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Applications of the CXS to Cancer Medicine E.C. Landahl, J. Boggan, W. Frederick, N.C. Luhmann, Jr. Departments of Applied Science and Electrical and Computer Engineering, University of California, Davis D. Matthews Medical Technologies Program, Lawrence Livermore National Laboratory V. Cooper, K. Iwamoto, A. Norman, T. Solberg Departments of Radiation Oncology and Biomedical Physics, University of California Los Angeles Dose and Contrast for Radiography For a given target dimension x, what dose is needed to achieve the desired contrast? Contrast as Well as Spatial Resolution is Important for Radiography m1 m2 m1 T N ( SNR) (1 R) e A e Dm 2 x 4 2 x Contrast relative to normal breast tissue 1 T Dm x 1 e C 1 R R is the ratio of scattered to primary radiation, SNR is the desired Signal-to-Noise ratio, e is the detector efficiency, and N/A is the number of photons per unit area Improvements in Image Receptors Motivate Smaller X-Ray Source Sizes F is the intrinsic receptor unsharpness 1 a UT F 1 2 m m F2 1 2 m is the magnification .01 .001 1 mm glandular tissue 10 20 30 40 50 Energy (keV) Source: NIST After S. Webb, The Physics of Medical Imaging • Contrast decreases rapidly with photon energy • Low energy means a high patient dose • Ideally, energy would be tuned to reach a desired contrast Application of the Compton X-Ray Source to Mammography UT is the total unsharpness 2 0.1 mm calcification .1 100 mm calcification SNR = 5 men/r = 0.439 cm2/g Dm = 3.6 mm-1 R = 200% Ex = 20 keV e = 30% T = 20 cm A = 100 cm2 a is the source size Total Unsharpness / Intrinsic Receptor Unsharpness Total Unsharpness vs. Magnification 2.5 Conventional 2 a / F = 4 (large source) New 1.5 a/F=2 1 a/F=1 0.5 a / F = 0 (small source) Compton X-Ray Source 0 1 1.2 1.4 1.6 Magnification 1.8 2 CXS-1000 Flux 1.2 mGy is a typical dose for a cranio-caudad projection X-Ray Phototherapy for Integrated Targeted Cancer Diagnosis and Treatment Data #1 1 10 0.1 Survival fraction Dose to Tumor is Doubled 8 DEF XPT Simultaneous Imaging and Treatment of Canine Brain Tumors 20 mg I/ml 10 mg I/ml 5 mg I/ml 6 4 2 7 mg I/ml 14 mg I/ml 0.001 20 40 60 80 100 120 0.0001 0 1 2 3 4 Dose (Gy) Energy (keV) Dose to Bone is Halved Results of UIP Monoenergetic X-Ray Phototherapy Study Before Treatment Polyenergetic XRay Phototherapy 0.01 0 0 Conventional 10 MV Radiation Therapy 0 mg I/ml During Treatment 4X Increase in Therapeutic Ratio from Monoenergeti c X-Rays •Calculated Dose Enhancement Factors (DEF) show wide variation over the energy distributions of conventional xray devices •Data taken at APS December 2001 shows contrast media has anticipated PC3 cell kill in conjunction with 60 keV monoenergetic x-rays During Treatment After Treatment •Large errors due to the difficulties of using synchrotrons for this type of research CXS will be used for this type of research in the future Non-invasive Molecular Cancer Treatment Utilizing the CXS in Combination with Targeting Agents Radiation Induced Single Strand Break Cisplatin-DNA adduct Repair Cisplatin-DNA adduct Repair Non-repairable damage Non-repairable damage Cell death In conventional external beam radiation therapy, sparsely ionizing x-rays pass through a target cell, only occasionally depositing energy In X-Ray Phototherapy, sparsely ionizing x-rays are selectively absorbed by high Z atoms which are likely localized in extracellular regions near target cells. If contrast agents can be introduced into sub-cellular regions, the x-ray energy could be tuned closer to the absorption edge, reducing the range of the radiation byproducts so that they are densely ionizing and more likely to create DNA double strand breaks CXS Chemoradiotherapy. Left: Cisplatin-DNA adducts (green) and radiation-induced singlestrand breaks (red) in close proximity result in nonrepairable damage and cell death. Right: CXS xrays (red arrow) tuned to the Pt absorption edge are absorbed in proximity to the adduct and deposit radiation byproducts (orange) creating nearby single strand breaks and increasing likelihood of non repairable damage and cell death. Advanced Treatment Methods •Unique radiation responses to targeted sub-cellular X-Ray Phototherapy may be a new parameter to adjust during radiation therapy •Specific x-ray energy / contrast agent combinations may alter patient response to treatment based upon a predetermined molecular cancer profile •X-Ray Phototherapy radiation inducible promoters for gene therapy could have improved targeting or efficiency over existing promoters CXS monoenergetic x-rays Chimeric promoter/ cytotoxic gene Tumor cell Heavy metal containing targeting agent Cell death Induced Gene Expression •Advanced agents may incorporate a resonant x-ray triggered conformation change to deliver chemotherapeutics only upon external activation