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<ul><li><p>+</p><p>THE NEXT GENERATION OF RADIOBIOLOGY EXPERIMENTS </p><p>P. A. Posocco Imperial College London The Cockcroft Institute Gunnar Nilssons Cancerstiftelse </p></li><li><p>+Content </p><p>1 Why we (still) need Radiobiological experiments </p><p>2 What we have learned from previous experiments </p><p>3 Rationale for new experiments </p><p>4 Radiobiological experiments: the next generation </p><p>02/10/2013 P.A. Posocco - Imperial College London </p><p>2 </p></li><li><p>+The concept of RBE (Relative Biological Effectiveness) </p><p>Definition of RBE </p><p>RBE =D </p><p>Dprotonseffect</p><p>0.001 </p><p>0.01 </p><p>0.1 </p><p>1 </p><p>0 1 2 3 4 5 6 7 8 Dose [Gy] </p><p>Cel</p><p>l Sur</p><p>viva</p><p>l </p><p>protons </p><p>Introduction n Based on the clonogenic assay: n Growing cells in the incubator; </p><p>n Counting them (density); </p><p>n Plating them; </p><p>n Irradiating them; </p><p>n Re-plating them; </p><p>n Leaving them in the incubator (for approx. 2 weeks) to grow further; </p><p>n Counting the number of cells which have generated colonies (visually); </p><p>n Repeating the process for different dose levels </p><p>In-vitro radiobiology </p><p>02/10/2013 P.A. Posocco - Imperial College London </p><p>3 </p><p>Linear Quadratic (LQ) function </p><p>N.A.P. Franken, H.M. Rodermond, J. S, J. Haveman and C. van Bree, Clonogenic assay of cells in vitro, Nature Protocols, Vol.1, No.5 2006, pp. 2315-19. </p></li><li><p>+ and its implications for treatments </p><p>RBE as a function of particle energy / LET</p><p>An increasing RBE with depth cause anextended biologically effective range (1-2 mm)</p><p>119-1126</p><p>100</p><p>120biological dose</p><p>2000:27,11</p><p>tons</p><p>60</p><p>80</p><p>physical dose</p><p>Med.Phys.</p><p>Pro</p><p>20</p><p>40</p><p>2 G tti,Goitein:</p><p>depth in water [cm]</p><p>1.5 2.0 2.5 3.0 3.5</p><p>0</p><p>2 Gy</p><p>Paganetdepth in water [cm]</p><p>RBE (depth) for Carbon beamsRBE as a function of particle energy / LET</p><p>son</p><p> Ion</p><p>Car</p><p>boC</p><p>RBE effect for protons Example of flat SOBP for C-12 </p><p>Spread Out Bragg Peak (SOBP) </p><p>02/10/2013 P.A. Posocco - Imperial College London </p><p>4 </p></li><li><p>+ with some exceptions </p><p>n 2 opposite fields: </p><p>n RBE effect is practically cancelled due to field compensation! </p><p>n Unfortunately not every case is as simple as this one </p><p>Ideal Proton Therapy Patient in the US Treatment Modality </p><p>Prostate cancer </p><p>tum</p><p>or </p><p>dos</p><p>e depth </p><p>tum</p><p>or </p><p>dos</p><p>e </p><p>depth </p><p>w/o RBE </p><p>with RBE </p><p>02/10/2013 P.A. Posocco - Imperial College London </p><p>5 </p></li><li><p>+The PIDE* (Particle Irradiation Data Ensemble) n Its a database containing results </p><p>of more than 800 cell survival experiments from different laboratories all over the world, using different cell types and different ions at various energies. </p><p>n It only includes publications for which the LQ parameters of the response to photons as reference radiation were available or derivable </p><p>What is it? Overview of the results </p><p>02/10/2013 P.A. Posocco - Imperial College London </p><p>6 </p><p>* T. Friedrich, U. Scholz, T. Elssser, M. Durante and M. Scholz, Systematic analysis of RBE and related quantities using a database of cell survival experiments with ion beam irradiation, Journal of Radiation Research, 2012, pp 121 </p><p>Early responding Late responding </p></li><li><p>+Statistics about source of radiation in PIDE </p><p>Photons Ions </p><p>02/10/2013 P.A. Posocco - Imperial College London </p><p>7 </p><p>Photons of different energy have different RBE </p></li><li><p>+ and region and year </p><p>Region </p><p>Year </p><p>02/10/2013 P.A. Posocco - Imperial College London </p><p>8 </p><p>Dominated by the experiments at HIMAC / RIKEN </p><p>ICRU, 2007, Report 78 </p><p>Number of Particle facilities around the world </p><p>38 </p><p>56 </p><p>ICRU, 2007, Report 78 </p></li><li><p>+Challenges (1/2): Heterogeneities </p><p>n 80 different cell lines investigated. The same cell line may behave differently depending on experimental factors or age of the cell line. </p><p>n 44% human, 56% rodent </p><p>n 21% cancer, 79% normal </p><p>Cell cycle Types of cells </p><p>02/10/2013 P.A. Posocco - Imperial College London </p><p>9 </p><p>ESTRO Conference W. Drr </p></li><li><p>+Challenges (2/2): Dosimetry and Statistics </p><p>n Experimental data must be fitted with the LQ function </p><p>n Data show big error bars: n Hor.: dosimetry. The dose can </p><p>be measured directly using RadioChromic Films previously calibrated for a specific LET or counting the number of particles and estimating the LET; </p><p>n Ver.: statistics. The number of cells per sample which can be easily counted is approx. 50, the number of samples is limited to maintain the same experimental conditions throughout the whole curve. </p><p>02/10/2013 P.A. Posocco - Imperial College London </p><p>10 </p><p>J.C.G. Jeynes, et al., High throughput hadron irradiation of mammalian cells using a vertical facility, Radiation and Environmental Biophysics, 0301-634X, 2013. </p></li><li><p>+What have we learned from those experiments? The RBE value depends: </p><p>n On the dose level (survival fraction); </p><p>n On the cell type; </p><p>n On the mass and energy of the particles (LET value). </p><p>02/10/2013 P.A. Posocco - Imperial College London </p><p>11 </p><p>W. Weyrather et al. ,IJRB 1999; 75:135764. </p><p>B. Jones, Preliminary analysis on PIDE data </p><p>proton </p><p>He </p><p>C </p><p>Ne </p><p>Nor</p><p>mal</p><p>ised</p><p> RBE</p><p>RBE turnover point </p></li><li><p>+New generation of Radiobiological Experiments </p><p>n Experiments set up to prove a specific aspect of the RBE model, maintaining most of the parameters fixed </p><p>n Large database of response upon variation of all parameters </p><p>n Optimisation of experimental conditions </p><p>This can lead to only one solution: </p><p>n Accelerator totally dedicated to these experiments, and </p><p>n Located close or in the radiobiology departments, same as the photon irradiators </p><p>n A table-top (around 10 m2) multi-TW Ti : Sapphire laser system: n Femtoseconds pulse length n Power density of ~1019 W/cm2 n Spot size of a few microns n Solid targets ~10 um thick </p><p>n Why? Because: n Standard equipment for the plasma </p><p>groups working on laser-plasma particle acceleration </p><p>n Strong interest from the community in developing such systems for various applications </p><p>n Starting with a medical application could facilitate its development towards a proper particle therapy facility </p><p>n 10 MeV protons are already available </p><p>02/10/2013 P.A. Posocco - Imperial College London </p><p>12 </p><p>Must have Possible solution </p></li><li><p>+Radiobiological experiments with laser accelerated protons </p><p>D. Doria et al., Belfast (2012) S.D. Kraft et al., Dresden (2010) </p><p>02/10/2013 P.A. Posocco - Imperial College London </p><p>13 </p><p>J. Bin et al., Munich (2012) </p></li><li><p>+Proposal of Imperial College </p><p>02/10/2013 P.A. Posocco - Imperial College London </p><p>14 </p><p>2 Gabor lenses </p><p>Permanent magnets 90 deg FFAG bend </p><p>cells </p><p>Come to see our posters: THPSM10 THPSM11 THPSM12 THPSM13 </p><p>Ti-Sapphire laser </p></li><li><p>+Thank you! </p><p>n Henry Tsang and Hugo Larose (UG students at Imperial College) for their hard work during a very hot summer </p><p>n Prof B. Jones (Oxford) for the fruitful discussions and material </p><p>n The CRUK centre in Hammersmith for their financial support </p><p>Patients who benefit most from hadron therapy Acknowledgments </p><p>02/10/2013 P.A. Posocco - Imperial College London </p><p>15 </p></li></ul>


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