Preoperative relative cerebral blood volume analysis in gliomas predicts survival and mitigates risk of biopsy sampling error.

Appropriate management of adult gliomas requires an accurate histopathological diagnosis. However, the heterogeneity of gliomas can lead to misdiagnosis and undergrading, especially with biopsy. We evaluated the role of preoperative relative cerebral blood volume (rCBV) analysis in conjunction with histopathological analysis as a predictor of overall survival and risk of undergrading. We retrospectively identified 146 patients with newly diagnosed gliomas (WHO grade II-IV) that had undergone preoperative MRI with rCBV analysis. We compared overall survival by histopathologically determined WHO tumor grade and by rCBV using Kaplan-Meier survival curves and the Cox proportional hazards model. We also compared preoperative imaging findings and initial histopathological diagnosis in 13 patients who underwent biopsy followed by subsequent resection. Survival curves by WHO grade and rCBV tier similarly separated patients into low, intermediate, and high-risk groups with shorter survival corresponding to higher grade or rCBV tier. The hazard ratio for WHO grade III versus II was 3.91 (p = 0.018) and for grade IV versus II was 11.26 (p < 0.0001) and the hazard ratio for each increase in 1.0 rCBV units was 1.12 (p < 0.002). Additionally, 3 of 13 (23%) patients initially diagnosed by biopsy were upgraded on subsequent resection. Preoperative rCBV was elevated at least one standard deviation above the mean in the 3 upgraded patients, suggestive of undergrading, but not in the ten concordant diagnoses. In conclusion, rCBV can predict overall survival similarly to pathologically determined WHO grade in patients with gliomas. Discordant rCBV analysis and histopathology may help identify patients at higher risk for undergrading.

Phase 1 trial of TPI 287, a microtubule stabilizing agent, in combination with bevacizumab in adults with recurrent glioblastoma.

Background: Recurrent glioblastoma (rGBM) has limited treatment options. This phase 1 protocol was designed to study the safety and preliminary efficacy of TPI 287, a central nervous system penetrant microtubule stabilizer, in combination with bevacizumab (BEV) for the treatment of rGBM. Methods: GBM patients with up to 2 prior relapses without prior exposure to anti-angiogenic therapy were eligible. A standard 3 + 3 design was utilized to determine the maximum tolerated dose (MTD) of TPI 287. Cohorts received TPI 287 at 140-220 mg/m2 every 3 weeks and BEV 10 mg/kg every 2 weeks during 6-week cycles. An MRI was performed after each cycle, and treatment continued until progression as determined via response assessment in neuro-oncology criteria. Results: Twenty-four patients were enrolled at 6 centers. Treatment was generally well tolerated. Fatigue, myelosuppression, and peripheral neuropathy were the most common treatment emergent adverse events. Dose-limiting toxicity was not observed, thus the MTD was not determined. Twenty-three patients were evaluable for median and 6-month progression-free survival, which were 5.5 months (mo) and 40%, respectively. Median and 12-month overall survival were 13.4 mo and 64%, respectively. The optimal phase 2 dose was determined to be 200 mg/m2. Conclusions: TPI 287 can be safely combined with BEV for the treatment of rGBM and preliminary efficacy supports further investigation of this combination.

Brainstem ischemic syndrome in juvenile NF2.

OBJECTIVE: A new case of brainstem ischemic necrosis in a young woman with de novo neurofibromatosis type 2 (NF2) is reported, and given notable similarities to 7 prior cases of brainstem stroke in the literature, features defining a possible syndrome were sought. METHODS: Case review including detailed clinical assessment, neuroimaging analysis, genetic testing, and brain biopsy, followed by a multicase analysis. RESULTS: Brainstem ischemia in juvenile NF2 typically occurs in teenagers without previously known NF2 as an acute, monophasic presentation with restricted diffusion in the midbrain or pons following a recent hypoperfusion event, normal vascular imaging, obvious intracranial imaging features of NF2, typical inactivating NF2 alterations, biopsy showing necrosis without small vessel pathology, and subsequent aggressive NF2 lesion progression. CONCLUSIONS: Brainstem ischemia in juvenile NF2 is a rare syndrome of unclear etiology, possibly reflecting an unknown underlying vascular abnormality; a digenic effect is not excluded.

Development of the 40Hz steady state auditory evoked magnetic field from ages 5 to 52.

OBJECTIVE: Adults exhibit strong auditory 40 Hz magnetic steady state responses (SSR). Although EEG measured SSR has been studied in children, the developmental course of the magnetic SSR is unknown. METHODS: Sixty-nine healthy subjects ranging in age from 5 to 52 years participated in a magnetoencephalographic (MEG) study. Stimuli were monaural 500 ms duration click trains with a 25 ms inter-click interval. Contralateral magnetic responses for both hemispheres were recorded with a 37-channel MEG system. Responses were averaged and examined using wavelet-based time-frequency analysis. Source analyses were also conducted on a subset of the data. RESULTS: Gamma power from 200 to 500 ms post-stimulus onset was computed and was significantly related to subject age in both hemispheres. Hemispheric asymmetry was observed for the anterior-posterior SSR source locations, suggestive of asymmetry similar to that previously described for the SSR and other auditory evoked magnetic field components. CONCLUSIONS: The 40 Hz power findings are generally consistent with previous EEG studies of steady state responses in children showing age-related changes in the 40 Hz SSR. SIGNIFICANCE: Age-related changes in the strength of the magnetic 40 Hz SSR may continue to develop well beyond early childhood, which should be taken into consideration in planning future studies using adolescents and young adults.

Treatment of Aggressive Prolactin-Secreting Pituitary Adenomas with Adjuvant Temozolomide Chemotherapy: A Review.

Most prolactin-secreting pituitary adenomas demonstrate slow growth and are effectively managed with medical/surgical therapy. Rarely, these tumors can behave aggressively with rapid growth and invasion of local tissues, and are refractory to medical, surgical, or radio-surgical therapies. We report a case of a prolactin-secreting adenoma in a young woman, which became progressively aggressive and refractory to usual treatment modalities, but responded to treatment with the chemotherapeutic agent temozolomide. In addition, we review the literature for treatment of refractory adenomas with temozolomide. The clinical and pathologic characteristics of aggressive prolactin-secreting adenomas are reviewed, as well as their response to dopamine agonists, surgery, radiotherapy, and chemotherapy.

Anomalous somatosensory cortical localization in schizophrenia.

OBJECTIVE: Schizophrenia has been reported to be associated with altered localization of regions responding to sound in the auditory cortex, suggesting possible cortical reorganization accompanying the disorder, but it is not clear whether such disturbances are present in any primary sensory cortex other than the auditory. This study examines magnetoencephalographic localization of field sources evoked by tactile stimulation generated in area 3b of the primary somatosensory cortex in patients with schizophrenia compared with normal subjects. METHOD: A total of 29 subjects participated; 14 were patients with schizophrenia, and 15 were normal comparison subjects. Equivalent current dipole generators in both hemispheres were used to model the sources of the 50-msec latency somatosensory evoked field (M50) components produced by contralateral tactile mechanoreceptor stimulation of the tip of the index finger. RESULTS: Compared with normal subjects, patients with schizophrenia demonstrated reversed asymmetry (left anterior to right) and relatively anterior and inferior displacement of the M50 equivalent current dipole location in the left hemisphere. CONCLUSIONS: Cerebral lateralization and localization of the M50 distinguished patients with schizophrenia from normal subjects. These findings suggest the possibility of anatomical displacement and/or disturbed organization of the primary sensory cortex in schizophrenia.

Hippocampus and amygdala volumes in parents of children with autistic disorder.

OBJECTIVE: Structural and functional abnormalities in the medial temporal lobe, particularly the hippocampus and amygdala, have been described in people with autism. The authors hypothesized that parents of children with a diagnosis of autistic disorder would show similar changes in these structures. METHOD: Magnetic resonance imaging scans were performed in 17 biological parents of children with a diagnosis of DSM-IV autistic disorder. The scans were compared with scans from 15 adults with autistic disorder and 17 age-matched comparison subjects with no personal or familial history of autism. The volumes of the hippocampus, amygdala, and total brain were measured in all participants. RESULTS: The volume of the left hippocampus was larger in both the parents of children with autistic disorder and the adults with autistic disorder, relative to the comparison subjects. The hippocampus was significantly larger in the adults with autistic disorder than in the parents of children with autistic disorder. The left amygdala was smaller in the adults with autistic disorder, relative to the other two groups. No differences in total brain volume were observed between the three groups. CONCLUSIONS: The finding of larger hippocampal volume in autism is suggestive of abnormal early neurodevelopmental processes but is partly consistent with only one prior study and contradicts the findings of several others. The finding of larger hippocampal volume for the parental group suggests a potential genetic basis for hippocampal abnormalities in autism.

Smaller left hemisphere planum temporale in adults with autistic disorder.

The structure of the planum temporale is often disturbed in disorders with associated communication problems, particularly in auditory and language processing areas in the brain. We hypothesized that people with autism would have reduced left hemisphere volumes in the planum temporale, a language related brain structure. We performed magnetic resonance imaging scans of 15 adults with autistic disorder and 15 comparison subjects, and measured the volume of gray matter in the planum temporale and Heschl's gyrus (HG) in both hemispheres. Planum temporale volume reduced in the left hemisphere of the autism group (P<0.003). No differences in HG volumes were observed between the two groups. The volume reduction seen in the left hemisphere of the autism group may suggest an early neurodevelopmental disturbance in autism that impacts language development.

Determination of the sphere origin for MEG source modelling in temporal regions.

This paper addresses the choice of spherical volume used in modelling MEG data recorded from temporal (auditory cortex) brain regions. We used MRI data sets to compute best-fitting spheres for the cranial cavity or inner skull table, and for the outer scalp surface. In addition, a 'generic' sphere was computed as the mean of the origin coordinates for the cranial spheres. The effects of these sphere choices were evaluated by estimating equivalent current dipoles as source generators for the M100 component of the auditory evoked field, and comparing the goodness-of-fit and 95% confidence volumes. Results indicate that for this area the cranial cavity is a better choice of surface to fit than the outer scalp. The 'generic' sphere results were also superior to those obtained using individual outer surfaces.