- Email: [email protected]
62 TEST OF DIFFERENT PIXEL DETECTORS FOR LASER-DRIVEN ACCELERATED PARTICLE BEAMS
S21 excluded from the study, because the questionnaire wasn’t filled out completely. The Ex consisted of 49 patients and the rest 149 were included in the nonexercise group (nEx). Between the 2 groups the clinical characteristics of the study groups didn’t differ significantly. The median age and body mass index of the Ex and nEx was as follows {( ) shows the range} ; age 59 (31-76) years , 53 (28-80) years, BMI 21.8 (16.430.2), 21.6 (15.2-34.3), respectively. As we introduced hypo-fractionated radiotherapy in September 2010, we had 2 types of treatment schedules. The percentage of patients underwent the conventional one (50 Gy to the total breast + 0-10Gy boost for total of 5-6 weeks; 2Gy/fraction) and the hypo-fractionated one (43.2Gy to the total breast + 0-7.1G boost for total of 4 weeks; 2.7Gy/fraction) were 57% and 43% in the Ex and 56% and 44% in the nEx. Tangential field with 4MV X-ray was used and for the boost electron (6-10Mev, depend of the size of the breast) was used. The median exercise days per week and median duration time of each training in both groups were as follows: Ex; 3(2-7) days, 60 (20-180) minutes, nEx; 0 (0-7) days, 0 (0-240) minutes. The grade of acute skin toxicity of the two groups were as follows; Ex median 0 (0-2), nEx 1 (0-2). There was no higher than grade 2 acute skin toxicity. Grade 2 acute skin toxicity were observed in 1 of the Ex and 19 of the nEx (p=0.03). The patient with once a week 240 minute exercise was included in the nEx but did not showed a sever skin toxicity. However the patient with 10 minutes exercise every day, who was included into nEx, showed grade 2 skin toxicity. There were 2 patients who experience radiation pneumonitis. Both have not done any exercise during the radiotherapy period. The HAD (full score 18) of both group was as follows: anxiety; Ex 3 (0-8), nEx 5 (0-13) (p=0.04), depression Ex 2 (0-6), nEx 3 (0-18) (p=0.02). Conclusion: The patients of Ex group showed significantly lower rate of sever skin toxicity. Besides, their HAD scale for both anxiety and depression showed significantly lower scale. Exercise during the period of adjuvant radiotherapy for breast-conserving surgery has a possibility to be an effective method to prevent sever skin toxicity and in the same time relieve anxiety and depression in cancer patient. 61 EFFECTS OF EGFR-INHIBITION AND RADIOTHERAPY ON HYPOXIA, PROLIFERATION AND TUMOR GROWTH DELAY IN HUMAN TUMOR XENOGRAFTS H. Stegeman1, P. Span1, A.J. van der Kogel1, D. Wheeler2, J. Kaanders1, J. Bussink1 1 Department of Radiation Oncology, Radboud University Nijmegen MC, Nijmegen, The Netherlands 2 Department of Human Oncology, University of Wisconsin, School of Medicine and Public Health, USA Objective: The Epidermal Growth Factor Receptor (EGFR) and downstream signaling pathways are associated with major radiation resistance mechanisms, including hypoxia and proliferation. Inhibition of EGFR signaling improves the effect of radiotherapy significantly in head and neck cancer. However, a substantial proportion of these patients does not benefit from the addition of these new molecular targeted therapies. Identification of biological tumor characteristics that predict treatment response will
ICTR-PHE 2012 allow better selection of patients for these intensified treatments. Material and Methods: In search of predictive biological tumor characteristics, we treated four human larynx carcinoma xenograft lines (SCCNij), exhibiting distinct EGFR expression patterns, with radiotherapy (10 or 20 Gy), Cetuximab (C225, monoclonal antibody against EGFR), and concurrent C225 and radiotherapy treatment. Effects on tumor growth delay, hypoxia and proliferation were studied as well as proteins involved in the downstream signaling of the EGFR. Results: Concerning EGFR expression, we found SCCNij202>> SCCNij153 = SCCNij185>> SCCNij167. There was no correlation between EGFR and AKT activation (phospho-Akt) in these tumor lines. Using a growth delay assay, we observed that the tumor line with high EGFR expression (SCCNij202) was highly sensitive to C225, but showed only little growth delay in response to radiotherapy. In contrast, SCCNij167 tumors with low EGFR were resistant to C225 treatment, but particular radiosensitive. In both tumor lines no synergistic effect of C225 on radiosensitivity was observed. SSCNij185 and SCCNij153 tumors, with intermediate EGFR expression, were both insensitive to C225 alone, but showed opposing effects when C225 was combined with radiotherapy: no synergistic effect of C225 with radiotherapy in SCCNij153, while C225 strongly enhanced the effect of radiotherapy in SCCNij185. Molecular characterization of the tumor models by western blot suggested that expression of other growth factor receptors (including c-MET) in SCCNij153 tumors could be involved in this difference in response to C225 between the different tumor models. Additional immunohistochemical analyses were performed to study the effect of C225 and/or radiotherapy on hypoxia and proliferation. In SCCNij202, C225 decreased both hypoxia and proliferation. However, a single dose of radiotherapy alone (10 Gy) did not affect these parameters. On the other hand, radiotherapy caused a clear decrease in proliferation in SCCNij167 tumors. Both these treatment effects correspond to the results obtained in the tumor growth delay assay. Conclusions: We identified 4 xenograft models with distinct EGFR expression patterns, and diverse response patterns to treatment with EGFR-inhibition and/or radiotherapy. Differences in basal expression of growth factor receptors and the effects on hypoxia and proliferation correlate with response to treatment. Results of the effects of C225 and/or radiotherapy on hypoxia and proliferation in tumor lines with intermediate EGFR expression and effects on DNA repair, another radioresistance mechanism, will be presented. By studying multiple tumor models with similar origin and histology, we increase the understanding of the mechanisms involved in treatment response and provide a tool to improve patient selection and consequently treatment outcome. 62 TEST OF DIFFERENT PIXEL DETECTORS FOR LASER-DRIVEN ACCELERATED PARTICLE BEAMS S. Reinhardt1, C. Granja1, W. Assmann1, F. Krejci2 1 Ludwig-Maximilians University, München, Germany 2 Institute of Experimental and Applied Physics, Czech Technical University, Prague, Czech Republic
S22 Laser driven accelerated (LDA) particle beams have due to the unique acceleration process very special properties. In particular they are created in ultra-short bunches of high intensity typically up to 109 particles/cm2/ns. Characterization of these beams is very limited with conventional particle detectors especially with non-electronic detectors like radiochromic films, imaging plates or nuclear track detectors which are still broadly used at present. Moreover, all these detectors give only offline information about the particle pulse position and intensity as they require minutes to hours to be processed, calling for a new highly sensitive online device. Therefore, we are using pixel detectors for real time detection of LDA ion pulses. As each pixel represents a small detector unit in itself, only a small fraction of the whole beam will be detected by it and so problems due to detector saturation might be overcome by this new approach. Besides beam flux monitoring with high spatial and temporal resolution, additional knowledge about beam energy is also advantageous. Tests have been performed at the Munich 14MV Tandem accelerator in an 8-20 MeV proton beam in dc and pulsed irradiation mode, the latter simulating LDA-like ns ion pulses. For detection tests we chose the position-sensitive quantum-counting semiconductor pixel detector Timepix which also provides per-pixel energy- or time-sensitivity. Additionally other types of commercially available pixel detectors are being evaluated such as the RadEyeTM 1, a large area (25 x 50 mm2) CMOS image sensor based on a photodiode array in a matrix of 512 x 1024 pixels with 48 micron pixel pitch. All of these devices are able to resolve individual particles of the beam with high spatial- and energyresolution down to the level of μm and tens of keV, respectively. Various beam delivering parameters of the accelerator were thus evaluated and verified. The different readout modes of the Timepix detector which is operated with an integrated USB-based readout interface allow online visualization of single and timeintegrated events. Therefore Timepix offers the greatest potential in analyzing the beam parameters. This work is carried out in frame of the Medipix Collaboration and the Munich Centre for Advanced Photonics (MAP). 63 IN VIVO RADIOSENSITIZER EFFECT OF THE HDAC INHIBITOR S78454 ON ORTHOTOPIC HUMAN GLIOBLASTOMA. C. Toulas1, E. Cohen-Jonathan Moyal1, J. Martinez Gala1, C; Delmas1, H. Lelièvre2, A. Jacquet-Bescond3, L. Kraus-Berthier3, S. Depil3 1 INSERM U1037, ICR, Toulouse, France 2 Institut de Recherche International Servier, France 3 IRIS Glioblastoma is an aggressive primary brain tumor with poor outcome, despite a treatment associating surgery and radiotherapy combined with temozolomide. Recent data have shown an in vitro synergy of the HDAC inhibitor S78454 (also called PCI24781) with ionizing radiation, via inhibition of homologous recombinational (HR) repair of DNA double-strand breaks. We propose in this study to investigate the in vivo radiosensitizer effect of S78454
ICTR-PHE 2012 on human glioblastoma model. For this, we generated orthotopic U87 human glioblastoma xenografts in nude mice. Intra-peritoneal (i.p.) S 78454 treatment was performed daily starting 10 days after the engraftment. Irradiation was performed in one daily 2 Gy localized fraction during 4 days followed by a second similar 4 days treatment performed after 3 days off (for a total dose of 16 Gy administrated on 11 days). Survival experiments were conducted in mice bearing xenografts in the four different groups of treatment (vehicle, S 78454 alone, radiation alone, S 78454 + radiation). Mice bearing orthotopic xenografts were sacrificed at the onset of neurological signs. Survival curves were then performed. We first determined the S78454 dosing schedule to obtain a pharmacodynamic effect of the compound in the xenograft. Inhibition of RAD 51 expression, histone H3 and tubulin acetylation in the tumor were obtained 24 hours after daily i.p. treatment with 50mg/kg S78454. These results allowed us to define the schedule treatment combining S78454 with radiotherapy: mice were treated with S78454 50 mg/kg/d i.p., daily from Days 10 to14 and then from Days 17 to 21; one 2 Gy fraction radiotherapy was performed daily from Days 11 to14 and Days 18 to 21. In these conditions of treatment, S78454 was well tolerated Survival of the mice treated with S78454 alone was not significantly increased while the survival of the mice treated with irradiation alone was significantly increased compared to the control group (P<0.05). In contrast, the survival of the mice treated with the combined treatment was significantly increased compared to the group of animals treated with irradiation alone (P<0.05) and to the group treated with S78454 alone (P<0.01). Effect of S78454 on angiogenesis will be presented. Our results demonstrate that the HDAC inhibitor S78454 radiosensitizes human glioblastoma in vivo and strongly suggest that S78454 may be an interesting drug to combine with radiotherapy in clinical trials for patients with glioblastoma. 64 PET-CT IN CARDIO-VASCULAR DISEASES: EXPANDING THE FIELD OF NON-INVASIVE IMAGING D. Le Guludec1, F. Rouzet2 1 Hôpital Bichat, APHP and University P7, Paris, France 2 Hôpital Bichat and Inserm U 698, Paris, France We aim to focus on the clinical potential of PET/CT for the evaluation of cardiovascular diseases. Nuclear cardiology has mainly been based on the use of SPECT technology with accurate results for the evaluation of coronary artery disease (CAD) with stress and rest myocardial perfusion. Cardiac PET has only been performed with short-lived isotopes at centres with access to a cyclotron, and is not yet a routine clinical test in Europe. The marked increase of PET scanners together with the introduction of generator-produced 82 Rubidium may change the respective role of the two modalities. Quantitative assessment of regional myocardial blood flow (MBF) both at rest and during various forms of pharmacologic stress provides insight into early and subclinical abnormalities in coronary arterial vascular function and/or structure, extending the scope of conventional myocardial perfusion
ICTR-PHE 2012 allow better selection of patients for these intensified treatments. Material and Methods: In search of predictive biological tumor characteristics, we treated four human larynx carcinoma xenograft lines (SCCNij), exhibiting distinct EGFR expression patterns, with radiotherapy (10 or 20 Gy), Cetuximab (C225, monoclonal antibody against EGFR), and concurrent C225 and radiotherapy treatment. Effects on tumor growth delay, hypoxia and proliferation were studied as well as proteins involved in the downstream signaling of the EGFR. Results: Concerning EGFR expression, we found SCCNij202>> SCCNij153 = SCCNij185>> SCCNij167. There was no correlation between EGFR and AKT activation (phospho-Akt) in these tumor lines. Using a growth delay assay, we observed that the tumor line with high EGFR expression (SCCNij202) was highly sensitive to C225, but showed only little growth delay in response to radiotherapy. In contrast, SCCNij167 tumors with low EGFR were resistant to C225 treatment, but particular radiosensitive. In both tumor lines no synergistic effect of C225 on radiosensitivity was observed. SSCNij185 and SCCNij153 tumors, with intermediate EGFR expression, were both insensitive to C225 alone, but showed opposing effects when C225 was combined with radiotherapy: no synergistic effect of C225 with radiotherapy in SCCNij153, while C225 strongly enhanced the effect of radiotherapy in SCCNij185. Molecular characterization of the tumor models by western blot suggested that expression of other growth factor receptors (including c-MET) in SCCNij153 tumors could be involved in this difference in response to C225 between the different tumor models. Additional immunohistochemical analyses were performed to study the effect of C225 and/or radiotherapy on hypoxia and proliferation. In SCCNij202, C225 decreased both hypoxia and proliferation. However, a single dose of radiotherapy alone (10 Gy) did not affect these parameters. On the other hand, radiotherapy caused a clear decrease in proliferation in SCCNij167 tumors. Both these treatment effects correspond to the results obtained in the tumor growth delay assay. Conclusions: We identified 4 xenograft models with distinct EGFR expression patterns, and diverse response patterns to treatment with EGFR-inhibition and/or radiotherapy. Differences in basal expression of growth factor receptors and the effects on hypoxia and proliferation correlate with response to treatment. Results of the effects of C225 and/or radiotherapy on hypoxia and proliferation in tumor lines with intermediate EGFR expression and effects on DNA repair, another radioresistance mechanism, will be presented. By studying multiple tumor models with similar origin and histology, we increase the understanding of the mechanisms involved in treatment response and provide a tool to improve patient selection and consequently treatment outcome. 62 TEST OF DIFFERENT PIXEL DETECTORS FOR LASER-DRIVEN ACCELERATED PARTICLE BEAMS S. Reinhardt1, C. Granja1, W. Assmann1, F. Krejci2 1 Ludwig-Maximilians University, München, Germany 2 Institute of Experimental and Applied Physics, Czech Technical University, Prague, Czech Republic
S22 Laser driven accelerated (LDA) particle beams have due to the unique acceleration process very special properties. In particular they are created in ultra-short bunches of high intensity typically up to 109 particles/cm2/ns. Characterization of these beams is very limited with conventional particle detectors especially with non-electronic detectors like radiochromic films, imaging plates or nuclear track detectors which are still broadly used at present. Moreover, all these detectors give only offline information about the particle pulse position and intensity as they require minutes to hours to be processed, calling for a new highly sensitive online device. Therefore, we are using pixel detectors for real time detection of LDA ion pulses. As each pixel represents a small detector unit in itself, only a small fraction of the whole beam will be detected by it and so problems due to detector saturation might be overcome by this new approach. Besides beam flux monitoring with high spatial and temporal resolution, additional knowledge about beam energy is also advantageous. Tests have been performed at the Munich 14MV Tandem accelerator in an 8-20 MeV proton beam in dc and pulsed irradiation mode, the latter simulating LDA-like ns ion pulses. For detection tests we chose the position-sensitive quantum-counting semiconductor pixel detector Timepix which also provides per-pixel energy- or time-sensitivity. Additionally other types of commercially available pixel detectors are being evaluated such as the RadEyeTM 1, a large area (25 x 50 mm2) CMOS image sensor based on a photodiode array in a matrix of 512 x 1024 pixels with 48 micron pixel pitch. All of these devices are able to resolve individual particles of the beam with high spatial- and energyresolution down to the level of μm and tens of keV, respectively. Various beam delivering parameters of the accelerator were thus evaluated and verified. The different readout modes of the Timepix detector which is operated with an integrated USB-based readout interface allow online visualization of single and timeintegrated events. Therefore Timepix offers the greatest potential in analyzing the beam parameters. This work is carried out in frame of the Medipix Collaboration and the Munich Centre for Advanced Photonics (MAP). 63 IN VIVO RADIOSENSITIZER EFFECT OF THE HDAC INHIBITOR S78454 ON ORTHOTOPIC HUMAN GLIOBLASTOMA. C. Toulas1, E. Cohen-Jonathan Moyal1, J. Martinez Gala1, C; Delmas1, H. Lelièvre2, A. Jacquet-Bescond3, L. Kraus-Berthier3, S. Depil3 1 INSERM U1037, ICR, Toulouse, France 2 Institut de Recherche International Servier, France 3 IRIS Glioblastoma is an aggressive primary brain tumor with poor outcome, despite a treatment associating surgery and radiotherapy combined with temozolomide. Recent data have shown an in vitro synergy of the HDAC inhibitor S78454 (also called PCI24781) with ionizing radiation, via inhibition of homologous recombinational (HR) repair of DNA double-strand breaks. We propose in this study to investigate the in vivo radiosensitizer effect of S78454
ICTR-PHE 2012 on human glioblastoma model. For this, we generated orthotopic U87 human glioblastoma xenografts in nude mice. Intra-peritoneal (i.p.) S 78454 treatment was performed daily starting 10 days after the engraftment. Irradiation was performed in one daily 2 Gy localized fraction during 4 days followed by a second similar 4 days treatment performed after 3 days off (for a total dose of 16 Gy administrated on 11 days). Survival experiments were conducted in mice bearing xenografts in the four different groups of treatment (vehicle, S 78454 alone, radiation alone, S 78454 + radiation). Mice bearing orthotopic xenografts were sacrificed at the onset of neurological signs. Survival curves were then performed. We first determined the S78454 dosing schedule to obtain a pharmacodynamic effect of the compound in the xenograft. Inhibition of RAD 51 expression, histone H3 and tubulin acetylation in the tumor were obtained 24 hours after daily i.p. treatment with 50mg/kg S78454. These results allowed us to define the schedule treatment combining S78454 with radiotherapy: mice were treated with S78454 50 mg/kg/d i.p., daily from Days 10 to14 and then from Days 17 to 21; one 2 Gy fraction radiotherapy was performed daily from Days 11 to14 and Days 18 to 21. In these conditions of treatment, S78454 was well tolerated Survival of the mice treated with S78454 alone was not significantly increased while the survival of the mice treated with irradiation alone was significantly increased compared to the control group (P<0.05). In contrast, the survival of the mice treated with the combined treatment was significantly increased compared to the group of animals treated with irradiation alone (P<0.05) and to the group treated with S78454 alone (P<0.01). Effect of S78454 on angiogenesis will be presented. Our results demonstrate that the HDAC inhibitor S78454 radiosensitizes human glioblastoma in vivo and strongly suggest that S78454 may be an interesting drug to combine with radiotherapy in clinical trials for patients with glioblastoma. 64 PET-CT IN CARDIO-VASCULAR DISEASES: EXPANDING THE FIELD OF NON-INVASIVE IMAGING D. Le Guludec1, F. Rouzet2 1 Hôpital Bichat, APHP and University P7, Paris, France 2 Hôpital Bichat and Inserm U 698, Paris, France We aim to focus on the clinical potential of PET/CT for the evaluation of cardiovascular diseases. Nuclear cardiology has mainly been based on the use of SPECT technology with accurate results for the evaluation of coronary artery disease (CAD) with stress and rest myocardial perfusion. Cardiac PET has only been performed with short-lived isotopes at centres with access to a cyclotron, and is not yet a routine clinical test in Europe. The marked increase of PET scanners together with the introduction of generator-produced 82 Rubidium may change the respective role of the two modalities. Quantitative assessment of regional myocardial blood flow (MBF) both at rest and during various forms of pharmacologic stress provides insight into early and subclinical abnormalities in coronary arterial vascular function and/or structure, extending the scope of conventional myocardial perfusion