Suketaka Momoshima

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.

Transplantation of human neural stem cells for spinal cord injury in primates

Recent studies have shown that delayed transplantation of neural stem/progenitor cells (NSPCs) into the injured spinal cord can promote functional recovery in adult rats. Preclinical studies using nonhuman primates, however, are necessary before NSPCs can be used in clinical trials to treat human patients with spinal cord injury (SCI). Cervical contusion SCIs were induced in 10 adult common marmosets using a stereotaxic device. Nine days after injury, in vitro‐expanded human NSPCs were transplanted into the spinal cord of five randomly selected animals, and the other sham‐operated control animals received culture medium alone. Motor functions were evaluated through measurements of bar grip power and spontaneous motor activity, and temporal changes in the intramedullary signals were monitored by magnetic resonance imaging. Eight weeks after transplantation, all animals were sacrificed. Histologic analysis revealed that the grafted human NSPCs survived and differentiated into neurons, astrocytes, and oligodendrocytes, and that the cavities were smaller than those in sham‐operated control animals. The bar grip power and the spontaneous motor activity of the transplanted animals were significantly higher than those of sham‐operated control animals. These findings show that NSPC transplantation was effective for SCI in primates and suggest that human NSPC transplantation could be a feasible treatment for human SCI.

Differences in CT Perfusion Maps Generated by Different Commercial Software: Quantitative Analysis by Using Identical Source Data of Acute Stroke Patients

PURPOSE To examine the variability in the qualitative and quantitative results of computed tomographic (CT) perfusion imaging generated from identical source data of stroke patients by using commercially available software programs provided by various CT manufacturers. MATERIALS AND METHODS Institutional review board approval and informed consent were obtained. CT perfusion imaging data of 10 stroke patients were postprocessed by using five commercial software packages, each of which had a different algorithm: singular-value decomposition (SVD), maximum slope (MS), inverse filter (IF), box modulation transfer function (bMTF), and by using custom-made original software with standard (sSVD) and block-circulant (bSVD) SVD methods. Areas showing abnormalities in cerebral blood flow (CBF), mean transit time (MTT), and cerebral blood volume (CBV) were compared with each other and with the final infarct areas. Differences among the ratios of quantitative values in the final infarct areas and those in the unaffected side were also examined. RESULTS The areas with CBF or MTT abnormalities and the ratios of these values significantly varied among software, while those of CBV were stable. The areas with CBF or MTT abnormalities analyzed by using SVD or bMTF corresponded to those obtained with delay-sensitive sSVD, but overestimated the final infarct area. The values obtained from software by using MS or IF corresponded well with those obtained from the delay-insensitive bSVD and the final infarct area. Given the similarities between CBF and MTT, all software were separated in two groups (ie, sSVD and bSVD). The ratios of CBF or MTTs correlated well within both groups, but not across them. CONCLUSION CT perfusion imaging maps were significantly different among commercial software even when using identical source data, presumably because of differences in tracer-delay sensitivity.

Visualization of peripheral nerve degeneration and regeneration: monitoring with diffusion tensor tractography.

We applied diffusion tensor tractography (DTT), a recently developed MRI technique that reveals the microstructures of tissues based on its ability to monitor the random movements of water molecules, to the visualization of peripheral nerves after injury. The rat sciatic nerve was subjected to contusive injury, and the data obtained from diffusion tensor imaging (DTI) were used to determine the tracks of nerve fibers (DTT). The DTT images obtained using the fractional anisotropy (FA) threshold value of 0.4 clearly revealed the recovery process of the contused nerves. Immediately after the injury, fiber tracking from the designated proximal site could not be continued beyond the lesion epicenter, but the intensity improved thereafter, returning to its pre-injury level by 3 weeks later. We compared the FA value, a parameter computed from the DTT data, with the results of histological and functional examinations of the injured nerves, during recovery. The FA values of the peripheral nerves were more strongly correlated with axon-related (axon density and diameter) than with myelin-related (myelin density and thickness) parameters, supporting the theories that axonal membranes play a major role in anisotropic water diffusion and that myelination can modulate the degree of anisotropy. Moreover, restoration of the FA value at the lesion epicenter was strongly correlated with parameters of motor and sensory functional recovery. These correlations of the FA values with both the histological and functional changes demonstrate the potential usefulness of DTT for evaluating clinical events associated with Wallerian degeneration and the regeneration of peripheral nerves.

Aging of the Cervical Spine in Healthy Volunteers : A 10-Year Longitudinal Magnetic Resonance Imaging Study

Study Design. Prospective longitudinal study, mean follow-up period; 11.7 ± 0.8 years was conducted from 1995 to 2007. Objective. To clarify normal aging process of cervical spine and correlation between progression of disc degeneration and development of clinical symptoms. Summary of Background Data. Aging of the cervical spine can inevitably occur in anyone. Long-term longitudinal studies following the same individuals are necessary to elucidate the accurate aging processes of the cervical spine. Methods. Two hundred twenty-three subjects of 497 original cohorts (123 men, 100 women, mean age: 39.0 ± 15.0, follow-up rate: 44.9%). Subjects, who underwent MRI 10 years ago, underwent another MRI, neurologic examination, and questionnaire survey regarding symptoms related to cervical spine and life style. Following 5 MR findings representing intervertebral disc degeneration were evaluated: (1) decrease in signal intensity of disc, (2) anterior compression of dura and spinal cord, (3) posterior disc protrusion (PDP), (4) disc space narrowing (DSN), and (5) foraminal stenosis (FS). Results. Progression of degenerative findings was observed in 189 subjects (81.1%). Progression of decrease in signal intensity of disc was observed in 59.6%, anterior compression of dura and spinal cord in 61.4%, PDP in 70.0%, DSN in 26.9%, and FS in 9.0%. Logistic regression analysis revealed that incidence of progression of PDP, DSN, FS was higher in elderly subjects. There were no correlations between any degenerative MR findings and sex, smoking, alcohol, sport, or body mass index. Neck pain, shoulder stiffness, and numbness in upper extremities were recognized in 9.9%, 30.0%, and 4.0% of subjects, and 1 or more clinical symptoms have developed in 34.1% during 10 years. Conclusion. Progression of degeneration of cervical spine on MRI was frequently observed during 10-year period, with development of symptoms in 34% of subjects. No factor related to progression of degeneration of cervical spine was identified except for age.

Establishment of graded spinal cord injury model in a nonhuman primate: The common marmoset

Most previous studies on spinal cord injury (SCI) have used rodent models. Direct extrapolation of the results obtained in rodents to clinical cases is difficult, however, because of neurofunctional and anatomic differences between rodents and primates. In the present study, the development of histopathologic changes and functional deficits were assessed quantitatively after mild, moderate, and severe spinal cord contusive injuries in common marmosets. Contusive SCI was induced by dropping one of three different weights (15, 17, or 20 g) at the C5 level from a height of 50 mm. Serial magnetic resonance images showed significant differences in the intramedullary T1 low signal and T2 high signal areas among the three groups. Quantitative histologic analyses revealed that the number of motor neurons, the myelinated areas, and the amounts of corticospinal tract fibers decreased significantly as the injury increased in severity. Motor functions were evaluated using the following tests: original behavioral scoring scale, measurements of spontaneous motor activity, bar grip test, and cage‐climbing test. Significant differences in all test results were observed among the three groups. Spontaneous motor activities at 10 weeks after injury were closely correlated with the residual myelinated area at the lesion epicenter. The establishment of a reliable nonhuman primate model for SCI with objective functional evaluation methods should become an essential tool for future SCI treatment studies. Quantitative behavioral and histopathologic analyses enabled three distinct grades of injury severity (15‐g, 17‐g, and 20‐g groups) to be characterized with heavier weights producing more serious injuries, and relatively constant behavioral and histopathologic outcomes.

Anterior Cervical Decompression and Fusion Accelerates Adjacent Segment Degeneration: Comparison With Asymptomatic Volunteers in a Ten-Year Magnetic Resonance Imaging Follow-up Study

Study Design. Prospective 10-year follow-up magnetic resonance imaging (MRI) study of patients who underwent anterior cervical decompression and fusion (ACDF) and healthy control subjects. Objective. To clarify the incidence of adjacent segment degeneration during 10 years after ACDF. Summary of Background Data. There have been few studies which investigated incidence of progression of degenerative changes at adjacent segments in patients treated by ACDF comparing with healthy subjects. Methods. Sixty-four patients who underwent ACDF (48 males, 16 females, mean age 47.3 years, mean follow-up 12.1 year) and 201 asymptomatic volunteers who underwent MRI in our previous study (113 males, 88 females, mean age; 41.1 year, mean follow-up; 11.7 years) were included in this study. The patients and control subjects underwent follow-up MRI in this study. Following MR findings were evaluated using a numerical grading system from C2–C3–C7–T1: (1) Decrease in signal intensity of disc (DSI), (2) Posterior disc protrusion (PDP), (3) Disc space narrowing, and (4) Foraminal stenosis. When an increase in at least one grade in any of the radiographic parameters was detected between the 2 time points, progression of disc degeneration was judged as present at the level of interest. Results. Progression of DSI was significantly more frequent in ACDF group than in control group at C4–C5, while progression of PDP was significantly more frequent in ACDF group than in control group at all levels except for C5–C6. Progression of disc space narrowing and foraminal stenosis was significantly more frequent in ACDF group at C3–C4 and at C6–C7, respectively. Conclusion. Although both ACDF patients and control subjects demonstrated progression of disc degeneration during 10 years, ACDF patients had significantly higher incidence of progression of disc degeneration at adjacent segments than control subjects, while progression of disc degeneration at adjacent segments was not always related to development of clinical symptoms.

In Vivo Tracing of Neural Tracts in the Intact and Injured Spinal Cord of Marmosets by Diffusion Tensor Tractography

In spinal cord injury, axonal disruption results in motor and sensory function impairment. The evaluation of axonal fibers is essential to assess the severity of injury and efficacy of any treatment protocol, but conventional methods such as tracer injection in brain parenchyma are highly invasive and require histological evaluation, precluding clinical applications. Previous advances in magnetic resonance imaging technology have led to the development of diffusion tensor tractography (DTT) as a potential modality to perform in vivo tracing of axonal fibers. The properties and clinical applications of DTT in the brain have been reported, but technical difficulties have limited DTT studies of the spinal cord. In this study, we report the effective use of DTT to visualize both intact and surgically disrupted spinal long tracts in adult common marmosets. To verify the feasibility of spinal cord DTT, we first performed DTT of postmortem marmosets. DTT clearly illustrated spinal projections such as the corticospinal tract and afferent fibers in control animals, and depicted the severed long tracts in the injured animals. Histology of the spinal cords in both control and injured groups were consistent with DTT findings, verifying the accuracy of DTT. We also conducted DTT in live marmosets and demonstrated that DTT can be performed in live animals to reveal in vivo nerve fiber tracing images, providing an essential tool to evaluate axonal conditions in the injured spinal cord. Taken together, these findings demonstrate the feasibility of applying DTT to preclinical and clinical studies of spinal cord injury.

Population-averaged standard template brain atlas for the common marmoset (Callithrix jacchus)

Advanced magnetic resonance (MR) neuroimaging analysis techniques based on voxel-wise statistics, such as voxel-based morphometry (VBM) and functional MRI, are widely applied to cognitive brain research in both human subjects and in non-human primates. Recent developments in imaging have enabled the evaluation of smaller animal models with sufficient spatial resolution. The common marmoset (Callithrix jacchus), a small New World primate species, has been widely used in neuroscience research, to which voxel-wise statistics could be extended with a species-specific brain template. Here, we report, for the first time, a tissue-segmented, population-averaged standard template of the common marmoset brain. This template was created by using anatomical T(1)-weighted images from 22 adult marmosets with a high-resolution isotropic voxel size of (0.2 mm)(3) at 7-Tesla and DARTEL algorithm in SPM8. Whole brain templates are available at International Neuroinformatics Japan Node website, http://brainatlas.brain.riken.jp/marmoset/.

Cell Therapy for Spinal Cord Injury by Neural Stem/Progenitor Cells Derived from iPS/ES Cells

Reports of functional recovery from spinal cord injury after the transplantation of rat fetus-derived neural stem cells and embryonic stem cells has raised great expectations for the successful clinical use of stem cell transplantation therapy. However, the ethical issues involved in destroying human embryos or fertilized oocytes to obtain stem cells have been a major obstacle to developing clinically useful stem cell sources, and the transplantation of stem cells isolated from other human embryonic tissues has not yet been developed for use in clinical applications. Recently, induced pluripotent stem cells, which can serve as a source of cells for autologous transplantation, have been attracting a great deal of attention as a clinically viable alternative to stem cells obtained directly from tissues. In this review, we outline the neural induction of mouse embryonic stem cells and induced pluripotent stem cells, their therapeutic efficacy in spinal cord injury, and their safety in vivo.