title: A Quantitative Diffuse Reflectance Imaging (QDRI) System for Comprehensive Surveillance of the Morphological Landscape in Breast Tumor Margins.
abstract: In an ongoing effort to address the clear clinical unmet needs surrounding breast conserving surgery (BCS), our group has developed a next-generation multiplexed optical-fiber-based tool to assess breast tumor margin status during initial surgeries. Specifically detailed in this work is the performance and clinical validation of a research-grade intra-operative tool for margin assessment based on diffuse optical spectroscopy. Previous work published by our group has illustrated the proof-of-concept generations of this device; here we incorporate a highly optimized quantitative diffuse reflectance imaging (QDRI) system utilizing a wide-field (imaging area = 17 cm(2)) 49-channel multiplexed fiber optic probe, a custom raster-scanning imaging platform, a custom dual-channel white LED source, and an astronomy grade imaging CCD and spectrograph. The system signal to noise ratio (SNR) was found to be greater than 40 dB for all channels. Optical property estimation error was found to be less than 10%, on average, over a wide range of absorption (μa = 0-8.9 cm(-1)) and scattering (μs' = 7.0-9.7 cm(-1)) coefficients. Very low inter-channel and CCD crosstalk was observed (2% max) when used on turbid media (including breast tissue). A raster-scanning mechanism was developed to achieve sub-pixel resolution and was found to be optimally performed at an upsample factor of 8, affording 0.75 mm spatially resolved diffuse reflectance images (λ = 450-600 nm) of an entire margin (area = 17 cm(2)) in 13.8 minutes (1.23 cm(2)/min). Moreover, controlled pressure application at the probe-tissue interface afforded by the imaging platform reduces repeated scan variability, providing <1% variation across repeated scans of clinical specimens. We demonstrate the clinical utility of this device through a pilot 20-patient study of high-resolution optical parameter maps of the ratio of the β-carotene concentration to the reduced scattering coefficient. An empirical cumulative distribution function (eCDF) analysis is used to reduce optical property maps to quantitative distributions representing the morphological landscape of breast tumor margins. The optimizations presented in this work provide an avenue to rapidly survey large tissue areas on intra-operative time scales with improved sensitivity to regions of focal disease that may otherwise be overlooked.
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, United States of America.
authors.forename: Brandon S
authors.initials: BS
authors.lastname: Nichols
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, United States of America.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Schindler
authors.affiliation: Zenalux Biomedical, Research Triangle Park, NC, United States of America; Department of Biomedical Engineering, Tulane University, New Orleans, LA, United States of America.
authors.forename: Jonathon Q
authors.initials: JQ
authors.lastname: Brown
authors.affiliation: Department of Surgery, The University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Lee G
authors.initials: LG
authors.lastname: Wilke
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, United States of America.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Mulvey
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, United States of America; Zenalux Biomedical, Research Triangle Park, NC, United States of America.
authors.forename: Marlee S
authors.initials: MS
authors.lastname: Krieger
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gallagher
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, NC, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Geradts
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC, United States of America.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Greenup
authors.affiliation: Zenalux Biomedical, Research Triangle Park, NC, United States of America; The Division of Environmental Sciences and Policy, Duke University, Durham, NC, United States of America.
authors.forename: Jesko A
authors.initials: JA
authors.lastname: Von Windheim
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, United States of America; Zenalux Biomedical, Research Triangle Park, NC, United States of America.
authors.forename: Nirmala
authors.initials: N
authors.lastname: Ramanujam
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000818:Animals; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000473:pathology* / Q000601:surgery; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D015674:Mammary Neoplasms, Animal; D015412:Mastectomy, Segmental; D008875:Middle Aged; D061848:Optical Imaging / Q000295:instrumentation / Q000379:methods*; D015203:Reproducibility of Results; D059629:Signal-To-Noise Ratio