Mitchel S. Berger

Prognostic significance of type 1 neurofibromatosis (von Recklinghausen Disease) in childhood optic glioma.

Although the association between optic glioma and neurofibromatosis is well recognized, few studies have systematically compared the outcomes of patients with optic gliomas and neurofibromatosis and patients with optic gliomas without neurofibromatosis. In the present study, patients with optic gliomas and Type 1 neurofibromatosis (NF-1) were compared with patients with optic gliomas without NF-1, with respect to survival, time to tumor progression, and tumor location. Forty-four patients with optic gliomas who were evaluated between 1949 and 1991 were studied retrospectively. Sixteen of 44 patients (36%) met the National Institutes of Health criteria for NF-1. The medical records of all patients were examined, and letters of inquiry were sent to every living patient to ascertain current health statuses. Death certificates were obtained to determine causes of death. Follow-up averaged 7.2 years (10.2 yr for patients with NF-1, 5.4 yr for patients without NF-1). The 5- and 10-year survival rates for patients with optic gliomas and NF-1 were 93 and 81%, respectively. For those patients with optic gliomas who did not have NF-1, 5- and 10-year survival rates were 83 and 76%, respectively. Seventeen patients experienced tumor progression (5 with NF-1, 12 without NF-1). A difference was observed in the mean time to tumor progression (first relapse) between the two groups (mean time with NF-1, 8.37 yr; without NF-1, 2.39 yr [P < 0.01]). However, no significant difference in overall survival, as evaluated by a log-rank test of the respective Kaplan-Meier survival curves, was observed between the two groups. A significant difference in distribution of tumor location between the group with NF-1 and the group without NF-1 was also noted (Fishers exact test, P = 0.0338), although the number of patients evaluated in this series was too small to determine whether this difference in tumor location influenced relapse rate. We conclude that optic gliomas in patients with neurofibromatosis have a different distribution of location as opposed to those in patients without neurofibromatosis, and, for first relapse, the presence of neurofibromatosis is a significant favorable factor.

Resection of intrinsic tumors from nondominant face motor cortex using stimulation mapping: Report of two cases ☆

We report two right-handed patients who underwent resection of intrinsic glial tumors from the nondominant hemisphere, face motor cortex. Both patients underwent preoperative assessment with computed tomography and magnetic resonance imaging localizing the tumor in the inferior region of the Rolandic cortex. With the patients under general anesthesia and without muscular paralysis, the tumor volume was determined by intraoperative ultrasound and resective surgery accomplished with the aid of cortical and subcortical stimulation mapping techniques. Radical resection of the tumor from the face motor cortex was achieved in both patients. A transient contralateral facial weakness and apraxia were noted in each patient, and this resolved within 6 to 8 weeks following surgery. Removal of intrinsic tumors involving the nondominant face motor cortex may be safely achieved using brain mapping techniques to localize inferior Rolandic cortex and avoid resection of the hand motor cortex and descending subcortical motor pathways. Permanent disability will be prevented due to the bilateral representation of face motor function at the neocortical level. However, due to language localization in cortical zones contiguous with the dominant hemisphere, face motor cortex, we do not recommend resection of this region.

Seizure Outcome in Children with Hemispheric Tumors and Associated Intractable Epilepsy: The Role of Tumor Removal Combined with Seizure Foci Resection

Children harboring hemispheric tumors associated with intractable epilepsy were retrospectively reviewed to assess seizure outcome following tumor resection and electrocorticography-guided seizure foci removal. Thirteen (93%) of our patients have remained seizure-free, off anticonvulsants or on tapering doses, following surgery with a mean follow-up of 33 months. Fifteen of 16 (93%) seizure foci examined histologically were void of tumor infiltration. A review of the literature is provided regarding the controversy of tumor removal versus additional seizure foci removal at the time of tumor removal in providing optimal seizure control.

Corpus callosum involvement as a prognostic factor for patients with high-grade astrocytoma

PURPOSEnTo evaluate corpus callosum involvement as a prognostic factor for patients with high-grade astrocytoma.nnnMETHODSnFrom 1986 through 1994, 141 adult patients with Karnofsky performance status (KPS) > or = 40 underwent primary treatment for anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) at the University of Washington Medical Center. Preoperative magnetic resonance imaging and/or computed tomography to assess corpus callosum involvement was available for 105 of these patients. Corpus callosum involvement was evaluated as a prognostic factor for survival using recursive partitioning analysis and multivariate analysis with a Cox proportional hazards model.nnnRESULTSnFor the 105 patients evaluable for corpus callosum involvement, the median and 2-year survival were 59 weeks and 28%, respectively. On multivariate analysis, the only independent prognostic factors were KPS (p = 0.0001) and histology (p = 0.042). On recursive partitioning analysis, the first significant split occurred at KPS < 70 vs. KPS > or = 70. Patients with KPS > or = 70 were split by age (< 50 years vs. > or = 50 years), with those younger than 50 years further split by absence or presence of corpus callosum involvement. Among patients with KPS > or = 70 and age < 50 years, median survival was 57 weeks if the corpus callosum was involved (35% 2-year survival) and 105 weeks if the corpus callosum was not involved (56% 2-year survival).nnnCONCLUSIONnCorpus callosum involvement based on preoperative imaging is an unfavorable prognostic factor for survival among the subgroup of young, good-performance-status patients with high-grade astrocytoma.

Nerve growth factor receptor expression in medulloblastomas and the potential role of nerve growth factor as a differentiating agent in medulloblastoma cell lines

Nerve growth factor (NGF) has the potential to induce cellular differentiation in various neoplastic and nonneoplastic cell lines. In this study, our aim was to determine NGF receptor (NGFr) status in medulloblastoma specimens and cell lines and to investigate whether NGF could act as a potential differentiating agent for this common pediatric brain tumor. Paraffin-embedded tumor tissue from 10 patients with the diagnosis of medulloblastoma was retrospectively analyzed to determine the frequency of NGFr expression. Of the 10 tumor specimens evaluated, 4 were positive for NGFr; however, NGFr staining was confined to only 5 to 8% of the cells in a randomly scattered pattern. No colocalization was present with neuronal, glial, or vascular structures. In addition, two medulloblastoma cell lines established in our laboratory were also evaluated for NGFr. In this study, we also examined the effects of retinoic acid, 12-O-tetradecanoyl-phorbol-13-acetate, and NGF on medulloblastoma cell lines to evaluate their effect on morphological differentiation and NGFr expression. Although these agents failed to cause NGFr expression in our cell lines, morphological alteration was noticed in only one of the cell lines with retinoic acid. Therefore, because of the lack of de novo or induced NGFr expression, it is unlikely that NGF will be useful as a potential therapeutic differentiating agent for medulloblastomas.

Paragangliomas of the Sellar Region

Two cases of paraganglioma arising from the parasellar region are presented. Both occurred in middle-aged women who sought treatment of headaches but who had no endocrinological dysfunction; one case was associated with ophthalmoplegia from cavernous sinus involvement. Diagnosis in both cases was confirmed by typical histological appearance and cytochemical demonstration of immunoreactive chromogranin in tumor cells. The pathological features and possible pathogenesis of parasellar paragangliomas are discussed.

COMPARATIVE ANALYSES OF RELATIVE ERCC3 AND ERCC6 MRNA LEVELS IN GLIOMAS AND ADJACENT NON-NEOPLASTIC BRAIN

Nucleotide excision repair (NER) is an ordered process in nonmalignant cells, in both human and nonhuman systems. We previously reported that in human brain, there is discordant mRNA expression of excision repair cross‐complementing (ERCC) 1 and ERCC2 in malignant tissues, concurrent with excellent concordance of these genes in nonmalignant tissues from the same patients. Here we have extended these studies to compare low‐grade tumors to high‐grade tumors and to include ERCC3 (which links DNA repair with DNA transcription) and ERCC6 (which is essential for gene‐specific repair). Glial tumor and adjacent normal brain specimens from 19 individuals were studied. Paired malignant and nonmalignant tissues were obtained from 12 of these patients. For ERCC3, there was excellent concordance of mRNA expression between malignant and nonmalignant tissues from the same individuals (P = 0.003). For ERCC6, no concordance was observed (P = 0.314). Tumor tissue from patients with high‐grade gliomas exhibited marked discordance of mRNA expression patterns in situations in which good concordance was observed in tumor tissue from low‐grade gliomas. We previously established that malignant brain tumors show increased disorder of genes in the NER process, as compared with nonmalignant tissues. These data suggest that increasing disorder in the NER process may occur as cells move from low‐grade to high‐grade malignancy.

Pathophysiology of Isolated Lateral Ventriculomegaly in Shunted Myelodysplastic Children

Eight myelodysplastic children developed isolated lateral ventriculomegaly following shunt insertion for progressive hydrocephalus after closure of a myelomeningocele. In all patients a low-pressure distal slit valve (Uni-shunt) system preceded development of an isolated contralateral ventricle. Six of 8 children required a second contralateral shunt for a symptomatic isolated ventricle. Magnetic resonance imaging demonstrated a collapsed ventricle ipsilateral to the shunt secondary to distortion of the foramen of Monro. This was clearly depicted using three-dimensional color reconstructions of the ventricular anatomy. Low-pressure distal slit valves should be avoided in myelodysplastic children to prevent postshunt ventricle isolation.

Pituitary oncocytomas: clinical features, characteristics in cell culture, and treatment recommendations

To determine whether there are significant differences between oncocytomas and pituitary adenomas, we evaluated clinical features, treatment regimens and outcome in 23 males and 9 females (average age 64 years, range 43–81 years) with the histologic diagnosis of pure pituitary oncocytomas (>95% oncocytes). Symptom duration was six to twelve months in 6 cases (19%) and more than one year in 19 cases (59%). Three patients presented with sudden onset of symptoms, and were found to have hemorrhage within their tumors. Visual loss (69%) and symptoms of hypopituitarism (44%) were the most common presenting complaints. Preoperative endocrine profiles revealed abnormalities in most cases, including pituitary insufficiency in 56% and hyperprolactinemia in 59%. The tumors were typically large at presentation; all but one had suprasellar extension. 28 patients underwent transsphenoidal tumor resections; 4 underwent subfrontal craniotomies. Gross dural invasion was found at surgery in 11 cases. At a mean followup of 31 months (range 2–68 months), recurrent tumor was identified in 4 patients (12.5%). Tumor size, dural invasion, preoperative endocrine profile, and postoperative radiotherapy did not correlate with recurrence. Among seven oncocytomas grown in culture, five demonstrated two distinct cell types consisting of oncocytes and typical adenoma cells, respectively. Oncocytomas often have a different clinical presentation than functional pituitary adenomas.

p53 Expression in four human medulloblastoma-derived cell lines

Abstractp53 is a tumor suppressor gene found on the short arm of chromosome 17. Loss of onep53 allele and alteration of the other is found in a variety of tumors, including highgrade glial tumors. Point mutations in the remaining allele occur in a highly conserved region of the gene encompassing exons 5–8. Although 40–50% of medulloblastomas lose sequences on the short arm of chromosome 17, alteration ofp53 in these tumors is infrequent. To further characterize genetic alteration ofp53 in medulloblastoma, we performed a mutational analysis of four medulloblastoma-derived cell lines established by our laboratory. Using two variable-number tandem repeat markers which map distally top53, we found evidence indicating loss of sequences on the distal end of chromosome 17 p in all four lines. However, no gross alterations of thep53 gene were detected. Northern analysis revealed expression of equivalent amounts of full-lengthp53 messenger RNA in each cell line. Using the polymerase chain reaction to amplify exons 5–8 of thep53 gene, we directly sequenced the amplified fragments and detected no mutations in any of the cell lines. Our results demonstrate that loss ofp53 function through gene deletion and/or recesive mutation is not required for growth in our cell lines.