Object Whole-brain radiation therapy (WBRT), open resection, and stereotactic radiosurgery (SRS) are widely used for treatment of metastatic brain lesions, and many physicians recommend WBRT for multiple brain metastases. However, WBRT can be performed only once per patient, with rare exceptions. Some patients may require SRS for multiple metastatic brain lesions, particularly those patients harboring more than 10 lesions. In this paper, treatment results of SRS for brain metastasis were analyzed, and an attempt was made to determine whether SRS is effective, even in cases involving multiple metastatic brain lesions. Methods The authors evaluated the cases of 323 patients who underwent SRS between October 2005 and October 2008 for the treatment of metastatic brain lesions. Treatment was performed using the Gamma Knife model C or Perfexion. The patients were divided into 4 groups according to the number of lesions visible on MR images: Group 1, 1–5 lesions; Group 2, 6–10 lesions: Group 3, 11–15 lesions; and Group 4, > 15 lesions. Patient survival and progression-free survival times, taking into account both local and distant tumor recurrences, were analyzed. Results The patients consisted of 172 men and 151 women with a mean age at SRS of 59 years (range 30–89 years). The overall median survival time after SRS was 10 months (range 8.7–11.4 months). The median survival time of each group was as follows: Group 1, 10 months; Group 2, 10 months; Group 3, 13 months; and Group 4, 8 months. There was no statistical difference between survival times after SRS (log-rank test, p = 0.554), although the probability of development of new lesions in the brain was greater in Group 4 (p = 0.014). Local tumor control rates were not statistically different among the groups (log-rank test, p = 0.989); however, remote disease progression was more frequent in Group 4 (log-rank test, p = 0.014). Conclusions In this study, patients harboring more than 15 metastatic brain lesions were found to have faster development of new lesions in the brain. This may be due to the biological properties of the patients' primary lesions, for example, having a greater tendency to disseminate hematogenously, especially to the brain, or a higher probability of missed or invisible lesions (microscopic metastases) to treat on stereotactic MR images at the time of radiosurgery. However, the mean survival times after SRS were not statistically different between groups. According to the aforementioned results, SRS may be a good treatment option for local control of metastatic lesions and for improved survival in patients with multiple metastatic brain lesions, even those patients who harbor more than 15 metastatic brain lesions, who, after SRS, may have early and easily detectable new metastatic lesions.

Background: The purpose of this study was to introduce a combination procedure with double C-shaped skin incision and an adjusted dual-floor burr hole to prevent skin complications on the scalp with deep brain stimulation (DBS) surgery. Methods: Between March 2000 and March 2010, 504 DBS electrodes were implanted in 268 patients. We included both bilateral and unilateral DBS surgery cases for Parkinson’s disease, tremor, pain, obsessive-compulsive disorder and intractable seizure accompanied with cranial and IPG insertion procedure, but excluded motor cortex stimulation, and spinal cord stimulation. We used a straight skin incision in 118 patients, double C-shaped skin incision only in 113 patients since March 2006, and combined a double C-shaped skin incision and dual-floor burr hole in 37 patients since August 2009. We compared scalp wound complications and the height subscale of the Vancouver Scar Scale between previous straight or C-shaped skin incision and the combination procedure. Results: We had eight scalp erosions associated with infection (3.0%) and six disconnection (2.2%) cases among 268 patients. Before the use of the double C- skin incision or adjusted dual-floor burr hole technique, we had 5 (4.2%) scalp erosion cases among 118 patients. With the introduction of the C-shaped incision, only 3 patients (2.7%) developed scalp erosion. However, no patient among 37 patients developed scalp erosion after using both double C-shaped skin incision and dual-floor burr hole technique. Scalp bump measured by the height subscale of the Vancouver Scar Scale was more cosmetic in the combination procedure. Conclusion: The combination procedure prevents skin complications associated with DBS surgery, with tensile strength, less impaired vascular supply and better cosmetic outcome. This promising approach prevents unwanted skin complications associated with DBS surgery and improves patient satisfaction.

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Although MER can facilitate accurate positioning of electrodes, multi-track MER may increase the risk of intracranial hemorrhage. The accuracy of electrode positioning appears to be acceptable under single track MER during STN DBS with careful electrophysiological and neurological monitoring. The risk of intracranial hemorrhage appears to be minimal, especially in elderly patients with atrophic brains.

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BackgroundUp to 15% of all patients with brain metastases have no clearly detected primary site despite intensive evaluation, and this incidence has decreased with the use of improved imaging technology. Radiosurgery has been evaluated as one of the treatment modality for patients with limited brain metastases. In this study, we evaluated the effectiveness of radiosurgery for brain metastases from unknown primary tumors.MethodsWe retrospectively evaluated 540 patients who underwent gamma knife radiosurgery (GKRS) for brain metastases radiologically diagnosed between August 1992 and September 2007 in our institution. First, the brain metastases were grouped into metachronous, synchronous, and precocious presentations according to the timing of diagnosis of the brain metastases. Then, synchronous and precocious brain metastases were further grouped into 1) unknown primary; 2) delayed known primary; and 3) synchronous metastases according to the timing of diagnosis of the primary origin. We analyzed the survival time and time to new brain metastasis in each group.ResultsOf the 540 patients, 29 (5.4%) presented precocious or synchronous metastases (34 GKRS procedures for 174 lesions). The primary tumor was not found even after intensive and repeated systemic evaluation in 10 patients (unknown primary, 34.5%); found after 8 months in 3 patients (delayed known primary, 1.2%); and diagnosed at the same time as the brain metastases in 16 patients (synchronous metastasis, 55.2%). No statistically significant differences in survival time and time to new brain metastasis were found among the three groups.ConclusionIdentification of a primary tumor before GKRS did not affect the patient outcomes. If other possible differential diagnoses were completely excluded, early GKRS can be an effective treatment option for brain metastases from unknown primary tumor.

Background Glioblastoma Multiforme (GBM) is a malignant primary brain tumor in which the standard treatment, ionizing radiation (IR), achieves a median survival of about 15 months. GBM harbors glioblastoma stem-like cells (GSCs), which play a crucial role in therapeutic resistance and recurrence. Methods Patient-derived GSCs, GBM cell lines, intracranial GBM xenografts, and GBM sections were used to measure mRNA and protein expression and determine the related molecular mechanisms by qRT-PCR, immunoblot, immunoprecipitation, immunofluorescence, OCR, ECAR, live-cell imaging, and immunohistochemistry. Orthotopic GBM xenograft models were applied to investigate tumor inhibitory effects of glimepiride combined with radiotherapy. Results We report that GSCs that survive standard treatment radiation upregulate Speedy/RINGO cell cycle regulator family member A (Spy1) and downregulate CAP-Gly domain containing linker protein 3 (CLIP3, also known as CLIPR-59). We discovered that Spy1 activation and CLIP3 inhibition coordinately shift GBM cell glucose metabolism to favor glycolysis via two cellular processes: transcriptional regulation of CLIP3 and facilitating Glucose transporter 3 (GLUT3) trafficking to cellular membranes in GBM cells. Importantly, in combination with IR, glimepiride, an FDA-approved medication used to treat type 2 diabetes mellitus, disrupts GSCs maintenance and suppresses glycolytic activity by restoring CLIP3 function. In addition, combining radiotherapy and glimepiride significantly reduced GBM growth and improved survival in a GBM orthotopic xenograft mouse model. Conclusions Our data suggest that radioresistant GBM cells exhibit enhanced stemness and glycolytic activity mediated by the Spy1-CLIP3 axis. Thus, glimepiride could be an attractive strategy for overcoming radioresistance and recurrence by rescuing CLIP3 expression.

Glioblastoma multiforme (GBM) is a malignant primary brain tumor with poor patient prognosis. Although the standard treatment of GBM is surgery followed by chemotherapy and radiotherapy, often a small portion of surviving tumor cells acquire therapeutic resistance and become more aggressive. Recently, altered kinase expression and activity have been shown to determine metabolic flux in tumor cells and metabolic reprogramming has emerged as a tumor progression regulatory mechanism. Here we investigated novel kinase-mediated metabolic alterations that lead to acquired GBM radioresistance and malignancy. We utilized transcriptomic analyses within a radioresistant GBM orthotopic xenograft mouse model that overexpresses the dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3). We find that within GBM cells, radiation exposure induces DYRK3 expression and DYRK3 regulates mammalian target of rapamycin complex 1 (mTORC1) activity through phosphorylation of proline-rich AKT1 substrate 1 (PRAS40). We also find that DYRK3 knockdown inhibits dynamin-related protein 1 (DRP1)-mediated mitochondrial fission, leading to increased oxidative phosphorylation (OXPHOS) and reduced glycolysis. Importantly, enforced DYRK3 downregulation following irradiation significantly impaired GBM cell migration and invasion. Collectively, we suggest DYRK3 suppression may be a novel strategy for preventing GBM malignancy through regulating mitochondrial metabolism.