On the Use of DSC-MRI for Measuring Vascular Permeability.

BACKGROUND AND PURPOSE: Contrast agent extravasation has been shown to confound brain tumor perfusion measurements with DSC-MR imaging, necessitating the use of correction techniques (eg, Weisskoff, Bjornerud). Leakage parameters (K2 and K(a)) postulated to reflect vessel permeability can be extracted from these correction methods; however, the biophysical interpretation of these parameters and their relationship to commonly used MR imaging measures of vascular permeability (eg, contrast agent volume transfer constant, [K(trans)]) remain unclear. Given that vascular density, as assessed by blood volume, and vascular permeability, as reflected by K(trans) (and potentially K2 or K(a)), report on unique and clinically informative vascular characteristics, there is a compelling interest to simultaneously assess these features. MATERIALS AND METHODS: We acquired multiecho DSC-MR imaging data, allowing the simultaneous computation and voxelwise comparison of single- and dual-echo derived measures of K2, K(a) and K(trans) in patients with glioma. This acquisition enabled the investigation of competing T1 and T2* leakage effects and TE dependency on these parameters. RESULTS: K2 and K(a) displayed nonsignificant (P = .150 and P = .060, respectively) voxelwise linear correlations with K(trans), while a significant (P < .001) inverse relationship was observed between K2 and Ka (coefficient of determination [r(2)] = 0.466-0.984). Significantly different (P < .005) mean estimates were found between voxels exhibiting predominately T1 and T2* effects for K2 and K(a). K(trans), however, was observed to be similar between these voxels (0.109 versus 0.092 minutes(-1)). Significant differences (P < .001) in extracellular-extravascular volume fraction (v(e)) (0.285 versus 0.167) were also observed between cohorts. Additionally, K2 and K(a) were found to have a significant quadratic relationship (P = .031 and P = .005, respectively) with v(e). CONCLUSIONS: Estimates of vascular permeability in brain tumors may be simultaneously acquired from multiple-echo DSC-MR imaging via K(trans); however, caution should be used in assuming a similar relationship for K2 and K(a).

Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine.

DepoCyte is a slow-release formulation of cytarabine designed for intrathecal administration. The goal of this multi-centre cohort study was to determine the safety and efficacy of DepoCyte for the intrathecal treatment of neoplastic meningitis due to breast cancer. DepoCyte 50 mg was injected once every 2 weeks for one month of induction therapy; responding patients were treated with an additional 3 months of consolidation therapy. All patients had metastatic breast cancer and a positive CSF cytology or neurologic findings characteristic of neoplastic meningitis. The median number of DepoCyte doses was 3, and 85% of patients completed the planned 1 month induction. Median follow up is currently 19 months. The primary endpoint was response, defined as conversion of the CSF cytology from positive to negative at all sites known to be positive, and the absence of neurologic progression at the time the cytologic conversion was documented. The response rate among the 43 evaluable patients was 28% (CI 95%: 14-41%); the intent-to-treat response rate was 21% (CI 95%: 12-34%). Median time to neurologic progression was 49 days (range 1-515(+)); median survival was 88 days (range 1-515(+)), and 1 year survival is projected to be 19%. The major adverse events were headache and arachnoiditis. When drug-related, these were largely of low grade, transient and reversible. Headache occurred on 11% of cycles; 90% were grade 1 or 2. Arachnoiditis occurred on 19% of cycles; 88% were grade 1 or 2. DepoCyte demonstrated activity in neoplastic meningitis due to breast cancer that is comparable to results reported with conventional intrathecal agents. However, this activity was achieved with one fourth as many intrathecal injections as typically required in conventional therapy. The every 2 week dose schedule is a major advantage for both patients and physicians.

Myasthenia gravis after allogeneic bone marrow transplantation for lymphoblastic lymphoma.

A 31-year-old female with lymphoblastic lymphoma developed myasthenia gravis (MG) 26 months after receiving an allogeneic bone marrow transplant (BMT) from an HLA-identical sister. She presented with classic symptoms and electromyographic evidence of the disorder approximately 2 weeks after electing to abruptly discontinue her immunosuppressive medications. She initially responded to steroids and acetylcholinesterase inhibitors. Her subsequent course has been characterized by episodes of moderately severe weakness that respond to intravenous immunoglobulin and prednisone. This case of post-transplant MG is only the second reported to have occurred in association with BMT for lymphoblastic lymphoma. Potential risk factors for the development of post-transplant MG are discussed including underlying hematological disorder, HLA phenotype, family history of MG, the presence of chronic GVHD, and recent cessation of immune suppression.

Pitfalls in the management of patients with malignant gliomas.

Neurooncology requires the integration of the clinical history, physical examination, neuroimaging studies, neuropathology, surgery, radiation therapy, and chemotherapy in order to properly diagnose and treat patients with suspected brain tumors. The review herein serves to illustrate and emphasize the pitfalls that can potentially occur during each step of the process of managing patients with malignant gliomas. Familiarity with these pitfalls will enhance the neurologist's ability to successfully manage patients with neurooncological disease.

Transforming growth factor beta as a potential tumor progression factor among hyperdiploid glioblastoma cultures: evidence for the role of platelet-derived growth factor.

Among early-passage, near-diploid gliomas in vitro, transforming growth factor type beta (TGF beta) has been previously shown to be an autocrine growth inhibitor. In contrast, hyperdiploid (> or = 57 chromosomes/metaphase) glioblastoma multiforme (HD-GM) cultures were autocrinely stimulated by the TGF beta. The mechanism of this 'conversion' from autocrine inhibitor to mitogen is not understood; previous studies have suggested that platelet-derived growth factor (PDGF) might be modulated by TGF beta. The similar expression of TGF beta types 1-3, PDGF-AA; -BB, as well as the PDGF receptor alpha and beta subunits (a/beta PDGFR) between biopsies of the HD-GM and near-diploid, TGF beta-inhibited glioblastomas (GM) by immunohistochemistry did not explain the discrepancy in their regulatory responses. Flow cytometry demonstrated that TGF beta's mitogenic effect was selective for the aneuploid subpopulations of two of three selected HD-GM cultures, while the diploid cells were inhibited. Among the HD-GM, TGF beta 1 induced the RNA of PDGF-A, c-sis and TGF beta 1. The amount of PDGF-AA secreted following TGF beta treatment was sufficient to stimulate the proliferation of a HD-GM culture. Antibodies against PDGF-AA, -BB, -AB, alpha PDGFR and/or beta PDGFR subunits effectively neutralized TGF beta's induction of DNA synthesis among the HD-GM cell lines, indicating that PDGF served as the principal mediator of TGF beta's growth stimulatory effect. By comparison, TGF beta induced only the RNA of PDGF-A and TGF beta 1 among the near-diploid GM, c-sis was not expressed at all. However, the amount of PDGF-A which was secreted in response to TGF beta 1 was insufficient to prevent TGF beta's arrest of the near-diploid cultures in G1 phase. Thus, the emergence of hyperdiploidy was associated with qualitative and quantitative differences in TGF beta's modulation of PDGF-A and c-sis, which provided a mechanism by which the aneuploid glioma cells might achieve 'clonal dominance'. We hypothesize that TGF beta may serve as an autocrine promoter of GM progression by providing a selective advantage to the hyperdiploid subpopulation through the loss of a tumor suppressor gene which mediates TGF beta's inhibitory effect.

The course of seizure disorders in patients with malignant gliomas.

OBJECTIVE: To describe the morbidity associated with seizures and the efficacy of anticonvulsant therapy in adult patients with malignant gliomas (MGs). STUDY DESIGN: A retrospective review of charts was performed to determine the occurrence of seizures at diagnosis, the frequency and character of subsequent seizures, and the use and toxic side effects of anticonvulsants. PATIENTS: Sixty-five consecutive adult patients with supratentorial MGs who were examined in the neurooncology clinic at a university medical center were studied. The diagnosis was glioblastoma in 47 of the patients, and it was anaplastic astrocytoma in 18 patients. The mean age of the patients was 49.5 years. The median Karnofsky status score was 80. The median survival was 18 months. RESULTS: Twenty-nine patients presented with seizures, and 21 of these had subsequent (eg, "recurrent") seizures while they were receiving anticonvulsant therapy. Ten of 36 patients who were free of seizures at diagnosis experienced seizures after diagnosis (eg, "late onset") while they were being treated with anticonvulsants, including five patients who had single seizures. Long-term seizure frequency in excess of one per month was observed in 13 patients. Ten patients had episodes of partial motor status epilepticus. Most recurrent and late-onset seizures occurred despite therapeutic anticonvulsant levels, and without evidence of tumor progression. Rash associated with anticonvulsants was observed in 26% of the patients. Other clinically important toxic side effects were observed in 14% of the patients who were receiving long-term anticonvulsant therapy. CONCLUSIONS: Seizures contributed substantially to the neurologic morbidity of MGs in at least 25% of these patients. The occurrence of seizures at diagnosis was a strong predictor of subsequent seizures, and in many patients, seizures proved to be refractory to standard anticonvulsant therapy. Long-term anticonvulsant toxic side effects are relatively common in patients with MGs. The use of long-term seizure prophylaxis for patients with MGs who are free of seizures at presentation is not clearly beneficial and should be studied in a prospective trial.

Optimal cutoff levels of F-18 fluorodeoxyglucose uptake in the differentiation of low-grade from high-grade brain tumors with PET.

PURPOSE: To determine the optimal cutoff level of fluorine-18-labeled fluorodeoxyglucose (FDG) uptake in the differentiation of low-grade from high-grade cerebral tumors at position emission tomography (PET). MATERIALS AND METHODS: The authors retrospectively reviewed images from PET, magnetic resonance imaging, and computed tomography performed in 58 consecutive patients with histologically proved brain tumors. There were 32 high-grade tumors (20 gliomas) and 26 low-grade tumors (18 gliomas). RESULTS: The best cutoff level of FDG uptake ratios in the differentiation of high-grade from low-grade tumors was 1.5 for tumor-to-white matter (T/WM) ratios and 0.6 for tumor-to-cortex (T/C) ratios. These levels were the same when only gliomas were analyzed and when all tumors were analyzed. When a T/WM ratio of more than 1.5 was considered indicative of a high-grade tumor, the sensitivity and specificity were 94% and 77%, respectively. The results were similar for the T/C ratio. CONCLUSION: Cutoff levels of 1.5 for the T/WM FDG uptake ratio and 0.6 for the T/C ratio are useful in the differentiation of low-grade from high-grade gliomas with PET.

Prolonged survival in carcinomatous meningitis associated with breast cancer.

We describe a patient who survived for more than 7 years after the diagnosis of meningeal carcinomatosis associated with breast cancer. Meningeal carcinomatosis occurs in 1% to 5% of patients with breast cancer. The median survival ranges from 3 to 7 months, but most reports include a small number of patients who survive considerably longer, with up to 11% surviving more than 1 year. Early diagnosis, aggressive treatment of neurologic involvement, limited systemic tumor burden, and varied rates of progression are factors that may relate to extended duration of survival in these patients with breast cancer. Our patient, with a hormonally responsive adenocarcinoma of the breast and without systemic metastases, illustrates that meningeal carcinomatosis, like other forms of breast cancer metastasis, can run an indolent course. In such patients the delayed sequelae of therapy for metastasis to the central nervous system can profoundly influence the course of the illness.

Inhibitory motor seizures: correlation with centroparietal structural and functional abnormalities.

Six adults and 2 children with focal inhibitory motor seizures (ictal paralysis) were evaluated during a 4-year period. Paresthesias at seizure onset occurred during some seizures in all patients, and focal clonic activity followed paralysis in 4. EEG-CCTV recordings of the seizures in 2 patients showed that ictal paralysis coincided with an ictal discharge starting in one centroparietal area. MRI showed centroparietal structural lesions in six patients. One patient with a normal MRI scan had right centroparietal hypometabolism on PET. Inhibitory motor seizures must be differentiated from transient ischemic attacks and migraine. In our patients a centroparietal epileptogenic focus was suggested by neuroimaging studies, and in 2 instances by ictal EEG.

Expression of transforming growth factor alpha in human gliomas.

Expression of transforming growth factor alpha (TGF alpha) is frequently associated with the development of human and animal tumors. Using a sensitive immunohistochemical assay, which can be applied on formalin-fixed, paraffin-embedded tissue, we have examined the expression of TGF alpha in 71 human gliomas (63 untreated and 8 recurrent tumors). Tumors were graded by a 3-grade-system: grade I = low grade gliomas, grade II = anaplastic gliomas and grade III = glioblastomas. A strong positive correlation between tumor grade and extent of TGF alpha expression was found (P less than 0.0001). Polymerase chain reaction (PCR) was used to amplify the fourth exon of the TGF alpha gene of 8 glioma DNA specimens and increasing amounts of normal human DNA, which served as a standard. No amplification of the TGF alpha gene copy number in tumors could be detected.