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).

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.

A case of 'tropical' myelopathy.

We present a case of lower limb sensory disturbances and weakness in a patient originating from Mali. MRI showed a diffuse myelopathy of the cervical and thoracic spinal cord. Serological evaluation of blood and cerebrospinal fluid pointed towards schistosomiasis as the cause. Histological confirmation was made on bladder-biopsy. Treatment with praziquantel and steroids brought marked clinical improvement. This case illustrates the need to keep in mind more exotic causes of myelopathy in those patients coming from endemic regions.

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.

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.

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.

Diffusion-weighted MR imaging of intracerebral masses: comparison with conventional MR imaging and histologic findings.

BACKGROUND AND PURPOSE: The purposes of this study were to find the role of diffusion-weighted MR imaging in characterizing intracerebral masses and to find a correlation, if any, between the different parameters of diffusion-weighted imaging and histologic analysis of tumors. The usefulness of diffusion-weighted imaging and apparent diffusion coefficient (ADC) maps in tumor delineation was evaluated. Contrast with white matter and ADC values for tumor components with available histology were also evaluated. METHODS: Twenty patients with clinical and routine MR imaging/CT evidence of intracerebral neoplasm were examined with routine MR imaging and echo-planar diffusion-weighted imaging. The routine MR imaging included at least the axial T2-weighted fast spin-echo and axial T1-weighted spin-echo sequences before and after contrast enhancement. The diffusion-weighted imaging included an echo-planar spin-echo sequence with three b values (0, 300, and 1200 s/mm(2)), sensitizing gradient in the z direction, and calculated ADC maps. The visual comparison of routine MR images with diffusion-weighted images for tumor delineation was performed as was the statistical analysis of quantitative diffusion-weighted imaging parameters with histologic evaluation. RESULTS: For tumors, the diffusion-weighted images and ADC maps of gliomas were less useful than the T2-weighted spin-echo and contrast-enhanced T1-weighted spin-echo images in definition of tumor boundaries. Additionally, in six cases of gliomas, neither T2-weighted spin-echo nor diffusion-weighted images were able to show a boundary between tumor and edema, which was present on contrast-enhanced T1-weighted and/or perfusion echo-planar images. The ADC values of solid gliomas, metastases, and meningioma were in the same range. In two cases of lymphomas, there was a good contrast with white matter, with strongly reduced ADC values. For infection, the highest contrast on diffusion-weighted images and lowest ADC values were observed in association with inflammatory granuloma and abscess. CONCLUSION: Contrary to the findings of previous studies, we found no clear advantage of diffusion-weighted echo-planar imaging in the evaluation of tumor extension. The contrast between gliomas, metastases, meningioma, and white matter was generally lower on diffusion-weighted images and ADC maps compared with conventional MR imaging. Unlike gliomas, the two cases of lymphomas showed hyperintense signal on diffusion-weighted images whereas the case of cerebral abscess showed the highest contrast on diffusion-weighted images with very low ADC values. Further study is required to find out whether this may be useful in the differentiation of gliomas and metastasis from lymphoma and abscess.

The surgical management of cerebral cavernous angiomas.

Cavernous angioma (CA) is a hamartomatous hemorrhagic lesion which has received a great deal of attention in recent years due to improvement of neuroimaging with magnetic resonance and heightened clinical awareness. Long considered to be rare, its actual prevalence is now recognized to be of 0.9%. Cavernous angiomas may be multiple, particularly in patients with familial form. It may be associated with a variety of clinical syndromes attributed to focal microhemorrhages or less frequently to gross bleeding. CA are usually diagnosed between the age of 20 and 50 with a highest clinical incidence in the fourth decade. A female predominance is observed in regard to bleeding. The male patients are more at risk for seizures. The recent series of MR imaging confirm that CA even when multiple can be asymptomatic in a significant number of cases. Surgery is the treatment of choice in order to eliminate the risk of hemorrhage and improve the control of seizures. Minimally invasive approaches are now adopted with reduced post-operative morbidity. We report our experience in surgical management of cerebral CA and suggest a classification of the lesions according to surgical accessibility and residual morbidity.

Deep benign fibrous histiocytoma of the knee: CT and MR features with pathologic correlation.

Magnetic resonance imaging and pathologic findings in a 28-year-old patient with a giant deep benign fibrous histiocytoma in the popliteal fossa of the right knee are described. The MR imaging findings include a well-delineated oval mass with low signal intensity on T1-, and high signal intensity on T2-weighted, images, and marked peripheral contrast enhancement. To the best of our knowledge, this is the first report on the MR findings in this entity.

Cranial disjunction and visual failure in a slit ventricle syndrome with patent shunt.

A 6.5-year-old child who received a shunt at 3 weeks of age for triventricular hydrocephalus related to his congenital toxoplasmosis developed symptoms of intracranial hypertension and papilloedema. Computed tomographic scan demonstrated slit ventricles. The shunt device was shown to be patent on isotope transit study. Spontaneously the cranial sutures widened and headaches disappeared, but loss of vision occurred and did not reverse despite optic nerve sheath fenestration. We suspect that a rapid drop in intracranial pressure played a role in the pathogenesis of our patient's blindness. This possible complication should be taken into account when calvarial expansion is planned in a patient with an intracranial hypertension syndrome with papilloedema in the presence of slit ventricles and a patent shunt.

Cognitive recovery in idiopathic normal pressure hydrocephalus: a prospective study.

Idiopathic normal-pressure hydrocephalus remains difficult to treat. Controversy exists as to whether or not shunting can really improve cognitive functions and whether quantified intracranial pressure monitoring (ICP-Mo) can predict postoperative improvement rates. Several studies have drawn attention to the lack of a prospective study concerning the surgical outcome of this condition. We have performed such a study on idiopathic normal-pressure hydrocephalus patients shunted on the basis of ICP-Mo when "high" waves (amplitude > 9 mm Hg) were present. Twenty-three patients underwent surgery. The preoperative and postoperative clinical states were assessed by a quantitative procedure blind to the ICP-Mo results. A clear postshunting improvement was seen in 96% of the patients at 1 year with a statistically significant correlation between high wave relative frequency and the grade of improvement (P < 0.05). At the same time, 66.6% of shunted patients showed a significant improvement in cognitive functions. Complications of shunting were successfully managed without residual deficits in this series. We recommend the use of quantitative ICP-Mo as a criterion for surgery and to predict the improvement grade.

Brain oedema induced by ventricular puncture. A study by magnetic resonance on a series of forty-one normal-pressure hydrocephalic patients.

After ventricular catheterization magnetic resonance (MR) imaging very often demonstrates a focal area of high signal along the drain track which corresponds to parenchymal oedema. This high signal seemed to be more pronounced when the frontal area was catheterized than when the junctional parieto-temporo-occipital parenchyma (or trigonal area) was catheterized. In order to confirm this impression, we prospectively studied 41 consecutive patients with normal-pressure hydrocephalus in whom both of these brain regions were catheterized for intracranial pressure monitoring. Each patient was evaluated by serial MR. The extent of the MR hypersignal induced by both catheterizations was computed from digitized MR masks. The extent of the MR high signal area was significantly greater when the frontal area was catheterized compared to the trigonal area suggesting that the frontal area could be more prone to injury.

Morphological quantitative analysis of intracranial pressure waves in normal pressure hydrocephalus.

This work presents a prospective morphological and quantitative analysis of 43 intracranial pressure recordings performed on normal pressure hydrocephalic patients. This analysis led us to separate Lundberg's B waves into different subtypes and to refine the definition of the 'Plateau' wave. Two B wave subtypes named Great Symmetrical wave and Intermediate wave appeared correlated with the surgical improvement. In addition, the degree of post-operative improvement was correlated with the frequency of Intermediate wave. An extended quantitative classification of intracranial pressure waves is proposed that can be used alone to determine which patients should undergo a shunting procedure and which one should the most improve.

Atropine administration in experimental electromechanical dissociation.

Atropine can have a place during cardiopulmonary resuscitation (CPR) in the management of asystole, where parasympathetic influence might be excessive. However, the beneficial effects of atropine in electromechanical dissociation (EMD) have not been clearly demonstrated. The authors studied the effects of atropine in combination with epinephrine on an experimental model of EMD in the closed-chested dog. In 15 pentobarbital-anesthetized, mechanically ventilated dogs (mean weight 20 kg), EMD was induced by ventricular fibrillation followed by an external countershock, and was observed for 2 minutes before CPR was started. After 5 minutes of chest compression using a CPR thumper, either atropine 0.5 mg or D5W was administered, and the same injection was repeated every 5 minutes until recovery. Epinephrine 1 mg was administered in alternans. Each dog was submitted to two successive episodes of CPR, using either atropine or D5W, in a randomized order. Of a total of 28 CPRs, five were successful with chest compression alone. In the treatment groups, 10 of 11 were successful with atropine, but only eight of 12 with D5W (P < .01). The duration of CPR was also significantly shorter when atropine was used (9 minutes 56 seconds +/- 14 seconds versus 12 minutes 08 seconds +/- 43 seconds, P < .001). During the recovery period, atropine-treated animals had higher arterial pressure, heart rate, cardiac output and stroke volume. On this experimental model, the administration of high doses of atropine together with epinephrine enhances the recovery from EMD and results in a better cardiac function during recovery.

Traumatic brain edema induced by ventricular puncture. A study by magnetic resonance imaging.

Magnetic resonance imaging demonstrates after ventricular catheterization a focal brain hypersignal corresponding to a parenchymal edema along the drain track. In the course of our daily clinical activity, this hypersignal extension seemed more pronounced when catheterizing the frontal area than the junctional parieto-temporo-occipital parenchyma (or trigonal area). In order to confirm this impression, we prospectively studied ten consecutive patients with normal pressure hydrocephalus in whom both of these brain regions were successively catheterized first by a frontal puncture for intracranial pressure monitoring and then by a trigonal one for a ventricular shunt. Each patient was evaluated by serial magnetic resonance imaging. The extension of the hypersignal induced by both catheterizations was estimated on a scale of five grades (0 to 4) of hypersignal extension. A statistically significant more important hypersignal extension was demonstrated at the level of frontal area when compared to the trigonal one. We discuss the likely underlying mechanisms of this phenomenon.