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116: Dual energy CT to reduce range uncertainties in hadrontherapy
ICTR-PHE – 2014 experimental data show discrepancies for both energy and angular distributions. Experimental results and GEANT4 simulations of 95 MeV/A 12C cross sections on the different targets will be presented. The prediction capabilities of the different models applied to a 95 MeV/A 12C beam will be discussed. Keywords: fragmentation, GEANT4, hadrontherapy References: [1] B. Braunn et al., Nucl Inst Meth B 269 (2011) [2] J. Dudouet et al., Phys Rev C 88 (2013) 115 Targeting carbonic anhydrase IX by nitroimidazole based sulfamides enhances the therapeutic effect of tumor irradiation and doxorubicin treatment: a new concept of dual targeting drugs P. Lambin1,, S.G.J.A. Peeters1, S.J.A. van Kuijk1, A. Yaromina1,2, N.G. Lieuwes1, R. Saraya1, R. Biemans1, M. Rami3, N.K. Parvathaneni1,3, D. Vullo4, M. Vooijs1, C.T. Supuran4, J.Y. Winum3, L. Dubois1, 1 Dept. of Radiation Oncology (MAASTRO Lab), GROW – School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands 2 OncoRay - National Center for Radiation Research in Oncology Medical Faculty and University Hospital Carl Gustav Carus Technische Universität Dresden, Germany 3 Institut des Biomolecules Max Mousseron, UMR 5247 CNRS, University of Montpellier1 & 2, Montpellier, France 4 Dept. of Chemistry, Laboratory of Bioinorganic Chemistry, Università degli Studi di Firenze, Florence, Italy Carbonic anhydrase IX (CAIX) is a membrane-bound, hypoxiainducible enzyme highly expressed in solid tumors, with restricted expression in normal tissues. CAIX plays an important role in processes critical for tumor cell growth and metastasis. Several carbonic anhydrase inhibitors have been developed that selectively inhibit hypoxic CAIX activity, thereby reducing extracellular acidosis. The aim of this study was to evaluate the antitumor activity of a newly designed class of dual targeting nitroimidazole based sulfamide drugs (DD) with high affinity for CAIX. We hypothesize that these compounds specifically block CAIX activity, reduce tumor growth and sensitize tumors to irradiation in a CAIX dependent manner. Methods: Colorectal carcinoma cells harboring a shCAIX (KD) or control shRNA (EV) construct were incubated with DD at varying oxygen levels and extracellular acidification was determined. Tumor-bearing mice received DD (1x/day 10 mg/kg for 5 days) at a volume of 250 mm³ and tumor irradiation (single dose 10Gy) was performed at day 3 of the injection period. Tumor growth, volume doubling time (VDT) and potential treatment toxicity were monitored. Results: From a series of nitroimidazole based sulfamides we identified a novel nanomolar DD (N-[2-(2-methyl-5-nitroimidazol-1-yl)ethyl]sulfamide; DH348) which showed the most pronounced in vitro reduction in hypoxia-induced extracellular acidosis. In vivo, irradiation as a single treatment resulted in an increased doubling time (P < 0.001) in both tumor models. Animals treated with DH348 monotherapy showed a significant slower growth (VDT = 6.32; P = 0.004) in the EV tumor (vehicle VDT 3.01) as well as a sensitization for radiotherapy (VDT = 8.59; P = 0.019). Therapeutic sensitization was only observed in the CAIX expressing tumors, proving the absence of any “off-target” effect. In vivo testing of the lead molecule in the sulfamide series, in cotreatment with doxorubicin, demonstrated a chemosensitization of CA IX containing tumors. Our interpretation is that the more acidic tumour cells (pH i) increase the uptake of the more basic doxorubicin.
S57 Conclusion: A newly designed nitroimidazole and sulfamide dual targeting drug is able to reduce hypoxic extracellular acidification, increase intracellular acidification, slows down tumour growth at nontoxic dose and sensitizes tumors in a CAIX dependent manner to irradiation and doxorubicin. The dual drug enhances sensitization towards radiotherapy and certain chemotherapeutic drugs compared to single published CAIX targeting compounds. Our data therefore indicate the potential utility of a dual drug approach as a new strategy for tumor-specific targeting. Dual drugs of the second generation are under development. Keywords: Carbonic Anhydrase IX, sulfonamides, dual targeting drugs References: L. Dubois, et al. (2013). Radiother Oncol 108(3):523-8 M. Rami, et al. (2013). J Med Chem. Oct 31 116 Dual energy CT to reduce range uncertainties hadrontherapy G. Landry1,2, J. Seco3, K. Parodi1, F. Verhaegen2 1 LMU, Garching, Germany 2 Maastro clinic, The Netherlands 3 MGH
in
Purpose: The full exploitation of the advantageous dose deposition characteristics of protons and carbon ions in hadrontherapy can be marred by uncertainties in the calculation of their range in heterogeneous body tissues. The conversion of single energy CT (SECT) data to stopping power ratio (SPR) is considered a major source of uncertainty in the treatment planning process. While in-vivo range verification techniques based on PET imaging to estimate 15O or 11C production rates have shown promise of reducing range uncertainties by estimating range during treatment, the difficulty in assigning tissue elemental composition (TC) required to predict production rates from SECT data is a confounding factor. Dual energy CT (DECT), which yields estimates of the relative electron density e and effective atomic number Zeff, shows promise of reducing range uncertainty by providing better estimates of 1) SPR through higher e accuracy and 2) TC through Zeff. Materials/methods: A DECT calibration procedure based on scans of a Gammex 467 phantom was developed to obtain estimates of e and Zeff without the need of prior CT scanner spectral knowledge. By employing a fit of the mean ionization potential to Zeff and the Bethe Bloch equation, DECT estimates of SPR were obtained for each insert of the calibration phantom. The DECT procedure was compared to the conventional SECT procedure. Furthermore TC was assigned on the basis of DECT and SECT scans. Accuracy in SPR and TC were compared for DECT and SECT. All SECT and DECT acquisitions were performed with matched imaging radiation dose levels to enable noise comparison.
S58
ICTR-PHE – 2014
Results:
of the patients was extracted from buffy coats and genotyped using Illumina OmniExpressExome BeadChips. Results: Genes differentially expressed between the ‘resistant’ and ‘sensitive’ gene expression profile groups were identified by prediction analysis of microarrays (PAM). PAM was performed on the difference in gene expression between irradiated and non-irradiated cells (differential gene expression) as well as the gene expression in non-irradiated control cells. For the differential gene expression PAM identified 282 probes and for control cells 121 probes were identified. 48 probes were found in both analyses whereas 234 probes were unique for the differential gene expression and 73 were unique for gene expression in control cells. The majority of genes found in our PAM analyses encode proteins involved in cell cycle, DNA replication, and DNA repair as shown by enriched Gene Ontology (GO) term categories. For probes unique for differential gene expression enriched GO term categories also include ‘calcium ion binding’ and ‘extracellular region’. eQTL analyses (Bioconductor ‘MatrixEQTL’ and ‘iBMQ’ packages) were performed using the genes identified in PAM analyses, and a number of candidate SNPs associated with the gene expression profile predictive for radiation induced fibrosis were identified. Conclusion: We have identified DNA sequence variants associated with a gene expression profile predictive for radiation induced fibrosis. These will have to be independently validated in a larger patient cohort.
Figure 1 presents the accuracy (mean and standard deviation) on SPR obtained for regions of interest (ROIs) centered on each insert of the Gammex 467 phantom for DECT and SECT scans obtained using equivalent exposures. SPR errors are limited to less than 0.02 units of SPR when using DECT, as opposed to errors of up to -0.06 units of SPR with SECT. On the other hand at equivalent imaging dose DECT data is significantly noisier. Figure 1 also shows that, depending on the radiation dose employed in DECT imaging, the error on TC assignment (oxygen concentration in this case) can be reduced compared to SECT. The higher noise sensitivity of DECT based TC assignment may require higher imaging radiation dose than SECT to achieve optimal results for the technique. Conclusion: DECT performs better than SECT for the tasks of estimating proton SPR and TC and shows promise of contributing to the reduction of range uncertainties in proton and carbon ion radiotherapy.
Keywords: radiation induced fibrosis, SNPs, eQTL
Keywords: dual energy CT, proton therapy, range uncertainty 117 Identification of DNA sequence variants associated with a gene expression profile predictive for radiation induced fibrosis L.V. Laursen, J. Alsner, C.N. Andreassen, J. Overgaard Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark Purpose: It was previously shown that risk of radiation induced fibrosis can be predicted based on gene expression patterns in cultured fibroblasts irradiated in vitro (1). The aim of this study is to identify DNA single nucleotide polymorphisms (SNPs) associated with these gene expression patterns by expression quantitative trait loci (eQTL) analysis. Materials and methods: Fibroblast cultures established from skin biopsies from 48 head and neck cancer patients were irradiated in vitro using a fractionation scheme of 3 X 3.5 Gy. Based on a 9 gene classifier (2) 24 patients were previously identified as having a ‘resistant gene expression profile’ and 24 had a ‘sensitive gene expression profile’. RNA from irradiated cells as well as non-irradiated control cells was isolated and gene expression analysis was performed using Illumina BeadArray HT12 microarrays. Genomic DNA from 47
References: [1] Alsner J, Rødningen OK, Overgaard J. Differential gene expression before and after ionizing radiation of subcutaneous fibroblasts identifies breast cancer patients resistant to radiation-induced fibrosis.Radiother Oncol 2007;83:261-266. [2] Andreassen CN, Overgaard J, Alsner J. Independent prospective validation of a predictive test for risk of radiation induced fibrosis based on the gene expression pattern in fibroblasts irradiated in vitro. Radiother Oncol (in press). 118 Ultimate Time Resolution in Time-of-Flight PET P. Lecoq, E. Auffray, S. Gundacker CERN, Switzerland Purpose: Highest time resolution in scintillator-based detectors is becoming more and more important, in particular for High Energy Physics and for medical Imaging applications. In medical detector physics L(Y)SO scintillators are commonly used for time of flight positron emission tomography (TOF-PET). Coincidence time resolutions (CTRs) smaller than 100ps FWHM are desirable in order to select a centimeter range region of interest, to consequently improve the image signal to noise ratio and thus give benefit to the patient by smaller injected doses or shorter scanning times. To achieve these goals it is important to study the whole chain, i.e. the gamma-ray interaction in the crystal, the scintillation process itself, the scintillation light transfer in the crystal, the light extraction efficiency, the conversion process in the photodetector and the readout electronics. Materials and methods: This study aims at determining the experimental and theoretical limits of timing using L(Y)SO based scintillators coupled to silicon photomultipliers (SiPMs). Measurements are based on the time-over-threshold method in a coincidence setup utilizing the ultra-fast amplifier-discriminator NINO and a fast oscilloscope. Because of their slightly better timing performance LSO:Ce codoped 0.4% Ca crystals grown by Agile and coupled to a commercially available SiPM (Hamamatsu S10931-050P MPPC) have been chosen for this study.
S57 Conclusion: A newly designed nitroimidazole and sulfamide dual targeting drug is able to reduce hypoxic extracellular acidification, increase intracellular acidification, slows down tumour growth at nontoxic dose and sensitizes tumors in a CAIX dependent manner to irradiation and doxorubicin. The dual drug enhances sensitization towards radiotherapy and certain chemotherapeutic drugs compared to single published CAIX targeting compounds. Our data therefore indicate the potential utility of a dual drug approach as a new strategy for tumor-specific targeting. Dual drugs of the second generation are under development. Keywords: Carbonic Anhydrase IX, sulfonamides, dual targeting drugs References: L. Dubois, et al. (2013). Radiother Oncol 108(3):523-8 M. Rami, et al. (2013). J Med Chem. Oct 31 116 Dual energy CT to reduce range uncertainties hadrontherapy G. Landry1,2, J. Seco3, K. Parodi1, F. Verhaegen2 1 LMU, Garching, Germany 2 Maastro clinic, The Netherlands 3 MGH
in
Purpose: The full exploitation of the advantageous dose deposition characteristics of protons and carbon ions in hadrontherapy can be marred by uncertainties in the calculation of their range in heterogeneous body tissues. The conversion of single energy CT (SECT) data to stopping power ratio (SPR) is considered a major source of uncertainty in the treatment planning process. While in-vivo range verification techniques based on PET imaging to estimate 15O or 11C production rates have shown promise of reducing range uncertainties by estimating range during treatment, the difficulty in assigning tissue elemental composition (TC) required to predict production rates from SECT data is a confounding factor. Dual energy CT (DECT), which yields estimates of the relative electron density e and effective atomic number Zeff, shows promise of reducing range uncertainty by providing better estimates of 1) SPR through higher e accuracy and 2) TC through Zeff. Materials/methods: A DECT calibration procedure based on scans of a Gammex 467 phantom was developed to obtain estimates of e and Zeff without the need of prior CT scanner spectral knowledge. By employing a fit of the mean ionization potential to Zeff and the Bethe Bloch equation, DECT estimates of SPR were obtained for each insert of the calibration phantom. The DECT procedure was compared to the conventional SECT procedure. Furthermore TC was assigned on the basis of DECT and SECT scans. Accuracy in SPR and TC were compared for DECT and SECT. All SECT and DECT acquisitions were performed with matched imaging radiation dose levels to enable noise comparison.
S58
ICTR-PHE – 2014
Results:
of the patients was extracted from buffy coats and genotyped using Illumina OmniExpressExome BeadChips. Results: Genes differentially expressed between the ‘resistant’ and ‘sensitive’ gene expression profile groups were identified by prediction analysis of microarrays (PAM). PAM was performed on the difference in gene expression between irradiated and non-irradiated cells (differential gene expression) as well as the gene expression in non-irradiated control cells. For the differential gene expression PAM identified 282 probes and for control cells 121 probes were identified. 48 probes were found in both analyses whereas 234 probes were unique for the differential gene expression and 73 were unique for gene expression in control cells. The majority of genes found in our PAM analyses encode proteins involved in cell cycle, DNA replication, and DNA repair as shown by enriched Gene Ontology (GO) term categories. For probes unique for differential gene expression enriched GO term categories also include ‘calcium ion binding’ and ‘extracellular region’. eQTL analyses (Bioconductor ‘MatrixEQTL’ and ‘iBMQ’ packages) were performed using the genes identified in PAM analyses, and a number of candidate SNPs associated with the gene expression profile predictive for radiation induced fibrosis were identified. Conclusion: We have identified DNA sequence variants associated with a gene expression profile predictive for radiation induced fibrosis. These will have to be independently validated in a larger patient cohort.
Figure 1 presents the accuracy (mean and standard deviation) on SPR obtained for regions of interest (ROIs) centered on each insert of the Gammex 467 phantom for DECT and SECT scans obtained using equivalent exposures. SPR errors are limited to less than 0.02 units of SPR when using DECT, as opposed to errors of up to -0.06 units of SPR with SECT. On the other hand at equivalent imaging dose DECT data is significantly noisier. Figure 1 also shows that, depending on the radiation dose employed in DECT imaging, the error on TC assignment (oxygen concentration in this case) can be reduced compared to SECT. The higher noise sensitivity of DECT based TC assignment may require higher imaging radiation dose than SECT to achieve optimal results for the technique. Conclusion: DECT performs better than SECT for the tasks of estimating proton SPR and TC and shows promise of contributing to the reduction of range uncertainties in proton and carbon ion radiotherapy.
Keywords: radiation induced fibrosis, SNPs, eQTL
Keywords: dual energy CT, proton therapy, range uncertainty 117 Identification of DNA sequence variants associated with a gene expression profile predictive for radiation induced fibrosis L.V. Laursen, J. Alsner, C.N. Andreassen, J. Overgaard Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark Purpose: It was previously shown that risk of radiation induced fibrosis can be predicted based on gene expression patterns in cultured fibroblasts irradiated in vitro (1). The aim of this study is to identify DNA single nucleotide polymorphisms (SNPs) associated with these gene expression patterns by expression quantitative trait loci (eQTL) analysis. Materials and methods: Fibroblast cultures established from skin biopsies from 48 head and neck cancer patients were irradiated in vitro using a fractionation scheme of 3 X 3.5 Gy. Based on a 9 gene classifier (2) 24 patients were previously identified as having a ‘resistant gene expression profile’ and 24 had a ‘sensitive gene expression profile’. RNA from irradiated cells as well as non-irradiated control cells was isolated and gene expression analysis was performed using Illumina BeadArray HT12 microarrays. Genomic DNA from 47
References: [1] Alsner J, Rødningen OK, Overgaard J. Differential gene expression before and after ionizing radiation of subcutaneous fibroblasts identifies breast cancer patients resistant to radiation-induced fibrosis.Radiother Oncol 2007;83:261-266. [2] Andreassen CN, Overgaard J, Alsner J. Independent prospective validation of a predictive test for risk of radiation induced fibrosis based on the gene expression pattern in fibroblasts irradiated in vitro. Radiother Oncol (in press). 118 Ultimate Time Resolution in Time-of-Flight PET P. Lecoq, E. Auffray, S. Gundacker CERN, Switzerland Purpose: Highest time resolution in scintillator-based detectors is becoming more and more important, in particular for High Energy Physics and for medical Imaging applications. In medical detector physics L(Y)SO scintillators are commonly used for time of flight positron emission tomography (TOF-PET). Coincidence time resolutions (CTRs) smaller than 100ps FWHM are desirable in order to select a centimeter range region of interest, to consequently improve the image signal to noise ratio and thus give benefit to the patient by smaller injected doses or shorter scanning times. To achieve these goals it is important to study the whole chain, i.e. the gamma-ray interaction in the crystal, the scintillation process itself, the scintillation light transfer in the crystal, the light extraction efficiency, the conversion process in the photodetector and the readout electronics. Materials and methods: This study aims at determining the experimental and theoretical limits of timing using L(Y)SO based scintillators coupled to silicon photomultipliers (SiPMs). Measurements are based on the time-over-threshold method in a coincidence setup utilizing the ultra-fast amplifier-discriminator NINO and a fast oscilloscope. Because of their slightly better timing performance LSO:Ce codoped 0.4% Ca crystals grown by Agile and coupled to a commercially available SiPM (Hamamatsu S10931-050P MPPC) have been chosen for this study.