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188: Hpv Status and Effect on Radiosensitivity in Head and Neck Cancer Tumor Xenografts
S92
ICTR-PHE – 2014
(a)
Figure 1. CBCT image with simulated motion and motion compensated reconstruction Conclusions: The motion-compensated CGLS was applied to dual modality of CBCT/EIT, which uses the motion signal extracted from EIT images to compensate in CBCT image reconstruction. The results showed that the motion signal extracted from EIT images could be used to compensate the motion artefact in CBCT image reconstruction by using proposed motion-compensated CGLS algorithm. Keywords: Electrical impedance tomography, lung radiation therapy, cone beam CT 187 Different detector concepts for several imaging scenarios: from hadrontherapy monitoring to clinical imaging P. Solevi1, J. Barrio1, J. Cabello1,2, J. Gillam1,3, C. Lacasta1, G. Llosá1, J. F. Oliver1, M. Rafecas1, C. Solaz1, I. TorresEspallardo1, M. Trovato1 1 IFIC (CSIC/UV), Valencia, Spain 2 Klinikum rechts der Isar der Technischen Universität München, Germany 3 Brain & Mind Research Institute, University of Sidney, Australia Purpose: Emission Tomography (ET) covers a wide number of applications, from the standard clinical imaging to the more recent Hadrontherapy (HT) treatment monitoring. For all aforementioned applications different trends in detector have geen explored, attempting at find the optimal one. We present a comprehensive study of conventional and novel detector concepts crytal based, employed for Positron Emission Tomography (PET) and Single Photon Imaging, mostly developed within the ENVISION network. Defining the detector of choice over a wide dynamic range is one of the main objectives of the presented work. Materials and methods: ET employs crystal based detectors given their capability to merge high detection efficiency, good energy and spatial resolution with fast timing. We compare monolithic crystal detectors an LaBr3 crysta block read out by a Silicon Photo-Multipliers matrix and AS-PET, a novel detector with axially oriented crystals. The latter is based on individually read out LYSO crystals, 10 cm long, axially arranged. Both systems have been experimentally validated and extensively studied at simulation level by means of dedicated Geant4 and GATE Monte Carlo, for different applications, further optimizing the geometry and readout. HT monitoring requires special detector arrangement and acquisition, in order to minimize the background mostly due to nuclei fragments and gammas uncorrelated with the original hadron path in the patient. Some of the geometries and systems investigated are shown in Fig. 1 ((a) to (c) for the monolithic crystal, (d) and (e) for the AX-PET system).
(b)
(c)
(d)
(e)
(f)
Results: Different sources are simulated in order to evaluate the systems capability with respect to different scenarios: mono-energetic hadron beams (as in Fig.1, (f)), more complex hadron treatment plans and linear sources for both 511 keV back-to-back gammas and single photons at different energies. The discretized geometry of AX-PET yields a large tracking capability of the photons within the detector matrix, partially lost in continuous crystals. Therefore it provides a larger sensitivity, important for both clinical and HT PET, and exhibits a potential for single photon detection. Still the individual crystal readout poses some limitations to the dynamic range of the detector, thus moving to higher energy prompt-gamma detection would imply further adjustments, feasible thanks to the flexible design. Monolithic crystals, with a concept pretty far from the highly granular AX-PET, still perform very well, offering a wider dynamic range. Both detectors provide a few millimeters spatial resolution in PET modality, in the hadron range determination too. Conclusions: Two very different detector concepts have been extensively studied and compared, the compact monolithic crystal and the highly granular AX-PET device. Both detectors perform well in the investigated applications, PET and Single Photon Imaging. Keywords: hadrontherapy, PET, Single Photon Imaging 188 Hpv Status and Effect on Radiosensitivity in Head and Neck Cancer Tumor Xenografts B.S. Sørensen1, M. Busk1, A. Minchinton2, A. Kyle2, M. Horsman1, J. Alsner1, J. Overgaard1 1 Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark 2 BC Cancer Research Centre, Department of Integrative Oncology, Vancouver, Canada Purpose: HPV associated Head and neck squamous cell carcinoma (HNSCC) represent a distinct subgroup of HNSCC characterized by a favourable prognosis and a distinct molecular biology. Previous data from the randomized DAHANCA 5 trial indicated HPV positive tumours did not benefit from hypoxic modifications by Nimorazole during radiotherapy, whereas a significant benefit was observed in the HPV negative tumours. However, more studies, have demonstrated equal frequencies of hypoxia amongst HPVpositive and HPV-negative tumours. We have in an in vitro study demonstrated that hypoxia lowers radiosensitivity in both HPV positive and HPV negative HNSCC cell lines and that sensitivity can be partly restored by Nimorazole treatment. However, HPV positive HNSCC cell lines shows significantly elevated inherent radiosensitivity compared to HPV negative cell lines. The aim of the study was to confirm that the demonstrated difference in radiosensitivity observed in vitro also applies to tumour xenografts grown from HPV positive and HPV negative HNSCC cells. Moreover, the aim was to identify and quantify differences in the microenvironment related to HPV-status. Methods: Tumor xenografts were established from HPV negative (FaDuDD, UTSCC33) and HPV positive (UD2 and UMSCC47) HNSCC cell lines. Tumors were treated with 10 Gy or 20 Gy and the effect on the tumour microenvironment was studied at different timepoints after treatment. Cryosections were imaged for
ICTR-PHE – 2014 factors such as apoptosis, necrosis, cell proliferation, hypoxia, vessel density and vessel perfusion. To assess the spatial distribution of hypoxia in response to the treatment in the different tumour models two hypoxia markers were used. EF5 was administered prior to treatment, whereas PIMO was injected at different time points after irradiation. Results: The HPV positive and HPV negative tumour xenografts displayed comparable pre-treatment levels in vessel density and hypoxic fraction. With the observed endpoints, HPV positive tumour xenografts were found to be more radiosensitive than HPV negative tumours. Conclusion: There is a range of unresolved questions regarding the different biology and clinical outcome of HPV positive HNSCC, the purpose of the present project was to obtain insight into the biology of treatment responsiveness of HPV-related HNSCC. The markedly higher radiosensitivity, which may account for the favourable clinical prognosis, previously found in vitro in HPV positive cells, was also observed in vivo in tumour xenografts in the present study. Keywords: HPV, HNSCC, Radiosensitivity 189 Nuclear techniques for studying soft matter at ISOLDE/CERN M. Stachura1, A. Gottberg1, L. Hemmingsen2, K. Hohnston3, M. Kowalska1 1 CERN, Geneva, Switzerland 2 University of Copenhagen, Denmark 3 University of Saarland, Germany Due to the complexity of “living systems” nuclear techniques are not commonly used in biology and biochemistry even though they offer powerful insights to local properties. The ISOLDE facility is, however, a perfect place to carry out experiments with Perturbed Angular Correlation of γ-rays (PAC) spectroscopy. This technique is suitable for addressing different biological problems, such as: heavy metal ion protein interaction, dynamics of protein folding or protein – protein interaction, providing information on the molecular and electronic structure at the metal site [1]. A short overview of recent ISOLDE studies on de novo designed peptides, natural proteins, plants and bacteria will be presented. Furthermore, recently a new avenue of research in the fields of wet chemistry and biochemistry has been opened at ISOLDE: β-NMR spectroscopy has been successfully applied in the first ever experiment on liquid samples. The method is over a billion times more sensitive than conventional NMR on liquids and thus may be applied to elements which are otherwise difficult to explore spectroscopically, such as Mg2+, Zn2+ or Cu+. The setup and the first β-NMR results of 31Mg implanted into an ionic liquid will be shown [2].
S93 Purpose: The qualitative positron emission tomography for the dose monitoring in ion beam therapy (PT-PET) has been approved for static tumors under clinical conditions. The detection of dose deviations is based on a comparison between the measured and an anticipated β+-activity distribution. Also for intra-fractionally moving targets, the 4D simulation [1] as well as the 4D reconstruction [2] of in-beam PET data has been established. Within dedicated experiments the results of the comparison between measured and anticipated activities were investigated with regard to the detection of failures in the motion mitigated ion beam delivery. Materials/methods: PMMA targets have been irradiated with 12 + -activity distributions were determined by in-beam PET measurements using the installed double-head scanner BASTEI [3]. The targets were periodically moved perpendicular to the incident ion beam direction. Motion mitigation by means of beam tracking or gating has been applied. In some measurements, failures in motion mitigation were induced systematically or by chance. The reconstructed activity distributions were compared to those measurements with static targets or with correct motion mitigation or to the anticipated distribution from a 4D simulation. Results: Failures in beam tracking are manifested in a lateral and distal broadening of the β+-activity distribution, but an algorithm for such an automatic quantitative evaluation is still missing. The breakdown of a gating sensor led partly to an irradiation without motion compensation. In such a case, an activity distribution with similar shape is anticipated by the 4D simulation (cf. figure 1). Only a deeper search in the simulation input data or a static target simulation could reveal the treatment error.
Keywords: PAC, NMR, soft matter References: [1] L. Hemmingsen et al., Chem. Rev. 2004, 104, 4027. [2] A. Gottberg et al., manuscript in preparation. 190 The (non-) detectability of failures in motion mitigated ion beam delivery by means of in-beam PET K. Stützer1, W. Enghardt1, M. Priegnitz2, C. Bert3, N. Saito3, K. Parodi4, F. Fiedler2 1 OncoRay – National Center for Radiation Research in Oncology, Dresden, Germany 2 Helmholtz-Zentrum Dresden-Rossendorf, Germany 3 GSI Helmhotzzentrum für Schwerionenforschung Darmstadt and University Hospital Erlangen, Germany 4 Heidelberg University Clinics and LMU Munich, Germany
Figure 5. Bird’s eye view of the measured and the simulated activity distribution (a) within a target (dashed) irradiated with mono-energetic beams (impinging from the left). Motion mitigation (parallel y) was insufficient due to a gating breakdown. Profiles taken along the vertical lines show similar progression (b) which differs clearly from the symmetric profile gained from a static target simulation.
ICTR-PHE – 2014
(a)
Figure 1. CBCT image with simulated motion and motion compensated reconstruction Conclusions: The motion-compensated CGLS was applied to dual modality of CBCT/EIT, which uses the motion signal extracted from EIT images to compensate in CBCT image reconstruction. The results showed that the motion signal extracted from EIT images could be used to compensate the motion artefact in CBCT image reconstruction by using proposed motion-compensated CGLS algorithm. Keywords: Electrical impedance tomography, lung radiation therapy, cone beam CT 187 Different detector concepts for several imaging scenarios: from hadrontherapy monitoring to clinical imaging P. Solevi1, J. Barrio1, J. Cabello1,2, J. Gillam1,3, C. Lacasta1, G. Llosá1, J. F. Oliver1, M. Rafecas1, C. Solaz1, I. TorresEspallardo1, M. Trovato1 1 IFIC (CSIC/UV), Valencia, Spain 2 Klinikum rechts der Isar der Technischen Universität München, Germany 3 Brain & Mind Research Institute, University of Sidney, Australia Purpose: Emission Tomography (ET) covers a wide number of applications, from the standard clinical imaging to the more recent Hadrontherapy (HT) treatment monitoring. For all aforementioned applications different trends in detector have geen explored, attempting at find the optimal one. We present a comprehensive study of conventional and novel detector concepts crytal based, employed for Positron Emission Tomography (PET) and Single Photon Imaging, mostly developed within the ENVISION network. Defining the detector of choice over a wide dynamic range is one of the main objectives of the presented work. Materials and methods: ET employs crystal based detectors given their capability to merge high detection efficiency, good energy and spatial resolution with fast timing. We compare monolithic crystal detectors an LaBr3 crysta block read out by a Silicon Photo-Multipliers matrix and AS-PET, a novel detector with axially oriented crystals. The latter is based on individually read out LYSO crystals, 10 cm long, axially arranged. Both systems have been experimentally validated and extensively studied at simulation level by means of dedicated Geant4 and GATE Monte Carlo, for different applications, further optimizing the geometry and readout. HT monitoring requires special detector arrangement and acquisition, in order to minimize the background mostly due to nuclei fragments and gammas uncorrelated with the original hadron path in the patient. Some of the geometries and systems investigated are shown in Fig. 1 ((a) to (c) for the monolithic crystal, (d) and (e) for the AX-PET system).
(b)
(c)
(d)
(e)
(f)
Results: Different sources are simulated in order to evaluate the systems capability with respect to different scenarios: mono-energetic hadron beams (as in Fig.1, (f)), more complex hadron treatment plans and linear sources for both 511 keV back-to-back gammas and single photons at different energies. The discretized geometry of AX-PET yields a large tracking capability of the photons within the detector matrix, partially lost in continuous crystals. Therefore it provides a larger sensitivity, important for both clinical and HT PET, and exhibits a potential for single photon detection. Still the individual crystal readout poses some limitations to the dynamic range of the detector, thus moving to higher energy prompt-gamma detection would imply further adjustments, feasible thanks to the flexible design. Monolithic crystals, with a concept pretty far from the highly granular AX-PET, still perform very well, offering a wider dynamic range. Both detectors provide a few millimeters spatial resolution in PET modality, in the hadron range determination too. Conclusions: Two very different detector concepts have been extensively studied and compared, the compact monolithic crystal and the highly granular AX-PET device. Both detectors perform well in the investigated applications, PET and Single Photon Imaging. Keywords: hadrontherapy, PET, Single Photon Imaging 188 Hpv Status and Effect on Radiosensitivity in Head and Neck Cancer Tumor Xenografts B.S. Sørensen1, M. Busk1, A. Minchinton2, A. Kyle2, M. Horsman1, J. Alsner1, J. Overgaard1 1 Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark 2 BC Cancer Research Centre, Department of Integrative Oncology, Vancouver, Canada Purpose: HPV associated Head and neck squamous cell carcinoma (HNSCC) represent a distinct subgroup of HNSCC characterized by a favourable prognosis and a distinct molecular biology. Previous data from the randomized DAHANCA 5 trial indicated HPV positive tumours did not benefit from hypoxic modifications by Nimorazole during radiotherapy, whereas a significant benefit was observed in the HPV negative tumours. However, more studies, have demonstrated equal frequencies of hypoxia amongst HPVpositive and HPV-negative tumours. We have in an in vitro study demonstrated that hypoxia lowers radiosensitivity in both HPV positive and HPV negative HNSCC cell lines and that sensitivity can be partly restored by Nimorazole treatment. However, HPV positive HNSCC cell lines shows significantly elevated inherent radiosensitivity compared to HPV negative cell lines. The aim of the study was to confirm that the demonstrated difference in radiosensitivity observed in vitro also applies to tumour xenografts grown from HPV positive and HPV negative HNSCC cells. Moreover, the aim was to identify and quantify differences in the microenvironment related to HPV-status. Methods: Tumor xenografts were established from HPV negative (FaDuDD, UTSCC33) and HPV positive (UD2 and UMSCC47) HNSCC cell lines. Tumors were treated with 10 Gy or 20 Gy and the effect on the tumour microenvironment was studied at different timepoints after treatment. Cryosections were imaged for
ICTR-PHE – 2014 factors such as apoptosis, necrosis, cell proliferation, hypoxia, vessel density and vessel perfusion. To assess the spatial distribution of hypoxia in response to the treatment in the different tumour models two hypoxia markers were used. EF5 was administered prior to treatment, whereas PIMO was injected at different time points after irradiation. Results: The HPV positive and HPV negative tumour xenografts displayed comparable pre-treatment levels in vessel density and hypoxic fraction. With the observed endpoints, HPV positive tumour xenografts were found to be more radiosensitive than HPV negative tumours. Conclusion: There is a range of unresolved questions regarding the different biology and clinical outcome of HPV positive HNSCC, the purpose of the present project was to obtain insight into the biology of treatment responsiveness of HPV-related HNSCC. The markedly higher radiosensitivity, which may account for the favourable clinical prognosis, previously found in vitro in HPV positive cells, was also observed in vivo in tumour xenografts in the present study. Keywords: HPV, HNSCC, Radiosensitivity 189 Nuclear techniques for studying soft matter at ISOLDE/CERN M. Stachura1, A. Gottberg1, L. Hemmingsen2, K. Hohnston3, M. Kowalska1 1 CERN, Geneva, Switzerland 2 University of Copenhagen, Denmark 3 University of Saarland, Germany Due to the complexity of “living systems” nuclear techniques are not commonly used in biology and biochemistry even though they offer powerful insights to local properties. The ISOLDE facility is, however, a perfect place to carry out experiments with Perturbed Angular Correlation of γ-rays (PAC) spectroscopy. This technique is suitable for addressing different biological problems, such as: heavy metal ion protein interaction, dynamics of protein folding or protein – protein interaction, providing information on the molecular and electronic structure at the metal site [1]. A short overview of recent ISOLDE studies on de novo designed peptides, natural proteins, plants and bacteria will be presented. Furthermore, recently a new avenue of research in the fields of wet chemistry and biochemistry has been opened at ISOLDE: β-NMR spectroscopy has been successfully applied in the first ever experiment on liquid samples. The method is over a billion times more sensitive than conventional NMR on liquids and thus may be applied to elements which are otherwise difficult to explore spectroscopically, such as Mg2+, Zn2+ or Cu+. The setup and the first β-NMR results of 31Mg implanted into an ionic liquid will be shown [2].
S93 Purpose: The qualitative positron emission tomography for the dose monitoring in ion beam therapy (PT-PET) has been approved for static tumors under clinical conditions. The detection of dose deviations is based on a comparison between the measured and an anticipated β+-activity distribution. Also for intra-fractionally moving targets, the 4D simulation [1] as well as the 4D reconstruction [2] of in-beam PET data has been established. Within dedicated experiments the results of the comparison between measured and anticipated activities were investigated with regard to the detection of failures in the motion mitigated ion beam delivery. Materials/methods: PMMA targets have been irradiated with 12 + -activity distributions were determined by in-beam PET measurements using the installed double-head scanner BASTEI [3]. The targets were periodically moved perpendicular to the incident ion beam direction. Motion mitigation by means of beam tracking or gating has been applied. In some measurements, failures in motion mitigation were induced systematically or by chance. The reconstructed activity distributions were compared to those measurements with static targets or with correct motion mitigation or to the anticipated distribution from a 4D simulation. Results: Failures in beam tracking are manifested in a lateral and distal broadening of the β+-activity distribution, but an algorithm for such an automatic quantitative evaluation is still missing. The breakdown of a gating sensor led partly to an irradiation without motion compensation. In such a case, an activity distribution with similar shape is anticipated by the 4D simulation (cf. figure 1). Only a deeper search in the simulation input data or a static target simulation could reveal the treatment error.
Keywords: PAC, NMR, soft matter References: [1] L. Hemmingsen et al., Chem. Rev. 2004, 104, 4027. [2] A. Gottberg et al., manuscript in preparation. 190 The (non-) detectability of failures in motion mitigated ion beam delivery by means of in-beam PET K. Stützer1, W. Enghardt1, M. Priegnitz2, C. Bert3, N. Saito3, K. Parodi4, F. Fiedler2 1 OncoRay – National Center for Radiation Research in Oncology, Dresden, Germany 2 Helmholtz-Zentrum Dresden-Rossendorf, Germany 3 GSI Helmhotzzentrum für Schwerionenforschung Darmstadt and University Hospital Erlangen, Germany 4 Heidelberg University Clinics and LMU Munich, Germany
Figure 5. Bird’s eye view of the measured and the simulated activity distribution (a) within a target (dashed) irradiated with mono-energetic beams (impinging from the left). Motion mitigation (parallel y) was insufficient due to a gating breakdown. Profiles taken along the vertical lines show similar progression (b) which differs clearly from the symmetric profile gained from a static target simulation.