Toxicity of Gamma Knife Radiosurgery May Be Greater in Patients with Lower Cranial Nerve Schwannomas.

Objective Gamma Knife stereotactic radiosurgery (GK-SRS) is a preferred treatment option for tumors of the jugular foramen. We hypothesized that GK-SRS toxicity is higher for lower cranial nerve schwannomas than for glomus jugulare tumors despite anatomically similar locations. Methods We performed a retrospective review of all patients who received GK-SRS for glomus jugulare tumors and lower cranial nerve schwannomas at our institution between 2006 and 2014. Because of small sample sizes, Fisher's exact tests and logistic regression techniques were employed using SPSS. Result We identified 20 glomus jugulare tumors and 6 lower cranial nerve schwannoma patients with a median follow-up of 17 months. Median marginal dose was 16 Gy (range 13-18 Gy) and 12.5 Gy (range 12-14 Gy), respectively. All except one patient had tumor control at last follow-up visit. No worsening of pre-existing neurological deficits was observed. There were seven patients who developed any new neurological deficit after GK-SRS, four from the glomus group, and three from the schwannoma group (20 and 50% of each group, respectively). Only two of seven patients had permanent new neurological deficits. Both of them were in the schwannoma group. Univariate analysis showed that only a diagnosis of schwannoma had a greater risk of permanent new cranial nerve complication after GK-SRS compared with diagnosis of glomus jugulare ( p = 0.046). Conclusion Although the marginal dose for glomus jugulare is greater, our study suggests that the risk of a new permanent neurological deficit after GK-SRS was higher in the schwannoma group compared with the glomus group.

Intramedullary Recurrence of a Thoracic Meningioma-Presentation of an Unusual Case and Review of the Literature.

BACKGROUND: Spinal meningiomas are typically extra-axial, slow-growing, benign tumors that arise from the arachnoid cap cells. Intramedullary spinal meningiomas are exceedingly rare with few cases reported in the literature. CASE DESCRIPTION: A 64-year-old man with a history of grade I thoracic meningioma at the T4 level resected initially in 1989 and who required reoperation in 2013 for intradural, extramedullary recurrence of tumor presented again in 2015 with gait difficulty. Magnetic resonance imaging revealed a soft tissue mass at the T3 to T4 levels on the left side of the canal that was mildly enhancing on T1 contrasted sequences. The patient was taken to the operating room, where a purely intramedullary recurrence was discovered without extramedullary extension or a dural-based attachment. The intramedullary tumor was completely resected, and postoperatively the patient recovered well and was at his neurologic baseline. The patient ultimately underwent proton beam radiotherapy because this tumor, although benign, had recurred twice. CONCLUSIONS: Intramedullary spinal meningiomas, particularly intramedullary low-grade recurrence of a previously extramedullary tumor, are rare phenomena. Although the pathogenic mechanisms are not well understood, intramedullary recurrence as described in this patient may reflect extrinsic factors related to prior surgical resections in addition to histologic progression. When operating on recurrent extramedullary lesions, aggressive arachnoid dissection may predispose patients to unusual patterns of recurrence.

Novel risk scores for survival and intracranial failure in patients treated with radiosurgery alone to melanoma brain metastases.

PURPOSE: Stereotactic radiosurgery (SRS) alone is an increasingly common treatment strategy for brain metastases. However, existing prognostic tools for overall survival (OS) were developed using cohorts of patients treated predominantly with approaches other than SRS alone. Therefore, we devised novel risk scores for OS and distant brain failure (DF) for melanoma brain metastases (MBM) treated with SRS alone. METHODS AND MATERIALS: We retrospectively reviewed 86 patients treated with SRS alone for MBM from 2009-2014. OS and DF were estimated using the Kaplan-Meier method. Cox proportional hazards modeling identified clinical risk factors. Risk scores were created based on weighted regression coefficients. OS scores range from 0-10 (0 representing best OS), and DF risk scores range from 0-5 (0 representing lowest risk of DF). Predictive power was evaluated using c-index statistics. Bootstrapping with 200 resamples tested model stability. RESULTS: The median OS was 8.1 months from SRS, and 54 (70.1 %) patients had DF at a median of 3.3 months. Risk scores for OS were predicated on performance status, extracranial disease (ED) status, number of lesions, and gender. Median OS for the low-risk group (0-3 points) was not reached. For the moderate-risk (4-6 points) and high-risk (6.5-10) groups, median OS was 7.6 months and 2.4 months, respectively (p < .0001). Scores for DF were predicated on performance status, ED status, and number of lesions. Median time to DF for the low-risk group (0 points) was not reached. For the moderate-risk (1-2 points) and high-risk (3-5 points) groups, time to DF was 4.8 and 2.0 months, respectively (p < .0001). The novel scores were more predictive (c-index = 0.72) than melanoma-specific graded prognostic assessment or RTOG recursive partitioning analysis tools (c-index = 0.66 and 0.57, respectively). CONCLUSIONS: We devised novel risk scores for MBM treated with SRS alone. These scores have implications for prognosis and treatment strategy selection (SRS versus whole-brain radiotherapy).

Stereotactic radiosurgery to the resection bed for intracranial metastases and risk of leptomeningeal carcinomatosis.

OBJECT: Following resection of a brain metastasis, stereotactic radiosurgery (SRS) to the cavity is an emerging alternative to postoperative whole-brain radiation therapy (WBRT). This approach attempts to achieve local control without the neurocognitive risks associated with WBRT. The authors aimed to report the outcomes of a large patient cohort treated with this strategy. METHODS: A retrospective review identified 91 patients without a history of WBRT who received Gamma Knife (GK) SRS to 96 metastasis resection cavities between 2007 and 2013. Patterns of intracranial control were examined in the 86 cases with post-GK imaging. Survival, local failure, and distant failure were estimated by the Kaplan-Meier method. Prognostic factors were tested by univariate (log-rank test) and multivariate (Cox proportional hazards model) analyses. RESULTS: Common primary tumors were non-small cell lung (43%), melanoma (14%), and breast (13%). The cases were predominantly recursive partitioning analysis Class I (25%) or II (70%). Median preoperative metastasis diameter was 2.8 cm, and 82% of patients underwent gross-total resection. A median dose of 16 Gy was delivered to the 50% isodose line, encompassing a median treatment volume of 9.2 cm(3). Synchronous intact metastases were treated in addition to the resection bed in 43% of cases. Patients survived a median of 22.3 months from the time of GK. Local failure developed in 16 cavities, for a crude rate of 18% and 1-year actuarial local control of 81%. Preoperative metastasis diameter ≥ 3 cm and residual or recurrent tumor at the time of GK were associated with local failure (p = 0.04 and 0.008, respectively). Distant intracranial failure occurred in 55 cases (64%) at a median of 7.3 months from GK. Salvage therapies included WBRT and additional SRS in 33% and 31% of patients, respectively. Leptomeningeal carcinomatosis developed in 12 cases (14%) and was associated with breast histology and infratentorial cavities (p = 0.024 and 0.012, respectively). CONCLUSIONS: This study bolsters the existing evidence for SRS to the resection bed. Local control rates are high, but patients with larger preoperative metastases or residual/recurrent tumor at the time of SRS are more likely to fail at the cavity. While most patients develop distant intracranial failure, an SRS approach spared or delayed WBRT in the majority of cases. The risk of leptomeningeal carcinomatosis does not appear to be elevated with this strategy.

Stage migration in planning PET/CT scans in patients due to receive radiotherapy for non-small-cell lung cancer.

INTRODUCTION: This study examined rates of tumor progression in treatment-naive patients with non-small-cell lung cancer (NSCLC) as determined by repeat treatment-planning fluorine-18 ((18)F) fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT). METHODS AND MATERIALS: This study assessed patients who underwent PET/CT simulation for NSCLC stage II/III, radiation-naive, nonmetastatic NSCLC. It compared planning PET/CT with previous PET/CT images. Patients were analyzed for change in stage, treatment intent, or both. Progression was defined as a change in TNM status leading to upstaging, and standardized uptake value (SUV) velocity was defined as [(SUVscan2 - SUVscan1)/interscan interval in days]. RESULTS: Of 149 consecutive patients examined between April 2009 and April 2011, 47 had prior PET/CT scans and were included. The median age was 68 years. New nodal disease or metastatic disease was identified in 24 (51%) of 47 patients. Fourteen (30%) had evidence of extrathoracic metastatic disease; the remaining 10 (21%) had new nodal disease that required substantial alteration of treatment fields. At a scan interval of 20 days, the rate of upstaging was 17%. SUV velocity was analyzed in the subset of patients who had their studies on the identical PET/CT scanner (n = 14). Nonupstaged patients had a mean SUV velocity of 0.074 units per day, compared with 0.11 units per day in patients that were upstaged by their second PET/CT scan (P = .020). CONCLUSION: Radiation treatment planning with hybrid PET/CT scans repeated within 120 days of an initial staging PET/CT scan identified significant upstaging in more than half of patients. For a subset of patients who underwent both scans on the same instrument, SUV velocity predicts upstaging, and the difference between those upstaged and those not was statistically significant.

Temozolomide-mediated radiosensitization of human glioma cells in a zebrafish embryonic system.

The zebrafish (Danio rerio) is a popular vertebrate model for biomedical research. The rapid development, transparency, and experimental accessibility of the embryo offer opportunities for assessing the developmental effects of anticancer treatment strategies. We therefore systematically investigated parameters for growing U251 human glioma cells expressing red fluorescent protein (U251-RFP) in zebrafish embryos. Factors optimized include injection volume, number of cells injected, anatomic site of injection, age of the embryo at the time of injection, and postinjection incubation temperature. After injection into the embryos, the U251-RFP cells proliferated and the resultant tumors, and even individual cells, could be visualized in real-time via fluorescence microscopy without the need for sacrifice. These tumors recruited host zebrafish vasculature, suggesting cancer cell-host tissue interactions. Having optimized parameters for introducing and growing these human cells in the zebrafish embryos, we exposed both embryos and transplanted cancer cells to ionizing radiation and temozolomide, either alone or in combination. The human tumors in each embryo were substantially diminished following exposure to ionizing radiation and the decrease was further enhanced by pretreatment with temozolomide. In contrast, temozolomide had no discernible effects on embryonic development. These results together support the relative safety of temozolomide during embryonic development, as well as its anticancer efficacy when combined with radiation. These results suggest the value of the zebrafish model for in vivo testing of the efficacy and safety of anticancer strategies, especially on the very young.

Identification and biological evaluation of a novel and potent small molecule radiation sensitizer via an unbiased screen of a chemical library.

For patients with solid tumors, the tolerance of surrounding tissues often limits the dose of radiation that can be delivered. Thus, agents that preferentially increase the cytotoxic effects of radiation toward tumor cells would significantly alter the therapeutic ratio and improve patient survival. Using a high-throughput, unbiased screening approach, we have identified 4'-bromo-3'-nitropropiophenone (NS-123) as a radiosensitizer of human glioma cells in vitro and in vivo. NS-123 radiosensitized U251 glioma cells in a dose-dependent and time-dependent manner, with dose enhancement ratios ranging from 1.3 to 2.0. HT-29 colorectal carcinoma and A549 lung adenocarcinoma cells were also radiosensitized by NS-123 in vitro, whereas NS-123 did not increase the radiation sensitivity of normal human astrocytes or developmental abnormalities or lethality of irradiated Zebrafish embryos. In a novel xenograft model of U251 cells implanted into Zebrafish embryos, NS-123 enhanced the tumor growth-inhibitory effects of ionizing radiation (IR) with no apparent effect on embryo development. Similar results were obtained using a mouse tumor xenograft model in which NS-123 sensitized U251 tumors to IR while exhibiting no overt toxicity. In vitro pretreatment with NS-123 resulted in accumulation of unrepaired IR-induced DNA strand breaks and prolonged phosphorylation of the surrogate markers of DNA damage H2AX, ataxia telangiectasia mutated protein, DNA-dependent protein kinase, and CHK2 after IR, suggesting that NS-123 inhibits a critical step in the DNA repair pathway. These results show the potential of this cell-based, high-throughput screening method to identify novel radiosensitizers and suggest that NS-123 and similar nitrophenol compounds may be effective in antiglioma modalities.

Zebrafish as a "biosensor"? Effects of ionizing radiation and amifostine on embryonic viability and development.

The zebrafish (Danio rerio) has emerged as a popular vertebrate model system for cancer and treatment-related research. Benefits include ease of care, rapid development, optical clarity of embryos, which allows visualization of major organ systems, and opportunities for genetic manipulation. However, specific parameters of radiation sensitivity have not been systematically documented. We investigated the effects of radiation and a radiomodifier on zebrafish viability and embryonic development. Embryos were exposed to gamma-radiation (5, 10, or 20 Gy) at sequential times postfertilization and serially assessed for viability and morphologic abnormalities. As expected, lethality and morphologic perturbations were more pronounced earlier in embryogenesis and with higher radiation doses and were partially reversed by amifostine. The effects of radiation and concurrent treatment with amifostine on the developmental organization of the eye and brain were striking. Radiation resulted in hypocellularity and disorganization of the cellular layers of the retina, effects partially reversed by amifostine, as well as lens opacification. Radiation strikingly reduced the volume of brain, but the volume loss was substantially blocked by amifostine. Increased terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling signal was noted in both the irradiated eye and brain, but reduced by amifostine. Finally, irradiating embryos resulted in caspase activation detectable in 96-well microplates, which was proportional to the number of embryos and radiation dose; the degree of activation was markedly reduced by amifostine. These results together suggest the power and versatility of the zebrafish in assessing the effects of radiation and radiomodifiers on organ and tissue development.