Earlier reports have suggested that the BCR/ABL oncogene, associated with chronic myeloid leukemia, induces a mutator phenotype; however, it is unclear whether this leads to long-term changes in chromosomes and whether the phenotype is found in primary chronic myelogeneous leukemia (CML) cells. We have addressed both these issues. BCR/ABL-expressing cell lines show an increase in DNA breaks after treatment with etoposide as compared to control cells. However, although BCR/ABL-expressing cell lines have an equivalent cell survival, they have an increase in chromosomal translocations after DNA repair as compared to control cells. This demonstrates that BCR/ABL expression decreases the fidelity of DNA repair. To see whether this is true in primary CML samples, normal CD34 + progenitor cells and CML progenitor cells were treated with etoposide. CML progenitor cells have equivalent survival but have an increase in DNA double-strand breaks (DSBs). Spectral karyotyping demonstrates new chromosomal translocations in CML cells, but not normal progenitor cells, consistent with error-prone DNA repair. Taken together, these data demonstrate that BCR/ABL enhances the accumulation of DSBs and alters the apoptotic threshold in CML leading to error-prone DNA repair.

#805 Background: Diffuse optical tomography (DOT) uses near-infrared light to non-invasively image total hemoglobin concentration and blood oxygen saturation in the human breast. Given its low cost, ease of use, and possibility of repeated measured over time, DOT is a promising adjunctive imaging modality for screening, diagnosis and monitoring of neoadjuvant therapy. In this study we explored the performance of DOT to differentiate benign and malignant breast lesions.
 Method and Materials: Forty-seven women with clinical or mammographic abnormalities were prospectively recruited for DOT. Most patients underwent gadolinium-enhanced MRI examination. Three-dimensional oxy-, deoxy-hemoglobin, total hemoglobin concentration, blood oxygen saturation and scattering coefficient images of each breast were reconstructed. Tumor-to-normal (T/N) ratios of these parameters were computed by defining tumor regions with guidance from MRI and radiology reports. In addition, optical index was constructed based on these parameters to maximize the T/N contrast. Only the biopsy-proven lesions were selected (51 breast lesions) and classified into three groups: benign lesions (N=10), malignant lesions where DOT preceded core biopsy (N=20) and malignant lesions where DOT was performed after core-biopsy (N=21). We fit a mixed effects model that estimated the mean optical T/N ratios and optical index for each group, and using the resulting standard errors developed 95% confidence intervals and tested the hypothesis that each optical contrast parameter was unity.
 Results: Malignant cancers showed statistically significant higher total hemoglobin concentration, scattering, oxy-hemoglobin concentration and optical index (P=0.01-0.04) compared to normal tissue. Furthermore, malignant lesions exhibited a two-fold average increase in an optical index derived from the endogenous optical parameters (95% CI: 1.4 - 2.4). To test whether bleeding due to core biopsy influence DOT results, we compared if there was statistically significant differences between two groups measured before or after core-biopsy. There were no statistically significant differences in these groups, suggesting that post biopsy hemorrhage did not alter the DOT results. Benign tumors did not show statistical significance in all of the T/N ratios. AUC of total hemoglobin concentration, scattering, oxy-hemoglobin and optical index suggested good discriminatory power with values between 0.90 and 0.99.
 Discussion: The data demonstrates the feasibility of differentiating benign and malignant lesions by quantitative three-dimensional DOT when the tumor location information is provided by other imaging modality. The main drawback of this study is the small number of benign lesions, which warrants further study. DOT technology is still at its developing stage and needs more investigation to find its niche in breast imaging. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 805.

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