#803 Background: Changes of tissue water state are related to physiological and pathological properties of breast tissues. For instance, MRI has measured water mobility in order to monitor local micro-structural changes in breast cancer tissues during chemotherapy. Diffuse Optical Spectroscopic Imaging (DOSI) measures water molecular vibrational states associated with macro-molecular complexes in tissues such as proteins. For DOSI measurements, breast tumors are line-scanned and spectral information on each point is spatially mapped to generate an image.
 Subjects & Methods: DOSI was employed to measure 15 infiltrating ductal carcinoma (IDC) patients before treatment. Five IDC and one infiltrating lobular carcinoma (ILC) tumors were also measured along the course of neoadjuvant chemotherapy. Patient responses were determined from standard pathology: complete (N=2), partial (N=2) and non-responders (N=2). The spectral features of tissue water absorption from 935 nm to 998nm were compared to those of a pure water spectrum measured at body temperature in order to acquire the Bound Water Index (BWI: the residual between tissue and pure water spectra). In spectroscopic images, the Cancer BWI Ratio (CBR) was calculated by counting the fraction of the BWI less than 20% of the BWI range of pre-chemo (baseline) measurement in a primary cancer. Lower BWI means the cancer has more free water. The CBR communicates the changes of tissue water state along the course of therapies in the similar way to Signal Enhanced Ratio (SER) used in contrast enhanced MRI.
 Results: In our in vivo clinical studies with 15 IDC tumors, a high inverse correlation between BWI and Nottingham Bloom-Richardson histopathological score (R=-0.87) was found. In the neoadjuvant chemotherapy studies, BWI increased during the entire course of the therapy in complete responders while it fluctuated then stayed close to baseline values in partial responders. In non-responders, the change amount of BWI was very small and the BWI values decreased below baseline values. Quantitatively, for complete responders, BWI increased (more bound water) 59% from baseline and CBR decreased (less pixels for cancer) 26.9% and the pixels presenting cancer property disappeared. In partial responders, BWI increased 4.7% and CBR decreased 8.2% whereas, in non-responders, BWI decreased 16.4% and CBR increased 28.7%.
 Discussion: The high correlation between BWI and histopathological score communicates that water state measurements using DOSI report on disease grades of breast cancer non-invasively. In the neoadjuvant chemotherapy studies, bigger tissue water state changes have been measured in complete than partial responders and the changes to the opposite direction in non-responders. There results demonstrate a potential of tissue water state with DOSI as a non-invasive pathological grade monitor during chemotherapy, which can be used as a substitute for a biopsy at any point during the treatment cycle. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 803.
Background: Breast cancer patients who do not respond to neoadjuvant chemotherapy undergo months of unwarranted side effects. Early, non-invasive markers of response would provide physicians a valuable tool to make evidence-based changes to treatment strategies. Methods: Diffuse Optical Spectroscopic Imaging (DOSI) was used to measure hemodynamic and metabolic information from tumors and surrounding normal tissue in 23 breast cancer patients undergoing neoadjuvant chemotherapy. DOSI uses temporally modulated near-infrared light to determine absolute tissue molar concentrations of oxyhemoglobin, deoxyhemoglobin, as well as water and lipid content and requires no exogenous contrast agent. Measurements are made using a simple handheld probe placed on the skin. Each measurement takes less than one minute and multiple measurements are made in a grid pattern over the tumor and surrounding normal areas of the breast. Functional images of the breast tissue are made and compared over sequential time points. Measurements were made before the start of treatment and during the first week after the first infusion. Patients received either doxorubicin + cyclophosphamide (AC) or paclitaxel + carboplatin at their first infusion. Overall response to therapy was determined by the decrease in anatomic tumor size. Results: A flare in tumoral oxyhemoglobin concentration occurred on day 1 after the start of chemotherapy in patients achieving a partial (PR) or pathologic complete response (pCR). Oxyhemoglobin concentration increased 44.5% (± 46.1% SD) in PR patients (n=11) and 41.4% (± 39.1% SD) in pCR patients (n=8) (see figure 1). Nonresponding (NR) patients (n=5) exhibited no oxyhemoglobin flare and an average decrease in concentration of -22.5% (± 5.10% SD) was observed on day 1. This flare was sufficient to perfectly discriminate non-responding patients from responding patients in this study cohort. Additionally, the spatial extend of elevated oxyhemoglobin over the anatomic tumor location increased during the flare. The oxyhemoglobin flare was observed in all responding patients regardless of specific chemotherapy regimen received, receptor status, age, tumor size and tumor grade. Discussion: We have shown, in this patient cohort, that a non-invasive optical measure can discriminate non-responding tumors on the first day after the start of neoadjuvant breast cancer chemotherapy. The observed flare in oxyhemoglobin may be due to either decreased cellular metabolism and subsequent decrease in conversion of oxy to deoxyhemoglobin, or to a transient increase in perfusion to the tumor. Increased perfusion may be due to an acute inflammatory response, characterized by vessel dilation and increased vascular permeability, and triggered by tumor cell-damage. Future studies will confirm these initial findings and help to elucidate the biological causes of the observed oxyhemoglobin flare. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-01-07.
Background: In our previous work, we have shown that biochemical tissue water state correlates with histopathological scores of breast cancer (R=-0.96). Based on the result, we extended our research to test whether the tissue water measurement can differentiate heterogeneous pathological structures of cancer tissues of different grades. Diffuse Optical Spectroscopic Imaging (DOSI) measures water molecular vibrational states associated with macro-molecular complexes in tissues such as proteins in a non-invasive way without compression of the breast. For DOSI measurements, a large region over breast tumors is scanned using a hand-held probe and spectral information on each point is spatially mapped to generate an image.Subjects and Methods: DOSI was employed to measure 19 primary cancers (18 IDC and 1 ILC). The spectral features of tissue water absorption from 935 nm to 998nm were compared to those of a pure water spectrum measured at body temperature in order to acquire the Bound Water Index (BWI: the residual between tissue and pure water spectra). In the spectroscopic images, the average and standard deviation of the pixels less than 20% of the range of the BWI in the image were calculated based on our previous finding that carcinoma tissues have lower BWI (more free water). The same parameters were calculated on normal tissues from the same patients in order to compare the tissue heterogeneity. The standard deviation was divided by the average value of each tissue type, and this value is communicated as a Heterogeneity Index (HI).Results: In our in vivo clinical studies, the cancer tissues showed 51% higher heterogeneity than the normal tissues (cancer HI: 0.046±0.018, normal HI: 0.024±0.018, p<0.001). Furthermore, the low (N=4), medium (N=9) and high grade (N=6) tumors, defined by the Nottingham Bloom-Richardson histopathological scores (3-5: low, 6-7: med and 8-9: high), demonstrated increasing heterogeneity in the water disposition with the tumor grade. The medium and high grade tumors had 10.5 and 28% more heterogeneity than the low grade tumors in average (low grade HI: 0.041±0.015, med: 0.045±0.02 and high: 0.052±0.017).Discussion: The tissue water measurement using DOSI showed its ability to measure increased pathological heterogeneity in more invasive cancer tissues. This result supports our earlier finding that the BWI can report on histopathological grades of cancer tissues. These pathological properties were acquired in a completely non-invasive way with non-ionizing low power light. The results of this study suggest that the water state measurement using DOSI may be used as a non-invasive optical biopsy with high specificity. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5008.
Background Imaging technologies monitoring and predicting breast cancer response to neoadjuvant chemotherapy (NAC) are of increasing interest. The utility of conventional imaging approaches varies and identifies the need for alternate functional imaging strategies. The use of model-based photon migration methods to quantitatively separate light absorption from scattering in multiply-scattering tissues is a type of near-infrared spectroscopy (NIRS) broadly referred to as diffuse optical spectroscopy (DOS) [Bevilacqua, et al. Applied Optics, 2000; Jakubowski, et al., J of Applied Optics, 2009]. DOSI is a promising experimental technology that allows patients undergoing NAC to be followed with a “no significant risk” device meeting Food and Drug Administration criteria for exempt status. The current design is a mobile device which offers increased accessibility and is relatively simple to perform and interpret, as compared to mammography, magnetic resonance imaging, and positron emission tomography. Due to its size and portability, DOSI is a low barrier-to-access technology, creating new opportunities for patients to receive personalized treatment and for physicians to gain new insight into response mechanisms. The long-term goal is to provide oncologists with a relatively simple, risk-free bedside tool that can be used to help inform medical decisions on chemotherapy regimen, duration, and timing of surgery, thereby maximizing therapeutic response and minimizing unnecessary toxicity. Trial design: In this phase I/II prospective single arm study, patients will receive SOC NAC at five (5) NCI Network for Translational Research in Optical Imaging (NTROI) clinical sites with identical DOSI instruments and procedures. Patients will receive four DOSI exams: at baseline before chemotherapy, at early therapy 5–10 days after NAC initiation, at mid therapy, and at post therapy prior to surgery. The protocol will evaluate a harmonized DOSI technology platform that has been standardized for NAC monitoring. Eligibility: Women who have been diagnosed with breast cancer, have had confirmation by pre-treatment biopsy, and are scheduled to receive NAC followed by surgery are eligible for this trial. Specific aims: The primary aim of this clinical trial is to determine whether the baseline to mid-therapy changes in the DOSI measurement of the quantitative tumor tissue optical index can predict final pathologic complete response in patients with breast cancer undergoing NAC. The secondary aims investigate the correlation between additional DOSI quantitative measurements of tumor biochemical composition obtained at other timepoints, the full range of pathologic response (i.e. complete, partial, and non-response), and any corresponding imaging measurements. Statistical methods: Logistic regression models will be used to study the relationships between pathological complete response and percent change in tissue optical index tumor to normal ratio at different imaging time points. Study size: A total of sixty (60) patients will be enrolled in this imaging study. Currently, one patient has accrued. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-05-02.
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