Next generation sequencing in adult patients with glioblastoma in Switzerland: a multi-centre decision analysis.

BACKGROUND: Glioblastoma is the most common malignant primary brain tumour in adults and driven by various genomic alterations. Next generation sequencing (NGS) provides timely information about the genetic landscape of tumours and might detect targetable mutations. To date, differences exist in the application and NGS assays used as it remains unclear to what extent these variants may affect clinical decision making. In this survey-based study, we investigated the use of NGS in adult patients with glioblastoma in Switzerland. METHODS: All eight primary care centres for Neuro-Oncology in Switzerland participated in this survey. The NGS assays used as well as the criteria for the application of NGS in newly diagnosed glioblastoma were investigated. Decision trees were analysed for consensus and discrepancies using the objective consensus methodology. RESULTS: Seven out of eight centres perform NGS in patients with newly diagnosed glioblastoma using custom made or commercially available assays. The criteria most relevant to decision making were age, suitability of standard treatment and fitness. NGS is most often used in fitter patients under the age of 60 years who are not suitable for standard therapy, while it is rarely performed in patients in poor general health. CONCLUSION: NGS is frequently applied in glioblastomas in adults in Neuro-Oncology centres in Switzerland despite seldom changing the course of treatment to date.

Malignant PRES and RCVS after brain surgery in the early postpartum period.

The management of women with brain tumors in the early post-partum period may be demanding as the patho-physiological changes that occur during pregnancy may also manifest in the early post-partum period. The aim of our paper is to report a case of late-onset post-partum pre-eclampsia after brain tumor surgery, complicated by posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS). Hemicraniectomy and intensive care management were necessary to obtain a favorable neurological outcome. The inherent literature on the subject is also analyzed through a systematic research. This is the first case of supratentorial decompressive hemicraniectomy in post-partum PRES, while there has been only one other case of posterior fossa decompression described in this cohort of patients. PRES and RCVS can complicate the neurosurgical management of women in the postpartum period. A careful evaluation of the clinical presentation is necessary as in some particular cases an aggressive medical and surgical treatment is required to obtain a favorable outcome.

Bevacizumab plus hypofractionated radiotherapy versus radiotherapy alone in elderly patients with glioblastoma: the randomized, open-label, phase II ARTE trial.

Background: The addition of bevacizumab to temozolomide-based chemoradiotherapy (TMZ/RT â†’ TMZ) did not prolong overall survival (OS) in patients with newly diagnosed glioblastoma in phase III trials. Elderly and frail patients are underrepresented in clinical trials, but early reports suggested preferential benefit in this population. Patients and methods: ARTE was a 2 : 1 randomized, multi-center, open-label, non-comparative phase II trial of hypofractionated RT (40 Gy in 15 fractions) with bevacizumab (10 mg/kg×14 days) (arm A, N = 50) or without bevacizumab (arm B, N = 25) in patients with newly diagnosed glioblastoma aged ≥65 years. The primary objective was to obtain evidence for prolongation of median OS by the addition of bevacizumab to RT. Response was assessed by RANO criteria. Quality of life (QoL) was monitored by the EORTC QLQ-C30/BN20 modules. Exploratory studies included molecular subtyping by 450k whole methylome and gene expression analyses. Results: Median PFS was longer in arm A than in arm B (7.6 and 4.8 months, P = 0.003), but OS was similar (12.1 and 12.2 months, P = 0.77). Clinical deterioration was delayed and more patients came off steroids in arm A. Prolonged PFS in arm A was confined to tumors with the receptor tyrosine kinase (RTK) I methylation subtype (HR 0.25, P = 0.014) and proneural gene expression (HR 0.29, P = 0.025). In a Cox model of OS controlling for established prognostic factors, associations with more favorable outcome were identified for age <70 years (HR 0.52, P = 0.018) and Karnofsky performance score 90%-100% (HR 0.51, P = 0.026). Including molecular subtypes into that model identified an association of the RTK II gene methylation subtype with inferior OS (HR 1.73, P = 0.076). Conclusion: Efficacy outcomes and exploratory analyses of ARTE do not support the hypothesis that the addition of bevacizumab to RT generally prolongs survival in elderly glioblastoma patients. Molecular biomarkers may identify patients with preferential benefit from bevacizumab. Clinical trial registration number: NCT01443676.

Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma.

This corrects the article DOI: 10.1038/bjc.2014.209.

Extra central nervous system metastases from glioblastoma: a new possible trigger event?

Extra-cranial metastases of glioblastoma (GBM) represent a rare event, and the biological-genetic mechanisms involved in the pathogenesis have not yet been determined. We report the case of a young patient with multiple visceral and osseous metastases occurred after 4 years after first diagnosis of GBM. The strangeness as well as the rarity of this event does not allow to identify an effective treatment for GBM metastases, making the management of this ominous tumor an even greater challenge.

Recent advances in the management of atypical meningiomas.

Based on the 2007 WHO classification, the proportion of atypical meningiomas has steeply increased. Complete resection is usually considered curative, however, the recurrence rate remains high. The treatment of more aggressive meningiomas remains problematic. We performed a literature review via the PubMed database with specific attention to radiological, pathological, genetic and molecular aspects particular to WHO grade II meningiomas and current therapeutic strategies. We also reviewed the role of surgery and summarized the results of the principal studies dealing with adjuvant strategies based on the most recent evidence. Adjuvant radiotherapy, administered as stereotactic radiosurgery or conventional external beam irradiation, should be strongly considered in selected cases. Limited data exist regarding the role of hormonal treatment or chemotherapy as adjunct therapy. A target therapy modulating the altered molecular balance may be the key to revolutionize the prognosis of these patients.

Patterns of care in recurrent glioblastoma in Switzerland: a multicentre national approach based on diagnostic nodes.

Despite moderate improvements in outcome of glioblastoma after first-line treatment with chemoradiation recent clinical trials failed to improve the prognosis of recurrent glioblastoma. In the absence of a standard of care we aimed to investigate institutional treatment strategies to identify similarities and differences in the pattern of care for recurrent glioblastoma. We investigated re-treatment criteria and therapeutic pathways for recurrent glioblastoma of eight neuro-oncology centres in Switzerland having an established multidisciplinary tumour-board conference. Decision algorithms, differences and consensus were analysed using the objective consensus methodology. A total of 16 different treatment recommendations were identified based on combinations of eight different decision criteria. The set of criteria implemented as well as the set of treatments offered was different in each centre. For specific situations, up to 6 different treatment recommendations were provided by the eight centres. The only wide-range consensus identified was to offer best supportive care to unfit patients. A majority recommendation was identified for non-operable large early recurrence with unmethylated MGMT promoter status in the fit patients: here bevacizumab was offered. In fit patients with late recurrent non-operable MGMT promoter methylated glioblastoma temozolomide was recommended by most. No other majority recommendations were present. In the absence of strong evidence we identified few consensus recommendations in the treatment of recurrent glioblastoma. This contrasts the limited availability of single drugs and treatment modalities. Clinical situations of greatest heterogeneity may be suitable to be addressed in clinical trials and second opinion referrals are likely to yield diverging recommendations.

Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma.

BACKGROUND: Sorafenib (Sb) is a multiple kinase inhibitor targeting both tumour cell proliferation and angiogenesis that may further act as a potent radiosensitizer by arresting cells in the most radiosensitive cell cycle phase. This phase I open-label, noncontrolled dose escalation study was performed to determine the safety and maximum tolerated dose (MTD) of Sb in combination with radiation therapy (RT) and temozolomide (TMZ) in 17 patients with newly diagnosed high-grade glioma. METHODS: Patients were treated with RT (60 Gy in 2 Gy fractions) combined with TMZ 75 mg m(-2) daily, and Sb administered at three dose levels (200 mg daily, 200 mg BID, and 400 mg BID) starting on day 8 of RT. Thirty days after the end of RT, patients received monthly TMZ (150-200 mg m(-2) D1-5/28) and Sb (400 mg BID). Pharmacokinetic (PK) analyses were performed on day 8 (TMZ) and on day 21 (TMZ&Sb) (Clinicaltrials ID: NCT00884416). RESULTS: The MTD of Sb was established at 200 mg BID. Dose-limiting toxicities included thrombocytopenia (two patients), diarrhoea (one patient) and hypercholesterolaemia (one patient). Sb administration did not affect the mean area under the curve(0-24) and mean Cmax of TMZ and its metabolite 5-amino-imidazole-4-carboxamide (AIC). Tmax of both TMZ and AIC was delayed from 0.75 (TMZ alone) to 1.5 h (combined TMZ/Sb). The median progression-free survival was 7.9 months (95% confidence interval (CI): 5.4-14.55), and the median overall survival was 17.8 months (95% CI: 14.7-25.6). CONCLUSIONS: Although Sb can be combined with RT and TMZ, significant side effects and moderate outcome results do not support further clinical development in malignant gliomas. The robust PK data of the TMZ/Sb combination could be useful in other cancer settings.

[Anti-neuronal antibodies: a rapidly developing field]. / Anticorps antineuronaux: un domaine en plein développement.

Anti-neuronal antibodies are implicated in various neurological syndromes that are sometimes associated with tumors. Depending on the antigenic target (nuclear, cytoplasmic or extracellular cell-surface or synaptic) the clinical presentation is different. In neurological syndromes associated with antibodies specific for intracellular antigens, the T-cell mediated immunological response predominates as pathogenic effector and the response to treatment is typically poor. In contrast, in syndromes related to antibodies against extracellular targets, the role of the antibodies is pathogenic and the neurological syndrome often responds better to immunomodulatory treatment, associated or not with an anti-tumoral treatment. We review the spectrum of anti-neuronal antibodies and their corresponding clinical and therapeutic characteristics.

Decision making and management of gliomas: practical considerations.

Over the last decade, diagnostic options and introduction of novel treatments have expanded the armamentarium in the management of malignant glioma. Combined chemoradiotherapy has become the standard of care in glioblastoma up to the age of 70 years, while treatment in elderly patients or with lower grade glioma is less well defined. Molecular markers define different disease subtypes and allow for adapted treatment selection. This review focuses on simple questions arising in the daily management of patients.

[Therapeutic strategies for the management of gliomas]. / Stratégies thérapeutiques pour le traitement des gliomes.

The management of gliomas remains challenging and requires a multidisciplinary approach that involves neurosurgeons, radiation therapists and oncologists. For patients with glioblastomas, progress has been made in recent years with the introduction of a combined modality treatment associating radiation therapy and concomitant chemotherapy with the novel alkylating agent temozolomide. This combination resulted in a significant prolongation of survival and increase in the number of patients with survival well beyond two years. Since then, interest in developing new agents in this disease has dramatically increased. In parallel, molecular markers, such as methylation status of MGMT or identification of the translocation of 1p and 19q in oligodendrogliomas have allowed to identify distinct subtypes with exquisite response to treatment or different prognosis. These developments have implications for the development of clinical trials of new potential drug treatments. In this article, we provide a review of the current management of low- and high-grade gliomas, including astrocytomas, oligodendrogliomas and glioblastomas and provide an outlook into future potential therapies.

Complete and long-term rescue of lesioned adult motoneurons by lentiviral-mediated expression of glial cell line-derived neurotrophic factor in the facial nucleus.

To date, delivery of neurotrophic factors has only allowed to transiently protect axotomized facial motoneurons against cell death. In the present report, long-term protection of these neurons was evaluated by continuously expressing the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) within the facial nucleus using a lentiviral vector system. The viral vector was injected unilaterally into the facial nucleus of 4-month-old Balb/C mice. In contrast to axotomy in other adult rodents, facial nerve lesion in these animals leads to a progressive and sustained loss and/or atrophy of >50% of the motoneurons. This model thus represents an attractive model to evaluate potential protective effects of neurotrophic factors for adult-onset motoneuron diseases, such as amyotrophic lateral sclerosis. One month after unilateral lentiviral vector injection, the facial nerve was sectioned, and the animals were killed 3 months later. Viral delivery of the GDNF gene led to long-term expression and extensive diffusion of GDNF within the brainstem. In addition, axotomized motoneurons were completely protected against cell death, because 95% of the motoneurons were present as demonstrated by both Nissl staining and choline acetyltransferase immunoreactivity. Furthermore, GDNF prevented lesion-induced neuronal atrophy and maintained proximal motoneuron axons, despite the absence of target cell reinnervation. This is the first evidence that viral-mediated delivery of GDNF close to the motoneuron cell bodies of the facial nucleus of adult mice can lead to complete and long-term protection against lesion-induced cell death.

The copper chelator d-penicillamine delays onset of disease and extends survival in a transgenic mouse model of familial amyotrophic lateral sclerosis.

A subpopulation of familial cases of amyotrophic lateral sclerosis has been linked to mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). There is in vitro evidence that certain SOD1 mutants, in addition to their normal dismutation function, show increased ability of the enzyme to act as a peroxidase. This reaction is sensitive to inhibition by copper chelators. To test this hypothesis in vivo, we administered the copper chelator d-penicillamine to a transgenic mouse model of familial amyotrophic lateral sclerosis overexpressing a mutated form of human SOD1. We demonstrate that oral administration of d-penicillamine is able to delay the onset of the disease and extend the survival of these mice. Histological studies also showed a decreased loss of facial motor neurons in d-penicillamine-treated transgenic mice, corroborating the slower evolution of the disease in these animals. These results suggest that copper chelators may benefit patients with familial amyotrophic lateral sclerosis linked to mutations in the SOD1 gene.

Amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam: quantitative neuropathology, immunohistochemical analysis of neuronal vulnerability, and comparison with related neurodegenerative disorders.

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (lytico-bodig) is a chronic neurodegenerative disorder with high prevalence among the native Chamorro population of Guam. Neuropathological, biochemical, and immunohistochemical analyses were performed on a relatively large series of Guamanian cases and compared to Alzheimer's disease cases. Thioflavin S and antibodies to amyloid beta A4 and tau proteins were used for analysis of pathological changes, and antibodies to the calcium-binding proteins parvalbumin and calretinin, and to a nonphosphorylated epitope on neurofilament protein to study select neuronal populations. A differential distribution of neurofibrillary tangles was observed in the neocortex of Guamanian cases compared to Alzheimer's disease cases, with much higher lesion counts in supragranular than in infragranular layers. Also, Guamanian cases with predominant parkinsonism had generally higher neurofibrillary tangle densities than cases with predominant amyotrophic lateral sclerosis. In addition, there was a certain degree of heterogeneity, qualitatively and quantitatively, in the biochemical distribution of tau proteins among Guamanian and Alzheimer's disease cases as revealed by Western blot analysis. Previous studies have suggested that the clinical symptomatology observed in patients suffering from Alzheimer's disease is related to the dramatic loss of specific corticocortically projecting neurons in the neocortex. Interestingly, a subset of neurofilament-rich pyramidal neurons known to be dramatically affected in Alzheimer's disease appears to be resistant in lytico-bodig. Finally, as in Alzheimer's disease, calcium-binding protein-containing interneurons are not affected. These data suggest that the set of projection neurons affected in Guamanian cases may not correspond to those involved in Alzheimer's disease, and that both disorders are characterized by specific patterns of neuronal vulnerability.