An agonistic anti-Tie2 antibody suppresses the normal-to-tumor vascular transition in the glioblastoma invasion zone.

Tumor progression is intimately associated with the vasculature, as tumor proliferation induces angiogenesis and tumor cells metastasize to distant organs via blood vessels. However, whether tumor invasion is associated with blood vessels remains unknown. As glioblastoma (GBM) is featured by aggressive invasion and vascular abnormalities, we characterized the onset of vascular remodeling in the diffuse tumor infiltrating zone by establishing new spontaneous GBM models with robust invasion capacity. Normal brain vessels underwent a gradual transition to severely impaired tumor vessels at the GBM periphery over several days. Increasing vasodilation from the tumor periphery to the tumor core was also found in human GBM. The levels of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) showed a spatial correlation with the extent of vascular abnormalities spanning the tumor-invading zone. Blockade of VEGFR2 suppressed vascular remodeling at the tumor periphery, confirming the role of VEGF-VEGFR2 signaling in the invasion-associated vascular transition. As angiopoietin-2 (ANGPT2) was expressed in only a portion of the central tumor vessels, we developed a ligand-independent tunica interna endothelial cell kinase 2 (Tie2)-activating antibody that can result in Tie2 phosphorylation in vivo. This agonistic anti-Tie2 antibody effectively normalized the vasculature in both the tumor periphery and tumor center, similar to the effects of VEGFR2 blockade. Mechanistically, this antibody-based Tie2 activation induced VE-PTP-mediated VEGFR2 dephosphorylation in vivo. Thus, our study reveals that the normal-to-tumor vascular transition is spatiotemporally associated with GBM invasion and may be controlled by Tie2 activation via a novel mechanism of action.

Comparison between Anterior Cervical Decompression with Fusion and Posterior Cervical Fusion with Wide Facetectomy for Treatment of Severe Bony Foraminal Stenosis.

OBJECTIVE: To compare the anterior cervical discectomy and fusion (ACDF) and posterior cervical fusion (PCF) with wide facetectomy in the treatment of parallel-shaped bony foraminal stenosis (FS). METHODS: Thirty-six patients underwent surgery due to one-or-two levels of parallel-shaped cervical FS. ACDF was performed in 16 patients, and PCF using CPS was performed in 20 patients. All patients were followed up at 1, 3, 6, and 12 months postoperatively. Standardized outcome measures such as Numeric rating scale (NRS) score for arm/neck pain and Neck disability index (NDI) were evaluated. Cervical radiographs were used to compare the C2-7 Cobb's angle, segmental angle, and fusion rates. RESULTS: There was an improvement in NRS scores after both approaches for radicular arm pain (mean change -6.78 vs. -8.14, p=0.012), neck pain (mean change -1.67 vs. -4.36, p=0.038), and NDI score (-19.69 vs. -18.15, p=0.794). The segmental angle improvement was greater in the ACDF group than in the posterior group (9.4°±2.7° vs. 3.3°±5.1°, p=0.004). However, there was no significant difference in C2-7 Cobb angle between groups (16.2°±7.9° vs. 14.8°±8.5°, p=0.142). As a complication, dysphagia was observed in one case of the ACDF group. CONCLUSION: In the treatment of parallel-shaped bony FS up to two surgical levels, segmental angle improvement was more favorable in patients who underwent ACDF. However, PCF with wide facetectomy using CPS should be considered as an alternative treatment option in cases where the anterior approach is burdensome.

Single-fraction versus hypofractionated stereotactic radiosurgery for medium-sized brain metastases of 2.5 to 3 cm.

PURPOSE: Given recently suggested utility of hypofractionated stereotactic radiosurgery (SRS) in treating large brain metastases (BMs) > 3 cm, we sought to prospectively control tumor size variable to investigate the efficacy and safety of hypofractionated SRS for medium-sized BMs (2.5 to 3 cm) compared with single-fraction SRS. METHODS: Between 2011 and 2015, a total of 100 patients with newly diagnosed BMs (n = 105) of 2.5 to 3 cm had been treated with either single-fraction (n = 67; median dose 20 Gy) or hypofractionated SRS (n = 38; median cumulative dose 35 Gy in 5 daily fractions). No patients received any prior or upfront whole brain radiotherapy. In each patient, treatment outcome was measured by local tumor control (LTC), overall and progression-free survival (OS and PFS), and the occurrence of radiation necrosis (RN). RESULTS: With a median follow-up of 14 months, significant differences were observed between the single-fraction versus hypofractionated SRS groups in the incidence of RN (29.9% vs. 5.3%, P < 0.001) and LTC (1-year LTC rates 66.6% vs. 92.4%, P = 0.028). There were no differences in PFS (median 6 months vs. 6 months, P = 0.381) and OS (median 13 months vs. 18 months, P = 0.239). Treatment-related adverse events ( ≥ grade 2 toxicity by CTCAE ver. 4.0) occurred more frequently in single-fraction group, although the difference did not reach statistical significance (56.3% vs. 36.1%, P = 0.084). CONCLUSIONS: Our results suggest a better safety and efficacy profile of hypofractionated SRS for medium-sized BMs compared with single-fraction SRS. Further prospective studies are needed to confirm these results.

Cervical vertebral body fracture with ankylosing spondylitis treated with cervical pedicle screw: A fracture body overlapping reduction technique.

We describe a patient with ankylosing spondylitis (AS) with cervical spinal fracture treated with cervical pedicle screw placement (CPS) through a single posterior approach. A 43-year-old male patient with AS visited our emergency centre due to paralysis following a trauma. Coronal reconstructed cervical spine computed tomography (CT) scan showed a C5 oblique fracture, and the bilateral pedicles were separated superiorly and inferiorly. The sagittal reconstructed CT image revealed bamboo spine and C5 vertebrae body fracture. Hyperextension between the fractured segments of the C5 body was noted because the fracture gap was anteriorly open. Magnetic resonance imaging (MRI) showed cord compression and injury at the C4-5 level. CPS was performed at the C3-6 levels. Because the left and right pedicles were displaced superiorly and inferiorly, dual compressions between the left C5 and left C6 pedicle screws and between the right C5 and right C4 pedicle screws were performed. Decompression at the C4 and C5 levels was performed after identifying good alignment. This posterior fusion surgery was performed for two hours. After surgery, the radiograph showed complete reduction and fracture gap apposition. The patient was rehabilitated, and his muscle strength improved. Postoperative CT and X-rays revealed complete fracture site fusion and correct CPS position. Considering increased morbidity of long-level or -duration surgery, our fracture body overlapping technique using CPS and posterior only approach seems to be a possible and good surgical method in traumatic cervical fracture with AS.

Hypofractionated stereotactic radiosurgery for pituitary metastases.

Pituitary metastases (PMs) are uncommon, representing only 1% of pituitary lesions. The diagnosis of PMs can be challenging and an optimal management remains to be determined. Here, we present a pilot clinical study on the efficacy and safety of hypofractionated stereotactic radiosurgery (SRS) with an optimized dosimetric plan in treating PMs. Between June 2013 and December 2014, seven consecutive patients (4 men and 3 women; median age 62 years) had been diagnosed with PMs based on their characteristic clinical and radiological features and subsequently treated using hypofractionated SRS. Primary cancers originated from the lung (n = 5) or the breast (n = 2). All patients presented with diabetes insipidus (DI). Anterior pituitary and visual dysfunction were combined in 4 and 3 patients, respectively. On magnetic resonance imaging (MRI), PMs involved the pituitary stalk and/or the posterior lobe in all patients. SRS of a cumulative marginal dose 31 Gy with dose-volume constraints for the optic apparatus was delivered in 5 daily fractions. As results, tumor was locally controlled in all patients with substantial responses on MRI (including complete remission in 4 patients). The median survival time was 14 months (range, 6-24 months) after SRS. DI and visual dysfunction improved in all patients, although anterior pituitary dysfunction did not recover. No patients experienced any deterioration in visual, pituitary, or other cranial nerve functions. These results suggest a promising role of hypofractionated SRS in treating PMs in terms of both tumor control and functional outcomes.