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The Simpson grading revisited: aggressive surgery and its place in modern meningioma management

Konstantinos Gousias, Johannes Schramm, and Matthias Simon

OBJECTIVE

Recent advances in radiotherapy and neuroimaging have called into question the traditional role of aggressive resections in patients with meningiomas. In the present study the authors reviewed their institutional experience with a policy based on maximal safe resections for meningiomas, and they analyzed the impact of the degree of resection on functional outcome and progression-free survival (PFS).

METHODS

The authors retrospectively analyzed 901 consecutive patients with primary meningiomas (716 WHO Grade I, 174 Grade II, and 11 Grade III) who underwent resections at the University Hospital of Bonn between 1996 and 2008. Clinical and treatment parameters as well as tumor characteristics were analyzed using standard statistical methods.

RESULTS

The median follow-up was 62 months. PFS rates at 5 and 10 years were 92.6% and 86.0%, respectively. Younger age, higher preoperative Karnofsky Performance Scale (KPS) score, and convexity tumor location, but not the degree of resection, were identified as independent predictors of a good functional outcome (defined as KPS Score 90–100). Independent predictors of PFS were degree of resection (Simpson Grade I vs II vs III vs IV), MIB-1 index (< 5% vs 5%–10% vs >10%), histological grade (WHO I vs II vs III), tumor size (≤ 6 vs > 6 cm), tumor multiplicity, and location. A Simpson Grade II rather than Grade I resection more than doubled the risk of recurrence at 10 years in the overall series (18.8% vs 8.5%). The impact of aggressive resections was much stronger in higher grade meningiomas.

CONCLUSIONS

A policy of maximal safe resections for meningiomas prolongs PFS and is not associated with increased morbidity.

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Polymorphisms of methionine metabolism and susceptibility to meningioma formation

Laboratory investigation

Alexander Semmler, Matthias Simon, Susanna Moskau, and Michael Linnebank

Object

Functionally relevant polymorphisms of methionine and folate metabolism have been shown to be associated with various human cancer entities including cerebral lymphoma and glioblastoma multiforme. The authors investigated the association of 7 functional polymorphisms of methionine metabolism with meningioma formation.

Methods

This case-controlled, monocenter association study included 290 patients of Caucasian origin undergoing surgical resection for intracranial meningioma (World Health Organization [WHO] Grade I, 190 cases; WHO Grade II, 82 cases; WHO Grade III, 18 cases) and 287 age- and sex-matched local controls. The authors analyzed the following genetic variants: dihydrofolate reductase c.594+59del19, 5,10-methylenetetrahydrofolate reductase c.677C > T and c.1298A > C, 5-methyltetrahydrofolate-homocysteine S-methyltransferase (MTR) c.2756A > G, reduced folate carrier 1 c.80G > A, cystathionine beta-synthase (CBS) c.844_855ins68 and transcobalamin 2 c.776C > G.

Results

The variant CBS c.844_855ins68—that is, the allele carrying the insertion (“ins” or “i”) as opposed to the wild-type allele designated as deletion (“del” or “d”)—was significantly overrepresented in meningioma patients (dd/ id/ii: 0.81/0.18/0.01) in comparison with the controls (dd/id/ii: 0.88/0.12/0; 2 df, chi-square 8.97, p = 0.011; multiple nominal regression with age and sex as covariables). In addition, explorative analyses revealed an association of the MTR c.2756A > G variant with meningioma WHO Grade III (AA/AG/GG: patients, 1.0/0/0; controls, 0.64/0.32/0.04; 2 df, chi-square 14.44, p = 0.001).

Conclusions

The results of this study suggest that genetic variants of methionine metabolism are associated with meningioma formation.

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Letter to the Editor. Function outcome related to aggressive surgery for meningioma?

Baoyin Shan, Jing Zhang, and Jianguo Xu

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Evidence for clonal spread in the development of multiple meningiomas

Jeffrey J. Larson, John M. Tew Jr., Matthias Simon, and Anil G. Menon

✓ Meningiomas are common intracranial tumors that arise from the arachnoid cells of the meninges. Occasionally patients develop multiple meningiomas. Because the underlying mechanism of multiple meningioma formation is unknown, the authors examined the pattern of X chromosome inactivation in multiple meningiomas. Fifteen intracranial meningiomas were resected in four patients with multiple meningiomas to determine whether the tumors in patients with multiple meningiomas originate from a common progenitor cell or arise independently. Specimens were examined using polymerase chain reaction assays to detect the pattern of X chromosome inactivation. In each patient, all tumors showed inactivation of the same X chromosome, suggesting that tumors arose from the same clone of cells (p <0.0005). The authors conclude that multiple meningiomas arise from the uncontrolled spread of a single progenitor cell.

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Update on the diagnostic value and safety of stereotactic biopsy for pediatric brainstem tumors: a systematic review and meta-analysis of 735 cases

Christina Hamisch, Philipp Kickingereder, Matthias Fischer, Thorsten Simon, and Maximilian I. Ruge

OBJECTIVE

Recent studies have shed light on the molecular makeup of diffuse intrinsic pontine gliomas and led to the identification of potential treatment targets for these lesions, which account for the majority of pediatric brainstem tumors (pedBSTs). Therefore, stereotactic biopsy–driven molecular characterization of pedBSTs may become an important prerequisite for the management of these fatal brain tumors. The authors conducted a systemic review and meta-analysis to precisely determine the safety and diagnostic success of stereotactic biopsy of pedBSTs.

METHODS

A systematic search of PubMed, EMBASE, and the Web of Science yielded 944 potentially eligible abstracts. Meta-analysis was conducted on 18 studies (including the authors’ own institutional series), describing a total of 735 biopsy procedures for pedBSTs. The primary outcome measures were diagnostic success and procedure-related complications. Pooled estimates were calculated based on the Freeman-Tukey double-arcsine transformation and DerSimonian-Laird random-effects model. Heterogeneity, sensitivity, and meta-regression analyses were also conducted.

RESULTS

The weighted average proportions across the analyzed studies were 96.1% (95% CI 93.5%–98.1%) for diagnostic success, 6.7% (95% CI 4.2%–9.6%) for overall morbidity, 0.6% (95% CI 0.2%–1.4%) for permanent morbidity, and 0.6% (95% CI 0.2%–1.3%) for mortality. Subgroup analyses at the study level identified no significant correlation between the outcome measures and the distribution of the chosen biopsy trajectories (transfrontal vs transcerebellar), age, year of publication, or the number of biopsy procedures annually performed in each center.

CONCLUSION

Stereotactic biopsy of pedBSTs is safe and allows successful tissue sampling as a prerequisite for the molecular characterization and the identification of potentially druggable targets toward more individualized treatment concepts to improve the outcome for children harboring such lesions.

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Insular gliomas: the case for surgical management

Clinical article

Matthias Simon, Georg Neuloh, Marec von Lehe, Bernhard Meyer, and Johannes Schramm

Object

Treatment for insular (paralimbic) gliomas is controversial. In this report the authors summarize their experience with microsurgical resection of insular tumors.

Methods

The authors analyzed complications, functional outcomes, and survival in a series of 101 operations performed in 94 patients between 1995 and 2005.

Results

A > 90% resection was achieved in 42%, and 70–90% tumor removal was accomplished in 51% of cases. Functional outcomes varied considerably between patient subgroups. For example, in neurologically intact patients ≤ 40 years of age with WHO Grade I–III tumors, good outcomes (Karnofsky Performance Scale Score 80–100) were seen in 91% of cases. Predictors of an unfavorable functional outcome included histological features of glioblastoma, advanced age, and a low preoperative Karnofsky Performance Scale score. One year after surgery, 76% of patients who had presented with epilepsy were seizure free or experienced only isolated, nondebilitating seizures. Surprisingly good survival rates were seen after surgery for anaplastic gliomas. The median survival for patients with anaplastic astrocytomas (WHO Grade III) was 5 years, and the 5-year survival rate for those with anaplastic oligodendroglial tumors was 80%. Independent predictors of survival included younger age, favorable histological features (WHO Grade I and oligodendroglial tumors), Yaşargil Type 5A/B tumors with frontal extensions, and more extensive resections.

Conclusions

Insular tumor surgery carries substantial complication rates. However, surprisingly similar figures have been reported in large unselected craniotomy series and also after alternative treatment regimens. In view of the oncological benefits of resective surgery, our data would therefore argue for microsurgery as the primary treatment for most patients with a presumed WHO Grade I–III tumor. Patients with glioblastomas and/or age > 60 years require a more cautious approach.

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NOTCH4 gene polymorphisms as potential risk factors for brain arteriovenous malformation development and hemorrhagic presentation

Daniel Delev, Anna Pavlova, Alexander Grote, Azize Boström, Anke Höllig, Johannes Schramm, Rolf Fimmers, Johannes Oldenburg, and Matthias Simon

OBJECTIVE

Arteriovenous malformations (AVMs) of the brain are a frequent and important cause of intracranial hemorrhage in young adults. Little is known about the molecular-genetic pathomechanisms underlying AVM development. Genes of the NOTCH family control the normal development of vessels and proper arteriovenous specification. Transgenic mice with constitutive expression of active NOTCH4 frequently develop AVMs. Here, the authors report a genetic association study investigating possible associations between NOTCH4 gene polymorphisms and formation and clinical presentation of AVMs.

METHODS

After PCR amplification and direct DNA sequencing or restriction digests, 10 single-nucleotide polymorphisms (SNPs) of the NOTCH4 gene were used for genotyping 153 AVM patients and 192 healthy controls (i.e., blood donors). Pertinent clinical data were available for 129 patients. Uni- and multivariate single-marker and explorative haplotype analyses were performed to identify potential genetic risk factors for AVM development and for hemorrhagic or epileptic presentation.

RESULTS

Eleven calculated haplotypes consisting of 3–4 SNPs (most of which were located in the epidermal growth factor–like domain of the NOTCH4 gene) were observed significantly more often among AVM patients than among controls. Univariate analysis indicated that rs443198_TT and rs915895_AA genotypes both were significantly associated with hemorrhage and that an rs1109771_GG genotype was associated with epilepsy. The association between rs443198_TT and AVM bleeding remained significant in the multivariate regression analysis.

CONCLUSIONS

The authors' results suggest NOTCH4 SNPs as possible genetic risk factors for the development and clinical presentation of AVMs and a role of NOTCH4 in the pathogenesis of this disease.

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Telomerase activity and expression of the telomerase catalytic subunit, hTERT, in meningioma progression

Matthias Simon, Tjoung-Won Park, Sven Leuenroth, Volkmar H. J. Hans, Thomas Löning, and Johannes Schramm

Object. In recent reports, 6 to 19% of meningiomas have been classified as atypical or anaplastic/malignant. Some atypical and anaplastic meningiomas appear to arise from benign tumors by progression. Telomerase activation has recently been associated with malignant progression of human tumors. The authors have investigated a series of benign, atypical, and anaplastic/malignant meningiomas for telomerase activity and expression of the telomerase catalytic subunit human telomerase reverse transcriptase (hTERT).

Methods. A quantitative telomeric repeat amplification protocol was used to detect telomerase enzyme activity in seven (21%) of 34 benign, but in nine (75%) of 12 atypical and in seven (100%) of seven anaplastic/malignant meningiomas. Very high levels of telomerase activity were observed only in highly aggressive tumors. Messenger (m)RNA expression of the catalytic subunit hTERT was found in 11 (33%) of 33 benign, 12 (92%) of 13 atypical, and all seven anaplastic/malignant tumors. All telomerase-positive lesions were also positive for hTERT mRNA, whereas no telomerase activity was detected in six (21%) of 29 hTERT-positive tumors. This indicates that upregulation of hTERT is the rate-limiting step for telomerase activation in the majority of meningiomas. Expression of telomerase and hTERT was seen in all four tumors with gross brain invasion. All recurrent tumors or meningiomas recurring during follow up expressed hTERT.

Conclusions. The results are consistent with a role for telomerase activation during the development of malignancy in meningiomas. Hence, expression of telomerase activity and hTERT might prove to be potentially useful markers for the evaluation of these tumors.

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Cavernoma-related epilepsy in cavernous malformations located within the temporal lobe: surgical management and seizure outcome

Patrick Schuss, Julia Marx, Valeri Borger, Simon Brandecker, Ági Güresir, Alexis Hadjiathanasiou, Motaz Hamed, Matthias Schneider, Rainer Surges, Hartmut Vatter, and Erdem Güresir

OBJECTIVE

Cavernoma-related epilepsy (CRE) is a frequent symptom in patients with cerebral cavernous malformations (CCMs). Reports on surgical management and seizure outcome of epileptogenic CCM often focus on intracranial cavernoma in general. Therefore, data on CCMs within the temporal lobe are scarce. The authors therefore analyzed their institutional data.

METHODS

From 2003 to 2018, 52 patients suffering from CCMs located within the temporal lobe underwent surgery for CRE at University Hospital Bonn. Information on patient characteristics, preoperative seizure history, preoperative evaluation, surgical strategies, postoperative complications, and seizure outcome was assessed and further analyzed. Seizure outcome was assessed 12 months after surgery according to the International League Against Epilepsy (ILAE) classification and stratified into favorable (ILAE class I) versus unfavorable (ILAE classes II–VI).

RESULTS

Overall, 47 (90%) of 52 patients with CCMs located in the temporal lobe and CRE achieved favorable seizure outcome. Pure lesionectomy was performed in 5 patients, extended lesionectomy with resection of the hemosiderin rim in 38 patients, and anterior temporal lobectomy in 9 patients with temporal lobe CCM. Specifically, 36 patients (69%) suffered from drug-resistant epilepsy (DRE), 3 patients (6%) from chronic CRE, and 13 patients (25%) sustained sporadic CRE. In patients with DRE, favorable seizure outcome was achieved in 32 (89%) of 36 patients. Patients with DRE were significantly older than patients with CCM-associated chronic or sporadic seizures (p = 0.02). Furthermore, patients with DRE more often underwent additional amygdalohippocampectomy following the recommendation of presurgical epileptological evaluation.

CONCLUSIONS

Favorable seizure outcome is achievable in a substantial number of patients with epileptogenic CCM located in the temporal lobe, even if patients suffered from drug-resistant CRE. For adequate counseling and monitoring, patients with CRE should undergo a thorough pre- and postsurgical evaluation in dedicated epilepsy surgery programs.

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Association of a polymorphism of the ACVRL1 gene with sporadic arteriovenous malformations of the central nervous system

Matthias Simon, Daniel Franke, Michael Ludwig, Ales F. Aliashkevich, Gertraud Köster, Johannes Oldenburg, Azize Boström, Andreas Ziegler, and Johannes Schramm

Object

Important central nervous system (CNS) manifestations in patients with hereditary hemorrhagic telangiectasia (HHT) include arteriovenous malformations (AVMs) and dural arteriovenous fistulas (DAVFs). Hereditary hemorrhagic telangiectasia is caused by germline mutations of two genes: ENG (HHT Type 1) and ACVRL1 (HHT Type 2). The ENG gene variations have been associated with the formation of intracranial aneurysms. The authors studied whether sequence variations in ACVRL1 or ENG are associated with the development of clinically sporadic arteriovenous dysplasias and aneurysms of the CNS.

Methods

The coding sequence (in 44 patients with AVMs and 27 with aneurysms) and the 5′ end and the polyA site (in 53 patients with AVMs) of the ACVRL1 gene were analyzed for sequence variations using direct sequencing and single-strand conformational polymorphism analysis. One ENG and three ACVRL1 gene polymorphisms were genotyped using restriction enzyme–based analysis in 101 patients with sporadic AVMs and DAVFs of the CNS, 79 patients treated for intracranial aneurysms, and 202 control volunteers.

The authors identified a statistically significant association between the IVS3 −35A/T polymorphism in intron 3 of the ACVRL1 gene and the development of AVMs and DAVFs (p = 0.004; odds ratio [OR] 1.73; 95% confidence interval [CI] 1.19–2.51; after adjustments for age and sex), but not aneurysms (crude OR 0.82; 95% CI 0.55–1.18).

Conclusions

The results of this study link ACVRL1 (HHT Type 2 gene) to the formation of the clinically sporadic variants of vascular malformations of the CNS most commonly seen in patients with HHT, that is, AVMs and DAVFs.