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At least 865 records · Page 48
All sourcesNASA NTRSDOE OSTI
DOE OSTI2010

Development of a Micro-Computed Tomography-Based Image-Guided Conformal Radiotherapy System for Small Animals

Purpose: To report on the physical aspects of a system in which radiotherapy functionality was added to a micro-computed tomography (microCT) scanner, to evaluate the accuracy of this instrument, and to and demonstrate the application of this technology for irradiating tumors growing within the lungs of mice. Methods and Materials: A GE eXplore RS120 microCT scanner was modified by the addition of a two-dimensional subject translation stage and a variable aperture collimator. Quality assurance protocols for these devices, including measurement of translation stage positioning accuracy, collimator aperture accuracy, and collimator alignment with the X-ray beam, were devised. Use of this system for image-guided radiotherapy was assessed by irradiation of a solid water phantom as well as of two mice bearing spontaneous MYC-induced lung tumors. Radiation damage was assessed ex vivo by immunohistochemical detection of {gamma}H2AX foci. Results: The positioning error of the translation stage was found to be <0.05 mm, whereas after alignment of the collimator with the X-ray axis through adjustment of its displacement and rotation, the collimator aperture error was <0.1 mm measured at isocenter. Computed tomography image-guided treatment of a solid water phantom demonstrated target localization accuracy to within 0.1 mm. Gamma-H2AX foci were detected within irradiated lung tumors in mice, with contralateral lung tissue displaying background staining. Conclusions: Addition of radiotherapy functionality to a microCT scanner is an effective means of introducing image-guided radiation treatments into the preclinical setting. This approach has been shown to facilitate small-animal conformal radiotherapy while leveraging existing technology.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Radiation Therapy for Pilocytic Astrocytomas of Childhood

Purpose: Though radiation therapy is generally considered the most effective treatment for unresectable pilocytic astrocytomas in children, there are few data to support this claim. To examine the efficacy of radiation therapy for pediatric pilocytic astrocytomas, we retrospectively reviewed the experience at our institution. Methods and Materials: Thirty-five patients 18 years old or younger with unresectable tumors and without evidence of neurofibromatosis have been treated since 1982. Patients were treated with local radiation fields to a median dose of 54 Gy. Six patients were treated with radiosurgery to a median dose of 15.5 Gy. Five patients were treated with initial chemotherapy and irradiated after progression. Results: All patients were alive after a median follow-up of 5.0 years. However, progression-free survival was 68.7%. None of 11 infratentorial tumors progressed compared with 6 of 20 supratentorial tumors. A trend toward improved progression-free survival was seen with radiosurgery (80%) compared with external beam alone (66%), but this difference did not reach statistical significance. Eight of the 9 patients progressing after therapy did so within the irradiated volume. Conclusions: Although the survival of these children is excellent, almost one third of patients have progressive disease after definitive radiotherapy. Improvements in tumor control are needed in this patient population, and the optimal therapy has not been fully defined. Prospective trials comparing initial chemotherapy to radiation therapy are warranted.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Long-Term Results of Brachytherapy With Temporary Iodine-125 Seeds in Children With Low-Grade Gliomas

Purpose: To retrospectively review the results of temporary I-125 brachytherapy in 94 children and adolescents with low-grade glioma. Methods and Materials: Treatment was performed in progressive tumors roughly spherical in shape with a diameter of up to 5 cm, including 79 astrocytomas, 5 oligodendrogliomas, 4 oligoastrocytomas, 1 ependymoma, and 5 other tumors. Location was suprasellar/chiasmal in 44, thalamic/basal ganglia in 18, hemispheric in 15, midbrain/pineal region in 13, and lower brainstem in 3. Initially, 8% of patients were free of symptoms, 47% were symptomatic but not disabled, and 30% were slightly, 6% moderately, and 3% severely disabled. Results: 5- and 10-year survival was 97% and 92%. The response to I-125 brachytherapy over the long term was estimated after a median observation period of 38.4 (range, 6.4-171.0) months. At that time, 4 patients were in complete, 27 in partial, and 18 in objective remission; 15 showed stable and 30 progressive tumors. Treatment results did not correlate with age, sex, histology, tumor size, location, or demarcation of the tumor. Secondary treatment became necessary in 36 patients, including 19 who underwent repeated I-125 brachytherapy. At final follow-up, the number of symptom-free patients had risen to 21%. Thirty-eight percent showed symptoms without functional impairment, 19% were slightly and 11% moderately disabled, and only 4% were severely disabled. Conclusions: Response rates similar to those of conventional radiotherapy or chemotherapy can be anticipated with I-125 brachytherapy in tumors of the appropriate size and shape. We believe it to be a useful contribution to the treatment of low-grade gliomas in children.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Local Therapy for Rhabdomyosarcoma of the Hands and Feet: Is Amputation Necessary? A Report From the Children's Oncology Group

Purpose: To evaluate the outcome of children with rhabdomyosarcoma (RMS) of the hand or foot treated with surgery and/or local radiotherapy (RT). Methods and Materials: Forty-eight patients with nonmetastatic RMS of the hand or foot were enrolled on Intergroup Rhabdomyosarcoma Study III, IV-Pilot, and IV. Patients received multiagent chemotherapy with surgery and/or RT. Twenty-four patients (50%) underwent surgery without local RT, of whom 4 had complete resection and 20 had an amputation. The remaining 24 patients (50%) underwent local RT, of whom 2 required RT for microscopic residual disease after prior amputation. Median follow-up for surviving patients was 9.7 years. Results: Actuarial 10-year local control was 100%; 10-year event-free survival and overall survival rates were 62% and 63%, respectively. Poor prognostic factors for recurrence included gross residual (Group III) disease and nodal involvement (p = 0.01 and 0.05, respectively). More patients in the RT group had alveolar histology, Group III disease, and nodal involvement, as compared with the surgery group. There was no difference in 10-year event-free survival (57% vs. 66%) or overall survival (63% vs. 63%) between patients who underwent surgery or local RT. Among relapsing patients, there were no long-term survivors. No secondary malignancies have been observed. Conclusions: Despite having high-risk features, patients treated with local RT achieved excellent local control. Complete surgical resection without amputation is difficult to achieve in the hand or foot. Therefore, we recommend either definitive RT or surgical resection that maintains form and function as primary local therapy rather than amputation in patients with hand or foot RMS.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Influence of Noncompliance With Radiation Therapy Protocol Guidelines and Operative Bed Recurrences for Children With Rhabdomyosarcoma and Microscopic Residual Disease: A Report From the Children's Oncology Group

Purpose: Postoperative radiation therapy (RT) is recommended for patients with rhabdomyosarcoma having microscopic disease. Sometimes RT dose/volume is reduced or omitted in an attempt to avoid late effects, particularly in young children. We reviewed operative bed recurrences to determine if noncompliance with RT protocol guidelines influenced local-regional control. Methods and Materials: All operative bed recurrences among 695 Group II rhabdomyosarcoma patients in Intergroup Rhabdomyosarcoma Study Group (IRS) I through IV were reviewed for deviation from RT protocol. Major/minor dose deviation was defined as >10% or 6-10% of the prescribed dose (40-60 Gy), respectively. Major/minor volume deviation was defined as tumor excluded from the RT field or treatment volume not covered by the specified margin (preoperative tumor volume and 2- to 5-cm margin), respectively. No RT was a major deviation. Results: Forty-six of 83 (55%) patients with operative bed recurrences did not receive the intended RT (39 major and 7 minor deviations). RT omission was the most frequent RT protocol deviation (19/46, 41%), followed by dose (17/46, 37%), volume (9/46, 20%), and dose and volume deviation (1/46, 2%). Only 7 operative bed recurrences occurred in IRS IV (5% local-regional failure) with only 3 RT protocol deviations. Sixty-three (76%) patients with recurrence died of disease despite retrieval therapy, including 13 of 19 nonirradiated children. Conclusion: Over half of the operative bed recurrences were associated with noncompliance; omission of RT was the most common protocol deviation. Three fourths of children die when local-regional disease is not controlled, emphasizing the importance of RT in Group II rhabdomyosarcoma.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Role of FDG-PET in the Definition of Involved-Field Radiation Therapy and Management for Pediatric Hodgkin's Lymphoma

Purpose: To evaluate positron emission tomography-computed tomography (PET-CT) influences in involved-field radiation therapy (IFRT) field design in pediatric Hodgkin's lymphoma (HL). Materials and Methods: From June 2003 to February 2008, 30 pediatric HL patients were treated at Children's Healthcare of Atlanta (CHOA) and Emory University Department of Radiation Oncology with both chemotherapy and IFRT. Diagnostic contrast-enhanced CT and PET-CT were coregistered using image fusion software. Both were reviewed for all potential sites of involvement and correlated to determine concordance and discordance. They were used in IFRT planning to determine the influence of PET-CT on target volumes and field design. Results: There were 546 regions analyzed by both PET and CT modalities. Image sets were concordant in 468 regions and discordant in 78, yielding 86% concordance overall. Analysis by weighted {kappa} statistic showed 'intermediate to good' fit overall and for nodal sites, but 'poor' agreement for extranodal sites. If discordant, a site was most likely PET+/CT-. Integration of PET information caused a change in staging in 15 (50%) patients, 7 upstaged and 8 downstaged. The IFRT volumes were adjusted on the basis of initial PET-CT finding in 21 (70%) patients, with 32 sites added and 15 excluded. There were four relapses, only one outside IFRT fields, but all were successfully salvaged. Conclusion: PET-CT represents an important tool in the management of pediatric patients with HL and has a substantial influence on both initial staging and radiation treatment target definition and field design.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

Tolerance of Arteries to Microplanar X-Ray Beams

Purpose: The purpose is to evaluate effects of a new radiotherapy protocol, microbeam radiation therapy, on the artery wall. In previous studies on animal models, it was shown that capillaries recover well from hectogray doses of X-rays delivered in arrays of narrow ({<=}50 {mu}m) beams with a minimum spacing of 200 {mu}m. Here, short- and long-term effects of comparable microplanar beam configurations on the saphenous artery of the mouse hind leg were analyzed in situ by use of nonlinear optics and compared with histopathologic findings. Methods and Materials: The left hind leg of normal mice including the saphenous artery was irradiated by an array of 26 microbeams of synchrotron X-rays (50 {mu}m wide, spaced 400 {mu}m on center) with peak entrance doses of 312 Gy and 2,000 Gy. Results: The artery remained patent, but narrow arterial smooth muscle cell layer segments that were in the microplanar beam paths became atrophic and fibrotic in a dose-dependent pattern. The wide tunica media segments between those paths hypertrophied, as observed in situ by two-photon microscopy and histopathologically. Conclusions: Clinical risks of long-delayed disruption or occlusion of nontargeted arteries from microbeam radiation therapy will prove less than corresponding risks from broad-beam radiosurgery, especially if peak doses are kept below 3 hectograys.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

Melanin-Covered Nanoparticles for Protection of Bone Marrow During Radiation Therapy of Cancer

Purpose: Protection of bone marrow against radiotoxicity during radioimmunotherapy and in some cases external beam radiation therapy such as hemi-body irradiation would permit administration of significantly higher doses to tumors, resulting in increased efficacy and safety of treatment. Melanin, a naturally occurring pigment, possesses radioprotective properties. We hypothesized that melanin, which is insoluble, could be delivered to the bone marrow by intravenously administrated melanin-covered nanoparticles (MNs) because of the human body's 'self-sieving' ability, protecting it against ionizing radiation. Methods and Materials: The synthesis of MNs was performed via enzymatic polymerization of 3,4-dihydroxyphenylalanine and/or 5-S-cysteinyl-3,4-dihydroxyphenylalanine on the surface of 20-nm plain silica nanoparticles. The biodistribution of radiolabeled MNs in mice was done at 3 and 24 h. Healthy CD-1 mice (Charles River Laboratories International, Inc., Wilmington, MA) or melanoma tumor-bearing nude mice were given MNs intravenously, 50 mg/kg of body weight, 3 h before either whole-body exposure to 125 cGy or treatment with 1 mCi of {sup 188}Re-labeled 6D2 melanin-binding antibody. Results: Polymerization of melanin precursors on the surface of silica nanoparticles resulted in formation of a 15-nm-thick melanin layer as confirmed by light scattering, transmission electron microscopy, and immunofluorescence. The biodistribution after intravenous administration showed than MN uptake in bone marrow was 0.3% and 0.2% of injected dose per gram at 3 and 24 h, respectively, whereas pre-injection with pluronic acid increased the uptake to 6% and 3% of injected dose per gram, respectively. Systemic MN administration reduced hematologic toxicity in mice treated with external radiation or radioimmunotherapy, whereas no tumor protection by MNs was observed. Conclusions: MNs or similar structures provide a novel approach to protection of bone marrow from ionizing radiation based on prevention of free radical formation by melanin.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Infant Ependymoma in a 10-Year AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) Experience With Omitted or Deferred Radiotherapy

Purpose: The protocols of the 1990s omitted or delayed irradiation, using upfront chemotherapy to spare the youngest children with ependymoma the sequelae of radiotherapy (RT). We treated 41 children under the age of 3 years with intracranial ependymoma between 1994 and 2003. Patients and Methods: After surgery, chemotherapy was given as follows: regimen I with four blocks of vincristine, high-dose methotrexate 5 g/m{sup 2}, and cyclophosphamide 1.5 g/m{sup 2} alternating with cisplatin 90 mg/m{sup 2} plus VP16 450 mg/m{sup 2} for 14 months; subsequently, regimen II was used: VEC (VCR, VP16 300 mg/m{sup 2}, and cyclophosphamide 3 g/m{sup 2}) for 6 months. Radiotherapy was planned for residual tumor after the completion of chemotherapy or for progression. Results: We treated 23 boys and 18 girls who were a median 22 months old; 14 were given regimen I, 27 were given regimen II; 22 underwent complete resection, 19 had residual tumor. Ependymoma was Grade 2 in 25 patients and Grade 3 in 16; tumors were infratentorial in 37 patients and supratentorial in 4. One child had intracranial metastases; 29 had progressed locally after a median 9 months. Event-free survival was 26% at 3 and 5 years and 23% at 8 years. One child died of sepsis, and another developed a glioblastoma 72 months after RT. Progression-free survival was 27% at 3, 5, and 8 years, and overall survival was 48%, 37%, and 28% at 3, 5, and 8 years, respectively. Of the 13 survivors, 6 never received RT; their intellectual outcome did not differ significantly in those children than in those without RT. Conclusions: Our results confirm poor rates of event-free survival and overall survival for up-front chemotherapy in infant ependymoma. No better neurocognitive outcome was demonstrated in the few survivors who never received RT.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Adherence to Vaginal Dilation Following High Dose Rate Brachytherapy for Endometrial Cancer

Purpose: We report demographic, clinical, and psychosocial factors associated with adherence to vaginal dilation and describe the sexual and marital or nonmarital dyadic functioning of women following high dose rate (HDR) brachytherapy for endometrial cancer. Methods and Materials: We retrospectively evaluated women aged 18 years or older in whom early-stage endometrial (IAgr3-IIB) cancers were treated by HDR intravaginal brachytherapy within the past 3.5 years. Women with or without a sexual partner were eligible. Patients completed questionnaires by mail or by telephone assessing demographic and clinical variables, adherence to vaginal dilation, dyadic satisfaction, sexual functioning, and health beliefs. Results: Seventy-eight of 89 (88%) eligible women with early-stage endometrial cancer treated with HDR brachytherapy completed questionnaires. Only 33% of patients were adherers, based on reporting having used a dilator more than two times per week in the first month following radiation. Nonadherers who reported a perceived change in vaginal dimension following radiation reported that their vaginas were subjectively smaller after brachytherapy (p = 0.013). Adherers reported more worry about their sex lives or lack thereof than nonadherers (p = 0.047). Patients reported considerable sexual dysfunction following completion of HDR brachytherapy. Conclusions: Adherence to recommendations for vaginal dilator use following HDR brachytherapy for endometrial cancer is poor. Interventions designed to educate women about dilator use benefit may increase adherence. Although sexual functioning was compromised, it is likely that this existed before having cancer for many women in our study.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

Proteomics of the Radioresistant Phenotype in Head-and-Neck Cancer: Gp96 as a Novel Prediction Marker and Sensitizing Target for Radiotherapy

Purpose: Radiotherapy is an integral part of the treatment modality for head-neck cancer (HNC), but in some cases the disease is radioresistant. We designed this study to identify molecules that may be involved in this resistance. Methods and Materials: Two radioresistant sublines were established by fractionated irradiation of the HNC cell lines, to determine differentially proteins between parental and radioresistant cells. Proteomic analysis and reverse-transcription polymerase chain reaction were used to identify and confirm the differential proteins. The siRNA knockdown experiments were applied to examine cellular functions of a radioresistant gene, with investigation of the alterations in colonogenic survival, cell cycle status, and reactive oxygen species levels. Xenografted mouse tumors were studied to validate the results. Results: IN all, 64 proteins were identified as being potentially associated with radioresistance, which are involved in several cellular pathways, including regulation of stimulus response, cell apoptosis, and glycolysis. Six genes were confirmed to be differentially expressed in both radioresistant sublines, with Gp96, Grp78, HSP60, Rab40B, and GDF-15 upregulated, and annexin V downregulated. Gp96 was further investigated for its functions in response to radiation. Gp96-siRNA transfectants displayed a radiation-induced growth delay, reduction in colonogenic survival, increased cellular reactive oxygen species levels, and increased proportion of the cells in the G2/M phase. Xenograft mice administered Gp96-siRNA showed significantly enhanced growth suppression in comparison with radiation treatment alone (p = 0.009). Conclusions: We identified 64 proteins and verified 6 genes that are potentially involved in the radioresistant phenotype. We further demonstrated that Gp96 knockdown enhances radiosensitivity both in cells and in vivo, which may lead to a better prognosis of HNC treatment.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

Sodium Selenite Radiosensitizes Hormone-Refractory Prostate Cancer Xenograft Tumors but Not Intestinal Crypt Cells In Vivo

Purpose: We have previously shown that sodium selenite (SSE) increases radiation-induced cell killing of human prostate carcinoma cells in vitro. In this study we further evaluated the in vivo radiosensitizing effect of SSE in prostate cancer xenograft tumors and normal radiosensitive intestinal crypt cells. Methods and Materials: Immunodeficient (SCID) mice with hormone-independent LAPC-4 (HI-LAPC-4) and PC-3 xenograft tumors (approximately 200 mm{sup 3}) were divided into four groups: control (untreated), radiation therapy (XRT, local irradiation), SSE (2 mg/kg, intraperitoneally, 3 times/week), and XRT plus SSE. The XRT was given at the beginning of the regimen as a single dose of 5 Gy for HI-LAPC-4 tumors and a single dose of 7 Gy followed by a fractional dose of 3 Gy/d for 5 days for PC-3 tumors. The tumor volume was measured 3 times per week. The radiosensitizing effect of SSE on normal intestinal epithelial cells was assessed by use of a crypt cell microcolony assay. Results: In the efficacy study, SSE alone significantly inhibited the tumor growth in HI-LAPC-4 tumors but not PC-3 tumors. Sodium selenite significantly enhanced the XRT-induced tumor growth inhibition in both HI-LAPC-4 and PC-3 tumors. In the toxicity study, SSE did not affect the intestinal crypt cell survival either alone or in combination with XRT. Conclusions: Sodium selenite significantly enhances the effect of radiation on well-established hormone-independent prostate tumors and does not sensitize the intestinal epithelial cells to radiation. These results suggest that SSE may increase the therapeutic index of XRT for the treatment of prostate cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Glioblastoma in Children: A Single-Institution Experience

Purpose: Current treatment recommendations for pediatric glioblastoma include surgery, chemotherapy, and radiation therapy. However, even with this multispecialty approach, overall survival remains poor. To assess outcome and evaluate treatment-related prognostic factors, we retrospectively reviewed the experience at our institution. Methods and Materials: Twenty-four glioblastoma patients under the age of 21 were treated with radiation therapy with curative intent at Washington University, St. Louis, from 1970 to 2008. Patients underwent gross total resection, subtotal resection or biopsy alone. Fourteen (58%) of the patients received chemotherapy. All patients received radiation therapy. Radiation consisted of whole-brain radiation therapy in 7 (29%) patients with a median dose of 50.4 Gy. Seventeen (71%) patients received three-dimensional conformal radiation therapy with a median dose of 54 Gy. Results: Median follow-up was 12.5 months from diagnosis. One and 2-year overall survival rates were 57% and 32%, respectively. Median overall survival was 13.5 months. There were no differences in overall survival based on patients' age, race, gender, tumor location, radiation volume, radiation dose, or the use of chemotherapy. There was a significant improvement in overall survival for patients in whom gross total resection was achieved (p = 0.023). Three patients were alive 5 years after gross total resection, and 2 patients were alive at 10 and 24 years after diagnosis. Conclusions: Survival for children with glioblastoma remains poor. Data from this and other studies demonstrate the importance of achieving a gross total resection. Continued investigation into new treatment options is needed in an attempt to improve outcome for these patients.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Dose-Volume Analysis of Radiation Nephropathy in Children: Preliminary Report of the Risk Consortium

Purpose: To characterize kidney function in children and adolescents who had undergone radiation treatment that included parts of the kidney. Methods and Materials: Patients receiving radiotherapy during childhood or adolescence were prospectively registered in Germany's Registry for the Evaluation of Side Effects after Radiation in Childhood and Adolescence (RiSK). Detailed information was recorded regarding radiation doses at the organs at risk since 2001 all over Germany. Toxicity evaluation was performed according to standardized Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. Results: Up to May 2009, 1086 patients from 62 centers were recruited, including 126 patients (median age, 10.2 years) who underwent radiotherapy to parts of the kidneys. Maximal late toxicity (median follow-up 28.5 months in 74 patients) was characterized as Grade 0 (n = 65), 1 (n = 7) or 2 (n = 2). All patients with late effects had received potentially nephrotoxic chemotherapy. A statistically significant difference between patients with and without Grade 1 toxicity, revealing higher exposed kidney volumes in patients with toxicity, was seen for the kidney volume exposed to 20 Gy (V20; p = 0.031) and 30 Gy (V30; p = 0.003). Conclusions: Preliminary data indicate that radiation-induced kidney function impairment is rare in current pediatric multimodal treatment approaches. In the future, RiSK will be able to provide further detailed data regarding dose-volume effect relationships of radiation-associated side effects in pediatric oncology patients.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

Ras-Related Small GTPases RalA and RalB Regulate Cellular Survival After Ionizing Radiation

Purpose: Oncogenic activation of Ras renders cancer cells resistant to ionizing radiation (IR), but the mechanisms have not been fully characterized. The Ras-like small GTPases RalA and RalB are downstream effectors of Ras function and are critical for both tumor growth and survival. The Ral effector RalBP1/RLIP76 mediates survival of mice after whole-body irradiation, but the role of the Ral GTPases themselves in response to IR is unknown. We have investigated the role of RalA and RalB in cellular responses to IR. Methods and Materials: RalA, RalB, and their major effectors RalBP1 and Sec5 were knocked down by stable expression of short hairpin RNAs in the K-Ras-dependent pancreatic cancer-derived cell line MIA PaCa-2. Radiation responses were measured by standard clonogenic survival assays for reproductive survival, {gamma}H2AX expression for double-strand DNA breaks (DSBs), and poly(ADP-ribose)polymerase (PARP) cleavage for apoptosis. Results: Knockdown of K-Ras, RalA, or RalB reduced colony-forming ability post-IR, and knockdown of either Ral isoform decreased the rate of DSB repair post-IR. However, knockdown of RalB, but not RalA, increased cell death. Surprisingly, neither RalBP1 nor Sec5 suppression affected colony formation post-IR. Conclusions: Both RalA and RalB contribute to K-Ras-dependent IR resistance of MIA PaCa-2 cells. Sensitization due to suppressed Ral expression is likely due in part to decreased efficiency of DNA repair (RalA and RalB) and increased susceptibility to apoptosis (RalB). Ral-mediated radioresistance does not depend on either the RalBP1 or the exocyst complex, the two best-characterized Ral effectors, and instead may utilize an atypical or novel effector.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

MAb 806 Enhances the Efficacy of Ionizing Radiation in Glioma Xenografts Expressing the de2-7 Epidermal Growth Factor Receptor

Purpose: Mutations of the epidermal growth factor receptor (EGFR) are common in glioma. The most frequent mutation, de2-7 EGFR/EGFRvIII, occurs in approximately 40% of high-grade gliomas and confers resistance to ionizing radiation (IR). We have previously shown that mAb 806, a novel EGFR-specific antibody, is able to inhibit the growth of U87MG.{Delta}2-7 glioma xenografts expressing the de2-7 EGFR and may have potential as a therapeutic. Methods and Materials: Nude mice bearing U87MG.{Delta}2-7 xenografts were treated with mAb 806 and/or IR. Comparison of tumor volumes, the effect of treatment on angiogenesis as determined by mean vessel density, and expression changes in prosurvival protein pAkt between treatment groups were undertaken. Results: Treatment of mice bearing U87MG.{Delta}2-7 xenografts with mAb 806 and IR resulted in schedule-dependent radiosensitization. Maximal benefit was obtained when antibody treatment was given before irradiation, with the greatest inhibition of both tumor angiogenesis and tumor growth. Combination treatment mediated radiosensitization by selectively blocking the phosphorylation of the prosurvival protein Akt at serine 473, a process that is independent of DNA-dependent protein kinase catalytic subunit. Conclusions: Our results provide a rationale for the use of mAb 806 in combination with IR for the treatment of glioma and potentially other solid tumors bearing the de2-7 EGFR.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

Insulin-Like Growth Factor-1 Preserves Salivary Gland Function After Fractionated Radiation

Purpose: Radiotherapy for head-and-neck cancer consists of fractionated radiation treatments that cause significant damage to salivary glands leading to chronic salivary gland dysfunction with only limited prevention and treatment options currently available. This study examines the feasibility of IGF-1 in preserving salivary gland function following a fractionated radiation treatment regimen in a pre-clinical model. Methods and Materials: Mice were exposed to fractionated radiation, and salivary gland function and histological analyses of structure, apoptosis, and proliferation were evaluated. Results: In this study, we report that treatment with fractionated doses of radiation results in a significant level of apoptotic cells in FVB mice after each fraction, which is significantly decreased in transgenic mice expressing a constitutively active mutant of Akt1 (myr-Akt1). Salivary gland function is significantly reduced in FVB mice exposed to fractionated radiation; however, myr-Akt1 transgenic mice maintain salivary function under the same treatment conditions. Injection into FVB mice of recombinant insulin-like growth factor-1 (IGF-1), which activates endogenous Akt, suppressed acute apoptosis and preserved salivary gland function after fractionated doses of radiation 30 to 90 days after treatment. FVB mice exposed to fractionated radiation had significantly lower levels of proliferating cell nuclear antigen-positive salivary acinar cells 90 days after treatment, which correlated with a chronic loss of function. In contrast, FVB mice injected with IGF-1 before each radiation treatment exhibited acinar cell proliferation rates similar to those of untreated controls. Conclusion: These studies suggest that activation of IGF-1-mediated pathways before head-and-neck radiation could modulate radiation-induced salivary gland dysfunction and maintain glandular homeostasis.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2010

Proteomic Analysis of Radiation-Induced Changes in Rat Lung: Modulation by the Superoxide Dismutase Mimetic MnTE-2-PyP{sup 5+}

Purpose: To identify temporal changes in protein expression in the irradiated rat lung and generate putative mechanisms underlying the radioprotective effect of the manganese superoxide dismutase mimetic MnTE-2-PyP{sup 5+}. Methods and Materials: Female Fischer 344 rats were irradiated to the right hemithorax with a single dose of 28 Gy and killed from day 1 to 20 weeks after irradiation. Proteomic profiling was performed to identify proteins that underwent significant changes in abundance. Some irradiated rats were administered MnTE-2-PyP{sup 5+} and changes in protein expression and phosphorylation determined at 6 weeks after irradiation. Results: Radiation induced a biphasic stress response in the lung, as shown by the induction of heme oxygenase 1 at 1-3 days and at 6-8 weeks after irradiation. At 6-8 weeks after irradiation, the down-regulation of proteins involved in cytoskeletal architecture (filamin A and talin), antioxidant defense (biliverdin reductase and peroxiredoxin II), and cell signaling ({beta}-catenin, annexin II, and Rho-guanosine diphosphate dissociation inhibitor) was observed. Treatment with MnTE-2-PyP{sup 5+} partially prevented the apparent degradation of filamin and talin, reduced the level of cleaved caspases 3 and 9, and promoted Akt phosphorylation as well as {beta}-catenin expression. Conclusion: A significant down-regulation of proteins and an increase in protein markers of apoptosis were observed at the onset of lung injury in the irradiated rat lung. Treatment with MnTE-2-PyP{sup 5+}, which has been demonstrated to reduce lung injury from radiation, reduced apparent protein degradation and apoptosis indicators, suggesting that preservation of lung structural integrity and prevention of cell loss may underlie the radioprotective effect of this compound.

62 RADIOLOGY AND NUCLEAR MEDICINE↗