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At least 883 records · Page 49
All sourcesNASA NTRSDOE OSTI
DOE OSTI2011

Regional Nodal Involvement and Patterns of Spread Along In-Transit Pathways in Children With Rhabdomyosarcoma of the Extremity: A Report From the Children's Oncology Group;Rhabdomyosarcoma; Regional failure; In-transit nodes; Radiotherapy; Extremity

Purpose: To evaluate the incidence and prognostic factors for regional failure, with attention to the in-transit pathways of spread, in children with nonmetastatic rhabdomyosarcoma of the extremity. Methods and Materials: The Intergroup rhabdomyosarcoma studies III, IV-Pilot, and IV enrolled 226 children with rhabdomyosarcoma of the extremity. Failure at the in-transit (epitrochlear/brachial and popliteal) and proximal (axillary/infraclavicular and inguinal/femoral) lymph nodes was evaluated. The median follow-up for the surviving patients was 10.4 years. Results: Of the 226 children, 55 (24%) had clinical or pathologic evidence of either in-transit and/or proximal lymph node involvement at diagnosis. The actuarial 5-year risk of regional failure was 12%. The prognostic factors for poor regional control were female gender and lymph node involvement at diagnosis. In the 116 patients with a distal extremity primary tumor, 5% had in-transit lymph node involvement at diagnosis. The estimated 5-year incidences of in-transit and proximal nodal failure was 12% and 8%, respectively. The in-transit failure rate was 0% for patients who underwent radiotherapy and/or underwent lymph node sampling of the in-transit nodal site but was 15% for those who did not (p = .07). However, the 5-year event-free survival rate did not differ between these two groups (64% vs. 55%, respectively, p = .47). Conclusion: The high incidence of regional involvement necessitates aggressive identification and treatment of regional lymph nodes in patients with rhabdomyosarcoma of the extremity. In patients with distal extremity tumors, in-transit failures were as common as failures in more proximal regional sites. Patients who underwent complete lymph node staging with appropriate radiotherapy to the in-transit nodal site, if indicated, were at a slightly lower risk of in-transit failure.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Patterns of Utilization of Adjuvant Radiotherapy and Outcomes in Black Women After Breast Conservation at a Large Multidisciplinary Cancer Center;Black women; Breast cancer; Radiotherapy; RT; Breast conservation

Purpose: Population-based studies have reported that as many of 35% of black women do not undergo radiotherapy (RT) after breast conservation surgery (BCS). The objective of the present study was to determine whether this trend persisted at a large multidisciplinary cancer center, and to identify the factors that predict for noncompliance with RT and determine the outcomes for this subset of patients. Methods and Materials: Between January 2002 and December 2007, 83 black women underwent BCS at Memorial Sloan-Kettering Cancer Center and were therefore eligible for the present study. Of the 83 women, 38 (46%) had Stage I, 38 (46%) Stage II, and 7 (8%) Stage III disease. Of the study cohort, 31 (37%) had triple hormone receptor-negative tumors. RT was recommended for 81 (98%) of the 83 patients (median dose, 60 Gy). Results: Of the 81 women, 12 (15%) did not receive the recommended adjuvant breast RT. Nonreceipt of chemotherapy (p = .003) and older age (p = .009) were associated with nonreceipt of RT. With a median follow-up of 70 months, the 3-year local control, locoregional control, recurrence-free survival, disease-free survival, and overall survival rate was 99% (actuarial 5-year rate, 97%), 96% (actuarial 5-year rate, 93%), 95% (actuarial 5-year rate, 92%), 92% (actuarial 5-year rate, 89%), and 95% (actuarial 5-year rate, 91%), respectively. Conclusion: We found a greater rate of utilization adjuvant breast RT (85%) among black women after BCS than has been reported in recent studies, indicating that excellent outcomes are attainable for black women after BCS when care is administered in a multidisciplinary cancer center.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Pain and Mean Absorbed Dose to the Pubic Bone After Radiotherapy Among Gynecological Cancer Survivors

Purpose: To analyze the relationship between mean absorbed dose to the pubic bone after pelvic radiotherapy for gynecological cancer and occurrence of pubic bone pain among long-term survivors. Methods and Materials: In an unselected, population-based study, we identified 823 long-term gynecological cancer survivors treated with pelvic radiotherapy during 1991-2003. For comparison, we used a non-radiation-treated control population of 478 matched women from the Swedish Population Register. Pain, intensity of pain, and functional impairment due to pain in the pubic bone were assessed with a study-specific postal questionnaire. Results: We analyzed data from 650 survivors (participation rate 79%) with median follow-up of 6.3 years (range, 2.3-15.0 years) along with 344 control women (participation rate, 72 %). Ten percent of the survivors were treated with radiotherapy; ninety percent with surgery plus radiotherapy. Brachytherapy was added in 81%. Complete treatment records were recovered for 538/650 survivors, with dose distribution data including dose-volume histograms over the pubic bone. Pubic bone pain was reported by 73 survivors (11%); 59/517 (11%) had been exposed to mean absorbed external beam doses <52.5 Gy to the pubic bone and 5/12 (42%) to mean absorbed external beam doses {>=}52.5 Gy. Thirty-three survivors reported pain affecting sleep, a 13-fold increased prevalence compared with control women. Forty-nine survivors reported functional impairment measured as pain walking indoors, a 10-fold increased prevalence. Conclusions: Mean absorbed external beam dose above 52.5 Gy to the pubic bone increases the occurrence of pain in the pubic bone and may affect daily life of long-term survivors treated with radiotherapy for gynecological cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

Metronomic Small Molecule Inhibitor of Bcl-2 (TW-37) Is Antiangiogenic and Potentiates the Antitumor Effect of Ionizing Radiation

Purpose: To investigate the effect of a metronomic (low-dose, high-frequency) small-molecule inhibitor of Bcl-2 (TW-37) in combination with radiotherapy on microvascular endothelial cells in vitro and in tumor angiogenesis in vivo. Methods and Materials: Primary human dermal microvascular endothelial cells were exposed to ionizing radiation and/or TW-37 and colony formation, as well as capillary sprouting in three-dimensional collagen matrices, was evaluated. Xenografts vascularized with human blood vessels were engineered by cotransplantation of human squamous cell carcinoma cells (OSCC3) and human dermal microvascular endothelial cells seeded in highly porous biodegradable scaffolds into the subcutaneous space of immunodeficient mice. Mice were treated with metronomic TW-37 and/or radiation, and tumor growth was evaluated. Results: Low-dose TW-37 sensitized primary endothelial cells to radiation-induced inhibition of colony formation. Low-dose TW-37 or radiation partially inhibited endothelial cell sprout formation, and in combination, these therapies abrogated new sprouting. Combination of metronomic TW-37 and low-dose radiation inhibited tumor growth and resulted in significant increase in time to failure compared with controls, whereas single agents did not. Notably, histopathologic analysis revealed that tumors treated with TW-37 (with or without radiation) are more differentiated and showed more cohesive invasive fronts, which is consistent with less aggressive phenotype. Conclusions: These results demonstrate that metronomic TW-37 potentiates the antitumor effects of radiotherapy and suggest that patients with head and neck cancer might benefit from the combination of small molecule inhibitor of Bcl-2 and radiation therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

Post Treatment With an FGF Chimeric Growth Factor Enhances Epithelial Cell Proliferation to Improve Recovery From Radiation-Induced Intestinal Damage

Purpose: A fibroblast growth factor (FGF) 1-FGF2 chimera (FGFC) was created previously and showed greater structural stability than FGF1. This chimera was capable of stimulating epithelial cell proliferation much more strongly than FGF1 or FGF2 even without heparin. Therefore FGFC was expected to have greater biologic activity in vivo. This study evaluated and compared the protective activity of FGFC and FGF1 against radiation-induced intestinal injuries. Methods and Materials: We administered FGFC and FGF1 intraperitoneally to BALB/c mice 24 h before or after total-body irradiation (TBI). The numbers of surviving crypts were determined 3.5 days after TBI with gamma rays at doses ranging from 8 to 12 Gy. Results: The effect of FGFC was equal to or slightly superior to FGF1 with heparin. However, FGFC was significantly more effective in promoting crypt survival than FGF1 (p < 0.01) when 10 {mu}g of each FGF was administered without heparin before irradiation. In addition, FGFC was significantly more effective at promoting crypt survival (p < 0.05) than FGF1 even when administered without heparin at 24 h after TBI at 10, 11, or 12 Gy. We found that FGFC post treatment significantly promoted 5-bromo-2'-deoxyuridine incorporation into crypts and increased crypt depth, resulting in more epithelial differentiation. However, the number of apoptotic cells in FGFC-treated mice decreased to almost the same level as that in FGF1-treated mice. Conclusions: These findings suggest that FGFC strongly enhanced radioprotection with the induction of epithelial proliferation without exogenous heparin after irradiation and is useful in clinical applications for both the prevention and post treatment of radiation injuries.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
DOE OSTI2011

Assessment of Out-of-Field Doses in Radiotherapy of Brain Lesions in Children

Purpose: To characterize the out-of-field doses in pediatric radiotherapy and to identify simple methods by which out-of-field dose might be minimized, with a view to reducing the risk of secondary cancers. Methods and Materials: With the aim of characterizing the peripheral doses under different treatment conditions, the dose measurements in an anthropomorphic child phantom were taken in various organs and critical structures outside the primary field using thermoluminescent dosimetry. The doses from a Varian 600C and Varian Trilogy linear accelerator, both at 6 MV, were investigated. Results: Larger field sizes have been shown to result in greater peripheral doses close to the primary beam, with the difference becoming less significant at large distances, indicating that most of out-of-field doses result from head leakage and collimator scatter >40 cm from the primary field. The use of lead shields has been shown to reduce the absorbed dose resulting from leakage. Aligning the craniocaudal axis of the patient with the x-plane of the collimator resulted in a dose reduction of 40%, for both machines. Out-of-field doses from the Varian Trilogy were shown to be approximately 40% greater than those from the 600C linear accelerator, despite being operated at the same energy. Conclusion: Out-of-field doses to pediatric patients can be minimized by using simple treatment options, such as using the single-energy mode linear accelerator rather than the multimode, orienting the couch and collimator such that the patient lies along the x-plane and avoiding fields directed along the trunk of the body.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

Development of a Porcine Delayed Wound-Healing Model and Its Use in Testing a Novel Cell-Based Therapy

Purpose: A delayed full-thickness wound-healing model was developed and used for examining the capacity of adipose-derived stem cells (ASCs), either alone or in platelet-rich fibrin gels, to promote healing. Methods and Materials: Four pigs received electron beam radiation to the dorsal skin surface. Five weeks after radiation, subcutaneous fat was harvested from nonirradiated areas and processed to yield ASCs. Two weeks later, 28 to 30 full-thickness 1.5-cm{sup 2} wounds were made in irradiated and nonirradiated skin. Wounds were treated with either saline solution, ASCs in saline solution, platelet-rich plasma (PRP) fibrin gel, ASCs in PRP, or non-autologous green fluorescence protein-labeled ASCs. Results: The single radiation dose produced a significant loss of dermal microvasculature density (75%) by 7 weeks. There was a significant difference in the rate of healing between irradiated and nonirradiated skin treated with saline solution. The ASCs in PRP-treated wounds exhibited a significant 11.2% improvement in wound healing compared with saline solution. Enhancement was dependent on the combination of ASCs and PRP, because neither ASCs nor PRP alone had an effect. Conclusions: We have created a model that simulates the clinically relevant late radiation effects of delayed wound healing. Using this model, we showed that a combination of ASCs and PRP improves the healing rates of perfusion-depleted tissues, possibly through enhancing local levels of growth factors.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

Adenoviral E4orf3 and E4orf6 Proteins, But Not E1B55K, Increase Killing of Cancer Cells by Radiotherapy in vivo

Purpose: Radiotherapy is widely used for treatment of many tumor types, but it can damage normal tissues. It has been proposed that cancer cells can be selectively sensitized to radiation by adenovirus replication or by using radiosensitizing transgenes. Adenoviral proteins E1B55K, E4orf3, and E4orf6 play a role in radiosensitization, by targeting the Mre11, Rad50, and NBS1 complex (MRN) and inhibiting DNA double-strand break (DSB) repair. We hypothesize that combined with irradiation, these adenoviral proteins increase cell killing through the impairment of DSB repair. Methods and Materials: We assessed the radiosensitizing/additive potential of replication-deficient adenoviruses expressing E1B55K, E4orf3, and E4orf6 proteins. Combination treatments with low-dose external photon beam radiotherapy were studied in prostate cancer (PC-3MM2 and DU-145), breast cancer (M4A4-LM3), and head and neck cancer (UT-SCC8) cell lines. We further demonstrated radiosensitizing or additive effects in mice with PC-3MM2 tumors. Results: We show enhanced cell killing with adenovirus and radiation combination treatment. Co-infection with several of the viruses did not further increase cell killing, suggesting that both E4orf6 and E4orf3 are potent in MRN inhibition. Our results show that adenoviral proteins E4orf3 and E4orf6, but not E1B55K, are effective also in vivo. Enhanced cell killing was due to inhibition of DSB repair resulting in persistent double-strand DNA damage, indicated by elevated phospho-H2AX levels at 24 h after irradiation. Conclusions: This knowledge can be applied for improving the treatment of malignant tumors, such as prostate cancer, for development of more effective combination therapies and minimizing radiation doses and reducing side effects.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

Effect of Hyperoxygenation on Tissue pO{sub 2} and Its Effect on Radiotherapeutic Efficacy of Orthotopic F98 Gliomas

Purpose: Lack of methods for repeated assessment of tumor pO{sub 2} limits the ability to test and optimize hypoxia-modifying procedures being developed for clinical applications. We report repeated measurements of orthotopic F98 tumor pO{sub 2} and relate this to the effect of carbogen inhalation on tumor growth when combined with hypofractionated radiotherapy. Methods and Materials: Electron paramagnetic resonance (EPR) oximetry was used for repeated measurements of tumor and contralateral brain pO{sub 2} in rats during 30% O{sub 2} and carbogen inhalation for 5 consecutive days. The T{sub 1}-enhanced volumes and diffusion coefficients of the tumors were assessed by magnetic resonance imaging (MRI). The tumors were irradiated with 9.3 Gy x 4 fractions in rats breathing 30% O{sub 2} or carbogen to determine the effect on tumor growth. Results: The pretreatment F98 tumor pO{sub 2} varied between 8 and 16 mmHg, while the contralateral brain had 41 to 45 mmHg pO{sub 2} during repeated measurements. Carbogen breathing led to a significant increase in tumor and contralateral brain pO{sub 2}; however, this effect declined over days. Irradiation of the tumors in rats breathing carbogen resulted in a significant decrease in tumor growth and an increase in the diffusion coefficient measured by MRI. Conclusions: The results provide quantitative measurements of the effect of carbogen inhalation on intracerebral tumor pO{sub 2} and its effect on therapeutic outcome. Such direct repeated pO{sub 2} measurements by EPR oximetry can provide temporal information that could be used to improve therapeutic outcome by scheduling doses at times of improved tumor oxygenation. EPR oximetry is currently being tested for clinical applications.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

Preferential Effect of Synchrotron Microbeam Radiation Therapy on Intracerebral 9L Gliosarcoma Vascular Networks

Purpose: Synchrotron microbeam radiation therapy (MRT) relies on spatial fractionation of the incident photon beam into parallel micron-wide beams. Our aim was to analyze the effects of MRT on normal brain and 9L gliosarcoma tissues, particularly on blood vessels. Methods and Materials: Responses to MRT (two arrays, one lateral, one anteroposterior (2 x 400 Gy), intersecting orthogonally in the tumor region) were studied during 6 weeks using MRI, immunohistochemistry, and vascular endothelial growth factor Western blot. Results: MRT increased the median survival time of irradiated rats (x3.25), significantly increased blood vessel permeability, and inhibited tumor growth; a cytotoxic effect on 9L cells was detected 5 days after irradiation. Significant decreases in tumoral blood volume fraction and vessel diameter were measured from 8 days after irradiation, due to loss of endothelial cells in tumors as detected by immunochemistry. Edema was observed in the normal brain exposed to both crossfired arrays about 6 weeks after irradiation. This edema was associated with changes in blood vessel morphology and an overexpression of vascular endothelial growth factor. Conversely, vascular parameters and vessel morphology in brain regions exposed to one of the two arrays were not damaged, and there was no loss of vascular endothelia. Conclusions: We show for the first time that preferential damage of MRT to tumor vessels versus preservation of radioresistant normal brain vessels contributes to the efficient palliation of 9L gliosarcomas in rats. Molecular pathways of repair mechanisms in normal and tumoral vascular networks after MRT may be essential for the improvement of such differential effects on the vasculature.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Craniospinal Irradiation Techniques: A Dosimetric Comparison of Proton Beams With Standard and Advanced Photon Radiotherapy

Purpose: To evaluate the dosimetric benefits of advanced radiotherapy techniques for craniospinal irradiation in cancer in children. Methods and Materials: Craniospinal irradiation (CSI) using three-dimensional conformal radiotherapy (3D-CRT), tomotherapy (TOMO), and proton beam treatment (PBT) in the scattering mode was planned for each of 10 patients at our institution. Dosimetric benefits and organ-specific radiation-induced cancer risks were based on comparisons of dose-volume histograms (DVHs) and on the application of organ equivalent doses (OEDs), respectively. Results: When we analyzed the organ-at-risk volumes that received 30%, 60%, and 90% of the prescribed dose (PD), we found that PBT was superior to TOMO and 3D-CRT. On average, the doses delivered by PBT to the esophagus, stomach, liver, lung, pancreas, and kidney were 19.4 Gy, 0.6 Gy, 0.3 Gy, 2.5 Gy, 0.2 Gy, and 2.2 Gy for the PD of 36 Gy, respectively, which were significantly lower than the doses delivered by TOMO (22.9 Gy, 4.5 Gy, 6.1 Gy, 4.0 Gy, 13.3 Gy, and 4.9 Gy, respectively) and 3D-CRT (34.6 Gy, 3.6 Gy, 8.0 Gy, 4.6 Gy, 22.9 Gy, and 4.3 Gy, respectively). Although the average doses delivered by PBT to the chest and abdomen were significantly lower than those of 3D-CRT or TOMO, these differences were reduced in the head-and-neck region. OED calculations showed that the risk of secondary cancers in organs such as the stomach, lungs, thyroid, and pancreas was much higher when 3D-CRT or TOMO was used than when PBT was used. Conclusions: Compared with photon techniques, PBT showed improvements in most dosimetric parameters for CSI patients, with lower OEDs to organs at risk.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

Combining Carbon Ion Radiotherapy and Local Injection of {alpha}-Galactosylceramide-Pulsed Dendritic Cells Inhibits Lung Metastases in an In Vivo Murine Model

Purpose: Our previous report indicated that carbon ion beam irradiation upregulated membrane-associated immunogenic molecules, underlining the potential clinical application of radioimmunotherapy. The antimetastatic efficacy of local combination therapy of carbon ion radiotherapy and immunotherapy was examined by use of an in vivo murine model. Methods and Materials: Tumors of mouse squamous cell carcinoma (NR-S1) cells inoculated in the legs of C3H/HeSlc mice were locally irradiated with a single 6-Gy dose of carbon ions (290 MeV/nucleon, 6-cm spread-out Bragg peak). Thirty-six hours after irradiation, {alpha}-galactosylceramide-pulsed dendritic cells (DCs) were injected into the leg tumor. We investigated the effects on distant lung metastases by counting the numbers of lung tumor colonies, making pathologic observations, and assessing immunohistochemistry. Results: The mice with no treatment (control) presented with 168 {+-} 53.8 metastatic nodules in the lungs, whereas the mice that received the combination therapy of carbon ion irradiation and DCs presented with 2.6 {+-} 1.9 (P = 0.009) at 2 weeks after irradiation. Immunohistochemistry showed that intracellular adhesion molecule 1, which activates DCs, increased from 6 h to 36 h after irradiation in the local tumors of the carbon ion-irradiated group. The expression of S100A8 in lung tissue, a marker of the lung pre-metastatic phase, was decreased only in the group with a combination of carbon ions and DCs. Conclusions: The combination of carbon ion radiotherapy with the injection of {alpha}-galactosylceramide-pulsed DCs into the primary tumor effectively inhibited distant lung metastases.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Effect of Radiotherapy Planning Complexity on Survival of Elderly Patients With Unresected Localized Lung Cancer

Purpose: To evaluate whether complex radiotherapy (RT) planning was associated with improved outcomes in a cohort of elderly patients with unresected Stage I-II non-small-cell lung cancer (NSCLC). Methods and Materials: Using the Surveillance, Epidemiology, and End Results registry linked to Medicare claims, we identified 1998 patients aged >65 years with histologically confirmed, unresected stage I-II NSCLC. Patients were classified into an intermediate or complex RT planning group using Medicare physician codes. To address potential selection bias, we used propensity score modeling. Survival of patients who received intermediate and complex simulation was compared using Cox regression models adjusting for propensity scores and in a stratified and matched analysis according to propensity scores. Results: Overall, 25% of patients received complex RT planning. Complex RT planning was associated with better overall (hazard ratio 0.84; 95% confidence interval, 0.75-0.95) and lung cancer-specific (hazard ratio 0.81; 95% confidence interval, 0.71-0.93) survival after controlling for propensity scores. Similarly, stratified and matched analyses showed better overall and lung cancer-specific survival of patients treated with complex RT planning. Conclusions: The use of complex RT planning is associated with improved survival among elderly patients with unresected Stage I-II NSCLC. These findings should be validated in prospective randomized controlled trials.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

Dose-Response Effect of Charged Carbon Beam on Normal Rat Retina Assessed by Electroretinography

Purpose: To compare the effects of carbon beam irradiation with those of proton beam irradiation on the physiology of the retina of rats. Methods and Materials: Eight-week-old Wister rats were used. The right eyes were irradiated with carbon beam (1, 2, 4, 8, and 16 Gy) or proton beam (4, 8, 16, and 24 Gy) with the rats under general anesthesia. Electroretinograms were recorded 1, 3, 6, and 12 months after the irradiation, and the amplitudes of the a and b waves were compared with those of control rats. Results: The amplitude of b waves was reduced more than that of a waves at lower irradiation doses with both types of irradiation. With carbon ion irradiation, the amplitudes of the b wave were significantly reduced after radiation doses of 8 and 16 Gy at 6 months and by radiation doses of 4, 8, and 16 Gy at 12 months. With proton beam irradiation, the b-wave amplitudes were significantly reduced after 16 and 24 Gy at 6 months and with doses of 8 Gy or greater at 12 months. For the maximum b-wave amplitude, a significant difference was observed in rats irradiated with carbon beams of 4 Gy or more and with proton beams of 8 Gy or more at 12 months after irradiation. Conclusions: These results indicate that carbon beam irradiation is about two times more damaging than proton beam irradiation on the rat retina at the same dose.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Dynamics of Delayed p53 Mutations in Mice Given Whole-Body Irradiation at 8 Weeks

Purpose: Ionizing irradiation might induce delayed genotoxic effects in a p53-dependent manner. However, a few reports have shown a p53 mutation as a delayed effect of radiation. In this study, we investigated the p53 gene mutation by the translocation frequency in chromosome 11, loss of p53 alleles, p53 gene methylation, p53 nucleotide sequence, and p53 protein expression/phosphorylation in p53{sup +/+} and p53{sup +/-} mice after irradiation at a young age. Methods and Materials: p53{sup +/+} and p53{sup +/-} mice were exposed to 3 Gy of whole-body irradiation at 8 weeks of age. Chromosome instability was evaluated by fluorescence in situ hybridization analysis. p53 allele loss was evaluated by polymerase chain reaction, and p53 methylation was evaluated by methylation-specific polymerase chain reaction. p53 sequence analysis was performed. p53 protein expression was evaluated by Western blotting. Results: The translocation frequency in chromosome 11 showed a delayed increase after irradiation. In old irradiated mice, the number of mice that showed p53 allele loss and p53 methylation increased compared to these numbers in old non-irradiated mice. In two old irradiated p53{sup +/-} mice, the p53 sequence showed heteromutation. In old irradiated mice, the p53 and phospho-p53 protein expressions decreased compared to old non-irradiated mice. Conclusion: We concluded that irradiation at a young age induced delayed p53 mutations and p53 protein suppression.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
DOE OSTI2011

Relative Biological Effectiveness of Carbon Ions for Local Tumor Control of a Radioresistant Prostate Carcinoma in the Rat

Purpose: To study the relative biological effectiveness (RBE) of carbon ion beams relative to X-rays for local tumor control in a syngeneic rat prostate tumor (Dunning subline R3327-AT1). Methods and Materials: A total of 198 animals with tumors in the distal thigh were treated with increasing single and split doses of either {sup 12}C ions or photons using a 20-mm spread-out Bragg peak. Endpoints of the study were local control (no tumor recurrence within 300 days) and volumetric changes after irradiation. The resulting values for D{sub 50} (dose at 50% tumor control probability) were used to determine RBE values. Results: The D{sub 50} values for single doses were 32.9 {+-} 0.9 Gy for {sup 12}C ions and 75.7 {+-} 1.6 Gy for photons. The respective values for split doses were 38.0 {+-} 2.3 Gy and 90.6 {+-} 2.3 Gy. The corresponding RBE values were 2.30 {+-} 0.08 for single and 2.38 {+-} 0.16 for split doses. The most prominent side effects were dry and moist desquamation of the skin, which disappeared within weeks. Conclusion: The study confirmed the effectiveness of carbon ion therapy for severely radioresistant tumors. For 1- and 2-fraction photon and {sup 12}C ion radiation, we have established individual D{sub 50} values for local tumor control as well as related RBE values.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Spinal Cord Tolerance to Single-Fraction Partial-Volume Irradiation: A Swine Model

Purpose: To determine the spinal cord tolerance to single-fraction, partial-volume irradiation in swine. Methods and Materials: A 5-cm-long cervical segment was irradiated in 38-47-week-old Yucatan minipigs using a dedicated, image-guided radiosurgery linear accelerator. The radiation was delivered to a cylindrical volume approximately 5 cm in length and 2 cm in diameter that was positioned lateral to the cervical spinal cord, resulting in a dose distribution with the 90%, 50%, and 10% isodose lines traversing the ipsilateral, central, and contralateral spinal cord, respectively. The dose was prescribed to the 90% isodose line. A total of 26 pigs were stratified into eight dose groups of 12-47 Gy. The mean maximum spinal cord dose was 16.9 {+-} 0.1, 18.9 {+-} 0.1, 21.0 {+-} 0.1, 23.0 {+-} 0.2, and 25.3 {+-} 0.3 Gy in the 16-, 18-, 20-, 22-, and 24-Gy dose groups, respectively. The mean percentage of spinal cord volumes receiving {>=}10 Gy for the same groups were 43% {+-} 3%, 48% {+-} 4%, 51% {+-} 2%, 57% {+-} 2%, and 59% {+-} 4%. The study endpoint was motor neurologic deficit determined by a change in gait during a 1-year follow-up period. Results: A steep dose-response curve was observed with a median effective dose for the maximum dose point of 20.0 Gy (95% confidence interval, 18.3-21.7). Excellent agreement was observed between the occurrence of neurologic change and the presence of histologic change. All the minipigs with motor deficits showed some degree of demyelination and focal white matter necrosis on the irradiated side, with relative sparing of the gray matter. The histologic findings were unremarkable in the minipigs with normal neurologic status. Conclusions: Our results have indicated that for a dose distribution with a steep lateral gradient, the pigs had a lower median effective dose for paralysis than has been observed in rats and more closely resembles that for rats, mice, and guinea pigs receiving uniform spinal cord irradiation.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

In Vivo Radiobiological Characterization of Proton Beam at the National Cancer Center in Korea: Effect of the Chk2 Mutation

Purpose: The relative biological effectiveness (RBE) in the presence or absence of CHK2 was estimated at the Korean National Cancer Center Proton Therapy Center (NCCPTC). Methods and Materials: The proton beam was fixed at 210 MeV with 6-cm spread-out Bragg peaks (SOBPs) because this is expected to be the most frequently used clinical setting. X-rays were obtained using a 6-MV conventional linear accelerator. The RBE was estimated from the survival of jejunal crypt in C3H/He and Chk2{sup -/-} mice. Results: The estimated RBEs of the NCCPTC at the middle of the SOBP were 1.10 and 1.05 in the presence and absence of CHK2, respectively. The doses that reduced the number of regenerated crypt per jejunal circumference to 20 (D{sub 20}) in C3H/He mice were 14.8 Gy (95% confidence interval [CI], 13.7-15.9) for X-rays and 13.5 Gy (95% CI, 14.5-15.5) for protons. By contrast, the doses of D{sub 20} in Chk2{sup -/-} mice were 15.7 Gy (95% CI, 15.0-16.4) and 14.9 Gy (95% CI, 14.0-15.8) for X-rays and protons, respectively. Conclusions: The RBE of the NCCPTC is clearly within the range of RBEs determined at other facilities and is consistent with the generic RBE value of 1.10 for 150- to 250-MeV beams. The mutation of Chk2 gave rise to radioresistance but exhibited similar RBE.

62 RADIOLOGY AND NUCLEAR MEDICINE↗