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144 FUSION BETWEEN BONE MARROW AND INTESTINE STROMAL CELLS CONTRIBUTES TO INTESTINE FIBROSIS AFTER RADIATION
S66 4. N. Arteaga-Marrero et al., Nucl. Instr. Meth. B 263 (2007) 523. 143 A POTENTIAL BEAM DELIVERY SYSTEM FOR RADIOTHERAPY WITH LASER-DRIVEN PROTON AND ION BEAMS J. Wilkens, S. Schell Dept. of Radiation Oncology, Klinikum rechts der Isar, München, Germany Laser-plasma acceleration of charged particles might in the future provide a compact and cost-efficient particle source for radiation therapy with protons and carbon ions. Currently, this technology is in a very early phase and major advancements (e.g. in terms of the achievable energies and repetition rates) are required before clinical applications for cancer treatment can be considered. In addition, laser-driven particle beams exhibit certain properties that are quite different from conventionally accelerated, monoenergetic beams: Laser-driven beams typically have a much broader energy spectrum and consequently a much broader depth dose curve without a sharp Bragg peak. Instead, the dose is spread over a larger axial area and laserdriven beams cannot be used in all parts of the target volume without further modifications. Furthermore, the time structure of laser-driven beams is different, since each laser shot accelerates a particle bunch that contains a certain amount of particles which cannot be split up into smaller units with active components like scanning magnets. Additionally, the number of these bunches is limited by the repetition rate of the laser. Simply trying to reproduce the exact properties of conventionally accelerated particle beams with laserbased technology is inefficient in terms of particle numbers and secondary radiation. Therefore, new beam delivery methods for radiation therapy with laser-driven particles are required that are adapted to the special properties of these beams.
Fig. 1 shows an outline of a dedicated beam delivery system that can transport, monitor and modify a laserdriven beam for therapeutic applications. The main components are an energy selection system, a particle selection system and a fluence selection system. The energy selection system addresses modifications of the energy spectrum by magnetic fields and adjustable apertures, which can be set to any desired transmission window. If the energy selection system is equipped with an additional scattering device to modify the number of transmitted particles per energy bin, spreadout Bragg peaks can be created with single laser shots. In order to separate different ion species, which may be present simultaneously in the laser-driven beam,
ICTR-PHE 2012 additional electric fields can act as a particle selection system. If the number of particles generated by a single laser shot is higher than necessary for the irradiation of a certain voxel within the target volume, a passive fluence selection system is required to remove a certain portion of particles from a single bunch. This can be realized by a scattering foil that broadens the beam laterally and a subsequent aperture (or multileaf collimator) that blocks the outer parts of the broadened beam. Further elements of the beam delivery system are detectors for online and offline monitoring of the beam properties as well as means for lateral field definition (either utilizing the multileaf collimator described above, or a magnetic scanning system operating between laser shots, or by well defined movements of the full treatment head including the laser-plasma interaction site). Since the initially generated particle beam has a certain angular distribution, beam focussing elements (like quadrupole doublets) are a critical component. The proposed beamline elements as well as their interactions are being investigated in terms of applicability and efficiency for broad energy spectra and pulsed beams. The beamline is complemented by dedicated treatment planning strategies that make the most efficient use of the available degrees of freedom, e.g. by using broader spectra where possible and by reducing the required number of laser shots as part of the treatment plan optimization process. Further refinements of the proposed concepts will be necessary before laser-driven particle beams can be applied in clinical practice. Supported by DFG Cluster of Excellence: MunichCentre for Advanced Photonics. 144 FUSION BETWEEN BONE MARROW AND INTESTINE STROMAL CELLS CONTRIBUTES TO INTESTINE FIBROSIS AFTER RADIATION H.J. Ch’ang, Y.-H. Chang, L.-M. Lin National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan Purpose: Bone marrow (BM) cells could repopulate damaged tissue and contribute to repair in nonhematopoietic tissues. Our previous observations demonstrated that the mitigating effect to acute repair of intestine was achieved through paracrine mediators released by BM cells. Maximal appearance of BM cells within lamina propria, however, occurred long after intestine mucosa recovered from radiation damage. Recent studies revealed cell fusion between BM and somatic cells were enhanced by chronic inflammation. There was a significant role of BM cells in triggering fibrotic responses and contribute to liver and renal fibrosis. We would like to explore the association between cell fusion and fibrosis within a murine model of whole body irradiation (WBI) and BM transplantation (BMT). Materials and Methods: Using gender-mismatched BM transplantation (BMT) and BMT from green fluorescence transgenic mice donors, we quantified and characterized the fusion phenomenon within intestine of mice after irradiation. The proliferating index was evaluated within intestine and in co-culture system of mouse BM and human intestine stroma cells. By using pravastatin, an HMG Co-A reductase
S67 inhibitor, to block fibrosis in mice after WBI, we evaluated the proliferation and fusion phenomenon by histology and biochemical test. The fusion ratio, fusion signaling proteins (macrophage fusion receptor and CD47) and fibrosis markers (CCN2, fibronectin, collagen) were examined. Fibrosis score within intestine and mucosa lysates of mice after WBI+BMT were evaluated after Clodronate liposome to deplete macrophage/myelomonocytic cells. Results: Most BM cells fused with intestine stromal cells after BMT to mice after WBI. BM derived macrophage/myelomonocytic cells contributed mostly to the fusion phenomenon. Proliferation index within intestine increased maximally at 6 weeks after WBI+BMT when BM derived cells within lamina propria reached a plateau. The maximal fusion phenomenon occurred before significant level of fibrosis appeared within intestine of mice after WBI+BMT. Intestine mucosa lysates from mice receiving clodronate after WBI and BMT revealed decreased cell fusion and fibrosis in histology as well as in biochemical examination. Pravastatin suppressed the cell fusion protein expression, fusion phenomenon and the proliferation index within fused cells. Conclusions: BM derived macrophage/myelomonocytic cells fuse with intestine stromal cells and induce proliferation of BM derived cells within lamina propria of intestine. The fusion phenomenon is associated with chronic intestine fibrosis after radiation. Intestine fibrosis may be ameliorated by depleting macrophage/myelomonocytic cells. The fusion phenomenon can be diminished by antifibrosis strategy. Fusion between BM and intestine stromal cells contributes to chronic intestine fibrosis. 145 RECTAL TOXICITY 6 YEARS AFTER HIGH-DOSE RADIATION FOR PROSTATE CANCER: CLINICAL AND DOSIMETRIC PREDICTORS T. Rancati1, G. Fellin2, C. Fiorino3, V. Vavassori4, E. Cagna5, G. Girelli6, F. Mauro7, G. Maliverni8, V. Riccardo1 1 Fondazione IRCCS - Istituto dei Tumori, Milan, Italy 2 Ospedale Santa Chiara, Trento, Italy 3 Istituto Scientifico San Raffaele, Milano, Italy 4 Humanitas – Gavazzeni, Bergamo, Italy 5 Ospedale Sant’Anna, Como, Italy 6 Ospedale ASL 9, Ivrea, Italy 7 Ospedale Villa Maria Cecilia, Lugo, Italy 8 Ospedale Mauriziano, Torino, Italy Purpose: To evaluate the prevalence of late rectal bleeding (lrb) and of late fecal incontinence (linc) after high-dose radiotherapy (RT) in prostate cancer patients (pts) accrued in AIROPROS 0102 trial (RT doses: 7080Gy, 1.8-2Gy/fr) and to model the relationship between lrb/linc and clinical/dosimetric factors. Materials/Methods: Self-reported questionnaires of 515 pts with a minimum follow up of 6 yrs were analyzed with respect to lbr and linc. G1 lrb was defined as lrb less than 2 times/week, G2 if lrb more than twice/week, G3 if daily lrb is present or if any number of blood transfusion and/or laser coagulation was necessary. G1 linc was scored if unintentional stool discharge was ”sometimes” experienced, G2 linc if unintentional stool discharge was ”often” experienced or if pts sporadically used sanitary pads; G3 if pts
ICTR-PHE 2012 reported daily unintentional stool discharge or use of sanitary pad >2 times/week. The correlation between pre-treatment morbidities, hormonal therapy, drug prescription, presence of diabetes or hypertension, abdominal surgery prior to RT, presence of RTOG greater than 1 toxicity, presence of G2-G3 acute fecal incontinence, pelvic nodes and seminal vesicles irradiation, mean rectal dose, dose-volume histograms constraints (from V20Gy to V75Gy) and lrb/linc was investigated by uni- and multivariate (MVA) logistic analyses. 347/515 pts had at least 3 toxicity questionnaires in the first 36 mos after the end of RT. Correlation between the mean score of fecal incontinence in the first 36 mos and linc at 6 yrs was also investigated. Results: 32/515 G1, 2/515 G2 and 3/515 G3 lrb were registered. 50/515 G1, 3/515 G2 and 3/515 G3 linc were reported. Lrb was only correlate to V75Gy (continuous variable): p=0.02, OR=1.07. The prevalence of lrbí1 at 6 yrs was significantly correlated with incidence of G2-G3 lrb in the first 3 yrs after RT treatment: 42.3% in pts with G2-G3 bleeding in the first 3 yrs vs 5.6% in non-lrb pts (p<0.0001, chi-squared). Linc was correlated to multiple variables. In MVA, V40Gy (continuous variable, p=0.09, OR=1.015), use of antihypertensives (protective factors, p=0.005, OR=0.38), presence of abdominal surgery before RT (p=0.004, OR=4.7), presence of haemorrhoids (p=0.008, OR=2.6) and presence of G2-G3 acute incontinence (p=0.007, OR=4.4) resulted to be correlated to linc. The figure shows the nomogram which was developed starting from MVA results. In the nomogram V40Gy was inserted as a binary variables, with a cutoff=80% (p=0.05, OR=1.92). Linc at 6 yrs was also correlated to the mean incontinence scores in the first 36 mos (p<0.0001): pts without linc at 6 yrs had a mean score of 0.1 during the first 36 mos, while pts with G1 and with G2-G3 linc at 6 yrs had a mean score of 0.5 and 0.78 during the first 36 mos, respectively. The prevalence of lincí1 at 6 yrs was significantly correlated with the mean incontinence scores in the first 3 yrs after RT treatment: 37.3% in pts with mean score í0.5 vs 10% in pts with mean score < 0.5 (p<0.0001, chi-squared). Conclusions: A fraction of pts is still experiencing rectal toxicity symptoms 6 yrs after RT: 7.2% lrb and 10.9% linc. Prevalence of toxicity at 6 yrs is significantly correlated to incidence in the first 3 yrs after RT treatment, this is an indication of a chronicization of symptoms, with late fecal incontinence playing the major role. Mean score for incontinence during the first 36 mos after RT can be used as a surrogate endpoint for late (>6yrs) fecal incontinence. A nomogram for linc prediction at 6 yrs was development. Linc is correlated to clinical and dosimetric risk factors and individualised toxicity prediction can be performed through the proposed nomogram.
Fig. 1 shows an outline of a dedicated beam delivery system that can transport, monitor and modify a laserdriven beam for therapeutic applications. The main components are an energy selection system, a particle selection system and a fluence selection system. The energy selection system addresses modifications of the energy spectrum by magnetic fields and adjustable apertures, which can be set to any desired transmission window. If the energy selection system is equipped with an additional scattering device to modify the number of transmitted particles per energy bin, spreadout Bragg peaks can be created with single laser shots. In order to separate different ion species, which may be present simultaneously in the laser-driven beam,
ICTR-PHE 2012 additional electric fields can act as a particle selection system. If the number of particles generated by a single laser shot is higher than necessary for the irradiation of a certain voxel within the target volume, a passive fluence selection system is required to remove a certain portion of particles from a single bunch. This can be realized by a scattering foil that broadens the beam laterally and a subsequent aperture (or multileaf collimator) that blocks the outer parts of the broadened beam. Further elements of the beam delivery system are detectors for online and offline monitoring of the beam properties as well as means for lateral field definition (either utilizing the multileaf collimator described above, or a magnetic scanning system operating between laser shots, or by well defined movements of the full treatment head including the laser-plasma interaction site). Since the initially generated particle beam has a certain angular distribution, beam focussing elements (like quadrupole doublets) are a critical component. The proposed beamline elements as well as their interactions are being investigated in terms of applicability and efficiency for broad energy spectra and pulsed beams. The beamline is complemented by dedicated treatment planning strategies that make the most efficient use of the available degrees of freedom, e.g. by using broader spectra where possible and by reducing the required number of laser shots as part of the treatment plan optimization process. Further refinements of the proposed concepts will be necessary before laser-driven particle beams can be applied in clinical practice. Supported by DFG Cluster of Excellence: MunichCentre for Advanced Photonics. 144 FUSION BETWEEN BONE MARROW AND INTESTINE STROMAL CELLS CONTRIBUTES TO INTESTINE FIBROSIS AFTER RADIATION H.J. Ch’ang, Y.-H. Chang, L.-M. Lin National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan Purpose: Bone marrow (BM) cells could repopulate damaged tissue and contribute to repair in nonhematopoietic tissues. Our previous observations demonstrated that the mitigating effect to acute repair of intestine was achieved through paracrine mediators released by BM cells. Maximal appearance of BM cells within lamina propria, however, occurred long after intestine mucosa recovered from radiation damage. Recent studies revealed cell fusion between BM and somatic cells were enhanced by chronic inflammation. There was a significant role of BM cells in triggering fibrotic responses and contribute to liver and renal fibrosis. We would like to explore the association between cell fusion and fibrosis within a murine model of whole body irradiation (WBI) and BM transplantation (BMT). Materials and Methods: Using gender-mismatched BM transplantation (BMT) and BMT from green fluorescence transgenic mice donors, we quantified and characterized the fusion phenomenon within intestine of mice after irradiation. The proliferating index was evaluated within intestine and in co-culture system of mouse BM and human intestine stroma cells. By using pravastatin, an HMG Co-A reductase
S67 inhibitor, to block fibrosis in mice after WBI, we evaluated the proliferation and fusion phenomenon by histology and biochemical test. The fusion ratio, fusion signaling proteins (macrophage fusion receptor and CD47) and fibrosis markers (CCN2, fibronectin, collagen) were examined. Fibrosis score within intestine and mucosa lysates of mice after WBI+BMT were evaluated after Clodronate liposome to deplete macrophage/myelomonocytic cells. Results: Most BM cells fused with intestine stromal cells after BMT to mice after WBI. BM derived macrophage/myelomonocytic cells contributed mostly to the fusion phenomenon. Proliferation index within intestine increased maximally at 6 weeks after WBI+BMT when BM derived cells within lamina propria reached a plateau. The maximal fusion phenomenon occurred before significant level of fibrosis appeared within intestine of mice after WBI+BMT. Intestine mucosa lysates from mice receiving clodronate after WBI and BMT revealed decreased cell fusion and fibrosis in histology as well as in biochemical examination. Pravastatin suppressed the cell fusion protein expression, fusion phenomenon and the proliferation index within fused cells. Conclusions: BM derived macrophage/myelomonocytic cells fuse with intestine stromal cells and induce proliferation of BM derived cells within lamina propria of intestine. The fusion phenomenon is associated with chronic intestine fibrosis after radiation. Intestine fibrosis may be ameliorated by depleting macrophage/myelomonocytic cells. The fusion phenomenon can be diminished by antifibrosis strategy. Fusion between BM and intestine stromal cells contributes to chronic intestine fibrosis. 145 RECTAL TOXICITY 6 YEARS AFTER HIGH-DOSE RADIATION FOR PROSTATE CANCER: CLINICAL AND DOSIMETRIC PREDICTORS T. Rancati1, G. Fellin2, C. Fiorino3, V. Vavassori4, E. Cagna5, G. Girelli6, F. Mauro7, G. Maliverni8, V. Riccardo1 1 Fondazione IRCCS - Istituto dei Tumori, Milan, Italy 2 Ospedale Santa Chiara, Trento, Italy 3 Istituto Scientifico San Raffaele, Milano, Italy 4 Humanitas – Gavazzeni, Bergamo, Italy 5 Ospedale Sant’Anna, Como, Italy 6 Ospedale ASL 9, Ivrea, Italy 7 Ospedale Villa Maria Cecilia, Lugo, Italy 8 Ospedale Mauriziano, Torino, Italy Purpose: To evaluate the prevalence of late rectal bleeding (lrb) and of late fecal incontinence (linc) after high-dose radiotherapy (RT) in prostate cancer patients (pts) accrued in AIROPROS 0102 trial (RT doses: 7080Gy, 1.8-2Gy/fr) and to model the relationship between lrb/linc and clinical/dosimetric factors. Materials/Methods: Self-reported questionnaires of 515 pts with a minimum follow up of 6 yrs were analyzed with respect to lbr and linc. G1 lrb was defined as lrb less than 2 times/week, G2 if lrb more than twice/week, G3 if daily lrb is present or if any number of blood transfusion and/or laser coagulation was necessary. G1 linc was scored if unintentional stool discharge was ”sometimes” experienced, G2 linc if unintentional stool discharge was ”often” experienced or if pts sporadically used sanitary pads; G3 if pts
ICTR-PHE 2012 reported daily unintentional stool discharge or use of sanitary pad >2 times/week. The correlation between pre-treatment morbidities, hormonal therapy, drug prescription, presence of diabetes or hypertension, abdominal surgery prior to RT, presence of RTOG greater than 1 toxicity, presence of G2-G3 acute fecal incontinence, pelvic nodes and seminal vesicles irradiation, mean rectal dose, dose-volume histograms constraints (from V20Gy to V75Gy) and lrb/linc was investigated by uni- and multivariate (MVA) logistic analyses. 347/515 pts had at least 3 toxicity questionnaires in the first 36 mos after the end of RT. Correlation between the mean score of fecal incontinence in the first 36 mos and linc at 6 yrs was also investigated. Results: 32/515 G1, 2/515 G2 and 3/515 G3 lrb were registered. 50/515 G1, 3/515 G2 and 3/515 G3 linc were reported. Lrb was only correlate to V75Gy (continuous variable): p=0.02, OR=1.07. The prevalence of lrbí1 at 6 yrs was significantly correlated with incidence of G2-G3 lrb in the first 3 yrs after RT treatment: 42.3% in pts with G2-G3 bleeding in the first 3 yrs vs 5.6% in non-lrb pts (p<0.0001, chi-squared). Linc was correlated to multiple variables. In MVA, V40Gy (continuous variable, p=0.09, OR=1.015), use of antihypertensives (protective factors, p=0.005, OR=0.38), presence of abdominal surgery before RT (p=0.004, OR=4.7), presence of haemorrhoids (p=0.008, OR=2.6) and presence of G2-G3 acute incontinence (p=0.007, OR=4.4) resulted to be correlated to linc. The figure shows the nomogram which was developed starting from MVA results. In the nomogram V40Gy was inserted as a binary variables, with a cutoff=80% (p=0.05, OR=1.92). Linc at 6 yrs was also correlated to the mean incontinence scores in the first 36 mos (p<0.0001): pts without linc at 6 yrs had a mean score of 0.1 during the first 36 mos, while pts with G1 and with G2-G3 linc at 6 yrs had a mean score of 0.5 and 0.78 during the first 36 mos, respectively. The prevalence of lincí1 at 6 yrs was significantly correlated with the mean incontinence scores in the first 3 yrs after RT treatment: 37.3% in pts with mean score í0.5 vs 10% in pts with mean score < 0.5 (p<0.0001, chi-squared). Conclusions: A fraction of pts is still experiencing rectal toxicity symptoms 6 yrs after RT: 7.2% lrb and 10.9% linc. Prevalence of toxicity at 6 yrs is significantly correlated to incidence in the first 3 yrs after RT treatment, this is an indication of a chronicization of symptoms, with late fecal incontinence playing the major role. Mean score for incontinence during the first 36 mos after RT can be used as a surrogate endpoint for late (>6yrs) fecal incontinence. A nomogram for linc prediction at 6 yrs was development. Linc is correlated to clinical and dosimetric risk factors and individualised toxicity prediction can be performed through the proposed nomogram.