Randomized phase II trial comparing axitinib with the combination of axitinib and lomustine in patients with recurrent glioblastoma.

Axitinib is a small molecule tyrosine kinase inhibitor with high affinity and specificity for the family of vascular endothelial growth factor receptors. It has previously demonstrated anti-tumor activity in a small cohort of patients with recurrent glioblastoma (rGB). We conducted a non-comparative randomized phase II clinical trial investigating axitinib monotherapy versus axitinib plus lomustine (LOM) in patients with rGB. Primary endpoint was 6 month progression-free survival (6mPFS). Patients who progressed on axitinib-monotherapy were allowed to cross-over. Between August 2011 and July 2015, 79 patients were randomized and initiated axitinib monotherapy (n = 50; AXI) or axitinib plus lomustine (n = 29; AXILOM). Median age was 55y [range 18-80], 50M/28F. Baseline characteristics were well balanced between study arms. Nineteen patients in the AXI-arm crossed-over at the time of progression. Treatment was generally well tolerated. AXILOM patients were at higher risk for grade 3/4 neutropenia (0 vs. 21%) and thrombocytopenia (4 vs. 29%). Best Overall Response Rate (BORR) in the AXI-arm was 28 vs. 38% in the AXILOM-arm. 6mPFS was 26% (95% CI 14-38) versus 17% (95% CI 2-32) for patients treated in the AXI versus AXILOM-arms, respectively. Median overall survival was 29 weeks (95% CI 20-38) in the AXI-arm and 27.4 weeks (95% CI 18.4-36.5) in the AXILOM-arm. MGMT-promoter hypermethylation and steroid treatment at baseline correlated significantly with PFS and OS. We conclude from these results that axitinib improves response rate and progression-free survival in patients with rGB compared to historical controls. There is no indication that upfront combination of axitinib with LOM improves results (European Clinical Trials Database (EudraCT) Study Number: 2011-000900-16).

Randomized phase II study of axitinib versus physicians best alternative choice of therapy in patients with recurrent glioblastoma.

We conducted a randomized, non-comparative, multi center, phase II clinical trial in order to investigate the efficacy of axitinib, an oral small molecule tyrosine kinase inhibitor with high affinity and specificity for the vascular endothelial growth factor receptors, in patients with recurrent glioblastoma following prior treatment with radiation and temozolomide. Forty-four patients were randomly assigned to receive treatment with axitinib (5 mg BID starting dose; N = 22) or "physicians best alternative choice of therapy" that consisted of bevacizumab (N = 20) or lomustine (N = 2). Six-month progression-free survival served as the primary endpoint. The estimated 6-month progression-free survival rate was 34 % (95 % CI 14-54) for patients treated with axitinib and 28 % (95 % CI 8-48) with best alternative treatment; median overall survival was 29 and 17 weeks, respectively. Objective responses according to RANO criteria were documented in 28 % of patients treated with axitinib and 23 % of patients treated with best alternative therapy. A decrease in maximal uptake of 18F-fluoro-ethyL-tyrosine (18F-FET) by the glioblastoma on PET imaging was documented in 85 % of patients at the time of response on axitinib. Corticosteroid treatment could be stopped in four and tapered in seven out of the 15 patients who were treated with steroids at baseline in the axitinib cohort. Most frequent axitinib related grade ≥3 adverse events consisted of fatigue (9 %), diarrhea (9 %), and oral hyperesthesia (4.5 %). We conclude that axitinib has single-agent clinical activity and a manageable toxicity profile in patients with recurrent glioblastoma.

Nasal heterotopia versus pilocytic astrocytoma: A narrow border.

Failure of the anterior neuropore can lead to three main types of anomalies: nasal dermal sinus, encephalocele and nasal glioma or heterotopia. In this report, we describe a case of intracranial and extracranial glial heterotopia that probably resulted from a common failure of anterior neuropore development. We describe the prenatal radiological assessment based on ultrasound and MRI results, and consider their limitation for early fetal diagnosis. We also discuss the embryogenesis and the possible pathogenic mechanisms involved.

Trigeminal melanoma metastasis.

We present the case of a 70-year-old patient presented to our institution for paresthesia of the right hemiface associated with dysarthria in aggravation since 1 year. He was diagnosed with right trigeminal melanoma metastasis. This case is characterized by a thickening of the right trigeminal nerve from his cisternal segment to his mandibular branch V3. MRI demonstrated an intensive perineural spread by a melanotic melanoma.

An observational study of the first experience with bevacizumab for the treatment of patients with recurrent high-grade glioma in two belgian university hospitals.

Background. Bevacizumab (BEV), a humanized immunoglobulin G1 monoclonal antibody that inhibits VEGF has demonstrated activity against recurrent high-grade gliomas (HGG) in phase II clinical trials. Patients and Methods. Data were collected from patients with recurrent HGG who initiated treatment with BEV outside a clinical trial protocol at two Belgian university hospitals. Results. 19 patients (11 M/8 F) were administered a total of 138 cycles of BEV (median 4, range 1-31). Tumor response assessment by MRI was available for 15 patients; 2 complete responses and 3 partial responses for an objective response rate of 26% for the intent to treat population were observed on gadolinium-enhanced T1-weighted images; significant regressions on T2/FLAIR were documented in 10 out of 15 patients (67%). A reduced uptake on PET was documented in 3 out of 4 evaluable patients. The six-month progression-free survival was 21% (95% CI 2.7-39.5). Two patients had an ongoing tumor response and remained free from progression after 12 months of BEV treatment. Conclusions. The activity and tolerability of BEV were comparable to results from previous prospective phase II trials. Reduced uptake on PET suggests a metabolic response in addition to an antiangiogenic effect in some cases with favorable clinical outcome.

Phase II study of sunitinib malate in patients with recurrent high-grade glioma.

Receptor tyrosine kinase signaling causes profound neo-angiogenesis in high-grade gliomas (HGG). The KIT, PDGFR-α, and VEGFR2 genes are frequently amplified and expressed in HGG and are molecular targets for therapeutic inhibition by the small-molecule kinase inhibitor sunitinib malate. Twenty-one patients with progressive HGG after prior radiotherapy and chemotherapy received a daily dose of 37.5 mg sunitinib until progression or unacceptable toxicity. Magnetic resonance imaging (MRI) and dynamic susceptibility contrast (DSC)-enhanced perfusion measurements were performed before and during therapy. Cerebral blood volume (CBV) and cerebral blood flow (CBF) lesion-to-normal-white matter ratios were measured to evaluate the antiangiogenic effects of sunitinib. The most frequent grade ≥3 adverse events were skin toxicity, neutropenia, thrombocytopenia, and lymphocytopenia. None of the patients achieved an objective response, whereas a decrease in CBV and CBF within the lesion compared with the normal brain was documented in four out of 14 (29%) patients evaluable for DSC-enhanced perfusion measurements. All patients experienced progression of their disease before or after eight weeks of therapy. Median time-to-progression and overall survival were 1.6 (95%CI 0.8-2.5) and 3.8 (95% CI 2.2-5.3) months, respectively. No correlation could be established between VEGFR2, PDGFR-α, and KIT gene copy numbers or protein expression and the effects of sunitinib. Single-agent sunitinib at 37.5 mg/day had insufficient activity to warrant further investigation of this monotherapy regimen in recurrent HGG.

Primary leptomeningeal anaplastic oligodendroglioma with a 1p36-19q13 deletion: report of a unique case successfully treated with Temozolomide.

Primary leptomeningeal oligodendroglioma occurs very rarely and in only one patient a deletion of chromosome 1p has been reported. We describe a 60-year-old man with a prior history of an epileptic seizure three years earlier, who was referred because of depression and a rapid evolving cognitive impairment. Brain MRI showed a diffuse right parieto-occipital subarachnoid enhancing lesion without intra-axial extension. The diagnosis of an anaplastic oligodendroglioma (WHO grade 3) was made on pathological examination. Molecular analysis using the FISH technique revealed a combined deletion of chromosomes 1p36 and 19q13. A rapid progression of the lesion was shown on MRI with leptomeningeal spinal metastases. The patient was treated with Temozolomide (TMZ) 150 mg/m(2) for 5 days every 4 weeks and showed a marked clinical recovery. Serial MRI disclosed a near complete regression of the lesions with no residual enhancement left after 6 cycles of chemotherapy. At progression following 8 cycles of TMZ the patient underwent craniospinal radiotherapy with complete response of his disease. To our knowledge this is the first report of a patient with a primary leptomeningeal anaplastic oligodendroglioma with diffuse spinal seeding bearing a 1p36/19q13 deletion. Our patient achieved a durable clinical and radiological remission following TMZ treatment. Molecular analysis with determination of chromosome 1p/19q deletions should be performed in all cases of leptomeningeal gliomas to select those patients who might benefit from TMZ chemotherapy.

Fatal intracerebral haemorrhage following carotid endarterectomy in a patient with cerebral amyloid angiopathy.

A 68-year-old man underwent carotid endarterectomy for symptomatic carotid artery stenosis. Immediately after surgery the patient suffered dramatic neurological deterioration, due to massive cerebral bleeding. Pathological examination revealed cerebral amyloid angiopathy. This condition is known to predispose to spontaneous, as well as anticoagulation induced, cerebral haemorrhage. Surgical intervention needing anticoagulation in elderly patients at risk for congophilic angiopathy should be performed with extreme caution.

Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma.

BACKGROUND: To evaluate the antitumor activity and toxicity of single-agent cetuximab in patients with recurrent high-grade glioma (HGG) after failure of surgery, radiation therapy, and chemotherapy. PATIENTS AND METHODS: In this two-arm, open-label, phase II study patients were stratified according to their epidermal growth factor receptor (EGFR) gene amplification status. Cetuximab was administered intravenously at a dose of 400 mg/m(2) on week 1 followed by weekly dose of 250 mg/m(2). The primary end point for this study was the response rate in both study arms separately. RESULTS: Fifty-five eligible patients (28 with and 27 without EGFR amplification) tolerated cetuximab well. Three patients (5.5%) had a partial response and 16 patients (29.6%) had stable disease. The median time to progression was 1.9 months [95% confidence interval (CI) 1.6-2.2 months]. Whereas the progression-free survival (PFS) was <6 months in the majority (n = 50/55) of patients, five patients (9.2%) had a PFS on cetuximab of >9 months. Median overall survival was 5.0 months (95% CI 4.2-5.9 months). No significant correlation was found between response, survival and EGFR amplification. CONCLUSIONS: Cetuximab was well tolerated but had limited activity in this patient population with progressive HGG. A minority of patients may derive a more durable benefit but were not prospectively identified by EGFR gene copy number.

MGMT promoter hypermethylation correlates with a survival benefit from temozolomide in patients with recurrent anaplastic astrocytoma but not glioblastoma.

AIMS: To investigate the correlation between O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation and benefit from temozolomide in patients with recurrent high-grade glioma. PATIENTS AND METHODS: A real-time, quantitative, methylation-specific PCR assay was performed on archival tissue blocks from patients treated with temozolomide at the first recurrence. RESULTS: A subgroup of 38 patients who were chemotherapy-naive at recurrence was analysed (22 glioblastoma, 12 anaplastic astrocytoma [AA] and 4 anaplastic oligoastrocytoma [AOA]); none had 1p/19q loss. Among 10 (26%) patients with a hypermethylated MGMT promoter, none experienced disease progression within the first two treatment cycles compared with 12 of 28 (43%) patients with an unmethylated promoter (p=0.016). By Cox multivariate analysis, tumour grade and MGMT promoter methylation correlated with time to progression (p<0.05); MGMT promoter methylation correlated with superior overall survival in AA/AOA but not in glioblastoma. CONCLUSIONS: MGMT promoter methylation predicted a survival benefit in patients with 1p/19q intact AA/AOA treated with temozolomide at recurrence.

Increased incidence of sporadic Creutzfeldt-Jakob disease in the age groups between 70 and 90 years in Belgium.

From 1998 a prospective surveillance study of Creutzfeldt-Jakob disease (CJD) has been initiated in Belgium. In addition to epidemiological data, information on cerebrospinal fluid biomarkers, prion protein gene and brain neuropathology was collected. From 1-1-1998 to 31-12-2004, 188 patients were referred to the surveillance system. In 85 patients a 'definite' diagnosis of sporadic CJD (sCJD) could be made, whereas 26 patients remained 'probable'. We further identified two unrelated patients with an E200K mutation, and two patients with a seven octapeptide repeat insertion in one family. In one patient a familial history was noted but genetic analysis was not performed. In 72 patients different final diagnoses were made, Alzheimer's disease being the most frequent (N = 20). The demographic parameters of the Belgian population were similar to those observed in the rest of Europe. We did notice a significantly increased age-specific incidence (> 6/10(6)/year) of sCJD patients between 70 and 90 years old in the period 2002-2004 compared to 1998-2001 and retrospectively obtained data (1990-1997, p < 0.01). We undertook a detailed clinical and biochemical analysis to investigate this increase but could not identify any reason other than an increased vigilance for the diagnosis. In conclusion, our study identified that in the past sCJD may have been underestimated in patients over age 70 although these patients are both clinically and neurobiochemically similar to the general sCJD phenotype.

Prognostic value of perfusion-weighted imaging in brain glioma: a prospective study.

OBJECT: Biopsy targeting based on MR imaging alone may fail to identify malignant areas in brain gliomas. Considering the differences in relative Cerebral Blood Volume (rCBV) ratios reported among tumour grades, we evaluated whether perfusion-weighted MR imaging (PWI) could usefully implement the routine preoperative imaging by detecting those areas bearing a higher yield for malignancy to guide the stereotactic biopsy or the surgical removal. CLINICAL MATERIAL AND METHODS: We studied a series of 55 consecutive patients with newly diagnosed brain glioma using both conventional MR imaging and PWI in the preoperative assessment. The pathological diagnosis was established by stereotactic biopsy in 29 cases and by craniotomy in 24 cases. We evaluated the patient survival to detect undergrading. DISCUSSION: Independent from contrast-enhancement, perfusion-weighted MR imaging improved the target selection in stereotactic biopsy guidance and the removal of malignant areas in tumours amenable to surgery. Particularly sensitive to the perfused part of the tumour as to small regional changes, rCBV maps allowed a better detection of malignant areas. The rCBV ratios correlated significantly to the tumour grade and the final outcome (p < 0.01). CONCLUSIONS: We found PWI valuable in the preoperative assessment of brain gliomas, discriminating high from low-grade gliomas. PWI can easily be performed on widely available MR imaging systems as part of the routine imaging of gliomas.

Postischemic mild hypothermia reduces neurotransmitter release and astroglial cell proliferation during reperfusion after asphyxial cardiac arrest in rats.

The present study investigated whether postischemic mild hypothermia attenuates the ischemia-induced striatal glutamate (GLU) and dopamine (DA) release, as well as astroglial cell proliferation in the brain. Anesthetized rats were exposed to 8 min of asphyxiation, including 5 min of cardiac arrest. The cardiac arrest was reversed to restoration of spontaneous circulation (ROSC), by brief external heart massage and ventilation within a period of 2 min. After the insult and during reperfusion, the extracellular glutamate and dopamine overflow increased to, respectively, 3000% and 5000% compared with the baseline values in the normothermic group and resulted in brain damage, ischemic neurons and gliosis. However, when hypothermia was induced for a period of 60 min after the insult and restoration of spontaneous circulation, the glutamate and dopamine overflows were not significantly different from that in the sham group. Histological analysis of the brain showed that postischemic mild hypothermia reduced brain damage, ischemic neurons, as well as astroglial cell proliferation. Thus, postischemic mild hypothermia reduces the excitotoxic process, brain damage, as well as astroglial cell proliferation during reperfusion. Moreover, these results emphasize the trigger effect of dopamine on the excitotoxic pathway.

Neuropathological and molecular aspects of low-grade and high-grade gliomas.

Gliomas are the most frequent primary brain tumors. They are derived from glial cells of astrocytic, oligodendroglial and ependymal origin. According to the WHO classification of brain tumors gliomas are divided in low-grade (grades I and II) and high-grade (grades III and IV) tumors. Low-grade tumors are well-differentiated, slow-growing lesions. Grade I tumors are well-circumscribed and often surgically curable, whereas grade II tumors are diffuse, infiltrating lesions with a marked potential over time for progression towards a high-grade malignant tumor. The optimal management of low-grade gliomas is still debated. Important prognostic factors such as histology, grade and location of the tumor, age and functional status of the patient, must be taken into consideration to select the most appropriate treatment. Major advances in the molecular genetic assessment of brain tumors and of gliomas in particular have lead to the identification of several molecular markers playing a crucial role in the development of gliomas and in their malignant transformation. Some of those markers were found very useful to assist in the histological diagnosis and to predict survival and response to therapy. A combined deletion of chromosomes arms 1p and 19q can be found in more than 50% of Grade II and III oligodendrogliomas and has been associated with chemosensitivity and a better prognosis. Once limited to the field of research, molecular biology has now entered the daily neuropathological practice and will undoubtedly play an increasing role in future classification and treatment of brain tumors.

Recent developments in the neuropathological diagnosis of Parkinson's disease and parkinsonism.

The diagnosis of Parkinson's disease (PD) is based mainly on clinical criteria. Large clinicopathological studies reveal however a different diagnosis in up to 25% of the cases (Hughes et al., 1992). Recent advances in molecular biology have shown that some proteins, especially tau and alpha-synuclein, play an essential role in the pathogenesis of parkinsonian and dementing disorders. Such diseases are now classified as tauopathies and synucleinopathies. Progressive supranuclear palsy and corticobasal degeneration are the major tauopathies. To the synucleinopathies belong PD, Lewy body dementia and multiple system atrophy. In pathological conditions abnormal proteins will aggregate in neurons and glial cells and form inclusion bodies. Lewy bodies are the hallmark of Parkinson's disease and Lewy body dementia. Identification of these inclusions and other specific lesions in parkinsonian disorders is facilitated by the routine application on formalin fixed brain of immunohistochemistry for alpha-synuclein, tau and ubiquitin. The purpose of this paper is to briefly review and illustrate the value of these new techniques in the postmortem diagnosis of parkinsonian disorders. Neuropathological examination of the brain is however time consuming and immunohistochemistry represents additional costs. As the selection of brain samples for microscopical examination and antibodies for immunohistochemistry depends on the underlying pathology, some clinical information should be provided to the pathologist such as the clinical diagnosis and when indicated the results of brain imaging studies. A close co-operation between the neurologist and neuropathologist is thus essential to select the most appropriate brains for complete neuropathological investigation.

Meningioma of the fourth ventricle presenting with intermittent behaviour disorders: a case report and review of the literature.

Intraventricular meningiomas are rare, representing 0.5-5% of all intracranial meningiomas. They arise mostly within the lateral ventricles and more rarely in the third ventricle. Meningiomas of the fourth ventricle are exceptional. They are clearly defined as meningiomas arising from the choroid plexus and lying strictly within the fourth ventricle. We report a 76 year old male patient presenting with a 2-week history of headache and cognitive disorders with agitation and restlessness particularly exacerbated at night or when lying down. CT scan and MR imaging showed a contrast-enhancing lesion located purely within the whole fourth ventricle, with slight ventricular enlargement. At surgery, we totally removed a well-vascularised, greyish encapsulated mass attached to the choroid plexus. Pathological examination revealed a WHO grade I fibroblastic meningioma. We reviewed the literature concerning this unusual meningioma location.