Primary melanotic tumors of the nervous system: a consecutive case series.

BACKGROUND AND PURPOSE: Primary melanotic tumors of the nervous system (PMTNS) are thought to be an exceedingly rare group of tumors not captured by tumor registries. We aimed to determine relative incidence, clinical presentation, diagnostic findings, patient management, and outcome. METHODS: We retrospectively searched the database of the Section of Neuro-Oncology at the Yale Cancer Center for patients with primary or metastatic melanotic lesions of the nervous system. For patients with PMTNS, we recorded demographic data, clinical presentation, histopathological and imaging findings, therapy, and outcome. RESULTS: A total of 116 patients with melanotic lesions were identified, including four patients with PMTNS. The relative incidence of PMTNS was therefore calculated as 3.4%. Histology of PMTNS patients revealed melanocytoma in three patients and psammomatous melanotic schwannoma in one patient. Symptoms were non-specific and attributed to tumor mass effect. Magnetic resonance imaging showed hyperintensity on pre-contrast T1-weighted imaging, hypointensity on T2-weighted imaging, and homogenous contrast enhancement in all PMTNS patients. Definitive diagnosis was based on tissue analysis, with detection of melanin-containing cells on conventional histology and S100-positivity on immunohistochemistry. Molecular analysis for GNAQQ209L mutation assisted in establishing diagnosis when only small amounts of tissue were available. Aggressive surgical treatment showed favorable outcomes in all cases; radiation therapy was used for residual or relapsed disease. The median follow-up was 7.5 ± 5 years, and all patients were alive on the day of database closure. CONCLUSION: Primary melanotic tumors of the nervous system are rare nervous system tumors. Outcome appears excellent, and complete surgical resection may form the basis for favorable outcome. Radiation therapy may represent a therapeutic approach for residual or relapsed disease.

Patterns of functional magnetic resonance imaging activation in association with structural lesions in the rolandic region: a classification system.

OBJECT: Functional magnetic resonance (fMR) imaging of the motor cortex is a potentially powerful tool in the preoperative planning of surgical procedures in and around the rolandic region. Little is known about the patterns of fMR imaging activation associated with various pathological lesions in that region or their relation to motor skills before surgical intervention. METHODS: Twenty-two control volunteers and 44 patients whose pathologies included arteriovenous malformations (AVMs; 16 patients), congenital cortical abnormalities (11 patients), and tumors (17 patients) were studied using fMR imaging and a hand motor task paradigm. Activation maps were constructed for each participant, and changes in position or amplitude of the motor activation on the lesion side were compared with the activation pattern obtained in the contralateral hemisphere. A classification scheme of plasticity (Grades 1-6) based on interhemispheric pixel asymmetry and displacement of activation was used to compare maps between patients, and relative to hand motor dexterity and/or weakness. There was 89.4% interobserver agreement on classification of patterns of fMR imaging activation. Displacement of activation by mass effect was more likely with tumors. Cortical malformations offer a much higher functional reorganization than AVMs or tumors. High-grade plasticity is recruited to compensate for severe motor impairment. CONCLUSIONS: Pattern modification of fMR imaging activation can be systematized in a classification of motor cortex plasticity. This classification has shown good correlation among grading, brain lesions, and motor skills. This proposal of a classification scheme, in addition to facilitating data collection and processing from different institutions, is well suited for comparing risks associated with surgical intervention and patterns of functional recovery in relation to preoperative fMR imaging categorization. Such studies are underway at the authors' institution.

Transcallosal approach for tumors of the lateral and third ventricles.

Tumors that arise within the ventricles present a unique surgical challenge. Because of their deep location, relatively large size, and their association with hydrocephalus, surgical planning requires a careful assessment of the optimal method to access the lesion and to provide adequate exposure for tumor resection. The transcallosal approach to the lateral ventricles often is the best procedure by which to achieve these goals. Partial sectioning of the corpus callosum does not cause significant neurological deficits; however, if the surgery induces additional brain injury, the neurological deficits can be more severe in the presence of a callosotomy. Knowledge of the techniques of transcallosal surgery and careful preoperative planning can reduce the risk of permanent neurological impairment; these range from protection of the cortical veins that drain into the superior sagittal sinus to brain relaxation and ventricular drainage, as well as proper identification of anatomical landmarks within the ventricle. The transcallosal approach can offer a relatively easy access to the lateral and third ventricles, and with proper planning it can reduce the morbidity associated with resection of lesions within these compartments.

Complications and expected outcome of glioma surgery.

The management of patients with intracerebral glioma is focused upon the selection of treatment modalities that prolong survival while minimizing the risk of complications and maintaining an adequate quality of life. In the author's experience, patients with low-grade gliomas are best treated with gross total resection in order to decrease the risk of recurrence with higher grade lesions. In patients with high-grade glioma, age, Karnofsky Performance Status, histology and the use of radiotherapy are major predictors of survival. The extent of surgical resection is less important than these factors, but recent series support a survival advantage in patients that undergo more extensive surgery. The major complication from surgical resection is neurologic impairment. Careful preoperative planning with the assistance of functional MRI and intraoperative mapping is useful for accomplishing the maximum safe resection.

Polarographic measurements of oxygen tension in human glioma and surrounding peritumoural brain tissue.

This study quantifies the spatial distribution of pO2 in glioma and in the surrounding brain tissue. Both glioma and peritumoural brain contain regions at oxygen tensions less than 2.5 mmHg. Modalities targeting hypoxia to improve the efficacy of therapy may have an important role in the management of this disease.

Suppression of matrix metalloproteinase-2-mediated cell invasion in U87MG, human glioma cells by anti-microtubule agent: in vitro study.

Because microtubules are important components of cell motility and intracellular transport, it is reasonable to propose that the depolymerizing effect of an antimicrotubule agent, estramustine, on glioma microtubules would modulate cell invasiveness. To determine whether matrix metalloproteinases, key factors in cell invasion, are affected by exposure to estramustine, a cell proliferation assay, a zymogram, a collagenolysis assay and a haptoinvasion assay were used in this study. The zymogram revealed that an activated (62 kDa) form of matrix metalloproteinase-2 diminished with increasing estramustine concentrations. The collagenolysis assay demonstrated approximately 2.5- to 21-fold lower rates of enzymatic activity suppressed by estramustine in a dose-dependent manner at estramustine concentrations of 1, 5, and 10 microM, compared with the control group. On the haptoinvasion assay, no statistically significant difference was seen in the 0.5 microM estramustine group, whereas 1-10 microM estramustine groups revealed significant suppression of invasion from 6 to 24 h in a dose-dependent manner. The results suggest that estramustine suppresses the invasion of U87MG cells in vitro using the decreasing available matrix metalloproteinase-2, an effect caused by the disassembly of microtubules. Suppression of the infiltrative capacity of malignant glioma cells could be of significant value in the treatment of this disease.

Low-grade gliomas: introduction and overview.

This issue of the Journal of Neuro-Oncology is devoted to recent investigations of low-grade gliomas. The purpose of this issue is not to debate the relative merits and liabilities of different management strategies for low-grade gliomas, but to present new data concerning novel and innovative approaches to evaluating these lesions. The common theme of many of these reports represents a departure from grading systems that primarily depend on a morphology-based analysis from light microscopy to classify these tumors. The purpose of this review is to present the reasoning behind the selection of authors for this issue of the Journal of Neuro-Oncology and to provide a format for presentation of new ideas concerning these interesting tumors. It is clear that standard classification systems that address only the morphological characteristics of tumor cells can not adequately represent the wide variation in biological activity that is found with these lesions. It is hoped that these articles will stimulate further interest and research into low-grade gliomas that will one day lead to more effective therapy.

Low-grade gliomas of chronic epilepsy: a distinct clinical and pathological entity.

The authors present a summary of their recent experience regarding the management of patients with a variety of low-grade gliomas found during the evaluation for chronic epilepsy. These tumors are notable because the long-term patient outcome in this population is significantly better than the anticipated results of patients with the same tumors who do not have chronic epilepsy. Based on the long history of preoperative seizures (median 14 years), the frequent cortical location, and the absence of tumor recurrence or anaplastic transformation and the lack of mortality in this population, low-grade gliomas of chronic epilepsy appear to define a specific pathological entity that separates them from other histologically similar low-grade gliomas. Low-grade gliomas of chronic epilepsy also are notable for the absence of morphological features that characterize with dysembryoplastic neuroepithelial tumors (DNTs). Our evidence suggests that low-grade gliomas of chronic epilepsy should be recognized as a distinct pathological entity.

Tumors and approaches to the lateral ventricles. Introduction and overview.

There are a variety of tumors that arise within the lateral ventricles and they present a unique surgical challenge. These lesions commonly are benign and because they frequently are slowly expanding and cause non-specific symptoms they can grow to a large size before they reach medical attention. This report presents an introduction to and an overview of the problems caused by lateral ventricular tumors and summarizes the author's experience in the evaluation and management of these lesions. The most consistent neurological problems associated with lateral ventricular tumors are cognitive impairments commonly associated with hydrocephalus. Consequently, effective management not only requires successful surgical therapy, but also returning the patient to normal neurological and cognitive function. Recognition of these problems and minimizing further injury are the best methods of providing for an optimal outcome.

Targeting microtubule-associated proteins in glioblastoma: a new strategy for selective therapy.

BACKGROUND: This report presents a summary of preclinical data concerning the use of estramustine, an antimicrotubule agent against human glioblastoma cells. The strategy for the investigation of estramustine is predicated on the unique affinity of this agent for microtubule-associated proteins (MAPs). METHODS: A series of laboratory investigations were used to demonstrate antiproliferative effects (MTT assay, colony forming assay, thymidine incorporation), cell cycle synchronization (flow cytometry), intracellular localization of binding sites (immunocytochemistry, electron microscopy), and activity in subcutaneous xenografts of human glioblastoma. RESULTS: Estramustine has potent in vitro activity against human glioblastoma cells and can enhance the cytotoxic effects of ionizing radiation. Estramustine-binding protein was abundantly expressed in glioblastoma cells and may contribute to the selective effects of estramustine on neoplastic cells. This agent has activity against subcutaneous xenografts of human glioblastoma. Synthesized novel estrogen carbamates also can inhibit proliferation of glioblastoma cells. CONCLUSIONS: Cytoskeletal elements (MAPs) of glioblastoma cells may provide a useful target for therapy with agents like estramustine because of the potent antimitotic effects of this agent and its affinity to a protein that is expressed in glioma cells. These observations have stimulated a search for other estrone carbamates with antimitotic activity that exceeds more conventional antimicrotubule agents.

Estramustine in malignant glioma.

Estramustine, a carbamate ester combining 17 beta-estradiol and nornitrogen mustard, has primarily been employed in the treatment of advanced prostatic carcinoma. However, a significant amount of preclinical investigation has been directed toward estramustine's activity against human malignant glioma. These studies have demonstrated that estramustine has potent antiproliferative effects against malignant glioma both in vitro and in vivo. Similar antimitotic effects also have been demonstrated for other carbamate esters. Estramustine does not impair proliferation of nonneoplastic astrocytes at concentrations that inhibit glioma cells. Although the reasons for this selective activity remain to be determined, it has been shown that malignant gliomas expresses an estramustine-specific binding site, estramustine-binding protein, more than brain tissue. In the clinical situation, an uptake and accumulation of estramustine in human glioma tissue have been demonstrated. Estramustine has been shown to enhance the cytotoxic effects of irradiation in relatively radioresistant glioma cells both in cell culture and in a rat glioma model. Estramustine has been regarded as mainly an anti-mitotic drug but recently other effects such as inhibition of DNA synthesis, induction of apoptosis, and membrane alterations have been shown. This report summarizes the preclinical observations concerning the effects of estramustine and related compounds on human malignant gliomas. These findings form the basis for proposing further laboratory and clinical investigation regarding estramustine and human malignant gliomas.

In vitro inhibition of cell proliferation, viability, and invasiveness in U87MG human glioblastoma cells by estramustine phosphate.

OBJECTIVE: Several determinants of cell motility are highly dependent on the cytoskeleton, in particular, microtubules. To our knowledge, there have been no previous reports regarding the anti-invasive ability by an antimicro-tubule agent, estramustine phosphate (EMP), on glioblastoma cell lines. We investigated the modulated cell proliferation and invasiveness by EMP in vitro. METHODS: We determined the relative survival rate by cell proliferation assay and the percent survival fraction by monotetrazolium assay. Furthermore, an invasion index was used to quantify the migrating and invasive potential of the human glioblastoma cell line, U87MG, in Boiden's chamber with reconstituted basement membrane (Matrigel; Collaborative Research, Lexington, MA). RESULTS: We found that 0.5 mumol/L EMP had no effect in any of the assays. Concentrations of 1, 5, and 10 mumol/L demonstrated a concentration- and time-dependent depression in all of the assays. A range of drug concentration of EMP, 1 to 10 mumol/L, in which cell invasiveness was successfully inhibited, was comparable with antiproliferative capacity. CONCLUSION: The data add to the findings that EMP not only offers selective antiproliferative activity against glioblastoma but also reduces invasiveness, consistent with its main mechanism of action. Such findings form the basis for the development of agents that use non-DNA targets for the treatment of glioblastomas and may improve control over tumor proliferation and invasion.

BEHAB (brain enriched hyaluronan binding) is expressed in surgical samples of glioma and in intracranial grafts of invasive glioma cell lines.

Malignant gliomas aggressively invade the surrounding normal brain, whereas brain metastases of nonglial tumors do not. The invasive behavior of gliomas may be mediated by tissue- or tumor-specific extracellular proteins. mRNA for the brain-specific extracellular brain enriched hyaluronan-binding protein (BEHAB) is not detectable in normal adult human cortex or in any nonglioma tumor examined. BEHAB is consistently expressed in surgical samples of glioma (n = 27). Glioma cell lines maintained under standard cell culture conditions or grown as s.c. tumors do not express BEHAB. When grown as intracranial grafts, glioma cell lines that invade the brain express BEHAB, whereas noninvasive cell lines do not. BEHAB is a unique and selective marker for glioma and may play a role in tumor invasion.

In vitro and in vivo inhibition of glioblastoma and neuroblastoma with MDL101731, a novel ribonucleoside diphosphate reductase inhibitor.

We examined the effects of MDL101731, a novel ribonucleoside reductase inhibitor, against human glioblastomas and neuroblastoma, both in vitro and in xenograft models, to determine its activity against malignant brain tumors. MDL101731 produced a concentration-dependent inhibition of both glioblastoma cell lines (HS683 and J889H) and neuroblastoma (SK-N-MC) in nanomolar concentrations (IC50, 30-90 nM). s.c. xenografts of human glioblastoma (D54) in athymic mice increased to five times their initial volume at a median of 7.4 days in control animals, while tumor regression occurred in 12 of 12 animals treated with MDL101731 (100 mg/kg, i.p., two times/week) during 22 days of treatment (P < 0.0001). Intracerebral implants of D54 carried a median survival of 20 days in control animals, whereas animals receiving MDL101731 (100 mg/kg, i.p., two times/week, days 10-35) had a median survival of 46.5 days (P < 0.0001). Intracerebral xenografts of SK-N-MC in athymic mice resulted in a median survival of 23 days in control animals and 26 days in animals treated with carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea 20 mg/kg/week, i.v. x 2; difference not significant). There was 90% survival in animals treated with MDL101731 (200 mg/kg, i.v., two times/week, days 7-35) up to 90 days after implant. These studies indicate that MDL101731 has potent antiproliferative activity against human malignant brain tumors.

Yale neurosurgery program.

Organized neurosurgery at Yale began in 1918 with Dr. Sam Harvey. In 1928, Dr. William German became the first surgeon at Yale who was dedicated to neurosurgery. Both of these surgeons were trained by Harvey Cushing, and upon the arrival of Drs. Cushing and Eisenhardt in 1934, Yale developed a strong tradition in surgery of the nervous system. In 1967, Dr. William Collins established a training program for residents that integrated laboratory research and clinical experience. This tradition has continued under the guidance of Dr. Dennis Spencer since 1987. This article provides a brief overview of the history of neurosurgery at Yale, its current practice, and plans for the future.

Verapamil treatment attenuates immunoreactive GFAP at cerebral cortical lesion site.

Cerebral cortical lesions were produced using a stereotactic injection system in Sprague-Dawley rats randomly assigned to three groups: (1) needle lesioned and uninjected (Lesioned), (2) needle lesion and simultaneous local injection of 50 or 100 microliters 0.9% saline (L/Saline), and (3) needle lesion and simultaneous local injection of 50 or 100 microliters Verapamil-HCl (VHCL) (2.5 mg/ml (5 mM) Abbott Labs, Chicago, IL), a passive, L-type calcium channel blocker (L/VHCL). The lesioning induced expression of glial fibrillary acidic protein (GFAP), a type of intermediate filament protein expressed in reactive astrocytes, at the lesion site. There was a reduction in GFAP-like immunoreactivity (GFAP-IR) in the L/VHCL group versus the Lesioned and the L/Saline groups. There was a five-fold increase of GFAP-IR at 24 h post lesion in the L/Saline group, but no statistically significant increase seen in the Lesioned or L/VHCL groups at either volume. Pretreatment of the anti-GFAP with VHCL did not impair the antigen labeling. To determine whether differences in pHs, or volume could account for these findings, a second experiment was performed using pH-matched saline or VHCL in 10 microliters volume injected into contralateral hemispheres at the time of lesioning. There was an 80% reduction in GFAP-IR in the L/VHCL group at 72 h compared with the L/Saline group. These data suggest that VHCL may suppress the early increase of GFAP-IR in response to cortical lesion and that reducing transmembrane calcium flux through L-type calcium channels may be the mechanism involved.