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M S Berger

Publications and source records attributed to M S Berger.

At least 37 records · Page 2Linked to original sources
PubMed2001

Functional activity within brain tumors: a magnetic source imaging study.

OBJECTIVE: To determine whether low-grade gliomas contain functional cortical activity more often than high-grade gliomas within radiologically defined abnormal tissue. METHODS: Patients with intra-axial cerebral lesions located in the vicinity of eloquent brain cortex preoperatively underwent magnetic source imaging. A dual 37-channel biomagnetometer was used to perform the imaging. Evoked magnetic fields were analyzed using the single-equivalent dipole representation to ascertain the neuronal source. Stimuli included painless tactile somatosensory stimulation of fingers, toes, and lips and auditory presentation of pure sinusoidal tones. RESULTS: A retrospective analysis of 106 nonconsecutively treated patients, who had undergone preoperative magnetic source imaging between February 1996 and December 1999, revealed that 24.5% of the patients had been at risk for neurological deficits, because functionally active tissue was located within or at the border of the tumor. Functional activity was found within the radiologically defined lesion in 18% of Grade 2 tumors, in 17% of Grade 3 tumors, and in 8% of Grade 4 tumors. CONCLUSION: The results confirm that, regardless of tumor grade, intra-axial brain tumors may involve or directly border on functional cortex. The degree of involvement of functionally viable cortex appeared greater for low-grade tumors than for high-grade lesions. On the other hand, high-grade lesions were more likely to be associated with functional cortex at their margins or within peritumoral edema. To safely maximize tumor resection, preoperative functional imaging and intraoperative electrophysiological mapping of the cerebral cortex and the white matter tracts are deemed necessary.

Brain Mapping↗
PubMed2001

Permanent low-activity (125)I seed placement for the treatment of pediatric brain tumors: preliminary experience.

Although external beam radiation therapy is effective in the treatment of many pediatric brain neoplasms its use in this patient population has been associated with the development of significant cognitive and endocrine dysfunction and is severely limited as an option in previously irradiated patients. Therefore, we have adopted a strategy for management of residual microscopic disease by implantation of low-activity (125)I seeds in the tumor bed at the time of surgery. Six patients aged 2-14 years with recurrent tumors including two supratentorial primitive neuroectodermal tumors (n = 2), one medulloblastoma, one malignant ependymoma (n = 1), glioblastoma (n = 1) and one pleomorphic xanthoastrocytoma were implanted at the time of reoperation. A total of 11-126 seeds were implanted resulting in total doses of 16-21.8 Gy (after theoretical infinite time) at a depth of 5 mm from the implanted resection bed. Five patients had prior external beam radiation while the other patient (2 years old at initial diagnosis) progressed after surgery and chemotherapy. Two patients had lasting local tumor control. One patient is alive at 390 weeks of follow-up and another who died of distant failure at 366 weeks had no recurrence on MRI at 333 weeks' follow-up. Only 2 patients had first local failures. These results suggest that the use of permanent low-activity (125)I seeds as an adjunct to surgery can provide good local tumor control and is a suitable treatment option for pediatric patients.

Adolescent↗
PubMed2001

Pharmacokinetics of gemtuzumab ozogamicin, an antibody-targeted chemotherapy agent for the treatment of patients with acute myeloid leukemia in first relapse.

The purpose of this study was to characterize the pharmacokinetics of gemtuzumab ozogamicin (Mylotarg; Wyeth-Ayerst Laboratories, St. Davids, PA) in patients with acute myeloid leukemia (AML) in first relapse. Gemtuzumab ozogamicin is an antibody-chemotherapeutic conjugate characterized as antibody-targeted chemotherapy, consisting of an engineered human anti-CD33 antibody (hP67.6) linked to a potent cytotoxic agent, N-acetyl-gamma calicheamicin DMH. The pharmacokinetics of gemtuzumab ozogamicin was evaluated in 59 adult AML patients in first relapse, enrolled in a phase II study. Plasma was collected following each dose at specified times, and the pharmacokinetics was characterized by measures of hP67.6, total calicheamicin derivatives, and unconjugated calicheamicin derivatives. After administration of the first 9 mg/m2 dose of gemtuzumab ozogamicin, the pharmacokinetic parameters (mean +/- SD) of hP67.6 following the first dose were as follows: peak plasma concentration, 2.86 +/- 1.35 mg/L; AUC, 123 +/- 105 mg x h/L; t 1/2, 72.4 +/- 42.0 hours; and clearance, 0.265 +/- 0.229L/h. Increased concentrations were observed after the second dose and are believed to be due to a decrease in clearance by CD33-positive blast cells, a result of the reduced tumor burden following the first dose. The concentration profiles of calicheamicin followed the same time course as hP67.6, evidence that calicheamicin remained conjugated to the antibody and delivered to leukemic cells. No relationship was found between plasma concentration and response at the recommended dose. The pharmacokinetics of gemtuzumab ozogamicin has been characterized in AML patients receiving doses at the proposed therapeutic level.

Acute Disease↗
PubMed2001

Multiple sclerosis and oligodendroglioma.

Two cases of multiple sclerosis (MS) and oligodendroglioma are reviewed, increasing the total number of reported cases to II. In this series, the clinical onset of MS preceded the discovery of the tumor by a mean of 15 years. No distinguishing features of oligodendroglioma were characteristic of MS-associated cases. However, there was an overrepresentation of benign MS. Although this could result from biased ascertainment, other possibilities, including effective remyelination mediated by mitotically active oligodendrocytes, or secretion of immunosuppressive cytokines by the tumor tissue, cannot be excluded. It is likely that the coexistence of MS and oligodendroglioma is due to chance alone, nonetheless the possibility that glioma derived factors can moderate the disease course in MS is deserving of further study.

Adult↗
PubMed2001

Impact of age and gender on the pharmacokinetics of gemtuzumab ozogamicin.

STUDY OBJECTIVE: To determine the pharmacokinetic parameters of the components of gemtuzumab ozogamicin and to assess the possible influence of age and gender on the values. DESIGN: Phase II, multicenter, open-label, nonrandomized, parallel study SETTING: Hospitals and outpatient oncology clinics. PATIENTS: Fifty-eight patients with acute myeloid leukemia in first relapse participated. Demographic data included 29 men and 29 women; 34 were younger than 60 years of age (mean age 53+/-16 yrs). INTERVENTION: Patients received gemtuzumab ozogamicin as a single 2-hour infusion of 9 mg/m2. Serial plasma samples were collected over 10 days after the beginning of the infusion. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of components of gemtuzumab ozogamicin (hP67.6 antibody, total and unconjugated calicheamicin derivatives) were measured by validated enzyme-linked immunosorbent assays. Pharmacokinetic parameters were determined by noncompartmental methods and comparisons between groups were made by analysis of variance. No significant differences were seen between men and women or between those over 60 and those less than 60 years of age in maximum concentration, time to maximum concentration, area under the curve, clearance, or volume of distribution for components of gemtuzumab ozogamicin. CONCLUSION: No differences occur in the pharmacokinetics of the components of gemtuzumab ozogamicin (hP67.6 or calicheamicin) based on gender or age.

Adult↗
PubMed2001

Magnetic source imaging of late evoked field responses to vowels: toward an assessment of hemispheric dominance for language.

OBJECT: The goal of this study was to determine whether the late neuromagnetic field elicited by simple speech sounds, which is detected by magnetoencephalography, may be used to estimate hemispheric dominance for language and to guide or constrain the intraoperative search for essential language sites. If sufficiently robust, a noninvasive method for assessing hemispheric dominance for language could reduce the necessity for amobarbital testing and the extent of intraoperative cortical stimulation-based mapping, both of which carry the risk of morbidity. METHODS: Fifteen patients undergoing surgery for tumors during which intraoperative language mapping would be performed and two additional patients in whom intracarotid amobarbital testing confirmed right-hemisphere language dominance participated. Following a primary auditory response sources of late neuromagnetic fields elicited by vowel stimuli were modeled and coregistered using magnetic resonance images to form magnetic source (MS) images. A laterality index (LI) was calculated by summing the number of equivalent current dipolar sources in the late fields detected from each hemisphere. In 14 right-handed patients, 10 displayed left asymmetric LIs (0.37 +/- 0.16. mean +/- standard error of the mean in 14 patients). For both right-hemisphere dominant patients in whom an LI was obtainable, the LI was rightward. Stimulation-mapped essential language sites were found in 7 of 15 patients. For six of these seven patients, the MS image-derived LI was leftward. CONCLUSIONS: Asymmetry in single equivalent dipole modeling of the late neuromagnetic field evoked by simple speech sounds correlates with hemispheric language dominance, although not to the degree necessary for individual clinical predictions. With further development, MS imaging of simple language tasks may be used preoperatively to predict language dominance and even to identify or constrain the intraoperative search for likely sites of essential language cortex.

Acoustic Stimulation↗
PubMed2001

Diagnosis and management of pituitary abscess: a review of twenty-four cases.

OBJECT: Pituitary abscess is a rare but serious intrasellar infection. To better determine the salient signs and symptoms that help in making the diagnosis, and to determine the most appropriate treatment, the authors reviewed their experience in a series of 24 patients treated at the University of California at San Francisco. METHODS: Nine of the patients were female and 15 were male, and their mean age was 41.2 years (range 12-71 years). Surprisingly, most patients in our series presented with complaints and physical findings consistent with a pituitary mass, but rarely with evidence of a serious infection. Headache, endocrine abnormalities, and visual changes were the most common clinical indicators; fever, peripheral leukocytosis, and meningismus were present in 33% or fewer of the patients. Imaging tests demonstrated a pituitary mass in all patients, but the features evident on computerized tomography and magnetic resonance studies did not distinguish pituitary abscesses from other, more common intrasellar lesions. Because of the ambiguous clinical features and imaging findings, most abscesses were not diagnosed before treatment; rather, the diagnosis was made during surgical exploration of the sella turcica, when the surgeon encountered a cystic mass containing pus. There were only two deaths in this series (8.3%). Patients presenting with headache and visual changes noted improvement in almost all cases; patients with endocrine dysfunction generally did not recover normal pituitary function, but were easily treated with hormone replacement therapy. CONCLUSIONS: Antibiotic therapy is suggested for patients who have symptoms of sepsis, or for patients in whom specific organisms are identified from cultures obtained during surgery. The transsphenoidal approach is recommended over open craniotomy for surgical drainage.

Abscess↗
PubMed2001

Low-grade hemispheric gliomas in adults: a critical review of extent of resection as a factor influencing outcome.

OBJECT: The goal of this study was to perform a critical review of literature pertinent to low-grade gliomas of the cerebral hemisphere in adults and, on the basis of this review, to evaluate systematically the prognostic effect of extent of resection on survival and to determine if treatment-related guidelines could be established for patients in whom these tumors have been newly diagnosed. Quality of evidence for current treatment options, guidelines, and standards as well as methodological limitations were evaluated. METHODS: Several prognostic factors thought to affect outcome in patients with low-grade gliomas include the patient's age and neurological status, tumor volume and histological characteristics, and treatment-related variables such as timing of surgical intervention, extent of resection, postoperative tumor volume, and radiation therapy. Patient age and the histological characteristics of the lesion are generally accepted prognostic factors. Among treatment-related factors, timing and extent of resection are controversial because of the lack of randomized controlled trials addressing these issues and the difficulty in obtaining information from available studies that have methodological limitations. All English-language studies on low-grade gliomas published between January 1970 and April 2000 were reviewed. Thirty studies that included statistical analyses were further evaluated with regard to the prognostic effect of extent of resection. Of these 30 studies, those that included pediatric patients, unless adults were analyzed separately, were excluded from further study because of the favorable outcome associated with the pediatric age group. Also excluded were studies including pilocytic and gemistocytic astrocytomas, because the natural histories of these histological subtypes are significantly different from that of low-grade gliomas. Series in which there were small numbers of patients (< 75) were also excluded. Results for oligodendrogliomas are reported separately. Currently, for patients with low-grade glial tumors located in the cerebral hemisphere, the only management standard based on high-quality evidence is tissue diagnosis. All other treatment methods are practice options supported by evidence that is inconclusive or conflicting. The majority of published series that the authors identified had design-related limitations including a small study size, a small number of events (that is, deaths for survival studies), inclusion of pediatric patients, and/or inclusion of various histological types of tumors with different natural histories. Of the 30 series addressing the issue of timing and extent of surgery, almost all had additional design limitations. Methods used to determine the extent of resection were subjective and qualitative in almost all studies. Only five of the 30 series met the authors' criteria, and these studies are discussed in detail. CONCLUSIONS: Management of low-grade gliomas is controversial and practice parameters are ill defined. This is caused by limited knowledge regarding the natural history of these tumors and the lack of high-quality evidence supporting various treatment options. Although a prospective randomized study seems unlikely, both retrospective matched studies and prospective observational trials will improve the clinician's ability to understand the importance of various prognostic factors.

Brain Neoplasms↗
PubMed2001

O6-Methylguanine-DNA methyltransferase in pediatric primary brain tumors: relation to patient and tumor characteristics.

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) confers resistance to methylating and chloroethylating agents in pediatric medulloblastoma- and glioma-derived cell lines and xenografts. Here, we assayed MGMT activity in 110 pediatric brain tumors to establish correlates with patient and tumor characteristics. We also assayed MGMT in histologically normal brain adjacent to 22 tumors to characterize changes in activity accompanying neurocarcinogenesis. MGMT activity was detected in 94% of tumors, ranging ca. 1,500-fold from 0.34 to 498 fmol/10(6) cells (approximately 205-300,000 molecules/cell). Mean activity was 25 +/- 66 fmol/10(6) cells, including six specimens with undetectable activity (Mer- phenotype; <0.25 fmol/10(6) cells or 151 molecules/cell). MGMT content varied 10-fold among diagnostic groups and was associated with degree of malignancy, as evidenced by a 4-fold difference in activity between high- and low-grade tumors (P = 0.03). Tumor MGMT content was age dependent, being 5-fold higher in children 3-12 years old than in infants (P = 0.015) and adolescents (P = 0.015). Mean activity in tumors was 9-fold higher than in adjacent histologically normal brain (21 +/- 44 versus 2.4 +/- 4.0 fmol/10(6) cells; P = 0.05). By comparing tumor and adjacent normal tissue from the same patient, we found that 68% of cases exhibited an elevation of tumor activity that ranged from 2- to >590-fold. Moreover, 67% of Mer- normal tissue was accompanied by Mer+ tumor. These observations indicate that MGMT activity is frequently elevated during pediatric neurocarcinogenesis. Significantly, enhanced MGMT activity may heighten resistance to alkylating agents, suggesting a potential role for MGMT inhibitors in therapy.

Adolescent↗
PubMed2001

Apurinic/apyrimidinic endonuclease activity is elevated in human adult gliomas.

Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair activity that confers resistance to ionizing radiation and alkylating agents in human cell lines. The major Ap endo in human cells is Ape1, an abundant multi-functional protein also known as Ref-1, Hap-1, and Apex. In this work, we assayed Ap endo activity in human adult gliomas to establish correlates with tumor characteristics, and in histologically normal brain adjacent to tumors to characterize changes in activity accompanying neurocarcinogenesis. To our knowledge, this is the first available analysis of Ap endo activity in human brain tumors. Mean activity in 84 gliomas of different diagnostic types and grades was 0.072 +/- 0.095 fmol abasic sites incised/cell/min, ranging approximately 550-fold from 0.00077 to 0.42. The mean for high-grade gliomas was 3.5-fold greater than for low-grade tumors (P < or = 4.0 x 10(-5)), a difference observed within all diagnostic types. Activity was correlated with the fraction of S-phase cells in diploid gliomas (P < or = 0.02), suggesting that proliferation could be a determinant of activity in these tumors. Activity was also correlated with S-phase fraction in the majority of aneuploid gliomas (P < or = 0.03). Moreover, within the aneuploid tumors, there was a significant relationship between activity and the fraction of aneuploid cells (P < or = 4.0 x 10(-4)). In the 58 cases analyzed, mean activity was 7.3-fold higher in gliomas than in adjacent histologically normal brain (0.070 +/- 0.10 versus 0.0096 +/- 0.012 fmol/cell/min; P < or = 3.0 x 10(-5)). Increased tumor activity was observed in 93% of tumor/normal pairs, indicating that elevation of Ap endo activity is characteristic of human gliomagenesis. The elevation was large within most pairs, being 13-fold on average and > or = 10-fold in 43% of cases. A concomitant increase in Ape1 protein was observed by Western blotting in the subset of tumor/normal pairs examined. A clinically important consequence of the increase in Ap endo activity that accompanies neurocarcinogenesis may be enhanced resistance to the radiotherapy and alkylating agent-based chemotherapy that are mainstays of adjuvant therapy for malignant gliomas.

Adolescent↗
PubMed2000

Basic concepts of immunology and neuroimmunology.

The immune system is a complex network of specialized cells and organs that defends the human body against attack from foreign pathogens. The major lymphocytes involved in protecting the body against potential infections are B and T cells, which also play an important role in combating tumor growth. The cells of the immune system patrol the tissues and organs through both blood and lymphatic vessels, but some organs--including cornea, testes, and brain--are usually not patrolled by these cells. The brain has been thought to be an immune-privileged site because of the tight blood-brain barrier (BBB) that protects it. Few cells migrate to the brain under normal circumstances, because the BBB permits only certain molecules to cross into brain tissue. Recently, however, studies have shown that activated T cells exposed to antigen can cross the intact BBB and migrate into brain. This finding opens the path to developing effective means of immunotherapy for lesions of the central nervous system. The authors discuss basic facets of the immune system, review the current knowledge about human neuroimmunology, and survey current strategies for developing immunotherapy-based treatments for human brain tumors.

Allergy and Immunology↗
PubMed2000

Colocalization and coassembly of two human brain M-type potassium channel subunits that are mutated in epilepsy.

Acetylcholine excites many central and autonomic neurons through inhibition of M-channels, slowly activating, noninactivating voltage-gated potassium channels. We here provide information regarding the in vivo distribution and biochemical characteristics of human brain KCNQ2 and KCNQ3, two channel subunits that form M-channels when expressed in vitro, and, when mutated, cause the dominantly inherited epileptic syndrome, benign neonatal familial convulsions. KCNQ2 and KCNQ3 proteins are colocalized in a somatodendritic pattern on pyramidal and polymorphic neurons in the human cortex and hippocampus. Immunoreactivity for KCNQ2, but not KCNQ3, is also prominent in some terminal fields, suggesting a presynaptic role for a distinct subgroup of M-channels in the regulation of action potential propagation and neurotransmitter release. KCNQ2 and KCNQ3 can be coimmunoprecipitated from brain lysates. Further, KCNQ2 and KCNQ3 are coassociated with tubulin and protein kinase A within a Triton X-100-insoluble protein complex. This complex is not associated with low-density membrane rafts or with N-methyl-d-aspartate receptors, PSD-95 scaffolding proteins, or other potassium channels tested. Our studies thus provide a view of a signaling complex that may be important for cognitive function as well as epilepsy. Analysis of this complex may shed light on the unknown transduction pathway linking muscarinic acetylcholine receptor activation to M-channel inhibition.

Brain↗
PubMed2000

Presurgical mapping with magnetic source imaging: comparisons with intraoperative findings.

We compare noninvasive preoperative mapping with magnetic source imaging to intraoperative cortical stimulation mapping. These techniques were directly compared in 17 patients who underwent preoperative and postoperative somatosensory mapping of a total of 22 comparable anatomic sites (digits, face). Our findings are presented in the context of previous studies that used magnetic source imaging and functional magnetic resonance imaging as noninvasive surrogates of intraoperative mapping for the identification of sensorimotor and language-specific brain functional centers in patients with brain tumors. We found that magnetic source imaging results were reasonably concordant with intraoperative mapping findings in over 90% of cases, and that concordance could be defined as "good" in 77% of cases. Magnetic source imaging therefore provides a viable, if coarse, identification of somatosensory areas and, consequently, can guide and reduce the time taken for intraoperative mapping procedures.

Brain Mapping↗
PubMed2000

Molecular remission of Philadelphia/bcr-abl-positive acute myeloid leukaemia after treatment with anti-CD33 calicheamicin conjugate (gemtuzumab ozogamicin, CMA-676).

The anti-CD33 monoclonal antibody linked to NAc-gamma calicheamicin gemtuzumab ozogamicin (CMA-676) was used to treat a patient with Philadelphia/bcr-abl-positive acute myeloid leukaemia. We report a morphological and cytogenetic complete remission after treatment with two doses of gemtuzumab ozogamicin as a single agent. Using real-time polymerase chain reaction (PCR), gemtuzumab ozogamicin treatment resulted in a 3-log tumour mass reduction in bone marrow.

Acute Disease↗