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Abstract

In vivo tumor labeling with fluorescent agents may assist endoscopic and surgical guidance for cancer therapy as well as create opportunities to directly observe cancer biology in patients. However, malignant and nonmalignant tissues are usually distinguished on fluorescence images by applying empirically determined fluorescence intensity thresholds. Here, we report the development of fSTREAM, a set of analytic methods designed to streamline the analysis of surgically excised breast tissues by collecting and statistically processing hybrid multiscale fluorescence, color, and histology readouts toward precision fluorescence imaging. fSTREAM addresses core questions of how to relate fluorescence intensity to tumor tissue and how to quantitatively assign a normalized threshold that sufficiently differentiates tumor tissue from healthy tissue. Using fSTREAM we assessed human breast tumors stained in vivo with fluorescent bevacizumab at microdose levels. Showing that detection of such levels is achievable, we validated fSTREAM for high-resolution mapping of the spatial pattern of labeled antibody and its relation to the underlying cancer pathophysiology and tumor border on a per patient basis. We demonstrated a 98% sensitivity and 79% specificity when using labeled bevacizumab to outline the tumor mass. Overall, our results illustrate a quantitative approach to relate fluorescence signals to malignant tissues and improve the theranostic application of fluorescence molecular imaging.  

​Author information​

Koch M1,2, de Jong JS3, Glatz J1,2, Symvoulidis P1,2, Lamberts LE4, Adams AL5, Kranendonk ME3, Terwisscha van Scheltinga AG4,6, Aichler M7, Jansen L8, de Vries J8, Lub-de Hooge MN6, Schröder CP4, Jorritsma-Smit A6, Linssen MD6, de Boer E8, van der Vegt B9, Nagengast WB10, Elias SG11, Oliveira S12, Witkamp AJ13, Mali WP5, Van der Wall E14, Garcia-Allende PB1,2, van Diest PJ3, de Vries EG4, Walch A7, van Dam GM8,15, Ntziachristos V16,2.

1Chair for Biological Imaging, Technical University of Munich, München, Germany.

2Institute for Biological and Medical Imaging, Helmholtz Zentrum München, München, Germany.

3Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.

4Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

5Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands.

6Hospital and Clinical Pharmacy, University of Groningen, University Medical Center Groningen, the Netherlands.

7Research Unit Analytical Pathology, Helmholtz Zentrum München, München, Germany.

8Department of Surgery, University of Groningen, University Medical Center Groningen, the Netherlands.

9Department of Pathology, University of Groningen, University Medical Center Groningen, the Netherlands.

10Department of Gastroenterology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

11Julius Center for Health Sciences and Primary Care, Cell Biology, University Medical Center Utrecht, Utrecht, the Netherlands.

12Department of Biology, University Medical Center Utrecht, Utrecht, the Netherlands.

13Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.

14Department of Medical Oncology, Utrecht University, University Medical Center Utrecht, Utrecht, the Netherlands.

15Department of Nuclear Medicine and Molecular Imaging and Intensive Care, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

16Chair for Biological Imaging, Technical University of Munich, München, Germany. v.ntziachristos@tum.de.