ii33 NEURO-ONCOLOGY ADVANCES • December 2019 remains debated. We investigated clinical features a... more ii33 NEURO-ONCOLOGY ADVANCES • December 2019 remains debated. We investigated clinical features and prognostic significance of newly defined immunohistochemical subtypes that were identified by expression patterns of three B-cell differentiation markers in PCNSL. In addition, we analyzed a factor related to responsiveness to high-dose methotrexate (HD-MTX) chemotherapy. METHODS: Tumors from 32 PCNSL patients were immunohistochemically evaluated regarding expression of CD10, BCL-6, and MUM-1 and classified into subtypes according to the expression patterns of these markers. Clinical features and prognostic outcome of these subtypes were investigated. RESULTS: Twenty-three patients were treated with HD-MTX-based chemotherapy followed by whole-brain radiation therapy (WBRT), and nine were treated with WBRT alone. Three immunohistochemical subtypes were identified, including A-type expressing CD10, BCL-6, and MUM-1 (12 patients), B-type expressing BCL-6 and MUM-1 (12 patients) and C-type expressing MUM-1 only (8 patients). Response rate in the HD-MTX therapy group was 57.1% (4/7) in A-type, 87.5% (7/8) in B-type, and 75% (6/8) in C-type. C-type with the lowest metabolic activity showed significantly longer overall survival than A-type with the higher uptake of methionine (71.6 versus 39.6 months). CON-CLUSIONS: Immunohistochemical identification of PCNSL based on the B-cell differentiation stage revealed three types of tumors, showing different metabolic activity and survival time. Refined immunohistochemical classification of PCNSL subtypes may become a useful tool for predicting more accurate prognosis and accessing the sensitivity to HD-MTX therapy.
NEURO-ONCOLOGY • NOVEMBER 2016 ment in young adults (age<50) and older adults (age≥50). RESULTS: ... more NEURO-ONCOLOGY • NOVEMBER 2016 ment in young adults (age<50) and older adults (age≥50). RESULTS: In total, 264 of 726 of the patients were older patients (OP), and 462 were young patients (YP). Among all GBM patients and OP with anaplastic gliomas, patients assigned to RT plus TMZ had significantly longer OS and PFS than patients assigned to RT alone (P<0.05). In contrast, among YP with anaplastic gliomas, a more favorable survival benefit was not observed in the RT plus TMZ treatment group compared to the RT only group. CONCLUSIONS: We observed no survival benefit in young adult patients (age<50) with anaplastic glioma when TMZ was added to RT. Our findings should provoke discussion in relation to younger patients with anaplastic glioma who are receiving radiotherapy plus TMZ chemotherapy.
Glioblastoma (GBM) is the most common and deadliest malignant brain cancer in adults despite aggr... more Glioblastoma (GBM) is the most common and deadliest malignant brain cancer in adults despite aggressive chemoradiotherapy. Recently, Tumor Treating Fields (TTFields) were approved in combination with adjuvant temozolomide chemotherapy for newly diagnosed GBM. The addition of TTFields resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules' assembly, leading to disrupted chromosomal segregation and cell death. However, many TTFields responders eventually develop progression. The mechanism of TTFields resistance remains largely unexplored. Understanding how cancer cells gain the ability to circumvent the biophysical forces of TTFields and their downstream effects will provide new opportunities to improve therapeutic efficacy of this novel anti-cancer treatment. To accomplish these objectives, we have developed several human GBM cell lines that demonstrated relative resistance to the cytotoxic effects of TTFields compared to the parental cells. Importantly TTFieldsinduced chromosomal instability such as the formation of micronuclei was unchanged in resistant cells compared to their sensitive counterparts. In contrast, TTFields-induced inflammatory response was severely suppressed in resistant cells, suggesting that resistance to TTFields may be conferred by a selective loss of the deleterious effects downstream of the biophysical insults. Importantly, this acquired TTFields resistance phenotype of GBM cells was associated with a transition to a stem-like state. Using a systems approach aided by a suite of innovative computational platforms, we methodically dissected this renewed stemness program in resistant cells to identify master regulators of the resistance mechanism. Our long-term goal is to develop targeted therapies that prevent tumor's resistance to TTFields.
Continuous theta-burst stimulation (cTBS) is a noninvasive repetitive brain stimulation protocol ... more Continuous theta-burst stimulation (cTBS) is a noninvasive repetitive brain stimulation protocol that suppresses the excitability of the primary motor cortex. It induces cerebral cortical inhibition by increasing inhibitory interneuronal excitability that is associated with increases in gamma-aminobutyric acid (GABA) concentration in the stimulated cortices. cTBS has been applied in the rehabilitation of stroke patients to modulate interhemispheric imbalance. However, the precise mechanisms of cTBS in remote brain areas remain uncertain. We evaluated cTBS-induced GABA level changes in bilateral sensorimotor cortices using GABA-edited magnetic resonance spectroscopy, alternations of motor evoked potentials (MEPs), and resting-state networks (RSNs) using resting-state functional magnetic resonance imaging in 24 healthy right-handed adults (mean age: 34.4 ± 5.0 years). GABA levels in the stimulated left hemisphere significantly increased from baseline (p = 0.013), which was comparable with those of previous reports. GABA levels in the unstimulated right hemisphere showed a trend decrease. cTBS induced a significant decrease in right hand-MEP amplitudes (22.06% ± 43.50%) from baseline (p = 0.026) in accordance with GABA concentrations. However, multiple RSNs, including the default mode and primary motor networks, did not show any obvious differences between pre-and post-stimulus comparisons in the sensorimotor network using the dual regression approach. These results suggest that cTBS simultaneously increases ipsilateral GABA in the stimulated left hemisphere and decreases contralateral GABA in the unstimulated right hemisphere. Neuromodulation following cTBS may be associated with the interhemispheric inhibition because of alterations in GABA levels between the stimulated and unstimulated cortices.
Bright light exposure (BL) induces neurogenesis in the rat hippocampal dentate gyrus (DG). We had... more Bright light exposure (BL) induces neurogenesis in the rat hippocampal dentate gyrus (DG). We had previously conducted a randomized controlled trial (RCT) in which a 4-week period of BL in healthy participants resulted in increased volume of the left DG-head. This study aimed to investigate the effects of BL on the DG in patients with mood disorders. A 4-week RCT was conducted in which patients with mood disorders were randomly assigned to either a BL group (10,000 lx) or dim light exposure group (DL group; 50 lx). All patients underwent clinical assessment and magnetic resonance imaging at baseline and after the intervention. The study registration number is UMIN000019220. Our nal sample included 24 patients (BL group, n = 12; DL group, n = 12). A signi cant effect of time and group was detected in the volumes of the left DG-head (F (1, 62.9) = 11.6, partial η2 = 0.35, p = 0.003) and left DG-total (left DG-total = left DG-head + left DG-body; [F (1, 86.8) = 6.5, partial η2 = 0.23, p = 0.02]). Additionally, the BL group demonstrated a signi cant increase in the volume of the left DG-head (95% CI: -5.4 to -1.6, d = 1.2, p = 0.002) and left DG-total (95% CI: -6.3 to -1.5, d = 1.06, p = 0.005) as well as a positive correlation between the percentage change in the volume of the left DG-total and the percentage change in the scores of the mood visual analogue scale (r = 0.58, p = 0.04). In conclusion, our study results suggest that compared to DL, BL leads to a signi cantly greater increase in the left DG volume in patients with mood disorders. This increase in the left DG volume may be associated with mood improvement in the patients.
A 26-year-old man with recurrent episodes of right upper limb weakness presented with severe sten... more A 26-year-old man with recurrent episodes of right upper limb weakness presented with severe stenosis of the left internal carotid artery and multiple cerebral infarctions. The cause of juvenile cerebral infarctions was investigated during acute treatment and stenosis of the peripheral right coronary artery, and a shade defect was detected, prompting suspicion of a thrombus in the abdominal aorta. Additionally, the patient displayed hypervolemia and tested positive for the Janus kinase 2 mutation, leading to a diagnosis of true polycythemia vera. Treatment with ruxolitinib led to rapid carotid plaque regression. This case suggests that a combination of antiplatelet and antitumor agents may be useful in preventing cerebral infarctions in patients with JAK2 mutations. Furthermore, although many studies have reported multiple thromboembolisms in patients with true polycythemia vera, we believe that it is valuable to describe temporal changes in the source of the emboli.
Sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) is a new immune checkpoint molecule... more Sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) is a new immune checkpoint molecule and its role of primary central nervous system lymphoma (PCNSL) tumor microenvironment has been unclear. We explored the Siglec-15 and programed death-ligand 1 (PD-L1) expression in tumor tissues and analyzed the association between the expression of these molecules and overall survival in newly diagnosed PCNSL. A total of 60 patients diagnosed with diffuse large B-cell lymphoma in PCNSL were included in this study. The Siglec-15 and PD-L1 expression on tumor cells, intratumoral macrophages and peritumoral macrophages were immunohistochemically evaluated. The expression of Siglec-15 and PD-L1 was greater in macrophages than in tumor cells. Regarding peritumoral macrophages, the number of Siglec-15-positive samples (n = 24) was greater than the number of PD-L1-positive samples (n = 16). A multivariate Cox analysis showed that the Siglec-15 positivity of peritumoral macrophages and performance of high-dose methotrexate-based chemotherapy were independent predictors of overall survival (hazard ratio: 0.295 and 0.322, respectively). The Kaplan-Meier survival curves showed that patients with Siglec-15-positive peritumoral macrophages had longer overall survival than those with Siglec-15-negative peritumoral macrophages (median overall survival: 3018 days and 746 days, respectively; p = 0.0290). Our findings indicate that the expression of Siglec-15 on peritumoral macrophages induces a favorable outcome in PCNSL patients.
Objective: Transcranial Magnetic Stimulation (TMS) is a noninvasive technique that stimulates a l... more Objective: Transcranial Magnetic Stimulation (TMS) is a noninvasive technique that stimulates a localized brain region underneath a coil. Recently, the application of repetitive Transcranial Magnetic Stimulation (rTMS) to the primary motor cortex (M1) has been used to promote functional recovery in stroke patients with hemiparesis. Highfrequency rTMS (5 Hz or greater) was applied over the affected hemisphere to reactivate hypoactive regions. Because of recent advances in MRI technology and, in particular, the gradient coils, high-frequency whole brain rTMS-fMRI is possible. The use of interleaved rTMS-fMRI during stimulation at a frequency of 5 Hz aids in understanding how the brain is modulated during stimulation. We measured BOLD signal changes in whole brain during interleaved rTMS-fMRI (5Hz) using 3T MRI. Image processing and statistical analyses were carried out using the Statistical Parametric Mapping (SPM8) software. Results: Distinct BOLD signal changes extending to the remote motor network during 5 Hz-rTMS over the M1 were successfully demonstrated using interleaved rTMS-fMRI. Negative BOLD responses were observed in the contralateral M1, the dorsal premotor cortex (PMd), and the bilateral supplementary motor cortex (SMA), even though no significant BOLD signal changes were observed in the stimulated M1. The negative BOLD responses gradually became marked during (3 mins 57 sec). Therefore, long-lasting plastic changes may occur within 4 mins. Negative BOLD responses in remote regions away from the directly stimulated M1 suggest that subthreshold high frequency rTMS over the motor cortex induced neuromodulation via neuronal networks. The remarkable negative BOLD responses in the contralateral M1 induced by high-frequency rTMS may be useful for identifying a treatment strategy involving M1 stimulation.
Pineal parenchymal tumors of intermediate differentiation (PPTIDs), which were recognized in the ... more Pineal parenchymal tumors of intermediate differentiation (PPTIDs), which were recognized in the 2007 World Health Organization (WHO) classi cation, are rare, accounting for less than 1% of all central nervous system tumors. This rarity and novelty complicate the diagnosis and treatments of PPTID. We therefore aimed to evaluate the clinicopathological signi cance of this tumor. At 11 institutions participating in the Kyushu Neuro-Oncology Study Group, data for patients diagnosed with PPTID were collected. Central pathology review and KBTBD4 mutation analysis were applied to attain the diagnostically accurate cohort. PPTID was o cially diagnosed in 28 patients: 11 (39%) with WHO grade 2 and 17 (61%) with WHO grade 3 tumors. Median age was 49 years, and the male:female ratio was 1:2.1. Symptom was headache in 50% (14/28). Surgery was attempted in all 28 patients, and gross total resection (GTR) was achieved in 46% (13/28). Adjuvant radiotherapy and chemotherapy were administered to, respectively, 82% (23/28) and 46% (13/28). The 5-year progression-free and overall survival rates were 64.9% and 70.4% respectively. Female sex (p = 0.02) and GTR (p < 0.01) were found to be independent prognostic factors. Initial and second recurrences were most often leptomeningeal (67% and 100% respectively). 80% (20/25) of patients harbored a KBTBD4 mutation. Female sex and GTR were independent prognostic factors in our patients with PPTID. Leptomeningeal recurrence was observed to be particularly characteristic of this tumor. The rate of KBTBD4 mutation observed in our cohort was acceptable and this could prove the accuracy of our PPTID cohort.
する軽症脳炎・脳症 (clinically mild encephalitis/encephalopathy with a reversible splenial lesion; MERS) を... more する軽症脳炎・脳症 (clinically mild encephalitis/encephalopathy with a reversible splenial lesion; MERS) を強 く疑われた．MERS は高齢であっても鑑別診断として考慮する必要がある．
Background: We report on the case of a patient with meningioma that was correctly identified thro... more Background: We report on the case of a patient with meningioma that was correctly identified through biopsy. Case Description: A 69-year-old woman presented with slight headache and was then examined at our hospital. Neurologic and physical examinations found no abnormality. Magnetic resonance imaging demonstrated a well-enhanced huge, dural-based, and plaque-like mass extending throughout the parietooccipital convexity and the posterior fossa. Tumors pressed the adjacent brain cortex while extending along the Virchow-Robin space. A CT scan also showed hyperostosis on the parietooccipital bone. Angiography demonstrated a vascular blush that appeared to be of a tumor-like shape. A biopsy was performed to confirm the diagnosis. The histologic findings demonstrated meningothelial meningioma with infiltration into the Virchow-Robin space. Conclusions: Many radiographic patterns of meningioma have been reported, but the present case is quite rare. The radiographic and pathologic findings in our patient are discussed.
ABSTRACT We report a case of a ruptured basilar top aneurysm that was accompanied by a right aort... more ABSTRACT We report a case of a ruptured basilar top aneurysm that was accompanied by a right aortic arch. A 72-year-old woman presented with consciousness disturbance. Computed tomography revealed a diffuse subarachnoid hemorrhage. Magnetic resonance angiography and digital subtraction angiography revealed a ruptured aneurysm in the basilar top accompanied by a right aortic arch. Coil embolization was performed for this ruptured aneurysm with a combination of the balloon-assisted technique and double-catheter technique on day 1. Postoperative digital subtraction angiography showed no aneurysm, and she did not suffer from symptomatic vasospasm. However, she was affected by consciousness disturbance due to hydrocephalus; hence, a ventriculoperitoneal shunt was performed to treat her hydrocephalus on day 35. A right aortic arch is a rare anomaly and is difficult to catheterize. However, we were able to cure our patient’s ruptured basilar top aneurysm with a combination of the balloon-assisted technique and double-catheter technique.
The multifunctional protein -tissue inhibitor of metalloproteinases-1 (TIMP-1) -has been associat... more The multifunctional protein -tissue inhibitor of metalloproteinases-1 (TIMP-1) -has been associated with poor prognosis in several types of cancers including glioblastomas. Glioblastomas are the most common and malignant primary brain tumor known for being highly invasive and resistant to therapy. New treatment strategies are continuously being explored and currently vascular endothelial growth factor (VEGF) inhibitors administered in combination with Irinotecan is the most promising second line treatment. TIMP-1 has been associated with decreased response to chemotherapy in breast and colorectal cancer and especially the family of topoisomerase (TOP) inhibitors, such as Irinotecan, has been suggested to be affected by TIMP-1. In the present study, we investigated whether a high TIMP-1 expression in glioblastoma cells played a role in TOP inhibitor resistance. We established two TIMP-1 over-expressing cell lines and evaluated the sensitivity towards the TOP1 inhibitor SN-38 and the TOP2 inhibitor Epirubicin using a viability and a cytotoxicity assay. In addition, we investigated the invasive features of the cells in a brain slice culture model as well as in an orthotopic xenograft model. The results showed that TIMP-1 over-expressing U87MG cell line sub-clones were significantly more resistant than the controls when exposed to SN-38 and Epirubicin. The same tendency was seen for the TIMP-1 over-expressing A172 sub-clones. No significant differences in invasion patterns were observed for TIMP-1 over-expressing sub-clones when compared to controls. In conclusion, the present study suggests that TIMP-1 over-expression reduces the effect of TOP inhibitors in the glioblastoma cell line U87MG. There was no significant effect of TIMP-1 over-expression on tumor cell invasion. The association found between TIMP-1 cellular levels and the effect of TOP inhibitors needs to be validated in clinical patient material.
The present study evaluates motor functional recovery after C2 spinal cord hemisection with or wi... more The present study evaluates motor functional recovery after C2 spinal cord hemisection with or without contralateral brachial root transection, which causes a condition that is similar to the crossed phrenic phenomenon on rats. Descending motor pathways, including the reticulospinal extrapyramidal tract and corticospinal pyramidal tracts, were evaluated by transcranial magnetic motor-evoked potentials (mMEPs) and direct cortical electrical motor-evoked potentials (eMEP), respectively. All MEPs recorded from the left forelimb were abolished immediately after the left C2 hemisection. Left mMEPs recovered dramatically immediately after contralateral right brachial root transection. Corticospinal eMEPs never recovered, regardless of transection. The facilitation of mMEPs in animals that had undergone combined contralateral root transection was well correlated with open-field behavioral motor performance. Both electrophysiological and neurological facilitations were significantly attenuated by the selective serotonin synthesis inhibitor para-chlorophenylalanine ( p-CPA). These results suggest that serotonergic reticulospinal fibers located contralateral to hemisection contribute to the behavioral and electrophysiological improvement that immediately follows spinal cord injury (SCI).
Cerebral cavernous malformations (CCMs) are congenital abnormalities of the cerebral vessels. The... more Cerebral cavernous malformations (CCMs) are congenital abnormalities of the cerebral vessels. The de novo development of new lesions in this disease has been reported. However, the underlying mechanism of progressive CCMs in such patients remains unclear. This report documents two cases of multiple probable CCMs that showed a progressive behaviour. The plasma levels of vascular endothelial growth factor (VEGF), and transforming growth factor-β1 (TGF-β1) were measured using an enzyme-linked immunosorbent assay (ELISA). The concentration of both VEGF and TGF-β1 in plasma was increased in these patients. A relationship was observed between high concentrations of growth factors and progressive CCMs. Even though a causal linkage between these conditions cannot be confirmed, a continuous high VEGF level in plasma could be a possible clinical indicator for subsequent intracerebral haemorrhages in the CCM patients.
A stable, reliable, non-invasive, quantitative assessment of swallowing function remains to be es... more A stable, reliable, non-invasive, quantitative assessment of swallowing function remains to be established. Transcranial magnetic stimulation (TMS) is commonly used to aid in the diagnosis of dysphagia. Most diagnostic applications involve single-pulse TMS and motor evoked potential (MEP) recordings, the use of which is not clinically suitable in patients with severe dysphagia given the large variability in MEPs measured from the muscles involved in swallowing. Previously, we developed a TMS device that can deliver quadripulse theta-burst stimulation in 16 monophasic magnetic pulses through a single coil, enabling the measurement of MEPs related to hand function. We applied a system for MEP conditioning that relies on a 5 ms interval-monophasic quadripulse magnetic stimulation (QPS5) paradigm to produce 5 ms interval-four sets of four burst trains; quadri-burst stimulation (QBS5), which is expected to induce long-term potentiation (LTP) in the stroke patient motor cortex. Our analys...
N and Fujiki M ( ) Quantitative GABA magnetic resonance spectroscopy as a measure of motor learni... more N and Fujiki M ( ) Quantitative GABA magnetic resonance spectroscopy as a measure of motor learning function in the motor cortex after subarachnoid hemorrhage.
American Journal of Physical Medicine & Rehabilitation, 2010
ABSTRACT This study examined whether repetitive transcranial magnetic stimulation applied over th... more ABSTRACT This study examined whether repetitive transcranial magnetic stimulation applied over the left dorsolateral prefrontal cortex (DLPFC) affected cognition or mood in poststroke patients. The study was a single-center, prospective, double-blind, sham-controlled preliminary study. Eighteen patients (10 males and 8 females; average age, 62.9 yrs) were enrolled. All participants were randomly assigned to one of three treatment groups: low-frequency (1 Hz) stimulation, high-frequency (10 Hz) stimulation, and sham stimulation (control). Each patient underwent 10 consecutive treatment sessions (five times per week for 2 wks). A Computerized Neuropsychological Test was used to evaluate cognitive function, the Tower of London test was used to assess executive function, the Modified Barthel Index score was used to assess activity of daily living function, and the Beck Depression Inventory was used to assess mood status. These evaluations were conducted in all patients before and after treatment. Treatment had no significant effect on any cognitive function parameter, including the Tower of London scores, in any of the three groups. In contrast, high-frequency repetitive transcranial magnetic stimulation resulted in significantly lower Beck Depression Inventory scores compared with baseline and compared with the other two groups. The Modified Barthel Index scores significantly increased in all three groups. These preliminary data suggest that there was a positive effect on mood, but the study was not powered to detect any measurable effect on cognition.
ii33 NEURO-ONCOLOGY ADVANCES • December 2019 remains debated. We investigated clinical features a... more ii33 NEURO-ONCOLOGY ADVANCES • December 2019 remains debated. We investigated clinical features and prognostic significance of newly defined immunohistochemical subtypes that were identified by expression patterns of three B-cell differentiation markers in PCNSL. In addition, we analyzed a factor related to responsiveness to high-dose methotrexate (HD-MTX) chemotherapy. METHODS: Tumors from 32 PCNSL patients were immunohistochemically evaluated regarding expression of CD10, BCL-6, and MUM-1 and classified into subtypes according to the expression patterns of these markers. Clinical features and prognostic outcome of these subtypes were investigated. RESULTS: Twenty-three patients were treated with HD-MTX-based chemotherapy followed by whole-brain radiation therapy (WBRT), and nine were treated with WBRT alone. Three immunohistochemical subtypes were identified, including A-type expressing CD10, BCL-6, and MUM-1 (12 patients), B-type expressing BCL-6 and MUM-1 (12 patients) and C-type expressing MUM-1 only (8 patients). Response rate in the HD-MTX therapy group was 57.1% (4/7) in A-type, 87.5% (7/8) in B-type, and 75% (6/8) in C-type. C-type with the lowest metabolic activity showed significantly longer overall survival than A-type with the higher uptake of methionine (71.6 versus 39.6 months). CON-CLUSIONS: Immunohistochemical identification of PCNSL based on the B-cell differentiation stage revealed three types of tumors, showing different metabolic activity and survival time. Refined immunohistochemical classification of PCNSL subtypes may become a useful tool for predicting more accurate prognosis and accessing the sensitivity to HD-MTX therapy.
NEURO-ONCOLOGY • NOVEMBER 2016 ment in young adults (age<50) and older adults (age≥50). RESULTS: ... more NEURO-ONCOLOGY • NOVEMBER 2016 ment in young adults (age<50) and older adults (age≥50). RESULTS: In total, 264 of 726 of the patients were older patients (OP), and 462 were young patients (YP). Among all GBM patients and OP with anaplastic gliomas, patients assigned to RT plus TMZ had significantly longer OS and PFS than patients assigned to RT alone (P<0.05). In contrast, among YP with anaplastic gliomas, a more favorable survival benefit was not observed in the RT plus TMZ treatment group compared to the RT only group. CONCLUSIONS: We observed no survival benefit in young adult patients (age<50) with anaplastic glioma when TMZ was added to RT. Our findings should provoke discussion in relation to younger patients with anaplastic glioma who are receiving radiotherapy plus TMZ chemotherapy.
Glioblastoma (GBM) is the most common and deadliest malignant brain cancer in adults despite aggr... more Glioblastoma (GBM) is the most common and deadliest malignant brain cancer in adults despite aggressive chemoradiotherapy. Recently, Tumor Treating Fields (TTFields) were approved in combination with adjuvant temozolomide chemotherapy for newly diagnosed GBM. The addition of TTFields resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules' assembly, leading to disrupted chromosomal segregation and cell death. However, many TTFields responders eventually develop progression. The mechanism of TTFields resistance remains largely unexplored. Understanding how cancer cells gain the ability to circumvent the biophysical forces of TTFields and their downstream effects will provide new opportunities to improve therapeutic efficacy of this novel anti-cancer treatment. To accomplish these objectives, we have developed several human GBM cell lines that demonstrated relative resistance to the cytotoxic effects of TTFields compared to the parental cells. Importantly TTFieldsinduced chromosomal instability such as the formation of micronuclei was unchanged in resistant cells compared to their sensitive counterparts. In contrast, TTFields-induced inflammatory response was severely suppressed in resistant cells, suggesting that resistance to TTFields may be conferred by a selective loss of the deleterious effects downstream of the biophysical insults. Importantly, this acquired TTFields resistance phenotype of GBM cells was associated with a transition to a stem-like state. Using a systems approach aided by a suite of innovative computational platforms, we methodically dissected this renewed stemness program in resistant cells to identify master regulators of the resistance mechanism. Our long-term goal is to develop targeted therapies that prevent tumor's resistance to TTFields.
Continuous theta-burst stimulation (cTBS) is a noninvasive repetitive brain stimulation protocol ... more Continuous theta-burst stimulation (cTBS) is a noninvasive repetitive brain stimulation protocol that suppresses the excitability of the primary motor cortex. It induces cerebral cortical inhibition by increasing inhibitory interneuronal excitability that is associated with increases in gamma-aminobutyric acid (GABA) concentration in the stimulated cortices. cTBS has been applied in the rehabilitation of stroke patients to modulate interhemispheric imbalance. However, the precise mechanisms of cTBS in remote brain areas remain uncertain. We evaluated cTBS-induced GABA level changes in bilateral sensorimotor cortices using GABA-edited magnetic resonance spectroscopy, alternations of motor evoked potentials (MEPs), and resting-state networks (RSNs) using resting-state functional magnetic resonance imaging in 24 healthy right-handed adults (mean age: 34.4 ± 5.0 years). GABA levels in the stimulated left hemisphere significantly increased from baseline (p = 0.013), which was comparable with those of previous reports. GABA levels in the unstimulated right hemisphere showed a trend decrease. cTBS induced a significant decrease in right hand-MEP amplitudes (22.06% ± 43.50%) from baseline (p = 0.026) in accordance with GABA concentrations. However, multiple RSNs, including the default mode and primary motor networks, did not show any obvious differences between pre-and post-stimulus comparisons in the sensorimotor network using the dual regression approach. These results suggest that cTBS simultaneously increases ipsilateral GABA in the stimulated left hemisphere and decreases contralateral GABA in the unstimulated right hemisphere. Neuromodulation following cTBS may be associated with the interhemispheric inhibition because of alterations in GABA levels between the stimulated and unstimulated cortices.
Bright light exposure (BL) induces neurogenesis in the rat hippocampal dentate gyrus (DG). We had... more Bright light exposure (BL) induces neurogenesis in the rat hippocampal dentate gyrus (DG). We had previously conducted a randomized controlled trial (RCT) in which a 4-week period of BL in healthy participants resulted in increased volume of the left DG-head. This study aimed to investigate the effects of BL on the DG in patients with mood disorders. A 4-week RCT was conducted in which patients with mood disorders were randomly assigned to either a BL group (10,000 lx) or dim light exposure group (DL group; 50 lx). All patients underwent clinical assessment and magnetic resonance imaging at baseline and after the intervention. The study registration number is UMIN000019220. Our nal sample included 24 patients (BL group, n = 12; DL group, n = 12). A signi cant effect of time and group was detected in the volumes of the left DG-head (F (1, 62.9) = 11.6, partial η2 = 0.35, p = 0.003) and left DG-total (left DG-total = left DG-head + left DG-body; [F (1, 86.8) = 6.5, partial η2 = 0.23, p = 0.02]). Additionally, the BL group demonstrated a signi cant increase in the volume of the left DG-head (95% CI: -5.4 to -1.6, d = 1.2, p = 0.002) and left DG-total (95% CI: -6.3 to -1.5, d = 1.06, p = 0.005) as well as a positive correlation between the percentage change in the volume of the left DG-total and the percentage change in the scores of the mood visual analogue scale (r = 0.58, p = 0.04). In conclusion, our study results suggest that compared to DL, BL leads to a signi cantly greater increase in the left DG volume in patients with mood disorders. This increase in the left DG volume may be associated with mood improvement in the patients.
A 26-year-old man with recurrent episodes of right upper limb weakness presented with severe sten... more A 26-year-old man with recurrent episodes of right upper limb weakness presented with severe stenosis of the left internal carotid artery and multiple cerebral infarctions. The cause of juvenile cerebral infarctions was investigated during acute treatment and stenosis of the peripheral right coronary artery, and a shade defect was detected, prompting suspicion of a thrombus in the abdominal aorta. Additionally, the patient displayed hypervolemia and tested positive for the Janus kinase 2 mutation, leading to a diagnosis of true polycythemia vera. Treatment with ruxolitinib led to rapid carotid plaque regression. This case suggests that a combination of antiplatelet and antitumor agents may be useful in preventing cerebral infarctions in patients with JAK2 mutations. Furthermore, although many studies have reported multiple thromboembolisms in patients with true polycythemia vera, we believe that it is valuable to describe temporal changes in the source of the emboli.
Sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) is a new immune checkpoint molecule... more Sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) is a new immune checkpoint molecule and its role of primary central nervous system lymphoma (PCNSL) tumor microenvironment has been unclear. We explored the Siglec-15 and programed death-ligand 1 (PD-L1) expression in tumor tissues and analyzed the association between the expression of these molecules and overall survival in newly diagnosed PCNSL. A total of 60 patients diagnosed with diffuse large B-cell lymphoma in PCNSL were included in this study. The Siglec-15 and PD-L1 expression on tumor cells, intratumoral macrophages and peritumoral macrophages were immunohistochemically evaluated. The expression of Siglec-15 and PD-L1 was greater in macrophages than in tumor cells. Regarding peritumoral macrophages, the number of Siglec-15-positive samples (n = 24) was greater than the number of PD-L1-positive samples (n = 16). A multivariate Cox analysis showed that the Siglec-15 positivity of peritumoral macrophages and performance of high-dose methotrexate-based chemotherapy were independent predictors of overall survival (hazard ratio: 0.295 and 0.322, respectively). The Kaplan-Meier survival curves showed that patients with Siglec-15-positive peritumoral macrophages had longer overall survival than those with Siglec-15-negative peritumoral macrophages (median overall survival: 3018 days and 746 days, respectively; p = 0.0290). Our findings indicate that the expression of Siglec-15 on peritumoral macrophages induces a favorable outcome in PCNSL patients.
Objective: Transcranial Magnetic Stimulation (TMS) is a noninvasive technique that stimulates a l... more Objective: Transcranial Magnetic Stimulation (TMS) is a noninvasive technique that stimulates a localized brain region underneath a coil. Recently, the application of repetitive Transcranial Magnetic Stimulation (rTMS) to the primary motor cortex (M1) has been used to promote functional recovery in stroke patients with hemiparesis. Highfrequency rTMS (5 Hz or greater) was applied over the affected hemisphere to reactivate hypoactive regions. Because of recent advances in MRI technology and, in particular, the gradient coils, high-frequency whole brain rTMS-fMRI is possible. The use of interleaved rTMS-fMRI during stimulation at a frequency of 5 Hz aids in understanding how the brain is modulated during stimulation. We measured BOLD signal changes in whole brain during interleaved rTMS-fMRI (5Hz) using 3T MRI. Image processing and statistical analyses were carried out using the Statistical Parametric Mapping (SPM8) software. Results: Distinct BOLD signal changes extending to the remote motor network during 5 Hz-rTMS over the M1 were successfully demonstrated using interleaved rTMS-fMRI. Negative BOLD responses were observed in the contralateral M1, the dorsal premotor cortex (PMd), and the bilateral supplementary motor cortex (SMA), even though no significant BOLD signal changes were observed in the stimulated M1. The negative BOLD responses gradually became marked during (3 mins 57 sec). Therefore, long-lasting plastic changes may occur within 4 mins. Negative BOLD responses in remote regions away from the directly stimulated M1 suggest that subthreshold high frequency rTMS over the motor cortex induced neuromodulation via neuronal networks. The remarkable negative BOLD responses in the contralateral M1 induced by high-frequency rTMS may be useful for identifying a treatment strategy involving M1 stimulation.
Pineal parenchymal tumors of intermediate differentiation (PPTIDs), which were recognized in the ... more Pineal parenchymal tumors of intermediate differentiation (PPTIDs), which were recognized in the 2007 World Health Organization (WHO) classi cation, are rare, accounting for less than 1% of all central nervous system tumors. This rarity and novelty complicate the diagnosis and treatments of PPTID. We therefore aimed to evaluate the clinicopathological signi cance of this tumor. At 11 institutions participating in the Kyushu Neuro-Oncology Study Group, data for patients diagnosed with PPTID were collected. Central pathology review and KBTBD4 mutation analysis were applied to attain the diagnostically accurate cohort. PPTID was o cially diagnosed in 28 patients: 11 (39%) with WHO grade 2 and 17 (61%) with WHO grade 3 tumors. Median age was 49 years, and the male:female ratio was 1:2.1. Symptom was headache in 50% (14/28). Surgery was attempted in all 28 patients, and gross total resection (GTR) was achieved in 46% (13/28). Adjuvant radiotherapy and chemotherapy were administered to, respectively, 82% (23/28) and 46% (13/28). The 5-year progression-free and overall survival rates were 64.9% and 70.4% respectively. Female sex (p = 0.02) and GTR (p < 0.01) were found to be independent prognostic factors. Initial and second recurrences were most often leptomeningeal (67% and 100% respectively). 80% (20/25) of patients harbored a KBTBD4 mutation. Female sex and GTR were independent prognostic factors in our patients with PPTID. Leptomeningeal recurrence was observed to be particularly characteristic of this tumor. The rate of KBTBD4 mutation observed in our cohort was acceptable and this could prove the accuracy of our PPTID cohort.
する軽症脳炎・脳症 (clinically mild encephalitis/encephalopathy with a reversible splenial lesion; MERS) を... more する軽症脳炎・脳症 (clinically mild encephalitis/encephalopathy with a reversible splenial lesion; MERS) を強 く疑われた．MERS は高齢であっても鑑別診断として考慮する必要がある．
Background: We report on the case of a patient with meningioma that was correctly identified thro... more Background: We report on the case of a patient with meningioma that was correctly identified through biopsy. Case Description: A 69-year-old woman presented with slight headache and was then examined at our hospital. Neurologic and physical examinations found no abnormality. Magnetic resonance imaging demonstrated a well-enhanced huge, dural-based, and plaque-like mass extending throughout the parietooccipital convexity and the posterior fossa. Tumors pressed the adjacent brain cortex while extending along the Virchow-Robin space. A CT scan also showed hyperostosis on the parietooccipital bone. Angiography demonstrated a vascular blush that appeared to be of a tumor-like shape. A biopsy was performed to confirm the diagnosis. The histologic findings demonstrated meningothelial meningioma with infiltration into the Virchow-Robin space. Conclusions: Many radiographic patterns of meningioma have been reported, but the present case is quite rare. The radiographic and pathologic findings in our patient are discussed.
ABSTRACT We report a case of a ruptured basilar top aneurysm that was accompanied by a right aort... more ABSTRACT We report a case of a ruptured basilar top aneurysm that was accompanied by a right aortic arch. A 72-year-old woman presented with consciousness disturbance. Computed tomography revealed a diffuse subarachnoid hemorrhage. Magnetic resonance angiography and digital subtraction angiography revealed a ruptured aneurysm in the basilar top accompanied by a right aortic arch. Coil embolization was performed for this ruptured aneurysm with a combination of the balloon-assisted technique and double-catheter technique on day 1. Postoperative digital subtraction angiography showed no aneurysm, and she did not suffer from symptomatic vasospasm. However, she was affected by consciousness disturbance due to hydrocephalus; hence, a ventriculoperitoneal shunt was performed to treat her hydrocephalus on day 35. A right aortic arch is a rare anomaly and is difficult to catheterize. However, we were able to cure our patient’s ruptured basilar top aneurysm with a combination of the balloon-assisted technique and double-catheter technique.
The multifunctional protein -tissue inhibitor of metalloproteinases-1 (TIMP-1) -has been associat... more The multifunctional protein -tissue inhibitor of metalloproteinases-1 (TIMP-1) -has been associated with poor prognosis in several types of cancers including glioblastomas. Glioblastomas are the most common and malignant primary brain tumor known for being highly invasive and resistant to therapy. New treatment strategies are continuously being explored and currently vascular endothelial growth factor (VEGF) inhibitors administered in combination with Irinotecan is the most promising second line treatment. TIMP-1 has been associated with decreased response to chemotherapy in breast and colorectal cancer and especially the family of topoisomerase (TOP) inhibitors, such as Irinotecan, has been suggested to be affected by TIMP-1. In the present study, we investigated whether a high TIMP-1 expression in glioblastoma cells played a role in TOP inhibitor resistance. We established two TIMP-1 over-expressing cell lines and evaluated the sensitivity towards the TOP1 inhibitor SN-38 and the TOP2 inhibitor Epirubicin using a viability and a cytotoxicity assay. In addition, we investigated the invasive features of the cells in a brain slice culture model as well as in an orthotopic xenograft model. The results showed that TIMP-1 over-expressing U87MG cell line sub-clones were significantly more resistant than the controls when exposed to SN-38 and Epirubicin. The same tendency was seen for the TIMP-1 over-expressing A172 sub-clones. No significant differences in invasion patterns were observed for TIMP-1 over-expressing sub-clones when compared to controls. In conclusion, the present study suggests that TIMP-1 over-expression reduces the effect of TOP inhibitors in the glioblastoma cell line U87MG. There was no significant effect of TIMP-1 over-expression on tumor cell invasion. The association found between TIMP-1 cellular levels and the effect of TOP inhibitors needs to be validated in clinical patient material.
The present study evaluates motor functional recovery after C2 spinal cord hemisection with or wi... more The present study evaluates motor functional recovery after C2 spinal cord hemisection with or without contralateral brachial root transection, which causes a condition that is similar to the crossed phrenic phenomenon on rats. Descending motor pathways, including the reticulospinal extrapyramidal tract and corticospinal pyramidal tracts, were evaluated by transcranial magnetic motor-evoked potentials (mMEPs) and direct cortical electrical motor-evoked potentials (eMEP), respectively. All MEPs recorded from the left forelimb were abolished immediately after the left C2 hemisection. Left mMEPs recovered dramatically immediately after contralateral right brachial root transection. Corticospinal eMEPs never recovered, regardless of transection. The facilitation of mMEPs in animals that had undergone combined contralateral root transection was well correlated with open-field behavioral motor performance. Both electrophysiological and neurological facilitations were significantly attenuated by the selective serotonin synthesis inhibitor para-chlorophenylalanine ( p-CPA). These results suggest that serotonergic reticulospinal fibers located contralateral to hemisection contribute to the behavioral and electrophysiological improvement that immediately follows spinal cord injury (SCI).
Cerebral cavernous malformations (CCMs) are congenital abnormalities of the cerebral vessels. The... more Cerebral cavernous malformations (CCMs) are congenital abnormalities of the cerebral vessels. The de novo development of new lesions in this disease has been reported. However, the underlying mechanism of progressive CCMs in such patients remains unclear. This report documents two cases of multiple probable CCMs that showed a progressive behaviour. The plasma levels of vascular endothelial growth factor (VEGF), and transforming growth factor-β1 (TGF-β1) were measured using an enzyme-linked immunosorbent assay (ELISA). The concentration of both VEGF and TGF-β1 in plasma was increased in these patients. A relationship was observed between high concentrations of growth factors and progressive CCMs. Even though a causal linkage between these conditions cannot be confirmed, a continuous high VEGF level in plasma could be a possible clinical indicator for subsequent intracerebral haemorrhages in the CCM patients.
A stable, reliable, non-invasive, quantitative assessment of swallowing function remains to be es... more A stable, reliable, non-invasive, quantitative assessment of swallowing function remains to be established. Transcranial magnetic stimulation (TMS) is commonly used to aid in the diagnosis of dysphagia. Most diagnostic applications involve single-pulse TMS and motor evoked potential (MEP) recordings, the use of which is not clinically suitable in patients with severe dysphagia given the large variability in MEPs measured from the muscles involved in swallowing. Previously, we developed a TMS device that can deliver quadripulse theta-burst stimulation in 16 monophasic magnetic pulses through a single coil, enabling the measurement of MEPs related to hand function. We applied a system for MEP conditioning that relies on a 5 ms interval-monophasic quadripulse magnetic stimulation (QPS5) paradigm to produce 5 ms interval-four sets of four burst trains; quadri-burst stimulation (QBS5), which is expected to induce long-term potentiation (LTP) in the stroke patient motor cortex. Our analys...
N and Fujiki M ( ) Quantitative GABA magnetic resonance spectroscopy as a measure of motor learni... more N and Fujiki M ( ) Quantitative GABA magnetic resonance spectroscopy as a measure of motor learning function in the motor cortex after subarachnoid hemorrhage.
American Journal of Physical Medicine & Rehabilitation, 2010
ABSTRACT This study examined whether repetitive transcranial magnetic stimulation applied over th... more ABSTRACT This study examined whether repetitive transcranial magnetic stimulation applied over the left dorsolateral prefrontal cortex (DLPFC) affected cognition or mood in poststroke patients. The study was a single-center, prospective, double-blind, sham-controlled preliminary study. Eighteen patients (10 males and 8 females; average age, 62.9 yrs) were enrolled. All participants were randomly assigned to one of three treatment groups: low-frequency (1 Hz) stimulation, high-frequency (10 Hz) stimulation, and sham stimulation (control). Each patient underwent 10 consecutive treatment sessions (five times per week for 2 wks). A Computerized Neuropsychological Test was used to evaluate cognitive function, the Tower of London test was used to assess executive function, the Modified Barthel Index score was used to assess activity of daily living function, and the Beck Depression Inventory was used to assess mood status. These evaluations were conducted in all patients before and after treatment. Treatment had no significant effect on any cognitive function parameter, including the Tower of London scores, in any of the three groups. In contrast, high-frequency repetitive transcranial magnetic stimulation resulted in significantly lower Beck Depression Inventory scores compared with baseline and compared with the other two groups. The Modified Barthel Index scores significantly increased in all three groups. These preliminary data suggest that there was a positive effect on mood, but the study was not powered to detect any measurable effect on cognition.
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Papers by Minoru Fujiki