title: Real-time intraoperative detection of breast cancer using near-infrared fluorescence imaging and Methylene Blue.
abstract: BACKGROUND
  Despite recent developments in preoperative breast cancer imaging, intraoperative localization of tumor tissue can be challenging, resulting in tumor-positive resection margins during breast conserving surgery. Based on certain physicochemical similarities between Technetium((99m)Tc)-sestamibi (MIBI), an SPECT radiodiagnostic with a sensitivity of 83-90% to detect breast cancer preoperatively, and the near-infrared (NIR) fluorophore Methylene Blue (MB), we hypothesized that MB might detect breast cancer intraoperatively using NIR fluorescence imaging.
  
  
  METHODS
  Twenty-four patients with breast cancer, planned for surgical resection, were included. Patients were divided in 2 administration groups, which differed with respect to the timing of MB administration. N = 12 patients per group were administered 1.0 mg/kg MB intravenously either immediately or 3 h before surgery. The mini-FLARE imaging system was used to identify the NIR fluorescent signal during surgery and on post-resected specimens transferred to the pathology department. Results were confirmed by NIR fluorescence microscopy.
  
  
  RESULTS
  20/24 (83%) of breast tumors (carcinoma in N = 21 and ductal carcinoma in situ in N = 3) were identified in the resected specimen using NIR fluorescence imaging. Patients with non-detectable tumors were significantly older. No significant relation to receptor status or tumor grade was seen. Overall tumor-to-background ratio (TBR) was 2.4 ± 0.8. There was no significant difference between TBR and background signal between administration groups. In 2/4 patients with positive resection margins, breast cancer tissue identified in the wound bed during surgery would have changed surgical management. Histology confirmed the concordance of fluorescence signal and tumor tissue.
  
  
  CONCLUSIONS
  This feasibility study demonstrated an overall breast cancer identification rate using MB of 83%, with real-time intraoperative guidance having the potential to alter patient management.
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Q R J G
authors.initials: QR
authors.lastname: Tummers
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: F P R
authors.initials: FP
authors.lastname: Verbeek
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: B E
authors.initials: BE
authors.lastname: Schaafsma
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: M C
authors.initials: MC
authors.lastname: Boonstra
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: J R
authors.initials: JR
authors.lastname: van der Vorst
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: G-J
authors.initials: GJ
authors.lastname: Liefers
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: C J H
authors.initials: CJ
authors.lastname: van de Velde
authors.affiliation: Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: J V
authors.initials: JV
authors.lastname: Frangioni
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: a.l.vahrmeijer@lumc.nl.
authors.forename: A L
authors.initials: AL
authors.lastname: Vahrmeijer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001707:Biopsy, Needle; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000473:pathology / Q000601:surgery*; D005260:Female; D005453:Fluorescence; D006801:Humans; D007089:Image Enhancement / Q000379:methods; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D007430:Intraoperative Care / Q000379:methods*; D015411:Mastectomy, Modified Radical / Q000379:methods; D015412:Mastectomy, Segmental / Q000379:methods; D008751:Methylene Blue; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D011446:Prospective Studies; D019265:Spectroscopy, Near-Infrared / Q000379:methods*; D025321:Surgery, Computer-Assisted / Q000379:methods
chemical_list: D008751:Methylene Blue
keywords: Breast cancer; Image-guided surgery; Methylene Blue; Near-infrared fluorescence imaging