Intracranial germ cell tumors (IGCTs) are a group of rare heterogeneous brain tumors which are clinically and histologically similar to the more common gonadal GCTs. IGCTs show great variation in their geographic and gender distribution, histological composition and treatment outcomes. The incidence of IGCTs is historically 5–8 fold greater in Japan and other East Asian countries than in Western countries1 with peak incidence near the time of puberty2. About half of the tumors are located in the pineal region. The male-to-female incidence ratio is approximately 3–4:1 overall but even higher for tumors located in the pineal region3. Due to the scarcity of tumor specimens available for research, little is currently known about this rare disease. Here we report the analysis of 62 cases by next generation sequencing, SNP array and expression array. We find the KIT/RAS signaling pathway frequently mutated in over 50% of IGCTs including novel recurrent somatic mutations in KIT, its downstream mediators KRAS and NRAS, and its negative regulator CBL. Novel somatic alterations in the AKT/mTOR pathway included copy number gain of the AKT1 locus at 14q32.33 in 19% of patients, with corresponding upregulation of AKT1 expression. We identified loss-of-function mutations in BCORL1, a transcriptional corepressor and tumor suppressor. We report significant enrichment of novel and rare germline variants in JMJD1C, a histone demethylase and coactivator of the androgen receptor, among Japanese IGCT patients. This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potentially promising therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway.

Background and Purpose-Early goal-directed hemodynamic therapy is of particular importance for adequate cerebral circulation of patients with vasospasm after subarachnoid hemorrhage but is often precluded by the invasiveness of established cardiac output determination using a pulmonary artery catheter. This study was undertaken to validate the usefulness of less invasive goal-directed hemodynamic monitoring by transpulmonary thermodilution technique in patients after subarachnoid hemorrhage. Methods-One hundred sixteen patients with subarachnoid hemorrhage who underwent surgical clipping within 24 hours of ictus were investigated. Validation of transpulmonary thermodilution-derived intermittent/continuous cardiac output and cardiac preload (global end diastolic volume) were compared with pulmonary artery catheter-derived reference cardiac output and pulmonary capillary wedge pressure or central venous pressure in 16 patients diagnosed with vasospasm. In a subsequent trial of 100 consecutive cases, clinical results between the new and standard management paradigms were compared. Results-Transpulmonary thermodilution-derived intermittent cardiac output and transpulmonary thermodilution-derived continuous cardiac output showed close agreement to catheter-derived reference cardiac output with high correlation (rϭ0.85 and 0.77) and low percentage error (13.5% and 18.0%). Fluid responsiveness to defined volume loading was predicted better with global end diastolic volume than with pulmonary capillary wedge pressure and central venous pressure for larger receiver operating characteristic curve area. Patients receiving early goal-directed management by transpulmonary thermodilution experienced reduced frequencies of vasospasm and cardiopulmonary complications compared with those managed with standard therapy (PϽ0.05), whereas their functional outcomes at 3 months were not different (Pϭ0.06). Conclusions-Goal-directed hemodynamic management guided by transpulmonary thermodilution appears to have a therapeutic advantage for optimizing the prognosis of patients with subarachnoid hemorrhage with vasospasm over conventional methods.

• This study tested the validity of noninvasive electrical conductivity measurements by MRI. • This study also evaluated the electrical conductivity characteristics of diffuse glioma. • Gliomas have higher electrical conductivity values than the normal brain parenchyma. • Noninvasive electrical conductivity measurement can be helpful for better characterisation of glioma.

Sonodynamic therapy is expected to be a novel therapeutic strategy for malignant gliomas. The titanium dioxide (TiO 2 ) nanoparticle, a photosensitizer, can be activated by ultrasound. In this study, by using water-dispersed TiO 2 nanoparticles, an in vitro comparison was made between the photodynamic and sonodynamic damages on U251human glioblastoma cell lines. Water-dispersed TiO 2 nanoparticles were constructed by the adsorption of chemically modified polyethylene glycole (PEG) on the TiO 2 surface (TiO 2 /PEG). To evaluate cytotoxicity, U251 monolayer cells were incubated in culture medium including 100 μg/ml of TiO 2 /PEG for three hours and subsequently irradiated by

).q RSNA, 2015 Purpose:To develop and independently validate prognostic imaging biomarkers for predicting survival in patients with glioblastoma on the basis of multiregion quantitative image analysis. Materials and Methods:This retrospective study was approved by the local institutional review board, and informed consent was waived. A total of 79 patients from two independent cohorts were included. The discovery and validation cohorts consisted of 46 and 33 patients with glioblastoma from the Cancer Imaging Archive (TCIA) and the local institution, respectively. Preoperative T1-weighted contrast material-enhanced and T2-weighted fluid-attenuation inversion recovery magnetic resonance (MR) images were analyzed. For each patient, we semiautomatically delineated the tumor and performed automated intratumor segmentation, dividing the tumor into spatially distinct subregions that demonstrate coherent intensity patterns across multiparametric MR imaging. Within each subregion and for the entire tumor, we extracted quantitative imaging features, including those that fully capture the differential contrast of multimodality MR imaging. A multivariate sparse Cox regression model was trained by using TCIA data and tested on the validation cohort. Results:The optimal prognostic model identified five imaging biomarkers that quantified tumor surface area and intensity distributions of the tumor and its subregions. In the validation cohort, our prognostic model achieved a concordance index of 0.67 and significant stratification of overall survival by using the log-rank test (P = .018), which outperformed conventional prognostic factors, such as age (concordance index, 0.57; P = .389) and tumor volume (concordance index, 0.59; P = .409). Conclusion:The multiregion analysis presented here establishes a general strategy to effectively characterize intratumor heterogeneity manifested at multimodality imaging and has the potential to reveal useful prognostic imaging biomarkers in glioblastoma.q RSNA, 2015

BackgroundBrain radiation necrosis (BRN) can be a complication of radiotherapy for primary and secondary brain tumors, as well as head and neck tumors. Since vascular endothelial growth factor (VEGF) is also a vascular permeability factor in the brain, bevacizumab, a humanized antibody that inhibits VEGF, would be expected to reduce perilesional edema that often accompanies BRN.MethodsPatients with surgically untreatable, symptomatic BRN refractory to conventional medical treatments (eg, corticosteroid, anticoagulants, or hyperbaric oxygen therapy) were enrolled. We judged that a major cause of perilesional edema with a lesion-to-normal brain ratio ≤1.8 on 11C-methionine or ≤2.5 on 18F-boronophenylalanine PET was BRN, not tumor recurrence, and 6 cycles of biweekly bevacizumab (5 mg/kg) were administered. The primary endpoint was a ≥30% reduction from the patients' registration for perilesional edema continuing for ≥1 month.ResultsOf the 41 patients enrolled, 38 were fully eligible for the response assessment. The primary endpoint was achieved in 30 of the 38 (78.9%) patients at 3.0 months (median) after enrollment. Sixteen patients (42.1%) experienced improvement of their Karnofsy Performance Score. Corticosteroid use could be reduced in 29 patients (76.3%). Adverse events at grade ≥3 occurred in 10 patients (24.4%).ConclusionsBevacizumab treatment offers certain clinical benefits for patients with surgically untreatable, symptomatic BRN. The determination of BRN using amino-acid PET, not biopsy, is adequate and less invasive for determining eligibility to receive bevacizumab.

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor and its prognosis is significantly poorer than those of less malignant gliomas.Pathologically, necrosis is one of the most important characteristics that differentiate GBM from lower grade gliomas; therefore, we hypothesized that 18 F fluoromisonidazole (FMISO), a radiotracer for hypoxia imaging, accumulates in GBM but not in lower grade gliomas. We aimed to evaluate the diagnostic value of FMISO PET for the differential diagnosis of GBM from lower grade gliomas. Methods: This prospective study included 23 patients with pathologically confirmed gliomas. All the patients underwent FMISO PET and FDG PET within a week. FMISO images were acquired 4 hours after intravenous administration of 400 MBq of FMISO. Tracer uptake in the tumor was visually assessed. Lesion-to-normal tissue ratios and FMISO uptake volume were calculated. Results: Thirteen of the 23 glioma patients were diagnosed as having GBM (grade IV glioma in WHO classification 2007), and the others were diagnosed as having non-GBM (5 grade III and 4 grade II). In visual assessment, all the GBM patients showed FMISO uptake in the tumor greater than that in the surrounding brain tissues, whereas all the non-GBM patients showed FMISO uptake in the tumor equal to that in the surrounding brain tissues (p<0.001). One GBM patient was excluded 2 from FDG PET study because of hyperglycemia. All the GBM patients and 3 of the 9 (33 %) non-GBM patients showed FDG uptake greater than or equal to that in the gray matter. The sensitivity and specificity for diagnosing GBM were 100 % and 100 % for FMISO, and 100 % and 66 % for FDG, respectively. The lesion-to-cerebellum ratio of FMISO uptake was higher in GBM patients (2.74±0.60, range: 1.71 -3.81) than in non-GBM patients (1.22±0.06, range: 1.09 -1.29, p<0.001) with no overlap between the groups. The lesion-to-gray matter ratio of FDG was also higher in GBM patients (1.46±0.75, range: 0.91 -3.79) than in non-GBM patients (1.07±0.62, range: 0.66 -2.95, p<0.05); however, overlap of the ranges did not allow clear differentiation between GBM and non-GBM. Uptake volume of FMISO was larger in GBM (27.18±10.46 %, range: 14.02 -46.67 %) than in non-GBM (6.07±2.50 %, range: 2.12 -9.22 %, p<0.001). Conclusion: These preliminary data suggest that FMISO PET may distinguish GBM from lower grade gliomas.

The results of previous studies suggest that early goal-directed fluid therapy (EGDT) reduces the incidence of DCI after aneurysmal SAH, 10,14 but the effects of EGDT on clinical outcomes are still unclear. This prospective study aimed to determine whether EGDT improves outcomes compared with standard less-invasive hemodynamic therapy. The outcomes after EGDT were also evaluated in subgroups of patients with poor clinical grade 10,11,15 or concurrent cardiopulmonary complications, [16][17][18] which are well-known risk factors for DCI and poor outcome. Methods Patient SelectionThis 2-center, prospective, randomized, nonblinded clinical trial enrolled patients who were admitted for the treatment of SAH at Teine Keijinkai Hospital and the Research Institute for Brain and Blood Vessels-AKITA between April 2009 and September 2013. Patients were screened for enrollment after obliteration of the causative aneurysm. The inclusion and exclusion criteria are shown in Figure I and Background and Purpose-The results of previous studies suggest that early goal-directed fluid therapy (EGDT) reduces delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage, but the effects of EGDT on clinical outcomes are still unclear. This study aimed to determine whether EGDT improves outcomes compared with standard less-invasive hemodynamic therapy. Methods-This study included 160 patients treated within 24 hours after subarachnoid hemorrhage, randomized to receive either (1) EGDT guided by preload volume and cardiac output monitored by transpulmonary thermodilution (treatment group) or (2) standard therapy guided by fluid balance or central venous pressure, assisted by uncalibrated less-invasive cardiac output monitoring during hyperdynamic therapy in patients with clinical or radiological indications of DCI (control group). DCI determined by clinical or radiological findings and functional outcome determined by the modified Rankin Scale score at 3 months were compared between groups. Results-For all clinical grades combined, there were no significant differences in the rates of DCI (33% versus 42%; P=0.33) or modified Rankin Scale score of 0 to 3 at 3 months (67% versus 57%; P=0.