The irregular breathing effect on target volume and coverage for lung stereotactic body radiotherapy.

The major challenge in treating a mobile target is obtaining the temporal and spatial information imaging and treatment details. This phantom study quantitatively evaluates the geometric and dosimetric effects of various treatment techniques under different respiratory patterns. The regular motion model was a sinusoidal waveform with a longitudinal range of ±1.5 cm and a period of 4 sec, while irregular motion models were generated by extracting signals from clinical cases. Helical CT for a static target and 4D CT with retrospective sorting were acquired. Phase bin, maximum, and average intensity projection (MIP and AIP) CT datasets were reconstructed. RapidArc and IMRT plans were generated on static and moving target CT datasets with different motion patterns using the phase-based gating and nongating treatment. Dose measurements were performed using EBT3 films. Dose profile and gamma analysis (±3%/1 mm criteria) were used for dose comparisons. For the irregular motions, internal target volume variations between AIP and MIP datasets (AIP/MIP) had slight differences (-6.2% to -7.7%) for gated plans, and larger differences (-12.3% to -15.2%) for nongated plans. Dosimetric measurements showed a high gamma passing rate (>98.5%) for the static plan in the target region, while the AIP and MIP gated plans had average passing rates of 92.2% ± 5.7% and 85.8% ± 9.5%, respectively. Nongated plans had significantly lower and deviated passing rates, while the AIP and MIP plans had passing rates of 43.6% ± 22.2% and 66.7% ± 28.2%, respectively (p < 0.05). Lung stereotactic body radiotherapy treatment delivered with the gated technique did not compromise the gross tumor volumes coverage, and was insensitive to the breathing irregularities and plan techniques. Adequate margins should be accounted to cover the mis-gating effect when using the phase-based gating under irregular motion.

Memantine Attenuates Delayed Vasospasm after Experimental Subarachnoid Hemorrhage via Modulating Endothelial Nitric Oxide Synthase.

Delayed cerebral vasospasm is an important pathological feature of subarachnoid hemorrhage (SAH). The cause of vasospasm is multifactorial. Impairs nitric oxide availability and endothelial nitric oxide synthase (eNOS) dysfunction has been reported to underlie vasospasm. Memantine, a low-affinity uncompetitive N-methyl-d-aspartate (NMDA) blocker has been proven to reduce early brain injury after SAH. This study investigated the effect of memantine on attenuation of vasospasm and restoring eNOS functionality. Male Sprague-Dawley rats weighing 350-450 g were randomly divided into three weight-matched groups, sham surgery, SAH + vehicle, and SAH + memantine groups. The effects of memantine on SAH were evaluated by assessing the severity of vasospasm and the expression of eNOS. Memantine effectively ameliorated cerebral vasospasm by restoring eNOS functionality. Memantine can prevent vasospasm in experimental SAH. Treatment strategies may help combat SAH-induced vasospasm in the future.

Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment.

PURPOSE: To demonstrate the feasibility of using focused ultrasound to enhance delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to glioblastomas in rats with induced tumors and determine if such an approach increases treatment efficacy. MATERIALS AND METHODS: All animal experiments were approved by the animal committee and adhered to the experimental animal care guidelines. A 400-kHz focused ultrasound generator was used to transcranially disrupt the blood-brain barrier (BBB) in rat brains by delivering burst-tone ultrasound energy in the presence of microbubbles. The process was monitored in vivo by using magnetic resonance (MR) imaging. Cultured C6 glioma cells implanted in Sprague-Dawley rats were used as the tumor model. BCNU (13.5 mg/kg) was administered intravenously and its concentration in brains was quantified by using high-performance liquid chromatography. MR imaging was used to evaluate the effect of treatments longitudinally, including analysis of tumor progression and animal survival, and brain tissues were histologically examined. Methods including the two-tailed unpaired t test and the Mantel-Cox test were used for statistical analyses, with a significance level of .05. RESULTS: Focused ultrasound significantly enhanced the penetration of BCNU through the BBB in normal (by 340%) and tumor-implanted (by 202%) brains without causing hemorrhaging. Treatment of tumor-implanted rats with focused ultrasound alone had no beneficial effect on tumor progression or on animal survival up to 60 days. Administration of BCNU only transiently controlled tumor progression; nevertheless, relative to untreated controls, animal survival was improved by treatment with BCNU alone (increase in median survival time [IST(median)], 15.7%, P = .023). Treatment with focused ultrasound before BCNU administration controlled tumor progression (day 31: 0.05 cm(3) + or - 0.1 [standard deviation] vs 0.28 cm(3) + or - 0.1) and improved animal survival relative to untreated controls (IST(median), 85.9%, P = .0015). CONCLUSION: This study demonstrates a means of increasing localized chemotherapeutic drug delivery for brain tumor treatment and strongly supports the feasibility of this treatment in a clinical setting.

Memantine alleviates brain injury and neurobehavioral deficits after experimental subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) causes brain injury via glutamate excitotoxicity, which leads to an excessive Ca(2+) influx and this starts an apoptotic cascade. Memantine has been proven to reduce brain injury in several types of brain insults. This study investigated the neuro-protective potential of memantine after SAH and explored the underlying mechanisms. An endovascular perforation rat model of SAH was used and Sprague-Dawley rats were randomized into sham surgery, SAH + vehicle, and SAH + memantine groups. The effects of memantine on SAH were evaluated by assessing the neuro-behavioral functions, blood-brain barrier (BBB) permeability and neuronal cell preservation. The mechanisms of action of memantine, with its N-methyl-D-aspartate (NMDA) antagonistic characteristics on nitric oxide synthase (NOS) expression and peroxynitrite formation, were also investigated. The apoptotic cascade after SAH was suppressed by memantine. Neuronal NOS (nNOS) expression, peroxynitrite formation, and subsequent oxidative/nitrosative stress were also reduced. Memantine effectively preserved BBB integrity, rescued neuronal injury, and improved neurological outcome in experimental SAH. Memantine has neuro-protective potential in experimental SAH and may help combat SAH-induced brain damage in the future.

Stroke suggests increased risk of dementia.

BACKGROUND: Stroke is a major cause of disability in the elderly and considerably increases the risk of dementia, which is another important source of disability. This population-based study aimed to examine the risk of dementia in patients with stroke compared with non-stroke cases with similar comorbidities. METHODS: Using the Taiwan National Health Insurance databank covering the period 2001-2007, this retrospective cohort study evaluated the risk of dementia in 10,884 patients with first stroke who had no history of dementia. In this study, we performed a 1:5 case-control matched analysis, in which cases were matched to controls based on their estimated propensity scores, which were estimated with demographics and associated risk factors. This approach reduced selection bias. Cox proportional hazards regression analysis was then used to estimate the risk of dementia in stroke patients. RESULTS: During the 5-year follow-up period, 1,487 (13.74%) stroke and 1,402 (2.59%) non-stroke patients suffered dementia. Stroke was independently associated with a 6.09 (95% confidence interval [CI], 5.66 to 6.55) times greater risk of dementia 5 years after stroke. Older age was associated with a higher incidence of dementia after stroke. Each stroke type had different impacts on the occurrence of dementia. The hazard ratio of dementia among hemorrhagic stroke patients was much higher than those of ischemic stroke and controls. CONCLUSION: The findings of this study suggest that stroke confers an increased risk of dementia, especially in the elderly and in patients with hemorrhagic stroke. We advocate the need for close observation and enhanced health education programs to benefit patients with stroke.

Opening of the blood-brain barrier by low-frequency (28-kHz) ultrasound: a novel pinhole-assisted mechanical scanning device.

Disruption of the blood-brain barrier (BBB) may be transiently achieved via high-frequency focused spherical ultrasound in the presence of microbubbles. In this experimental animal study, we sought to determine whether focal reversible opening of the BBB may be achieved using low-frequency (i.e., 20-30 kHz) planar ultrasonic waves. In the presence of microbubbles, we were able to obtain BBB opening using non-focused ultrasound irradiation with a frequency as low as 28 kHz. We also achieved a tight regulation of the ultrasound patterns by using a mechanical scanning device equipped with a pinhole. Histologic examination of the brains supported the feasibility of our system. The areas of BBB disruption obtained with this method were large enough to cover a typical circumscribed cerebral tumor mass. The inherent advantages of our BBB opening method include an improved portability, the possibility to obtain fairly wide areas of BBB opening and a low incidence of hemorrhagic complications. In addition, our system has the potential to reduce the need for image guidance for treating superficial brain lesions.