[en] Purpose The selenoprotein anti-oxidant glutathione peroxidase (GPX) is a critical enzyme in the detoxification of hydrogen peroxide and lipid peroxides. The Chinese hamster ovary (CHO) cell line AA8 has been previously shown to respond to selenium supplementation with a four-fold increase in activity of GPX. The current work is undertaken to evaluate the relationship between selenium supplementation in CHO AA8 cells and the associated increase in GPX activity, and to examine the effects of selenium and/or GPX on the radiation response. Materials and Methods GPX activity was increased independent of selenium supplementation using a cDNA expression construct. The construct consists of a plasmid vector with the bovine GPX cDNA transcribed from a CMV promotor. CHO AA8 cells were transfected with the construct using Lipofectin reagent and clones were isolated by selection with the antibiotic G418. GPX mRNA levels were evaluated by northern blot analysis. GPX activity was measured by a coupled spectrophotometric assay and expressed as nanomoles NADPH/min/mg protein. Cells were irradiated with 250 kVp x-rays to a dose of 8 Gray. Results Following transfection with the GPX expression construct, several clones were isolated and northern blot analysis revealed high levels of GPX mRNA generated from the construct. Clones transfected with vector alone showed only endogenous GPX mRNA. The transfected cells with complete construct showed significantly increased GPX enzyme activity without selenium supplementation compared to controls. Two representative clones had GPX levels of 38.0 ± 8.5 and 34.0 ± 1.0 compared to control cells with levels of 13.75 ± 4.25. When cells were supplemented with selenium, clones containing the construct had GPX levels further increased (132.0 ± 4.5 and 113.5 ± 11.5) to levels significantly higher than that of control (37.5 ± 3.0). No difference in radiosensitivity is seen between the non-selenium supplemented transfected clones and controls. Conclusions Increases in GPX activity which approximate those seen in CHO AA8 cells supplemented with selenium can be achieved independent of selenium status by genetic engineering. This system provides a framework upon which to study the in vitro effects of altered GPX levels and help elucidate the effects and mechanisms of action of selenium supplementation. Additional studies evaluating radiation response will be designed to assess the respective roles of GPX and selenium

[en] Purpose: A prospective phase II trial was conducted to determine the efficacy and rate of organ preservation of alternate week concomitant chemoradiotherapy in stage II and III head and neck cancer. Methods: Forty-nine patients (10 stage II and 39 stage III) with squamous cell carcinoma of the head and neck region have been entered into a prospective phase II trial. Pretreatment evaluation included history and physical examination, computed tomography of the neck, bone scan, chest x-ray, panendoscopy and biopsy confirmation of malignancy. Therapy is given in 2 week cycles consisting of 5 days of concomitant chemoradiotherapy followed by a nine day break during which no treatment is given. Each cycle of treatment consists of 1.0 gm hydroxyurea P.O. every 12 hours for 6 days (11 doses per cycle) and 800mg/m²/d continuous infusion 5-fluorouracil along with concomitant radiation therapy (RT) administered in 1.8-2.0 Gy daily fractions for five days. This alternate week (week on/week off) schedule is continued for a total of 7 cycles resulting in an overall treatment time of 13 weeks and a total RT dose of 70 Gy. Extent of initial surgery included biopsy only (59.2%), minimal laser debulking (12.2%), and resection with or without neck dissection (28.6%). Results: The majority of patients are male (71.4%), with a median age of 61.3 years. Primary sites included oral cavity (16.3%), oropharynx (12.2%), larynx (57.1%), hypopharynx (8.1%), and nasopharynx (4.1%). T stage included T3 (32 patients, 65.3%), T2 (16 patients, 32.7%), and T1 (1 patient). N stage included N1 (17 patients, 34.7%), and N0 (32 patients, 65.3%). With a median follow-up of 27 months, the overall response rate is 100% (91.7 complete response, and 8.3% partial response). The 5 year actuarial local control, disease free survival, and overall survival is 90.1%, 88.3%, and 65.0%, respectively. One patient has failed with distant disease alone. Four patients had isolated local failures and (3(4)) were salvaged with surgery giving an actuarial 5 year ultimate control rate of 97.8%. Local control is similar regardless of extent of initial surgery; 89.5% with biopsy or minimal debulking vs. 92.6% with resection of primary +/- neck dissection (p=0.86). The incidence of in field grade 3 and 4 mucositis is 43.8% and 10.4%, while in field grade 3 and 4 dermatitis is 20.8% and 0%, respectively. Grade 3 and 4 neutropenia occurred in 43.8% and 8.3% of patients, respectively. No grade 3 or 4 throbocytopenia occurred. Conclusions: 1. Concomitant hydroxyurea, 5-fluorouracil, and RT administered on an alternate week (week on/week off) schedule is an effective regimen with excellent local control and potential for organ preservation. 2. Prospective randomized trials comparing this approach to standard therapy are needed. 3. Our results suggest that traditional concepts of time-dose do not apply in the setting of concomitant chemotherapy and radiation therapy

[en] Purpose: To investigate the impact of radiographic parameter and radiation technique on the volumetric dose of lung and heart for intact breast radiation. Methods and Materials: Forty patients with both two-dimensional (2D) and computed tomographic (CT) simulations were enrolled in the study. Central lung distance (CLD), maximal heart distance (MHD), and maximal heart length (MHL) were measured under virtual simulation. Four plans were compared for each patient. Plan A used a traditional 2D tangential setup. Plan B used clinical target volume (CTV) based three-dimensional (3D) planning. Both plans C and D used a combination of a medial breast field with shallow tangents. Plan D is a further modification of plan C. Results: Under the traditional tangential setup, the mean ipsilateral lung dose and volume at 20, 30, and 40 Gy correlated linearly with CLD (R = 0.85∼0.91). The mean ipsilateral lung dose (Gy) approximated 4 times the CLD value (cm), whereas the percentage volume (%) of ipsilateral lung at 20, 30, and 40 Gy was about 10 times the CLD (cm). The mean heart dose and percentage volume at 20, 30, and 40 Gy correlated with MHD (R = 0.76∼0.80) and MHL (R 0.65∼0.75). The mean heart dose (Gy) approximated 3 times the MHD value (cm), and the percentage volume (%) of the heart at 10, 20, 30, and 40 Gy was about 6 times MHD (cm). Radiation technique impacted lung and heart dose. The 3D tangential plan (plan B) failed to reduce the volumetric dose of lung and heart from that of the 2D plan (plan A). The medial breast techniques (plans C and D) significantly decreased the volume of lung and heart receiving high doses (30 and 40 Gy). Plan D further decreased the 20 Gy volumes. By use of the medial breast technique, the lung and heart dose were not impacted by original CLD and MHD/MHL. Therefore, the improvement from the tangential technique was more remarkable for patients with CLD ≥ 3.0 cm (p<0.001). Conclusions: The CLD and MHD impact the volumetric dose of lung and heart. The application of 3D planning for tangential breast irradiation does not decrease heart and lung dose. Adding a medial breast port significantly decreases percentage volume (PV) of lung and heart receiving high doses, especially when the CLD is excessive

[en] Purpose: To develop tools to plan modulated electron radiotherapy (MERT) and to compare the MERT plans to conventional or intensity modulated radiotherapy (IMRT) treatment plans. Methods: Monte Carlo dose calculations of electron fields shaped with the inherent photon multileaf collimators (MLCs) were investigated in this study. Treatment plans for four postmastectomy breast cancer patients were generated using MERT. The distances from the patient skin surfaces to the distal planning target volume surfaces were computed along the beam axis direction to determine the physical depth. Electron beam energies were selected to provide target coverage at these depths and energy bins were generated. A custom built MERT treatment planning graphical user interface (MERTgui) was used to shape the electron bins into deliverable electron segments. Monte Carlo dose distribution simulations were performed using the MLC-defined segments generated from the MERTgui. A custom built superposition gui was used to combine doses for each segment using relative weights and final MERT treatment plans were compared to the conventional or IMRT treatment plans. In addition, a demonstration of combined MERT and IMRT treatment plans was performed. Results: The MERT treatment plans provided acceptable target organ coverage in all cases. Relative to 3D conventional or IMRT treatment plans, the MERT plans predicted lower heart doses in all cases; average of the heart D₂₀ of all plans was reduced from 14.1 to 3.3 Gy. The contralateral breast and contralateral lung doses decreased substantially with MERT planning compared to IMRT (on average, contralateral breast heart D₂₀ was reduced from 8.7 to 0.7 Gy and contralateral lung D₂₀ was reduced from 8.4 to 1.2 Gy with MERT). Ipsilateral lung D₂₀ was lower with MERT than with the conventional plans (44.6 vs 29.2 Gy with MERT), but greater when compared against IMRT treatment plans (25.4 vs 28.9 Gy with MERT). A MERT and IMRT combination plan was generated to benefit from the complementary advantages of MERT and IMRT, resulting in satisfactory target coverage and reduced organ at risk doses. Conclusions: MERT tools can facilitate treatment planning and provide plans for treatment of shallow targets such as the postmastectomy chest wall.

[en] Background and purpose: The interest in IMRT for the treatment of pediatric malignancies has raised concern about possible increased total body dose. This study examines the pediatric peripheral dose resulting from IMRT compared to 3D conformal therapy. Methods and materials: Five brain or base of skull pediatric cases were planned with both IMRT and 3D conformal techniques. A pediatric-sized anthropomorphic phantom was created and ion chambers were placed at interest points approximating the position of the thyroid, breast, ovary and testes. Measured peripheral doses at the interest points were compared for both IMRT and 3D conformal techniques for the 5 cases. Results: While tumor coverage was similar for both techniques, the IMRT delivery resulted in lower peripheral doses at points near the target (thyroid) presumably due to reduced internal scatter from a smaller effective field size for sliding window dynamic multi-leaf collimation. The IMRT delivery resulted in higher doses to the more distant points, presumably due to the higher monitor units and resulting increased head leakage. Since the magnitude of dose at the distant points was much smaller than that of the thyroid point, the overall absolute peripheral dose was similar for both techniques. Conclusions: Peripheral dose is difficult to predict by monitor units alone. In this study, interest points closer to the beam received less dose with IMRT. This difference may result from the competing factors of reduced internal scatter from dynamic multileaf collimation IMRT and reduced head leakage for 3D conformal therapy

[en] Breast cancer is the second most common cause of brain metastases in the United States. Although breast cancer induced brain metastases represent an incurable condition, some patients experience prolonged survival. In this retrospective study, we examine a cohort of patients with brain metastases from breast cancer treated with Gamma Knife stereotactic radiosurgery to identify factors that predict better outcomes. A retrospective database of 100 patients treated for brain metastases due to breast cancer via Gamma Knife radiosurgery (GKS) from July 1998 through March 2009 was reviewed. Patients who received radiosurgery as sole treatment, as a planned boost after whole brain radiotherapy or surgical resection, or as salvage after prior whole brain radiation therapy (WBRT) or surgical resection were included. Prognostic factors identified to be significant for survival in previous brain metastasis studies were analyzed for significance by univariate and multivariate Cox analysis. Overall, the median brain progression-free survival time was 7.1 months and the median survival time was 12.3 months. No prognostic variables were significant for brain progression-free survival. For patients treated with a planned GKS after WBRT, GKS as sole treatment, GKS salvage after WBRT, GKS boost after surgery, or GKS for surgical salvage the median survival times (MSTs) were as follows: 12.2 months, 12.4 months, 9.5 months, 27.6 months and 33.4 months respectively. Differences between the groups were not significant (p = 0.06); however, GKS boost after surgery and GKS for salvage after surgery did have a trend toward better overall survival. The MST for patients of age <65 years was 14.5 months, compared to age ≥65 which was 7.7 months (p = 0.06) and remained a significant prognostic factor for overall survival on multivariate analysis. The MST for patients with a single lesion was 16.9 months, not significantly different than the MST of 14.5 months for patients with 2–3 lesions. However patients with >3 lesions had a MST of 5.9 months, which was significantly worse. Breast cancer subtype as approximated by biomarkers and KPS were not significant predictors of overall survival and stage at initial diagnosis was inversely associated with survival. Stereotactic radiosurgery offers good local control and prolonged survival in selected patients. Age and number of lesions are strong predictors of overall survival

[en] 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.

[en] 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.

[en] Irradiation of the axillary nodes is often indicated in the clinical radiotherapy of patients with lymphoma and breast cancer. The relative location of the axillary nodes and the humeral head has historically been estimated based on lymphangiographic data. Since CT offers more precise definition, the axillary nodal region in relation to the humeral head was systematically studied in 61 patients undergoing CT simulation for breast conservation therapy. Differences in arm position (degree of abduction) significantly affected the location of the axillary nodal region in relation to the humeral head. With the arm abducted beyond 55 degrees, humeral head blocking would result in blocking of some of the axillary nodes

[en] Purpose: To evaluate the dose distribution outside of a cyst instilled with phosphorous-32 (P-32, an electron emitter with a short effective range of 2-8 mm and average energy of 0.69 MeV, used to treat cystic craniopharyngioma) as a function of cyst size with and without plating (migration and adhesion of P-32 to the cyst surface). Methods and Materials: A cystic craniopharyngioma treated with instillation of P-32 was approximated by a sphere of uniformly distributed and plated chromic P-32 colloid. The percent depth dose was calculated along a radial position vector exterior to the sphere with a three-dimensional convolution integral and a dose point kernel. Results: The percent depth dose variation of surface or volume source external to a family of spheres was plotted. Complex cyst geometry is amenable to evaluation by approximation with simple spheres. Error estimates are calculated for the dose outside of truncated sphere segments. Plating might occur and raise the dose outside the cyst by more than a factor of 5.0. This has the potential to cause damage to adjacent tissues, including the optic chiasm. Conclusion: Clinicians are faced with a number of treatment options for cystic craniopharyngioma, including intracystic instillation of colloid P-32. Unfortunately, plating might occur and potentially damage adjacent normal tissues. It is recommended that the propensity for a craniopharyngioma to plate be evaluated before full treatment, especially after previous treatment