Accelerator-based BNCT for patients with recurrent glioblastoma: a multicenter phase II study.

BACKGROUND: Boron neutron capture therapy (BNCT) utilizes tumor-selective particle radiation. This study aimed to assess the safety and efficacy of accelerator-based BNCT (AB-BNCT) using a cyclotron-based neutron generator (BNCT 30) and 10B-boronophenylalanine (SPM-011) in patients with recurrent malignant glioma (MG) (primarily glioblastoma [GB]). METHODS: This multi-institutional, open-label, phase II clinical trial involved 27 recurrent MG cases, including 24 GB cases, who were enrolled from February 2016 to June 2018. The study was conducted using the abovementioned AB-BNCT system, with 500 mg/kg SPM-011 (study code: JG002). The patients were bevacizumab-naïve and had recurrent MG after standard treatment. The primary endpoint was the 1-year survival rate, and the secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results were compared to those of a previous Japanese domestic bevacizumab trial for recurrent GB (JO22506). RESULTS: The 1-year survival rate and median OS of the recurrent GB cases in this trial were 79.2% (95% CI: 57.0-90.8) and 18.9 months (95% CI: 12.9-not estimable), respectively, whereas those of JO22506 were 34.5% (90% CI: 20.0-49.0) and 10.5 months (95% CI: 8.2-12.4), respectively. The median PFS was 0.9 months (95% CI: 0.8-1.0) by the RANO criteria. The most prominent adverse event was brain edema. Twenty-one of 27 cases were treated with bevacizumab following progressive disease. CONCLUSIONS: AB-BNCT demonstrated acceptable safety and prolonged survival for recurrent MG. AB-BNCT may increase the risk of brain edema due to re-irradiation for recurrent MG; however, this appears to be controlled well with bevacizumab.

PET findings in lymphomatosis and gliomatosis of the brain: a comparison of C-11 methionine PET/CT and F-18 FDG PET/CT.

BACKGROUND: Positron emission tomography (PET) findings for gliomatosis and lymphomatosis have been rarely reported. PURPOSE: To compare PET/computed tomography (CT) findings using 11C-methionine (MET) from PET/CT findings using 18F-fluorodeoxy glucose (FDG) for patients with lymphomatosis or gliomatosis of the brain. MATERIAL AND METHODS: Participants comprised all 10 patients with lymphomatosis or gliomatosis of the brain treated at our institution in the past 12 years. Underlying pathologies comprised intravascular lymphoma (n = 1), lymphomatosis (n = 3), and gliomatosis (n = 6). All cases were pathologically diagnosed. In seven patients, both MET-PET/CT and FDG-PET/CT were performed simultaneously in a single study. In three patients, only FDG-PET/CT was performed. The degree of tracer accumulation to the lesion was evaluated qualitatively. Quantitatively, the ratio of maximum standard uptake value (SUVmax) in tumor to that in normal tissue (T/N ratio) was measured and compared between FDG and MET. RESULTS: Qualitatively, MET accumulated to part of the lesion in six of seven patients and almost all of the lesion in one in seven patients. FDG accumulated to part of the lesion in three of ten patients and almost all of the lesion in one of ten patients. No FDG accumulation was seen in the lesion in six patients. Quantitatively, mean ± SD T/N ratio was significantly higher with MET (2.11 ± 0.63) than with FDG (1.18 ± 0.84; P < 0.05, Wilcoxon signed-rank test). CONCLUSION: In lymphomatosis and gliomatosis, FDG accumulates in only part of the lesion. FDG is thus less suitable than MET for depicting these lesions.

Correlations Between Serum Cholesterol and Vascular Lesions in Fabry Disease Patients.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder and shows globotriosylceramide (Gb3) accumulation in multiple organs, resulting from a deficiency of α-galactosidase. In patients with Fabry disease, cardiovascular disease occurs at an early age. Previous studies have shown that serum levels of high-density lipoprotein-cholesterol (HDL-C) increase in this disease, yet its clinical significance for cardiovascular disease remains unclear. Methods and Results: In order to determine why the serum HDL-cholesterol is high in various cardiovascular diseases of Fabry disease patients, we evaluated the serum lipid profiles, ocular vascular lesions, and levels of serum vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 in 69 patients with Fabry disease diagnosed by genetic examination. The serum HDL-C/total cholesterol (T-Chol) ratio was significantly high, especially in male patients (41.5±1.7%) regardless of body mass index. Ocular vascular lesions were more likely to occur in female patients with a high HDL-C/T-Chol ratio compared with most male patients. Female patients with a high HDL-C/T-Chol ratio also presented a high serum VEGF level, suggesting that vascular endothelium dysfunction and arteriosclerotic changes progress more severely than in patients with a normal HDL-C/T-Chol ratio. In most patients, enzyme replacement therapy improved serum Gb3 and lyso-Gb3 levels, but these Gb3 and lyso-Gb3 still remained higher than in healthy controls, which appears to result in continuous vascular arteriosclerotic changes. CONCLUSIONS: We concluded that increased low-density lipoprotein-cholesterol uptake to the vascular wall caused by endothelial dysfunction is likely to contribute to the high HDL-C/T-Chol ratio observed in Fabry disease patients.

11C-Methionine Positron Emission Tomography/Computed Tomography Versus 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Evaluation of Residual or Recurrent World Health Organization Grades II and III Meningioma After Treatment.

OBJECTIVE: The aim of this study was to determine the assessment of positron emission tomography-computed tomography using C-methionine (MET PET/CT) for World Health Organization (WHO) grades II and III meningiomas; MET PET/CT was compared with PET/CT using F-fluorodeoxy glucose (FDG PET/CT). METHODS: This study was performed in 17 cases with residual and/or recurrent WHO grades II and III meningiomas. Two neuroradiologists reviewed both PET/CT scans. For agreement, the κ coefficient was measured. Difference in tumor-to-normal brain uptake ratios (T/N ratios) between 2 PET/CT scans was analyzed. Correlation between the maximum tumor size and T/N ratio in PET/CT was studied. RESULTS: For agreement by both reviewers, the κ coefficient was 0.51 (P < 0.05). The T/N ratio was significantly higher for MET PET/CT (3.24 ± 1.36) than for FDG PET/CT (0.93 ± 0.44) (P < 0.01). C-methionine ratio significantly correlated with tumor size (y = 8.1x + 16.3, n = 22, P < 0.05), but FDG ratio did not CONCLUSIONS: C-methionine PET/CT has superior potential for imaging of WHO grades II and III meningiomas with residual or recurrent tumors compared with FDG PET/CT.

Accumulation of 11C-methionine in the normal pituitary gland on 11C-methionine PET.

Background For pituitary tumors, positron emission tomography (PET) with 11C-methonine (MET) has been reported as feasible to facilitate diagnosis. MET is well-known to accumulate in the normal pituitary glands, but almost no studies have examined the degree of MET accumulation in the normal pituitary gland. Purpose To investigate accumulation of MET in normal pituitary gland on PET/CT. Material and Methods Among patients who underwent PET/CT using MET over the past 7 years, 77 patients who fulfilled our criteria for normal pituitary glands were retrospectively selected. Maximum standardized uptake value (SUVmax) for the pituitary gland was measured. Results SUVmax of MET in the pituitary gland was in the range of 0.9-6.6 (mean ± standard deviation = 2.60 ± 1.04). A negative correlation between SUVmax and patient age (y = -0.032 × + 4.29, n = 77, r = 0.55) was found by linear regression analysis. SUVmax of the pituitary gland did not differ significantly between women and men. Conclusion MET shows strong accumulation in normal pituitary gland. PET/CT would thus be feasible to differentiate between normal and abnormal pituitary glands.

Successful management of enzyme replacement therapy in related fabry disease patients with severe adverse events by switching from agalsidase Beta (fabrazyme(®)) to agalsidase alfa (replagal (®)).

BACKGROUND: Enzyme replacement therapy (ERT) is the only approved therapy for Fabry disease. In June 2009, there was a worldwide shortage of agalsidase beta, necessitating dose reductions or switching to agalsidase alfa in some patients. CASE PRESENTATION: We present two cases of Fabry disease (a parent and a child) who received agalsidase beta for 27 months at the licensed dose and 10 months at a reduced dose, followed by a switch to agalsidase alfa for 28 months. Case 1, a 26-year-old male had severe coughing and fatigue during ERT with agalsidase beta requiring antitussive and asthmatic drug therapy. After switching to agalsidase alfa, the coughing gradually resolved completely. Case 2, a 62-year-old female had advanced cardiac manifestations at the time of diagnosis. Despite receiving ERT with the approved dose of agalsidase beta, she experienced aggravation of congestive heart failure and was hospitalized. After switching to agalsidase alfa with standard care in heart disease, BNP level, echocardiographic parameters, eGFR rate and lyso-Gb3 levels were improved or stabilized. CONCLUSIONS: We report on two Fabry disease patients who experienced severe adverse events while on approved and/or reduced doses of agalsidase beta. Switching to agalsidase alfa associated with standard care in heart disease led to resolution or improvement in the cardiorespiratory status. And reduction in dose associated with standard care in respiratory disease was useful for decrease in cough and fatigue. Plasma BNP level was useful for monitoring heart failure and the effects of ERT.

[Intracranial germinoma associated with Down syndrome: case report and review of literature].

It is well known that Down syndrome is sometimes associated with leukemia. However, there have been only a few case reports of a relationship between Down syndrome and brain tumors. The case was that of a 35-year-old man with Down syndrome complaining of gait disturbance. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a mass lesion in the pineal and bilateral cerebello-pontine cistern and spinal cord, marked hydrocephalus. Endoscopic biopsy and third ventriculostomy was performed. Surgical specimens showed typical germinoma. The patient was treated with a combination of chemotherapy with carboplatin and etposide, and irradiation. However he finally died 35 months after these therapies. Cases of malignant tumors other than leukemia, which are associated with Down syndrome, are extremely rare. We reviewed such rare cases of Down syndrome and intracranial germ cell tumor.

Transgenic rice plants harboring the grain hardness-locus region of Aegilops tauschii.

Grain hardness of wheat is determined by the hardness (Ha)-locus region, which contains three friabilin-related genes: puroindoline-a (Pina), puroindoline-b (Pinb) and GSP-1. In our previous study, we produced the transgenic rice plants harboring the large genomic fragment of the Ha-locus region of Aegilops tauschii containing Pina and GSP-1 genes by Agrobacterium-mediated transformation. To examine the effects of the transgenes in the rice endosperms, we firstly confirmed the homozygosity of the T-DNAs in four independent T2 lines by using fluorescence in situ hybridization (FISH) and DNA gel blot analyses. The transgenes, Pina and GSP-1, were stably expressed in endosperms of the T3 and T4 seeds at RNA and protein levels, indicating that the promoters and other regulatory elements on the wheat Ha-locus region function in rice, and that multigene transformation using a large genomic fragment is a useful strategy. The functional contribution of the transgene-derived friabilins to the rice endosperm structure was considered as an increase of spaces between compound starch granules, resulting in a high proportion of white turbidity seeds.

[Postoperative patterns of improvement of symptoms and degrees of satisfaction in families of patients after operations for definite idiopathic normal pressure hydrocephalus: a long-term follow-up study].

PURPOSE: To clarify the patterns of improvement of pre- and post-operative symptoms and family satisfaction in patients with definite idiopathic normal pressure hydrocephalus (iNPN) who responded well to shunt intervention. SUBJECTS AND METHODS: The subjects included 40 patients definitively diagnosed with iNPH and who were followed up for one year or longer (age, 61-85; male-to-female ratio, 18: 22). The study focused on (1) preoperative clinical symptoms, (2) improvements in symptoms at 1, 3, 5, and 12 months after surgery, and the satisfaction of the families based on medical results of the Zarit caregiver burden interview, and infomation through questionnaires to medical personnel. RESULTS: (1) The major symptoms were gait disturbance (G, n=38), dementia (D, n=10), and urinary incontinence (U, n=23). G and D appeared as initial symptoms in 30 and 10 cases, respectively. (2) The rates of postoperative improvement at 1, 3, 5, and 12 months were 94.7%, 94.7%, 97.4%, and 94.7% for G, 43.8%, 62.5%, 71.9%, and 84.4% for D, and 78.3%, 86.96%, 86.96%, and 91.3% for U, respectively. G and U cases improved during the postoperative early stage, and D improved gradually from after the third postoperative month. The family satisfaction before surgery and at 1, 3, 5, and 12 months after surgery was 72.5 +/- 12.8, 68.1 +/- 15.4, 55.7 +/- 9.6, 52.9 +/- 11.4, and 47.3 +/- 7.9 points, respectively. The rate of improvement in satisfaction was higher for D. The satisfaction of the medical personnel was 88 percent (+) at 1 month and tended to remain high for 12 months. CONCLUSION: (1) Preoperative gait disturbance is a major initial symptom in definitively diagnosed iNPN. (2) Postoperative improvement of G and U is obtained at an early stage. In contrast, D tends to improve gradually from after the third postoperative month. The family satisfaction increases as the symptom of D improve. The satisfaction of the medical personnel tends to remain high after the first postoperative month. This study investigated the results of quantitative analyses of the patients symptoms.

Pathophysiology of cerebral circulatory disorders in idiopathic normal pressure hydrocephalus.

This study was conducted to elucidate the pathologic conditions of cerebral circulatory disorders in idiopathic normal pressure hydrocephalus (iNPH). Among 44 possible iNPH patients, 40 patients underwent shunt surgery based on diagnostic flow charts plotted by the Southern Tohoku method and were evaluated to be shunt-effective at the end of the first post-surgical month. The cerebral blood flow (CBF) was measured by N-isopropyl-((123)I)-P-iodo-amphetamine single photon emission computed tomography (mean, mCBF; cortical region, cCBF; thalamus-basal ganglia region, tbCBF on autoradiography [ARG] method) and the perfusion patterns of the cerebral cortex were measured based on three-dimensional stereotactic surface projection (3D-SSP) Z-score images, before and 1 month after the surgery in all 40 subjects. The mCBF rose significantly from 32.1 +/- 2.74 ml/100 g/min before surgery to 39.8 +/- 3.02 ml/100 g/min after surgery (p < 0.03). Investigation of the change of CBF revealed reductions in the cCBF (3 cases), tbCBF (9 cases), and cCBF + tbCBF (28 cases), with the reduced-cCBF group totaling 31 cases and the reduced-tbCBF group totaling 37 cases. Investigation of cerebral cortex hypoperfusion by 3D-SSP Z-score revealed 31 cases with hypoperfusion (frontal lobe type [19 cases], occipitotemporal lobe type [5 cases], mixed type [7 cases]) and nine cases with cortical normoperfusion (N). The pattern of reduction of the cortical blood flow on ARG method was favorably correlated with the pattern of hypoperfusion of the cerebral cortex on 3D-SSP Z-score images before surgery. A reduction of blood flow was found in the thalamus-basal ganglia region of all N type cases. The blood flow improved in 19 of 31 (61.3%) cases of the reduced-cCBF group and in 32 of 37 (86.5%) cases of the reduced-tbCBF group. All of the cases without detectable improvement exhibited increased blood flow in non-reduction areas. Investigation of the hypoperfusion patterns of the cerebral cortex on 3D-SSP Z-score images, revealed a reduction or disappearance of the hypoperfusion site in 19 of 31 (61.3%) cases, either no-change or a shift of the hypoperfusion site in 12 of 31 (38.7%) cases, and a correlation between the pattern of cortical blood flow reduction on ARG method and the pattern of cerebral cortex hypoperfusion on 3D-SSP Z-score images after surgery. Cerebral circulatory disorders in iNPH manifest as either of two pathophysiological conditions: the "circulatory disorder of the cerebral cortical region" and the "circulatory disorder of the thalamus-basal ganglia region." Various patterns develop according to the disease stage.

[Reinvestigation of CSF outflow resistance value in idiopathic normal pressure hydrocephalus--comparing epidural pressure monitoring with lumbar subarachnoid cerebrospinal fluid pressure monitoring].

PURPOSE: To compare the cerebrospinal fluid (CSF) outflow resistance values (Ro) with epidural pressure (EDP) monitoring and lumbar subarachnoid CSF pressure (L-CSFP) monitoring. SUBJECTS AND METHODS: The subjects were 14 patients with possible iNPH (age: 59-74 years old, ratio of male and female 8:6). All the patients were subjected to an infusion test by a single bolus injection method (1 ml/sec., deltaV: 5 ml, t2: 2 min) as prescribed in the Standard of SINPHONI. EDP was monitored by continuous monitoring and the L-CSFP values By intermittent simple glass tube method (SINPHONI) were measured simultaneously. The Ro (RoEDP, RoL-CSFP) calculated from both methods, (1) the correlation of Ro and (2) the Ro threshold in a shunt effective group (E: nine cases) and a non effective group (NE, five cases) were compared. RESULTS: (1) Although a favorable correlation was found between both Ro measurements (r=0.784), the RoEDP was always higher than the RoL-CSFP. (2) The mean Ro values in the E and NE groups were 36.8 +/- 15.7 mmHg/ml/min, and 10 +/- 2.05 mmHg/ml/min for Ro-EDP, 22.1 +/- 13.95 mmg/ml/min and 6.4 +/- 1.7 mmHg/ml/min for RoL-CSFP, respectively. The approximate thresholds in the E and NE groups were 15 mmHg/ml/min for RoEDP and 10 mmHg/ml/min for RoL-CSFP. CONCLUSION: (1) Although the RoEDP is always higher than the RoL-CSFP, a favorable correlation is found between the RoEDP and RoL-CSFP, (2) The Ro thresholds of the E and NE groups in the infusion test are about 15 mmHg/ml/min for RoEDP and 10 mmHg/ml/min for RoL-CSFP. (3) After this, Ro calculation ought to execute by standard of SINPHONI and the Ro threshold of the E and NE groups is about 10 mmHg/ml/min.

[Significance of shunt efficacy decision of SPECT on idiopathic normal pressure hydrocephalus].

PURPOSE: The purpose of this study was to investigate the significance of the shunt-effect evaluation of SPECT in idiopathic normal pressure hydrocephalus (iNPH). SUBJECTS AND METHODS: The subjects were 15 patients with possible iNPH, aged 62-83 (mean 75.3, the ratio of males to females to 6:9), who were treated at our department during the period from June to September, 2004. All patients received the lumbar tap test (LTT) at the outpatient section before surgery. An L-P shunt was conducted on patients whose the LTT positive or negative with cerebrospinal fluid outflow resistance value (Ro) was 10 mmHg/ml/min. or higher patients. As for SPECT, a 3D-SSP Z-score, as well as an mCBF, was conducted before and after the LTT and within one month after surgery. Comparisons were made for (1) the shunt effect, (2) mCBF before and after the LTT and after surgery, (3) mean cerebral blood flow increase rate (mIR) after the LTT, and (4) 3D-SSP before and after surgery. RESULTS: (1) The shunt was effective for all the patients. (2) The mCBF levels was 30.8 +/- 4.02 ml/100 g/min. before the LTT, 37.1 +/- 100 g/min. after the LTT, and 38.6 +/- 3.4 ml/100 g/min. after surgery. A significant increase in mCBF was observed both after the LTT and after surgery (p < 0.05). (3) The mean mIR after the LTT was 21.2 +/- 8.01%, with all the patients showing 10% or higher. (4) The ischemic patterns in the SD-SSP Z-score before surgery were the frontal type (F: 10 cases, 66.7%), the occipitotemporal type (OT: 3 cases, 20%), and the mixed type (M: 2 cases, 13.3%), but not the parietal localized type. The post-operative course showed no-change in 4 cases, disappearance-reduction in 9 cases, and shift to OT in 2 cases. CONCLUSION: The evaluation factors in the measurement of the cerebral blood flow for evaluation of the shunt effect were the following two items. (1) The mIR of mCBF after the LIT was 10% or higher. (2) As for the preoperative cerebral ischemic patterns, there were many F cases and no parietial localized types found.