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AD-4 Status Report 2010

32 Scientists from 13 Institutions. AD-4 Status Report 2010. Aarhus University Hospital University of Aarhus University of Athens Queen’s University Belfast CERN , Geneva Hôpital Universitaire de Geneve German Cancer Research Center, Heidelberg Universita d’Insubria , Como

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AD-4 Status Report 2010

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  1. 32 Scientists from 13 Institutions AD-4 Status Report 2010 Aarhus University Hospital University of Aarhus University of Athens Queen’s University Belfast CERN, Geneva HôpitalUniversitaire de Geneve German Cancer Research Center, Heidelberg Universitad’Insubria, Como Max Planck Institute for Nuclear Physics, Heidelberg University of Montenegro, Podgorica University of New Mexico, Albuquerque University of Umeå University of Texas Biological Effects of Antiprotons Are Antiprotons a Candidate for Cancer Therapy?

  2. Rationale for Conformal Radiotherapy Dose and tumor control are limited due to organs at risk. Tumor control Complications Therapeutic gain Complications Probability (%) Therapeutic window Dose (arb. Gy) January 17, 2012

  3. Physical Advantage of Antiprotons January 17, 2012

  4. Potential Clinical Advantages? • Each Particle Type shows distinct features • Protons are well known and easy to plan (RBE = 1) which is the reason they are most widely adopted. • Antiprotons have lowest entrance dose for the price of an extended isotropic low dose halo. • Carbon ions have sharpest lateral penumbra but comparatively higher entrance dose than even protons (no RBE included here), and show forward directed tail due to in beam fragmentation. Detailed dose plans (including RBE) will need to be developed to assess applicability of particle types for different tumor types and locations! January 17, 2012

  5. The AD-4 Experiment at CERN • INGREDIENTS: • V-79 Chinese Hamster cells embedded in gelatin • Antiproton beam from AD(126 MeV) V79 Developed by Ford and Yerganian in 1958 from lung tissue of a young male Chinese Hamster (Cricetulusgriseus) • METHOD: • Irradiate cells with dose levels to give survival in the peak is between 0 and 90 % • Slice samples, dissolve gel, incubate cells, and look for number of colonies ANALYSIS: • Study cell survival in peak (tumor), plateau (skin), and along the entire beam path. Compare the results toprotons (and carbon ions) January 17, 2012

  6. The Gel-Tube Method Peak Plateau Beam January 17, 2012

  7. The Gel-Tube Method January 17, 2012

  8. Biological Analysis Method January 17, 2012

  9. Relative Biological Efficiency (RBE) RBE0.1 1.56 SF0.1 3.31 Gy SF0.1 5.17 Gy January 17, 2012

  10. Cell Survival vs. Dose for 2010 Data RBEpeak/plateau = 1.52 January 17, 2012

  11. 4 Years of Running – 4 Depth DoseDistributions January 17, 2012

  12. Combining different years Two issues: Shift of DDD due to additional beam monitor Different shape of SOBP January 17, 2012

  13. Combining different years Correction applied for insertion of Mimotera Detector January 17, 2012

  14. Combined RBEplateau for 2007 and 2010 Preliminary January 17, 2012

  15. Problems with 2011 Data Set 4 wells seeded with identical number of cells – only two show colonies! January 17, 2012

  16. RBE Analysis for Antiprotons • Physical Dose Calculations requires exact Knowledge of Beam Parameters • Changes in FLUKA code necessitate new benchmark measurements and new calculations for all years using identical FLUKA version • Biological Variability necessitates multiple Independent Experiments under Identical Conditions ==> We definitley need more beam time! January 17, 2012

  17. DNA Damage and Repair • Quantify DNA damage in human cells along and around a 126 MeV antiproton beam at CERN. • Investigate immediate and longer term DNA damage. • Investigate non-targeted effects outside the beam path due to secondary particles or bystander signaling. January 17, 2012

  18. DNA Damage and Repair Assays • There is more to biology than just clonogenics – especially outside the targeted area: • Immediately after attack on DNA proteins are recruited to the site • This event signals cell cycle arrest to allow repair • If damage is too extensive to repair programmed cell death (apoptosis) is induced • Cells also deficient of cell cycle check point proteins may enter mitosis (cancer cells are often deficient in repair proteins and continue dividing) g-H2AX: Phosphorylation of H2AX in the presence of Double Strand Breaks Micronuclei: Fluorescent detection of micronuclei (parts of whole chromosomes) formed due to DNA damage, which are indicating potential of tumorigenesis g-H2AX and Micronucleus assays are typically used to study immediate and long term DNA damage respectively January 17, 2012

  19. Micro-Nuclei Studies Micro-nuclei produced by annihilating antiprotons are substantially larger and more persistent than those produced by x-rays or antiprotons in-flight January 17, 2012

  20. Effects of Secondary Particle Dose January 17, 2012

  21. Summary and Outlook Achievements 2011 • Biological measurements on clonogenic survival failed for unknown reason • Started combined analysis of Biological Effect of Antiprotons for preliminary dose planning studies • DNA damage assays for studies of late effects achieved higher resolution • 2012 will be “last chance” to significantly improve statistics on measurement of RBE for antiprotons January 17, 2012

  22. Summary and Outlook STILL TO DO IN 2012 • Add two more independent data sets (identical conditions) to improve RBE results • Perform low LET reference measurements • Benchmark FLUKA code against measured depth dose distributions. • Recalculate DDD’s for all years with identical code • Combine all years for final result to publish January 17, 2012

  23. Beam Time Request 2 weeks of 126 MeV (500 MeV/c) antiprotons Week 25 and last week of run time • Survival measurements on V-79 cell lines:Complete data set on RBEImprove error analysisAchieve publishable result • Benchmarking Studies for FLUKA code:Provide additional data to FLUKA team to modify code for correct description of antiproton interaction at low energies • IF there is any beam left after this:Absolute dosimetry with Alanine, Liquid Ionization Chamber studies, DNA damage, etc. January 17, 2012

  24. Summary and Outlook Recent Publications • Stefan Sellner, Carsten P. Welsch, Michael Holzscheiter; ‘Real-time imaging of antiprotons stopping in biological targets - Novel uses of solid state detectors’; Radiation Measurements 46 (2011) 1770 - 1772 • R. Boll, M. Caccia, C.P. Welsch, M.H. Holzscheiter; ‘Using Monolithic Active Pixel Sensors for fast monitoring of therapeutic hadron beams’; Radiation Measurements 46 (2011) 1971 - 1973 • J.N. Kavanagh, F.J. Currell, D.J.  Timson, M.H. Holzscheiter, N. Bassler, R. Herrmann, G. Schettino; ‘Experimental setup and first measurements of DNA damage induced along and around an antiproton beam’; European Physical Journal D 60 (2010) 209 - 214 • NielsBassler, IoannisKantemiris, Julia Engelke, Michael Holzscheiter, Jørgen B. Petersen, ‘Comparison of Optimized Single and Multifield Irradiation Plans of Antiproton, Proton and Carbon Ion Beams’, submitted to Radiotherapy and Oncology 95 (2010) 87 - 93 • Bassler, N., Holzscheiter, M.H., Petersen, J.B., ‘Neutron Fluence in Antiproton Radiotherapy, Measurements and Simulations', ActaOncologica 49 (2010) 1149 – 1159 January 17, 2012

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