembly Concepts), Ken Thomas and Fernando Irizarry (Sure Design), Paul Bistline and Phil Bonnette (Medical Technique, Inc.), Mathew Silverstein (L-com), and Jim Cuthbertson (Nashua Circuits).

Financial Disclosure

This study was supported by the following grants from the National Institutes of Health (National Cancer Institute) to JVF: Bioengineering Research Partnership grant #R01-CA-115296 and Quick Trials for Imaging grant #R21-CA-130297. All intellectual property associated with the FLARETM imaging system is owned by the Beth Israel Deaconess Medical Center, which has licensed it nonexclusively to GE Healthcare. As inventor of the technology, Dr. Frangioni may someday receive royalties if a product is commercialized. No other authors have any financial interest in this study.


  1. 1.
    Frangioni JV. New technologies for human cancer imaging. J Clin Oncol. 2008;26:4012–21.CrossRefPubMedGoogle Scholar
  2. 2.
    Frangioni JV. In vivo near-infrared fluorescence imaging. Curr Opin Chem Biol. 2003;7:626–34.CrossRefPubMedGoogle Scholar
  3. 3.
    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].Google Scholar
  4. 4.
    Kitai T, Inomoto T, Miwa M, Shikayama T. Fluorescence navigation with indocyanine green for detecting sentinel lymph nodes in breast cancer. Breast Cancer. 2005;12:211–5.CrossRefPubMedGoogle Scholar
  5. 5.
    Ogasawara Y, Ikeda H, Takahashi M, Kawasaki K, Doihara H. Evaluation of breast lymphatic pathways with indocyanine green fluorescence imaging in patients with breast cancer. World J Surg. 2008;32:1924–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Sevick-Muraca EM, Sharma R, Rasmussen JC, et al. Imaging of lymph flow in breast cancer patients after microdose administration of a near-infrared fluorophore: feasibility study. Radiology. 2008;246:734–41.CrossRefPubMedGoogle Scholar
  7. 7.
    Kusano M, Tajima Y, Yamazaki K, Kato M, Watanabe M, Miwa M. Sentinel node mapping guided by indocyanine green fluorescence imaging: a new method for sentinel node navigation surgery in gastrointestinal cancer. Dig Surg. 2008;25:103–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Miyashiro I, Miyoshi N, Hiratsuka M, et al. Detection of sentinel node in gastric cancer surgery by indocyanine green fluorescence imaging: comparison with infrared imaging. Ann Surg Oncol. 2008;15:1640–3.CrossRefPubMedGoogle Scholar
  9. 9.
    Nakayama A, del Monte F, Hajjar RJ, Frangioni JV. Functional near-infrared fluorescence imaging for cardiac surgery and targeted gene therapy. Mol Imaging. 2002;1:365–77.CrossRefPubMedGoogle Scholar
  10. 10.
    De Grand AM, Frangioni JV. An operational near-infrared fluorescence imaging system prototype for large animal surgery. Technol Cancer Res Treat. 2003;2:553–62.PubMedGoogle Scholar
  11. 11.
    Gioux S, De Grand AM, Lee DS, Yazdanfar S, Idoine JD, Lomnes SJ, Frangioni JV. Improved optical sub-systems for intraoperative near-infrared fluorescence imaging. SPIE Proc. 2005;6009:39–48.Google Scholar
  12. 12.
    Tanaka E, Choi HS, Fujii H, Bawendi MG, Frangioni JV. Image-guided oncologic surgery using invisible light: completed pre-clinical development for sentinel lymph node mapping. Ann Surg Oncol. 2006;13:1671–81.CrossRefPubMedGoogle Scholar
  13. 13.
    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).Google Scholar
  14. 14.
    Bhushan KR, Misra P, Liu F, Mathur S, Lenkinski RE, Frangioni JV. Detection of breast cancer microcalcifications using a dual-modality SPECT/NIR fluorescent probe. J Am Chem Soc. 2008;130:17648–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Choi HS, Liu W, Misra P, et al. Renal clearance of quantum dots. Nat Biotechnol. 2007;25:1165–70.CrossRefPubMedGoogle Scholar
  16. 16.
    Frangioni JV, Kim SW, Ohnishi S, Kim S, Bawendi MG. Sentinel lymph node mapping with type-II quantum dots. Methods Mol Biol. 2007;374:147–59.PubMedGoogle Scholar
  17. 17.
    Humblet V, Lapidus R, Williams LR, et al. High-affinity near-infrared fluorescent small-molecule contrast agents for in vivo imaging of prostate-specific membrane antigen. Mol Imaging. 2005;4:448–62.PubMedGoogle Scholar
  18. 18.
    Kim S, Lim YT, Soltesz EG, et al. Near-infrared fluorescent type II quantum dots for sentinel lymph node mapping. Nat Biotechnol. 2004;22:93–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Kim SW, Zimmer JP, Ohnishi S, Tracy JB, Frangioni JV, Bawendi MG. Engineering InAs(x)P(1-x)/InP/ZnSe III-V alloyed core/shell quantum dots for the near-infrared. J Am Chem Soc. 2005;127:10526–32.CrossRefPubMedGoogle Scholar
  20. 20.
    Lenkinski RE, Ahmed M, Zaheer A, Frangioni JV, Goldberg SN. Near-infrared fluorescence imaging of microcalcification in an animal model of breast cancer. Acad Radiol. 2003;10:1159–64.CrossRefPubMedGoogle Scholar
  21. 21.
    Liu F, Bloch N, Bhushan KR, et al. Humoral bone morphogenetic protein 2 is sufficient for inducing breast cancer microcalcification. Mol Imaging. 2008;7:175–86.PubMedGoogle Scholar
  22. 22.
    Liu W, Choi HS, Zimmer JP, Tanaka E, Frangioni JV, Bawendi M. Compact cysteine-coated CdSe(ZnCdS) quantum dots for in vivo applications. J Am Chem Soc. 2007;129:14530–1.CrossRefPubMedGoogle Scholar
  23. 23.
    Nakayama A, Bianco AC, Zhang CY, Lowell BB, Frangioni JV. Quantitation of brown adipose tissue perfusion in transgenic mice using near-infrared fluorescence imaging. Mol Imaging. 2003;2:37–49.CrossRefPubMedGoogle Scholar
  24. 24.
    Ohnishi S, Vanderheyden JL, Tanaka E, et al. Intraoperative detection of cell injury and cell death with an 800 nm near-infrared fluorescent Annexin V derivative. Am J Transplant. 2006;6:2321–31.CrossRefPubMedGoogle Scholar
  25. 25.
    Parungo CP, Colson YL, Kim SW, Kim S, Cohn LH, Bawendi MG, Frangioni JV. Sentinel lymph node mapping of the pleural space. Chest. 2005;127:1799–804.CrossRefPubMedGoogle Scholar
  26. 26.
    Parungo CP, Ohnishi S, De Grand AM, et al. In vivo optical imaging of pleural space drainage to lymph nodes of prognostic significance. Ann Surg Oncol. 2004;11:1085–92.CrossRefPubMedGoogle Scholar
  27. 27.
    Parungo CP, Soybel DI, Colson YL, et al. Lymphatic drainage of the peritoneal space: a pattern dependent on bowel lymphatics. Ann Surg Oncol. 2007;14:286–98.CrossRefPubMedGoogle Scholar
  28. 28.
    Tanaka E, Ohnishi S, Laurence RG, Choi HS, Humblet V, Frangioni JV. Real-time intraoperative ureteral guidance using invisible near-infrared fluorescence. J Urol. 2007;178:2197–202.CrossRefPubMedGoogle Scholar
  29. 29.
    Zaheer A, Lenkinski RE, Mahmood A, Jones AG, Cantley LC, Frangioni JV. In vivo near-infrared fluorescence imaging of osteoblastic activity. Nat Biotechnol. 2001;19:1148–54.CrossRefPubMedGoogle Scholar
  30. 30.
    Zaheer A, Murshed M, De Grand AM, Morgan TG, Karsenty G, Frangioni JV. Optical imaging of hydroxyapatite in the calcified vasculature of transgenic animals. Arterioscler Thromb Vasc Biol. 2006;26:1132–6.CrossRefPubMedGoogle Scholar
  31. 31.
    Zimmer JP, Kim SW, Ohnishi S, Tanaka E, Frangioni JV, Bawendi MG. Size series of small indium arsenide-zinc selenide core-shell nanocrystals and their application to in vivo imaging. J Am Chem Soc. 2006; 128:2526–7.CrossRefPubMedGoogle Scholar
  32. 32.
    Soltesz EG, Kim S, Kim SW, et al. Sentinel lymph node mapping of the gastrointestinal tract by using invisible light. Ann Surg Oncol. 2006;13:386–96.CrossRefPubMedGoogle Scholar
  33. 33.
    Parungo CP, Ohnishi S, Kim SW, et al. Intraoperative identification of esophageal sentinel lymph nodes with near-infrared fluorescence imaging. J Thorac Cardiovasc Surg. 2005;129:844–50.CrossRefPubMedGoogle Scholar
  34. 34.
    Soltesz EG, Kim S, Laurence RG, et al. Intraoperative sentinel lymph node mapping of the lung using near-infrared fluorescent quantum dots. Ann Thorac Surg. 2005;79:269–77.CrossRefPubMedGoogle Scholar
  35. 35.
    Ohnishi S, Garfein ES, Karp SJ, Frangioni JV. Radiolabeled and near-infrared fluorescent fibrinogen derivatives create a system for the identification and repair of obscure gastrointestinal bleeding. Surgery. 2006;140:785–92.CrossRefPubMedGoogle Scholar
  36. 36.
    Ohnishi S, Lomnes SJ, Laurence RG, Gogbashian A, Mariani G, Frangioni JV. Organic alternatives to quantum dots for intraoperative near-infrared fluorescent sentinel lymph node mapping. Mol Imaging. 2005;4:172–81.PubMedGoogle Scholar
  37. 37.
    Bhushan KR, Tanaka E, Frangioni JV. Synthesis of conjugatable bisphosphonates for molecular imaging of large animals. Angew Chem Int Ed Engl. 2007;46:7969–71.CrossRefPubMedGoogle Scholar
  38. 38.
    Soltesz EG, Laurence RG, De Grand AM, Cohn LH, Mihaljevic T, Frangioni JV. Image-guided quantification of cardioplegia delivery during cardiac surgery. Heart Surg Forum. 2007;10:E381–6.CrossRefPubMedGoogle Scholar
  39. 39.
    Tanaka E, Choi HS, Humblet V, Ohnishi S, Laurence RG, Frangioni JV. Real-time intraoperative assessment of the extrahepatic bile ducts in rats and pigs using invisible near-infrared fluorescent light. Surgery. 2008;144:39–48.CrossRefPubMedGoogle Scholar
  40. 40.
    Knapp DW, Adams LG, Degrand AM, et al. Sentinel lymph node mapping of invasive urinary bladder cancer in animal models using invisible light. Eur Urol. 2007;52:1700–8.CrossRefPubMedGoogle Scholar
  41. 41.
    Flaumenhaft R, Tanaka E, Graham GJ, et al. Localization and quantification of platelet-rich thrombi in large blood vessels with near-infrared fluorescence imaging. Circulation. 2007;115:84–93.CrossRefPubMedGoogle Scholar
  42. 42.
    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).Google Scholar
  43. 43.
    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.Google Scholar
  44. 44.
    Zakaria S, Hoskin TL, Degnim AC. Safety and technical success of methylene blue dye for lymphatic mapping in breast cancer. Am J Surg. 2008;196:228–33.CrossRefPubMedGoogle Scholar

Copyright information

© Society of Surgical Oncology 2009

Authors and Affiliations

  • Susan L. Troyan
    • 1
  • Vida Kianzad
    • 2
  • Summer L. Gibbs-Strauss
    • 2
  • Sylvain Gioux
    • 2
  • Aya Matsui
    • 2
  • Rafiou Oketokoun
    • 2
    • 3
  • Long Ngo
    • 4
  • Ali Khamene
    • 3
  • Fred Azar
    • 3
  • John V. Frangioni
    • 2
    • 5
  1. 1.Breast Care Center, Department of SurgeryBeth Israel Deaconess Medical CenterBostonUSA
  2. 2.Division of Hematology/Oncology, Department of MedicineBeth Israel Deaconess Medical CenterBostonUSA
  3. 3.Siemens Corporate ResearchPrincetonUSA
  4. 4.Division of General Medicine, Department of MedicineBeth Israel Deaconess Medical CenterBostonUSA
  5. 5.Department of RadiologyBeth Israel Deaconess Medical CenterBostonUSA

Personalised recommendations