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.

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.

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.

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.

Oxygen consumption by frog skin and its isolated epithelial layers as a function of their sodium-transporting activity.

The metabolic cost (in terms of oxygen consumption) of transcellular sodium transport was assessed on ventral frog skin and its isolated epithelial layers, by measuring the decrease in oxygen consumption by the tissue upon transient withdrawal of sodium from the outside solution. The same number of sodium ions was transported per molecule oxygen consumed whole skin (17.4 +/- 2.3) and its isolated epithelium (17.3 +/- 2.4). The metabolic cost of sodium transport could not be estimated properly when this process was blocked by amiloride or ouabain, as these drugs were found to bring about an increase in oxygen consumpton by the tissue when no sodium was available for transport.

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.

Frontal impairment and hypoperfusion in neuroacanthocytosis.

Cerebral blood flow tomography, by xenon 133 inhalation or HMPAO (99mTc-d, l-hexamethyl-propylene amine oxime) technetium Tc 99m injection, revealed a severe hypoperfusion in both frontal lobes of a 40-year-old woman with confirmed neuroacanthocytosis. This finding occurred in conjunction with neuropsychological deficits consistent with selective frontal lobe dysfunction. This observation is the first documentation of this type of dementia in neuroacanthocytosis.

Dissociated ipsilateral horizontal gaze palsy in one-and-a-half syndrome: a clinicopathologic study.

We report a patient with a one-and-a-half syndrome due to an isolated small infarction in the left rostral part of the paramedian pontine reticular formation and the ipsilateral medial longitudinal fasciculus. Oculocephalic movements toward the left were preserved (dissociated ipsilateral horizontal conjugate gaze palsy).

Expression of pituitary adenylate cyclase activating polypeptide and receptors in human brain tumors.

The capacity of brain tumor samples to synthesize pituitary adenylate cyclase activating polypeptide (PACAP) was evaluated by the reverse transcriptase-polymerase chain reaction technique (RT-PCR). The expression of PACAP receptors was assessed by a combination of RT-PCR techniques, conventional binding techniques, and also by the ability of PACAP to stimulate adenylate cyclase activity. A weak PACAP mRNA and PACAP receptor mRNA expression was detected in only 3 of 16 meningiomas. A weak PACAP-stimulated adenylate cyclase activity (+20%) was detected in 10 of the 16 samples but binding of labeled PACAP was never observed. In the 16 gliomas studied (including two oligodendrogliomas and two ependymomas), PACAP mRNA was identified in 13 samples and PACAP receptor mRNA in 15 samples. PACAP receptors were identified in all the samples by binding studies and/or by PACAP stimulation of the adenylate cyclase activity. PACAP mRNA was never detected in pituitary adenomas (three prolactinomas, two mixed PRL-GH-producing tumors, three GH-secreting tumors, three gonadotrophinomas, one ACTH-producing tumor, two nonsecreting tumors) whereas PACAP receptor mRNA was highly expressed in all the tumors except prolactinomas, where it was at the limit of detection, confirming the binding and adenylate cyclase activation results. Thus, it is unlikely that the neuropeptide PACAP could influence meningioma's cell growth; PACAP secreted from extratumoral areas may influence pituitary tumors and PACAP could participate to gliomas development.

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.

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.

Intracranial facial nerve rhabdomyoma. Case report.

Nerve rhabdomyomas are exceedingly rare benign tumors of the peripheral nerves consisting of well-differentiated striated muscle fibers admixed with parental nerve fibers. Only one case of intracranial nerve rhabdomyoma has been described, which affected the trigeminal nerve. This report presents the detailed neuropathological description of a nerve rhabdomyoma arising in the schwannian portion of the facial nerve root in a 41-year-old Caucasian man. The nerve fibers were arranged chaotically as in a traumatic neuroma. Because of the intimate intermingling of this slow-growing tumor with the parental nerve fibers, complete excision should be avoided.

Pyruvate dehydrogenase deficiency: clinical and biochemical diagnosis.

A female neonate with pyruvate dehydrogenase (PDH) deficiency is presented with clinical, radiologic, biochemical, neuropathologic, and molecular genetic data. She was dysmorphic, with a high forehead, lowset ears, thin upper lip, upturned nose, and rhizomelic limbs. Cranial MRI revealed severe cortical atrophy, ventricular dilatation, and corpus callosum agenesis. Pyruvate and lactate levels were increased in CSF and blood. Urinary organic acid profile was compatible with PDH deficiency. PDH activity was normal in fibroblasts, lymphocytes, and muscle. The PDH E1-alpha gene was sequenced and a single base mutation was found within the regulatory phosphorylation site in exon 10. It is postulated that this mutation causes a cerebral form of PDH deficiency. Tissue-specific expression of the disease could be explained by differential X chromosome inactivation because the PDH E1-alpha gene is located on this chromosome. Dysmorphism with severe cerebral malformations in female patients merits a metabolic evaluation, including determination of lactate and pyruvate levels in CSF.

Calcified, cystic brain metastases.

Calcifications are uncommon in metastases. Adenocarcinoma, osteopenic, osteosarcoma, lung and breast carcinoma can be the origin. A rare case of calcified cystic brain metastasis deriving from papillary cystadenocarcinoma is reported.

Brain stem infarction as a complication of giant-cell arteritis.

Two cases of brain stem infarction as an early and fatal complication of giant-cell arteritis are reported. These complications occurred despite adequate treatment with corticosteroids. The findings at autopsy are compared with those of the literature. The possible pathogenetic mechanisms of vertebro basilar occlusion and the therapeutical implications are discussed.

Recurrent forms of sporadic brachial plexus neuropathy. A report of two cases.

Two patients presenting a relapsing form of sporadic brachial plexus neuropathy, the so-called Parsonage Turner syndrome, are reported. The diagnosis is based on clinical and electromyographic features. Recurrent attacks, although infrequently encountered, have been well described in the past. Sporadic cases of this syndrome must be differentiated from the familial varieties of neuralgic amyotrophy in which, two main subgroups of patients are distinguished: those showing facial dysmorphic features and those with findings of a tomaculous neuropathy predisposing them to pressure palsies. Apart from the obvious difference as regards familial occurrence, the familial and non-familial varieties of neuralgic amyotrophy differ in a number of respects: associated congenital defects, early age of onset and high rate of recurrence in the former. Finally some possible pathogenetic mechanisms of the syndrome are briefly reviewed.

Recurrent brachial plexus neuropathy and giant cell arteritis.

A 73-year-old women presented with a recurrent form of sporadic brachial plexus neuropathy, the so-called Parsonage and Turner syndrome. This diagnosis is based on clinical and electromyographic findings. Interestingly a biopsy of the temporal artery demonstrated a giant cell arteritis. The clinical picture started 2 weeks after an upper respiratory tract illness. The possible viral etiology of giant cell arteritis is considered. We think an immunological rather than ischemic disturbance may have caused the recurrent brachial plexus neuropathy. This case report suggests that giant cell arteritis be considered in the investigation of the Parsonage and Turner syndrome.

Unilateral seizures in a patient with hairy cell leukemia treated with interferon.

A patient is described who developed unilateral seizures whilst being treated with recombinant interferon for hairy cell leukemia. Special features included the relatively low dose of interferon, the focal aspect of the epilepsy and the high resistance to anticonvulsants. Oligoclonal banding of cerebrospinal fluid proteins may have resulted from polyclonal activation of bone marrow plasma cells during interferon treatment. Disturbances of consciousness, dysphasia, visual hallucinations, upper motor neuron deficit, tremor, dizziness, numbness, myalgia and headache, all of them neurological complications of interferon treatment, are discussed.