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Macroscopic optical physiological parameters correlate with microscopic proliferation and vessel area breast cancer signatures.

Chung SH, Feldman MD, Martinez D, Kim H, Putt ME, Busch DR, Tchou J, Czerniecki BJ, Schnall MD, Rosen MA, DeMichele A, Yodh AG, Choe R - Breast Cancer Res. (2015)

Bottom Line: The tumor-to-normal relative ratio of Ki67-positive nuclei is positively correlated with DOT-measured relative tissue blood oxygen saturation (R = 0.89, p-value: 0.001), and lower tumor-to-normal deoxy-hemoglobin concentration is associated with higher expression level of Ki67 nuclei (p-value: 0.01).Finally, we find that cell nuclei tend to have more elongated shapes in less oxygenated DOT-measured environments.Overall, the observations corroborate expectations that macroscopic measurements of breast cancer physiology using DOT and DCS can reveal microscopic pathological properties of breast cancer and hold potential to complement pathological biomarker information.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics and Astronomy, University of Pennsylvania, 209 S. 33rd St., Philadelphia, PA, 19104, USA. sochung@sas.upenn.edu.

ABSTRACT

Introduction: Non-invasive diffuse optical tomography (DOT) and diffuse correlation spectroscopy (DCS) can detect and characterize breast cancer and predict tumor responses to neoadjuvant chemotherapy, even in patients with radiographically dense breasts. However, the relationship between measured optical parameters and pathological biomarker information needs to be further studied to connect information from optics to traditional clinical cancer biology. Thus we investigate how optically measured physiological parameters in malignant tumors such as oxy-, deoxy-hemoglobin concentration, tissue blood oxygenation, and metabolic rate of oxygen correlate with microscopic histopathological biomarkers from the same malignant tumors, e.g., Ki67 proliferation markers, CD34 stained vasculature markers and nuclear morphology.

Methods: In this pilot study, we investigate correlations of macroscopic physiological parameters of malignant tumors measured by diffuse optical technologies with microscopic histopathological biomarkers of the same tumors, i.e., the Ki67 proliferation marker, the CD34 stained vascular properties marker, and nuclear morphology.

Results: The tumor-to-normal relative ratio of Ki67-positive nuclei is positively correlated with DOT-measured relative tissue blood oxygen saturation (R = 0.89, p-value: 0.001), and lower tumor-to-normal deoxy-hemoglobin concentration is associated with higher expression level of Ki67 nuclei (p-value: 0.01). In a subset of the Ki67-negative group (defined by the 15 % threshold), an inverse correlation between Ki67 expression level and mammary metabolic rate of oxygen was observed (R = -0.95, p-value: 0.014). Further, CD34 stained mean-vessel-area in tumor is positively correlated with tumor-to-normal total-hemoglobin and oxy-hemoglobin concentration. Finally, we find that cell nuclei tend to have more elongated shapes in less oxygenated DOT-measured environments.

Conclusions: Collectively, the pilot data are consistent with the notion that increased blood is supplied to breast cancers, and it also suggests that less conversion of oxy- to deoxy-hemoglobin occurs in more proliferative cancers. Overall, the observations corroborate expectations that macroscopic measurements of breast cancer physiology using DOT and DCS can reveal microscopic pathological properties of breast cancer and hold potential to complement pathological biomarker information.

No MeSH data available.


Related in: MedlinePlus

Instrumental setup for the diffuse optical tomography (DOT) system, and DOT images acquired from a 53-year-old woman with a 2.2-cm (longest dimension) invasive ductal carcinoma. Bottom left depicts a three-dimensional tumor region (red). The images of rHb, rHbO2 and rStO2 are for relative (i.e., tumor-to-normal ratio) deoxyhemoglobin and oxyhemoglobin concentration and tissue oxygenation, respectively. Black solid line in the images indicates the region identified as tumor. FD frequency domain, CCD charge-coupled-device camera
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Fig1: Instrumental setup for the diffuse optical tomography (DOT) system, and DOT images acquired from a 53-year-old woman with a 2.2-cm (longest dimension) invasive ductal carcinoma. Bottom left depicts a three-dimensional tumor region (red). The images of rHb, rHbO2 and rStO2 are for relative (i.e., tumor-to-normal ratio) deoxyhemoglobin and oxyhemoglobin concentration and tissue oxygenation, respectively. Black solid line in the images indicates the region identified as tumor. FD frequency domain, CCD charge-coupled-device camera

Mentions: Details of the DOT system, measurement procedure and reconstruction algorithm are described in Choe et al. [6]. Briefly, the instrument employed the parallel-plate geometry for source and detector planes; a breast box was utilized wherein breasts were positioned while the subject was lying in a prone position. The breasts were compressed mildly to hold them in a stable position. An outline of the breast surface was obtained by a 16-bit charge-coupled-device (CCD) camera. An Intralipid/ink (Baxter, Deerfield, IL) solution with optical properties similar to breast tissue filled the box to form a background diffuse medium and thereby reduce dynamic-range requirements. Four lasers at 690, 750, 786 and 830 nm were modulated at 70 MHz, and two lasers at 650 and 905 nm were used in continuous-wave (CW) mode. Laser light was delivered to 45 source locations using optical switches shown as red dots in Fig. 1. The source plane also had nine fibers embedded within it (yellow dots in Fig. 1) for detection of modulated light in the remission geometry. These frequency-domain (FD) measurements provided bulk optical properties that served as initial guesses for further reconstruction. CW-domain transmission measurements were made through a transparent window utilizing the CCD camera. The 45 source locations and the CCD camera enabled collection of a very large dataset for reconstruction of 3-D optical images. The diffuse optical data for the images were acquired in 8–12 minutes. Following the subject measurement, a phantom calibration measurement was performed after fully filling the breast box with the same Intralipid/ink solution and covering the top of the box with a silicone slab to mimic the chest wall. A brief description on the reconstruction steps for generating 3-D optical images is included in Additional file 1. Three-dimensional images of oxyhemoglobin, deoxyhemoglobin and total hemoglobin concentrations, tissue oxygenation and reduced-scattering coefficients were obtained.Fig. 1


Macroscopic optical physiological parameters correlate with microscopic proliferation and vessel area breast cancer signatures.

Chung SH, Feldman MD, Martinez D, Kim H, Putt ME, Busch DR, Tchou J, Czerniecki BJ, Schnall MD, Rosen MA, DeMichele A, Yodh AG, Choe R - Breast Cancer Res. (2015)

Instrumental setup for the diffuse optical tomography (DOT) system, and DOT images acquired from a 53-year-old woman with a 2.2-cm (longest dimension) invasive ductal carcinoma. Bottom left depicts a three-dimensional tumor region (red). The images of rHb, rHbO2 and rStO2 are for relative (i.e., tumor-to-normal ratio) deoxyhemoglobin and oxyhemoglobin concentration and tissue oxygenation, respectively. Black solid line in the images indicates the region identified as tumor. FD frequency domain, CCD charge-coupled-device camera
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4487833&req=5

Fig1: Instrumental setup for the diffuse optical tomography (DOT) system, and DOT images acquired from a 53-year-old woman with a 2.2-cm (longest dimension) invasive ductal carcinoma. Bottom left depicts a three-dimensional tumor region (red). The images of rHb, rHbO2 and rStO2 are for relative (i.e., tumor-to-normal ratio) deoxyhemoglobin and oxyhemoglobin concentration and tissue oxygenation, respectively. Black solid line in the images indicates the region identified as tumor. FD frequency domain, CCD charge-coupled-device camera
Mentions: Details of the DOT system, measurement procedure and reconstruction algorithm are described in Choe et al. [6]. Briefly, the instrument employed the parallel-plate geometry for source and detector planes; a breast box was utilized wherein breasts were positioned while the subject was lying in a prone position. The breasts were compressed mildly to hold them in a stable position. An outline of the breast surface was obtained by a 16-bit charge-coupled-device (CCD) camera. An Intralipid/ink (Baxter, Deerfield, IL) solution with optical properties similar to breast tissue filled the box to form a background diffuse medium and thereby reduce dynamic-range requirements. Four lasers at 690, 750, 786 and 830 nm were modulated at 70 MHz, and two lasers at 650 and 905 nm were used in continuous-wave (CW) mode. Laser light was delivered to 45 source locations using optical switches shown as red dots in Fig. 1. The source plane also had nine fibers embedded within it (yellow dots in Fig. 1) for detection of modulated light in the remission geometry. These frequency-domain (FD) measurements provided bulk optical properties that served as initial guesses for further reconstruction. CW-domain transmission measurements were made through a transparent window utilizing the CCD camera. The 45 source locations and the CCD camera enabled collection of a very large dataset for reconstruction of 3-D optical images. The diffuse optical data for the images were acquired in 8–12 minutes. Following the subject measurement, a phantom calibration measurement was performed after fully filling the breast box with the same Intralipid/ink solution and covering the top of the box with a silicone slab to mimic the chest wall. A brief description on the reconstruction steps for generating 3-D optical images is included in Additional file 1. Three-dimensional images of oxyhemoglobin, deoxyhemoglobin and total hemoglobin concentrations, tissue oxygenation and reduced-scattering coefficients were obtained.Fig. 1

Bottom Line: The tumor-to-normal relative ratio of Ki67-positive nuclei is positively correlated with DOT-measured relative tissue blood oxygen saturation (R = 0.89, p-value: 0.001), and lower tumor-to-normal deoxy-hemoglobin concentration is associated with higher expression level of Ki67 nuclei (p-value: 0.01).Finally, we find that cell nuclei tend to have more elongated shapes in less oxygenated DOT-measured environments.Overall, the observations corroborate expectations that macroscopic measurements of breast cancer physiology using DOT and DCS can reveal microscopic pathological properties of breast cancer and hold potential to complement pathological biomarker information.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics and Astronomy, University of Pennsylvania, 209 S. 33rd St., Philadelphia, PA, 19104, USA. sochung@sas.upenn.edu.

ABSTRACT

Introduction: Non-invasive diffuse optical tomography (DOT) and diffuse correlation spectroscopy (DCS) can detect and characterize breast cancer and predict tumor responses to neoadjuvant chemotherapy, even in patients with radiographically dense breasts. However, the relationship between measured optical parameters and pathological biomarker information needs to be further studied to connect information from optics to traditional clinical cancer biology. Thus we investigate how optically measured physiological parameters in malignant tumors such as oxy-, deoxy-hemoglobin concentration, tissue blood oxygenation, and metabolic rate of oxygen correlate with microscopic histopathological biomarkers from the same malignant tumors, e.g., Ki67 proliferation markers, CD34 stained vasculature markers and nuclear morphology.

Methods: In this pilot study, we investigate correlations of macroscopic physiological parameters of malignant tumors measured by diffuse optical technologies with microscopic histopathological biomarkers of the same tumors, i.e., the Ki67 proliferation marker, the CD34 stained vascular properties marker, and nuclear morphology.

Results: The tumor-to-normal relative ratio of Ki67-positive nuclei is positively correlated with DOT-measured relative tissue blood oxygen saturation (R = 0.89, p-value: 0.001), and lower tumor-to-normal deoxy-hemoglobin concentration is associated with higher expression level of Ki67 nuclei (p-value: 0.01). In a subset of the Ki67-negative group (defined by the 15 % threshold), an inverse correlation between Ki67 expression level and mammary metabolic rate of oxygen was observed (R = -0.95, p-value: 0.014). Further, CD34 stained mean-vessel-area in tumor is positively correlated with tumor-to-normal total-hemoglobin and oxy-hemoglobin concentration. Finally, we find that cell nuclei tend to have more elongated shapes in less oxygenated DOT-measured environments.

Conclusions: Collectively, the pilot data are consistent with the notion that increased blood is supplied to breast cancers, and it also suggests that less conversion of oxy- to deoxy-hemoglobin occurs in more proliferative cancers. Overall, the observations corroborate expectations that macroscopic measurements of breast cancer physiology using DOT and DCS can reveal microscopic pathological properties of breast cancer and hold potential to complement pathological biomarker information.

No MeSH data available.


Related in: MedlinePlus