Abstract
Purpose
During lung surgery, identification of surgical margins is challenging. We hypothesized that molecular imaging with a fluorescent probe to pulmonary adenocarcinomas could enhance residual tumor during resection.
Procedures
Mice with flank tumors received a contrast agent targeting folate receptor alpha. Optimal dose and time of injection was established. Margin detection was compared using traditional methods versus molecular imaging. A pilot study was then performed in three humans with lung adenocarcinoma.
Results
The peak tumor-to-background ratio (TBR) of murine tumors was 3.9. Fluorescence peaked at 2 h and was not improved beyond 0.1 mg/kg. Traditional inspection identified 30 % of mice with positive margins. Molecular imaging identified an additional 50 % of residual tumor deposits (p < 0.05). The fluorescent probe visually enhanced all human tumors with a mean TBR of 3.5.
Conclusions
Molecular imaging is an important adjunct to traditional inspection to identify surgical margins after tumor resection.
References
Aliperti LA, Predina JD, Vachani A, Singhal S (2011) Local and systemic recurrence is the Achilles heel of cancer surgery. Ann Surg Oncol 18:603–607
Osarogiagbon RU, Phelps G, McFarlane J, Bankole O (2011) Causes and consequences of deviation from multidisciplinary care in thoracic oncology. J Thorac Oncol 6:510–516
Detterbeck FC, Tanoue LT, Boffa DJ (2010) Anatomy, biology and concepts, pertaining to lung cancer stage classification. Zhongguo Fei Ai Za Zhi 13:1–8
Pisters KM, Le Chevalier T (2005) Adjuvant chemotherapy in completely resected non-small-cell lung cancer. J Clin Oncol 23:3270–3278
Vaidya A, Hawke C, Tiguert R, Civantos F, Soloway M (2001) Intraoperative T staging in radical retropubic prostatectomy: is it reliable? Urology 57:949–954
Singhal S, Nie S, Wang MD (2001) Nanotechnology applications in surgical oncology. Annu Rev Med 61:359–373
Madajewski B, Judy BF, Mouchli A, Kapoor V, Holt D, Wang MD, Nie S, Singhal S (2012) Intraoperative near-infrared imaging of surgical wounds after tumor resections can detect residual disease. Clin Cancer Res 18:5741–5751
van der Vorst JR, Schaafsma BE, Hutteman M et al (2013) Near-infrared fluorescence-guided resection of colorectal liver metastases. Cancer 119:3411–3418
van Dam GM, Themelis G, Crane LM et al (2011) Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-alpha targeting: first in-human results. Nat Med 17:1315–1319
Kelemen LE (2006) The role of folate receptor alpha in cancer development, progression and treatment: cause, consequence or innocent bystander? Int J Cancer 119:243–250
Low PS, Antony AC (2004) Folate receptor-targeted drugs for cancer and inflammatory diseases. Adv Drug Deliv Rev 56:1055–1058
Low PS, Henne WA, Doorneweerd DD (2008) Discovery and development of folic-acid-based receptor targeting for imaging and therapy of cancer and inflammatory diseases. Acc Chem Res 41:120–129
Xia W, Low PS (2010) Folate-targeted therapies for cancer. J Med Chem 53:6811–6824
O’Shannessy DJ, Yu G, Smale R et al (2012) Folate receptor alpha expression in lung cancer: diagnostic and prognostic significance. Oncotarget 3:414–425
Lu Y, Sega E, Leamon CP, Low PS (2004) Folate receptor-targeted immunotherapy of cancer: mechanism and therapeutic potential. Adv Drug Deliv Rev 56:1161–1176
Low PS, Kularatne SA (2009) Folate-targeted therapeutic and imaging agents for cancer. Curr Opin Chem Biol 13:256–262
Davis MR, Manning LS, Whitaker D et al (1992) Establishment of a murine model of malignant mesothelioma. Int J Cancer 52:881–886
Lu Y, Xu LC, Parker N et al (2006) Preclinical pharmacokinetics, tissue distribution, and antitumor activity of a folate-hapten conjugate-targeted immunotherapy in hapten-immunized mice. Mol Cancer Ther 5:3258–3267
Lu Y, Low PS (2002) Folate targeting of haptens to cancer cell surfaces mediates immunotherapy of syngeneic murine tumors. Cancer Immunol Immunother 51:153–162
Predina JD, Judy B, Fridlender ZG et al (2012) A positive-margin resection model recreates the postsurgical tumor microenvironment and is a reliable model for adjuvant therapy evaluation. Cancer Biol Ther 13:745–755
Judy BF, Aliperti LA, Predina JD et al (2012) Vascular endothelial-targeted therapy combined with cytotoxic chemotherapy induces inflammatory intratumoral infiltrates and inhibits tumor relapses after surgery. Neoplasia 14:352–359
Fedor D, Johnson WR, Singhal S (2013) Local recurrence following lung cancer surgery: incidence, risk factors, and outcomes. Surg Oncol 22:156–161
Gomez DR, Komaki R (2012) Postoperative radiation therapy for non-small cell lung cancer and thymic malignancies. Cancers (Basel) 4:307–322
Trajkovic-Arsic M, Mohajerani P, Sarantopoulos A et al (2014) Multimodal molecular imaging of integrin alphavbeta3 for in vivo detection of pancreatic cancer. J Nucl Med 55:446–451
Metildi CA, Kaushal S, Pu M et al (2014) Fluorescence-guided surgery with a fluorophore-conjugated antibody to carcinoembryonic antigen (CEA), that highlights the tumor, improves surgical resection and increases survival in orthotopic mouse models of human pancreatic cancer. Ann Surg Oncol 21:1405–1411
Hiroshima Y, Maawy A, Metildi CA et al (2014) Successful fluorescence-guided surgery on human colon cancer patient-derived orthotopic xenograft mouse models using a fluorophore-conjugated anti-CEA antibody and a portable imaging system. J Laparoendosc Adv Surg Tech A 24:241–247
Sturm MB, Joshi BP, Lu S et al (2013) Targeted imaging of esophageal neoplasia with a fluorescently labeled peptide: first-in-human results. Sci Transl Med 5:184ra161
Yang L, Sajja HK, Cao Z et al (2013) uPAR-targeted optical imaging contrasts as theranostic agents for tumor margin detection. Theranostics 4:106–118
Chi C, Du Y, Ye J et al (2014) Intraoperative imaging-guided cancer surgery: from current fluorescence molecular imaging methods to future multi-modality imaging technology. Theranostics 4:1072–1084
Jacques SL (2013) Optical properties of biological tissues: a review. Phys Med Biol 58:37–61
Funding
This work was supported by the National Institutes of Health RO1 CA163256.
Conflict of Interest
Dr. Low is a consultant and stakeholder in OnTarget Laboratories LLC. Dr. Nie discloses a relationship as a consultant for Spectropath Inc.
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Keating, J.J., Okusanya, O.T., De Jesus, E. et al. Intraoperative Molecular Imaging of Lung Adenocarcinoma Can Identify Residual Tumor Cells at the Surgical Margins. Mol Imaging Biol 18, 209–218 (2016). https://doi.org/10.1007/s11307-015-0878-9
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DOI: https://doi.org/10.1007/s11307-015-0878-9