Skip to main content
SpringerLink
Log in

Intraoperative Localization of Insulinoma and Normal Pancreas Using Invisible Near-Infrared Fluorescent Light

  • Endocrine Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Neuroendocrine tumors of the pancreas, such as insulinoma, are difficult to localize, and complete resection is essential for cure. Our hypothesis is that a near-infrared (NIR) fluorophore exhibiting uptake in insulinoma could provide high-sensitivity detection intraoperatively.

Materials and Methods

The optical properties of methylene blue (MB) were measured in vitro in 100% serum at 37°C and in vivo after tissue uptake. MB was injected as a rapid intravenous bolus at doses ranging from 0.25 to 2 mg/kg into wildtype rats and pigs, and into insulinoma-bearing transgenic mice. The FLARE™ imaging system was used to acquire color video and NIR fluorescence images simultaneously and in real-time. The signal-to-background ratios (SBR) of tissues and tumors were quantified using FLARE™ software.

Results

When appropriately diluted, MB exhibits moderate NIR fluorescence emission peaking at 688 nm. At doses ≥1 mg/kg, certain normal tissues, such as pancreas, accumulate MB and remain NIR fluorescent for up to 1 h with an SBR ≥ 1.6. MB spectral properties are maintained after uptake into tissue. Interestingly, insulinoma exhibits even higher MB signal than normal pancreas, resulting in insulinoma-to-pancreas ratios of 3.7 and insulinoma-to-muscle ratios of 16.2. MB permitted high-sensitivity, real-time localization of primary, multicentric, and metastatic insulinoma and permitted differentiation among tumor, normal pancreas, and other abdominal structures.

Conclusion

A single intravenous injection of a clinically available, commonly used NIR fluorophore provides prolonged intraoperative localization of normal pancreas and insulinoma using invisible NIR fluorescent light.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Tucker ON, Crotty PL, Conlon KC. The management of insulinoma. Br J Surg. 2006;93:264–75.

    Article  CAS  PubMed  Google Scholar 

  2. Nikfarjam M, Warshaw AL, Axelrod L, Deshpande V, Thayer SP, Ferrone CR, Fernandez-del Castillo C. Improved contemporary surgical management of insulinomas: a 25-year experience at the Massachusetts General Hospital. Ann Surg. 2008;247:165–72.

    Article  PubMed  Google Scholar 

  3. Warner RR. Enteroendocrine tumors other than carcinoid: a review of clinically significant advances. Gastroenterology. 2005;128:1668–84.

    Article  PubMed  Google Scholar 

  4. Pedrazzoli S, Pasquali C, Alfano D’Andrea A. Surgical treatment of insulinoma. Br J Surg. 1994;81:672–6.

    Article  CAS  PubMed  Google Scholar 

  5. McAuley G, Delaney H, Colville J, Lyburn I, Worsley D, Govender P, Torreggiani WC. Multimodality preoperative imaging of pancreatic insulinomas. Clin Radiol. 2005;60:1039–50.

    Article  CAS  PubMed  Google Scholar 

  6. Guettier JM, Kam A, Chang R, Skarulis MC, Cochran C, Alexander HR, et al. Localization of insulinomas to regions of the pancreas by intraarterial calcium stimulation: the NIH experience. J Clin Endocrinol Metab. 2009;94:1074–80.

    Article  CAS  PubMed  Google Scholar 

  7. Adams S, Baum R, Rink T, Schumm-Drager PM, Usadel KH, Hor G. Limited value of fluorine-18 fluorodeoxyglucose positron emission tomography for the imaging of neuroendocrine tumours. Eur J Nucl Med. 1998;25:79–83.

    Article  CAS  PubMed  Google Scholar 

  8. Fedorak IJ, Ko TC, Gordon D, Flisak M, Prinz RA. Localization of islet cell tumors of the pancreas: a review of current techniques. Surgery. 1993;113:242–9.

    CAS  PubMed  Google Scholar 

  9. Ko TC, Flisak M, Prinz RA. Selective intra-arterial methylene blue injection: a novel method of localizing gastrinoma. Gastroenterology. 1992;102:1062–4.

    CAS  PubMed  Google Scholar 

  10. Prinz RA. Selective intraarterial methylene blue for pancreatic and duodenal endocrine tumors. J Heptobiliary Pancreat Surg. 1994;1:517–21.

    Article  Google Scholar 

  11. Keaveny TV, Fitzgerald PA, McMullin JP. Selective parathyroid and pancreatic staining. Br J Surg. 1969;56:595–7.

    Article  CAS  PubMed  Google Scholar 

  12. Keaveny TV, Tawes R, Belzer FO. A new method for intra-operative identification of insulinomas. Br J Surg. 1971;58:233–4.

    Article  CAS  PubMed  Google Scholar 

  13. 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;138:133–40.

    Article  CAS  PubMed  Google Scholar 

  14. Frangioni JV. In vivo near-infrared fluorescence imaging. Curr Opin Chem Biol. 2003;7:626–34.

    Article  CAS  PubMed  Google Scholar 

  15. Sens R, Drexhage KH. Fluorescence quantum yield of oxazine and carbazine laser dyes. J Lumin. 1981;24:709–12.

    Article  Google Scholar 

  16. Troyan SL, Kianzad V, Gibbs-Strauss SL, Gioux S, Matsui A, Oketokou R, et al. The FLARE™ intraoperative near-infrared fluorescence imaging system: A first-in-human clinical trial in breast cancer sentinel lymph node mapping. Ann Surg Oncol. 2009:16:2943–52.

    Article  PubMed  Google Scholar 

  17. 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;8:156–65.

    CAS  PubMed  Google Scholar 

  18. Hamaguchi K, Gaskins HR, Leiter EH. NIT-1, a pancreatic beta-cell line established from a transgenic NOD/Lt mouse. Diabetes. 1991;40:842–9.

    Article  CAS  PubMed  Google Scholar 

  19. Abboud B, Boujaoude J. Occult sporadic insulinoma: localization and surgical strategy. World J Gastroenterol. 2008;14:657–65.

    Article  PubMed  Google Scholar 

  20. Imamura M, Hosotani R, Shimada Y. The Zollinger-Ellison syndrome: Review of recent progress in diagnosis and treatment. J Heptobiliary Pancreat Surg. 1996;3:33–9.

    Article  Google Scholar 

  21. Tseng LM, Chen JY, Won JG, Tseng HS, Yang AH, Wang SE, Lee CH. The role of intra-arterial calcium stimulation test with hepatic venous sampling (IACS) in the management of occult insulinomas. Ann Surg Oncol. 2007;14:2121–7.

    Article  PubMed  Google Scholar 

  22. Gordon DL, Airan MC, Suvanich S. Visual identification of an insulinoma using methylene blue. Br J Surg. 1974;61:363–4.

    Article  Google Scholar 

  23. Gordon DL, Airan MC, Thomas W, Seidman LH. Parathyroid identification by methylene blue infusion. Br J Surg. 1975;62:747–9.

    Article  CAS  PubMed  Google Scholar 

  24. Keaveny TV, FitzGerald P. Selective parathyroid staining. Lancet. 1968;2:284.

    Article  CAS  PubMed  Google Scholar 

  25. Patel PN. Methylene blue for management of Ifosfamide-induced encephalopathy. Ann Pharmacother. 2006;40:299–303.

    Article  CAS  PubMed  Google Scholar 

  26. Traynor S, Adams JR, Andersen P, Everts E, Cohen J. Appropriate timing and velocity of infusion for the selective staining of parathyroid glands by intravenous methylene blue. Am J Surg. 1998;176:15–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

We thank Barbara L. Clough for editing and Lorissa A. Moffitt and Eugenia Trabucchi for administrative assistance. This study was supported by Bioengineering Research Partnership grant No. R01-CA-115296 to JVF from the National Institutes of Health (National Cancer Institute) and a sponsored research agreement from GE Healthcare. All intellectual property is owned by the Beth Israel Deaconess Medical Center. As inventor of the technology, Dr. Frangioni may someday receive royalties if products are ever commercialized.

Author information

Authors and Affiliations

  1. Department of Surgery, Brigham and Women’s Hospital, Boston, MA, USA

    Joshua H. Winer MD & Yolonda L. Colson MD, PhD

  2. Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Hak Soo Choi PhD, Summer L. Gibbs-Strauss PhD, Yoshitomo Ashitate MD & John V. Frangioni MD, PhD

  3. Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA, USA

    John V. Frangioni MD, PhD

Authors
  1. Joshua H. Winer MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hak Soo Choi PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Summer L. Gibbs-Strauss PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshitomo Ashitate MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yolonda L. Colson MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John V. Frangioni MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John V. Frangioni MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Winer, J.H., Choi, H.S., Gibbs-Strauss, S.L. et al. Intraoperative Localization of Insulinoma and Normal Pancreas Using Invisible Near-Infrared Fluorescent Light. Ann Surg Oncol 17, 1094–1100 (2010). https://doi.org/10.1245/s10434-009-0868-8

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-009-0868-8

Keywords

Search

Navigation