Search

OBJECTIVE Diffusion MRI is attracting increasing interest for tissue characterization of gliomas, especially after the introduction of antiangiogenic therapy to treat malignant gliomas. The goal of the current study is to elucidate the actual magnitude of the correlation between diffusion MRI and cell density within the tissue. The obtained results were further extended and compared with metabolic imaging with

The prognostic impact of TERT mutations has been controversial in IDH-wild tumors, particularly in glioblastomas (GBM). The controversy may be attributable to presence of potential confounding factors such as MGMT methylation status or patients’ treatment. This study aimed to evaluate the impact of TERT status on patient outcome in association with various factors in a large series of adult diffuse gliomas. We analyzed a total of 951 adult diffuse gliomas from two cohorts (Cohort 1, n = 758; Cohort 2, n = 193) for IDH1/2, 1p/19q, and TERT promoter status. The combined IDH/TERT classification divided Cohort 1 into four molecular groups with distinct outcomes. The overall survival (OS) was the shortest in IDH wild-type/TERT mutated groups, which mostly consisted of GBMs (P

A 34-year-old man with a 1-week history of diplopia was referred to the authors' hospital. Neurological examination revealed left abducens nerve palsy. Computed tomography showed a lesion in the left sphenoid sinus involving the medial wall of the left internal carotid artery (ICA) and osteolytic change at the clivus bordering the lesion. Magnetic resonance imaging demonstrated an extensive soft-tissue mass occupying the left sphenoid sinus. Surgical intervention by the endoscopic transnasal method allowed most of the lesion to be removed. Only the portion attached to the medial wall of the ICA was not removed. Postoperatively, the lesion was diagnosed as a giant cell tumor (GCT) and the patient received 120 mg of subcutaneous denosumab every 4 weeks, with additional doses on Days 8 and 15 during the first month of therapy. MRI a week after starting denosumab revealed shrinkage of the initially fast-growing residual tumor. The patient was discharged upon completion of the third denosumab administration. GCT is an aggressive stromal tumor developing mainly in young adults. Complete resection is recommended for GCT in the literature. However, size and location of the CGT often limit this approach. Various adjuvant treatments for skull base GCTs have been reported, including radiation and chemotherapy. However, the roles of adjuvant therapies have yet to be clearly defined. Denosumab, a monoclonal antibody, was recently approved for GCT in several countries. Denosumab may permit less invasive treatments for patients with GCTs while avoiding deleterious outcomes, and may also limit disease progression and recurrence.

Immunotherapy has been highlighted because we have obtained much evidence, which includes theoretical backborn as well as favorable results from clinical trials. As immunotherapy gives an apparently different cytotoxic mechanism and a little adverse event, the promising results are getting a lot of attention. In this article, cancer immunotherapy for gliomas is reviewed thoroughly from the literature, focusing on the clinical trial results.

The pleiotropic transcription factor, Wilms’ tumor 1 (WT1), is expressed in the majority of glioblastomas, the most common malignant brain tumors of adulthood. Despite intensive treatment, including surgery and chemoradiotherapy, the prognosis for patients with glioblastoma remains very poor. Encouragingly, immunotherapy targeting WT1 has proven to be effective in recurrent glioblastoma, suggesting that this approach may be an important new treatment modality for the disease. However, WT1 appears to function as a context-dependent tumor suppressor or oncogene, and the functional roles of WT1 in the pathogenesis of glioblastoma, and other types of brain tumors, have not been extensively studied. With this in mind, we briefly review WT1 expression data for a range of different brain tumor classes and address the role of WT1 in the regulation of proliferation and apoptosis in glioblastoma. We generated WT1 knockdown glioblastoma cells by using shRNA-expressing lentivirus. Proliferation was reduced and apoptosis increased in WT1 knockdown glioblastoma cells compared with control cells in vitro. Consistent with these data, when WT1 knockdown glioblastoma cells or control glioblastoma cells were intracranially injected into the immunodeficient mice, tumor growth was significantly reduced in WT1 knockdown cells compared with that in control cells. Thus, WT1 is an oncogene that regulates cell proliferation and apoptosis in glioblastoma.

BACKGROUND: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner. METHODS: We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival. FINDINGS: We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084). INTERPRETATION: The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection. FUNDING: Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research.

A 5-year-old male was referred to our department for evaluation of a firm elastic mass at the back of his head. Clinical examination revealed no abnormalities but the local area was tender. Further clinical and radiological examinations yielded no pathological findings and no other lesions were detected. The lesion was located in the diploic layer of the left parietal bone. The inner layer of the skull intact but the outer layer showed osteolytic change. The lesion did not adhere to the dura mater. The tumor was completely removed with the surrounding bone. Histological examination revealed a mesenchymal tumor comprised of myoid spindle-shaped cells arranged in whorls between muscle cells and fibroblasts and a vascular component around the spindle cells. The final diagnosis was myofibroma. The patient recovered well after the operation and he was discharged from hospital 10 days after surgery. Clinical and radiological follow-up 6 and 12 months later showed neither recurrence of the primary lesion nor any indications of lesions at other sites. Myofibroma is a benign neoplasm composed of myoid cells with thin-walled blood vessels. This tumor, reported to have a wide range of clinical manifestations, is one of the cranial vault tumors. These tumors occur mainly in children although a few affected infants have been reported. Surgical intervention may contribute significantly to the diagnosis of solitary myofibroma and complete removal achieves good outcomes. Herein, we report a 5-year-old male with solitary myofibroma of the skull, presenting as a firm elastic mass in the left parietal bone.

The linear correlation between (11)C-methionine PET and tumor cell density is not well conserved at the tumor border in glioma. A novel imaging analysis method, voxelwise (18)F-FDG-(11)C-methionine PET decoupling analysis (decoupling score), was evaluated to determine whether it could be used to quantitatively assess glioma cell infiltration in MRI-nonenhancing T2 hyperintense lesions.Data collection was performed in a prospective fashion. Fifty-four MRI-nonenhancing T2 hyperintense specimens were stereotactically obtained from 23 glioma patients by intraoperative navigation guidance. The decoupling score and tumor-to-normal tissue (T/N) ratio of (11)C-methionine PET were calculated at each location. Correlations between the tumor cell density at these lesions, decoupling score, and T/N ratio of (11)C-methionine PET were then evaluated.Both the decoupling score and the T/N ratio showed a linear correlation with tumor cell density at these specimens (R(2) = 0.52 and 0.53, respectively). Use of the decoupling score (cutoff = 3.0) allowed the detection of specimens with a tumor cell density of more than 1,000/mm(2), with a sensitivity and specificity of 93.5% and 87.5%, respectively, whereas conventional (11)C-methionine PET (cutoff = 1.2 in T/N ratio) was able to detect with a sensitivity and specificity of 87.0% and 87.5%, respectively. Reconstructed images (decoupling map) using the decoupling score enabled the visualization of glioma lesions that were difficult to visualize by (11)C-methionine PET alone.The decoupling score showed better performance in detecting glioma cell infiltration than (11)C-methionine uptake alone, thus suggesting that (18)F-FDG-(11)C-methionine uptake decoupling analysis is a powerful imaging modality for assessing glioma invasion.

Object Immunotherapy targeting the Wilms tumor 1 (WT1) gene product is a promising treatment modality for patients with malignant gliomas, and there have been reports of encouraging results. It has become clear, however, that Gd-enhanced MR imaging does not reflect prognosis, thereby necessitating a more robust imaging evaluation system for monitoring response to WT1 immunotherapy. To meet this demand, the authors performed a voxel-wise parametric response map (PRM) analysis of 11C-methionine PET (MET-PET) in WT1 immunotherapy and compared the data with the overall survival after initiation of WT1 immunotherapy (OSWT1). Methods Fourteen patients with recurrent malignant glioma were included in the study, and OSWT1 was compared with: 1) volume and length change in the contrast area of the tumor on Gd-enhanced MR images; 2) change in maximum uptake of 11C-methionine; and 3) a more detailed voxel-wise PRM analysis of MET-PET pre- and post-WT1 immunotherapy. Results The PRM analysis was able to identify the following 3 areas within the tumor core: 1) area with no change in 11C-methionine uptake pre- and posttreatment; 2) area with increased 11C-methionine uptake posttreatment (PRM+MET); and 3) area with decreased 11C-methionine uptake posttreatment. While the results of Gd-enhanced MR imaging volumetric and conventional MET-PET analysis did not correlate with OSWT1 (p = 0.270 for Gd-enhanced MR imaging length, p = 0.960 for Gd-enhanced MR imaging volume, and p = 0.110 for MET-PET), the percentage of PRM+MET area showed excellent correlation (p = 0.008) with OSWT1. Conclusions This study describes the limited value of Gd-enhanced MR imaging and highlights the potential of voxel-wise PRM analysis of MET-PET for monitoring treatment response in immunotherapy for malignant gliomas. Clinical trial registration no.: UMIN000002001.

Object The precise natural history of incidentally discovered meningiomas (IDMs) remains unknown. It has been reported that for symptomatic meningiomas, tumor location can be used to predict growth. As to whether the same is true for IDMs has not been reported. This study aims to answer this question and provide biological evidence for this assumption by extending the study to involve symptomatic cases. Methods A total of 113 IDMs were analyzed by fine volumetry. A comparison of growth rates and patterns between skull base and non–skull base IDMs was made. Subsequently, materials obtained from 210 patients with symptomatic meningiomas who were treated in the authors' hospital during the same period were included for a biological comparison between skull base and non–skull base tumors using the MIB-1 index. Results The 110 patients with IDMs included 93 females and 17 males, with a mean follow-up period of 46.9 months. There were 38 skull base (34%) and 75 non–skull base (66%) meningiomas. Forty-two (37%) did not exhibit growth of more than 15% of the volume, whereas 71 (63%) showed growth. Only 15 (39.5%) of 38 skull base meningiomas showed growth, whereas 56 (74.7%) of 75 non–skull base meningiomas showed growth (p = 0.0004). In the 71 IDMs (15 skull base and 56 non–skull base), there was no statistical difference between the 2 groups in terms of mean age, sex, follow-up period, or initial tumor volume. However, the percentage of growth (p = 0.002) was significantly lower and the doubling time (p = 0.008) was significantly higher in the skull base than in the non–skull base tumor group. In subsequently analyzed materials from 94 skull base and 116 non–skull base symptomatic meningiomas, the mean MIB-1 index for skull base tumors was markedly low (2.09%), compared with that for non–skull base tumors (2.74%; p = 0.013). Conclusions Skull base IDMs tend not to grow, which is different from non–skull base tumors. Even when IDMs grow, the rate of growth is significantly lower than that of non–skull base tumors. The same conclusion with regard to biological behavior was confirmed in symptomatic cases based on MIB-1 index analyses. The authors' findings may impact the understanding of the natural history of IDMs, as well as strategies for management and treatment of IDMs and symptomatic meningiomas.

Randomized trials failed to prove the efficacy of Bevacizumab on OS of newly diagnosed glioblastomas, but improvement of PFS was revealed. Based on these results, Japanese national health insurance approved Bevacizumab (Bev) for both primary and recurrent glioblastoma treatment in 2013. And at same period, BCNU wafer was also able to be administered. The objective of this study was to examine the influence upon treatment of Glioblastoma that these new therapeutic modalities had, and to find the most popular treatment for glioblastomas in Kansai region, Japan. For this purpose, we retrospectively reviewed clinical data of 223 newly diagnosed glioblastoma patients which were collected for molecular biological analysis by Kansai Molecular Diagnosis Network for CNS Tumors between 2006 and 2016. We examined how treatments of glioblastoma altered after 2013. In 79 patients diagnosed before June 2013, 68 (86.1%) were received concomitant chemoradiotherapy (CCRT) with temozolomide (TMZ), three (3.8%) radiation therapy (RT) only, four (5.1%) chemotherapy (CMT) only, and four (5.1%) none. In 144 patients after that, 113 (78.5%) were received CCRT, six (4.2%) RT only, 19 (13.8%) CMT only, and six (4.2%)none. Bevacizumab was used for 29 patients (20.1%) at initial treatment, 21 (14.6%) at recurrence, and 13 (9.0%) throughout. That is, only about half of glioblastoma patients were treated with Bev. We also found that TMZ were still most frequently used for treatment after recurrence, and nitrosourea was not used at all since 2013. Significant alterations observed were increase of TMZ chemotherapy without RT and use of reduced radiation dose, which were mainly selected based on methylation status of MGMT promoter and patients’ age. Finally, it seems that more personalized treatment for glioblastoma has been introducing in these days, but additional treatment resulting to improvement of prognosis has not become popular.

For improvement of prognosis for glioblastoma patients, which remains poor, identification and targeting of glioblastoma progenitor cells are crucial. In this study, we found that the Cluster of Differentiation (CD)166/activated leukocyte cell adhesion molecule (ALCAM) was highly expressed on CD133 1 glioblastoma progenitor cells. ALCAM 1 CD133 1 cells were highly enriched with tumor sphere-initiating cells in vitro. Among gliomas with isocitrate dehydrogenase-1/R132H mutation, the frequencies of ALCAM 1 cells were significantly higher for glioblastomas than for World Health Organization grade II or III gliomas. The function of ALCAM in glioblastoma was then investigated. An in vitro invasion assay showed that transfection of ALCAM small interfering RNA or small hairpin RNA into glioblastoma cells significantly increased cell invasion without affecting cell proliferation. A soluble isoform of ALCAM (sALCAM) was also expressed in all glioblastoma samples and at levels that correlated well with ALCAM expression levels. In vitro invasion of glioblastoma cells was significantly enhanced by administration of purified sALCAM. Furthermore, overexpression of sALCAM in U87MG glioblastoma cells promoted tumor progression in i.c. transplants into immune-deficient mice. In summary, we were able to show that ALCAM constitutes a novel glioblastoma progenitor cell marker. We could also demonstrate that ALCAM and its soluble isoform are involved in the regulation of glioblastoma invasion and progression.

The clinical course of meningioma varies from case to case, despite similar characteristics on magnetic resonance (MR) imaging. Functional imaging including 11C-methionine and 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) has been widely studied for noninvasive preoperative evaluation of brain tumors. However, few reports have examined correlations between meningiomas and findings on 11C-methionine and FDG PET. The objective of this study was to clarify the relationship between tumor characteristics and 11C-methionine and FDG uptake in meningiomas. For 68 meningiomas in 51 cases, 11C-methionine uptake was evaluated by measuring both mean and maximum tumor/normal (T/N) ratio for the whole area of the tumors. FDG uptake in 44 of those meningiomas was also analyzed. Tumor size was measured volumetrically, and tumor-doubling time was estimated. Histopathological evaluation was performed in 19 surgical cases. Mean and maximum T/N ratios of 11C-methionine PET were significantly higher in skull-base lesions than in non-skull-base lesions. Correlations of mean and maximum T/N ratio of 11C-methionine PET with tumor-doubling time, MIB-1 labeling index, microvessel density and World Health Organization grading were not significant. Mean T/N ratio of 11C-methionine PET correlated significantly with tumor volume according to logarithm regression modeling (P < 0.0001, R = 0.544). However, mean and maximum T/N ratio of FDG-PET correlated with none of the tumor characteristics described above. These results suggest that 11C-methionine uptake correlates with tumor volume, but not with tumor aggressiveness.

Discriminating tumor infiltrative and vasogenic brain edema in malignant gliomas is important although challenging in clinical settings. This study challenged this issue by performing voxel-wise analysis of (18)F-fluorodeoxy glucose (FDG) and (11)C-methionine positron emission tomography (PET) in peritumoral brain edemas. The authors studied ten malignant glioma and nine meningioma patients with peritumoral brain edema. A voxel-wise analysis of FDG and (11)C-methionine PET was performed in order to quantify the correlation between uptake of these tracers in normal brain tissue and peritumoral brain edema. Decoupling score of the uptake of two tracers was calculated as the z-score from the estimated correlation between uptake of the two tracers in normal brain tissue. The decoupling score was also converted into images for visual inspection. Average decoupling score in the peritumoral brain edema was calculated and compared between those obtained from malignant gliomas and meningiomas. FDG and (11)C-methionine uptake showed a reproducible linear correlation in normal brain tissue. This correlation was preserved in peritumoral edema of meningioma, but not in that of malignant gliomas. In malignant gliomas, higher (11)C-methionine uptake compared to that estimated by the FDG uptake in normal brain tissue was observed, thus suggesting that decoupling was caused by tumor infiltration. Visual inspection of the decoupling score enabled discrimination of tumor infiltrative and vasogenic edema. The average decoupling scores of the peritumoral brain edema in malignant gliomas were significantly higher than those in meningiomas (2.9 vs. 0.7, P = 0.0003). As a conclusion, FDG/(11)C-methionine uptake decoupling score can be used for the discrimination of tumor infiltrative and vasogenic brain edema. The proposed method also suggests the possibility of accurately detecting tumor infiltration into brain tissues in gliomas, providing significant information for treatment planning and follow-up.

BACKGROUND: The extent of tumor resection is acknowledged as 1 of the prognostic factors for glioma. 5-Aminolevulinic acid (5-ALA)-induced fluorescence guidance and neuronavigation integrated with 11C-methionine positron emission tomography (PET) are widely utilized under the expectation of improving the extent of resection. These 2 novel approaches are beneficial for glioma resections, and the combination of these approaches appears rational. However, biological characteristics reflecting 5-ALA-induced fluorescence and 11C-methionine uptake have not been clearly elucidated, and studies about the relationship between 5-ALA-induced fluorescence and 11C-methionine uptake have been limited. The present study aimed to clarify this issue. METHODS: Data from 11 consecutive patients harboring astrocytic tumors were analyzed: 2 grade II and 2 grade III, and 7 grade IV tumors were included. Thirty samples from these patients were obtained from the relative periphery of each tumor. Relationships among histology, 5-ALA-induced fluorescence and 11C-methionine uptake were analyzed by stereotactic sampling and image analysis. RESULTS: Uptake of 11C-methionine correlated with cell density (R2 = 0.322, P = .0059). Cell density was higher in fluorescence-positive areas than in negative areas (2760 ± 1080 vs 1450 ± 1380/mm2, P = .0132). Although both 11C-methionine uptake and fluorescence seemed to correlate with cell density, no significant difference in 11C-methionine uptake was seen between fluorescence-positive and -negative areas (P = .367). Multiple linear regression analysis revealed 11C-methionine uptake and 5-ALA-induced fluorescence as independent indices for tumor cell density. CONCLUSIONS: These results indicate that 5-ALA fluorescence and 11C-methionine PET image are separate index markers for cytoreduction surgery of gliomas. Cancer 2011;. © 2011 American Cancer Society.

Hepatitis B virus (HBV) reactivation during anticancer chemotherapy or immunosuppressive therapy in chronic carriers can lead to fatal liver failure. We report a rare case of severe HBV reactivation during postoperative radiotherapy with concomitant and adjuvant temozolomide (TMZ) for malignant glioma. A 49-year-old Japanese woman with a history of HBV carrier status with positive results for hepatitis B surface antigen presented with persistent headache due to a tumor in the left frontal lobe. The tumor was partially resected and anaplastic astrocytoma was diagnosed. Postoperative liver function was normal and radiotherapy plus concomitant and adjuvant TMZ was started. Impaired liver function became apparent just before administration of adjuvant TMZ, and acute liver failure developed. Antiviral therapy including entecavir, a nucleoside analog, led to a successful outcome and the patient survived. This case underlines the possibility of HBV reactivation due to TMZ and suggests the utility of HBV screening and antiviral prophylaxis before administration of TMZ to patients with malignant glioma.

Four kinds of bio-based polyurethanes bearing hydroxy groups in the pendants were synthesized by the polyaddition of D-mannitol- and D,L-erythritol-derived diols (1,2:5,6-di-O-isopropylidene-D-mannitol and 1,2-O-isopropylidene-D,L-erythritol) with hexamethylene diisocyanate and methyl (S)-2,6-diisocyanatohexanoate and the subsequent deprotection of the isopropylidene groups. They were hydrolyzed much more quickly than the corresponding protected polyurethanes at 50 °C and pH 7.0, although their hydrolytic degradation rate was lower than that of polyurethanes with saccharic and glucuronic lactone groups, which had been reported in our previous articles. The introduction of D-mannitol units to the polyether-polyurethanes containing poly(oxytetramethylene) glycol units also enhanced their hydrolyzibility.

The trigeminocardiac reflex (TCR) is defined as a reproducible hypotension and bradycardia coinciding with the manipulation around the trigeminal nerve. Here, we report a case of sudden bradycardia with falcine manipulation. As the falx cerebri is innervated by the nervus tentorii, which is a recurrent branch of the ophthalmic nerve, the observed asystole is highly possible to be caused by TCR. Anesthesiologists and neurosurgeons should be fully aware of the anatomical innervation of the falx cerebri and that the posterior third of the falx cerebri is one of the highest risk structures for TCR induction for safe operation around this region.

There have been few studies investigating neuro-oncologists’ attitudes toward the disclosure of the diagnosis. This study aimed to determine the current status of disclosure to glioma patients in Japan and to analyze the factors associated with disclosure. A set of questionnaires about disclosure to patients with malignant glioma was distributed by e-mail to 191 physicians participating in the 27th Annual Meeting of the Japan Society for Neuro-Oncology. The response rate was 73.8% (141/191). Of these, 44.3% disclosed the correct diagnosis to glioblastoma patients aged

Lessons Learned A shortened infusion of ramucirumab (from 60 to 20 minutes) was safe and feasible without infusion-related reactions. Twenty-minute infusions of ramucirumab can be an option for patients with no infusion-related reactions during the first 60-minute treatment. Background Ramucirumab is usually administered over 60 minutes, during which it is unlikely to cause infusion-related reactions (IRRs). This prospective study evaluated the safety of a shortened infusion of ramucirumab. Methods Patients who received their first dose of ramucirumab in a 60-minute infusion without developing IRRs were eligible and received their second ramucirumab dose for 20 minutes. The primary study endpoint was incidence of IRR during the first short-term infusion, and the secondary endpoints were incidence of IRR at any time and adverse events other than IRR. Results Of the 40 patients enrolled (median age, 68.5 years), 20 (55%) were male, 27 (67.5%) had stage IV gastric cancer, 25 (62.5%) received ramucirumab in combination with taxane-based chemotherapy, and 24 (60%) received only a single administration of ramucirumab prior to their enrollment. Notably, no IRR was observed during the first short-term infusion (IRR rate, 0%; 95% confidence interval [CI], 0%–0.72%). Among the 149 short-term infusions performed, there were no instances of IRRs or unexpected adverse events related to the treatment (Table 1). Conclusion For patients without development of IRRs upon the first ramucirumab administration, shortening infusion time (from 60 to 20 minutes) is safe and feasible.

We report the case of a 28-year-old man who presented with the sole complaint of lumbago. Spinal magnetic resonance imaging (MRI) revealed a solitary, well-defined intramedullary mass at the L1-L2 level typical of a primary spinal cord germinoma. However, cranial magnetic resonance imaging (MRI) showed a concomitant lesion in the suprasellar region. This article describes a rare case of simultaneously detected intracranial and intramedullary spinal cord germinoma and its possible etiopathology.

Previous reports have shown that a unique bacterial dye-decolorizing peroxidase from the cyanobacterium Anabaena sp. strain PCC7120 (AnaPX) efficiently oxidizes both recalcitrant anthraquinone dyes (AQ) and typical aromatic peroxidase substrates. In this study, site-directed mutagenesis to replace five Met residues in AnaPX with high redox residues Ile, Leu, or Phe was performed for the improvement of the enzyme stability toward H(2)O(2). The heme cavity mutants M401L, M401I, M401F, and M451I had significantly increased H(2)O(2) stabilities of 2.4-, 3.7-, 8.2-, and 5.2-fold, respectively. Surprisingly, the M401F and M451I retained 16% and 5% activity at 100 mM H(2)O(2), respectively, in addition to maintaining high dye-decolorization activity toward AQ and azo dyes at 5 mM H(2)O(2) and showing a slower rate of heme degradation than the wildtype enzyme. The observed stabilization of AnaPX may be attributed to the replacement of potentially oxidizable Met residues either increasing the local stability of the heme pocket or limiting of the self-inactivation electron transfer pathways due to the above mutations. The increased stability of AnaPX variants coupled with the broad substrate specificity can be potentially useful for the further practical application of these enzymes especially in bioremediation of wastewater contaminated with recalcitrant AQ.

The use of Wilms' tumor 1 (WT1) immunotherapy is considered to be an innovative approach for the treatment of malignant gliomas. Because of its novelty, tools that can accurately predict response to this therapy are still lacking. In this article, we investigated the role of WT1 protein expression level (score 1-4) and MIB-1 staining index in predicting survival outcome after therapy in patients with recurrent or progressive glioblastoma multiforme. Tumor samples from 37 patients enrolled in a phase II clinical trial on WT1 immunotherapy were immunohistochemically analyzed for WT1 levels and MIB-1 index. Results showed that median progression-free survival (PFS) was longer in the WT1 high expression group (score 3 and 4) compared with that of the low expression group (score 1 and 2) (20.0 weeks vs. 8.0 weeks; P = 0.022), and that the median overall survival (OS) was likewise longer in the former compared to the latter group (54.4 weeks vs. 28.4 weeks; P = 0.035). Furthermore, within the WT1 high expression group, tumors with intermediate staining intensity (WT1 score 3) have both the longest median PFS and OS, 24.4 weeks and 69.4 weeks, respectively. On the other hand, no significant correlation was noted between MIB-1 staining index and survival. In conclusion, our study has shown that WT1 protein expression level, not MIB-1 staining index, can be used as a prognostic marker to foretell outcome after immunotherapy, and that patients whose tumors have intermediate WT1 expression have the best survival outcome.

Object Event-related cerebral oscillatory changes reflect regional brain activation. In a previous study, the authors proposed a new method to determine language dominance: examine frontal oscillatory changes during silent reading by using synthetic aperture magnetometry (SAM). The authors' aims in the present study were to establish a normal template for this method, to confirm the results of their previous study with a larger patient population, and to evaluate their method with respect to language localization. Methods A statistical group analysis of 14 healthy volunteers was conducted to establish a normal control. Language dominance and localization were then evaluated in a larger population of 123 consecutive patients. Study participants were instructed to silently read 100 visually presented words. Using SAM, the spatial distribution of the oscillatory changes was obtained as the Student t statistic by comparing the current density for each voxel between 1 second before and 1 second after each word presentation. Group analyses of the healthy volunteers were performed using statistical nonparametric mapping. Language dominance in the patients was determined according to the laterality index (LI) calculated using peak t values of the left and right frontal desynchronizations. Language dominance was prospectively assessed, and the results were compared with those of the Wada test (63 patients). Language localization results were quantitatively compared with those of stimulation mapping (17 patients). Results Group analysis of the healthy volunteers indicated β to low γ band desynchronization in the left frontal area and α to β desynchronization in the left parietotemporal areas. In patients, the frontal language areas were detected in 118 persons (95.9%). Lateralization of β or low γ desynchronization in the inferior or middle frontal gyri corresponded well with language dominance. The introduction of the LI resulted in a quantitative evaluation of language dominance, whose results were concordant with those of the Wada test in 51 (85.0%) of 60 cases. The distance between the estimated frontal language areas and stimulation-positive sites was 6.0 ± 7.1 mm (mean ± SD). Conclusions This study is the first in which magnetoencephalography (MEG) was used to determine language dominance in a large population, and the results were compared with those of the Wada test. Moreover, language localization results obtained using MEG were compared with those obtained by invasive mapping. The authors' method, which is based on neuromagnetic oscillatory changes, is a new approach for noninvasively evaluating the frontal language areas, a procedure that has been problematic using MEG dipole methods. Synthetic aperture magnetometry is a noninvasive alternative to Wada testing for language dominance and helps to determine stimulation sites for invasive mapping.

Primary central nervous system lymphoma (PCNSL) remains a devastating disease with poor prognosis, despite the improvement offered by methotrexate (MTX)-based chemotherapy. Several studies have attempted to identify biomarkers predictive of prognosis, which are expected to be both clinically useful and biologically important for understanding PCNSL. The present study attempts to classify human immunodeficiency virus (HIV)-unrelated PCNSL patients treated with radiation combined with rapid high-dose MTX chemotherapy according to B-cell differentiation status, and retrospectively examines the prognostic impact. Initial response to MTX was a strong predictor of favorable prognosis in terms of both progression-free survival (PFS) and overall survival (OS). Thirteen out of 29 cases were CD10(-)/BCL-6(+)/MUM-1(+), being more frequent compared with systemic peripheral nodal lymphoma. Although post-germinal-center B-cell-originating PCNSLs (CD10(-)/BCL-6(-)/MUM-1(+)) showed a trend towards better response to MTX and progression-free survival than did germinal-center-related B-cell-originating PCNSLs (CD10(+) OR CD10(-)/BCL-6(+)/MUM-1(+)), the difference was only marginal (P = 0.04 Gehan-Breslow-Wilcoxon, P = 0.17 log-rank). Our results imply that different B-cell stages in PCNSL have significant relevance in terms of biological behavior. However, clinical use as a prognostic marker requires further investigation.

Posttransplant lymphoproliferative disorder (PTLD) is one of the life-threatening complications of organ transplantation. PTLD sometimes involves the central nervous system (CNS), but the clinical characteristics are not well recognized. A total of 631 patients received kidney transplantation at Osaka University Hospital between March 1965 and December 2008. Two of the 631 patients (0.32%) developed CNS PTLD. A 40-year-old Japanese woman suffered onset of CNS PTLD 5 years after renal transplantation. After diagnosis based on histological examination by open biopsy, she obtained remission with dose increase of steroid and dose reduction of mycophenolate mofetil. She experienced relapse 20 months after first remission. She underwent second biopsy and the diagnosis was recurrent CNS PTLD. Further reduction of mycophenolate mofetil and increase of steroid led to second remission. The disease remained in complete remission at 60 months after first onset. A 61-year-old woman suffered onset of CNS PTLD 19 years after renal transplantation. After tumor removal, whole brain irradiation was performed. The disease remained in remission at 54 months after onset. Histological examination showed polymorphic-type PTLD in both cases. The first case of polymorphic CNS PTLD was successfully treated by modulation of immunosuppressants without radiation therapy even at recurrence. PTLD should be included in the differential diagnosis of brain tumors in recipients of solid organ transplantation, and histological subtype should be carefully identified to establish the correct treatment strategy.

The open reading frame alr1585 of Anabaena sp. strain PCC 7120 encodes a heme-dependent peroxidase ( Anabaena peroxidase [AnaPX]) belonging to the novel DyP-type peroxidase family (EC 1.11.1.X). We cloned and heterologously expressed the active form of the enzyme in Escherichia coli . The purified enzyme was a 53-kDa tetrameric protein with a pI of 3.68, a low pH optima (pH 4.0), and an optimum reaction temperature of 35°C. Biochemical characterization revealed an iron protoporphyrin-containing heme peroxidase with a broad specificity for aromatic substrates such as guaiacol, 4-aminoantipyrine and pyrogallol. The enzyme efficiently catalyzed the decolorization of anthraquinone dyes like Reactive Blue 5, Reactive Blue 4, Reactive Blue 114, Reactive Blue 119, and Acid Blue 45 with decolorization rates of 262, 167, 491, 401, and 256 μM·min −1 , respectively. The apparent K m and k cat / K m values for Reactive Blue 5 were 3.6 μM and 1.2 × 10 7 M −1 s −1 , respectively, while the apparent K m and k cat / K m values for H 2 O 2 were 5.8 μM and 6.6 × 10 6 M −1 s −1 , respectively. In contrast, the decolorization activity of AnaPX toward azo dyes was relatively low but was significantly enhanced 2- to ∼50-fold in the presence of the natural redox mediator syringaldehyde. The specificity and catalytic efficiency for hydrogen donors and synthetic dyes show the potential application of AnaPX as a useful alternative of horseradish peroxidase or fungal DyPs. To our knowledge, this study represents the only extensive report in which a bacterial DyP has been tested in the biotransformation of synthetic dyes.

Diffusion tensor imaging (DTI) by magnetic resonance imaging (MRI) is now used not only for delineating white matter fiber tracts, but also for assessing the histological characteristics of pathological tissues. Among these uses, predicting the extent or existence of tumor cell invasion into white matter by DTI is under extensive investigation. The previously reported tumor infiltration index (TII) holds great potential for the discrimination of pure vasogenic edema from tumor-infiltrated edema. However, conflicting data are being reported questioning the clinical value of TII. The present investigation reevaluated the utility of TII in patients with meningioma or glioma. We found that TII was unable to discriminate vasogenic from tumor-infiltrated edema. Conversely, detailed voxel-by-voxel comparison of TII and (11)C-methionie PET in the T2-hyperintense area of gliomas showed that TII and (11)C-methionie PET has a positive correlation, suggesting that, although TII is unable to discriminate the cause of edema, the extent of tumor cell invasion into white matter is depicted in gliomas by TII. These data suggest that TII involves both vasogenic and tumor-infiltrated factors, rather than only a single factor. A more intensive investigation is required to reach a complete understanding of TII.

Object Due to advances in neuroimaging and the increasing use of imaging to screen for brain disease (“brain checkups”), meningiomas are now often detected as an incidental finding. The natural history of these asymptomatic meningiomas remains unclear, however. In this study, the authors investigated the natural history and growth pattern of incidentally detected meningiomas using serial volumetric assessment and regression analysis. Methods In 70 patients with incidentally discovered meningiomas who underwent follow-up for longer than 1 year, tumor volumes were calculated volumetrically at each follow-up visit, and tumor growth was determined. In patients with tumor growth, regression analysis was performed to determine the pattern of growth. Results Forty-four tumors exhibited growth and 26 did not. In a regression analysis, 16 of the tumors that grew followed an exponential growth pattern and 15 exhibited linear growth patterns. The presence of calcification was the only imaging characteristic that significantly distinguished the group with tumor growth from that without, although no radiological characteristics significantly distinguished the exponential growth group from the linear growth group. Two patients with obvious tumor growth underwent surgical removal and the pathological specimens extracted showed a high proliferative potential. Conclusions The authors found that incidentally discovered meningiomas did not always follow an exponential growth pattern but often exhibited more complex patterns of growth. Serial monitoring of tumor volumes and regression analysis may reveal the growth pattern of incidental meningiomas and provide information useful for determining treatment strategy.

Central post-stroke pain (CPSP) is one of the most common types of intractable pain. We reported that repetitive transcranial magnetic stimulation (rTMS) of primary motor cortex relieves pain for patients who were refractory to medical treatment. But the mechanism is unclear. In the present study, we investigated relations between the characteristics of CPSP and the results of fiber tracking, which is the only noninvasive method of evaluating the anatomical connectivity of white matter pathways. Fiber tracking of the corticospinal tract (CST) and thalamocortical tract (TCT) was investigated in 17 patients with CPSP. The stroke lesion was located in a supratentorial region in all cases (corona radiata, one case; thalamus, seven cases; putamen, nine cases). Relations between the delineation ratio (defined as the ratio of the cross section of the affected side to that of the unaffected side) of the CST and of the TCT, manual muscle test score, pain score, region of pain, and efficacy of rTMS were evaluated. Fiber tracking was successful in 13 patients with the stroke lesion involving the TCT. The rTMS-effective group had higher delineation ratio of the CST (p = 0.02) and the TCT (p = 0.005) than the rTMS-ineffective group. Previous studies suggested that an intact CST allows pain control but did not discuss the TCT. Our results suggest that the TCT also plays a role in pain reduction by rTMS of the primary motor cortex and that the efficacy of rTMS for patients with CPSP is predictable by fiber tracking.

A noninvasive technique for assessing tumor tissue characteristics is required to assist preoperative surgical planning for malignant brain tumors. Preoperative information on tumor cell density within a tumor would help better define the target for tumor biopsy, resulting in more accurate diagnosis and grading of malignant brain tumors. One possible source of this information is diffusion tensor imaging (DTI), although to date studies have focused on its ability to delineate white matter fiber tracks by fiber-tracking and to detect tumor infiltration around the tumor and normal white matter interface. However, the use of DTI for providing information on cell density has also been examined, although with the controversial results. In addition the exact relationships between cell density and the two key values that DTI provides, namely fractional anisotropy (FA) and mean diffusivity (MD), still need to be investigated. In the present study we performed a retrospective investigation of tumor cell density and FA and MD values in biopsy cases. We found that FA has a good positive correlation (R=0.75) and MD has a good negative correlation (R=0.70) with tumor cell density within the tumor core. Similar correlation was observed between the Ki-67 labeling index and FA (R=0.71) and MD (R=0.62). Thus, measurement of both FA and MD within the tumor core has a potential to provide detailed information on tumor cell density within the tumor. Although data obtained from DTI should be interpreted carefully and comprehensively with other imaging modalities such as positron emission tomography, DTI seems to be informative for planning the best biopsy target containing the highest cell density.

Object The object of this study was to investigate the safety and clinical responses of immunotherapy targeting the WT1 (Wilms tumor 1) gene product in patients with recurrent glioblastoma multiforme (GBM). Methods Twenty-one patients with WT1/HLA-A*2402–positive recurrent GBM were included in a Phase II clinical study of WT1 vaccine therapy. In all patients, the tumors were resistant to standard therapy. Patients received intra-dermal injections of an HLA-A*2402–restricted, modified 9-mer WT1 peptide every week for 12 weeks. Tumor size, which was obtained by measuring the contrast-enhanced area on magnetic resonance images, was determined every 4 weeks. The responses were analyzed according to Response Evaluation Criteria in Solid Tumors (RECIST) 12 weeks after the initial vaccination. Patients who achieved an effective response continued to be vaccinated until tumor progression occurred. Progression-free survival and overall survival after initial WT1 treatment were estimated. Results The protocol was well tolerated; only local erythema occurred at the WT1 vaccine injection site. The clinical responses were as follows: partial response in 2 patients, stable disease in 10 patients, and progressive disease in 9 patients. No patient had a complete response. The overall response rate (cases with complete or partial response) was 9.5%, and the disease control rate (cases with complete or partial response as well as those in which disease was stable) was 57.1%. The median progression-free survival (PFS) period was 20.0 weeks, and the 6-month (26-week) PFS rate was 33.3%. Conclusions Although a small uncontrolled nonrandomized trial, this study showed that WT1 vaccine therapy for patients with WT1/HLA-A*2402–positive recurrent GBM was safe and produced a clinical response. Based on these results, further clinical studies of WT1 vaccine therapy in patients with malignant glioma are warranted.

Angiotensin I converting enzyme (ACE)-inhibitory peptides were screened from a random peptide-displayed phage library using ACE-coupled liposomes. Among four kinds of inhibitory peptides selected by biopanning with two different elution strategies, a peptide (LSTLRSFCA) showed the highest inhibitory activity with an IC(50) value of 3microM. By measuring inhibitory activities of fragments of the peptide, it was found that the RSFCA region was a functional site to inhibit strongly the ACE catalytic activity, and particularly both Arg and Cys residues were essential for the strong inhibitory activity. The inhibitory activity of RRFCA was slightly increased, while that of the RSFRA, in which the Cys residue was replaced by Arg, was decreased to greater extent in comparison with the inhibitory activity of RSFCA. Taking into account the results obtained from the SPOT analysis, it was suggested that the Arg and Phe residues in RSFCA were important for a specific interaction with ACE, and the Cys residue inhibited the ACE activity. The cystein-based ACE-inhibitory peptides have not been isolated from processed food materials. These findings suggested that the biopanning method utilizing protein-coupled liposomes and random peptide libraries might have a possibility to screen new functional peptides that are not found in processed food materials.

BACKGROUND: Novel molecular aberrations are found and their prognostic or predictive values are reported. We have established a network for genetical analysis for central nervous system tumors in Kansai area, Japan. METHODS: We retrospectively reviewed clinical records of histologically proven 144 glioma patients (grade4: 88, grade3; 30, grade2: 30) treated by institutes accompanied with Kansai network for molecular diagnosis of central nervous system tumors between 2004-2014. Surgical specimen which were obtained at an initial surgery were used for molecular characterization. We investigated methylation status of MGMT promoter by methylation specific realtime PCR. Mutation of IDH1(R132H), IDH2 and TERT promoter were analyzed by Sanger method. Survival proportion was calculated by Kaplan Meyer method. RESULTS: Median time of overall survival (OS) of grade 4 and grade3 gliomas were 77 and 190 weeks, respectively, OS of grade4 and grade3 patients with methylated MGMT promoter was significantly longer than those without methylation status (151 versus 75.6 weeks, p = 0.0027). IDH1 mutation was found in 23/30, 16/30 and 5/88 cases of grade2, grade3 and grade, respectively. Mutation of TERT promoter was detected in 16/30, 13/30 and 40/87 cases of grade2, grade3 and grade, respectively. CONCLUSION: These data bring us important information to decide how to treat glioma patients. And analysis of glioma patients include who do not match for clinical trial may reveal more practical clinical course and aspects.

Immunotherapy is a promising area of therapy in patients with neuro-oncological malignancies. However, early-phase studies show unique challenges associated with the assessment of radiological changes in response to immunotherapy reflecting delayed responses or therapy-induced inflammation. Clinical benefit, including long-term survival and tumour regression, can still occur after initial disease progression or after the appearance of new lesions. Refinement of the response assessment criteria for patients with neuro-oncological malignancies undergoing immunotherapy is therefore warranted. Herein, a multinational and multidisciplinary panel of neuro-oncology immunotherapy experts describe immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria based on guidance for the determination of tumour progression outlined by the immune-related response criteria and the RANO working group. Among patients who demonstrate imaging findings meeting RANO criteria for progressive disease within 6 months of initiating immunotherapy, including the development of new lesions, confirmation of radiographic progression on follow-up imaging is recommended provided that the patient is not significantly worse clinically. The proposed criteria also include guidelines for the use of corticosteroids. We review the role of advanced imaging techniques and the role of measurement of clinical benefit endpoints including neurological and immunological functions. The iRANO guidelines put forth in this Review will evolve successively to improve their usefulness as further experience from immunotherapy trials in neuro-oncology accumulate.

PURPOSE: To test this hypothesis that different genetic backgrounds of lung cancers could affect spatial distribution of brain metastasis. EXPERIMENTAL DESIGN: CT or MR images of 200 patients with a total of 1033 treatment naive brain metastases from lung cancer were retrospectively collected. All images were deformed and standardized to MNI 152 standard human brain MRI. Locations of the lesions, depths of the lesions from brain surface, and sizes of the lesions after image standardization were analyzed and compared between histological subtypes of the primary lesion as well as EGRF mutation status. RESULTS: The posterior fossa, the anatomic watershed areas and the grey-white matter junction were confirmed to be predilection areas of lung cancer brain metastasis and brain metastasis with L858R occurred more often in caudate, cerebellum and temporal lobe than those with Ex19Del. Among adenocarcinoma lung cancer patients, depths of the lesions from brain surface were 15.7 ± 9.1mm for Ex19Del, 12.6 ± 8.5mm for L858R and 16.1 ± 8.5mm for WT. The lesions with L858R were located statistically significantly closer to the brain surface than the lesions with Ex19Del or WT (p = 0.0032 and p < 0.0001, respectively). On the other hand, there was no statistically significant difference in tumor size among different EGFR mutation status (p = 0.086). Furthermore, brain metastases of adenocarcinoma lung cancer patients with history of chemotherapy treatment were located statistically significantly deeper from brain surface (p = 0.0002). History of molecular targeted therapy did not have any effect on the depth of the lesion. CONCLUSIONS: This analysis is the first to reveal the relationship between tumor's molecular biological characteristics, namely EGFR mutation status and spatial distribution of brain metastases of lung cancer.

We have completed two clinical trials on WT1 peptide vaccination against gliomas; phase II trial for recurrent ones (Izumoto, Hashimoto et al., J Neurosurg, 2008) and phase I trial for newly diagnosed glioblastomas focusing on the safe combination with temozolomide (Hashimoto et al., Cancer Immunol Immunother, 2015). Although patients' survival data have been shown in the past SNO meetings, recently updated data for longer follow-up period will be presented. Especially, WT1 vaccination combined with Stupp regimen in the latter trial against glioblastomas produced progression free survival over 48 months in 5 of 7 patients recruited. Subsequent analyses from those trials revealed some immunological and non-immunological biomarkers on response to the vaccination. High level of WT1 protein and HLA class I expression on tumor cells were predictive of longer survival. Immunologically, increased WT1-specific T cells and WT1 antibody in peripheral blood after the vaccination were also predictive, and positive change of delayed type hypersensitivity (DTH) within 3 months from the start of vaccination was also a biomarker; those should rather be thought as “proof of concept” of this immunotherapy. Samples from 20 non-responders who required surgical intervention after vaccination revealed that tumor cells might have escaped from immunological attack by decreasing WT1 and HLA expression, by comparing with pre-vaccination samples in the same patients. On the response assessment, we reported that methionine PET was more accurate than enhancing MRI, when assuming survivals (Chiba, Hashimoto et al., J Neurosurg, 2012). Among MRI-based response assessments of RECIST, Macdonald, immune-related response criteria (irRC) and RANO, our analyses using 60 patients have revealed that RANO was the most appropriate surrogate of survivals in early phase, although more accurate criteria specific to immunotherapy on brain tumors were warranted.

Prognosis of glioblastoma multiforme (GBM) patients still remains poor. To improve its prognosis, it is important to identify new therapeutic targets. CD166/ALCAM is a member of the immunoglobulin superfamily and is widely expressed in various tissues such as neurons, fibroblasts, endothelial cells. Furthermore it is also reported to be a colon cancer stem cell marker as well as mesenchymal stem cell marker. CD166/ALCAM is also expressed on endothelial cells and is involved in angiogenesis. In this study, we aim to analyze the functional roles of CD166/ALCAM in glioblastoma. Transfection of CD166/ALCAM siRNA to U87MG and U251 cells significantly increased cell invasion in matrigel invasion assay without affecting cell proliferation. Transfection of ALCAM shRNA to U87MG glioblastoma cells significantly increased the tumor vessel area of U87MG xenograft in immune-deficient mice. Furthermore, over-expression of soluble isoform of CD166/ALCAM in U87MG GBM cells promoted tumor progression in intracranial transplant to immune-deficient mice. We also found that CD166/ALCAM was highly expressed on the CD133+ glioblastoma stem cell populations. In the CD133+ glioblastoma cell population, CD166/ALCAM positive cells were highly enriched with tumor-sphere-initiating cells in vitro. In summary, CD166/ALCAM is involved in glioblastoma invasion, angiogenesis, and tumor progression in glioblastoma. In addition CD166/ALCAM can be a candidate for glioblastoma progenitor markers. All these findings suggest that CD166/ALCAM is a potent therapeutic target against glioblastoma.

Immunotherapy represents a promising area of therapy among neuro-oncology patients. However, early phase studies reveal unique challenges associated with assessment of radiological changes reflecting delayed responses or therapy-induced inflammation. Clinical benefit, including long-term survival and tumor regression, can still occur following initial apparent progression or appearance of new lesions. Refinement of response assessment criteria for neuro-oncology patients undergoing immunotherapy is therefore warranted. A multinational and multidisciplinary panel of neuro-oncology immunotherapy experts describes immunotherapy response assessment for neuro-oncology (iRANO) criteria that are based on guidance for determination of tumor progression outlined by the immune-related response criteria (irRC) and the response assessment in neuro-oncology (RANO) working group. Among patients who demonstrate imaging findings meeting RANO criteria for progressive disease (PD) within six months of initiating immunotherapy including the development of new lesions, confirmation of radiographic progression on follow-up imaging is recommended provided that the patient is not significantly worse clinically. The proposed criteria also include guidelines for use of corticosteroids. The role of advanced imaging techniques and measurement of clinical benefit endpoints including neurologic and immunologic functions are reviewed. The iRANO guidelines put forth herein will evolve successively to improve their utility as further experience from immunotherapy trials in neuro-oncology accumulate.

BACKGROUND The purpose of this study was to test the hypothesis that the genetic backgrounds of lung cancers could affect the spatial distribution of brain metastases. METHODS CT or MR images of 200 patients with a total of 1033 treatment-naive brain metastases from lung cancer were retrospectively reviewed (23 by CT and 177 by MRI). All images were standardized to the human brain MRI atlas provided by the Montreal Neurological Institute 152 database. Locations, depths from the brain surface, and sizes of the lesions after image standardization were analyzed. RESULTS The posterior fossa, the anatomic "watershed areas," and the gray-white matter junction were confirmed to be more commonly affected by lung cancer brain metastases, and brain metastases with epidermal growth factor receptor (EGFR) L858R mutation occurred more often in the caudate, cerebellum, and temporal lobe than those with exon 19 deletion of EGFR. Median depths of the lesions from the brain surface were 13.7 mm (range, 8.6-21.9) for exon 19 deleted EGFR, 11.5 mm (6.6-16.8) for L858R mutated, and 15.0 mm (10.0-20.7) for wild-type EGFR. Lesions with L858R mutated EGFR were located significantly closer to the brain surface than lesions with exon 19 deleted or wild-type EGFR (P = .0032 and P < .0001, respectively). Furthermore, brain metastases of adenocarcinoma lung cancer patients with a history of chemotherapy but not molecular targeted therapy were located significantly deeper from the brain surface (P = .0002). CONCLUSION This analysis is the first to reveal the relationship between EGFR mutation status and the spatial distribution of brain metastases of lung cancer.

Neurosurgical patties are the most frequently used instruments during neurosurgical procedures, and their high performance is required to ensure safe operations. They must offer cushioning, water-absorbing, water-retaining, and non–tissue adherent characteristics. Here, the authors describe a revised neurosurgical patty that is superior in all respects to the conventional patty available in Japan. Patty characteristics were critically and scientifically evaluated using various in vitro assays. Moreover, a novel ex vivo evaluation system focusing on the adherent characteristics of the neurosurgical patty was developed. The proposed assay could provide benchmark data for comparing different neurosurgical patties, offering neurosurgeons objective data on the performance of patties. The newly developed patty was also evaluated in real neurosurgical settings and showed superb performance during various neurosurgical procedures.

We investigated the feasibility of using radiologic characteristics to predict the proliferative potential in meningiomas. Our statistical analysis revealed that the presence of peritumoral edema, an ambiguous brain-tumor border, and irregular tumor shape were significantly correlated with a higher MIB-1 staining index (SI) value. We developed the following scoring system for specific features in each tumor: peritumoral edema (tumor with edema = 1, tumor without edema = 0); brain-tumor border (tumor with any ambiguous border = 1, tumor circumscribed by a distinct rim = 0); and tumor shape (tumor with irregular shape = 1, tumor with smooth shape = 0). Using Spearman's correlation coefficient analysis, we found a significant correlation (P < 0.005) between total score calculated for each patient and SI value. Our findings suggest that the proliferative potential of meningiomas can be predicted using a less invasive preoperative examination focusing on the presence of peritumoral edema, ambiguous brain-tumor border, and irregular tumor shape.

Medulloblastoma (MB) is the most frequent infratentorial malignant brain tumor in children. In contrast, primitive neuroectodermal tumor (PNET) is defined as a supratentorial malignant tumor generated from the cerebral hemisphere. These tumors have considerable histological overlap but have different clinical outcomes including overall survival period, recurrence rate, and chemosensitivity. We investigated the amplification and/or deletion of genes and the chromosomal gain and/or loss in 10 MBs and 3 PNETs with a genomic DNA microarray system. Genes that are frequently amplified in these both these tumors include MSH2, N-myc, AKT3, and EGFR. Amplifications of SNRPN, MYB, and PTEN are observed only in MB. The genes associated with Wnt/APC and Shh/PTCH pathways also have some aberrations. Common chromosomal aberrations include gains at 17q and 7q and losses at 17p. Minor chromosomal losses were also detected at 1p, 8p + q, 11p, 10p + q, 13q, 16q, and Xp + q in MB. SPNETs tend to contain fewer chromosomal and genetic abnormalities than MBs. In conclusion, there are gene expression and chromosomal differences between MBs and SPNETs. These differences may correlate with the prognosis.