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Standardization and Optimization of Intraoperative Molecular Imaging for Identifying Primary Pulmonary Adenocarcinomas

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Abstract

Purpose

Intraoperative molecular imaging (IMI) is an emerging technology used to locate pulmonary adenocarcinomas and identify positive margins during surgery. Background noise and tissue autofluorescence have been major obstacles. The goal of this study is to optimize the image quality of folate receptor alpha (FRα) targeted IMI for pulmonary adenocarcinomas by modifying emission data.

Procedures

A total of 15 lung cancer patients were enrolled in a pilot study. In the first cohort, FRα upregulation within pulmonary adenocarcinoma tumors was confirmed by analyzing specimens from five pulmonary adenocarcinoma patients with flow cytometry and immunohistochemistry. Next, in a cohort of five additional patients, autofluorescence of intrathoracic structures and tissues was quantified. Lastly, five patients with tumors at various depths from the pleural surface were enrolled and received the FRα-targeted optical contrast agent, EC17. In this final cohort, resected pulmonary adenocarcinomas were imaged at a wide range of fluorescence exposure times (0 to 200 ms), various laser powers, and with unique filter configurations. Tumor-to-noise ratio (TNR) for images was generated using region of interest software.

Results

Pulmonary adenocarcinomas highly express FRα. Significant autofluorescence from native thoracic tissues was found with the highest fluorescent signals at the bronchial stump (547 ± 98, range 423–699), the pulmonary artery (267 ± 64, range 200–374), and cortical bone (266 ± 17, range 243–287). High levels of autofluorescence were appreciated after systemic administration of EC17; however, TNR was improved by altering exposure settings at the time of the imaging. Optimal fluorescent exposure time occurs at 40 ms (25 frames/s).

Conclusions

Exposure properties can be manipulated to maximize TNR thus allowing for successful intraoperative detection of pulmonary adenocarcinomas during surgery. Optimization of the conditions for intraoperative molecular imaging sets the stage for future clinical trials utilizing targeted IMI techniques which can aid the surgeon at the time of cancer resection.

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References

  1. 2013 United States Procedure Volumes Database (2013). Thomas Reuters., Ed. Reuters T. United States

  2. National Inpatient Sample (NIS). (2011). Agency for Healthcare Research and Quality. http://www.hcup-us.ahrq.gov/nisoverview.jsp., Ed. Quality AfHRa

  3. 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

    Article  PubMed  Google Scholar 

  4. Fedor D, Johnson WR, Singhal S (2013) Local recurrence following lung cancer surgery: incidence, risk factors, and outcomes. Surg Oncol 22:156–161

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kelsey CR, Marks LB, Hollis D et al (2009) Local recurrence after surgery for early stage lung cancer: an 11-year experience with 975 patients. Cancer 115:5218–5227

    Article  PubMed  Google Scholar 

  6. Sugimura H, Nichols FC, Yang P et al (2007) Survival after recurrent nonsmall-cell lung cancer after complete pulmonary resection. Ann Thorac Surg 83:409–417 discussioin 417-408

    Article  PubMed  Google Scholar 

  7. Okusanya OT, Madajewski B, Segal E, et al. (2015a) Small portable interchangeable imager of fluorescence for fluorescence guided surgery and research. Technol Cancer Res Treatment. 14

  8. Madajewski B, Judy BF, Mouchli A et al (2012) Intraoperative near-infrared imaging of surgical wounds after tumor resections can detect residual disease. Clin Cancer Res 18:5741–5751

    Article  PubMed  PubMed Central  Google Scholar 

  9. 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

    Article  PubMed  Google Scholar 

  10. van der Vorst JR, Schaafsma BE, Hutteman M et al (2013) Near-infrared fluorescence-guided resection of colorectal liver metastases. Cancer 119:3411–3418

    Article  PubMed  PubMed Central  Google Scholar 

  11. Jiang JX, Keating JJ, Jesus EM et al (2015) Optimization of the enhanced permeability and retention effect for near-infrared imaging of solid tumors with indocyanine green. Am J Nucl Med Mol Imaging 5:390–400

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Okusanya OT, DeJesus EM, Jiang JX et al (2015b) Intraoperative molecular imaging can identify lung adenocarcinomas during pulmonary resection. J Thorac Cardiovasc Surg 150(28–35):e21

    Google Scholar 

  13. Holt D, Okusanya O, Judy R et al (2014) Intraoperative near-infrared imaging can distinguish cancer from normal tissue but not inflammation. PLoS One 9:e103342

    Article  PubMed  PubMed Central  Google Scholar 

  14. Thiberville L, Moreno-Swirc S, Vercauteren T, Peltier E, Cave C, Bourg Heckly G (2007) In vivo imaging of the bronchial wall microstructure using fibered confocal fluorescence microscopy. Am J Resp Crit Care Med 175:22–31

    Article  PubMed  Google Scholar 

  15. Thiberville L, Salaun M, Lachkar S et al (2009) Human in vivo fluorescence microimaging of the alveolar ducts and sacs during bronchoscopy. Eur Resp J 33:974–985

    Article  CAS  Google Scholar 

  16. Low PS, Kularatne SA (2009) Folate-targeted therapeutic and imaging agents for cancer. Curr Opin Chem Biol 13:256–262

    Article  CAS  PubMed  Google Scholar 

  17. Parker N, Turk MJ, Westrick E et al (2005) Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Anal Biochem 338:284–293

    Article  CAS  PubMed  Google Scholar 

  18. 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

    PubMed  PubMed Central  Google Scholar 

  19. Mantovani LT, Miotti S, Menard S et al (1994) Folate binding protein distribution in normal tissues and biological fluids from ovarian carcinoma patients as detected by the monoclonal antibodies MOv18 and MOv19. Eur J Cancer 30A:363–369

    Article  CAS  PubMed  Google Scholar 

  20. Tummers QR, Hoogstins CE, Gaarenstroom KN et al (2016) Intraoperative imaging of folate receptor alpha positive ovarian and breast cancer using the tumor specific agent EC17. Oncotarget 7:32144–32155

    Article  PubMed  PubMed Central  Google Scholar 

  21. Guzzo TJ, Jiang J, Keating J et al (2016) Intraoperative molecular diagnostic imaging can identify renal cell carcinoma. J Urol 195:748–755

    Article  PubMed  Google Scholar 

  22. De Jesus E, Keating JJ, Kularatne SA et al (2015) Comparison of folate receptor targeted optical contrast agents for intraoperative molecular imaging. Int J Mol Imaging 2015:469047

    Article  PubMed  PubMed Central  Google Scholar 

  23. Judy RP, Keating JJ, DeJesus EM et al (2015) Quantification of tumor fluorescence during intraoperative optical cancer imaging. Sci Rep 5:16208

    Article  PubMed  PubMed Central  Google Scholar 

  24. Okusanya OT, Madajewski B, Segal E et al (2015c) Small portable interchangeable imager of fluorescence for fluorescence guided surgery and research. Tech Cancer Res Treatment 14:213–220

    Article  CAS  Google Scholar 

  25. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Eruslanov E, Daurkin I, Ortiz J, Vieweg J, Kusmartsev S (2010) Pivotal advance: tumor-mediated induction of myeloid-derived suppressor cells and M2-polarized macrophages by altering intracellular PGE(2) catabolism in myeloid cells. J Leukoc Biol 88:839–848

    Article  CAS  PubMed  Google Scholar 

  27. Lin Y, Weissleder R, Tung CH (2002) Novel near-infrared cyanine fluorochromes: synthesis, properties, and bioconjugation. Bioconjug Chem 13:605–610

    Article  PubMed  Google Scholar 

  28. Low PS, Antony AC (2004) Folate receptor-targeted drugs for cancer and inflammatory diseases. Adv Drug Deliv Rev 56:1055–1058

    Article  CAS  PubMed  Google Scholar 

  29. 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

    Article  CAS  PubMed  Google Scholar 

  30. Xia W, Low PS (2010) Folate-targeted therapies for cancer. J Med Chem 53:6811–6824

    Article  CAS  PubMed  Google Scholar 

  31. 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

    Article  CAS  PubMed  Google Scholar 

  32. Sjoback R, Nygren J, Kubista M (1995) Absorption and fluorescence properties of fluorescein. Spectrochim Acta A 51:L7–L21

    Article  Google Scholar 

  33. Monici M (2005) Cell and tissue autofluorescence research and diagnostic applications. Biotech Annual Rev 11:227–256

    Article  CAS  Google Scholar 

  34. Kennedy GT, Okusanya OT, Keating JJ et al (2015) The optical biopsy: a novel technique for rapid intraoperative diagnosis of primary pulmonary adenocarcinomas. Ann Surg 262:602–609

    Article  PubMed  Google Scholar 

  35. de Boer E, Warram JM, Tucker MD et al (2015) In vivo fluorescence immunohistochemistry: localization of fluorescently labeled cetuximab in squamous cell carcinomas. Sci Rep 5:10169

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, Perelman School of Medicine, University of Pennsylvania School of Medicine, 6 White Building, 3400 Spruce Street, Philadelphia, PA, 19104, USA

    Jarrod D. Predina, Olugbenga Okusanya, Andrew D. Newton & Sunil Singhal

  2. Center for Precision Surgery, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA

    Jarrod D. Predina, Olugbenga Okusanya, Andrew D. Newton & Sunil Singhal

  3. Department of Chemistry, Purdue University, West Lafayette, IN, USA

    Philip Low

Authors
  1. Jarrod D. Predina
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  2. Olugbenga Okusanya
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  3. Andrew D. Newton
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  4. Philip Low
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  5. Sunil Singhal
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Corresponding author

Correspondence to Sunil Singhal.

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Funding Sources

JDP was supported by a grant by the American Philosophical Society, an NIH F32 (1F32CA210409), and an Association for Academic Surgery Research Grant. SS was supported by a federal funding including an NIH R01 (CA193556).

Conflict of Interest

PL is on the Board of Directors for OnTarget Laboratories, manufacturer of EC17.

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Predina, J.D., Okusanya, O., D. Newton, A. et al. Standardization and Optimization of Intraoperative Molecular Imaging for Identifying Primary Pulmonary Adenocarcinomas. Mol Imaging Biol 20, 131–138 (2018). https://doi.org/10.1007/s11307-017-1076-8

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  • DOI: https://doi.org/10.1007/s11307-017-1076-8

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