Matthieu Peyre

Prolonged response without prolonged chemotherapy: a lesson from PCV chemotherapy in low-grade gliomas

Previous studies with temozolomide suggest that a prolonged duration of chemotherapy is important for treating low-grade gliomas (LGGs). PCV (procarbazine, CCNU, vincristine) chemotherapy has demonstrated efficacy in treating LGGs, but this therapy cannot be used for a prolonged period because of the cumulative toxicity. The aim of the present study was to evaluate the impact of first-line PCV chemotherapy on LGGs growth kinetics. The mean tumor diameter (MTD) of 21 LGGs was measured on serial magnetic resonance images before (n=13), during, and after PCV onset (n=21). During PCV treatment, a decrease in the MTD was observed in all patients. After PCV discontinuation, an ongoing decrease in MTD was observed in 20 of the 21 patients. Median duration of the MTD decrease was 3.4 years (range, 0.8-7.7) after PCV onset and 2.7 years (range, 0-7) after the end of PCV treatment with 60% of LGGs, demonstrating an ongoing and prolonged (>2 years) response despite chemotherapy no longer being administered. According to McDonalds criteria, the rates of partial and minor responses were 5% and 38% at the end of PCV but 38% and 42% at the time of maximal MTD decrease, which occurred after a median period of 3.4 years after PCV onset. These results challenge the idea that a prolonged duration of chemotherapy is necessary for treating LGGs and raise the issue of understanding the mechanisms involved in the persistent tumor volume decrease once chemotherapy is terminated.

Pseudotumoral presentation of a cervical extracranial vertebral artery aneurysm in neurofibromatosis type 1: Case report

OBJECTIVENeurofibromatosis Type 1 (NF1) is known to be associated with vascular lesions. Association with an extracranial vertebral artery aneurysm is very rare. We report the case of such an aneurysm mimicking a cervical neurofibroma in NF1. CLINICAL PRESENTATIONAn 18-year-old woman with previously diagnosed NF1 presented with a C6 radiculopathy. There were no clinical features suggesting a vascular origin for the lesion. The computed tomographic and standard magnetic resonance imaging scans showed a C5–C6 contrast-enhancing lesion responsible for bony erosion. Subsequent, magnetic resonance angiography and digital subtraction angiography diagnosed the lesion as a C5–C6 vertebral artery aneurysm. INTERVENTIONThe lesion was treated by endovascular occlusion of both the aneurysm and the parent vertebral artery with an initial immediate disappearance of the pain. CONCLUSIONThis case serves as a reminder of the importance of ruling out a vertebral artery aneurysm with angiography when managing cervical lesions in patients with NF1.

Conservative management of bilateral vestibular schwannomas in neurofibromatosis type 2 patients: hearing and tumor growth results.

BACKGROUNDnAs new treatment modalities develop for the management of vestibular schwannomas (VS) in patients with neurofibromatosis type 2, it remains crucial to ascertain the natural history of the disease.nnnOBJECTIVEnTo determine the relationship between hearing and tumor growth in patients undergoing conservative VS management.nnnMETHODSnPatients harboring bilateral VS with at least 1 year of radiological follow-up were selected. Conservative management was proposed based on the small tumor size and/or serviceable hearing at presentation. Tumor size was calculated by using the 2-component box model and reported as mean tumor diameter. Hearing was evaluated by using pure-tone average and the American Academy of Otololaryngologists and Head and Neck Surgery classification.nnnRESULTSnForty-six patients harboring 92 VS were included. The mean clinical and radiological follow-up times were 6.0 and 4.2 years, respectively. The mean tumor diameter was 13 mm at presentation and 20 mm at the end of follow-up. Mean tumor growth rate was 1.8 mm/year. During follow-up, 17 patients (37%) underwent surgery for VS. Surgery-free rate for VS was 88% at 5 years. The number of patients with at least 1 serviceable ear was 39 (85%) at presentation and 34 (74%) at the end of follow-up, including 22 (66%) with binaural serviceable hearing maintained. There was no statistical correlation between tumor growth rate and preservation of serviceable hearing. Tumor growth rates and age at presentation were inversely correlated.nnnCONCLUSIONnThis study illustrates the high variability among neurofibromatosis type 2 patients regarding hearing status and VS growth rate and justifies the choice of initial conservative management in selected cases.nnnABBREVIATIONSn: AAO-HNS, American Academy of Otololaryngologists and Head and Neck Surgery classificationMTD, mean tumor diameterNF2, neurofibromatosis type 2PTA, pure-tone averageSDS, speech discrimination scoreVS, vestibular schwannomas.

Meningioma mouse models

Meningiomas, although mostly benign, may sometimes present aggressive features and raise issues concerning alternative treatment options besides surgery. In order to gain new insights in meningioma biology and develop alternative treatments, several meningioma mouse models have been engineered during the past two decades. As rodents very rarely develop spontaneous meningiomas, animal models have been first developed by implanting human meningioma cells derived from a primary tumor and meningioma cell lines subcutaneously into athymic mice. Induction of de novo meningiomas in rodents with mutagens, such as nitrosourea, has also been reported. Advances in our understanding of molecular genetics of meningioma have pinpointed the central role of NF2 tumor suppressor gene in the pathogenesis of those tumors. These discoveries have led to the creation of a genetically engineered model utilizing conditional mutagenesis to specifically inactivate the mouse Nf2 gene in arachnoidal cells, resulting in the formation of intracranial meningothelial hyperplasia and meningiomas and thus reproducing the main mechanism of human meningeal tumorigenesis. This powerful new technology significantly improves on prior models and may open avenues of investigation never before possible in meningioma research. We present here a review of current meningioma mouse models used in translational therapeutics with associated imaging and pre-clinical studies.

Multifocal choroid plexus papillomas: case report

Choroid plexus papillomas (CPP) are rare tumors of the central nervous system, usually occurring in the ventricular system. Apart from spinal drop metastases, CPPs are generally unique tumors. In this report, the authors present two exceptional adult cases involving multiple benign CPPs located in both intra- and extraventricular locations. The tumors were located in the fourth ventricle and Meckels cave in one case and the cerebellopontine angle, the frontotemporal region and the fourth ventricle in the other. A review of the literature revealed that these two cases represent the first reported occurrences of multiple choroid plexus papillomas involving Meckels cave and frontotemporal intraparenchymal locations.

Cytoplasmic overexpression of RNA-binding protein HuR is a marker of poor prognosis in meningioma, and HuR knockdown decreases meningioma cell growth and resistance to hypoxia

HuR regulates cytoplasmic mRNA stability and translatability, and the HuR expression level has been shown to correlate with poor disease outcome in several cancer types; however, the prognostic value and potential pro‐oncogenic properties of HuR in meningioma remain unclear. Thus, in the present study, we analysed 85 meningioma tissue samples to establish the relationship between HuR expression, tumour cell proliferation, and/or patient survival. In addition, we examined the anti‐proliferative effects of HuR knockdown in two meningioma cell lines (IOMM‐Lee and Ben‐Men‐1) and conducted transcriptome‐wide analyses (IOMM‐Lee cells) to elucidate the molecular consequences of HuR knockdown. The results of the present study showed HuR cytoplasmic expression to correlate positively with tumour grade (p = 1.2u2009×u200910−8) and negatively with progression‐free and overall survival (p = 0.01) time in human meningioma tissues. In vitro, siHuR‐induced HuR knockdown was shown to reduce the growth of both Ben‐Men‐1 (p = 2u2009×u200910−8) and IOMM‐Lee (p = 4u2009×u200910−9) cells. Transcriptome analyses revealed HuR knockdown in IOMM‐Lee cells to deregulate the HIF1A signalling pathway (p = 1.5u2009×u200910−6) and to up‐regulate the expression of genes essential for the assembly of the cytoplasmic mRNA processing body, global genome nucleotide‐excision repair, poly(A)‐specific ribonuclease activity, the positive regulation of apoptosis and of cell cycle arrest, and the negative regulation of RNA splicing [p(FDR)u2009<u20090.001]. Interestingly, HuR knockdown under hypoxic culture conditions further potentiated the effects of HuR knockdown on cell growth, apoptosis, and HIF1A expression. We thus conclude that cytoplasmic HuR expression is a marker of poor prognosis in meningioma and that HuR is a promising potential therapeutic target for use in tumours refractory to standard therapies. Copyright

Dramatic Shrinkage with Reduced Vascularization of Large Meningiomas After Cessation of Progestin Treatment

BACKGROUNDnThe relationship between long-term intake of progestin and meningioma growth is now well-known and has become a model of hormone-driven meningioma growth. Conversely, it has been demonstrated that cessation of treatment often leads to tumor regression. Consequently, watchful observation has become the strategy of choice in the case of multiple meningiomas in asymptomatic patients undergoing progestin treatment.nnnCASE DESCRIPTIONnIn 2 patients with large tumors (>60 cm3) scheduled for surgery, conservative management with cessation of progestin treatment produced a dramatic reduction of meningioma size from 64 to 11 cm3 (-83%) and 68 to 13 cm3 (-81%), respectively, during a 1-year period. This shrinkage was associated with spontaneous devascularization of the meningiomas as observed on T2-weighted images.nnnCONCLUSIONSnThis observation adds new insights into the role of progesterone in meningioma tumorigenesis and could lead to future discoveries on the molecular relationships between meningioma tumorigenesis, progesterone dependence, and tumor vascularization.

Diffuse midline skull base meningiomas: identification of a rare and aggressive subgroup of meningiomas

Skull base meningiomas may present as clinically aggressive tumors despite being histologically benign. Here we describe a clinico-radiological entity of diffuse midline skull base meningiomas responsible for several neurological morbidities, including hearing and vision loss, intracranial hypertension, secondary hydrocephalus and tonsillar herniation with spinal cord compression. Surgery and radiotherapy were ineffective in stopping the clinical course of those tumors. After targeted sequencing of known mutated genes in meningiomas, we discovered TRAF7 mutations in two out of four tumors, stressing the importance of focusing the research efforts of the meningioma community in understanding the mechanisms underlying TRAF7 related meningioma tumorigenesis.

Patterns of relapse and growth kinetics of surgery- and radiation-refractory meningiomas.

Patients with surgery- and radiation-refractory meningiomas have a poor outcome. Due to our lack of knowledge concerning multi-recurrent meningioma natural history, their clinical course is poorly defined. This retrospective study aims at defining patterns of relapse in order to help in the definition of response criteria in future clinical trials. We performed a retrospective review of surgery- and radiotherapy-refractory meningioma cases with interpretable radiological follow-up treated in our department. Tumor volumes were measured on 3D T1 Gadolinium volumetric sequences using a semi-automated algorithm for tumor segmentation. Twenty nine patients with multi-treated meningioma (11 WHO Grade II, 5 de novo WHO Grade III and 13 transformed WHO Grade III), were evaluated. Median PFS was 16xa0months for patients with Grade II meningiomas. In patients with Grade III meningiomas, the de novo subgroup had a median PFS of 4xa0months compared with 7xa0months in patients with malignant transformation. Volumetric analysis of tumor growth concerned 95 tumor nodules in 50 relapses. The mean growth rate of tumor nodules was 10.4xa0cm3/year (95xa0% CI 7.3–14.8xa0cm3/year). Three patterns of tumor growth were described: “classical” for 9 (31xa0%) patients, “local multi-nodular” for 6 (21xa0%) patients and “multi-nodular metastatic” for the last 14 (48xa0%) patients. Considering all tumor nodules, median time to tumor progression (TTP) was 3.7xa0months. Progressing tumors represent the most frequent histological subgroup of surgery and radiation-refractory meningiomas while tumors with multi-nodular metastatic dissemination are the prominent radiological pattern of progression.

Current treatment options for meningioma

ABSTRACT Introduction: With an annual incidence of 5/100,000, meningioma is the most frequent primary tumor of the central nervous system. Risk factors are radiotherapy and hormone intake. Most meningiomas are grade I benign tumors, but up to 15% are atypical and 2% anaplastic according to the WHO 2016 histological criteria. Areas covered: This review details the current standard therapy based on international guidelines and recent literature, and describes new approaches developed to treat refractory cases. First-line treatments are observation and surgery, but adjuvant radiotherapy/radiosurgery is discussed for atypical and indicated for anaplastic meningiomas. The most problematic cases include skull base meningiomas that enclose vasculo-nervous structures and surgery- and radiation-refractory tumors that present with significant morbidity and mortality. The treatment of recurrent tumors is based on radiotherapy and repeated surgery. Systematic therapies are not effective in general but several clinical trials are ongoing. Expert commentary: Molecular characterization of the tumors, based on genetic mutations such as NF2, SMO, TERT, TRAF7, and on the methylation profile are developing, completing the histological classification and giving new insights into prognosis and treatment options.