Linda Heier

PURPOSE: To evaluate response rate, event-free survival (EFS), and toxicity of two chemotherapeutic regimens for treatment of children younger than 36 months with malignant brain tumors and to estimate control intervals without irradiation in children with no residual tumor after initial surgery and induction chemotherapy and with delayed irradiation in patients with residual tumor or metastatic disease at diagnosis. PATIENTS AND METHODS: Patients were randomly assigned to one of two regimens of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide v vincristine, carboplatin, ifosfamide, and etoposide). Maintenance chemotherapy began after induction in children without progressive disease. Children with no residual tumors after induction therapy and no metastatic disease at diagnosis were not to receive radiation therapy unless their tumors progressed. RESULTS: Two hundred ninety-nine infants were enrolled. Forty-two percent of patients responded to induction chemotherapy. At 5 years from study entry, the EFS rate was 27% +/- 3%, and the survival rate was 43% +/- 3%. There was no significant difference between the two arms in terms of response rate or EFS. For medulloblastoma, supratentorial primitive neuroectodermal tumor, ependymoma, and rhabdoid tumors, 5-year EFS rates were 32% +/- 5%, 17% +/- 6%, and 32% +/- 6%, and 14% +/- 7%, respectively. Fifty-eight percent of patients who were alive 5 years after study entry had not received radiation therapy. CONCLUSION: Intensified induction chemotherapy resulted in a high response rate of malignant brain tumors in infants. Survival was comparable to that of previous studies, and most patients who survived did not receive radiation therapy.

Late infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive, neurodegenerative lysosomal storage disease affecting the CNS and is fatal by age 8 to 12 years. A total average dose of 2.5 10(12) particle units of an adeno-associated virus (AAV) serotype 2 vector expressing the human CLN2 cDNA (AAV2 CU h-CLN2) was administered to 12 locations in the CNS of 10 children with LINCL. In addition to safety parameters, a neurological rating scale (primary variable) and three quantitative magnetic resonance imaging (MRI) parameters (secondary variables) were used to compare the rate of neurological decline for 18 months in treated subjects compared with untreated subjects. Although there were no unexpected serious adverse events that were unequivocally attributable to the AAV2 CU hCLN2 vector, there were serious adverse effects, the etiology of which could not be determined under the conditions of the experiment. One subject died 49 days postsurgery after developing status epilepticus on day 14, but with no evidence of CNS inflammation. Four of the 10 subjects developed a mild, mostly transient, humoral response to the vector. Compared with control subjects, the measured rates of decline of all MRI parameters were slower, albeit the numbers were too small for statistical significance. Importantly, assessment of the neurologic rating scale, which was the primary outcome variable, demonstrated a significantly reduced rate of decline compared with control subjects. Although the trial is not matched, randomized, or blinded and lacked a contemporaneous placebo/sham control group, assessment of the primary outcome variable suggests a slowing of progression of LINCL in the treated children. On this basis, we propose that additional studies to assess the safety and efficacy of AAV-mediated gene therapy for LINCL are warranted.

High-field MR scans frequently show Virchow-Robin spaces, which conform to the path of the penetrating arteries as they enter either the basal ganglia or the cortical gray matter over the high convexities. A retrospective review of 816 MR scans was undertaken to determine the clinical significance and associations (if any) of this finding. The Virchow-Robin spaces were graded, as were the nonspecific white-matter lesions. The presence of atrophy, infarction, hydrocephalus, and miscellaneous disease was noted. Large Virchow-Robin spaces were identified in 314 cases. A study sample was created consisting of a positive group containing all the larger grade 2 and 3 Virchow-Robin spaces (67 patients) and a negative or control group of 109 randomly selected patients from the original 502 who did not have large Virchow-Robin spaces. The charts of this study sample were reviewed and the following patient variables were noted: age, gender, incidental white-matter lesions, infarction, dementia, hypertension, and atrophy. For each variable, the proportion of patients who were positive for that variable was calculated for each of the two groups and compared across groups by using a Fisher exact test. Multiple logistic regression analysis was used to determine whether any of these variables were jointly associated with being "positive" or "negative" for large Virchow-Robin spaces. Some variables were strongly associated with being positive for large Virchow-Robin spaces: age, hypertension, dementia, and incidental white-matter lesions. Logistic regression analysis revealed that when all of these variables are considered jointly, only age remains significant.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND AND PURPOSE: Malignant and atypical meningiomas are prone to recurrence and aggressive growth, which affects treatment planning and prognostication. Investigators have used diffusion-weighted imaging and apparent diffusion coefficient (ADC) maps to compare tumor grade and cellularity with the histopathologic findings of intraaxial primary brain neoplasms. The purpose of this study was to determine whether the signal characteristics of meningiomas on diffusion-weighted images correlate with the average diffusion constant (Dav) from ADC maps and histopathologic findings and whether the Dav can reliably distinguish benign from malignant and atypical meningiomas. METHODS: Seventeen patients (13 women and four men; average age, 55 years) with meningiomas were prospectively studied using routine MR imaging and diffusion-weighted imaging with a single-shot gradient-echo echo-planar pulse sequence (6000/100 [TR/TE]) and b values of 0 and 1000. Signal characteristics on routine MR and diffusion-weighted images were compared with the histopathologic findings after resection by using World Health Organization criteria. Dav values were calculated within the tumor mass from ADC maps before resection. RESULTS: Four meningiomas were malignant or atypical (World Health Organization grades II and III). Dav values were lower than normal brain values (average, 0.52 +/- 0.12 x 10(-5) cm2/s; range, 0.45-0.69 x 10(-5) cm2/s) and were hyperintense on diffusion-weighted images and hypointense on ADC maps. Thirteen meningiomas were benign. Dav values were higher than normal brain values (average, 1.03 +/- 0.29 x 10(-5) cm2/s; range, 0.62-1.8 x 10(-5) cm2/s). On diffusion-weighted images and ADC maps, most were isointense. Five benign meningiomas had very high Dav values, bright signal on ADC maps, and distinct histopathologic findings, including microcysts, necrotic infarct, and organizing intratumoral hemorrhage. The difference in Dav values between malignant and benign meningiomas was statistically significant (P < .00029). CONCLUSION: Albeit a small sample size, meningiomas with low Dav tended to be malignant or highly atypical (P < .00029) whereas meningiomas with the highest Dav had increased water content due to either a specific histologic subtype of meningioma or the presence of associated pathologic abnormality.

Functional neuroimaging methods hold promise for the identification of cognitive function and communication capacity in some severely brain-injured patients who may not retain sufficient motor function to demonstrate their abilities. We studied seven severely brain-injured patients and a control group of 14 subjects using a novel hierarchical functional magnetic resonance imaging assessment utilizing mental imagery responses. Whereas the control group showed consistent and accurate (for communication) blood-oxygen-level-dependent responses without exception, the brain-injured subjects showed a wide variation in the correlation of blood-oxygen-level-dependent responses and overt behavioural responses. Specifically, the brain-injured subjects dissociated bedside and functional magnetic resonance imaging-based command following and communication capabilities. These observations reveal significant challenges in developing validated functional magnetic resonance imaging-based methods for clinical use and raise interesting questions about underlying brain function assayed using these methods in brain-injured subjects.