Adult brainstem glioma presenting with isolated persistent hemifacial spasm or facial nerve palsy.

OBJECT: Adult brainstem gliomas are a rare group of heterogeneous brain tumors. Classical clinical presentation includes progressive impairment of cranial nerves associated with long tract signs. The prognosis and response to treatment are poor; nevertheless, some patients do have a long survival. The objective of this study was to describe a series of patients with an isolated persistent hemifacial spasm and/or facial nerve palsy as the presenting symptom of a brainstem glioma. METHODS: Fourteen patients from 3 French hospitals (Paris, Caen, Lille) were included. Clinical and radiological features and overall survival were retrospectively analyzed. A review of the literature of similar cases was performed. RESULTS: Mean age at diagnosis was 35 years (range 19-57 years). Mean duration of facial nerve involvement before diagnosis was 17 months (range 1-48 months). Tumors were characterized on MRI by a lateralized location in the pons, a T1-weighted hyposignal, a T2-weighted hypersignal and no contrast enhancement after Gadolinium injection except for 2 cases. Biopsies were performed in 10 cases and showed 8 low-grade and 2 high-grade gliomas. All the patients were initially treated with radiotherapy and 6 patients with chemotherapy after progression. Eleven patients died from tumor progression. Median survival time was 90 months. CONCLUSIONS: Adult brainstem gliomas revealed by a progressive isolated involvement of the facial nerve seem to have particular clinico-radiological features of slow progressive tumors and may be associated with long patient survival.

[(18)F]-fluoro-L-thymidine PET and advanced MRI for preoperative grading of gliomas.

PURPOSE: Conventional MRI based on contrast enhancement is often not sufficient in differentiating grade II from grade III and grade III from grade IV diffuse gliomas. We assessed advanced MRI, MR spectroscopy and [(18)F]-fluoro-l-thymidine ([(18)F]-FLT) PET as tools to overcome these limitations. METHODS: In this prospective study, thirty-nine patients with diffuse gliomas of grades II, III or IV underwent conventional MRI, perfusion, diffusion, proton MR spectroscopy ((1)H-MRS) and [(18)F]-FLT-PET imaging before surgery. Relative cerebral blood volume (rCBV), apparent diffusion coefficient (ADC), Cho/Cr, NAA/Cr, Cho/NAA and FLT-SUV were compared between grades. RESULTS: Cho/Cr showed significant differences between grade II and grade III gliomas (p = 0.03). To discriminate grade II from grade IV and grade III from grade IV gliomas, the most relevant parameter was the maximum value of [(18)F]-FLT uptake FLTmax (respectively, p < 0.001 and p < 0.0001). The parameter showing the best correlation with the grade was the mean value of [(18)F]-FLT uptake FLTmean (R(2) = 0.36, p < 0.0001) and FLTmax (R(2) = 0.5, p < 0.0001). CONCLUSION: Whereas advanced MRI parameters give indications for the grading of gliomas, the addition of [(18)F]-FLT-PET could be of interest for the accurate preoperative classification of diffuse gliomas, particularly for identification of doubtful grade III and IV gliomas.

Randomized phase II trial of irinotecan and bevacizumab as neo-adjuvant and adjuvant to temozolomide-based chemoradiation compared with temozolomide-chemoradiation for unresectable glioblastoma: final results of the TEMAVIR study from ANOCEF†.

BACKGROUND: Prognosis of unresectable glioblastoma (GB) remains poor, despite temozolomide (TMZ)-based chemoradiation. Activity of bevacizumab (BEV) and irinotecan (IRI) has been reported in recurrent disease. We evaluated BEV and IRI as neo-adjuvant and adjuvant treatment combined with TMZ-based chemoradiation for unresectable GB. PATIENTS AND METHODS: Patients with unresectable GB, age 18-70, IK ≥50 were eligible. The experimental arm (BEV/IRI) consisted of neo-adjuvant intravenous BEV, 10 mg/kg, and IRI, 125 mg/m(2), every 2 weeks for four cycles before radiotherapy (RT) (60 Gy), concomitant oral TMZ, 75 mg/m(2)/day, and BEV, 10 mg/kg every 2 weeks. Adjuvant BEV and IRI were given every 2 weeks for 6 months. The control arm consisted of concomitant oral TMZ, 75 mg/m(2)/day during RT, and 150-200 mg/m(2) for 5 days every 28 days for 6 months. The use of BEV was allowed at progression in the control arm. RESULTS: Patients (120) were included from April 2009 to January 2011. The working hypothesis was that treatment would increase the progression-free survival at 6 month (PFS-6) from 50% to 66%. The primary objective was not achieved, and only 30 out of 60 patients were alive without progression at 6 months (50.0% [IC95% (36.8; 63.1)] in the BEV/IRI arm when 37 out of 60 patients were required according to the Fleming decision rules. PFS-6 was 7.1 months in BEV/IRI versus 5.2 months in the control arm. The median overall survival was not different between the two arms (11.1 months). Main toxicities were three fatal intracranial bleedings, three bile duct or digestive perforations/infections (1 fatal), and six thrombotic episodes in the BEV/IRI arm, whereas there was one intracranial bleeding, two bile duct or digestive perforations/infections (1 fatal), and one thrombotic episode in the control arm. CONCLUSIONS: Neo-adjuvant and adjuvant BEV/IRI, combined with TMZ-radiation, is not recommended for further evaluation in the first-line treatment of unresectable GB. CLINICAL TRIAL REGISTRATION: Clinical trial registered under EUDRACT number 2008-002775-28 (NCT01022918).

[Anti-angiogenic strategies in glioblastoma]. / Stratégies anti-angiogéniques dans le glioblastome.

INTRODUCTION: Glioblastoma, a highly angiogenic tumor, has poor prognosis despite aggressive conventional therapies combining surgery, chemotherapy and radiotherapy. Anti-angiogenic strategies that have recently come to the clinic, are the most promising therapeutic approaches for these tumors. STATE OF ART: Tumor hypoxia is the main trigger of angiogenesis processes driven primarily by vascular endothelial growth factor (VEGF). Clinical data indicate that inhibitors of VEGF such as bevacizumab or VEGF receptors such as tyrosine kinase inhibitors are of potential interest in the treatment of recurrent glioblastoma, with an acceptable toxicity. However, despite high rate of initial radiological response and rapid clinical improvement in about half of patients, therapeutic failure is the rule. Mechanisms of resistance remain poorly understood but an invasive phenotype and alternative angiogenesis factors may contribute to tumor escape. CONCLUSIONS AND PERSPECTIVES: Anti-angiogenic strategies already play an important role in the management of recurrent glioblastoma. However, optimal combination and schedules of angiogenic inhibitors with radiotherapy and chemotherapy remain to be established. Important randomized clinical trials currently investigate therapeutic combinations for newly diagnosed glioblastoma.

Five-Year Longitudinal MRI Follow-up and (1)H Single Voxel MRS in 14 patients with Gliomatosis Treated with Temodal, Radiotherapy and Antiangiogenic Therapy.

Gliomatosis cerebri (GC) is a challenging tumor, considered to have a poor prognosis and poor response to treatments. The purpose of this study is to better understand glial tumor metabolism and post chemotherapy, radiotherapy and antiangiogenic variations in a longitudinal study to determine cerebral variation in MRS area, amplitude, and ratios of metabolites and spectral profiles during a five year longitudinal follow-up in 14 patients with gliomatosis without initial hyperperfusion and treated with chemotherapy (Temozolomide (Temodal(®))), radiotherapy and subsequent antiangiogenic therapy. The study also aimed to detect changes in infiltration, proliferation, lipids or glycolytic metabolism, as these changes could be monitored longitudinally in humans with glial brain tumors (low and high grade) after therapy, using conventional magnetic resonance imaging (MRI), spectroscopy (MRS) and MR perfusion. Most patients had first initial clinical and MRS improvement and stable MRI. After 12 to 24 chemotherapy treatment cycles MRS usually showed an increase in the Cho/Cr ratio (proliferation) and sometimes contrast enhancements. Later, the patients showed clinical deterioration and radiotherapy was started. There was an improvement with radiotherapy that lasted nine to 18 months. This was followed by a worsening that led to try antiangiogenic therapy. Later in the evolution for three patients with hyperperfusion this symptom disappeared, but proliferation, infiltration and glycolytic metabolism remained at a high level. Spectroscopic and metabolic changes often occur well before clinical deterioration and sometimes before improvement. Therefore, MRS could be more sensitive and could detect changes earlier than MRI and is sometimes predictive. Despite the difficulty, the variability and unknown factors, these repeated measurements give us a better insight into the nature of the different processes, tumor progression and could lead to better understanding of therapeutic response.

[Current management of brain metastases]. / Traitement actuel des métastases cérébrales.

INTRODUCTION: Cerebral metastases occur in 15 to 20% of cancers and their incidence is increasing. The majority occur at an advanced stage of the disease, but metastasis may be the inaugural sign of cancer. The aim of treatments, which are often palliative, is to preserve the neurological status of the patient with the best quality of life. STATE OF ART: Corticosteroids are widely used for symptomatic palliation, requiring close monitoring and regular dose adaptation. Antiepileptic drugs should be given only for patients who have had a seizure. In case of multiple cerebral metastases occurring at an advanced stage of the disease, whole brain radiation is the most effective therapy for rapid symptom control. However, radiotherapy moderately improves overall survival, which often depends on the progression of disseminated systemic disease. On the contrary, surgery is indicated in case of a solitary metastasis, particularly when the patient is young (less than 65 years), with good general status (Karnofsky greater than 70), and when the systemic disease is under control. Radiosurgery offers an attractive alternative for these patients with good prognostic factors and a small number of cerebral metastases (< or = 4). PERSPECTIVES: Chemotherapy, considered in the past as not effective, is taking on a more important place in patients with multiple nonthreatening metastases from chemosensitive cancers (breast, testes...). Radiosurgery and whole brain radiotherapy are complementary techniques. Their respective role in the management of multiple metastases (< 4) remains to be further investigated. CONCLUSIONS: Therapeutic options are increasingly effective to improve the functional prognosis of patients with cerebral metastases. Ideally, a multidisciplinary assessment offers the best choice of therapeutic modalities.

[Bevacizumab/irinotecan. An active treatment for recurrent high grade gliomas: preliminary results of an ANOCEF Multicenter Study]. / Bevacizumab/irinotecan. Un nouveau traitement actif dans les gliomes de haut grade récidivants: résultats préliminaires d'une étude multicentrique de l'Anocef.

RATIONALE: Second-line chemotherapy is disappointing in recurrent high-grade gliomas. Dramatic responses in recurrent high-grade gliomas have been reported in a recent monocentric trial with a novel association combining bevacizumab (anti-VEGF monoclonal antibody agent) and irinitecan. OBJECTIVE: To report the experience of the ANOCEF group (French speaking neuro-oncology association) using the bevacizumab-irinotecan combination in recurrent high-grade gliomas. METHODS: Eight centers were involved in this retrospective multicenter study. Bevacizumab-irinotecan was delivered as previously described in a compassional setting to non-selected patients suffering from a high-grade glioma (WHO grade III and IV). Response rate at two months of the onset of the treatment was analyzed using the Macdonald criteria. The toxicity profile of the treatment was also investigated. RESULTS: From 2006 to 2007, 77 patients were treated (median age: 52 years; median Karnofsky score: 70) for a recurrent high-grade glioma (49 grade IV, 28 grade III). At two months, the response rates were objective response=36% (54% in grade III and 27% in grade IV); stable disease=39%; progressive disease=13%; patients not evaluable because of a rapid fatal clinical deterioration=12%. Improvement was noted in 49% of patients. Among the main toxicities, we noted; intratumoral hemorrage (n=5 with spontaneous regression in three) and thromboembolic complications including venous thrombophlebitis (n=4), pulmonary embolism (n=2), myocardial infarction (n=1), grade III-IV hematotoxicity (n=2), reversible leukoencephalopathy (n=1). CONCLUSION: This retrospective multicenter study adds further arguments in favor of the promising results of this new combination and its potential rapidity of action in recurrent high-grade gliomas. Antiangiogenic agents expose the patients to a well-known risk of thromboembolic and hemorragic complications, necessitating careful follow-up and patient selection in light of the cardiovascular contraindications.

Dose-dense regimen of temozolomide given every other week in patients with primary central nervous system tumors.

BACKGROUND: Temozolomide has shown activity and limited toxicity in patients with primary brain tumors at doses of 150-200 mg/m(2)/day on days 1-5 every 4 weeks. In this study, a new alternative dose-dense regimen of temozolomide was explored in patients with recurrent brain tumors. PATIENTS AND METHODS: In this study, we evaluated the safety, dose-limiting toxicity, maximum tolerated dose, recommended dose and activity of temozolomide given on days 1-3 and 14-16 every 28 days (one cycle). The starting daily dose was 200 mg/m(2) in a group of at least six patients, with subsequent increments of 50 mg/m(2) in groups of at least 12 patients until unacceptable toxicity was reached. Oral ondansetron (8 mg) was given 1 h prior to temozolomide administration. McDonald's criteria were used to evaluate antitumor activity. RESULTS: Seventy patients with brain tumors entered this study. The median number of prior chemotherapy treatments was two (range 1-3). Patients were assigned to one of four groups to receive temozolomide at daily doses of 200 (seven patients), 250 (13 patients), 300 (38 patients) and 350 mg/m(2)/day (12 patients). The absence of dose-limiting toxicity at cycle 1 led us to establish dose recommendations based on toxicity after repeated cycles. A total of 23, 72, 192 and 83 cycles were given at daily doses of 200, 250, 300 and 350 mg/m(2), respectively. Grade 3-4 thrombocytopenia was observed in 0/7, 1/13, 5/38 and 4/12 patients treated at doses of 200, 250, 300 and 350 mg/m(2)/day, respectively. Grade 3-4 neutropenia was observed in 1/7, 0/13, 3/38 and 4/12 patients treated with 200, 250, 300 and 350 mg/m(2)/day temozolomide, respectively. At a dose of 350 mg/m(2), sustained grade 2-3 thrombocytopenia did not allow treatment to be resumed at day 14 in >40% of patients, and this dose was considered to be the maximum tolerated dose. Thus, a dose of 300 mg/m(2)/day that was associated with <20% treatment delay due to sustained hematological toxicity was considered as the recommended dose. Objective responses were reported in 13 patients. CONCLUSIONS: Temozolomide can be given safely using a dose-dense regimen of 300 mg/m(2)/day for 3 consecutive days every 2 weeks in patients with recurrent brain tumors.

Brain stem gliomas.

Brainstem gliomas are now regarded as a heterogeneous group of tumors that can be distinguished by age of onset, clinical and radiological presentation and biological behavior. This paper will focus on each subtype of tumor, in children and in adults, and on recent advances in diagnostic criteria and therapeutic options.

Brainstem gliomas in adults: prognostic factors and classification.

In contrast to childhood brainstem gliomas, adult brainstem gliomas are rare and poorly understood. The charts of 48 adults suffering from brainstem glioma were reviewed in order to determine prognostic factors, evaluate the effect of treatment and propose a classification of these tumours. Mean age at onset was 34 years (range 16-70 years). The main presenting symptoms were gait disturbance (61%), headache (44%), weakness of the limbs (42%) and diplopia (40%). Four patterns were identified on MRI, representing non-enhancing, diffusely infiltrative tumours (50%), contrast-enhancing localized masses (31%), isolated tectal tumours (8%) and other patterns (11%). Treatment consisted of partial resection (8%), radiotherapy (94%) and chemotherapy (56%). Overall median survival was 5.4 years. On univariate analysis, the following favourable prognostic factors were identified (P< 0.01): age of onset <40 years, duration of symptoms before diagnosis >3 months, Karnofski performance status >70, low-grade histology, absence of contrast enhancement and 'necrosis' on MRI. On multivariate analysis, the duration of symptoms, the appearance of 'necrosis' on MRI and the histological grade of the tumour remained significant and independent prognostic factors (P< 0.05). Eighty-five percent of the tumours could be classified into one of the following three groups on the basis of clinical, radiological and histological features. (i) Diffuse intrinsic low-grade gliomas (46%) usually occurred in young adults with a long clinical history before diagnosis and a diffusely enlarged brainstem on MRI that did not show contrast enhancement. These patients were improved by radiotherapy in 62% of cases and had a long survival time (median 7.3 years). Anaplastic transformation (appearance of contrast enhancement, 27%) and relentless growth without other changes (23%) were the main causes of death. (ii) Malignant gliomas (31%) occurred in elderly patients with a short clinical history. Contrast enhancement and necrosis were the rule on MRI. These tumours were highly resistant to treatment and the patients had a median survival time of 11.2 months. (iii) Focal tectal gliomas (8%) occurred in young patients and were often revealed by isolated hydrocephalus. The course was indolent and the projected median survival period exceeded 10 years. In conclusion, adult brainstem gliomas are different from the childhood forms and resemble supratentorial gliomas in adults. Low-grade tumours have a clinicoradiological pattern that is so characteristic that the need for a potentially harmful biopsy is debatable. The optimum timing of treatment for supratentorial low-grade tumours remains unclear. In high-grade gliomas, the prognosis remains extremely poor despite aggressive treatment with radiotherapy and chemotherapy.

Migration pathways of human glioblastoma cells xenografted into the immunosuppressed rat brain.

Diffuse invasion of the brain by tumor cells is a hallmark of human glioblastomas and a major cause for the poor prognosis of these tumors. This phenomenon is only partially reproduced by rodent models of gliomas that display a very high rate of proliferation and limited cell migration. We have analyzed the development of human glioblastoma cells (GL15) xenografted into the brain of immunosuppressed rats, in order to define the characteristics of tumor cell invasion. As identified by the specific immunolabeling of the tumor cells for the human HLA-ABC antigen, GL15 tumors reproduced the three types of intraparenchymal invasion observed in patients. First, a majority of multipolar tumor cells intermingled rapidly and profusely with host neural cells in the margin of the injection site. This progressively enlarging area was principally responsible for the tumor growth over time. Second, in the gray matter, columns of thin bipolar tumor cells aligned along capillary walls. Third, in the white matter, elongated bipolar isolated tumor cells were observed scattered between axonal fibers. The maximum migration distances along white matter fibers remained significantly higher than the maximum migration distances along blood vessels, up to two months after injection. Development of the tumor was associated with a significant increase of vascularization in the area of tumor spread. Xenografting of human GL15 glioblastoma cells into the immunosuppressed rat brain allowed to differentiate between the three classical types of invasion identified in the clinic, to quantify precisely the distances of migration, and to evaluate cell morphology for each of these routes. The present results support the existence of host/tumor cells interactions with specific characteristics for each type of invasion.

Vascular endothelial growth factor expression in oligodendrogliomas: a correlative study with Sainte-Anne malignancy grade, growth fraction and patient survival.

Microangiogenesis is a delayed but crucial event in the malignant progression of oligodendrogliomas. Accord-ingly, in the new Sainte-Anne grading system of oligodendrogliomas, endothelial hyperplasia and contrast enhancement, both being indicators of microangiogenesis, are key criteria for the distinction of grade A from grade B tumours. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor: a strong correlation between VEGF expression, Sainte-Anne malignancy grade and patient outcome might thus be expected. In order to assess this hypothesis, VEGF immunostaining was performed in a series of 34 oligodendrogliomas that included 11 grade B and 23 grade A, of which nine became grade B during the study period (mean clinical and imaging follow-up: 41 months). VEGF expression correlated strongly with Sainte-Anne tumour grade (P < 0.001), and inversely with patient survival (P < 0.001) and recurrence-free survival (P = 0.002). One hundred per cent of grade B but only 17% of grade A were VEGF-positive. By contrast, the MIB-1 labelling index did not correlate with VEGF expression, total survival or recurrence-free survival. In accordance with the grading system, this study showed that, in oligodendrogliomas, VEGF expression and microangiogenesis are progression-related phenomena that confer on these tumours a growth advantage by presumably reducing hypoxia-induced apoptotic cell death. These findings might have important implications in the future for the indication and timing of anti-angiogenic therapies.

[Acute transverse cervical myelitis following hepatitis B vaccination. Evolution of anti-HBs antibodies]. / Myélite transverse aiguë cervicale après vaccination contre le virus de l'hépatite B. Evolution sérologique des anticorps anti-HBs.

BACKGROUND: The cause and effect relationship between anti-HBV immunization using recombinant vaccine and the development of a neurological event, including flare-ups of multiple sclerosis, is a widely debated issue. CASE REPORT: A previously asymptomatic 16-year-old girl was a hyper-responder to anti-HBV vaccine. Subsequent to a booster shot of anti-HBV recombinant vaccine, she developed regressive acute cervical transverse myelitis with intrathecal oligochonal IgG secretion and a hypersignal on the MRI T2 sequences of the cord. DISCUSSION: The distinction between a first episode of multiple sclerosis or post-vaccinal acute myelitis in this case will depend upon subsequent course, but this observation points out the very high level of persistent post-vaccinal immunization which can be acquired by a hyper-responder.