The aim of this study was to empirically test the effect of chemotherapy-induced tissue changes in a glioma model as measured by several diffusion indices calculated from non-monoexponential ...formalisms over a wide range of b-values. We also compared these results to the conventional two-point apparent diffusion coefficient (ADC) calculation using nominal b-values.
Diffusion weighted imaging was performed over an extended range of b-values (120–4000s/mm
2
) on intracerebral rat 9L gliomas prior to and following a single dose of 1,3-bis(2-chloroethyl)-1-nitrosourea. Diffusion indices from three formalisms of DW signal decay ((a) two-point analytical calculation using either low or high b-values, (b) a stretched exponential formalism and (c) a biexponential fit) were tested for responsiveness to therapy-induced differences between control and treated groups.
Diffusion indices sensitive to “fast diffusion” produced the largest response to treatment, which resulted in significant differences between groups. These trends were not observed for “slow diffusion” indices. Although the highest rate of response was observed from the biexponential formalism, this was not found to be significantly different from the conventional monoexponential ADC method. In conclusion, parameters from the more complicated non-monoexponential formalisms did not provide additional sensitivity to treatment response in this glioma model beyond that observed from the two-point conventional monoexponential ADC method.
Cancer drug development generally performs
in vivo
evaluation of treatment effects that have traditionally relied on detection of morphologic changes. The emergence of new targeted therapies, which ...may not result in gross morphologic changes, has spurred investigation into more specific imaging methods to quantify response, such as targeted fluorescent probes and bioluminescent cells. The present study investigated tissue response to docetaxel or zoledronic acid (ZA) in a mouse model of bony metastasis. Intratibial implantations of breast cancer cells (MDA-MB-231) were monitored throughout this study using several modalities: molecular resonance imaging (MRI) tumor volume and apparent diffusion coefficient (ADC), micro-computed tomography (
µ
CT) bone volume, bioluminescence imaging (BLI) reporting cancer cell apoptosis, and fluorescence using Osteosense 800 and CatK 680-FAST. Docetaxel treatment resulted in tumor cell kill reflected by ADC and BLI increases and tumor volume reduction, with delayed bone recovery seen in
µ
CT prefaced by increased osteoblastic activity (Osteosense 800). In contrast, the ZA treatment group produced similar values in MRI, BLI, and Osteosense 800 fluorescence imaging readouts when compared to controls. However,
µ
CT bone volume increased significantly by the first week post-treatment and the CatK 680-FAST signal was slightly diminished by 4 weeks following ZA treatment. Multimodality imaging provides a more comprehensive tool for new drug evaluation and efficacy screening through identification of morphology as well as function and apoptotic signaling.
Abstract
Lung cancer accounts for 27% of all cancer deaths worldwide. 80% of these deaths are due to a specific subtype Non-small cell lung cancer (NSCLC). Almost half of all NSCLC patients carry ...gatekeeper mutations in the EGFR/KRAS pathway. Although KRAS mutations are the most prevalent mutations in human cancers, therapies targeting KRAS have fallen short. Tyrosine kinase inhibitors have been successful in NSCLC patients with mutant or amplified EGFR, however resistance to these inhibitors is common. Thus therapies targeting mutant KRAS or its downstream effectors are desperately needed for the treatment of NSCLC.
FAS Associated Death Domain (FADD) is a well characterized adaptor protein involved in death receptor mediated apoptosis, but more recently has been implicated in the regulation of other cellular functions such as cell cycle and proliferation. Increasing evidence suggests that it is FADD's phosphorylated state which regulates these non-apoptotic signaling pathways. We and others have previously identified phosphorylated FADD as a predictor of aggressiveness and clinical stage in lung and head and neck cancer patients, respectively.
Using non-invasive bioluminescence and µCT imaging in a Kras driven mouse model of NSCLC, we demonstrate the requirement for FADD in tumor progression. Lung-specific activation of KrasG12D and simultaneous FADD deletion resulted in reduced lung tumor burden. Furthermore lung lesions of KrasG12D FADD null mice were significantly smaller with a decrease in proliferative index. Similar findings were obtained in MEFs, where siRNA mediated Kras knockdown or the use of MEK inhibitors resulted in a Kras dependent decrease in FADD phosphorylation, decrease in cell cycle progression and cell proliferation. These data propound the phosphorylation of FADD as a downstream event of Kras signaling and demonstrate its requirement for Kras dependent neoplasia in a mouse model for NSCLC.
In summary our findings demonstrate that elevated FADD and phosphorylated FADD levels are predictive of poor survival in an animal model of NSCLC agreeing with clinical findings. Furthermore, it implicates phosphorylation of FADD downstream of KRAS activation and thus suggests FADD phosphorylation as a valid target in the treatment of NSCLC patients.
Citation Format: Brittany M. Bowman, Stefanie Galban, Benjamin A. Hoff, Kevin A. Heist, Jennifer L. Boes, Craig J. Galban, Rajiv M. Patel, Jianke Zhang, Brian D. Ross, Alnawaz Rehemtulla. A requirement for FADD and its phosphorylation for KRAS-driven oncogenesis. abstract. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 106. doi:10.1158/1538-7445.AM2014-106
RATIONALE:
Treatment of glioblastoma (GBM) remains challenging due in part to its histologic intratumoral heterogeneity that contributes to its overall poor treatment response. Our goal was to ...evaluate a voxel-based biomarker, the functional diffusion map (fDM), as an imaging biomarker to detect heterogeneity of tumor response in a radiation dose escalation protocol using a genetically engineered murine GBM model.
EXPERIMENTAL DESIGN:
Twenty-four genetically engineered murine GBM models Ink4a-Arf
-/-
/Pten
loxp/loxp
/Ntv-a RCAS/PDGF(+)/Cre(+) were randomized in four treatment groups (
n
= 6 per group) consisting of daily doses of 0, 1, 2, and 4 Gy delivered for 5 days. Contrast-enhanced T1-weighted and diffusion-weighted magnetic resonance imaging (MRI) scans were acquired for tumor delineation and quantification of apparent diffusion coefficient (ADC) maps, respectively. MRI experiments were performed daily for a week and every 2 days thereafter. For each animal, the area under the curve (AUC) of the percentage change of the ADC (AUC
ADC
) and that of the increase in fDM values (AUC
fDM+
) were determined within the first 5 days following therapy initiation.
RESULTS:
Animal survival increased with increasing radiation dose. Treatment induced a dose-dependent increase in tumor ADC values. The strongest correlation between survival and ADC measurements was observed using the AUC
fDM+
metric (
R
2
= 0.88).
CONCLUSION:
This study showed that the efficacy of a voxel-based imaging biomarker (fDM) was able to detect spatially varying changes in tumors, which were determined to be a more sensitive predictor of overall response
versus
whole-volume tumor measurements (AUC
ADC
). Finally, fDM provided for visualization of treatment-associated spatial heterogeneity within the tumor.
COPD is a heterogeneous syndrome. Many COPD subtypes have been proposed, but there is not yet consensus on how many COPD subtypes there are and how they should be defined. The COPD Genetic ...Epidemiology Study (COPDGene), which has generated 10-year longitudinal chest imaging, spirometry, and molecular data, is a rich resource for relating COPD phenotypes to underlying genetic and molecular mechanisms. In this article, we place COPDGene clustering studies in context with other highly cited COPD clustering studies, and summarize the main COPD subtype findings from COPDGene. First, most manifestations of COPD occur along a continuum, which explains why continuous aspects of COPD or disease axes may be more accurate and reproducible than subtypes identified through clustering methods. Second, continuous COPD-related measures can be used to create subgroups through the use of predictive models to define cut-points, and we review COPDGene research on blood eosinophil count thresholds as a specific example. Third, COPD phenotypes identified or prioritized through machine learning methods have led to novel biological discoveries, including novel emphysema genetic risk variants and systemic inflammatory subtypes of COPD. Fourth, trajectory-based COPD subtyping captures differences in the longitudinal evolution of COPD, addressing a major limitation of clustering analyses that are confounded by disease severity. Ongoing longitudinal characterization of subjects in COPDGene will provide useful insights about the relationship between lung imaging parameters, molecular markers, and COPD progression that will enable the identification of subtypes based on underlying disease processes and distinct patterns of disease progression, with the potential to improve the clinical relevance and reproducibility of COPD subtypes.
Abstract
Approximately 70% of patients with late stage cancers metastasize to the bone. RECIST identifies these tumors as “unmeasureable” for therapeutic response assessment. Cabozantinib (CABO), a ...tyrosine kinase inhibitor of MET and VEGFR2, has shown promise as an effective therapy for metastatic prostate cancer to the bone. Patients treated with CABO showed a reduction in Tc99m-bone scan signal suggesting tumor response to treatment. Nevertheless, a return in signal to pre-treatment levels was observed in these patients following therapy completion. It has yet to be determined if the response observed in bone scans results from tumor death, changes in bone metabolism or vascular alterations in the tumor-stromal microenvironment resulting in reduced transport of the imaging tracer. The study objective was to assess tumor and bone response to CABO in an animal model of bone metastasis using a quantitative multi-modal imaging approach.
Twenty-seven male SCID mice were implanted with PC3 cell line in the right tibia. PC3 cells were transfected with a plasmid expressing a bioluminescence imaging (BLI) reporter for measuring apoptosis. When tumor volumes reached 10mm3 by MRI, mice were distributed into 2 groups: CABO at 30 mg/kg (N=13) and vehicle (N=14). Treatments were delivered by oral gavage once a day for three weeks. Starting pre-treatment, MRI and BLI were acquired every third day and CT every week. Tumor and bone volumes were monitored by manually contouring volumes of interest (VOI) on anatomical MRI and CT images, respectively. The apparent diffusion coefficient (ADC), an indirect measure of tumor cellularity, was calculated from diffusion MRI.
Mice treated with CABO were found to have significantly higher ADC values and slower growth profile than controls (p<0.05) suggesting a drop in tumor cellularity. Following one week of treatment, BLI signal increased 7 fold over baseline values indicating a delay in tumor apoptosis. In contrast, ADC values and apoptosis activation were unchanged in the controls resulting in significant differences between groups (p<0.05). As determined by CT, control mice had significantly more loss in bone volume than what was observed in the CABO treated mice, with differences first observed at day 14 post-treatment initiation (p<0.05). CABO was found to activate cell death through apoptosis (BLI) resulting in reduced tumor cellularity (ADC) and inhibited tumor growth (anatomical MRI). Increased tumor burden may have reduced osteolytic processes causing less bone loss over controls. Quantitative diffusion MRI and CT, backed by preclinical optical techniques, provide highly sensitive temporal information on the tumor-stromal microenvironment and their interaction to a targeted therapeutic intervention. Translatable quantitative imaging techniques, i.e. MRI and CT, may provide individualized medicine to patients suffering from metastatic prostate cancer to the bone.
Citation Format: Joshua S. George, Craig J. Galban, Jean-Christophe Brisset, Benjamin Hoff, Stephanie Galban, Alnawaz Rehemtulla, Brian D. Ross. Imaging biomarker development for treatment efficacy for prostate cancer to the bone. abstract. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5595. doi:10.1158/1538-7445.AM2013-5595
We present an analysis of the effects of chemical exchange and changes in
T
1 on metabolite quantitation for heart, skeletal muscle, and brain using the one-pulse experiment for a sample which is ...subject to temporal variation. We use an optimization algorithm to calculate interpulse delay times, TRs, and flip angles, θ, resulting in maximal root-mean-squared signal-to-noise per unit time (
S/
N) for all exchanging species under 5 and 10% constraints on quantitation errors. The optimization yields TR and θ pairs giving signal-to-noise per unit time close or superior to typical literature values. Additional simulations were performed to demonstrate explicitly the dependence of the quantitation errors on pulse parameters and variations in the properties of the sample, such as may occur after an intervention. We find that (i) correction for partial saturation in accordance with the usual analysis neglecting variations in metabolite concentrations and rate constants may readily result in quantitation errors of 15% or more; the exact degree of error depends upon the details of the system under consideration; (ii) if
T
1's vary as well, significantly larger quantitation errors may occur; and (iii) optimal values of pulse parameters may minimize errors in quantitation with minimal
S/
N loss.
Despite good performance for medical image segmentation, deep convolutional neural networks (CNNs) have not been widely accepted in clinical practice as they are complex and tend to fail silently. ...Additionally, uncertainty in their predictions are not well understood, making them obscure and challenging to interpret. Automatically detecting possible failures in network predictions is important, as we can refer such cases for manual inspection or correction by human observers. In this paper, we analyse the uncertainty for deep CNN-based lung lobe segmentation in computed tomography (CT) scans by proposing a test-time augmentation-based aleatoric uncertainty measure. Through this analysis, we produce spatial uncertainty maps, from which a clinician can observe where and why a system thinks it is failing, and quantify the image-level prediction of failure. Our results show that such an uncertainty measure is highly correlated to segmentation accuracy and therefore presents an inherent measure of segmentation quality.
Metabolite concentration measurements in in vivo NMR are generally performed under partially saturated conditions, with correction for partial saturation performed after data collection using a ...measured saturation factor. Here, we present an experimental test of the hypothesis that quantitation errors can occur due to application of such saturation factor corrections in changing systems. Thus, this extends our previous theoretical work on quantitation errors due to varying saturation factors. We obtained results for two systems frequently studied by
31
P
NMR, the ischemic rat heart and the electrically stimulated rat gastrocnemius muscle. The results are interpreted in light of previous theoretical work which defined the degree of saturation occurring in a one-pulse experiment for a system with given spin–lattice relaxation times,
T
1s, equilibrium magnetizations,
M
0s, and reaction rates. We found that (i) the assumption of constancy of saturation factors leads to quantitation errors on the order of 40% in inorganic phosphate; (ii) the dominant contributor to the quantitation errors in inorganic phosphate is most likely changes in
T
1; (iii)
T
1 and
M
0 changes between control and intervention periods, and chemical exchange contribute to different extents to quantitation errors in phosphocreatine and γ-ATP; (iv) relatively small increases in interpulse delay substantially decreased quantitation errors for metabolites in ischemic rat hearts; (v) random error due to finite SNR led to approximately 4% error in quantitation, and hence was a substantially smaller contributor than were changes in saturation factors.
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