<i>In vivo</i> magnetic resonance imaging of the progression of murine ductal carcinoma <i>in situ</i>: finding timescales and predictors of future invasion.

Abstract Abstract #6011 Background: Understanding the natural history of breast cancer is important for effective patient management and treatment. For example, some evidence suggests that preinvasive ductal carcinoma in situ (DCIS) may be over-treated, since not all will progress to invasive cancer. Unfortunately, due to obligate surgical excision of newly diagnosed breast cancers, the natural history of disease is difficult to study in women. However, mouse models of breast cancer can serve as an alternative; the purpose of this study was to use magnetic resonance imaging (MRI) to investigate the progression of DCIS into invasive cancer in a transgenic model.&amp;#x2028; Methods:12 SV40 Tag mice were imaged every 2-3 weeks (wks) starting at 10 wks of age. SV40 mice develop mammary cancer similar to DCIS and IDC, and usually live to 22 wks when they succumb to breast cancer. T1-weighted gradient echo images of inguinal mammary glands were obtained. DCIS lesions and invasive tumors were identified and volumes were measured over time. For each lesion we measured: the time at initial development (TDCIS and Ttumor), the growth rate of DCIS and invasive tumors (calculated from 'V=V0exp(αt)'), and for DCIS lesions that progressed to invasive tumors the progression time Tprog was measured.&amp;#x2028; Results:DCIS (n=21) and invasive (n=16) tumors developed, at an average initial age of TDCIS =12.7±2.6 wks and Ttumor =16.3±3.1 wks, and at an initial volume of 0.3±0.2 mm3 and 1.7 mm3, respectively. The average growth rate for DCIS lesions was αDCIS= 0.08±0.23 wk-1, significantly smaller than that of invasive tumors (αtumor= 0.55±0.35 wk-1, p =0.001). 9/21 DCIS lesions progressed to invasive cancers in an average time of Tprog=4.56 ± 1.9 wks(Figure 1a). 11/21 DCIS did not progress within the study window and 5/21 were stable for over 8 wks (Figure 1b).&amp;#x2028; &amp;#x2028; The volume of DCIS was not a predictor of progression, but there was a trend for DCIS growth rate to be related to eventual development of invasiveness.&amp;#x2028; Discussion:To our knowledge, the results reported here are the first direct measurements of the timescales and characteristics of progression from in situ to invasive carcinoma. Surprisingly, even in transgenic mice that are strongly pre-disposed to develop cancer, some DCIS lesions did not progress to invasive cancer. Interestingly, DCIS volume did not predict future progression to invasive tumors, but growth rate may have been a predictor. The methods and data here provide a foundation for using MRI in pre-clinical studies of early cancer progression, prevention and targeted treatment. Extensions of this pilot study may yield image-based biomarkers of progressing vs. indolent DCIS. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6011.</jats:p

Different MR systems yield variable kinetic characteristics of malignant breast lesions.

Abstract Abstract #4025 Background: Dynamic contrast enhanced magnetic resonance imaging (DCEMRI) has demonstrated superior sensitivity for detecting earlier cancers compared with x-ray mammography, and is being used increasingly for high-risk screening, diagnostic imaging and to evaluate extent of malignant disease. When assessing lesion malignancy both the morphology and contrast uptake and washout—or kinetics—of the lesion are important. At our institution DCEMRI breast examinations have been performed on three different MR systems. The purpose of this study was to compare the MR kinetic curve data of malignant lesions acquired by these systems.&amp;#x2028; Methods: 445 patients with 485 malignant lesions were selected for an IRB approved review. The lesions were classified as ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and 'other'. Dynamic MR protocol: 1 pre and 3-7 post-contrast images, acquired on a system using a non fat-suppressed dynamic sequence (NFS) and 2 newer systems by different manufacturers using fat suppressed dynamic sequences (FS1 and FS2). Kinetic curve data was processed and displayed on a CADstream workstation. Analysis of kinetic curve shape was made by an experienced radiologist according to the BI-RADS lexicon. Several quantitative kinetic parameters were calculated, both directly from the curve data and after fitting to an empirical mathematical model (EMM). The kinetic parameters of malignant lesions were compared between the three systems.&amp;#x2028; Results: 299 malignant lesions (185 IDC, 57 DCIS) were imaged on NFS, 104 lesions (69 IDC, 21 DCIS) on FS1, and 82 on FS2 (61 IDC, 17 DCIS). Compared to both systems NFS and FS1, IDC lesions acquired on FS2 demonstrated significantly lower initial enhancement, longer time to peak enhancement and slower washout rate (p &amp;lt; 0.0004). 80% of IDC lesions acquired on FS1 were classified as 'washout', compared with only 46% of IDC lesions on FS2. On both FS1 and FS2, we did not find a difference in the kinetic parameters of IDC vs. DCIS lesions. However, IDC lesions imaged on NFS exhibited significantly higher contrast uptake, shorter time to peak and stronger washout compared to DCIS lesions (p &amp;lt; 0.0001).&amp;#x2028; Discussion: The kinetic curve data of malignant lesions acquired by one system exhibited significantly lower initial contrast uptake and different curve shape compared with the other two. In addition, on both newer systems, the kinetic parameters of DCIS were comparable with IDC, which is contrary to what was found on the older system. Differences in k-space sampling, T1 weighting or magnetization transfer effects may be possible explanations. The results of this study underscore the importance of developing standardized acquisition and analysis methods, to ensure that across all available systems (i) malignant lesions are sufficiently conspicuous and thus reliably detected and (ii) interpretation of kinetic data is consistent. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4025.</jats:p

Can DCEMRI assess the effect of green tea on the angiogenic properties of rodent prostate tumors?

The purpose of this research was to test whether dynamic contrast enhanced MRI could assess the effect of green tea on the angiogenic properties of transplanted rodent tumors. Copenhagen rats bearing AT6.1 prostate tumors inoculated in the hind limbs were randomly assigned to cages in which they were allowed to only drink either plain water (control group) or water containing green tea extract (treated group). Assignments were made after a baseline MRI experiment (week 0) was performed on each rat at 4.7T. All the rats were subsequently imaged at day 7 (week 1) and day 14 (week 2) to follow tumor growth and vascular development. The two-compartment pharmacokinetic model was used to analyze the dynamic contrast Gd-DTPA enhanced MRI data on a pixel-by-pixel basis over the tumor area to obtain the volume transfer constant (K(trans)) and extravascular extracellular space (v(e)). An identity Chi-squared test showed that the distributions of averaged histograms (n=6) of K(trans) and v(e) were significantly different from week 0 to both weeks 1 and 2 (p<0.001) in both the control and the treated rats due to increasing areas of tumor necrosis. However, the tumor growth rate was statistically indistinguishable between control and treated rats. There was no significant difference in the distributions of K(trans) and v(e) between control and treated rats. The results showed that no effects of green tea on tumor micro-vasculature were measurable by dynamic Gd-DTPA enhanced MRI

Can DCEMRI assess the effect of green tea on the angiogenic properties of rodent prostate tumors?

The purpose of this research was to test whether dynamic contrast enhanced MRI could assess the effect of green tea on the angiogenic properties of transplanted rodent tumors. Copenhagen rats bearing AT6.1 prostate tumors inoculated in the hind limbs were randomly assigned to cages in which they were allowed to only drink either plain water (control group) or water containing green tea extract (treated group). Assignments were made after a baseline MRI experiment (week 0) was performed on each rat at 4.7T. All the rats were subsequently imaged at day 7 (week 1) and day 14 (week 2) to follow tumor growth and vascular development. The two-compartment pharmacokinetic model was used to analyze the dynamic contrast Gd-DTPA enhanced MRI data on a pixel-by-pixel basis over the tumor area to obtain the volume transfer constant (K(trans)) and extravascular extracellular space (v(e)). An identity Chi-squared test showed that the distributions of averaged histograms (n=6) of K(trans) and v(e) were significantly different from week 0 to both weeks 1 and 2 (p<0.001) in both the control and the treated rats due to increasing areas of tumor necrosis. However, the tumor growth rate was statistically indistinguishable between control and treated rats. There was no significant difference in the distributions of K(trans) and v(e) between control and treated rats. The results showed that no effects of green tea on tumor micro-vasculature were measurable by dynamic Gd-DTPA enhanced MRI

2-Deoxyglucose Impairs Saccharomyces cerevisiae Growth by Stimulating Snf1-Regulated and α-Arrestin-Mediated Trafficking of Hexose Transporters 1 and 3

The glucose analog 2-deoxyglucose (2DG) inhibits the growth of Saccharomyces cerevisiae and human tumor cells, but its modes of action have not been fully elucidated. Yeast cells lacking Snf1 (AMP-activated protein kinase) are hypersensitive to 2DG. Overexpression of either of two low-affinity, high-capacity glucose transporters, Hxt1 and Hxt3, suppresses the 2DG hypersensitivity of snf1Δ cells. The addition of 2DG or the loss of Snf1 reduces HXT1 and HXT3 expression levels and stimulates transporter endocytosis and degradation in the vacuole. 2DG-stimulated trafficking of Hxt1 and Hxt3 requires Rod1/Art4 and Rog3/Art7, two members of the α-arrestin trafficking adaptor family. Mutations in ROD1 and ROG3 that block binding to the ubiquitin ligase Rsp5 eliminate Rod1- and Rog3-mediated trafficking of Hxt1 and Hxt3. Genetic analysis suggests that Snf1 negatively regulates both Rod1 and Rog3, but via different mechanisms. Snf1 activated by 2DG phosphorylates Rod1 but fails to phosphorylate other known targets, such as the transcriptional repressor Mig1. We propose a novel mechanism for 2DG-induced toxicity whereby 2DG stimulates the modification of α-arrestins, which promote glucose transporter internalization and degradation, causing glucose starvation even when cells are in a glucose-rich environment

Quantitative analysis of water proton spectral lineshape: a novel source of contrast in MRI.

Previous work in this laboratory has demonstrated improved anatomic and functional images produced from high spectral and spatial resolution (HiSS) MRI of the water proton signal. The present work tests the hypothesis that different Fourier components of the water resonance represent anatomically and/or physiologically distinct populations of water molecules within each small image voxel. HiSS datasets were acquired from tomatoes and rodent tumors at 4.7 T using echo-planar spectroscopic imaging (spatial and spectral resolutions were 117-150 microm and 1.5-3.1 Hz, respectively). Images of each Fourier component of the water resonance (referred to as Fourier component images, or FCIs) were produced. FCIs at frequencies offset from the peak of the water resonance ('off-peak' FCIs) were compared to images of the Fourier component with largest amplitude, i.e. the water peak-height image. Results demonstrate that off-peak FCIs differ significantly from the water peak-height image and that water resonances are often asymmetric. These results show that water signal at various frequency offsets from the peak of the water resonance come from water molecules in different anatomic/physiologic environments. Off-peak FCIs are a new source of structural and functional information and may have clinical utility

Hyperthermically induced changes in high spectral and spatial resolution MR images of tumor tissue--a pilot study.

This pilot study investigated the feasibility of using MRI based on BOLD (blood-oxygen-level-dependent) contrast to detect physiological effects of locally induced hyperthermia in a rodent tumor model. Nude mice bearing AT6.1 rodent prostate tumors inoculated in the hind leg were imaged using a 9.4 T scanner using a multi-gradient echo pulse sequence to acquire high spectral and spatial resolution (HiSS) data. Temperature increases of approximately 6 °C were produced in tumor tissue using fiber-optic-guided light from a 250 W halogen lamp. HiSS data were acquired over three slices through the tumor and leg both prior to and during heating. Water spectra were produced from these datasets for each voxel at each time point. Time-dependent changes in water resonance peak width were measured during 15 min of localized tumor heating. The results demonstrated that hyperthermia produced both significant increases and decreases in water resonance peak width. Average decreases in peak width were significantly larger in the tumor rim than in normal muscle (p = 0.04). The effect of hyperthermia in tumor was spatially heterogeneous, i.e. the standard deviation of the change in peak width was significantly larger in the tumor rim than in normal muscle (p = 0.005). Therefore, mild hyperthermia produces spatially heterogeneous changes in water peak width in both tumor and muscle. This may reflect heterogeneous effects of hyperthermia on local oxygenation. The peak width changes in tumor and muscle were significantly different, perhaps due to abnormal tumor vasculature and metabolism. Response to hyperthermia measured by MRI may be useful for identifying and/or characterizing suspicious lesions as well as guiding the development of new hyperthermia protocols