Resonant Spectroscopy for Cancer Diagnosis and Therapy “Resonant Spectroscopy Oncology Group”

2 * For those free of cancer at beginning of age interval. Based on cancer cases diagnosed during 2000 to Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 6.0 Statistical Research and Applications Branch, NCI, Lifetime Probability of Developing Cancer, by Site, Men, * SiteRisk All sites † 1 in 2 Prostate 1 in 6 Lung and bronchus1 in 13 Colon and rectum1 in 17 Urinary bladder ‡ 1 in 28 Non-Hodgkin lymphoma1 in 46 Melanoma1 in 52 Kidney1 in 64 Leukemia1 in 67 Oral Cavity1 in 73 Stomach1 in 82 ‡ Includes invasive and in situ cancer cases

3 Lifetime Probability of Developing Cancer, by Site, Women, US, * SiteRisk All sites † 1 in 3 Breast 1 in 8 Lung & bronchus 1 in 17 Colon & rectum 1 in 18 Uterine corpus 1 in 38 Non-Hodgkin lymphoma 1 in 55 Ovary 1 in 68 Melanoma 1 in 77 Pancreas 1 in 79 Urinary bladder ‡ 1 in 88 Uterine cervix 1 in 135 Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 6.0 Statistical Research and Applications Branch, NCI, * For those free of cancer at beginning of age interval. Based on cancer cases diagnosed during 2000 to ‡ Includes invasive and in situ cancer cases

4 X-Ray Diagnostic Imaging Includes planar x-ray (no depth resolution), CT, PET, other NM imaging modalities Used in screening, diagnostic work-up, image-guided biopsy and therapeutic delivery X-ray and CT: broadband, 20 – 200 keV, typically 80 – 120 keV Bone: photoionization; soft tissues: Compton scattering Relies on tissue density changes to detect soft tissue abnormality

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Energy range selection: Compromise between Image Contrast and Patient Dose (absorption)  Lower energy: greater contrast in transmission radiograph between different tissue compositions but needs higher exposure due to higher linear absorption

7 Resonant Spectroscopic Imaging: a paradigm change? Need: Narrowband (tunable?) light source Elemental composition differential between malignant and normal tissues Or tumor-seeking nanoparticles tagged with known metals (nanogold…) as exogenous contrast agents Significant difference between resonant absorption peaks and background cross sections (10^4?)

8 Radiation Therapy Mostly delivered by linear accelerators at 6 – 25 MV (broadband, spectral peak ~ 1/3 of max. accelerator energy) Sometimes delivered inside the tumor (“brachytherapy”) by various implantable radioisotopes, 20 – 600 keV Primarily Compton scattering Relies on geometric arrangement of multiple beams/sources to achieve optimized dose delivery to tumor and sparing of normal or critical tissue Expensive alternative: proton (or carbon ion) therapy, Bragg peak

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12 Resonant Activation Therapy: a paradigm change? Possible scenarios: Deliver energy-optimized radiation directly to preferentially dose tumor tissue based on elemental composition differences Two step process: high-energy radiation is directed to a site doped with heavy elements (nanoparticles), which would be thereby pumped to undergo fluorescent emission

13 Geraki 2004, City University, London X-ray fluorescence and energy dispersive x-ray diffraction for the quantification of elemental concentrations in breast tissue Synchrotron-based system used for detection of x-ray fluorescence emitted from iron, copper, zinc and potassium in healthy and cancerous breast tissues. All 4 elements are found in elevated levels in tumor (less pronounced for iron, copper and more for potassium and zinc) Kidane 1999, UCL X-ray scatter signatures for normal and neoplastic breast tissues 100 excised tissue samples measured by energy dispersive x-ray diffraction system over the momentum transfer range of 0.70 to 3.50 nm(-1) Shape of the scatter spectrum and relative intensity diagnostic. The shapes are significantly different between tissue types in the range 1.0 to 1.8 nm(-1) Fernandez 2002, U. Helsinki Small-angle x-ray scattering studies of human breast tissue samples Small-angle x-ray scattering patterns recorded from breast tissue samples containing healthy and cancerous regions, and compared with histo- pathological observations Average intensity of scattering from cancerous regions is an order of magnitude higher than the intensity from healthy regions. Differences of the SAXS patterns are large and distinctive enough to suggest diagnostic power. Arfelli 2000, U. Trieste Mammography with synchrotron radiation: phase-detection techniques Evaluated the effect of the use of synchrotron radiation to detect phase perturbation effects, which are higher than absorption effects for soft tissue in the energy range of keV Image quality of synchrotron radiation images was considerably higher, and the delivered dose was fully compatible with conventional techniques.

14 Marziani 2002, U. Ferrara & INFN Dual-energy tissue cancellation in mammography with quasi monochromatic x-rays Several images acquired in the energy range keV using a quasi- monochromatic x-ray source and a scintillator-coated CCD detector. Images acquired at high and low energies were nonlinearly combined to generate two energy-independent basis images. Suitable linear combinations of these two basis images result in the elimination of the contrast of a given material with respect to another. This makes it possible to selectively cancel certain details in the processed image. Carroll 1991, Vanderbilt U. Generation of "soft x-rays" by using the free electron laser as a proposed means of diagnosing and treating breast cancer The absence of Compton scatter and the photoelectric interaction within tissues improves conspicuity of lesions by 2 – 6 times. Increased attenuation of x- rays in malignant vs. normal tissues makes tumors more obvious. K-edge subtraction allows chemical analysis of tumors in vivo. Radiation dose 1/10 – 1/50 that delivered by conventional technique. This allows for an increased sensitivity and specificity and permits prediction of histology, negating necessity for biopsies. Carroll 1994 Attenuation of monochromatic X-rays by normal and abnormal breast tissues X-ray linear attenuation coefficients were measured in the energy range to 18 keV, using monoenergetic x-rays from beamline X-19A at the National Synchrotron Light Source at Brookhaven National Laboratory The mean of linear attenuation coefficients for cancers was 10.9% higher than the mean of normal tissues. CONCLUSIONS. Differences in the linear attenuation coefficients of monochromatic x-rays between and 18 keV do exist between normal and cancerous tissues, but there is some degree of overlap.

15 Summary Conventional diagnostic and therapeutic x-ray sources are not energy-optimized for selective targeting of cancer tissue Preliminary investigations suggest existence of a diagnostic/therapeutic advantage at selected energies Resonant Spectroscopy Oncology may open up a new field of biomedical research