Growth pattern of tumor recurrence following bis-chloroethylnitrosourea (BCNU) wafer implantation in malignant glioma.

Bis-chloroethylnitrosourea (BCNU; Gliadel, Eisai, Tokyo, Japan) is the only therapeutic agent for local chemotherapy of malignant gliomas approved by the US Food and Drug Administration and the European Medicines Agency. In a small patient cohort, it has previously been shown that glioblastomas recur locally despite treatment with BCNU. This raises concern about local treatment with BCNU as a stand-alone measure. The goal of this study was to analyze the growth pattern of tumor recurrence in a larger patient group: 41 patients were included in this study. Tumor recurrences were morphologically categorized as: local, diffuse, distant or multilocular. Thirty-three of the tumors (80%) that recurred were local or diffuse. These results show that BCNU implantation does not provide lasting local tumor control. Our data support the need to incorporate BCNU in to multimodal therapy schemes. The improved survival rates of patients who receive concomitant local and systemic adjuvant treatment support using local therapy to bridge the therapy-free interval of the initial postoperative phase.

Temporal changes in magnetic resonance imaging characteristics of Gliadel wafers and of the adjacent brain parenchyma.

Carmustine is used in the treatment of glioblastomas as locally applied chemotherapy in the form of biodegradable wafers, which are lined on the walls of the resection cavity at the end of the resection, to increase local concentrations and decrease systemic toxicity. A total of 44 patients with glioblastoma with gross macroscopic tumor removal were included. MRIs were performed at various times postoperatively (within 24 hours, 1 week, 1 month, 2 months, 3 months, 6 months, 9 months, and 1 year). MR protocols included a T2-, diffusion-weighted, and T1-weighted sequences with and without intravenous administration of gadolinium. On T1, the wafers change from their initial hypointense to an isointense appearance after a period during which they appear to be hypointense, with a hyperintense rim most prominent less than 1 month postoperatively. On T2 they change from a hypointense to an isointense appearance. Restricted diffusivity reshaping the silhouette of the wafer's surface at the rim of the resection cavity can be found as early as day 1 postoperatively; however, 1 month after implantation, they all show areas of restricted diffusion, which may remain up to 1 year. Contrast enhancement at the rim of the resection cavity can already be found at day 1 postoperatively, with a peak shortly after 1 month after surgery. These changes can easily be mistaken for an abscess and hamper the early differentiation between residual tumor tissue and normal postoperative changes. However, early changes in either appearance do not predict overall survival or the progression free interval.

Space-occupying cyst development in the resection cavity of malignant gliomas following Gliadel® implantation--incidence, therapeutic strategies, and outcome.

Gliadel® (Eisai Inc., Woodcliff Lake, NJ, USA) is the only therapeutic agent approved by the Food and Drug Administration and the European Medicines Agency for local chemotherapy of malignant gliomas. With increasing use of this treatment, characteristic side effects have become evident. While most side effects can be managed conservatively, cyst formation requires further intervention. From 2004 to 2009 at our institution 88 patients with malignant gliomas were treated with Gliadel®. Ten patients (11%) developed a space-occupying cyst in the resection cavity, seven of which caused clinical symptoms of mass effect that was most prominent 2 weeks after Gliadel® implantation (median=16, range=9-30). Despite dexamethasone treatment symptoms progressed, necessitating various surgical interventions. In four patients the cysts were drained percutaneously through a burrhole using a 19-gauge needle. If puncture was not possible (three patients) or not sufficient (two patients), an Ommaya reservoir was implanted for repetitive drainage. In two patients this treatment was combined with open decompression of the cyst. On average, cysts were drained three times. Eventually the symptoms subsided, corresponding to shrinkage of the cysts as shown on follow-up imaging. We describe a serious side effect of local chemotherapy, which may cause rapid clinical deterioration and require direct intervention. While reservoir implantation apparently represents a more elegant treatment option, our experience shows that draining the cyst, even only a few times, sufficiently ameliorates the symptoms and subsequently reverses and halts further cyst enlargement.

High-field iMRI in glioblastoma surgery: improvement of resection radicality and survival for the patient?

Since the first patients underwent intracranial tumor removal with the radicality control of intraoperative MRI (ioMRI) in September 2005 in our department, the majority of operations performed in the ioMRI room have been indicated for high grade gliomas. In order to elucidate the role of ioMRI scanning in patients harboring high-grade gliomas (HGG) on their survival, one hundred ninety three patients with gliomas WHO grades III and IV were operated either in a standard microsurgical neuronavigated fashion or using additionally ioMRI and were included in a follow-up study. The series started with surgeries from September 2005 until October 2007. Patient attribution to the two groups was based on the logistical availability of the ioMRI on a scheduled surgery day, and on the assumed "difficulty" of the surgery based on the location of the glioma in or near to an eloquent area. Surgery was intended to be as radical as possible without reduction of quality of life. First surgery was performed in 103 patients (75 WHO IV and 28 WHO III) and will be the main topic of this paper. In 60 patients, ioMRI was used, while in 43 patients standard microsurgical neuronavigated resection techniques were applied. Patients were followed in regular intervals mostly until death. Statistical analysis showed a median survival time for patients in whom ioMRI had been used of 20, 37 months compared to 10, 3 months in the cohort who had undergone conventional microsurgical removal. Major influencing concomitants were WHO grades and age which were balanced in both groups.

Incorporating BCNU wafers into malignant glioma treatment: European case studies.

Carmustine (BCNU: N,N'-bis[2-chloroethyl]-N-nitrosourea) wafers are a local chemotherapeutic agent for the treatment of malignant glioma. They avoid the problems of high toxicity and short half-life associated with systemic delivery, and can bridge the traditional 'treatment gap' between surgery and subsequent conventional chemo- or radiotherapy. Clinical trials have demonstrated significant improvements in survival and quality of life for patients after complete tumour resection and BCNU wafer implantation. In practice, clinicians may use BCNU wafers in conjunction with other radio- and chemotherapies, in order to maximize the chance of a beneficial patient outcome. The purpose of these case reports is to exemplify how four experienced European clinicians employ BCNU wafers for the management of malignant glioma, and to illustrate how BCNU wafers can be effectively incorporated into treatment regimens. Four patients are described in whom BCNU wafers were implanted during the course of treatment for glioblastoma multiforme, the most severe and common type of malignant glioma. These include three patients with recurrent disease, and a single patient with a newly diagnosed tumour. All four patients received additional radio- and chemotherapy as appropriate. Treatment was well tolerated and patient survival from diagnosis ranged from 56 to 132 weeks. This compared favourably with the survival of approximately 58 weeks seen in the recent EORTC-NCIC clinical trial of combined radiotherapy with concomitant and adjuvant temozolomide. BCNU wafers are an effective means of increasing survival and quality of life in patients diagnosed with malignant glioma, and are a valuable addition to the overall multimodal treatment strategy for these tumours.

Intraoperative MRI with 1.5 Tesla in neurosurgery.

1.5 Tesla High-field MRI has been successfully integrated into operating theatres. State-of-the-art microneurosurgical equipment and computer-assisted navigation are merged with the MR to form a comprehensive unit. The set-up of an intraoperative MRI solution is delineated with special regards to the workflow.

A case of rapid-growing anaplastic meningiomas.

Meningiomas are tumours originating from the leptomeningeal covering of the brain and spinal cord and are generally benign and slow growing. Rarely, they show malignant anaplastic characteristics with a high recurrence rate. A number of factors have been reported to predict this high recurrence. Such factors are histopathological ones, such as necrosis and hypercellularity, the World Health Organization (WHO) grade, mitotic index, positivity of proliferation markers (Ki-67 or MIB-1), clinical parameters such as age, gender, localisation, cytogenetic factors and radiation treatment. The present case reports a patient with a giant meningioma over the right frontal lobe who had almost all possible negative prognostic parameters and showed an explosive multifocal recurrence in a timespan of about 5 months.

Primary diffuse leptomeningeal gliomatosis in a 2-year-old girl.

BACKGROUND: Primary diffuse leptomeningeal gliomatosis is a rare tumor disease affecting the leptomeninx of the CNS. It is thought to originate from subarachnoidal glial cell nests. The symptoms are often rather unspecific. Surgery is not an option and despite the use of chemotherapy and radiotherapy patients rarely survive for more than 12 months. CASE DESCRIPTION: We present a case of PDLG in a 2-year-old girl, the youngest patient reported on so far. She presented with increasing somnolence, intermittent strabism, and vomiting. Magnetic resonance imaging of the cranium showed enlarged ventricles and contrast enhancement of the basal leptomeninx. Cerebrospinal fluid diagnostic studies showed a mild pleocytosis and elevated protein levels but no tumor cells or evidence of infection. A ventriculoperitoneal shunt was placed and a biopsy of the leptomeninx was taken in the right Sylvian fissure. The histopathology findings suggested a nonspecific meningeal inflammation. Because the girl developed spinal symptoms with paresthesia and hyperalgesia, a spinal MRI was performed which showed a similar contrast enhancement of the spinal leptomeninx. A spinal biopsy was taken and subsequently a paucicellular astrocytic tumor was diagnosed corresponding to a WHO I diffuse leptomeningeal gliomatosis. Chemotherapy with vincristine, carboplatin, and etoposide was initiated (Protocol SIOP-LGG 2004) but was stopped by the parents when the child was in partial remission after 50 weeks because of a neurologic deterioration. The girl has so far survived for more than 29 months. CONCLUSION: Primary diffuse leptomeningeal gliomatosis must be included in the differential diagnosis of diffuse leptomeningeal contrast enhancement in young children. There are promising treatment options that need to be carefully evaluated.

Posterior fossa tumors in children: how long does it take to establish the diagnosis?

OBJECTIVE: The aim of this study is to evaluate, for our patient population, the time interval from the first chart-documented symptom to the radiological diagnosis in children and infants with posterior fossa tumors. MATERIALS AND METHODS: We retrospectively analyzed 50 consecutive children (36 men, 14 women) with posterior fossa tumor treated at our department between January 1999 and December 2003. The mean age at time of diagnosis was 98 months (6 months-16 years). The mean follow up was 27 months (6-61 months). The diagnoses included astrocytoma (n = 17), medulloblastoma (n = 15), ependymoma (n = 6), and other tumors (n = 12). RESULTS: The mean time interval between onset of symptoms and radiographic diagnosis was 142 days (5-535 days), the median was 59 days. The mean time for Grade I and II tumors was 238 days (n = 19) and for tumors Grade III and IV 117 days (n = 31). The most common presenting symptoms were headache, nausea, vomiting, ataxia, and oculomotor deficits. Approximately half of the patients were initially diagnosed and treated for other diseases (gastrointestinal infection, appendicitis, psychological behavioral problems, cervical spine strains, different ophthalmologic entities). Specialists (ophthalmologists, orthopedics) tended to diagnose and treat their specific diagnoses (e.g., strabism, torticollis). Parents play a significant role in the process of establishing the correct diagnosis. CONCLUSION: We conclude that further information and education regarding symptomatology and diagnosis of posterior fossa tumors in children is necessary. Communication has to be improved between parents and referring physicians of all specialties and neurosurgeons.

De novo development of intraosseous cavernous hemangioma.

Intraosseous cavernous hemangiomas are rare and not often multifocal. De novo development of a skull cavernous hemangioma has not been described previously. We present a 20-year-old man who was operated upon for a skull cavernoma in the right frontal area and developed a new lesion 3 years later in the right occipital region. The first lesion was removed completely and the postoperative course was uneventful. Histology showed an intraosseous cavernous hemangioma. MRI follow-up revealed a new lesion in the right occipital region. At the time of the first operation this lesion was not seen on CT or MRI scan. Surgical removal was performed and histology again showed a cavernous hemangioma. The patient seems to be unique and it is important to keep young patients with the diagnosis of cavernous hemangioma under close follow-up. This supports the experience from parenchymatous cavernous hemangiomas that this malformation may become a dynamic disease.

Cannabinoid receptors in human astroglial tumors.

In animal models, cannabinoids are reported to inhibit the growth of tumors, including gliomas. These effects have been claimed to be mediated via cannabinoid receptors 1 and 2 (CB1, CB2). To elucidate a possible relevance for treatment of human gliomas, we investigated receptor subtype expression in surgical material of solid human astrocytomas, gliomas and cultivated glioma cells by quantitative reverse transcriptase polymerase chain reaction, western blot and immunohistochemistry and assayed their functionality. In normal brain, cultivated glioma cells and solid tumors, CB1 mRNA was expressed to a much greater extent than CB2, which in some samples was even undetectable. Expression of both receptor subtypes was unrelated to malignancy, varied between patients, and was not significantly increased in relation to normal brain tissues. In normal brain, CB1 protein was localized on astroglial and other cell types; in gliomas, it was found on astroglial/glioma cells. CB2 protein was detected on microglial cells/macrophages but rarely on astroglial cells. Functionally, CB1 receptor agonists reduced elevated cyclic AMP levels and slightly reduced proliferation of glioma cells in vitro, but did not induce apoptosis. We conclude that cannabinoid therapy of human gliomas targets not only receptors on tumor, but also on other cell types. Therefore, complex and potential side-effects should be considered carefully.

Management of tectal glioma in childhood.

Tectal glioma is a topographical diagnosis including tumors of different histology, mainly low-grade astrocytomas. Clinical symptoms are usually associated with increased intracranial pressure. This report discusses the management of this rare tumor in children. Clinical charts of 12 children with tectal glioma treated in our department between 1976 and 2001 were retrospectively reviewed. The mean age at the time of diagnosis was 6.75 years (range, 4 weeks to 16 years). The duration between first symptoms and the diagnosis of tectal glioma was in the range of 2 days to 9 years. Ten patients presented with symptoms associated with increased intracranial pressure, one patient presented with ataxia, and in one case tectal glioma was an incidental finding. First-line therapy was endoscopic third ventriculostomy in 5 cases (42%), ventriculoperitoneal shunting in 6 cases (50%), and combined partial tumor resection and shunting in one case. Histology was obtained in 5 cases (low-grade astrocytoma, n = 4; ependymoma, n = 1). All patients had good neurologic function at the end of follow-up. Tectal glioma represents a distinct subgroup of brainstem tumors associated with a good (or favorable) prognosis. Effective treatment for hydrocephalus is essential; the tumor should be monitored by regular clinical examination and magnetic resonance imaging. Biopsy is warranted in cases with tumor progression.

Treatment of intracranial broad-neck aneurysms with a new self-expanding stent and coil embolization.

BACKGROUND AND PURPOSE: Endovascular treatment of broad-neck intracranial aneurysms with detachable coils requires special techniques. Placement of a stent over the aneurysm neck and secondary coil embolization prevents coil migration and allows attenuated packing of the coils. However, access for the stent-delivery system can be technically limited in tortuous anatomy. We present six cases of broad-neck aneurysms treated with a new self-expanding stent and coil embolization. METHODS: Three aneurysms of the supraophthalmic internal carotid artery and three aneurysms of the basilar tip with extension to the origin of a posterior cerebral artery were treated. The stent was a new self-expanding stent with a 3F over-the-wire microcatheter delivery system. Coil embolization was performed with electrolytically detachable coils. Time-of-flight MR angiography was performed after treatment in five cases. Three other patients could not be treated with the stent because deployment was not possible after correct positioning of the delivery system. RESULTS: Access with the stent-delivery system was easy, and the aneurysm neck was covered sufficiently. After stent placement, total coil embolization was achieved in four and subtotal coil embolization was achieved in two. Parent arteries remained open, and no secondary coil migration was seen. On follow-up MR imaging, the stent was clearly visible and patency of the parent vessel and emerging branches was assessable. CONCLUSION: This new stent is a safe and efficient tool for the endovascular treatment of intracranial broad-neck aneurysms. Access to smaller vessels was easy, but the mechanism of deployment had to be improved. Follow-up MR imaging was sufficient.