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DNA damage checkpoints are complex signal transduction pathways that are critical for normal cellular recovery following potentially lethal genotoxic insults. The ataxia-telangiectasia mutated (ATM) protein kinase is a critical component in these pathways and integrates the cellular response to damage by phosphorylating key proteins involved in cell cycle regulation and DNA repair. Lack of normal ATM function in the inherited ataxia-telangiectasia (A-T) syndrome results in a pleiotropic clinical syndrome characterized by a marked increased risk of cancer and profound hypersensitivity to ionizing radiation. Cells derived from patients with A-T share some of these attributes with genomic instability, loss of normal cell cycle arrest pathways, defects in DNA repair and increased radiation sensitivity. The radiosensitivity of A-T cells suggests that pharmacological inhibitors of the ATM kinase should be effective radiosensitizing agents. In fact, caffeine inhibits ATM kinase activity at concentrations that result in an A-T—like phenotype with loss of cell cycle checkpoints and hypersensitivity to ionizing radiation. Although the clinical use of caffeine as a radiosensitizer is limited by potentially lethal systemic toxicities, more potent methyl xanthines may selectively inhibit the ATM pathway at clinically achievable levels. Interestingly, caffeine and other methyl xanthines preferentially radiosensitize cells that lack normal p53 function. Because p53 is commonly inactivated in epithelial malignancies, this suggests that small molecule inhibitors of ATM might selectively sensitize the majority of tumors to the lethal effects of ionizing radiation while sparing normal tissues.

Purpose To examine the incidence of seed migration detected on chest X-ray and to identify the predictors associated with its occurrence. Methods and materials Between May 1998 and April 2000, 102 patients underwent permanent prostate brachytherapy at our institution and 100 were eligible for the study. Chest X-rays obtained at follow-up were examined for the number and location of seeds. The patient and treatment variables potentially associated with the occurrence and number of seed migrations were analyzed. Results One or more seeds were identified on the chest X-rays of 55 (55%) of 100 patients. The mean number of intrathoracic seeds in patients with migration was 2.2 (range, 1–10), and the proportion of seeds that migrated to the thorax was 0.98%. The rate of extraprostatic seeds planned was 43.9%, and postimplant CT identified 37.9% in such a location. The number of seeds planned for extraprostatic placement and below the apex were statistically significant (α = 0.05) predictors in univariate logistic analysis. Multivariate analysis revealed the planned number of extraprostatic seeds as the only statistically significant predictor ( p = 0.04). Conclusion Extraprostatic placement of loose seeds is associated with an increased likelihood for, and frequency of, seed migration to the thorax. Nonetheless, the small proportion of implanted seeds that migrated (≤1%) is highly unlikely to have significant dosimetric consequences.

The mammalian target of rapamycin (mTOR) modulates key signaling pathways that promote uncontrolled proliferation of glioblastoma multiforme (GBM). Because rapid tumor proliferation may contribute to the clinical radioresistance of GBM tumors, the combination of rapamycin, a selective mTOR inhibitor, and radiation was studied in vitro and in vivo in a GBM model. In monolayer cultures of U87 and SKMG-3 cells, rapamycin had no impact on radiation sensitivity. In contrast, rapamycin significantly enhanced the efficacy of fractionated radiation of established U87 xenografts in nude mice. Similar effects were seen in U87 spheroids treated with rapamycin and radiation, which suggests that the sensitizing effects of this drug are dependent on disruption of mTOR signaling pathways specifically within tumor cells. Inhibition of these signaling pathways can lead to inhibition of G(1)-specific cyclin-dependent kinase activities, and this could contribute to the sensitizing effects of rapamycin. Consistent with this idea, roscovitine, a specific cyclin-dependent kinase inhibitor, also enhanced the efficacy of fractionated radiation in U87 spheroids. These data demonstrate that inhibition of tumor proliferation does not diminish the efficacy of fractionated radiation and suggest that disruption of key signal transduction pathways may significantly enhance the effectiveness of radiation therapy in malignant gliomas.

Purpose: The effect of high-dose radiation therapy on facial nerve grafts is controversial. Some authors believe radiotherapy is so detrimental to the outcome of facial nerve graft function that dynamic or static slings should be performed instead of facial nerve grafts in all patients who are to receive postoperative radiation therapy. Unfortunately, the facial function achieved with dynamic and static slings is almost always inferior to that after facial nerve grafts. In this retrospective study, we compared facial nerve function in irradiated and unirradiated nerve grafts. Methods and Materials: The medical records of 818 patients with neoplasms involving the parotid gland who received treatment between 1974 and 1997 were reviewed, of whom 66 underwent facial nerve grafting. Fourteen patients who died or had a recurrence less than a year after their facial nerve graft were excluded. The median follow-up for the remaining 52 patients was 10.6 years. Cable nerve grafts were performed in 50 patients and direct anastomoses of the facial nerve in two. Facial nerve function was scored by means of the House–Brackmann (H-B) facial grading system. Twenty-eight of the 52 patients received postoperative radiotherapy. The median time from nerve grafting to start of radiotherapy was 5.1 weeks. The median and mean doses of radiation were 6000 and 6033 cGy, respectively, for the irradiated grafts. One patient received preoperative radiotherapy to a total dose of 5000 cGy in 25 fractions and underwent surgery 1 month after the completion of radiotherapy. This patient was placed, by convention, in the irradiated facial nerve graft cohort. Results: Potential prognostic factors for facial nerve function such as age, gender, extent of surgery at the time of nerve grafting, preoperative facial nerve palsy, duration of preoperative palsy if present, or number of previous operations in the parotid bed were relatively well balanced between irradiated and unirradiated patients. However, the irradiated graft group had a greater proportion of patients with pathologic evidence of nerve invasion ( p = 0.007) and unfavorable type of nerve graft ( p = 0.04). Although the irradiated graft cohort had more potentially negative prognostic factors, there was no difference in functional outcome (H-B Grade III or IV) between irradiated and unirradiated graft patients. H-B Grades III, IV, V, and VI were the best postoperative facial nerve functions achieved in 35%, 39%, 13%, and 13% of patients, respectively. The patient with preoperative radiotherapy never recovered any facial nerve function (H-B Grade VI). Median time to best facial nerve function after surgery was longer in the irradiated patients (13.1 vs. 10.8 months), but this was not statistically significant ( p = 0.10). Presence of preoperative facial nerve palsy ( p = 0.005), duration of preoperative palsy ( p = 0.003), and age greater than 60 years at the time of grafting ( p = 0.04) were all negative prognostic factors for achieving a functional facial nerve on univariate analysis. Analysis of age as a continuous variable ( p = 0.12) and pathologic evidence of nerve invasion ( p = 0.1) revealed a trend toward negative prognostic factors. Gender, number of previous operations in the parotid bed, extent of surgery at the time of nerve grafting, and type of grafting procedure were not significant prognostic factors. Whether radiotherapy was delivered less than 6 weeks after nerve grafting or more than 6 weeks had no impact on achievement of a functional facial nerve. Conclusion: Negative prognostic factors for achieving a functional facial nerve in our series include the presence of preoperative facial nerve palsy, duration of preoperative palsy, and age greater than 60 years. Radiotherapy was not a negative prognostic factor. Comparing irradiated and unirradiated grafts revealed no difference in best facial nerve function achieved, despite the presence of a greater proportion of negative prognostic factors in the irradiated group. Therefore, planned postoperative radiation therapy is not a contraindication to facial nerve grafting. Consideration for regeneration of the facial nerve should not influence the timing of postoperative radiotherapy, because early initiation of radiotherapy after facial nerve grafting did not have a deleterious effect on facial nerve function. However, the time required to attain best facial nerve function postoperatively may be slightly longer in irradiated patients.

A 66-year-old man with coronary artery disease and a history of myocardial infarction underwent transperineal interstitial permanent prostate brachytherapy for localized prostatic adenocarcinoma in 1999. The 124 iodine loose radioactive seeds were implanted in the prostate and periprostatic tissues. On the day of brachytherapy a routine post-implant pelvic computerized tomography showed 46 seeds placed in extraprostatic locations immediately adjacent to the prostate. Two months following brachytherapy a chest x-ray revealed that 2 seeds had migrated to the mid right ventricle and 1 to the upper lobe of the right lung. Nine months after brachytherapy the patient died of acute cardiac dysrhythmia, which was unrelated to the presence of seeds in the heart. At postmortem examination the heart was dissected first by making several transverse slices through both ventricles. At the mid ventricular level 1 seed was discovered free in the lateral right ventricular cavity and 1 seed was next to it but adherent to the endocardium and encapsulated in a thin fibrous sheath (see figure). No gross or microscopic injury to the adjacent myocardium was present.