Naokatsu Saeki

Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study

BACKGROUND We aimed to examine whether stereotactic radiosurgery without whole-brain radiotherapy (WBRT) as the initial treatment for patients with five to ten brain metastases is non-inferior to that for patients with two to four brain metastases in terms of overall survival. METHODS This prospective observational study enrolled patients with one to ten newly diagnosed brain metastases (largest tumour <10 mL in volume and <3 cm in longest diameter; total cumulative volume ≤15 mL) and a Karnofsky performance status score of 70 or higher from 23 facilities in Japan. Standard stereotactic radiosurgery procedures were used in all patients; tumour volumes smaller than 4 mL were irradiated with 22 Gy at the lesion periphery and those that were 4-10 mL with 20 Gy. The primary endpoint was overall survival, for which the non-inferiority margin for the comparison of outcomes in patients with two to four brain metastases with those of patients with five to ten brain metastases was set as the value of the upper 95% CI for a hazard ratio (HR) of 1·30, and all data were analysed by intention to treat. The study was finalised on Dec 31, 2012, for analysis of the primary endpoint; however, monitoring of stereotactic radiosurgery-induced complications and neurocognitive function assessment will continue for the censored subset until the end of 2014. This study is registered with the University Medical Information Network Clinical Trial Registry, number 000001812. FINDINGS We enrolled 1194 eligible patients between March 1, 2009, and Feb 15, 2012. Median overall survival after stereotactic radiosurgery was 13·9 months [95% CI 12·0-15·6] in the 455 patients with one tumour, 10·8 months [9·4-12·4] in the 531 patients with two to four tumours, and 10·8 months [9·1-12·7] in the 208 patients with five to ten tumours. Overall survival did not differ between the patients with two to four tumours and those with five to ten (HR 0·97, 95% CI 0·81-1·18 [less than non-inferiority margin], p=0·78; pnon-inferiority<0·0001). Stereotactic radiosurgery-induced adverse events occurred in 101 (8%) patients; nine (2%) patients with one tumour had one or more grade 3-4 event compared with 13 (2%) patients with two to four tumours and six (3%) patients with five to ten tumours. The proportion of patients who had one or more treatment-related adverse event of any grade did not differ significantly between the two groups of patients with multiple tumours (50 [9%] patients with two to four tumours vs 18 [9%] with five to ten; p=0·89). Four patients died, mainly of complications relating to stereotactic radiosurgery (two with one tumour and one each in the other two groups). INTERPRETATION Our results suggest that stereotactic radiosurgery without WBRT in patients with five to ten brain metastases is non-inferior to that in patients with two to four brain metastases. Considering the minimal invasiveness of stereotactic radiosurgery and the fewer side-effects than with WBRT, stereotactic radiosurgery might be a suitable alternative for patients with up to ten brain metastases. FUNDING Japan Brain Foundation.

Alcohol consumption and frontal lobe shrinkage: study of 1432 non-alcoholic subjects

OBJECTIVES To evaluate the influences of chronic alcohol consumption on brain volume among social drinkers, as it is well known that alcohol misusers have a high risk of brain shrinkage. METHODS Frontal lobe volumes on MRI were compared with the current alcohol habits of consecutive 1432 non-alcoholic subjects. RESULTS After adjusting for other variables, age was found to be the most powerful promoting factor for the shrinkage with a odds ratio of 2.8 (95% confidence interval (95% CI) 1.23–3.06) for each 10 years of age. Regarding alcohol habit, 667 of the subjects were abstainers, and 157, 362, and 246 of the subjects were light (average 88.2 g ethanol/week), moderate (181.2 g/week), and heavy (418.1 g/week) drinkers, respectively. Moderate alcohol consumption did not increase the incidence of frontal lobe shrinkage (odds ratio 0.98; 95% CI 0.73–1.33), whereas heavy drinkers were at a higher risk compared with abstainers (1.80; 1.32–2.46). The contributory rate of alcohol consumption for frontal lobe shrinkage was 11.3%. CONCLUSION The brain tends to shrink physiologically with age. Heavy alcohol consumption seems to exaggerate this shrinkage in social drinkers. Moderate alcohol consumption does not seem to affect brain volume.

Polyamine Oxidase and Acrolein as Novel Biochemical Markers for Diagnosis of Cerebral Stroke

Background and Purpose— We found previously that plasma levels of acrolein (CH2=CHCHO) and spermine oxidase (SMO) were well correlated with the degree of severity of chronic renal failure. The aim of this study was to test whether the levels of these 2 markers and of acetylpolyamine oxidase (AcPAO) were increased in the plasma of stroke patients. Methods— The activity of AcPAO and SMO and the level of protein-conjugated acrolein in plasma of the stroke patients and normal subjects were measured by high-performance liquid chromatography and ELISA, respectively. Focal infarcts were estimated by MRI or computed tomography (CT). Results— The levels of AcPAO, SMO, and acrolein were significantly increased in the plasma of stroke patients. The size of stroke was nearly parallel with the multiplied value of acrolein and total polyamine oxidase (AcPAO plus SMO). After the onset of stroke, an increase in AcPAO first occurred, followed by increased levels of SMO and finally acrolein. In 1 case, an increase in AcPAO and SMO preceded focal damage as detected by MRI or CT. Furthermore, stroke was confirmed by MRI in a number of mildly symptomatic patients (11 cases) who had increased levels of total polyamine oxidase and acrolein. Among apparently normal subjects (8 cases) who had high values of acrolein×total polyamine oxidase, stroke was found in 4 cases by MRI. Conclusions— The results indicate that increased levels of AcPAO, SMO, and acrolein are good markers of stroke.

Microsurgical anatomy and clinical significance of the anterior communicating artery and its perforating branches.

OBJECTIVE Precise identification of the anomalous anterior communicating artery (ACoA) or the perforating branches of the ACoA is usually difficult on preoperative angiograms because of the vascular complexity around the ACoA and its small-caliber branches. The purpose of this study was to review the microsurgical anatomy of the ACoA and its branches to show their importance for the interhemispheric trans-lamina terminalis approach and ACoA aneurysmal surgery. METHODS In 30 cadaver brains, the ACoA and its branches were examined under magnification using a surgical microscope. RESULTS The ACoA was evident in all specimens and had variations consisting of plexiform (33%), dimple (33%), fenestration (21%), duplication (18%), string (18%), fusion (12%), median artery of the corpus callosum (6%), and azygous anterior cerebral artery (3%). The perforating branches were also observed in all cadaver brains. They were classified into subcallosal, hypothalamic, and chiasmatic branches according to their vascular territories. The subcallosal branch, usually single and the largest, supplied the bilateral subcallosal areas, branching off to the hypothalamic area. The hypothalamic branches, multiple and of small caliber, terminated in the hypothalamic area. CONCLUSION The incidence of anomalous ACoA was higher than has been previously reported, and any segment of the anomalous ACoA may have perforating branches regardless of diameter. Among the three branches, the subcallosal branch is the most important because it feeds bilateral subcallosal areas branching to the hypothalamic area.

Gamma knife treatment for multiple metastatic brain tumors compared with whole-brain radiation therapy.

The purpose of this paper was to note a potential source of error in magnetic resonance (MR) imaging. Magnetic resonance images were acquired for stereotactic planning for GKS of a vestibular schwannoma in a female patient. The images were acquired using three-dimensional sequence, which has been shown to produce minimal distortion effects. The images were transferred to the planning workstation, but the coronal images were rejected. By examination of the raw data and reconstruction of sagittal images through the localizer side plate, it was clearly seen that the image of the square localizer system was grossly distorted. The patient was returned to the MR imager for further studies and a metal clasp on her brassiere was identified as the cause of the distortion.A-60-year-old man with medically intractable left-sided maxillary division trigeminal neuralgia had severe cardiac disease, was dependent on an internal defibrillator and could not undergo magnetic resonance imaging. The patient was successfully treated using computerized tomography (CT) cisternography and gamma knife radiosurgery. The patient was pain free 2 months after GKS. Contrast cisternography with CT scanning is an excellent alternative imaging modality for the treatment of patients with intractable trigeminal neuralgia who are unable to undergo MR imaging.The authors describe acute deterioration in facial and acoustic neuropathies following radiosurgery for acoustic neuromas. In May 1995, a 26-year-old man, who had no evidence of neurofibromatosis Type 2, was treated with gamma knife radiosurgery (GKS; maximum dose 20 Gy and margin dose 14 Gy) for a right-sided intracanalicular acoustic tumor. Two days after the treatment, he developed headache, vomiting, right-sided facial weakness, tinnitus, and right hearing loss. There was a deterioration of facial nerve function and hearing function from pretreatment values. The facial function worsened from House-Brackmann Grade 1 to 3. Hearing deteriorated from Grade 1 to 5. Magnetic resonance (MR) images, obtained at the same time revealed an obvious decrease in contrast enhancement of the tumor without any change in tumor size or peritumoral edema. Facial nerve function improved gradually and increased to House-Brackmann Grade 2 by 8 months post-GKS. The tumor has been unchanged in size for 5 years, and facial nerve function has also been maintained at Grade 2 with unchanged deafness. This is the first detailed report of immediate facial neuropathy after GKS for acoustic neuroma and MR imaging revealing early possibly toxic changes. Potential explanations for this phenomenon are presented.In clinical follow-up studies after radiosurgery, imaging modalities such as computerized tomography (CT) and magnetic resonance (MR) imaging are used. Accurate determination of the residual lesion volume is necessary for realistic assessment of the effects of treatment. Usually, the diameters rather than the volume of the lesion are measured. To determine the lesion volume without using stereotactically defined images, the software program VOLUMESERIES has been developed. VOLUMESERIES is a personal computer-based image analysis tool. Acquired DICOM CT scans and MR image series can be visualized. The region of interest is contoured with the help of the mouse, and then the system calculates the volume of the contoured region and the total volume is given in cubic centimeters. The defined volume is also displayed in reconstructed sagittal and coronal slices. In addition, distance measurements can be performed to measure tumor extent. The accuracy of VOLUMESERIES was checked against stereotactically defined images in the Leksell GammaPlan treatment planning program. A discrepancy in target volumes of approximately 8% was observed between the two methods. This discrepancy is of lesser interest because the method is used to determine the course of the target volume over time, rather than the absolute volume. Moreover, it could be shown that the method was more sensitive than the tumor diameter measurements currently in use. VOLUMESERIES appears to be a valuable tool for assessing residual lesion volume on follow-up images after gamma knife radiosurgery while avoiding the need for stereotactic definition.This study was conducted to evaluate the geometric distortion of angiographic images created from a commonly used digital x-ray imaging system and the performance of a commercially available distortion-correction computer program. A 12 x 12 x 12-cm wood phantom was constructed. Lead shots, 2 mm in diameter, were attached to the surfaces of the phantom. The phantom was then placed inside the angiographic localizer. Cut films (frontal and lateral analog films) of the phantom were obtained. The films were analyzed using GammaPlan target series 4.12. The same procedure was repeated with a digital x-ray imaging system equipped with a computer program to correct the geometric distortion. The distortion of the two sets of digital images was evaluated using the coordinates of the lead shots from the cut films as references. The coordinates of all lead shots obtained from digital images and corrected by the computer program coincided within 0.5 mm of those obtained from cut films. The average difference is 0.28 mm with a standard deviation of 0.01 mm. On the other hand, the coordinates obtained from digital images with and without correction can differ by as much as 3.4 mm. The average difference is 1.53 mm, with a standard deviation of 0.67 mm. The investigated computer program can reduce the geometric distortion of digital images from a commonly used x-ray imaging system to less than 0.5 mm. Therefore, they are suitable for the localization of arteriovenous malformations and other vascular targets in gamma knife radiosurgery.

BMP inhibition enhances axonal growth and functional recovery after spinal cord injury

Bone morphogenetic proteins (BMPs) are multifunctional growth factors that belong to the transforming growth factor‐β superfamily. BMPs regulate several crucial aspects of embryonic development and organogenesis. The reemergence of BMPs in the injured adult CNS suggests their involvement in the pathogenesis of the lesion. Here, we demonstrate that BMPs are potent inhibitors of axonal regeneration in the adult spinal cord. The expression of BMP‐2/4 is elevated in oligodendrocytes and astrocytes around the injury site following spinal cord contusion. Intrathecal administration of noggin – a soluble BMP antagonist—leads to enhanced locomotor activity and reveals significant regrowth of the corticospinal tract after spinal cord contusion. Thus, BMPs play a role in inhibiting axonal regeneration and limiting functional recovery following injury to the CNS.

Transient expansion of vestibular schwannoma following stereotactic radiosurgery

OBJECT The authors prospectively analyzed volume changes in vestibular schwannomas (VSs) after stereotactic radiosurgery. METHODS One hundred consecutive patients with unilateral VS treated with Gamma Knife surgery (GKS) at Chiba Cardiovascular Center between 1998 and 2006 were analyzed in this study. For each lesion the Gd-enhanced volume was measured serially every 3 months in the 1st year, then every 6 months thereafter, using volumetric software. The frequency and degree of transient tumor expansion were documented and possible prognostic factors were analyzed. Concurrently, neurological deterioration involving trigeminal, facial, and cochlear nerve functions were also assessed. RESULTS The mean observation period was 65 months (range 25-100 months). There were 32 men and 68 women, whose mean age was 59.1 years (range 29-80 years). Tumor volumes at GKS averaged 2.7 cm3 (range 0.1-13.2 cm3), and the lesions were irradiated at the mean 52.2% isodose line for the tumor margin (range 50-67%), with a mean dose of 12.2 Gy (range 10.5-13 Gy) at the periphery. The tumor volume was increased by 23% at 3 months and 27% at 6 months. Tumors shrank to their initial size over a mean period of 12 months. The maximum volume increase was < 10% (no significant increase) in 26 patients, 10-30% in 23, 30-50% in 22, 50-100% in 16, and > 100% in 13. The peak tumor expansion averaged 47% (range 0-613%). A high-dose (> or = 3.5 Gy/min) treatment appears to be the greatest risk factor for transient tumor expansion, although the difference did not reach statistical significance. Transient facial palsy and facial dysesthesia correlated strongly with tumor expansion, but only half of the hearing loss was coincident with this phenomenon. CONCLUSIONS Transient expansion of VSs after GKS was found to be much more frequent than previously reported, strongly suggesting a correlation with deterioration of facial and trigeminal nerve functions.

Three-staged stereotactic radiotherapy without whole brain irradiation for large metastatic brain tumors.

PURPOSE To evaluate the efficacy and toxicity of staged stereotactic radiotherapy with a 2-week interfraction interval for unresectable brain metastases more than 10 cm(3) in volume. PATIENTS AND METHODS Subjects included 43 patients (24 men and 19 women), ranging in age from 41 to 84 years, who had large brain metastases (> 10 cc in volume). Primary tumors were in the colon in 14 patients, lung in 12, breast in 11, and other in 6. The peripheral dose was 10 Gy in three fractions. The interval between fractions was 2 weeks. The mean tumor volume before treatment was 17.6 +/- 6.3 cm(3) (mean +/- SD). Mean follow-up interval was 7.8 months. The local tumor control rate, as well as overall, neurological, and qualitative survivals, were calculated using the Kaplan-Meier method. RESULTS At the time of the second and third fractions, mean tumor volumes were 14.3 +/- 6.5 (18.8% reduction) and 10.6 +/- 6.1 cm(3) (39.8% reduction), respectively, showing significant reductions. The median overall survival period was 8.8 months. Neurological and qualitative survivals at 12 months were 81.8% and 76.2%, respectively. Local tumor control rates were 89.8% and 75.9% at 6 and 12 months, respectively. Tumor recurrence-free and symptomatic edema-free rates at 12 months were 80.7% and 84.4%, respectively. CONCLUSIONS The 2-week interval allowed significant reduction of the treatment volume. Our results suggest staged stereotactic radiotherapy using our protocol to be a possible alternative for treating large brain metastases.

Diagnostic value of thallium-201 chloride single-photon emission computerized tomography in differentiating tumor recurrence from radiation injury after gamma knife surgery for metastatic brain tumors.

OBJECT The authors assessed the diagnostic value of 201Tl Cl single-photon emission computerized tomography (SPECT), performed after gamma knife surgery (GKS) for metastatic brain tumors in differentiating tumor recurrence from radiation injury. METHODS Of 6503 metastatic brain tumors treated with GKS, 201Tl SPECT was required in 72 to differentiate between tumor recurrence and radiation injury. When the Tl index was greater than 5, the lesion was diagnosed as a tumor recurrence. When the index was < 3.0 it was called radiation injury. In cases with a Tl index between 3 and 5, 201Tl SPECT was repeated once per month until the Tl index was greater than 5 or less than 3. If the Tl index fluctuated between 3 and 5 for 2 months, the lesion was diagnosed as radiation injury. The final diagnosis was based on histological examination or clinical course. The sensitivity of the method was 91%; thus 201Tl SPECT is effective for differentiating between tumor recurrence and radiation injury in metastatic brain tumors treated with GKS. Caution is necessary, however, for the following reasons: 1) simple interinstitutional comparisons of Tl indices are not possible because measurement methods are institute specific; 2) steroid administration decreases the Tl index to a variable degree; and 3) a severe radiation injury lesion, as is often seen after repeated GKS or very high dose GKS, may have a Tl index greater than 5. CONCLUSIONS Used with critical insight 201Tl Cl SPECT can be useful in distinguishing between tumor regrowth and radiation necrosis in patients with cerebral metastases.

Lack of benefit of spinal irradiation in the primary treatment of intracranial germinoma : A multiinstitutional retrospective review of 180 patients

The current study assessed the contribution of spinal irradiation to the treatment outcome of patients with intracranial germinoma.