Contribution of nuclear medicine to the diagnosis and management of primary brain tumours.

Positron emission tomography (PET) is a powerful tool that can help physicians manage primary brain tumours at diagnosis and follow-up. In this context, PET imaging is used with three main types of radiotracers: 18F-FDG, amino acid radiotracers, and 68Ga conjugated to somatostatin receptor ligands (SSTRs). At initial diagnosis, 18F-FDG helps to characterize primary central nervous system (PCNS) lymphomas and high-grade gliomas, amino acid radiotracers are indicated for gliomas, and SSTR PET ligands are indicated for meningiomas. Such radiotracers provide information on tumour grade or type, assist in directing biopsies and help with treatment planning. During follow-up, in the presence of symptoms and/or MRI modifications, the differential diagnosis between tumour recurrence and post-therapeutic changes, in particular radiation necrosis, may be challenging, and there is strong interest in using PET to evaluate therapeutic toxicity. PET may also contribute to identifying specific complications, such as postradiation therapy encephalopathy, encephalitis associated with PCNS lymphoma, and stroke-like migraine after radiation therapy (SMART) syndrome associated with glioma recurrence and temporal epilepsy, originally illustrated in this review. This review summarizes the main contribution of PET to the diagnosis, management, and follow-up of brain tumours, specifically gliomas, meningiomas, and primary central nervous system lymphomas.

Innovative treatments for meningiomas.

Multi-recurrent high-grade meningiomas remain an unmet medical need in neuro-oncology when iterative surgeries and radiation therapy sessions fail to control tumor growth. Nevertheless, the last 10years have been marked by multiple advances in the comprehension of meningioma tumorigenesis via the discovery of new driver mutations, the identification of activated intracellular signaling pathways, and DNA methylation analyses, providing multiple potential therapeutic targets. Today, Anti-VEGF and mTOR inhibitors are the most used and probably the most active drugs in aggressive meningiomas. Peptide radioactive radiation therapy aims to target SSTR2A receptors, which are strongly expressed in meningiomas, but have an insufficient effect in most aggressive meningiomas, requiring the development of new techniques to increase the dose applied to the tumor. Based on the multiple potential intracellular targets, multiple targeted therapy clinical trials targeting Pi3K-Akt-mTOR and MAP kinase pathways as well as cell cycle and particularly, cyclin D4-6 are ongoing. Recently discovered driver mutations, SMO, Akt, and PI3KCA, offer new targets but are mostly observed in benign meningiomas, limiting their clinical relevance mainly to rare aggressive skull base meningiomas. Therefore, NF2 mutation remains the most frequent mutation and main challenging target in high-grade meningioma. Recently, inhibitors of focal adhesion kinase (FAK), which is involved in tumor cell adhesion, were tested in a phase 2 clinical trial with interesting but insufficient activity. The Hippo pathway was demonstrated to interact with NF2/Merlin and could be a promising target in NF2-mutated meningiomas with ongoing multiple preclinical studies and a phase 1 clinical trial. Recent advances in immune landscape comprehension led to the proposal of the use of immunotherapy in meningiomas. Except in rare cases of MSH2/6 mutation or high tumor mass burden, the activity of PD-1 inhibitors remains limited; however, its combination with various radiation therapy modalities is particularly promising. On the whole, therapeutic management of high-grade meningiomas is still challenging even with multiple promising therapeutic targets and innovations.

Challenges in diagnosis and management of adult spinal cord gliomas.

Intramedullary spinal cord gliomas have very low incidence rates. They are associated with difficulties in diagnosis and treatment, and cause significant morbidity. Their clinical presentation and their appearance at magnetic resonance imaging are not specific. They can mimic inflammatory, infectious, vascular disorders or other neoplastic lesions. Primary treatment is surgery. Surgical resection can often be total for ependymomas, but difficult for infiltrating astrocytomas. Radiotherapy is indicated for malignant tumors, but remains controversial in some indications. Chemotherapy is reserved for recurrence, but small retrospective series are available. Genetic studies have revealed genetic alterations which could have a potential impact on treatment in the near future.

Inhibitor of apoptosis protein expression in glioblastomas and their in vitro and in vivo targeting by SMAC mimetic GDC-0152.

Glioblastomas (GBMs) are the most aggressive primary brain tumors in adult and remain a therapeutic challenge. Targeting key apoptosis regulators with the ultimate aim to restore apoptosis in tumor cells could be an interesting therapeutic strategy. The inhibitors of apoptosis proteins (IAPs) are regulators of cell death and represent attractive targets, especially because they can be antagonized by SMAC mimetics. In this study, we first investigated the expression of cIAP1, cIAP2, XIAP and ML-IAP in human GBM samples and in four different cell lines. We showed that all GBM samples and GBM cell lines expressed all these IAPs, although the expression of each IAP varied from one case to another. We then showed that high level of ML-IAP predicted worse progression-free survival and overall survival in both univariate and multivariate analyses in two independent cohorts of 58 and 43 primary human GBMs. We then used GDC-0152, a SMAC mimetic that antagonizes these IAPs and confirmed that GDC-0152 treatment in vitro decreased IAPs in all the cell lines studied. It affected cell line viability and triggered apoptosis, although the effect was higher in U87MG and GL261 than in GBM6 and GBM9 cell lines. In vivo, GDC-0152 effect on U87MG orthotopic xenografts was dose dependent; it postponed tumor formation and slowed down tumor growth, significantly improving survival of GBM-bearing mice. This study revealed for the first time that ML-IAP protein expression correlates with GBM patient survival and that its antagonist GDC-0152 improves outcome in xenografted mouse.

Coping with a newly diagnosed high-grade glioma: patient-caregiver dyad effects on quality of life.

Patients with high-grade gliomas (HGG) and their caregivers have to confront a very aggressive disease that produces major lifestyle disruptions. There is an interest in studying the ability of patients and their caregivers to cope with the difficulties that affect quality of life (QoL). We examine, in a sample of patient-caregiver dyads in the specific context of newly diagnosed cases of HGG, whether the QoL of patients and caregivers is influenced by the coping processes they and their relatives use from a specific actor-partner interdependence model (APIM). This cross-sectional study involved 42 dyads with patients having recent diagnoses of HGG and assessed in the time-frame between diagnosis and treatment initiation. The self-reported data included QoL (Patient-Generated Index, EORTC QLQ-C30, and CareGiver Oncology QoL), emotional status, and coping strategies (BriefCope). The APIM was used to test the dyadic effects of coping strategies on QoL. Coping strategies, such as social support, avoidance, and problem solving, exhibited evidence of either an actor effect (degree to which the individual's coping strategies are associated with their own QoL) or partner effect (degree to which the individual's coping strategies are associated with the QoL of the other member of the dyad) for patients or caregivers. For positive-thinking coping strategies, actor and partner effect were not observed. This study emphasizes that the QoL for patients and their caregivers was directly related to the coping strategies they used. This finding suggests that targeted interventions should be offered to help patients and their relatives to implement more effective coping strategies.

Neuro-oncological patients admitted in intensive-care unit: predictive factors and functional outcome.

The prognosis of oncology patients admitted to the intensive care unit (ICU) is considered poor. Our objective was to analyze the characteristics and predictive factors of death in the ICU and functional outcome following ICU treatment for neuro-oncology patients. A retrospective study was conducted on all patients with primary brain tumor admitted to our institutional ICU for medical indications. Predictive impact on the risk of death in the ICU was analyzed as well as the functional status was evaluated prior and following ICU discharge. Seventy-one patients were admitted to the ICU. ICU admission indications were refractory seizures (41 %) and septic shock (17 %). On admission, 16 % had multi-organ failure. Ventilation was necessary for 41 % and catecholamines for 13 %. Twenty-two percent of patients died in the ICU. By multivariate analysis, predictive factors associated with an increased risk of ICU death were: non-neurological cause of admission [p = 0.045; odds ratio (OR) 5.405], multiple organ failure (p = 0.021; OR 8.027), respiratory failure (p = 0.006; OR 9.615), and hemodynamic failure (p = 0.008; OR 10.111). In contrast, tumor type (p = 0.678) and disease control status (p = 0.380) were not associated with an increased risk of ICU death. Among the 35 evaluable patients, 77 % presented with a stable or improved Karnofsky performance status following ICU hospitalization compared with the ongoing status before discharge. In patients with primary brain tumor admitted to the ICU, predictive factors of death appear to be similar to those described in non-oncology patients. ICU hospitalization is generally not associated with a subsequent decrease in the functional status.

LRP1B deletion is associated with poor outcome for glioblastoma patients.

INTRODUCTION: Deletion of the tumor suppressor gene LRP1B has been reported in glioblastoma, the most aggressive primary brain tumor in adults. Our objective was to analyze frequency and prognostic impact of LRP1B deletion and expression levels. METHODS: We retrospectively included all the primary IDH1/2 wild-type GBM patients with available clinical follow-up, DNA and RNA from our database. Deletions were analyzed by SNP-array. LRP1B mRNA expression was analyzed by reverse transcription quantitative polymerase chain reaction. RESULTS: 178 patients were included with a median age of 62.36 years. LRP1B deletions were observed for 10.1% of patients (complete: 2.8%, partial: 7.3%). LRP1B deletions were associated with poor progression-free survival (PFS) (p=0.004) and overall survival (OS) (p=0.001). By multivariate analysis, LRP1B deletions remained significant for both PFS (p=0.003, hazard ratio (HR): 2.261) and OS (p=0.001, HR: 2.609). LRP1B was down expressed with a mean relative expression of 46% comparatively to normal tissue. No association between LRP1B mRNA and patient outcome was observed. No correlation was found between the deletions and the mRNA down-expression. These results were validated using GBM TCGA data. CONCLUSION: LRP1B presents with frequent molecular alterations which impact patient outcome, highlighting the potential interest of this gene for glioblastoma patients.

BRAF mutation and anaplasia may be predictive factors of progression-free survival in adult pleomorphic xanthoastrocytoma.

BACKGROUND: Pleomorphic xanthoastrocytoma (PXA) is a rare, low-grade glioma that frequently occurs in pediatric patients. OBJECTIVE: To analyze adult patients diagnosed with PXA and to search for pathological and molecular markers of diagnosis and prognosis. METHODS: We retrospectively included patients older than 16 years with PXA who were referred to our institution between October 2003 and September 2013. All pathological diagnoses were reviewed by a neuropathologist. Histological characteristics and immunostaining of GFAP, OLIG2, neurofilament, CD34, Ki67, p53, p16, and IDH1 R132H were analyzed. The following molecular alterations were analyzed: mutations of IDH1/2, BRAF and the histone H3.3 and the EGFR amplification. Clinical data, treatment modalities, and patient outcome were recorded. RESULTS: We identified 16 adult patients with reviewed PXA diagnosis. No IDH neither histone H3.3 mutations were found; BRAF V600E mutation was recorded in six patients. Ten patients presented with anaplastic features. BRAF mutations were associated with lower Ki67, OLIG2 expression, and lack of p16 expression. Median PFS and OS were 41.5 months (95% CI: 11.4-71.6) and 71.4 months (95% CI: 15.5-127.3), respectively. BRAF mutation tended to be associated with greater PFS (p = 0.051), whereas anaplastic features were associated with minimal PFS (p = 0.042). CONCLUSION: PXA in adults PXA may present features distinct from pediatric PXA. Anaplastic features and BRAF mutation may potentially identify specific subgroups with distinct prognoses.

[HPV prophylactic vaccine coverage and factors impacting its practice among students and high school students in Marseilles' area]. / Vaccination anti-HPV : évaluation de la couverture vaccinale et des facteurs qui l'influencent chez les lycéennes et étudiantes de la région PACA.

OBJECTIVES: To assess the coverage of HPV vaccine among young women from Marseilles' area and factors influencing the probability of this vaccination. MATERIALS AND METHODS: An anonymous survey was conducted among 2124 high school and university students from Marseilles' area, France from December 2011 to May 2012. RESULTS: Mean age of participants was 20.4years (±SD: 3.3). Only 41.6% participants reported being vaccinated against HPV, of whom 768 (93.3) had completed the 3 injections scheme. Among non-vaccinated respondents, 33.6% acknowledged they would accept a catch-up vaccination. Factors influencing the probability of being vaccinated were young age (AOR: 0.728; 95% CI: 0.681-0.779; P<0.001), socioeconomic and/or education level of parents (AOR: 1.324; 95% CI: 1.006-1.742; P=0.045), information about vaccination (AOR: 24.279; 95% CI: 5.417-108.82; P<0.001) and having a general practitioner (GP) favourable to vaccination (AOR: 68.776; 95% CI: 34.511-137.061; P<0.001). Factors influencing the probability to accept a catch-up vaccination were age (AOR: 1.059; 95% CI: 1.001-1.120; P=0.046), socioeconomic and/or education level of parents (AOR: 1.637; 95% CI: 1.198-2.237; P=0.002) and having a GP favourable to vaccination (AOR: 4.381; 95% CI: 2.978-6.445; P<0.001). Only 35.5% of respondents were aware that screening remains necessary following HPV vaccination. CONCLUSION: The coverage of HPV vaccine among young women from Marseilles' area is insufficient. Factors influencing the probability of being vaccinated against HPV are age, socioeconomic and/or education level of parents and information regarding vaccination. GP plays a major role in the acceptance of HPV vaccine.

New IDH1 I113T mutation associated with BRAF V600E mutation: new driver of gliomagenesis?

BACKGROUND: IDH mutations and BRAF mutations are classically mutually exclusive and usually associated with infiltrative or circumscribed gliomas and glioneuronal tumors respectively. CASE REPORT: We report the case of a 26-year old man with intracranial hypertension revealing voluminous right frontal lesion. Surgical resection was performed and pathological examination found two distinct tumoral areas: a glioma-like area with calcification without mitosis; a second with pleomorphic glial cells with higher Mib index, high CD34 expression and endothelial proliferation. No necrosis was recorded. Molecular analyses revealed both IDH1 I113T and BRAF V600E mutations. Although this glioma was difficult to clarify, diagnosis of pleomorphic xanthoastrocytoma with anaplastic feature was suggested based on the association of some pathological feature (eosinophilic granular bodies, reticulin network and diffuse CD34 expression) and the BRAF V600E mutation. CONCLUSION: We report a new IDH1 mutation associated with BRAF mutation in a very unusual glial tumor.

Primary neurolymphomatosis diagnosis and treatment: a retrospective study.

BACKGROUND: To discuss the therapeutic approach for primary neurolymphomatosis. METHODS: We report all primary neurolymphomatosis cases referred to our institution, with descriptions of clinical, radiological, electrophysiological, histological features and long-term follow-up. We treated all patients with a combination of high-dose methotrexate and alkylating agents. RESULTS: Five patients were diagnosed with histologically confirmed primary neurolymphomatosis. The majority of them presented with painful asymmetric sensory-motor neuropathy. Magnetic resonance imaging was abnormal in 4 of 5 patients, as shown with gadolinium enhancements. Electroneuromyography revealed denervation in all 4 cases with contributive examinations. All our patients received a chemotherapy combination of high-dose methotrexate and alkylating agent. Median progression-free survival was 8 months (2 complete responses and 2 partial responses), and overall survival was 24 months. CONCLUSIONS: Primary neurolymphomatosis is rare and polymorphic; it represents a difficult diagnosis of neuropathy. In our cohort, treatment with a chemotherapy combination with high-dose methotrexate showed encouraging results.

Limited impact of prognostic factors in patients with recurrent glioblastoma multiforme treated with a bevacizumab-based regimen.

Bevacizumab has demonstrated activity in patients with recurrent glioblastoma. However, the impact of prognostic factors associated with recurrent glioblastoma treated with cytotoxic agents has not been determined in patients treated with bevacizumab. To analyze the prognostic factors and clinical benefits of bevacizumab and irinotecan treatment in patients with recurrent glioblastoma. This monocentric study retrospectively analyzed all patients with recurrent glioblastoma who were treated with at least one cycle of bevacizumab and irinotecan at our institution from April 2007 to May 2010. Multivariate analysis was used to analyze prognostic factors for overall survival (OS) from the initiation of bevacizumab administration. Among the 100 patients that were identified (M/F: 65/35), the median age was 57.9 years (range: 18-76). Karnofsky Performance Status (KPS) was <70 in 44 patients and ≥ 70 in 56 patients; 83 % of the patients were on steroids. The median tumor area was 2012 mm². The median progression free survival was 3.9 months (CI 95 %: 3.4-4.3). The median OS was 6.5 months (CI 95 %: 5.6-7.4). Multivariate analysis revealed that OS was affected by KPS (p = 0.024), but not by gender, age, steroid treatment, number of previous lines of treatment, tumor size, or time from initial diagnosis. KPS was improved in 30 patients, including 14/44 patients with an initial KPS <70. The median duration of maintained functional independence (KPS ≥ 70) was 3.75 months (CI 95 %: 2.9-4.6). The median OS from initial diagnosis was 18.9 months (CI 95 %: 17.5-20.3). In patients with recurrent glioblastoma treated with bevacizumab, KPS was revealed as the only factor to impact OS. The clinical benefits associated with this regimen appear valuable. A positive impact of bevacizumab administration on OS of patients with glioblastoma multiforme is suggested.