The Real-World status and risk factors for a poor prognosis in elderly patients with primary central nervous system malignant lymphomas: a multicenter, retrospective cohort study of the Tohoku Brain Tumor Study Group.

BACKGROUND: Elderly patients with primary central nervous system malignant lymphoma (EL-PCNSL) may not be given sufficient treatment due to their poor pre-treatment Karnofsky Performance Status (KPS) and comorbidities. Therefore, a retrospective, cohort study was performed to evaluate risk factors associated with a poor prognosis of EL-PCNSL in the Tohoku Brain Tumor Study Group. METHODS: Patients aged ≥ 71 years with PCNSL were enrolled from eight centers. Univariate analysis was performed with the log-rank test. A Cox proportional hazards model was used for multivariate analysis. RESULTS: Three of the total 142 cases received best supportive care (BSC). Treatment was given to 30 cases without a pathological diagnosis, 3 cases with cerebrospinal fluid (CSF) cytology, and 100 cases with a pathological diagnosis. After confirmation of no differences in progression-free survival (PFS) and overall survival (OS) between the group treated without pathology and the groups diagnosed by pathology or CSF cytology and between median age ≥ 76 years and < 76 years, a total of 133 patients were studied. The median pre-treatment KPS was 50%. Median PFS and median OS were 16 and 24 months, respectively. Risk factors associated with poor prognosis on Cox proportional hazards model analysis were pre-treatment cardiovascular disease and central nervous system disease comorbidities, post-treatment pneumonia and other infections, and the absence of radiotherapy or chemotherapy. CONCLUSIONS: Pre-treatment comorbidities and post-treatment complications would affect the prognosis. Radiation and chemotherapy were found to be effective, but no conclusions could be drawn regarding the appropriate content of chemotherapy and whether additional radiotherapy should be used.

Safety and efficacy of depatuxizumab mafodotin in Japanese patients with malignant glioma: A nonrandomized, phase 1/2 trial.

INTELLANCE-J was a phase 1/2 study of a potent antibody-drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin (Depatux-M), as a second- or first-line therapy, alone or combined with chemotherapy or chemoradiotherapy in 53 Japanese patients with World Health Organization (WHO) grade III/IV glioma. In second-line arms, patients with EGFR-amplified recurrent WHO grade III/IV glioma received Depatux-M plus chemotherapy (temozolomide) or Depatux-M alone regardless of EGFR status. In first-line arms, patients with newly diagnosed WHO grade III/IV glioma received Depatux-M plus chemoradiotherapy. The study was halted following lack of survival benefit with first-line Depatux-M in the global trial INTELLANCE-1. The primary endpoint was 6-month progression-free survival (PFS) in patients with EGFR-amplified tumors receiving second-line Depatux-M plus chemotherapy. Common nonocular treatment-emergent adverse events (TEAEs) with both second-line and first-line Depatux-M included lymphopenia (42%, 33%, respectively), thrombocytopenia (39%, 47%), alanine aminotransferase increase (29%, 47%), and aspartate aminotransferase increase (24%, 60%); incidence of grade ≥3 TEAEs was 66% and 53%, respectively. Ocular side effects (OSEs) occurred in 93% of patients receiving second-line Depatux-M plus chemotherapy and all patients receiving second-line Depatux-M alone or first-line Depatux-M plus chemoradiotherapy. Most OSEs were manageable with dose modifications and concomitant medications. The 6-month PFS estimate was 25.6% (95% confidence interval [CI] 11.4-42.6), and median PFS was 2.1 months (95% CI 1.9-3.9) with second-line Depatux-M plus chemotherapy in the EGFR-amplified subgroup. This study showed acceptable safety profile of Depatux-M alone or plus chemotherapy/chemoradiotherapy in Japanese patients with WHO grade III/IV glioma. The study was registered at ClinicalTrials.gov (NCT02590263).

Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in comparison with temozolomide alone.

PURPOSE: This study aimed to explore the genetic alterations and to identify good responders in the experimental arm in the tumor samples from newly diagnosed glioblastoma (GBM) patients enrolled in JCOG0911; a randomized phase II trial was conducted to compare the efficacy of interferonß (IFNß) plus temozolomide (TMZ) with that of TMZ alone. EXPERIMENTAL: DESIGN: Of 122 tumors, we performed deep targeted sequencing to determine the somatic mutations, copy number variations, and tumor mutation burden; pyrosequencing for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation; Sanger sequencing for the telomerase reverse transcriptase (TERT) promoter; and microsatellite instability (MSI) testing in 95, 91, 91 and 72 tumors, respectively. We performed a multivariable Cox regression analysis using backward stepwise selection of variables including clinical factors (sex, age, performance status, residual tumor after resection, tumor location) and genetic alterations. RESULTS: Deep sequencing detected an IDH1 mutation in 13 tumors (14%). The MGMT promoter methylation by quantitative pyrosequencing was observed in 41% of the tumors. A mutation in the TERT promoter was observed in 69% of the tumors. While high tumor mutation burden (> 10 mutations per megabase) was seen in four tumors, none of the tumors displayed MSI-high. The clinical and genetic factors considered as independent favorable prognostic factors were gross total resection (hazard ratio [HR]: 0.49, 95% confidence interval, 0.30-0.81, P = 0.0049) and MGMT promoter methylation (HR: 0.43, 0.21-0.88, P = 0.023). However, tumor location at the temporal lobe (HR: 1.90, 1.22-2.95, P = 0.0046) was an independent unfavorable prognostic factor. No predictive factors specific to the TMZ + IFNß + Radiotherapy (RT) group were found. CONCLUSION: This additional sub-analytical study of JCOG0911 among patients with newly diagnosed GBM showed that tumor location at the temporal lobe, gross total resection, and MGMT promoter methylation were significant prognostic factors, although no factors specific to IFNß addition were identified.

Reduced Hypoxic Tissue and Cognitive Improvement after Revascularization Surgery for Chronic Cerebral Ischemia.

BACKGROUND: Hypoxic but viable neural tissue is seen on 1-(2-18F-fluoro-1-[hydroxymethyl]ethoxy) methyl-2-nitroimidazole (18F-FRP170) positron emission tomography (PET) in patients with chronic cerebral ischemia with a combination of misery perfusion and moderately reduced oxygen metabolism. Cognitive function sometimes improves after revascularization surgery in patients with chronic cerebral ischemia. OBJECTIVES: We used brain perfusion single-photon emission computed tomography (SPECT) and 18F-FRP170 PET to determine whether hypoxic tissue was reduced following the restoration of cerebral perfusion after carotid endarterectomy (CEA) in patients with severe stenosis of the cervical internal carotid artery (ICA) and whether the reduction in hypoxic tissue was associated with cognitive improvement. METHOD: Eighteen patients with abnormally reduced cerebral blood flow (CBF) in the affected cerebral hemispheres on preoperative brain perfusion SPECT -underwent CEA. They underwent 18F-FRP170 PET and neuropsychological tests preoperatively and 6 months postoperatively. Brain perfusion SPECT was also performed 6 months postoperatively. Regions of interest were placed in the bilateral middle cerebral artery territories on SPECT and PET images, and the ratio of values in the affected versus contralateral hemispheres was calculated. RESULTS: The CBF ratio (p = 0.0006) and 18F-FRP170 ratio (p = 0.0084) were significantly increased and reduced, respectively, after surgery compared to the corresponding ratios before surgery. The difference in the 18F-FRP170 ratio (postoperative - preoperative value) was negatively correlated with the difference in the CBF ratio (ρ = -0.695; p = 0.0009). The difference in the 18F-FRP170 ratio was significantly lower in patients with postoperative improved cognition compared to that in those without (p = 0.0007). The area under the receiver operating characteristics curve for the difference in the 18F-FRP170 ratio for detecting postoperative improved cognition was significantly greater than that for the difference in the CBF ratio (difference between areas, 0.278; p = 0.0248). CONCLUSIONS: Hypoxic tissue is reduced following the restoration of cerebral perfusion with revascularization surgery in patients with severe atherosclerotic stenosis of the cervical ICA. The reduction in hypoxic tissue is associated with cognitive improvement in such patients.

JCOG0911 INTEGRA study: a randomized screening phase II trial of interferonß plus temozolomide in comparison with temozolomide alone for newly diagnosed glioblastoma.

PURPOSE: This study explored the superiority of temozolomide (TMZ) + interferonß (IFNß) to standard TMZ as treatment for newly diagnosed glioblastoma (GBM) via randomized phase II screening design. EXPERIMENTAL DESIGN: Eligibility criteria included histologically proven GBM, with 50% of the tumor located in supratentorial areas, without involvement of the optic, olfactory nerves, and pituitary gland and without multiple lesions and dissemination. Patients in the TMZ + radiotherapy (RT) arm received RT (2.0 Gy/fr/day, 30 fr) with TMZ (75 mg/m2, daily) followed by TMZ maintenance (100-200 mg/m2/day, days 1-5, every 4 weeks) for 2 years. Patients in the TMZ + IFNß + RT arm intravenously received IFNß (3 MU/body, alternative days during RT and day 1, every 4 weeks during maintenance period) and TMZ + RT. The primary endpoint was overall survival (OS). The planned sample size was 120 (one-sided alpha 0.2; power 0.8). RESULTS: Between Apr 2010 and Jan 2012, 122 patients were randomized. The median OS with TMZ + RT and TMZ + IFNß + RT was 20.3 and 24.0 months (HR 1.00, 95% CI 0.65-1.55; one-sided log rank P = 0.51). The median progression-free survival times were 10.1 and 8.5 months (HR 1.25, 95% CI 0.85-1.84). The incidence of neutropenia with the TMZ + RT and the TMZ + IFNß + RT (grade 3-4, CTCAE version 3.0) was 12.7 versus 20.7% during concomitant period and was 3.6 versus 9.3% during maintenance period. The incidence of lymphopenia was 54.0 versus 63.8% and 34.5 versus 41.9%. CONCLUSIONS: TMZ + IFNß + RT is not considered as a candidate for the following phase III trial, and TMZ + RT remained to be a most promising treatment. This trial was registered with the UMIN Clinical Trials Registry: UMIN000003466.

Opening the ventricle during surgery diminishes survival among patients with newly diagnosed glioblastoma treated with carmustine wafers: a multi-center retrospective study.

Carmustine wafers (CW) were approved in Japan for newly diagnosed and recurrent malignant gliomas during 2013. The ventricle is often opened during surgery to achieve maximum resection. While not generally recommended in such situations, CW might be safely achieved by occluding an opened ventricle using gelform or collagen sheets. However, whether CW implantation actually confers a survival benefit for patients who undergo surgery with an open ventricle to treat glioblastoma remains unclear. Clinical, imaging, and survival data were collected in this multicenter retrospective study of 122 consecutive patients with newly diagnosed glioblastoma to determine adverse events and efficacy. Overall, 54 adverse events of all grades developed in 35 (28.6%) patients, with the most common being new seizures (16%). Adverse events did not significantly differ between patients with opened and closed ventricles during surgery. The 10- and 21.7-month, median, progression-free (PFS) and overall survival (OS), respectively did not significantly differ according to resection rates. However, median PFS and OS were significantly longer among patients with closed, than open ventricles (12.8 vs. 7.4 months; p = 0.0039 and 26.9 vs. 18.6 months; p = 0.011, respectively). Implanting CW into the resection cavity during concomitant radiochemotherapy with temozolomide seems to yield better survival rates without increased adverse events. Occlusion of the ventricular opening during surgery might be safe for CW implantation, but less so for treating patients with newly diagnosed glioblastoma.

Brain temperature measured by 1H-magnetic resonance spectroscopy in acute and subacute carbon monoxide poisoning.

INTRODUCTION: Brain temperature (BT) is associated with the balance between cerebral blood flow and metabolism according to the "heat-removal" theory. The present study investigated whether BT is abnormally altered in acute and subacute CO-poisoned patients by using (1)H-magnetic resonance spectroscopy (MRS). METHODS: Eight adult CO-poisoned patients underwent 3-T magnetic resonance imaging in the acute and subacute phases after CO exposure. MRS was performed on deep cerebral white matter in the centrum semiovale, and MRS-based BT was estimated by the chemical shift difference between water and the N-acetyl aspartate signal. We defined the mean BT + 1.96 standard deviations of the BT in 15 healthy controls as the cutoff value for abnormal BT increases (p < 0.05) in CO-poisoned patients. RESULTS: BT of CO-poisoned patients in both the acute and subacute phases was significantly higher than that of the healthy control group. However, BT in the subacute phase was significantly lower than in the acute phase. On the other hand, no significant difference in body temperature was observed between acute and subacute CO-poisoned patients. BT weakly correlated with body temperature, but this correlation was not statistically significant (rho = 0.304, p = 0.2909). CONCLUSIONS: The present results suggest that BT in CO-poisoned patients is abnormally high in the acute phase and remains abnormal in the subacute phase. BT alteration in these patients may be associated with brain perfusion and metabolism rather than other factors such as systemic inflammation and body temperature.

Hypoxic viable tissue in human chronic cerebral ischemia because of unilateral major cerebral artery steno-occlusive disease.

BACKGROUND AND PURPOSE: Positron emission tomography (PET) with radiolabeled 2-nitroimidazoles directly detects hypoxic but viable tissue present in an acute ischemic area in the human brain. This study using PET with 1-(2-(18)F-fluoro-1-[hydroxymethyl]ethoxy) methyl-2-nitroimidazole ((18)F-FRP170) aimed to determine whether tissue with an abnormally elevated uptake of (18)F-FRP170 exists in human chronic cerebral ischemia because of unilateral atherosclerotic major cerebral artery steno-occlusive disease. METHODS: (18)F-FRP170 PET was performed, and cerebral blood flow and metabolism were assessed using (15)O-gas PET in 20 healthy subjects and 52 patients. A region of interest (ROI) was automatically placed in 3 segments of the middle cerebral artery territory in both cerebral hemispheres with a 3-dimensional stereotaxic ROI template using SPM2, and each PET value was determined in each ROI. The ratio of values in the affected versus contralateral hemispheres was calculated for the (18)F-FRP170 PET image. RESULTS: A significant correlation was observed between oxygen extraction fraction and (18)F-FRP170 ratios (ρ=0.509; P<0.0001) in a total of 156 ROIs in 52 patients. The specificity and positive-predictive value for a combination of an elevated oxygen extraction fraction and a moderately reduced cerebral oxygen metabolism for detection of an abnormally elevated (18)F-FRP170 ratio (19 ROIs: 12%) were significantly greater than those for the individual categories (elevated oxygen extraction fraction, moderately reduced cerebral oxygen metabolism, or reduced cerebral blood flow). CONCLUSIONS: Tissues with abnormally elevated uptake of (18)F-FRP170 exist in human chronic cerebral ischemia characterized by a combination of misery perfusion and moderately reduced oxygen metabolism because of unilateral atherosclerotic major cerebral artery steno-occlusive disease.

Treatment outcomes in glioblastoma patients aged 76 years or older: a multicenter retrospective cohort study.

Age is one of the most important prognostic factors in glioblastoma patients, but no standard treatment has been established for elderly patients with this condition. We therefore conducted a retrospective cohort study to evaluate treatment regimens and outcomes in elderly glioblastoma patients. The study population consisted of 79 glioblastoma patients aged ≥ 76 years (median age 78.0 years; 34 men and 45 women). The median preoperative Karnofsky performance status (KPS) score was 60. Surgical procedures were classified as biopsy (31 patients, 39.2 %), <95 % resection of the tumor (21 patients, 26.9 %), and ≥ 95 % resection of the tumor (26 patients, 33.3 %). Sixty-seven patients (81.0 %) received radiotherapy and 45 patients (57.0 %) received chemotherapy. The median overall progression-free survival time was 6.8 months, and the median overall survival time was 9.8 months. Patients aged ≥ 78 years were significantly less likely to receive radiotherapy (p = 0.004). Patients with a postoperative KPS score of ≥ 60 were significantly more likely to receive maintenance chemotherapy (p = 0.008). Multivariate analyses identified two independent prognostic factors: postoperative KPS score ≥ 60 (hazard ratio [HR] = 0.531, 95 % confidence interval [CI] 0.315-0.894, p = 0.017) and temozolomide therapy (HR = 0.442, 95 % CI 0.25-0.784, p < 0.001).The findings of this study suggest that postoperative KPS score is an important prognostic factor for glioblastoma patients aged ≥ 76 years, and that these patients may benefit from temozolomide therapy.

Glypican-1-targeted antibody-drug conjugate inhibits the growth of glypican-1-positive glioblastoma.

Glioblastoma is the deadliest form of brain tumor. The presence of the blood-brain barrier (BBB) significantly hinders chemotherapy, necessitating the development of innovative treatment options for this tumor. This report presents the in vitro and in vivo efficacy of an antibody-drug conjugate (ADC) that targets glypican-1 (GPC1) in glioblastoma. The GPC1-ADC was created by conjugating a humanized anti-GPC1 antibody (clone T2) with monomethyl auristatin E (MMAE) via maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl linkers. Immunohistochemical staining analysis of a glioblastoma tissue microarray revealed that GPC1 expression was elevated in more than half of the cases. GPC1-ADC, when bound to GPC1, was efficiently and rapidly internalized in glioblastoma cell lines. It inhibited the growth of GPC1-positive glioma cell lines by inducing cell cycle arrest in the G2/M phase and triggering apoptosis in vitro. We established a heterotopic xenograft model by subcutaneously implanting KALS-1 and administered GPC1-ADC intravenously. GPC1-ADC significantly inhibited tumor growth and increased the number of mitotic cells. We also established an orthotopic xenograft model by intracranially implanting luciferase-transfected KS-1-Luc#19. After injecting Evans blue and resecting brain tissues, dye leakage was observed in the implantation area, confirming BBB disruption. We administered GPC1-ADC intravenously and measured the luciferase activity using an in vivo imaging system. GPC1-ADC significantly inhibited tumor growth and extended survival. In conclusion, GPC1-ADC demonstrated potent intracranial activity against GPC1-positive glioblastoma in an orthotopic xenograft model. These results indicate that GPC1-ADC could represent a groundbreaking new therapy for treating glioblastoma beyond the BBB.

Detection of misery perfusion in the cerebral hemisphere with chronic unilateral major cerebral artery steno-occlusive disease using crossed cerebellar hypoperfusion: comparison of brain SPECT and PET imaging.

PURPOSE: In patients with unilateral internal carotid or middle cerebral artery (ICA or MCA) occlusive disease, the degree of crossed cerebellar hypoperfusion that is evident within a few months after the onset of stroke may reflect cerebral metabolic rate of oxygen in the affected cerebral hemisphere relative to that in the contralateral cerebral hemisphere. The aim of the present study was to determine whether the ratio of blood flow asymmetry in the cerebellar hemisphere to blood flow asymmetry in the cerebral hemisphere on positron emission tomography (PET) and single photon emission computed tomography (SPECT) correlates with oxygen extraction fraction (OEF) asymmetry in the cerebral hemisphere on PET in patients with chronic unilateral ICA or MCA occlusive disease and whether this blood flow ratio on SPECT detects misery perfusion in the affected cerebral hemisphere in such patients. METHODS: Brain blood flow and OEF were assessed using (15)O-PET and N-isopropyl-p-[(123)I]iodoamphetamine ((123)I-IMP) SPECT, respectively. All images were anatomically standardized using SPM2. A region of interest (ROI) was automatically placed in the bilateral MCA territories and in the bilateral cerebellar hemispheres using a three-dimensional stereotaxic ROI template, and affected-to-contralateral asymmetry in the MCA territory or contralateral-to-affected asymmetry in the cerebellar hemisphere was calculated. Sixty-three patients with reduced blood flow in the affected cerebral hemisphere on (123)I-IMP SPECT were enrolled in this study. RESULTS: A significant correlation was observed between MCA ROI asymmetry of PET OEF and the ratio of cerebellar hemisphere asymmetry of blood flow to MCA ROI asymmetry of blood flow on PET (r = 0.381, p = 0.0019) or SPECT (r = 0.459, p = 0.0001). The correlation coefficient was higher when reanalyzed in a subgroup of 43 patients undergoing a PET study within 3 months after the last ischemic event (r = 0.541, p = 0.0001 for PET; r = 0.609, p < 0.0001 for SPECT). The blood flow ratio on brain perfusion SPECT in all patients provided 100 % sensitivity and 58 % specificity, with 43 % positive and 100 % negative predictive values for detecting abnormally elevated MCA ROI asymmetry of PET OEF. CONCLUSION: The ratio of blood flow asymmetry in the cerebellar hemisphere to blood flow asymmetry in the cerebral hemisphere on PET and SPECT correlates with PET OEF asymmetry in the cerebral hemisphere, and this blood flow ratio on SPECT detects misery perfusion in the affected cerebral hemisphere.

Potential roles of hyperbaric oxygenation in the treatments of brain tumors.

Over the past 50 years hyperbaric oxygen (HBO2) therapy has been used in a wide variety of medical conditions, and one of them is cancer. Many clinical studies have been conducted to evaluate potential therapeutic effects of HBO2 as a part of cancer treatment. This review briefly summaries the potential role of HBO2 therapy in the treatment of malignant tumors and radiation injury of the brain. HBO2 therapy is used for the enhancement of radiosensitivity in the treatment of some cancers, including malignant brain tumors. Radiotherapy within 15 minutes following HBO2 exposure, a relatively new treatment regimen, has been studied at several institutes and has demonstrated promising clinical results for malignant gliomas of the brain. HBO2 therapy also increases sensitivity to some antineoplastic agents; non-randomized clinical trials using carboplatin-based chemotherapy combined with HBO2 show a significant advantage in survival for recurrent malignant gliomas. The possibilities of combining HBO2 therapy with radiotherapy and/or chemotherapy to overcome newly diagnosed and recurrent malignant gliomas deserve extensive clinical trials. HBO2 therapy also shows promising potential for the treatment and/or prevention of radiation injury of the brain after stereotactic radiosurgery for brain lesions. The possibilities with HBO2 to enhance the therapeutic effect of irradiation per se, and to even increase the radiation dose if there are ways to combat the side effects, should boost new scientific interest into the whole field of oncology looking for new armamentaria to fight cancer.

Utility of arterial spin labeling for objective assessment of intratumoral microvessels in diffuse hemispheric glioma, H3 G34R-mutant: A case report and literature review.

Imaging findings of diffuse hemispheric glioma H3 G34-mutant (DHG, H3 G34m), a new variant of glioma under the World Health Organization classification, have recently been vigorously debated. Here, we report a case of DHG, H3 G34m in which objective assessments of intratumoral microvessels using arterial spin labeling (ASL) were useful for preoperative diagnosis, selection of anti-tumor drugs, and tracking therapeutic responses. The patient was a 34-year-old woman who presented with weakness in the left arm. Preoperative magnetic resonance imaging (MRI) showed no specific findings of hyperintensity on fluid-attenuated inversion recovery imaging and faint enhancement on T1-weighted imaging with contrast media in the tumor. However, ASL showed a convincing finding of high blood flow in the entire tumor, allowing identification of the tumor as malignant glioma. Tumor specimens obtained from biopsy showed that the tumor comprised low-differentiated tumor cells, abundant histiocytes, and highly dense microvessels. Immunohistochemical findings such as positive findings for H3 G34R and p53, and negative findings for IDH-1, ATRX, and OLIG2 led to the diagnosis of DHG, H3 G34m. Based on findings of hyperperfusion on ASL and detection of vascular endothelial growth factor (VEGF), we administered the anti-VEGF antibody bevacizumab. The tumor shrank significantly but remained. However, the residual tumor showed hypoperfusion on ASL, strongly suggesting tumor remission. Objective assessments of blood flow using ASL are useful in clinical practice for patients with DHG, H3 G34 showing non-specific findings on conventional MRI.

Loss of large-diameter nerve sensory input changes perceived posture.

Our previous studies (Inui et al. in J Physiol 589:5775-5784, 2011, Exp Brain Res 218:487-494, 2012) showed that a fully flexed or extended finger, wrist, and elbow became perceived as an extended or flexed 'phantom' hand and arm as ischemic anesthesia progressed. Here, we examined what happened if the wrist was fixed in full extension while the elbow was in full flexion before and during the anesthesia, and vice versa. Ten healthy participants demonstrated the perceived postures of their right wrist and elbow during an ischemic block of the right upper arm with the left hand and arm. If the actual wrist was fully extended while the actual elbow was fully flexed, then the perceived position of the wrist moved toward flexion and that of the elbow moved toward extension. Conversely, if the actual wrist was fully flexed while the actual elbow was fully extended, then the wrist was perceived to extend and the elbow was perceived to flex. Following the loss of the afferent signal coming from the main muscles acting at the two joints, the two perceived postures moved toward the opposite direction independently. The changes in the perceived postures are a shift in the body schema depending on the balance of the proprioceptive inputs that determine limb posture.

Detecting damaged regions of cerebral white matter in the subacute phase after carbon monoxide poisoning using voxel-based analysis with diffusion tensor imaging.

INTRODUCTION: The present study aimed to detect the main regions of cerebral white matter (CWM) showing damage in the subacute phase for CO-poisoned patients with chronic neurological symptoms using voxel-based analysis (VBA) with diffusion tensor imaging (DTI). METHODS: Subjects comprised 22 adult CO-poisoned patients and 16 age-matched healthy volunteers as controls. Patients were classified into patients with transient acute symptoms only (group A) and patients with chronic neurological symptoms (group S). In all patients, DTI covering the whole brain was performed with a 3.0-T magnetic resonance imaging system at 2 weeks after CO exposure. As procedures for VBA, all fractional anisotropy (FA) maps obtained from DTI were spatially normalized, and FA values for all voxels in the whole CWM on normalized FA maps were statistically compared among the two patient groups and controls. RESULTS: Voxels with significant differences in FA were detected at various regions in comparisons between groups S and A and between group S and controls. In these comparisons, more voxels were detected in deep CWM, including the centrum semiovale, than in other regions. A few voxels were detected between group A and controls. Absolute FA values in the centrum semiovale were significantly lower in group S than in group A or controls. CONCLUSIONS: VBA demonstrated that CO-poisoned patients with chronic neurological symptoms had already suffered damage to various CWM regions in the subacute phase. In these regions, the centrum semiovale was suggested to be the main region damaged in the subacute phase after CO inhalation.

PET With 11C-Methyl-l-Methionine as a Predictor of Consequential Outcomes at the Time of Discontinuing Temozolomide-Adjuvant Chemotherapy in Patients With Residual IDH-Mutant Lower-Grade Glioma.

PURPOSE: The aim of this study was to clarify whether PET with 11C-methyl-l-methionine (11C-met PET) can predict consequential outcomes at the time of discontinuing temozolomide (TMZ)-adjuvant chemotherapy in patients with residual isocitrate dehydrogenase gene (IDH)-mutant lower-grade glioma. PATIENTS AND METHODS: Among 30 patients showing residual lesions of IDH-mutant lower-grade glioma, we compared the tumor-to-normal brain tissue ratio of standardized uptake values (SUVT/N) from 11C-met PET at the time of discontinuing TMZ-adjuvant chemotherapy with putative predictive factors including age, Karnofsky Performance Scale, number of courses of adjuvant therapy, residual tumor size, and promotor methylation status of O6-methylguanine-DNA methyl-transferase gene (MGMT). For each factor, progression-free survival (PFS) was compared between groups divided by cutoff values, determined to predict tumor relapse using receiver operating characteristic curves for each factor. Univariate and multivariate analyses were conducted using log-rank testing and Cox regression analysis, respectively. In addition, PFS was compared between patients grouped by combined findings from multiple predictors identified from univariate and multivariate analyses. RESULTS: Univariate and multivariate analyses identified SUVT/N from 11C-met PET and MGMT methylation status as independent predictors of outcomes after TMZ discontinuation. When comparing 3 groups assigned by the combination of MGMT and SUVT/N findings, PFS differed significantly among groups. CONCLUSIONS: The present study suggested that 11C-met PET at the time of discontinuing TMZ-adjuvant chemotherapy allows prediction of outcomes at least comparable to MGMT methylation status in patients with residual IDH-mutant lower-grade glioma. Further, 11C-met PET allows more precise prediction of outcomes by assessment in combination with MGMT findings.

Clinicopathological risk factors for a poor prognosis of primary central nervous system lymphoma in elderly patients in the Tohoku and Niigata area: a multicenter, retrospective, cohort study of the Tohoku Brain Tumor Study Group.

Clinicopathological risk factors for a poor prognosis were investigated in elderly patients with malignant lymphoma of the central nervous system. A total of 82 pathologically confirmed, CD20-positive, diffuse large B-cell lymphoma patients aged 71 years or older who underwent therapeutic intervention in the Tohoku and Niigata area in Japan were retrospectively reviewed. A univariate analysis was performed by the log-rank test using the Kaplan-Meier method. A Cox proportional hazards model was used for multivariate analysis of risk factors. Of the 82 patients, 39 were male and 43 were female, and their median age at onset was 75 years. At the end of the study, there were 34 relapse-free patients (41.5%), 48 relapse cases (58.5%), median progression-free survival was 18 months, and median overall survival (OS) was 26 months; there were 41 deaths and 41 survivors. Multivariate analysis of median OS showed that Karnofsky Performance Status less than 60% 3 months after treatment (p = 0.022, hazard ratio (HR) = 2.591) was the clinical risk factor, and double expressor lymphoma (p = 0.004, HR = 3.163), expression of programmed death-ligand 1 in tumor infiltrating lymphocytes or tumor-associated macrophages (p < 0.001, HR = 5.455), and Epstein-Barr virus infection (p = 0.031, HR = 5.304) were the pathological risk factors.

1H-magnetic resonance spectroscopy indicates damage to cerebral white matter in the subacute phase after CO poisoning.

OBJECTIVE: The authors examined whether (1)H-magnetic resonance spectroscopy (MRS) can identify damage to the centrum semiovale in the subacute phase after CO exposure. METHODS: Subjects comprised 29 adult patients who were treated with hyperbaric oxygenation within a range of 4-95 h (mean 18.7 h) after CO exposure. Subjects were classified into three groups according to clinical behaviours: Group A, patients with transit acute symptoms only; Group P, patients with persistent neurological symptoms; and Group D, patients with 'delayed neuropsychiatric sequelae' occurring after a lucid interval. MRS of bilateral centrum semiovale was performed 2 weeks after CO inhalation for all patients and 13 healthy volunteers. The mean ratios of choline-containing compounds/creatine ((mean)Cho/Cr) and N-acetylaspartate/Cr ((mean)NAA/Cr) for bilateral centrum semiovale were calculated and compared between the three CO groups and controls. Myelin basic protein (MBP) concentration in cerebrospinal fluid was examined at 2 weeks to evaluate the degree of demyelination in patients. RESULTS: MBP concentration was abnormal for almost all patients in Groups P and D, but was not abnormal for any Group A patients. The (mean)Cho/Cr ratios were significantly higher in Groups P and D than in Group A. No significant difference in (mean)NAA/Cr ratio was seen between the three pathological groups and controls. A significant correlation was identified between MBP and (mean)Cho/Cr ratio. CONCLUSIONS: These results suggest that the Cho/Cr ratio in the subacute phase after CO intoxication represents early demyelination in the centrum semiovale, and can predict chronic neurological symptoms.

Prediction of malignancy grading using computed tomography perfusion imaging in nonenhancing supratentorial gliomas.

Tumor grade differentiation is often difficult using routine neuroimaging alone. Computed tomography perfusion imaging (CTP) provides quantitative information on tumor vasculature that closely parallels the degree of tumor malignancy. This study examined whether CTP is useful for preoperatively predicting the grade of malignancy in glioma showing no enhancement on contrast-enhanced magnetic resonance imaging (MRI). Subjects comprised 17 patients with supratentorial glioma without enhancement on MRI. CTP was performed preoperatively, and absolute values and normalized ratios of parameters were calculated. Postoperatively, subjects were classified into two groups according to histological diagnosis of grade 3 (G3) glioma or grade 2 (G2) glioma. Absolute values and normalized ratios for each parameter were compared between G3 and G2. Accuracies of normalized ratios for cerebral blood flow (nCBF) and cerebral blood volume (nCBV) in predicting a diagnosis of G3 were assessed. In addition, nCBV was compared between diffuse astrocytoma, G2 oligodendroglial tumor (OT), and G3 OT. Values for nCBF and nCBV differed significantly between G3 and G2. Using nCBV of 1.6 as a cutoff, specificity and sensitivity for distinguishing G3 were 83.3% and 90.9%, respectively. No significant difference in nCBV was seen between diffuse astrocytoma and G2 OT, whereas differences were noted between G2 and G3 OTs, and between diffuse astrocytoma and G3 OT. CTP offers a useful method for differentiating between G3 and G2 in nonenhancing gliomas.