title: Threshold Analysis and Biodistribution of Fluorescently Labeled Bevacizumab in Human Breast Cancer.
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. Cancer Res; 77(3); 623-31. ©2016 AACR.
authors.affiliation: Chair for Biological Imaging, Technical University of Munich, München, Germany.|Institute for Biological and Medical Imaging, Helmholtz Zentrum München, München, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Koch
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Johannes S
authors.initials: JS
authors.lastname: de Jong
authors.affiliation: Chair for Biological Imaging, Technical University of Munich, München, Germany.|Institute for Biological and Medical Imaging, Helmholtz Zentrum München, München, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Glatz
authors.affiliation: Chair for Biological Imaging, Technical University of Munich, München, Germany.|Institute for Biological and Medical Imaging, Helmholtz Zentrum München, München, Germany.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Symvoulidis
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Laetitia E
authors.initials: LE
authors.lastname: Lamberts
authors.affiliation: Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Arthur L L
authors.initials: AL
authors.lastname: Adams
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Mariëtte E G
authors.initials: ME
authors.lastname: Kranendonk
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.|Hospital and Clinical Pharmacy, University of Groningen, University Medical Center Groningen, the Netherlands.
authors.forename: Anton G T
authors.initials: AG
authors.lastname: Terwisscha van Scheltinga
authors.affiliation: Research Unit Analytical Pathology, Helmholtz Zentrum München, München, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.affiliation: Department of Surgery, University of Groningen, University Medical Center Groningen, the Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Jansen
authors.affiliation: Department of Surgery, University of Groningen, University Medical Center Groningen, the Netherlands.
authors.forename: Jakob
authors.initials: J
authors.lastname: de Vries
authors.affiliation: Hospital and Clinical Pharmacy, University of Groningen, University Medical Center Groningen, the Netherlands.
authors.forename: Marjolijn N
authors.initials: MN
authors.lastname: Lub-de Hooge
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Carolien P
authors.initials: CP
authors.lastname: Schröder
authors.affiliation: Hospital and Clinical Pharmacy, University of Groningen, University Medical Center Groningen, the Netherlands.
authors.forename: Annelies
authors.initials: A
authors.lastname: Jorritsma-Smit
authors.affiliation: Hospital and Clinical Pharmacy, University of Groningen, University Medical Center Groningen, the Netherlands.
authors.forename: Matthijs D
authors.initials: MD
authors.lastname: Linssen
authors.affiliation: Department of Surgery, University of Groningen, University Medical Center Groningen, the Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: de Boer
authors.affiliation: Department of Pathology, University of Groningen, University Medical Center Groningen, the Netherlands.
authors.forename: Bert
authors.initials: B
authors.lastname: van der Vegt
authors.affiliation: Department of Gastroenterology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Wouter B
authors.initials: WB
authors.lastname: Nagengast
authors.affiliation: Julius Center for Health Sciences and Primary Care, Cell Biology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Sjoerd G
authors.initials: SG
authors.lastname: Elias
authors.affiliation: Department of Biology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Oliveira
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Arjen J
authors.initials: AJ
authors.lastname: Witkamp
authors.affiliation: Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Willem P T M
authors.initials: WP
authors.lastname: Mali
authors.affiliation: Department of Medical Oncology, Utrecht University, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Elsken
authors.initials: E
authors.lastname: Van der Wall
authors.affiliation: Chair for Biological Imaging, Technical University of Munich, München, Germany.|Institute for Biological and Medical Imaging, Helmholtz Zentrum München, München, Germany.
authors.forename: P Beatriz
authors.initials: PB
authors.lastname: Garcia-Allende
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.affiliation: Research Unit Analytical Pathology, Helmholtz Zentrum München, München, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.affiliation: Department of Surgery, University of Groningen, University Medical Center Groningen, the Netherlands.|Department of Nuclear Medicine and Molecular Imaging and Intensive Care, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Gooitzen M
authors.initials: GM
authors.lastname: van Dam
authors.affiliation: Chair for Biological Imaging, Technical University of Munich, München, Germany. v.ntziachristos@tum.de.|Institute for Biological and Medical Imaging, Helmholtz Zentrum München, München, Germany.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Ntziachristos
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001557:Benzenesulfonates / Q000493:pharmacokinetics; D000068258:Bevacizumab / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000000981:diagnostic imaging*; D005260:Female; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006801:Humans; D007090:Image Interpretation, Computer-Assisted / Q000379:methods*; D007211:Indoles / Q000493:pharmacokinetics; D008875:Middle Aged; D057054:Molecular Imaging / Q000379:methods*; D061848:Optical Imaging / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D005456:Fluorescent Dyes; C562366:IRDye 800CW; D007211:Indoles; D000068258:Bevacizumab