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TP-38 is a recombinant chimeric targeted toxin composed of the EGFR binding ligand TGF-alpha and a genetically engineered form of the Pseudomonas exotoxin, PE-38. After in vitro and in vivo animal studies that showed specific activity and defined the maximum tolerated dose (MTD), we investigated this agent in a Phase I trial. The primary objective of this study was to define the MTD and dose limiting toxicity of TP-38 delivered by convection-enhanced delivery in patients with recurrent malignant brain tumors. Twenty patients were enrolled in the study and doses were escalated from 25 ng/mL to 100 with a 40 mL infusion volume delivered by two catheters. One patient developed Grade IV fatigue at the 100 ng/mL dose, but the MTD has not been established. The overall median survival after TP-38 for all patients was 23 weeks whereas for those without radiographic evidence of residual disease at the time of therapy, the median survival was 31.9 weeks. Overall, 3 of 15 patients, with residual disease at the time of therapy, have demonstrated radiographic responses and one patient with a complete response and has survived greater than 83 weeks.

Purpose: We evaluated the usefulness of a treatment regimen that included high-dose chemotherapy (HDC) with autologous stem-cell rescue (ASCR) in patients with newly diagnosed pineoblastoma (PBL)., Patients and Methods: Twelve patients with PBL were initially treated with surgery and induction chemotherapy. All but two patients underwent radiotherapy. Subsequently, all patients received HDC using cyclophosphamide (CTX) + melphalan (MEL) or busulfan (Bu) + MEL regimens and ASCR., Results: A total of six children and six adults with median ages of 4.2 (range, 0.3 to 19.8 years) and 23 years (range, 23 to 43.7 years), respectively, were treated according to this strategy. Four patients had metastatic disease confined to the neuraxis. Five of 12 patients (42%) had a complete tumor resection at diagnosis. Ten patients received radiotherapy at median doses of 36.0 and 59.4 Gy to the neuraxis and pineal region, respectively. Eleven patients received HDC with CTX + MEL, and one patient received BU + MEL followed by ASCR. Nine patients are alive with no evidence of disease recurrence at a median of 62 months from diagnosis (range, 28 to 125 months), including three patients with metastatic disease and two infants who did not receive any radiotherapy. Three patients have died of progressive disease at 19, 32, and 37 months from diagnosis, respectively. The actuarial 4-year progression-free and overall survivals are 69% (95% confidence interval [CI], 39% to 99%) and 71% (95% CI, 43% to 99%), respectively., Conclusion: The use of HDC in addition to radiotherapy seems to be an effective treatment for patients with newly diagnosed pineoblastoma.

Background: Diffusion-weighted MRI (DWI) can depict acute ischemia based on decreased apparent diffusion coefficient (ADC) values. ADC maps, unlike DWI (which have contributions from T2 properties), solely reflect diffusion properties. Recent studies indicate that severity of neurological deficit corresponds with degree of ADC alteration., Purpose: To determine whether infarct volume on ADC maps correlates with length of hospitalization and clinical outcome in patients with acute ischemic middle cerebral artery (MCA) stroke., Study Population: Forty-five consecutive patients with acute (3 SDs below the average ADC value of a contralateral control region. Infarct volume was correlated with length of hospitalization and 6-month outcome assessed with Glasgow Outcome Scale (GOS), Modified Rankin Score (mRS), Barthel Index (BI) and a dichotomized outcome status with favorable outcome defined as GOS 1, mRS or=95., Results: Infarct volume on ADC maps ranged from 0.2 to 187 cm(3) and was significantly correlated with length of hospitalization (p < 0.001, r = 0.67). Furthermore, ADC infarct volume was significantly correlated with GOS (r = 0.73), mRS (r = 0.68), BI (r = 0.67) and outcome status (r = 0.65) (each p < 0.001). Multiple logistic regression revealed a statistically significant correlation between ADC infarct volume and outcome status (p < 0.05), but none for Canadian Neurological Scale score, age and gender (p >0.05 each)., Conclusion: Infarct volume measured by using a quantitative definition for infarcted tissue on ADC maps correlated significantly with length of hospitalization (as a possible surrogate marker for short-term outcome) and functional outcome after 6 months. ADC infarct volume may provide prognostic information for patients with acute ischemic MCA stroke., (Copyright 2003 S. Karger AG, Basel)

While several studies are available on the immediate effects of marijuana and its active ingredient tetrahydrocannabinol (THC) on regional cerebral blood flow (rCBF), we examined the effects of intravenous infusion of THC on rCBF and behavior over a 120-min. period using positron emission tomography. Indices of rCBF, intoxication and physiology were measured at baseline and 30, 60, 90 and 120 min. after a 20-min. intravenous infusion of 0.15 or 0.25 mg/min. of THC, or placebo given to 47 subjects. The rCBF remained increased up to 120 min. after the high-dose THC infusion. Significant increases were seen in global perfusion and in the frontal, insular and anterior cingulate regions. Changes were greater in the right hemisphere. After the high dose, cerebellar flow was increased at both 30 and 60 min. The anterioposterior ratio of cortical rCBF increased in both hemispheres, and remained significantly greater than in the placebo condition until 120 min. in the right hemisphere. Intoxication peaked at 30 min. and remained elevated at 120 min. THC had significant effects on global CBF and rCBF, and feeling intoxicated accounted for changes in rCBF better than plasma level of THC.

Advances in the immunohistochemical detection of neuron-specific and neuronal-associated antigens have resulted in the discovery of neuronal elements in certain primary human brain tumors. The results have been not only to expand what neuropathologists commonly recognize as gangliogliomas, including the tumors now known as glioneurocytic tumor with neuropil rosettes and papillary ganglioneuroma, but also to expand the spectrum of tumor types to now include tumors such as central neurocytoma, dysembryoplastic neuroepithelial tumor, and desmoplastic infantile ganglioglioma. These discoveries have helped us to better understand the biology of these tumors and to refine our classification of them. Distinctions among these tumors include sites of predilection, such as the temporal lobe with the dysembryoplastic neuroepithelial tumors, and a spectrum of clinical aggressiveness that spans indolent "quasi-hamartomatous" lesions, such as the dysembryoplastic neuroepithelial tumor, to high-grade, highly aggressive tumors, such as the supratentorial primitive neuroectodermal tumor (World Health Organization Grade IV). Many of these tumors also commonly exhibit a glial component, as determined by both their histologic appearance and their immunoreactivity for glial fibrillary acidic protein. This review covers these recently described lesions, including the desmoplastic infantile ganglioglioma, the dysembryoplastic neuroepithelial tumor, the papillary glioneuronal tumor, the glioneuronal tumor with neuropil rosettes, and the mixed glioblastoma-cerebral neuroblastoma (supratentorial primitive neuroectodermal tumor), as well as the known tumors, ganglioglioma, medulloepithelioma, and medulloblastoma. For pathologists confronted by this growing array of tumors and subtypes, it is appropriate to focus on them and understand the differential diagnosis to be considered when confronted by them.

Background and Purpose: Our purpose was to compare diffusion tensor MR and magnetization transfer imaging in assessing normal-appearing white matter (WM) regions in multiple sclerosis (MS)., Methods: Diffusion tensor, magnetization transfer, and conventional MR imaging were performed in 12 patients with MS. Fractional anisotropy, apparent diffusion coefficients (ADCs), and magnetization transfer ratios (MTRs) were measured in plaques, normal-appearing periplaque WM (PWM) regions, and normal-appearing WM regions remote from plaques. Mean fractional anisotropy, ADCs, and MTRs were calculated and compared in WM regions., Results: Fractional anisotropy was lower in normal-appearing PWM regions than in remote WM regions (P <.001) but higher than in plaques (P <.001). MTRs were lower (not significantly, P =.19) in normal-appearing PWM regions than in remote regions. MTRs were higher in normal-appearing PWM regions than in plaques (P <.001). ADCs were higher in normal-appearing PWM regions than in remote regions (P =.008) but lower than in plaques (P =.001). Correlation between fractional anisotropy and MTRs of individual lesions was poor (r = 0.18) and between fractional anisotropy and ADC, modest (r = -0.39)., Conclusion: In MS, diffusion tensor MR imaging can depict differences between WM regions that are not apparent on conventional MR images. Anisotropy measurements may be more sensitive than those of MTRs in detecting subtle abnormalities in PWM.

Background and Purpose: Previous studies have shown that lesions in posterior reversible encephalopathy syndrome are often isointense on diffusion-weighted MR images. We hypothesized that 1) apparent diffusion coefficient (ADC) maps using various thresholds would show larger abnormalities in posterior white matter (WM) and 2) isointense appearance of lesions on isotropic diffusion-weighted images results from a balance of T2 prolongation effects and diffusibility effects., Methods: T2-weighted MR images from 11 patients were reviewed. Hyperintense lesions were located in both anterior and posterior WM in eight patients and solely in posterior WM in three patients. The ADC maps were produced by use of ADC values > or = 3 SD and > or = 10 SD above the mean value of normal WM. Lesions on diffusion-weighted images were classified as isointense or hypointense. ADC values within lesions (ADC(L)) were compared with those of normal WM (ADC(N)), and compared for isointense lesions and hypointense lesions., Results: The distribution of lesions with ADC values > or = 3 SD was essentially identical to that on T2-weighted images. Regions with ADC values > or = 10 SD were found in both anterior WM and posterior WM in two patients and solely in posterior WM in nine patients. On diffusion-weighted images, lesions appeared isointense in seven patients and hypointense in four patients. Mean ADC(L)/ADC(N) for all lesions was 1.81; for hypointense lesions, 2.30., Conclusion: Vasogenic edema was more severe in posterior WM. Isointense lesions result from a balance of T2 effects and increased water diffusibility. Hypointense lesions have higher ADC values, which are not balanced by T2 effects.

Background and Purpose: Rasmussen encephalitis is a chronic, progressive encephalitis that manifests as an abrupt-onset, intractable seizure disorder in previously developmentally normal children. The objectives of the current study were to characterize the (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and MR imaging findings in Rasmussen encephalitis and to test the hypotheses that data from both imaging techniques are required to establish the diagnosis and identify the affected cerebral hemisphere in some cases., Methods: Eleven patients with Rasmussen encephalitis were identified from a review of a computer database. The MR (n = 10) and PET (n = 11) imaging data were reviewed retrospectively and conjointly., Results: On MR images, nine of 10 patients manifested bilateral cerebral atrophy that predominantly involved one hemisphere. One patient had purely unilateral cerebral atrophy. We observed foci of abnormally increased T2 signal intensity in nine of 10 patients. On FDG PET images, all patients showed extensive regions of hypometabolism within the cerebral hemisphere that showed the greatest atrophy. Discrete foci of hypermetabolism, indicative of seizure activity, were observed in six patients. The FDG PET and MR imaging findings were either stable or gradually progressive in patients with multiple imaging studies (MR, n = 5; FDG PET, n = 5)., Conclusion: Rasmussen encephalitis is characterized by diffuse, unilateral cerebral hypometabolism on FDG PET images, with corresponding regions of cerebral atrophy on MR images. Although MR imaging data alone are sufficient to suggest a diagnosis of Rasmussen encephalitis in many cases, correlation with FDG PET data increases diagnostic confidence and allows the unequivocal identification of the affected cerebral hemisphere in patients whose MR imaging findings are subtle or distributed bilaterally.

The March COM: A 16 year old female presented with headaches and cerebellar dysfunction. MR images showed a mass lesion of the right cerebellar hemisphere with mass effect on the medulla. The mass exhibited a striated pattern of alternating isointense and hypointense zones on T1-weighted images that did not contrast enhance. The lesion was hyperintense on T2-weighted images, and also showed a striated appearance. A suboccipital craniotomy and resection of the lesion was performed. Microscopically, the specimen consisted of widened folia and a disorganized cerebellar architectonic pattern in which the internal granular cell layer was occupied by a population of large dysmorphic nerve cell bodies. Patient's diagnosed with Lhermitte-Duclos disease must be adequately evaluated for Cowden's syndrome.

Even with novel chemotherapeutic agents and external beam radiation therapy, the prognosis of neoplastic meningitis secondary to malignant melanoma is still dismal. The authors report a case study of a 46-year-old white female who presented with progressive hearing loss, severe headaches, nausea, vomiting, and a rapid decline in neurologic status. She was referred to Duke University Medical Center after conventional chemotherapy for malignant melanoma failed. She was enrolled in a Phase I trial of (131)I-labeled monoclonal antibody Mel-14 F(ab')(2) fragment administered intrathecally. Within a year after her treatment, she recovered, having a normal neurologic exam except for residual bilateral hearing loss. The authors discuss dosimetry, preclinical, and clinical studies conducted with Mel-14 F(ab')(2) and introduce a potentially promising therapy option in the treatment of neoplastic meningitis in patients with malignant melanoma. Currently, the patient remains neurologically normal except for a mild bilateral hearing loss more than 4 years after treatment and has no radiographic evidence of neoplastic meningitis., (Copyright 2001 American Cancer Society.)

Purpose: To describe the changes in brain water diffusibility in five anatomic locations in children with neurofibromatosis type 1 (NF 1) compared with these changes in control subjects and to describe the water diffusibility changes associated with hyperintense basal ganglia lesions in children with NF 1., Materials and Methods: Twenty highly related pairs of children consisting of one child with NF 1 and one unaffected child were examined. Prospective comparisons of isotropic apparent diffusion coefficient (ADC) values at five anatomic locations were performed, with and without T2-hyperintense lesions included. Retrospective analysis of hyperintense globus pallidus lesions in 16 children and in the paired control subjects also was performed., Results: Significant increases in ADC values were seen in all five anatomic locations in the NF 1 group. The greatest increases were seen in the globus pallidus (14%; P =.002) and brachium pontis (10.8%; P =.003). With exclusion of hyperintense lesions, significant ADC increases were measured in four locations. Significant ADC increases were seen in hyperintense globus pallidus lesions in the NF 1 group compared with ADC values in the normal-appearing contralateral globus pallidus (4.9%; P =.02) and those in the globus pallidus of the paired control subjects (16%; P =.003)., Conclusion: Significant ADC increases were measured both in the hyperintense lesions and in the normal-appearing areas of the brain in children with NF 1.

Objective: The purpose of this study was to examine the frequency of change in size of pineal cysts on serial MR studies., Materials and Methods: Thirty-two patients (19 females, 13 males) with a diagnosis of pineal cyst at any time who underwent brain MR imaging more than once in a period of at least 6 months were identified by computerized search of radiology reports. Four patients underwent MR imaging to follow up pineal cysts, whereas the remaining patients were imaged for a variety of indications, including intracerebral neoplasms. Measurements of maximal cyst dimension on both initial and latest follow-up studies were obtained in all patients, and cyst volumes were calculated in 23 patients., Results: Length of follow-up ranged from 6 months to 9 years. All cysts were considered incidental and none were treated. Maximal cyst dimensions ranged from 0.5 to 2.2 cm. On average, there was no significant change in cyst volume. The maximal dimension of the cyst did not change in 24 (75%) of 32 patients. Two cysts resolved completely on follow-up, three cysts decreased by 2-4 mm, two cysts enlarged by 2-3 mm, and one cyst formed and grew to 1.2 cm., Conclusion: Whereas the size of pineal cysts as a whole remained unchanged on serial MR studies, cysts may either form or involute in individual patients. Small increases in cyst size did occur but were not associated with specific clinical findings. These findings suggest that typical pineal cysts may be followed up on a clinical basis alone rather than on imaging.

Purpose: To compare diffusion tensor magnetic resonance imaging with conventional T2-weighted imaging for evaluation of white matter changes in patients with Krabbe disease., Materials and Methods: In eight patients with Krabbe disease and eight age-matched control subjects, anisotropy maps were generated with diffusion tensor data by using echo-planar imaging with diffusion gradient encoding in six directions. Anisotropy maps and T2-weighted images were visually inspected. Relative anisotropy (RA) and normalized T2-weighted signal intensity in white matter tracts and gray matter nuclei were quantitatively compared between patients and controls (paired Student t test)., Results: Loss of diffusion anisotropy appeared on anisotropy maps as areas of decreased hyperintensity in patients with Krabbe disease. Differences in RA between Krabbe disease patients and control subjects were significant in eight of nine white matter structures studied (P =.001-.01) and in basal ganglia (P =.04). T2-weighted signal intensity was also significantly different in the same white matter structures (P =.006-.049) but not in basal ganglia. In the three patients imaged after stem cell transplantation, mean RA was between the RAs of untreated patients and control subjects., Conclusion: Diffusion tensor-derived anisotropy maps (a) provide a quantitative measure of abnormal white matter in patients with Krabbe disease, (b) are more sensitive than T2-weighted images for detecting white matter abnormality, and (c) may be a marker of treatment response.

A number of entities other than acute cerebral infarction can produce bright signal intensity on diffusion-weighted magnetic resonance images, and an understanding of the range of possible diagnoses for these hyperintense lesions is important for radiologists who must interpret these images.

Purpose: To determine the maximum-tolerated dose (MTD) of iodine-131 ((131)I)-labeled 81C6 antitenascin monoclonal antibody (mAb) administered clinically into surgically created resection cavities (SCRCs) in malignant glioma patients and to identify any objective responses with this treatment., Patients and Methods: In this phase I trial, newly diagnosed patients with malignant gliomas with no prior external-beam therapy or chemotherapy were treated with a single injection of (131)I-labeled 81C6 through a Rickham reservoir into the resection cavity. The initial dose was 20 mCi and escalation was in 20-mCi increments. Patients were observed for toxicity and response until death or for a minimum of 1 year after treatment., Results: We treated 42 patients with (131)I-labeled 81C6 mAb in administered doses up to 180 mCi. Dose-limiting toxicity was observed at doses greater than 120 mCi and consisted of delayed neurotoxicity. None of the patients developed major hematologic toxicity. Median survival for patients with glioblastoma multiforme and for all patients was 69 and 79 weeks, respectively., Conclusion: The MTD for administration of (131)I-labeled 81C6 into the SCRC of newly diagnosed patients with no prior radiation therapy or chemotherapy was 120 mCi. Dose-limiting toxicity was delayed neurologic toxicity. We are encouraged by the survival and toxicity and by the low 2.5% prevalence of debulking surgery for symptomatic radiation necrosis.

Purpose: The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O(6) position of guanine. O(6)-benzylguanine (O(6)-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O(6)-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O(6)-BG with recurrent or progressive malignant glioma., Patients and Methods: Patients were treated with O(6)-BG at a dose of 100 mg/m(2) followed 1 hour later by BCNU. Cohorts of three to six patients were treated with escalating doses of BCNU, and patients were observed for at least 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O(6)-BG, 8-oxo-O(6)-BG, and 8-oxoguanine concentration., Results: Twenty-three patients were treated (22 with glioblastoma multiforme and one with anaplastic astrocytoma). Four dose levels of BCNU (13.5, 27, 40, and 55 mg/m(2)) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O(6)-BG rapidly disappeared from plasma (elimination half-life = 0. 54 +/- 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O(6)-BG (elimination half-life = 5.6 +/- 2.7 hours) and further to 8-oxoguanine. There was no detectable O(6)-BG 5 hours after the start of the O(6)-BG infusion; however, 8-oxo-O(6)-BG and 8-oxoguanine concentrations were detected 25 hours after O(6)-BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O(6)-BG was 17.5 times greater than the mean AUC for O(6)-BG., Conclusion: These results indicate that the MTD of BCNU when given in combination with O(6)-BG at a dose of 100 mg/m(2) is 40 mg/m(2) administered at 6-week intervals. This study provides the foundation for a phase II trial of O(6)-BG plus BCNU in nitrosourea-resistant malignant glioma.

Objective: The purpose of our study was to test the hypothesis that the apparent diffusion coefficient (ADC) of normal-appearing white matter increases with advancing age., Subjects and Methods: We selected 38 patients with normal MR imaging findings from 332 patients undergoing clinical MR imaging. Diffusion-weighted MR imaging was performed with diffusion gradients applied in three orthogonal directions. For each patient, the average ADC on trace-weighted diffusion images of white matter at prespecified regions of interest and at the thalamus were compared with the patient's age., Results: For the white matter, ADC sorted by patient age in decades increased with advancing age. Patients at least 60 years old had significantly higher ADC (0.769 +/- 0.019 mm(2)/sec x 10(-3)) than patients less than 60 years old (0.740 +/- 0.013 mm(2)/sec x 10(-3)) (p < 0.001). Comparison of individual white matter ADC and age showed a significant increase with advancing age (p < 0.0001). For the thalamus, the average ADC among patients at least 60 years old (0.766 +/- 0.015 mm(2)/sec x 10(-3)) exceeded the average ADC for patients less than 60 years old (0.745 +/- 0.022 mm(2)/sec x 10(-3)) (p < 0.05). However, comparison of individual thalamic ADC and patient ages, although showing a trend to higher ADC with increasing age, did not reach statistical significance (p = 0.06)., Conclusion: Advancing age is associated with a small but statistically significant increase of water diffusibility in human white matter. A similar trend was present in the thalamus. These increases may reflect mild structural changes associated with normal aging.

Rationale and Objectives: The objective of the two pivotal phase 3 studies was to evaluate the safety and efficacy of OptiMARK (Gd-DTPA-bis(methoxyethylamide) [Gd-DTPA-BMEA]) compared with Magnevist (Gd-DTPA) in magnetic resonance imaging of the central nervous system., Methods: Two multicenter, randomized, double-blind, parallel group studies were conducted in 395 patients with known or suspected central nervous system pathology. Subjects were randomized to receive a single 0.1 mmol/kg intravenous injection of either Gd-DTPA-BMEA or Gd-DTPA. The safety of Gd-DTPA-BMEA and Gd-DTPA was monitored for up to 72 hours after study drug administration. Precontrast and postcontrast administration magnetic resonance scans were acquired using identical imaging planes and techniques., Results: No deaths or unexpected adverse events were reported in either group. A comparison of adverse events by intensity and relation demonstrated no statistically significant differences between the two groups. Gd-DTPA-BMEA and Gd-DTPA were equivalent with respect to confidence in diagnosis, conspicuity, and border delineation., Conclusions: Gd-DTPA-BMEA and Gd-DTPA demonstrated comparable efficacy profiles, and the safety profiles were considered similar.

Objective: The purpose of this study was to compare MR imaging features of gangliogliomas in children less than 10 years old with those seen in patients at least 10 years old., Materials and Methods: Our study population consisted of 15 female patients and 10 male patients with a mean age of 20 years. The early childhood group was composed of six children with a mean age of 5.5 years. The older group was composed of 19 patients with a mean age of 25.6 years. We assessed tumor volume, tumor location, percentage of tumor that was cystic, pattern of contrast enhancement, and degree of edema., Results: The temporal lobe was the most common tumor location in both groups. Mean tumor volume in the early childhood group was 83 cm3, which was significantly larger than the mean tumor volume (9.78 cm3) for the older group (p = 0.001). Cystic tumors were more common in the early childhood group (83%) than in the older group (63%), and the average percentage of cysts in the cystic tumors was much higher in the early childhood group (67%) than in the older group (30%). Contrast enhancement was seen in five of six early childhood tumors and 13 of 16 tumors in older patients. Four of six tumors in the early childhood group and five of 19 tumors in the older patient group had associated edema., Conclusion: The mean tumor volume of gangliogliomas in the early childhood group was significantly larger than that of the older patient group. This finding may be indicative of differences in tumor growth patterns in the two groups, ability of the hemicranium to adjust to mass effect in childhood, or sampling error as a result of a relatively small sample size.

Purpose: The objective of this study was to perform the dosimetry and evaluate the dose-response relationships in newly diagnosed patients with malignant brain tumors treated by direct injections of (131)I-labeled 81C6 monoclonal antibody (MAb) into surgically created resection cavities (SCRCs)., Methods and Materials: Absorbed doses to the 2-cm-thick shell as measured from the margins of the resection cavity interface were estimated for 42 patients with primary brain tumors. MR images were used to assess the enhanced-rim volume as a function of time after radiolabeled MAb therapy. Biopsy samples were obtained from 15 patients and 1 autopsy., Results: The average absorbed dose [range] to the 2-cm shell region was 32 [3-59] Gy. For the endpoint of minimal time to MR contrast enhancement, the optimal absorbed dose and initial dose-rate were 43 +/- 16 Gy and 0. 41 +/- 0.10 Gy/h, respectively. There was a correlation between the absorbed dose and dose rate to the shell region and biopsy outcome (tumor recurrence, radionecrosis, and tumor recurrence and/or radionecrosis). In this Phase I study, the maximum tolerated dose (MTD) was 120 mCi. At this MTD, the estimated average absorbed dose and initial dose rate to the 2-cm shell were 41 [9-89] Gy and 0.51 [0.24-1.13] Gy/h, respectively. These values are in agreement with the optimal values based on the time to MR lesion rim enhancement., Conclusions: The average absorbed dose to the 2-cm shell region varied considerably and mainly depended on cavity volume. In future clinical trials, the administered activity of (131)I-labeled 81C6 MAb may be adjusted based on cavity volume in order to deliver the optimal absorbed dose of 43 Gy rather than giving a fixed administered activity.

This review has highlighted some of the disease processes that produce diagnostic difficulty in the emergency neuroradiology setting. Because radiologists are often the first individuals to consider these entities, they must be familiar with the clinical features that suggest the diagnosis. Furthermore, acquaintance with the various imaging findings of these diseases will allow early diagnosis and will help limit the severe complications that follow these neurologic emergency conditions if left untreated.

Background: The focus of this report is on the possible role that the age of first use of marijuana may play on brain morphology and function., Methods: Magnetic resonance imaging (MRI) and positron emission tomography (PET) were utilized to study 57 subjects. Brain volume measures (whole brain, gray matter, white matter and lateral ventricle volumes), global cerebral blood flow (CBF) and body size were evaluated., Results: There are three primary findings related to age of first use of marijuana. Subjects who started using marijuana before age 17, compared to those who started later, had smaller whole brain and percent cortical gray matter and larger percent white matter volumes. Functionally, males who started using marijuana before 17 had significantly higher CBF than other males. Both males and females who started younger were physically smaller in height and weight, with the effects being greater in males., Conclusions: These findings suggest that the age at which exposure to marijuana begins is important. Early adolescence may be a critical period for effects that are not present when exposure begins later. These results are discussed in light of reported effects of marijuana on gonadal and pituitary hormones.

The major clinical use of diffusion-weighted imaging to date has been in evaluation of cerebral infarction, at which it excels. However, diffusion-weighted imaging has also shown promise for other applications, ranging from quantitative analysis of biologic changes that are not apparent from simple visual inspection of images (but are detectable after using regions of interest on apparent diffusion coefficient maps) to better characterization of other intracranial abnormalities (e.g., abscess and tumor). Both the clinical and research applications of diffusion-weighted imaging can be expected to increase, providing fresh insights into physiologic characteristics of both normal and abnormal tissue.

Objective: Our aim was to determine whether the contrast between white matter lesions and normal-appearing white matter in fast spin-echo fluid-attenuated inversion recovery (FLAIR) images can be improved by lengthening the effective TE and the echo train length., Subjects and Methods: Thirty patients with various white matter lesions were imaged using fast spin-echo FLAIR sequences (TR = 10,002 msec; inversion time = 2200) on a 1.5-T MR imaging system. For 14 patients, fast spin-echo FLAIR sequences with a TE of 165 msec and echo train length of 32 (fast spin-echo FLAIR 165/32) were compared with fast spin-echo FLAIR sequences with a TE of 125 msec and echo train length of 24 (fast spin-echo FLAIR 125/24). For 16 other patients, fast spin-echo FLAIR 165/32 sequences were compared with fast spin-echo FLAIR sequences with a TE of 145 msec and echo train length of 28 (fast spin-echo FLAIR 145/28). Signal difference-to-noise ratios were calculated between the lesions and normal-appearing white matter for a typical lesion in each patient., Results: In both groups, a small but statistically significant increase in the signal difference-to-noise ratio was found on the fast spin-echo FLAIR sequences using the longer TE and echo train length. In the first group, signal difference-to-noise ratio increased from 18.7 +/- 4.7 (mean +/- SD) for fast spin-echo FLAIR 125/24 to 20.1 +/- 4.5 for fast spin-echo FLAIR 165/32 (p < .05). In the second group, the signal difference-to-noise ratio increased from 15.4 +/- 4.0 for fast spin-echo FLAIR 145/28 to 16.8 +/- 4.6 for fast spin-echo FLAIR 165/32 (p <.01). In addition, fast spin-echo FLAIR sequences with a longer TE and echo train length were obtained more rapidly (6 min for fast spin-echo FLAIR 125/24, 5 min 20 sec for fast spin-echo FLAIR 145/28, and 4 min 41 sec for fast spin-echo FLAIR 165/32)., Conclusion: Lengthening the TE to 165 msec and echo train length to 32 in fast spin-echo FLAIR imaging allows both a mild improvement in the contrast between white matter lesions and normal-appearing white matter and shorter imaging times.

We used H(2)15O positron emission tomography (PET) to measure age-related changes in regional cerebral blood flow (rCBF) during a verbal recognition memory task. Twelve young adults (20 to 29 years) and 12 older adults (62 to 79 years) participated. Separate PET scans were conducted during Encoding, Baseline, and Retrieval conditions. Each of the conditions involved viewing a series of 64 words and making a two-choice response manually. The complete reaction time (RT) distributions in each task condition were characterized in terms of an ex-Gaussian model (convolution of exponential and Gaussian functions). Parameter estimates were obtained for the mean of the exponential component (tau), representing a task-specific decision process and the mean of the Gaussian component (mu) representing residual sensory coding and response processes. Independently of age group, both tau and mu were higher in the Encoding and Retrieval conditions than in the Baseline condition, and tau was higher during Retrieval than during Encoding. Age-related slowing in task performance was evident primarily in mu. For young adults, rCBF activation in the right prefrontal cortex, in the Retrieval condition, was correlated positively with mu but not with tau. For older adults, rCBF changes (both increases and decreases) in several cortical regions were correlated with both mu and tau. The data suggest that the attentional demands of this task are relatively greater for older adults and consequently lead to the recruitment of additional neural systems during task performance.

Purpose: To determine the activity, toxicity, and pharmacokinetics of irinotecan (CPT-11, Camptosar; Pharmacia & Upjohn, Kalamazoo, MI) in the treatment of adults with progressive, persistent, or recurrent malignant glioma., Patients and Methods: Patients with progressive or recurrent malignant gliomas were enrolled onto this study between October 1996 and August 1997. CPT-11 was given as a 90-minute intravenous (i.v.) infusion at a dose of 125 mg/m2 once weekly for 4 weeks followed by a 2-week rest, which comprised one course. Plasma concentrations of CPT-11 and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were determined in a subset of patients., Results: All 60 patients who enrolled (36 males and 24 females) were treated with CPT-11 and all were assessable for toxicity, response, and survival. Pharmacokinetic data were available in 32 patients. Nine patients (15%; 95% confidence interval, 6% to 24%) had a confirmed partial response, and 33 patients (55%) achieved stable disease lasting more than two courses (12 weeks). Toxicity observed during the study was limited to infrequent neutropenia, nausea, vomiting, and diarrhea. CPT-11, SN-38, and SN-38G area under the plasma concentration-time curves through infinite time values in these patients were approximately 40%, 25%, and 25%, respectively, of those determined previously in patients with metastatic colorectal cancer not receiving antiepileptics or chronic dexamethasone treatment., Conclusion: Response results document that CPT-11, given with a standard starting dose and treatment schedule, has activity in patients with recurrent malignant glioma. However, the low incidence of severe toxicity and low plasma concentrations of CPT-11 and SN-38 achieved in this patient population suggest that concurrent treatment with anticonvulsants and dexamethasone enhances drug clearance.

The recent advances made in CT and MR imaging have led to increased accuracy in making a number of diagnoses in the emergency room setting. Increasingly, radiologists are asked to perform these studies and accurately interpret the findings, which often have a dramatic impact on triaging and treatment of the patient. Future trials need to address further the relative merits of each of the techniques outlined previously in specific settings. In addition, given the increasing number of means of obtaining diagnostic information, cost effectiveness studies are needed to better formulate an appropriate algorithm for each diagnosis.

Background: From both epidemiologic and pathologic viewpoints, gangliogliomas exhibiting components of giant cell glioblastomas are extraordinary neoplasms. We report herein the case of a 6-year-old girl who presented initially with a World Health Organization grade IV anaplastic ganglioglioma (a mixed ganglion cell tumor-giant cell glioblastoma). Despite aggressive management, the patient died of disease in a relatively short period., Methods: Formalin-fixed, paraffin-embedded tissue blocks were sectioned at 5 microm for histochemical and immunohistochemical analyses. Hematoxylin-eosin-stained sections and immunohistochemically stained sections from the primary and secondary resections were reviewed. Reactivity for glial fibrillary acidic protein, neurofilament protein, synaptophysin, and Ki67 nuclear antigen was evaluated., Results: Histologically, 2 distinct cell populations were noted on both the primary and secondary resections. The primary resection revealed a neoplasm having a predominant glial component consistent with a glioblastoma. Interspersed were dysmorphic ganglion cells supporting a diagnosis of ganglioglioma. The second resection (following therapy) demonstrated a much more prominent dysmorphic ganglion cell component and a subdued glial component., Conclusion: Although immunohistochemical analysis clearly distinguished the 2 tumor cell populations, the identification of Nissl substance in neurons proved to be equally helpful. Although other cases of grade III gangliogliomas and rare cases of grade IV gangliogliomas have been reported, the present case is exceptional in that, to our knowledge, it is the only report of a patient who presented initially with a composite grade IV ganglioglioma and who was clinically followed up to the time of death. This case allows direct comparison between the histologic findings in a giant cell glioblastoma and a ganglioglioma and documents the aggressive biologic behavior of this complex neoplasm.

Objective: The purpose of this study was to correlate 18F-fluorodeoxyglucose positron emission tomography (PET) and MR imaging features of cerebral gangliogliomas before and after PET-MR image registration., Conclusion: After registration of PET and MR images, all six gangliogliomas in our series were shown to have heterogeneous metabolic activity. Areas of hypermetabolic activity were seen in all lesions. In five of the six cases, PET-MR image registration provided information regarding tumor metabolism that was not available on nonregistered hard-copy examinations.

Adult age differences are frequently observed in the performance of memory tasks, but the changes in neural function mediating these differences are largely unknown. We used (H2)15O positron emission tomography (PET) to measure changes in regional cerebral blood flow (rCBF) during Encoding, Baseline, and Retrieval conditions of a recognition memory task. Twelve young adults (20-29 years) and 12 older adults (62-79 years) participated. During each task condition, participants made a two-choice manual response to each of 64 words. Analyses of the performance data yielded evidence of age-related slowing of encoding and retrieval processes, and an age-related decline in the accuracy of yes/no recognition (d'). The rCBF activation associated with both encoding and retrieval was greater for older adults than for young adults, but this pattern was more clearly evident for memory retrieval. For young adults, rCBF activation during retrieval occurred primarily in right prefrontal cortex, whereas older adults exhibited a more bilateral pattern of prefrontal activation. Regression analyses predicting reaction time in the memory task from regional PET counts confirmed that the neural system mediating memory retrieval is more widely distributed for older adults than for young adults. Both age groups exhibited some decrease in rCBF activation in the second half of the test session, relative to the first half. The practice-related decrease in rCBF activation was more prominent for young adults, suggesting that the older adults' recruitment of additional neural systems reflects a more continual allocation of attention to support task performance.

Objective: Imaging studies of patients with bipolar disorder demonstrate changes in deep white matter and subcortical gray nuclei that are seen as focal hyperintensities on T2-weighted magnetic resonance imaging (MRI). The objective of this study was to examine MRIs in a family with a strong history of bipolar disorder to look for possible MRI abnormalities in members with and without affective illness., Method: The authors obtained MRIs of 21 members of a family with a strong history of bipolar disorder. Eight of the family members studied had bipolar illness, one had symptoms of bipolar disorder but did not meet full DSM-III-R criteria, two had unipolar disorder, and 10 did not have bipolar disorder., Results: Fifteen of the 21 family members had MRI findings, including six of 10 family members who had no affective disorder and all of those with bipolar disorder. Lesions of both white matter and subcortical gray nuclei were found., Conclusions: Although the clinical significance of these MRI findings is unknown, the high prevalence of MRI findings in both affected and unaffected family members suggests that MRI findings may potentially serve as a biological marker for bipolar disorder. Recent genetic studies have established a link between familial leukoencephalopathy and chromosome 19. If leukoencephalopathy appears to be related to bipolar disorder, it may allow clearer characterization of the genetics of the disorder.

In this study, the authors sought to investigate the response rate and toxicity of carboplatin in patients with progressive low-grade glioma (LGG). Thirty-two patients with progressive LGG were treated with carboplatin at a dosage of 560 mg/m(2). Treatment was given at 4-week intervals and continued until the disease progressed, unacceptable toxicity supervened, or for 12 additional courses after achieving maximal response. Patients with stable disease were treated with a total of 12 cycles. All patients were treated as outpatients. Patients were evaluated for response to treatment and toxicity. All patients received a minimum of two cycles of carboplatin, and were examined for response. A partial response was achieved in nine patients (28%) and a minimal response in two (6%), for an overall response rate of 34% (11 of 32 patients). Eighteen patients (56%) had stable disease. A partial response was achieved in the nine patients after a median of six cycles (range 4-11 cycles), a minimal response was achieved in the two patients after five cycles. Glioma progression was noted in three patients after three, five, and five cycles, respectively. The 11 patients in whom some response was achieved had either an optic pathway tumor or a juvenile pilocytic astrocytoma. Twenty-six of the 32 patients had those characteristics, making the response rate in that group 42% (11 of 26 patients). Thirty-two patients received a total of 387 cycles of chemotherapy. Hematological toxicity was moderate. Twenty-one patients developed thrombocytopenia (platelet count < 50,000/microl); three patients required one platelet transfusion each. Nine patients developed neutropenia (absolute neutrophil count < 500/microl); one developed fever and required administration of antibiotic agents. One dose adjustment in each of the patients prevented further thrombocytopenia and neutropenia. Two patients with stable disease died of respiratory complications. One patient developed Grade III ototoxicity after receiving five cycles, one patient developed hypersensitivity to carboplatin, and none developed nephrotoxicity. Carboplatin given at a dosage of 560 mg/m(2) every 4 weeks has activity in patients with progressive LGG. This drug regimen is relatively simple and well tolerated. Further investigation and longer follow-up study are warranted.

Purpose: The purpose of this study was to determine the frequency and types of abnormalities at arteriography in patients with antiphospholipid antibodies (APA) and ischemic cerebrovascular events., Methods: Twenty-three patients with APA and ischemic cerebrovascular events who underwent arteriography were identified. Patients over the age of 65 years were excluded. No patients met diagnostic criteria for systemic lupus erythematosus. All angiograms were reviewed by two neuroradiologists., Results: Seventeen patients (74%) between the ages of 28 and 64 years (average age, 40 years) had abnormal angiograms. Sixteen patients had arterial abnormalities and one had dural sinus thrombosis. Ten had solely intracranial abnormalities (nine arterial and one venous), six had solely extracranial arterial abnormalities, and one had both intracranial and extracranial arterial abnormalities. Intracranial arterial abnormalities included stem or branch occlusions of the cerebral or basilar arteries, which were generally solitary (six patients), and findings suggestive of vasculitis (four patients). Four patients had stenoses of the origins of two or more great vessels. Two patients had extracranial internal carotid artery stenoses or occlusions that were not typical of atheromatous disease, considered to be embolic in one patient. In another patient, a stenosis of the origin of the internal carotid artery was present that appeared typical of atheromatous disease. Infarctions were seen on CT or MR studies in 13 of 17 patients with abnormal angiograms., Conclusion: In our group of patients, typical atheromatous lesions at the common carotid artery bifurcation were rare. Some lesions that are infrequent in the general stroke population (eg, vasculitis-like findings and stenoses at the origin of great vessels) were common. Patients with APA and cerebrovascular events appear to differ from the general stroke population with regard to types of arterial abnormalities seen at arteriography.

Purpose: Our aim was to determine the thoracic manifestations of patients with antiphospholipid antibodies (APAs)., Method: We performed a retrospective review of the clinical records and thoracic imaging studies of 88 patients (63 women, 25 men; mean age 47 years) with APAs to determine the spectrum of thoracic disease., Results: Nine patients (10%) had thoracic abnormalities, including eight with pulmonary embolism (PE) and one with aortic thrombus. One patient with PE had subclavian vein thrombosis. Coexistent thromboses included deep venous thrombosis of the leg in six patients., Conclusion: PE was the most common thoracic abnormality in our patients. The presence of these antibodies should be suspected in patients with PE of otherwise unexplained etiology.

Objective: The purpose of this study was to determine the patterns of non-CNS thromboses in patients with a hypercoagulable state associated with antiphospholipid antibodies (APA)., Materials and Methods: A search of our institution's clinical coagulation and immunology laboratories' records of patients examined from January 1993 to January 1996 revealed 1290 patients with APA. Computerized records of radiologic studies were reviewed for evidence of thrombotic events, which were found in 93 patients (49 males and 44 females; average age, 40 years). The anatomic distribution of thrombotic events was recorded., Results: Fifty-five patients (59%; 29 males and 26 females; average age, 44.2 years) had solely venous thromboses, 26 patients (28%; 15 males and 11 females; average age, 33.1 years) had solely arterial thromboses, and 12 (13%; 5 males and 7 females; average age, 35.4 years) had both types of events. Deep vein thrombosis (DVT) of the legs was the most common finding, occurring in 45 patients (48%). Six patients had recurrent DVT. Other sites of venous thrombotic events included pulmonary embolism, 30 patients (32%); thoracic veins (superior vena cava, subclavian vein, or jugular vein), 10 patients (11%); and abdominal or pelvic veins, 18 events in 11 patients (12%). Sites of arterial thromboses included arteries supplying the upper limbs (great vessels arising from the aorta or the brachial, radial, ulnar, or digital arteries), 15 events in 12 patients (13%); aorta, one patient (1%); abdominal or pelvic arteries, 11 events in eight patients (9%); and arteries supplying the lower limbs (femoral or popliteal arteries), seven patients (8%)., Conclusion: Venous thromboses were more common than arterial thromboses in our patient group, with DVT being the most common. However, thromboses in sites that are unusual for the general population were also relatively common. APA should be suspected in patients with thromboses in unusual sites or recurrent thromboses of an otherwise unexplained cause.

Objective: The purpose of this study was to report the association of dural sinus thrombosis with a hypercoagulable state associated with activated protein C resistance., Conclusion: In our small study population, hemorrhagic venous infarction was common (three of four patients) among patients with dural sinus thrombosis and activated protein C resistance. Four of five patients with dural sinus thrombosis had positive tests for activated protein C resistance. This finding, in conjunction with data from other studies, suggests that patients with dural sinus thrombosis may need to be studied for the presence of activated protein C resistance. A positive finding for activated protein C resistance can be important not only in helping to explain the cause of thrombosis in affected individuals but also in identifying families at risk for thrombosis.

The causes of stroke in young adults differ substantially from those in older adults. In many instances, the diagnosis can be made by taking a clinical history and performing laboratory studies (e.g., in patients who have multiple thromboses associated with anti-phospholipid antibodies). In other circumstances, clues to the diagnosis can be found on routine CT and MR studies. However, in many circumstances, imaging tailored to a specific diagnosis is important (e.g., MR imaging of the neck in patients with suspected arterial dissection). In yet other cases, additional studies (e.g., echocardiography in suspected cardiogenic embolism) are important to establish the cause.

Central nervous system complications in AIDS patients are common and often the cause of severe morbidity and mortality. Most symptomatic central nervous system complications in AIDS patients involve the brain, principally in the form of HIV encephalitis, various other forms of infection, or development of neoplasms. The imaging findings are important to recognize because in many instances the underlying brain lesions are responsive to medical therapy.