Stereotactic radiosurgery for spinal neoplasms: current status and future perspective.

Stereotactic radiosurgery (SRS) is increasingly utilized for the treatment of primary and metastatic spinal tumors. SRS implies high dose per fraction radiation (typically >5 Gy per fraction) is delivered to an image-guided target in 1 to 5 fractions by using conformal radiation techniques. Its use is based on the radiobiological superiority of hypofractionated high dose radiation and precision of radiation delivery using real time image-guidance facilities. Spine SRS devices can be classified into two groups according to the type of treatment unit: Cyberknife (Accuray, Inc., Sunnyvale, CA, USA) and multileaf collimation (MLC) linear accelerator (LINAC) systems. The major indications for the use of SRS include primary and metastatic spine tumors. In spine metastasis, SRS was reported to be highly effective at decreasing pain, regardless of prior radiation, with an overall pain improvement rate of 85% and local control rate of approximately 90%. Improved local control could lead to more effective palliation and potentially longer survival. Some of benign spinal disease such as schwannoma, neurofibroma, meningioma, hemangioblastoma and vascular malformations were also treated. Complications associated with spinal SRS have been rarely reported, myelopathy risk is estimated to be 0.4% of treated patients. We believe that SRS is an established treatment for patients with spinal tumors, which is both safe and highly effective. The purpose of this review is to introduce principles of spinal SRS and summarize the literature regarding the usefulness of SRS for treatment of spinal neoplasms.

Stereotactic radiosurgery for primary and metastatic sarcomas involving the spine.

The treatment for spinal sarcomas is difficult due to inadequate surgical margin and an inability to deliver high dose radiation. Advanced technology of stereotactic radiosurgery (SRS) enabled higher biological effective doses of radiation to be delivered to spinal sarcomas by hypofractionation method. The authors evaluated local control rate following SRS for primary and metastatic spinal sarcomas. Thirty-two spinal sarcomas (10 primary tumors, 22 metastatic tumors) in 27 patients were treated by SRS from November 2002 to September 2009. Patients were assessed for pain status, neurological status and radiological response by regular follow-up. Overall survival and local progression-free survival were calculated and prognostic factors were sought. Median tumor volume was 18.6 ml. Radiation doses to the tumor margins ranged from 16 to 45 Gy in one to three fractions, and the median single session equivalent dose was 21.8 Gy. Follow-up ranged from 4 to 68 months (median, 22 months). Overall median survival was 29 months and no related prognostic factors were identified. During follow-up, pain was controlled in 89.3% (25/28) lesions at 6 months, in 68.2% (15/22) at 1 year, and in 61.5% (8/13) at 2 years. Tumor volume was found to be significantly related to post-SRS pain control rate. Radiological evaluation showed that local control was maintained in 96.7% (29/30) lesions at 6 months, in 78.3% (18/23) at 1 year, and in 76.9% (10/13) at 2 years. Radiation dose and tumor volume were found to be related to radiological control at 24 months following SRS. Nine cases developed recurrence between 2 and 33 months, median local progression-free survival was 23 months. Age was found to be predictive of local progression-free survival (P = 0.009). SRS proved to be an effective modality for the local control of primary and metastatic spinal sarcomas, and age was significantly related to local recurrence.

Partial deficiency of DNA-PKcs increases ionizing radiation-induced mutagenesis and telomere instability in human cells.

The correct repair of DNA double-strand breaks (DSBs) is essential to maintaining the integrity of the genome. Misrepair of DSBs is detrimental to cells and organisms, leading to gene mutation, chromosomal aberration, and cancer development. Nonhomologous end-joining (NHEJ) is one of the principal rejoining processes in most higher eukaryotic cells. NHEJ is facilitated by DNA-dependent protein kinase (DNA-PK), which is composed of a catalytic subunit, DNA-PKcs, and the heterodimeric DNA binding regulatory complex Ku70/86. Null mutation of DNA-PKcs leads to immunodeficiency, chromosomal aberration, gene mutation, telomeric end-capping failure, and cancer predisposition in animals and cells. However, it is unknown whether partial deficiency of DNA-PKcs as might occur in a fraction of the population (e.g., heterozygotes), influences cellular function. Using small interfering RNA (siRNA) transfection, we established partial deficiency of DNA-PKcs in human cells, ranging from 4 to 85% of control levels. Our results reveal for the first time, that partial deficiency of DNA-PKcs leads to increased ionizing radiation (IR)-induced mutagenesis, cell killing, and telomere dysfunction. Radiation mutagenesis was increased inversely with DNA-PKcs protein level, with the most pronounced effect being observed in cells with protein levels below 50% of controls. A small but statistically significant increase in IR-induced cell killing was observed as DNA-PKcs levels decreased, over the entire range of protein levels. Frequencies of IR-induced telomere-DSB fusion was increased at levels of DNA-PKcs as low as approximately 50%, similar to what would be expected in heterozygous individuals. Taken together, our results suggest that even partial deficiency of DNA repair proteins may represent a considerable risk to genomic stability.

The effects of NBS1 knockdown by small interfering RNA on the ionizing radiation-induced apoptosis in human lymphoblastoid cells with different p53 status.

Mutations of NBS1 are responsible for the human hereditary disease Nijmegen breakage syndrome (NBS), which is characterized by an extremely high cancer rate. In this study, we investigated the influence of NBS1 on ionizing radiation (IR) induced apoptosis. Using small interfering RNA (siRNA) transfection, we knocked down NBS1 protein in three closely related human lymphoblastoid cell lines differing in p53 status: TK6 with a wild-type p53, NH32 with a null mutation of p53, and WTK1 with a mutant p53. We found that up to 48h after 5Gy IR, all three lines showed an obvious induction of apoptosis regardless of the p53 status. The magnitude of apoptosis induction was TK6>NH32>WTK1. This suggested that although p53 is an important modulator of IR-induced apoptosis, other p53-independent apoptosis pathway also exists. Moreover, NBS1 knockdown led to reduction of IR-induced apoptosis in all three lines and both NBS1/ATM/p53/BAX and NBS1/ATM/CHK2/E2F1 apoptosis pathways were partially inactivated. Our results suggest that NBS1 plays an important role in IR-induced apoptosis via both p53-dependent and p53-independent mechanisms. The impaired apoptosis response to DNA damage in NBS1 deficient cells might be one of the important mechanisms of cancer predisposition in NBS patients.

NBS1 knockdown by small interfering RNA increases ionizing radiation mutagenesis and telomere association in human cells.

Hypomorphic mutations which lead to decreased function of the NBS1 gene are responsible for Nijmegen breakage syndrome, a rare autosomal recessive hereditary disorder that imparts an increased predisposition to development of malignancy. The NBS1 protein is a component of the MRE11/RAD50/NBS1 complex that plays a critical role in cellular responses to DNA damage and the maintenance of chromosomal integrity. Using small interfering RNA transfection, we have knocked down NBS1 protein levels and analyzed relevant phenotypes in two closely related human lymphoblastoid cell lines with different p53 status, namely wild-type TK6 and mutated WTK1. Both TK6 and WTK1 cells showed an increased level of ionizing radiation-induced mutation at the TK and HPRT loci, impaired phosphorylation of H2AX (gamma-H2AX), and impaired activation of the cell cycle checkpoint regulating kinase, Chk2. In TK6 cells, ionizing radiation-induced accumulation of p53/p21 and apoptosis were reduced. There was a differential response to ionizing radiation-induced cell killing between TK6 and WTK1 cells after NBS1 knockdown; TK6 cells were more resistant to killing, whereas WTK1 cells were more sensitive. NBS1 deficiency also resulted in a significant increase in telomere association that was independent of radiation exposure and p53 status. Our results provide the first experimental evidence that NBS1 deficiency in human cells leads to hypermutability and telomere associations, phenotypes that may contribute to the cancer predisposition seen among patients with this disease.

Surgical treatment for thoracic spinal stenosis.

OBJECTIVES: To describe the underlying causes, surgical results and prognostic factors in thoracic stenosis causing myelopathy. METHODS: The underlying causes and surgical results were analyzed retrospectively in 28 cases of thoracic spinal stenosis which caused myelopathy. Degenerative spondylosis was the most common cause, and three cases were associated with systemic diseases. Decompressive laminectomy was performed in 24 cases, anterior decompression in five cases, and combined decompression in one case. Ossification of ligamentum flavum was found in 18 cases, facet hypertrophy in 13, ossification of posterior longitudinal ligament in six, and ventral spur in four. Postoperatively 16 patients improved and four patients worsened. Follow-up ranged from 2 months to 5 years and 8 months). Statistical analysis was performed using a chi(2) test to investigate the relationship between subjects. Multivariant analysis (general linear model) was used to determine the factors which influence surgical outcome. RESULTS: There were neurological improvements in 16 patients, in whom Nurick grade changed from 3.3 preoperatively to 1.8 postoperatively. Eight patients showed no significant change in functional grade and four patients deteriorated after decompressive laminectomy. The group of which initial symptom duration was less than 2 years showed better results (P=0.006). The group with sufficient decompression and no additional proximal stenosis had better treatment outcome (P=0.005, P=0.002). CONCLUSION: Chronic severe myelopathy caused by thoracic spinal stenosis can be reversible with appropriate decompression. Surgical outcome was dependent on initial symptom duration, sufficient decompression and presence of additional proximal stenosis. SPONSORSHIP: This study was supported by a grant No. 02-1997-071-0 from the Seoul National University Hospital Research Fund.