title: Near-Infrared Intraoperative Molecular Imaging Can Locate Metastases to the Lung.
abstract: BACKGROUND
  Pulmonary metastasectomy is widely accepted for many tumor types because it may prolong survival and potentially cure some patients. However, intraoperative localization of pulmonary metastases can be technically challenging. We propose that intraoperative near-infrared (NIR) molecular imaging can be used as an adjunct during disease localization.
  
  
  METHODS
  We inoculated 50 C57BL/6 mice with Lewis lung carcinoma (LLC) flank tumors. After flank tumor growth, mice were injected through the tail vein with indocyanine green (ICG) before operation, and intraoperative imaging was used to detect pulmonary metastases. On the basis of these experiments, we enrolled 8 patients undergoing pulmonary metastasectomy into a pilot and feasibility clinical trial. Each patient received intravenous ICG 1 day before operation, followed by wedge or segmental resection. Samples were imaged on the back table with an NIR camera to confirm disease presence and margins. All murine and human tumors and margins were confirmed by pathologic examination.
  
  
  RESULTS
  Mice had an average of 4 ± 2 metastatic tumors on both lungs, with an average size of 5.1 mm (interquartile range [IQR] 2.2 mm to 7.6 mm). Overall, 200 of 211 (95%) metastatic deposits were markedly fluorescent, with a mean tumor-to-background ratio (TBR) of 3.4 (IQR 3.1 to 4.1). The remaining tumors had a TBR below 1.5. In the human study, intraoperative NIR imaging identified six of the eight preoperatively localized lesions. Intraoperative back table NIR imaging identified all metastatic lesions, which were confirmed by pathologic examination. The average tumor size was 1.75 ± 1.4 cm, and the mean ex vivo TBR was 3.3 (IQR 3.1 to 3.7). Pathologic examination demonstrated melanoma (n = 4), osteogenic sarcoma (n = 2), renal cell carcinoma (n = 2), chondrosarcoma (n = 1), leiomyosarcoma (n = 1), and colorectal carcinoma (n = 1).
  
  
  CONCLUSIONS
  Systemic ICG identifies subcentimeter tumor metastases to the lung in murine models, and this work provides proof of principle in humans. Future research is focused on improving depth of penetration into the lung parenchyma.
authors: Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania; Center for Precision Surgery, Abramson Cancer Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: Jane
authors: J
authors: Keating
authors: Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania; Center for Precision Surgery, Abramson Cancer Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: Andrew
authors: A
authors: Newton
authors: Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania; Center for Precision Surgery, Abramson Cancer Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: Ollin
authors: O
authors: Venegas
authors: Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania; Center for Precision Surgery, Abramson Cancer Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: Sarah
authors: S
authors: Nims
authors: Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania; Center for Precision Surgery, Abramson Cancer Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: Ryan
authors: R
authors: Zeh
authors: Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania; Center for Precision Surgery, Abramson Cancer Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: Jarrod
authors: J
authors: Predina
authors: Department of Pathology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: Charuhas
authors: C
authors: Deshpande
authors: Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania; Center for Precision Surgery, Abramson Cancer Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: John
authors: J
authors: Kucharczuk
authors: Departments of Biomedical Engineering and Chemistry, Emory University, Atlanta, Georgia.
authors: Shuming
authors: S
authors: Nie
authors: Department of Radiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors: E James
authors: EJ
authors: Delikatny
authors: Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania; Center for Precision Surgery, Abramson Cancer Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania. Electronic address: sunil.singhal@uphs.upenn.edu.
authors: Sunil
authors: S
authors: Singhal
mesh_terms: D000818:Animals; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007432:Intraoperative Period; D008175:Lung Neoplasms / Q000175:diagnosis / Q000556:secondary* / Q000601:surgery; D051379:Mice; D008810:Mice, Inbred C57BL; D057054:Molecular Imaging / Q000379:methods*; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental; D010865:Pilot Projects; D011013:Pneumonectomy / Q000379:methods*; D012189:Retrospective Studies; D019265:Spectroscopy, Near-Infrared / Q000379:methods*