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Published in: Annals of Surgical Oncology 4/2010

01-04-2010 | Endocrine Tumors

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

Authors: Joshua H. Winer, MD, Hak Soo Choi, PhD, Summer L. Gibbs-Strauss, PhD, Yoshitomo Ashitate, MD, Yolonda L. Colson, MD, PhD, John V. Frangioni, MD, PhD

Published in: Annals of Surgical Oncology | Issue 4/2010

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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.
Literature
1.
2.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
3.
go back to reference Warner RR. Enteroendocrine tumors other than carcinoid: a review of clinically significant advances. Gastroenterology. 2005;128:1668–84.CrossRefPubMed Warner RR. Enteroendocrine tumors other than carcinoid: a review of clinically significant advances. Gastroenterology. 2005;128:1668–84.CrossRefPubMed
4.
go back to reference Pedrazzoli S, Pasquali C, Alfano D’Andrea A. Surgical treatment of insulinoma. Br J Surg. 1994;81:672–6.CrossRefPubMed Pedrazzoli S, Pasquali C, Alfano D’Andrea A. Surgical treatment of insulinoma. Br J Surg. 1994;81:672–6.CrossRefPubMed
5.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
6.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
7.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
8.
go back to reference 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.PubMed 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.PubMed
9.
go back to reference Ko TC, Flisak M, Prinz RA. Selective intra-arterial methylene blue injection: a novel method of localizing gastrinoma. Gastroenterology. 1992;102:1062–4.PubMed Ko TC, Flisak M, Prinz RA. Selective intra-arterial methylene blue injection: a novel method of localizing gastrinoma. Gastroenterology. 1992;102:1062–4.PubMed
10.
go back to reference Prinz RA. Selective intraarterial methylene blue for pancreatic and duodenal endocrine tumors. J Heptobiliary Pancreat Surg. 1994;1:517–21.CrossRef Prinz RA. Selective intraarterial methylene blue for pancreatic and duodenal endocrine tumors. J Heptobiliary Pancreat Surg. 1994;1:517–21.CrossRef
11.
go back to reference Keaveny TV, Fitzgerald PA, McMullin JP. Selective parathyroid and pancreatic staining. Br J Surg. 1969;56:595–7.CrossRefPubMed Keaveny TV, Fitzgerald PA, McMullin JP. Selective parathyroid and pancreatic staining. Br J Surg. 1969;56:595–7.CrossRefPubMed
12.
go back to reference Keaveny TV, Tawes R, Belzer FO. A new method for intra-operative identification of insulinomas. Br J Surg. 1971;58:233–4.CrossRefPubMed Keaveny TV, Tawes R, Belzer FO. A new method for intra-operative identification of insulinomas. Br J Surg. 1971;58:233–4.CrossRefPubMed
13.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
14.
15.
go back to reference Sens R, Drexhage KH. Fluorescence quantum yield of oxazine and carbazine laser dyes. J Lumin. 1981;24:709–12.CrossRef Sens R, Drexhage KH. Fluorescence quantum yield of oxazine and carbazine laser dyes. J Lumin. 1981;24:709–12.CrossRef
16.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
17.
go back to reference 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.PubMed 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.PubMed
18.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
19.
go back to reference Abboud B, Boujaoude J. Occult sporadic insulinoma: localization and surgical strategy. World J Gastroenterol. 2008;14:657–65.CrossRefPubMed Abboud B, Boujaoude J. Occult sporadic insulinoma: localization and surgical strategy. World J Gastroenterol. 2008;14:657–65.CrossRefPubMed
20.
go back to reference 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.CrossRef 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.CrossRef
21.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
22.
go back to reference Gordon DL, Airan MC, Suvanich S. Visual identification of an insulinoma using methylene blue. Br J Surg. 1974;61:363–4.CrossRef Gordon DL, Airan MC, Suvanich S. Visual identification of an insulinoma using methylene blue. Br J Surg. 1974;61:363–4.CrossRef
23.
go back to reference Gordon DL, Airan MC, Thomas W, Seidman LH. Parathyroid identification by methylene blue infusion. Br J Surg. 1975;62:747–9.CrossRefPubMed Gordon DL, Airan MC, Thomas W, Seidman LH. Parathyroid identification by methylene blue infusion. Br J Surg. 1975;62:747–9.CrossRefPubMed
25.
go back to reference Patel PN. Methylene blue for management of Ifosfamide-induced encephalopathy. Ann Pharmacother. 2006;40:299–303.CrossRefPubMed Patel PN. Methylene blue for management of Ifosfamide-induced encephalopathy. Ann Pharmacother. 2006;40:299–303.CrossRefPubMed
26.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
Metadata
Title
Intraoperative Localization of Insulinoma and Normal Pancreas Using Invisible Near-Infrared Fluorescent Light
Authors
Joshua H. Winer, MD
Hak Soo Choi, PhD
Summer L. Gibbs-Strauss, PhD
Yoshitomo Ashitate, MD
Yolonda L. Colson, MD, PhD
John V. Frangioni, MD, PhD
Publication date
01-04-2010
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 4/2010
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-009-0868-8

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