An Integrated Widefield Imaging and Spectroscopy System for Contrast-Enhanced, Image-Guided Resection of Tumors

Tumor recurrence following surgery is a common and unresolved medical problem of great importance since surgery is the most widely used treatment for solid-mass tumors worldwide. A contributing factor to tumor recurrence is the presence of residual tumor remaining at or near the surgical site following surgery. Goal: The primary objective of this study was to develop and evaluate an image-guided surgery system based on a near-infrared, handheld excitation source and spectrograph in combination with a widefield video imaging system. Methods: This system was designed to detect the fluorescence of near-infrared contrast agents and, in particular, indocyanine green (ICG). The imaging system was evaluated for its optical performance and ability to detect the presence of ICG in tumors in an ectopic murine tumor model as well as in spontaneous tumors arising in canines. Results: In both settings, an intravenous ICG infusion provided tumor contrast. In both the murine models and surgical specimens from canines, ICG preferentially accumulated in tumor tissue compared to surrounding normal tissue. The resulting contrast was sufficient to distinguish neoplasia from normal tissue; in the canine surgical specimens, the contrast was sufficient to permit identification of neoplasia on the marginal surface of the specimen. Conclusion: These results demonstrate a unique concept in image-guided surgery by combining local excitation and spectroscopy with widefield imaging. Significance: The ability to readily detect ICG in canines with spontaneous tumors in a clinical setting exemplifies the potential for further clinical translation; the promising results of detecting neoplasia on the marginal specimen surface underscore the clinical utility.

[1]  Hiroshi Kobayashi,et al.  The Usefulness of Photodynamic Eye for Sentinel Lymph Node Identification in Patients with Cervical Cancer , 2010, Tumori.

[2]  Ricardo Ramina,et al.  Optimizing costs of intraoperative magnetic resonance imaging. A series of 29 glioma cases , 2009, Acta Neurochirurgica.

[3]  Miriam Scadeng,et al.  Surgery with molecular fluorescence imaging using activatable cell-penetrating peptides decreases residual cancer and improves survival , 2010, Proceedings of the National Academy of Sciences.

[4]  Les Irwig,et al.  Meta-analysis of the impact of surgical margins on local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy. , 2010, European journal of cancer.

[5]  Cornelis J H van de Velde,et al.  Optimization of Near-Infrared Fluorescent Sentinel Lymph Node Mapping in Cervical Cancer Patients , 2011, International Journal of Gynecologic Cancer.

[6]  Takeaki Ishizawa,et al.  Real‐time identification of liver cancers by using indocyanine green fluorescent imaging , 2009, Cancer.

[7]  Emil D. Kurniawan BMedSc,et al.  Predictors of Surgical Margin Status in Breast-Conserving Surgery Within a Breast Screening Program , 2008, Annals of Surgical Oncology.

[8]  R. Weissleder A clearer vision for in vivo imaging , 2001, Nature Biotechnology.

[9]  J. S. Reynolds,et al.  Measurement of the fluorescence lifetime in scattering media by frequency-domain photon migration. , 1999, Applied optics.

[10]  J. S. Reynolds,et al.  Imaging of Spontaneous Canine Mammary Tumors Using Fluorescent Contrast Agents , 1999, Photochemistry and photobiology.

[11]  M. Kattan,et al.  Prognostic impact of positive surgical margins in surgically treated prostate cancer: multi-institutional assessment of 5831 patients. , 2005, Urology.

[12]  Laurent Salomon,et al.  Long-term impact of positive surgical margins on biochemical recurrence after radical prostatectomy: Ten years of follow-up , 2014, Scandinavian journal of urology.

[13]  Pieter L Kubben,et al.  Intraoperative MRI-guided resection of glioblastoma multiforme: a systematic review. , 2011, The Lancet. Oncology.

[14]  Osamu Ishikawa,et al.  A novel image‐guided surgery of hepatocellular carcinoma by indocyanine green fluorescence imaging navigation , 2009, Journal of surgical oncology.

[15]  D R Walker,et al.  Fate of patients with residual tumour at the bronchial resection margin. , 1994, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[16]  Cornelis J H van de Velde,et al.  Near‐infrared fluorescence‐guided resection of colorectal liver metastases , 2013, Cancer.

[17]  Vasilis Ntziachristos,et al.  Current concepts and future perspectives on surgical optical imaging in cancer. , 2010, Journal of biomedical optics.

[18]  Shuming Nie,et al.  Small Portable Interchangeable Imager of Fluorescence for Fluorescence Guided Surgery and Research , 2015, Technology in cancer research & treatment.

[19]  M. Paoloni,et al.  Translation of new cancer treatments from pet dogs to humans , 2008, Nature Reviews Cancer.

[20]  Eva M. Sevick-Muraca,et al.  Near-Infrared Fluorescence Imaging in Humans with Indocyanine Green: A Review and Update~!2009-12-07~!2009-12-23~!2010-05-26~! , 2010 .

[21]  H. Maeda,et al.  The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. , 2013, Advanced drug delivery reviews.

[22]  S. Harms,et al.  Assessing margin status. , 1999, Surgical oncology.

[23]  Yoshifumi MoritaTakanori,et al.  Detection of hepatocellular carcinomas with near-infrared fluorescence imaging using indocyanine green: its usefulness and limitation , 2013 .

[24]  H. Dvorak,et al.  Vascular permeability to plasma, plasma proteins, and cells: an update , 2010, Current opinion in hematology.

[25]  May D. Wang,et al.  Hand-held spectroscopic device for in vivo and intraoperative tumor detection: contrast enhancement, detection sensitivity, and tissue penetration. , 2010, Analytical chemistry.

[26]  Yasuhiko Sugawara,et al.  Hepatobiliary surgery guided by a novel fluorescent imaging technique for visualizing hepatic arteries, bile ducts, and liver cancers on color images. , 2011, Journal of the American College of Surgeons.

[27]  I-Chih Tan,et al.  Near-Infrared Fluorescence Imaging in Humans with Indocyanine Green: A Review and Update. , 2010, Open surgical oncology journal.

[28]  D. Bostwick,et al.  Accuracy of frozen-section diagnosis of mammographically directed breast biopsies. Results of 1,490 consecutive cases. , 1995, The American journal of surgical pathology.

[29]  S. Meijer,et al.  Intraoperative ultrasound guidance for palpable breast cancer excision (COBALT trial): a multicentre, randomised controlled trial. , 2013, The Lancet. Oncology.

[30]  Malcolm Buchanan,et al.  Predictors of Surgical Margin Status in Breast-Conserving Surgery Within a Breast Screening Program , 2008, Annals of surgical oncology.

[31]  Shuming Nie,et al.  Nanotechnology applications in surgical oncology. , 2010, Annual review of medicine.

[32]  T. Krings,et al.  Course of brain shift during microsurgical resection of supratentorial cerebral lesions: limits of conventional neuronavigation , 2004, Acta Neurochirurgica.

[33]  L. Ngo,et al.  The FLARE™ Intraoperative Near-Infrared Fluorescence Imaging System: A First-in-Human Clinical Trial in Breast Cancer Sentinel Lymph Node Mapping , 2009, Annals of Surgical Oncology.

[34]  H. Feigelson,et al.  Variability in reexcision following breast conservation surgery. , 2012, JAMA.

[35]  May D. Wang,et al.  In vivo tumor targeting and spectroscopic detection with surface-enhanced Raman nanoparticle tags , 2008, Nature Biotechnology.

[36]  Milton V. Marshall,et al.  Imaging of lymph flow in breast cancer patients after microdose administration of a near-infrared fluorophore: feasibility study. , 2008, Radiology.

[37]  P Ott,et al.  Hepatic elimination of indocyanine green with special reference to distribution kinetics and the influence of plasma protein binding. , 1998, Pharmacology & toxicology.