Brain-derived neurotrophic factor promotes immune reconstitution following radiation injury via activation of bone marrow mesenchymal stem cells.

Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family which has been extensively studied for its roles in neural development, long-term memory, brain injury, and neurodegenerative diseases. BDNF signaling through tropomyosin receptor kinase B (TrkB) stimulates neuronal cell survival. For this reason, small molecule TrkB agonists are under pre-clinical develoment for the treatment of a range of neurodegenerative diseases and injuries. Our laboratory recently reported BDNF is secreted by pro-regenerative endothelial progenitor cells (EPCs) which support hematopoietic reconstitution following total body irradiation (TBI). Here we report BDNF-TrkB signaling plays a novel regenerative role in bone marrow and thymic regeneration following radiation injury. Exogenous administration of BDNF or TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) following myelosuppressive radiation injury promoted faster recovery of mature blood cells and hematopoietic stem cells capable of multi-lineage reconstitution. BDNF promotes hematopoietic regeneration via activation of PDGFRα+ bone marrow mesenchymal stem cells (MSCs) which increase secretion of hematopoietic cytokines interleukin 6 (IL-6) and leukemia inhibitory factor (LIF) in response to TrkB activation. These data suggest pharmacologic activation of the BDNF pathway with either BDNF or 7,8-DHF may be beneficial for treatment of radiation or chemotherapy induced myelosuppression.

Direct aperture optimization-based intensity-modulated radiotherapy for whole breast irradiation.

PURPOSE: To investigate the technical and dosimetric advantages and the efficacy of direct aperture optimized intensity-modulated radiation therapy (DAO-IMRT) over standard (e.g., beamlet optimized) IMRT and conventional three-dimensional conformal radiotherapy (3D-CRT) for whole breast irradiation in supine and prone positions. METHODS AND MATERIALS: We retrospectively designed DAO-IMRT plans for 15 breast cancer patients in supine (10 patients) and prone (5 patients) positions with a goal of uniform dose coverage of the whole breast. These DAO-IMRT plans were compared with standard IMRT using beamlet optimization and conventional 3D-CRT plans using wedges. All plans used opposed tangential beam arrangements. RESULTS: In all cases, the DAO-IMRT plans were equal to or better than those generated with 3D-CRT and standard beamlet-IMRT. For supine cases, DAO-IMRT provided higher uniformity index (UI, defined as the ratio of the dose to 95% of breast volume to the maximum dose) than either 3D-CRT (0.88 vs. 0.82; p = 0.026) or beamlet-IMRT (0.89 vs. 0.85; p = 0.003). Direct aperture optimized IMRT also gave lower lung doses than either 3D-CRT (V20 = 7.9% vs. 8.6%; p = 0.024) or beamlet-IMRT (V20 = 8.4% vs. 9.7%; p = 0.0008) for supine patients. For prone patients, DAO-IMRT provided higher UI than either 3D-CRT (0.89 vs. 0.83; p = 0.027) or beamlet-IMRT (0.89 vs. 0.85; p = 0.003). The planning time for DAO-IMRT was approximately 75% less than that of 3D-CRT. The monitor units for DAO-IMRT were approximately 60% less than those of beamlet-IMRT. CONCLUSION: Direct aperture optimized IMRT improved the overall quality of dose distributions as well as the planning and delivery efficiency for treating whole breast in both supine and prone positions.

Posttreatment visual acuity in patients treated with episcleral plaque therapy for choroidal melanomas: dose and dose rate effects.

PURPOSE: To determine the relationship between the long-term visual function and the dose and dose rates delivered to critical ocular structures in patients with choroidal melanoma treated with 125I episcleral plaque radiotherapy. MATERIALS AND METHODS: From 1987 to 1994, 63 patients underwent 125I episcleral plaque (Collaborative Ocular Melanoma Study [COMS] design) application for the treatment of choroidal melanoma. The mean tumor height was 4.5 mm (range 1.7-8.3). Doses and dose rates at the tumor apex, macula, and optic disc were calculated. Forty-three records were scored to assess whether a decrease in visual acuity of >2 lines on a standard Snellen eye chart had occurred. Patient age and the presence of hypertension or diabetes were noted. Statistical analysis was performed to assess both the rate at which visual decline had occurred and the presence of significant factors that had contributed to this decline. RESULTS: With a median follow-up of 36 months, the 3-year actuarial survival rate was 93.6%. The 3-year actuarial local control rate was 86.9%. The median time to visual loss after therapy was 18.7 months. The 3-year actuarial rate of visual preservation was 40.5%. Multivariate analysis demonstrated higher macula dose rates (p = 0.003) to forecast visual decline. Macula dose rates of 111 +/- 11.1 cGy/h were associated with a 50% risk of significant visual loss. CONCLUSION: Patients in our series treated with 125I plaque brachytherapy for choroidal melanoma experienced favorable tumor control, but with a measurable incidence of visual decline. Higher dose rates to the macula correlated strongly with poorer posttreatment visual outcome. This information may be valuable in selecting the optimal dose rates to treat choroidal melanomas and to predict the risk of visual decline.

Gamma knife surgery of vestibular schwannomas: volumetric dosimetry correlations to hearing loss suggest stria vascularis devascularization as the mechanism of early hearing loss.

OBJECTIVE: Determine which variables are correlated with early hearing changes after gamma knife surgery of vestibular schwannomas (VSs). STUDY DESIGN: Prospective clinical study of hearing outcomes, radiation dosimetry, conformity, and tumor size of all sporadic unilateral VS patients treated between June 2000 and July 2009. SETTING: Tertiary referral center. PATIENTS: : Fifty-nine VS patients with at least 6 months of follow-up data were studied. INTERVENTIONS: Audiometry and imaging were performed to determine auditory thresholds, speech discrimination, and tumor size. Radiation doses to 5 volumes were measured. MAIN OUTCOME MEASURES: Pretreatment and posttreatment comparisons were performed with regard to change in tumor size; radiation dose to specific volumes including the internal auditory canal, cochlea, basal turn of the cochlea, and modiolus; and conformity of the treatment. RESULTS: The mean follow-up was 63.76 months (standard deviation, ±29.02 mo; range, 9-109 mo). The median follow-up was 65.5 months. A statistically significant association between maximum radiation dose to the cochlea volume and 3-frequency pure-tone average in patients starting with 50 dB or lesser PTA3 was demonstrated using linear regression analysis. CONCLUSION: Longitudinal changes in hearing occur over time, with the largest changes seen in the first 12 months after treatment. With our study outcomes as basis, limiting the dose of radiation to the cochlea to no more than 4 Gy would likely reduce vascular injury to the stria vascularis and improve hearing outcomes. Shielding the cochlea during the treatment planning process would be one mechanism to accomplish this goal.