Renal collision tumours: three additional case reports.

BACKGROUND: Multiple kidney tumours are frequently seen in hereditary syndromes and familial diseases. Renal collision tumours (RCT) are characterized by the simultaneous existence of different and unrelated tumour types within the same location in the kidney, forming a single, heterogenous lesion. RCT are uncommon histological entities with distinctive features. The most frequent subtypes include clear cell renal cell carcinoma (CCRCC), papillary renal cell carcinoma (PRCC), chromophobe renal cell carcinoma (CRCC), and collecting duct carcinoma (CDC). CASE PRESENTATION: Here, we report three sporadic cases of RCT successfully treated by nephrectomy and confirmed by histological analysis. The first case was of a 64-year-old man diagnosed with RCT composed of a stage 2 nucleolar grade 3 CCRCC and a stage 1a nucleolar grade 2 type 1 PRCC. The second case was of a 68-year-old woman diagnosed with a combined nucleolar grade 2 type 1 PRCC and an angiomyolipoma (non-assessed stage), while the third case was of a 59-year-old woman diagnosed with a combined stage 1a nucleolar grade 3 CCRCC and a stage 1b CDC. CONCLUSIONS: Due to the rarity of RCT, there are no standard guidelines for their management. Hence, the prognosis is considered to be associated with the most aggressive component, possibly the tumour with the highest nucleolar grade and stage. The histogenesis of RCT remains debated, and increase in knowledge regarding this can help enable the development of targeted therapies for advanced or metastatic tumours.

Analysis of CDKN2A gene alterations in recurrent and non-recurrent meningioma.

PURPOSE: Assessment of the risk of recurrence is essential to determine the therapeutic strategy of meningioma treatment. Many relapsing or aggressive meningiomas show elevated mitotic and/or Ki67 indices, reflecting cell cycle deregulation. As CDKN2A is a key tumor suppressor gene involved in cell cycle control, we investigated whether CDKN2A alterations may be involved in tumor recurrence. METHODS: We carried out a comparative analysis of 17 recurrent and 13 non-recurrent meningiomas. CDKN2A single nucleotide variations (SNVs), deletions, methylation status of the promotor, and p16 expression were investigated. Results were correlated with the recurrent or non-recurrent status and clinicopathological data. RESULTS: We identified a CDKN2A SNV (NM_000077, exon2, c.G442A, p.Ala148Thr) in five meningiomas that was significantly associated with recurrence (p = 0.03). This mutation, confirmed by Sanger sequencing and referenced in the COSMIC database in various cancers, has not been reported in meningioma. The presence of one of the three following CDKN2A alterations-p.(Ala148Thr) mutation, whole homozygous or heterozygous gene loss, or promotor methylation > 8%-was observed in 13 of the 17 relapsing meningiomas and was strongly associated with recurrence (p < 0.0001) and a Ki67 labeling index > 7% (p = 0.004). CONCLUSION: We report an undescribed p.(Ala148Thr) CDKN2A mutation in meningioma that was only present in relapsing tumors. In our series, CDKN2A gene alterations were only found in recurrent meningiomas. However, our results need to be evaluated on a larger series to ensure that these CDKN2A alterations can be used as biomarkers of recurrence in meningioma.

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 = 1.2 × 10-8 ) 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 = 2 × 10-8 ) and IOMM-Lee (p = 4 × 10-9 ) cells. Transcriptome analyses revealed HuR knockdown in IOMM-Lee cells to deregulate the HIF1A signalling pathway (p = 1.5 × 10-6 ) 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) < 0.001]. 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 © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[Calcifying pseudoneoplasm of the neuraxis]. / Pseudo-tumeur calcifiante du névraxe.

Calcifying pseudoneoplasms of the neuraxis (CAPNON) are rare lesions of the central nervous system. To date, about 60 cases have been reported in literature. We present a case that had the peculiarity to occur in a pregnant woman. At 32 weeks of gestation, a 26-year-old woman was hospitalized to explore nocturnal epigastralgia. During the hospitalisation, the patient presented generalised seizures. As an eclampsia had been suspected, a caesarean delivery was performed. Post-operatively, the patient harboured memory disorders and neuro-imaging explorations were done. They showed an intracerebral calcified mass located in the left frontal lobe and surrounded by an oedema. A complete surgical resection was performed. Histological examination of the surgical specimen showed a calcified tissue containing a fibrillary or granular material. A dense and hyalinised eosinophilic material focally surrounded the calcifications and contained regular fusiform cells of fibroblastic type. Foci of lipomatous and osseous metaplasia were present. Immunohistochemical staining for EMA and STAT6 was negative. There was no associated meningioangiomatosis nor tumour proliferation. Forty-five months after surgery, the patient did not present any seizures and had no sequelae. CAPNON are rare lesions occurring at any age. Their location in the central nervous system is ubiquitous and they can be intra or extra axial. The treatment is surgical and the prognosis excellent. CAPNON must be recognized and distinguished from the other calcified lesions, tumoural or non-tumoural, to avoid an inadequate and potentially harmful treatment.

Autophagy and TrkC/NT-3 signaling joined forces boost the hypoxic glioblastoma cell survival.

Glioblastoma multiform (GBM), the most common and aggressive primary brain tumor, is characterized by a high degree of hypoxia and resistance to therapy because of its adaptation capacities, including autophagy and growth factors signaling. In this study, we show an efficient hypoxia-induced survival autophagy in four different GBM cell lines (U87MG, M059K, M059J and LN-18) and an activation of a particular neurotrophin signaling pathway. Indeed, the enhancement of both TrkC and NT-3 was followed by downstream p38MAPK phosphorylation, suggesting the occurrence of a survival autocrine loop. Autophagy inhibition increased the hypoxia-induced expression of TrkC and its phosphorylated form as well as the phosphorylation of p38, suggesting a complementary effect of the two processes, leading to cell survival. Alone, autophagy inhibition reduced cellular growth without inducing cell death. However, the double inhibition of autophagy and TrkC signaling was necessary to bring cells to death as shown by PARP cleavage, particularly important in hypoxia. Moreover, a very high expression of TrkC and NT-3 was found in tumor sections from GBM patients, highlighting the importance of neurotrophic signaling in GBM tumor cell survival. These data suggest that a combined treatment targeting these two pathways could be considered in order to induce the death of GBM cells.

Chemotherapy outcome predictive effectiveness by the Oncogramme: pilot trial on stage-IV colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) remains a major public concern. While conventional chemotherapeutic regimens have proved useful against advanced/metastatic diseases, progresses are to be made to effectively cure the large portion of patients not benefiting from these treatments. One direction to improve response rates is to develop chemosensitivity and resistance assays (CSRAs) efficiently assisting clinicians in treatment selection process, an already long preoccupation of oncologists and researchers. Several methods have been described to this day, none achieving yet sufficient reliability for recommended use in the clinical routine. METHODS: We led a pilot study on 19 metastatic CRC patients evaluating capacity of the Oncogramme, a standardized process using tumor ex vivo models, to provide chemosensitivity profiles and predict clinical outcome of patients receiving standard CRC chemotherapeutics. Oncogramme responses were categorized according to the method of percentiles to assess sensitivity, specificity and concordance. RESULTS: We report from a primary analysis a success rate of 97.4 %, a very good sensitivity (84.6 %), a below-average specificity (33.3 %), along with a global agreement of 63.6 % and a concordance between Oncogramme results and patients' responses (Kappa coefficient) of 0.193. A supplementary analysis, focusing on CRC patients with no treatment switch over a longer time course, demonstrated improvement in specificity and concordance. CONCLUSIONS: Results establish feasibility and usefulness of the Oncogramme, prelude to a larger-scale trial. Advantages and drawbacks of the procedure are discussed, as well as the place of CSRAs within the future arsenal of methods available to clinicians to individualize treatments and improve patient prognosis. TRIAL REGISTRATION: ClinicalTrials.gov database, registration number: NCT02305368.

Involvement and prognosis value of CD8(+) T cells in giant cell arteritis.

CD8(+) T cells participate in the pathogenesis of some vasculitides. However, little is known about their role in Giant Cell Arteritis (GCA). This study was conducted to investigate CD8(+) T cell involvement in the pathogenesis of GCA. Analyses were performed at diagnosis and after 3 months of glucocorticoid treatment in 34 GCA patients and 26 age-matched healthy volunteers. Percentages of CD8(+) T-cell subsets, spectratype analysis of the TCR Vß families of CD8(+) T cells, levels of cytokines and chemokines and immunohistochemistry of temporal artery biopsies (TAB) were assessed. Among total CD8(+) T cells, percentages of circulating cytotoxic CD8 T lymphocytes (CTL, CD3(+)CD8(+)perforin(+)granzymeB(+)), Tc17 (CD3(+)CD8(+)IL-17(+)), CD63(+)CD8(+) T cells and levels of soluble granzymes A and B were higher in patients than in controls, whereas the percentage of Tc1 cells (CD3(+)CD8(+)IFN-γ(+)) was similar. Moreover, CD8(+) T cells displayed a restricted TCR repertoire in GCA patients. Percentages of circulating CTL, Tc17 and soluble levels of granzymes A and B decreased after treatment. CXCR3 expression on CD8(+) T cells and its serum ligands (CXCL9, -10, -11) were higher in patients. Analyses of TAB revealed high expression of CXCL9 and -10 associated with infiltration by CXCR3(+)CD8(+) T cells expressing granzyme B and TiA1. The intensity of the CD8 T-cell infiltrate in TAB was predictive of the severity of the disease. This study demonstrates the implication and the prognostic value of CD8(+) T-cells in GCA and suggests that CD8(+) T-cells are recruited within the vascular wall through an interaction between CXCR3 and its ligands.

[Large cell calcifying Sertoli cell tumour: A case report]. / La tumeur à cellules de Sertoli à grandes cellules calcifiantes : à propos d'un cas.

A 19-year-old male Caucasian, without prior medical history, noticed a painless right testicular mass. Physical examination revealed neither gynecomastia nor abnormal skin pigmentation. Serum alpha-fetoprotein, ß-HCG and testosterone levels were normal. Sonography depicted an intratesticular diffusely hyperechoic lesion with acoustic shadowing. The patient underwent right orchiectomy. Histology revealed a benign large cell calcifying Sertoli cell tumour. This tumour is rare and may be associated with genetic abnormalities.

[Two cases reports of pancreatic endocrine microadenoma incidentally found]. / Découverte fortuite de micro-adénome endocrine pancréatique : à propos de deux cas.

A 59-year-old male, was admitted to our hospital for a tumor of the pancreatic tail. Serum CEA and CA 19-9 levels were normal. Splenopancreasectomy found a desmoid tumour. A 69-year-old male was referred to our institution for chronic anemia and inflammatory syndrome with splenomegaly. Splenectomy showed an important splenic congestion and siderosis. Both patients had a type 2 diabetes mellitus. Furthermore, histological examination revealed pancreatic endocrine microadenomas. The two patients' postoperative course was unremarkable. Eleven and 24 months respectively after the diagnosis, the patients are alive and well, with no tumor recurrence.

Comparative analysis of histopathological parameters, genome-wide copy number alterations, and variants in genes involved in cell cycle regulation in chordomas of the skull base and sacrum.

Chordomas are rare tumors of the axial skeleton that are refractory to conventional therapy. Few studies have compared the morphological and molecular characteristics of chordomas according to the skull base and sacral locations. Histopathological data and changes revealed by array comparative genomic hybridization (CGH) and next-generation sequencing (NGS) of cell cycle regulation genes were analyzed for 28 skull base (SBCs) and 15 sacral (SC) chordomas. All cases were conventional chordomas. SBCs were significantly more frequent in patients aged <40 years and SCs predominated in patients aged >60 years. Mitotic indices ≥2 mitoses/10 high-power fields were correlated with high degrees of nuclear atypia and Ki67 labeling indices ≥6%. We identified 321 genomic positions, and copy number variation losses were more frequent than gain. Moreover, we report a panel of 85 genetic variants of cell cycle genes and the presence of molecular clusters for chordoma as well in CGH as in NGS. These new data strengthen the view that the chordoma should not be considered as a single molecular entity.

Myxofibrosarcoma of the orbit: case report and review of literature.

A 17-year-old man was referred with a 6-month history of painless left inferior eyelid edema. Ophthalmic examination was normal except for the presence of a reddish conjunctiva in the left eye medial canthus. MRI demonstrated a 20-mm well-defined extraconical mass between the medial and inferior rectus muscle without destruction of the medial orbital wall. A low-grade myxofibrosarcoma was diagnosed on orbital biopsy. The tumor was locally excised, but the patient categorically refused left exenteration or conformal radiotherapy. He accepted to have annual clinical and radiologic checkup. To date, 2 years later, he has been followed up with no evidence of tumor recurrence. Orbital localization of myxofibrosarcoma is extremely rare, with only 2 cases reported in the literature. The differential diagnosis could be difficult: here, a fibromyxoid sarcoma and a myxoid variant of dedifferentiated liposarcoma have been especially discussed in terms of their histopathologic features. Risk of metastasis is related to the tumor grade. Management of these tumors associates surgery with orbital exenteration or globe-sparing approaches and postsurgical adjuvant radiation therapy.

[Guidelines for adult diffuse gliomas WHO grade II, III and IV: pathology and biology. Société franc¸aise de neuropathologie . Réseau de neuro-oncologie pathologique]. / Référentiel gliomes diffus de l'adulte de grade OMS II, III et IV : anatomie pathologique et biologie.

Pathological diagnosis plays a major role in the therapeutic management of adult diffuse gliomas. It is based on the histopathological analysis of a representative specimen. Therefore pathologists might be aware of the neuroradiological features of the lesions. Pathologists play a major role in the management of biological resources. Pathologists should classify adult gliomas according to WHO 2007 classification (histological subtype and grade). In addition, in order to provide the histomolecular classification of adult gliomas, search for molecular markers of diagnostic, prognostic or predictive of therapeutic responses must be performed by appropriate and validated immunohistochemical and molecular techniques. In all diffuse gliomas, whatever their grade, search for IDH1 R132H and P53 expression is required. Search for IDH1 minor mutations and IDH2 mutations is required in grade II and III IDH1 R132H negative gliomas whereas 1p19q codeletion should be searched for in grade II and III gliomas with an oligodendroglial component. Search for EGFR amplification and MGMT promoter methylation is recommended. It is strongly recommended to fill the standardized form for pathology and molecular features (validated by the French Society of Neuropathology) in all adult diffuse gliomas.

Transforming growth factor ß-receptor II protein expression in benign prostatic hyperplasia is associated with prostate volume and inflammation.

OBJECTIVE: To assess transforming growth factor ß-receptor II (TGFBRII) protein expression in benign prostatic hyperplasia (BPH) using immunohistochemistry analysis, and to compare the analysis with phenotypic properties. METHODS: TGFBRII protein expression was profiled using three clinical outcome tissue microarrays (TMAs), sampled from 231 patients who underwent surgery for BPH. Using these TMAs, five inflammatory cell markers were also assessed, including CD3, CD4, CD8, CD20, and CD163. The surgical procedure was open prostatectomy in 95 patients and transurethral resection of the prostate in 136 patients. RESULTS: TGFBRII protein expression was found in BPH epithelium cells for both basal and secretory cells, as well as in fibromuscular stromal cells. TGFBRII staining was also strong in most of the lymphocytes infiltrating the prostate. TGFBRII stromal staining was found to be significantly associated with prostate volume (P = 0.04), whereas TGFBRII epithelial staining was found to be significantly associated with 5-α-reductase-inhibitor medical therapy received by patients before surgery (P = 0.004). Both stromal and epithelial TGFBRII staining were found to be associated with CD4 T-lymphocyte infiltrate, independently of prostate volume (P < 0.001 and P = 0.002). CONCLUSIONS: TGFBRII protein expression in BPH is associated with prostate gland volume and with CD4 T-lymphocyte prostatitis. TGFBRII might be a promising therapeutic target to prevent prostate enlargement or even to decrease prostate volume.

Value of liver stiffness measured by transient elastography in the liver transplant pre-operative evaluation of the potential deceased liver donors: preliminary study.

The selection of a liver graft is crucial for the success of a transplantation. One of the determinant factors in the selection of a liver graft of quality is to assess the degree of steatosis. The aim of this study was to evaluate the feasibility of a FibroScan(®) during the liver retrieval procedure and to determine the interest of measuring liver stiffness (LS) using the FibroScan(®) as a criterion of objective assessment in the pre-donation selection of liver grafts. Of 16 FibroScan(®) performed on 16 livers of donors meeting conventional French criteria for the selection of liver grafts, the LS values were considered as abnormal in three donors (18.75%). The correspondence with the histologic analysis of the biopsies in terms of elevated steatosis was excellent. For 13 other liver grafts, the values of LS were normal as were the histologic analyses of the biopsies. A supplementary multicenter study is required in order to position the transient elastography as the objective examination in the pre-operative selection of liver grafts.

Alpha-fetoprotein and focal nodular hyperplasia: An unconventional couple.

We report the case of a 36-year-old patient who was initially managed for gynecomastia. The first biological analyses showed a moderately elevated alpha-fetoprotein (AFP) level. After an endocrine etiology was excluded, an abdominal computed tomography scan showed typical focal nodular hyperplasia (FNH) proven by biopsy and showing expression of AFP in FNH cells. After follow-up for 24 months, the serum AFP and liver radiology remained unchanged. The association between an elevated AFP and FNH is rarely described in the medical literature.

Isolated cerebral Rosai-Dorfman disease presenting as a sole mass protruding into the fourth ventricle: A case report.

Rosai-Dorfman disease is a non-Langherans cell histiocytosis typically revealed by a lymphadenopathy. Central nervous system involvement is rare, exceptionally isolated, and usually consists of dural masses mimicking meningioma. Very few reports have described non-dural-based lesions, especially with an intra-ventricular development. We report hereby the case of a Rosai-Dorfman disease in a 30-year-old man presenting as an isolated mass arising from the right cerebellar peduncle and protruding into the fourth ventricle. We provide the results of the MRI examination with a special focus on advanced MRI features. As the diagnosis relies on pathological examination, we also detail the results of the analysis that followed the surgical resection of the mass including the immunohistochemical profile. This report highlights the necessity to consider Rosai-Dorfman disease as a potential diagnosis in case of an infra-tentorial mass and/or intra-ventricular mass.

1p19q LOH patterns and expression of p53 and Olig2 in gliomas: relation with histological types and prognosis.

In glial tumors, the loss of heterozygosity of the 1p and 19q chromosomal arms is thought to be a marker of good prognosis in oligodendroglial tumors. However, 1p and 19q loss of heterozygosity may be telomeric, interstitial, centromeric or affect the whole arm of the chromosome and the associations between these different patterns and tumor type, other molecular markers and patient prognosis remain unclear. We analyzed microsatellite markers in a region spanning the chromosome from the telomere to the centromere, to characterize the pattern of 1p and 19q loss of heterozygosity in 39 infiltrative gliomas, including astrocytomas, glioblastomas, oligoastrocytomas and oligodendrogliomas. We then studied the association between loss of heterozygosity and the expression of p53 protein and Olig2, as analyzed using immunohistochemistry, and epidermal growth factor receptor (EGFR) gene amplification, as investigated using fluorescence in situ hybridization (FISH). Finally, we assessed the influence of molecular markers on the overall survival of patients. We identified five different 1p19q loss of heterozygosity patterns among the tumors studied and found that loss of heterozygosity over the whole 1p arm was associated with loss of heterozygosity over the whole 19q arm in 90% of cases. 1p19q whole loss was present in all the classical oligodendrogliomas, whereas other 1p19q loss patterns predominated in oligoastrocytomas. 1p19q whole loss was also significantly associated with Olig2 overexpression, but was never observed in tumors overexpressing p53 protein. We also found that, among patients with contrast-enhancing tumors, those with 1p19q whole loss tended to survive for longer. In combination with classical histological and immunohistochemical data, 1p19q status determination provides pertinent information useful for (1) discriminating between histological types of gliomas and (2) identifying a subgroup of tumors that are associated with a better prognosis.

Development of a Novel Orthotopic Primary Human Chordoma Xenograft Model: A Relevant Support for Future Research on Chordoma.

Chordomas are slow-growing rare malignant neoplasms. The aim of this study was to establish a primary model of chordoma in the lumbosacral orthotopic area, to compare the growth rate to the subcutaneous site, and to show that this new graft site optimizes tumor growth and bony invasion. Eleven chordoma samples were transplanted subcutaneously in the flank and/or in contact with the lumbosacral region and grown into nude mice. Engraftment rate was significantly more successful in the lumbosacral environment compared with the flank at P0. Two xenografts from 2 patients showed bone invasion. One tumor was maintained through multiple rounds of serial transplantation, creating a model for study. Histological and immunostaining analysis confirmed that tumor grafts recapitulated the primary tumor from which they were derived, consisting of a myxoid chordoma expressing brachyury, cytokeratin AE1, EMA, and VEGF. Clear destruction of the bone by the tumor cells could be demonstrated. Molecular studies revealed PIK3CA and PTEN mutations involved in PI3K signaling pathway and most of the frequently reported chromosomal alterations. We present a novel orthotopic primary xenograft model of chordoma implanted for the first time in the lumbosacral area showing bone invasion, PIK3CA, and PTEN mutations that will facilitate preclinical studies.

WHO grade II and III meningiomas: a study of prognostic factors.

Meningiomas represent one of the largest subgroups of intracranial tumors. They are generally benign, but may show a histological progression to malignancy. Grades II and III meningiomas have been less well studied and are not well controlled because of their aggressive behaviour and recurrences. There is no consensus on therapeutic strategies and no prognostic factors are known. In order to determine these parameters, a multi-institutional retrospective analysis was performed in France with the support of the Neuro-Oncology Club of the French Neurosurgical Society. This study was performed on 199 adults treated for WHO grade II (166 patients) or grade III (33 patients) meningiomas between 1990 and 2004 in the Neurosurgery Departments of five French University Hospitals. Data on epidemiology, clinical behaviour and therapy were collected. Overall survival and progression-free survival were analysed as a function of each possible prognostic factor. For patients with grade II meningiomas, the 5- and 10-year OS rates were 78.4 and 53.3%, respectively, while, for patients with grade III meningiomas, the corresponding values were 44.0 and 14.2%. For patients with grade II meningiomas, the 5- and 10-year PFS rates were 48.4 and 22.6%, respectively, the corresponding values for patients with grade III meningiomas being 8.4 and 0%. For the grade II meningiomas, univariate analysis showed that age < 60 years (P < 0.0001) and Simpson 1 resection (P = 0.055) were associated with a longer OS. For the grade III meningiomas, univariate analysis showed that age < 60 years (P < 0.0001) and RT (P = 0.036) were associated with a longer OS. Histological grade II was found to be associated with a longer PFS (P = 0.0032) and RT reduced the PFS in grade II meningiomas (P = 0.0006) There were no other prognostic factors in terms of PFS for grades II and III meningiomas in univariate analysis. Multivariate analysis confirmed that age (< 60 years), Simpson 1 and histological grade II were independent prognostic factors for survival. This retrospective study might improve the management of grades II and III meningiomas. Prospective trials should delineate strong therapeutic guidelines for high-grade meningiomas.