Meningioma risk factor

Meningioma risk factor

Several Familial Tumor Syndromes of the Central Nervous systems are characterized by increased meningioma risk, and the genetics of these syndromes provides mechanistic insight into sporadic disease. The best defined of these syndromes is neurofibromatosis type 2, which is caused by a mutation in the NF2 gene and has a meningioma incidence of approximately 50%. This finding led to the subsequent discovery that NF2 loss-of-function occurs in up to 60% of sporadic tumors. Other important familial diseases with increased meningioma risk include nevoid basal cell carcinoma syndromemultiple endocrine neoplasia 1 (MEN1), Cowden syndromeWerner syndromeBAP1 tumor predisposition syndrome, Rubinstein Taybi syndrome, and familial meningiomatosis caused by germline mutations in the SMARCB1 and SMARCE1 genes.

Other intrinsic risk factors (gender, ethnic groups, allergic conditions, familial and personal history, genetic polymorphisms)

They have been suspected to play a role in the etiology of meningiomas and their changes with time is likely to impact incidence trends. A causal link has been established only for ionising radiation but the role of many other factors have been hypothesised: electromagnetic fields, nutrition, pesticides, hormonal as well as reproductive factors. Considering the serious or even lethal potentiality of some meningiomas and the apparent rise in their incidence, all practitioners involved in neuro-oncology should feel concerned today of the necessity to better assess their public health burden and to study their epidemiological features 1).

Obesity but not overweight is associated with an increased risk of meningioma. Due to the limited number of studies, further research is needed to confirm the association 2).

Pregnancy has been associated with diagnosis or growth of meningiomas in several case reports, which has led to the hypothesis that pregnancy may be a meningioma risk factors. The aim of a study of Pettersson-Segerlind et al. was to test this hypothesis in a large population-based cohort study. Women born in Sweden 1958-2000 (N = 2,204,126) were identified and matched with the Medical Birth Register and the Cancer Register. The expected number of meningioma cases and risk ratios were calculated for parous and nulliparous women and compared to the observed number of cases. Compared to parous women, meningiomas were more common among nulliparous (SIR = 1.73; 95% CI 1.52-1.95). The number of meningioma cases detected during pregnancy was lower than the expected (SIR = 0.40; 95% CI 0.20-0.72). Moreover, no increased risk was found in the first-year post-partum (SIR = 1.04; 95% CI 0.74-1.41). Contrary to this hypothesis, there was no increased risk for diagnosing a meningioma during pregnancy or 1-year post-partum. A lower detection rate during pregnancy, may reflect under-utilization of diagnostic procedures, but the actual number of meningiomas was homogenously lower among parous than nulliparous women throughout the study period, indicating that pregnancy is not a risk factor for meningioma 3).


Baldi I, Engelhardt J, Bonnet C, Bauchet L, Berteaud E, Grüber A, Loiseau H.Epidemiology of meningiomas. Neurochirurgie. 2014 Sep 20. pii:S0028-3770(14)00112-X. doi: 10.1016/j.neuchi.2014.05.006. [Epub ahead of print] Review. PubMed PMID: 25249493.

Shao C, Bai LP, Qi ZY, Hui GZ, Wang Z. Overweight, obesity and meningioma risk: a meta-analysis. PLoS One. 2014 Feb 26;9(2):e90167. doi: 10.1371/journal.pone.0090167. eCollection 2014. PubMed PMID: 24587258.

Pettersson-Segerlind J, Mathiesen T, Elmi-Terander A, Edström E, Talbäck M, Feychting M, Tettamanti G. The risk of developing a meningioma during and after pregnancy. Sci Rep. 2021 Apr 28;11(1):9153. doi: 10.1038/s41598-021-88742-2. PMID: 33911184.

Factor V deficiency

Factor V deficiency

Factor V deficiency is also known as Owren’s disease or parahemophilia. It’s a rare bleeding disorder that results in poor clotting after an injury or surgery. Factor V deficiency shouldn’t be confused with factor V Leiden mutation, a much more common condition that causes excessive blood clotting.

Factor V deficiency may also occur at the same time as factor VIII deficiency, producing more severe bleeding problems. The combination of factor V and factor VIII deficiencies is considered to be a separate disorder.

FV inhibitors are a common complication of bovine thrombin exposure that can have devastating clinical consequences. Transfusion medicine specialists and hematologists can play a critical role in reducing the incidence of FV inhibitors by educating the medical community about safer alternative fibrin sealant1).

Case reports

Meidert et al., report the case of an 82 year old woman with incidentally diagnosed severe factor V deficiency, who developed a symptomatic chronic subdural hematoma, requiring burrhole craniostomy. Successful management was achieved by a multidisciplinary approach. Preoperatively, factor V activity was increased from 2 % to 50 % by administration of 25 ml/kg body weight of fresh frozen plasma (FFP) over 30 minutes under close cardiopulmonary monitoring on ICU. Straight afterwards, the patient was transferred to the operating room where surgery was performed under general anesthesia. Burr-hole craniostomy could be performed without perioperative complications. In the postoperative days there was no relevant recurrence of the subdural hematoma in the follow-up CT scans under frequent control of coagulation parameters. However, despite further transfusion of FFP, factor V activity did not increase above 16%.

The patient was discharged without any neurological deficits. In a hemostaseologic follow-up two months after surgery, factor V activity below 1% was confirmed with evidence of a factor V inhibitor in the modified Bethesda assay. Most likely, the patient suffered from an acquired form of factor V deficiency with preformed antibodies that had been boosted by the initial treatment with FFP.

They conclude that in this rare bleeding disorder, intracranial surgery was successfully managed due to a thoroughly planned perioperative therapeutic strategy. However, if there is time prior to surgery, a full check-up of the bleeding disorder is advisable 2).

Cavum vergae bleed in a term neonate with severe factor V deficiency 3).

Lee et al., reported a newborn infant girl, born to consanguineous parents, with recurrent intracranial hemorrhage secondary to congenital factor V deficiency with factor V inhibitor. Repeated transfusions of fresh-frozen plasma (FFP) and platelet concentrates, administrations of immunosuppressive therapy (prednisolone and cyclophosphamide), and intravenous immunoglobulin failed to normalize the coagulation profiles. Exchange transfusion followed-up by administrations of activated Prothrombin complex concentrate and transfusions of FFP and platelet concentrates caused a temporary normalization of coagulation profile, enabling an insertion of ventriculoperitoneal shunt for progressive hydrocephalus. The treatment was complicated by thrombosis of left brachial artery and ischemia of left middle finger. The child finally died from another episode of intracranial hemorrhage 10 days after insertion of the VP shunt. 4).



Streiff MB, Ness PM. Acquired FV inhibitors: a needless iatrogenic complication of bovine thrombin exposure. Transfusion. 2002 Jan;42(1):18-26. Review. PubMed PMID: 11896308.

Meidert AS, Kinzinger J, Möhnle P, Pekrul I, Spiekermann K, Thorsteinsdottir J, Briegel J, Huge V. Perioperative management of a patient with severe factor V deficiency presenting with chronic subdural hematoma: a clinical report. World Neurosurg. 2019 Apr 15. pii: S1878-8750(19)31072-1. doi: 10.1016/j.wneu.2019.04.080. [Epub ahead of print] PubMed PMID: 30999086.

Udayakumaran S. Cavum vergae bleed in a term neonate with severe factor V deficiency. J Pediatr. 2014 Apr;164(4):944. doi: 10.1016/j.jpeds.2013.11.005. Epub 2013 Dec 31. PubMed PMID: 24388321.

Lee WS, Chong LA, Begum S, Abdullah WA, Koh MT, Lim EJ. Factor V inhibitor in neonatal intracranial hemorrhage secondary to severe congenital factor V deficiency. J Pediatr Hematol Oncol. 2001 May;23(4):244-6. PubMed PMID: 11846304.

Update: Epidermal growth factor receptor

The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). Mutations affecting EGFR expression or activity could result in cancer.
Epidermal growth factor and its receptor was discovered by Stanley Cohen of Vanderbilt University. Cohen shared the 1986 Nobel Prize in Medicine with Rita Levi-Montalcini for their discovery of growth factors.

The receptor for epidermal growth factor (EGFR) is a prime target for cancer therapy across a broad variety of tumor types. As it is a tyrosine kinase, small molecule tyrosine kinase inhibitors (TKIs) targeting signal transduction, as well as monoclonal antibody against the EGFR, have been investigated as anti-tumor agents. However, despite the long-known enigmatic EGFR gene amplification and protein overexpression in glioblastoma, the most aggressive intrinsic human brain tumor, the potential of EGFR as a target for this tumor type has been unfulfilled 1).
This is in sharp contrast with the observations in EGFR-mutant lung cancer.

The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is the cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands.
Overexpression of epidermal growth factor receptor (EGFR) in glioblastoma multiforme (GBM) secondary to EGFR gene amplification is associated with a more aggressive tumor phenotype and a worse clinical outcome.

Epidermal growth factor receptor (EGFR), pMAPK, 4E-BP1, p4E-BP1, pS6, eIF4E, and peIF4E expression levels were evaluated using immunohistochemistry. Expression levels were semiquantitatively evaluated using a histoscore. Immunohistochemistry and PCR were used for IDH1 mutations. Statistical analysis was based on the following tests: chi-square, Student’s t, Pearson correlation, Spearman’s rho, and Mann-Whitney; ROC and Kaplan-Meier curves were constructed. A significant increase was observed between grades for expression of total and phosphorylated 4E-BP1 and for eIF4E, Ki67, EGFR, and cyclin D1. Although expression of EGFR, eIF4E, and Ki67 correlated with survival, only peIF4E was an independent predictor of survival in the multivariate analysis. Combining the evaluation of different proteins enables us to generate helpful diagnostic nomograms. In conclusion, cell signaling pathways are activated in DIAs; peIF4E is an independent prognostic factor and a promising therapeutic target. Joint analysis of the expression of 4E-BP1 and peIF4E could be helpful in the diagnosis of glioblastoma multiforme in small biopsy samples 2).

Ren et al., analyzed the microarray and proteomics profiles of tumor tissues from glioblastoma patients (N = 180), and identified potential RNA regulators of the Kininogen 1 (KNG1). Validation experiments in U87 glioblastoma cells showed that the regulation of KNG1 by CTU1, KIAA1274, and RAX was mediated by miR 138. The siRNA-mediated knockdown of CTU1, KIAA1274, or RAX in U87 cells and immortalized human endothelial cells (iHECs) significantly reduced KNG1 expression (P < 0.05 for all), which resulted in the upregulation of oncogenic EGFR signaling in both cell lines, and stimulated angiogenic processes in cultured iHECs and zebrafish and mouse xenograft models of glioblastoma-induced angiogenesis. Angiogenic transduction of iHECs occurred via the uptake of U87-derived exosomes enriched in miR-138, with the siRNA-mediated knockdown of KNG1, CTU1, KIAA1274, or RAX increasing the level of miR-138 enrichment to varying extents and enhancing the angiogenic effects of the U87-derived exosomes on iHECs. The competing endogenous RNA network of KNG1 represents potential targets for the development of novel therapeutic strategies for glioblastoma 3).


Fluorophore/nanoparticle labeled with anti-EGFR antibodies

Senders et al., systematically review all clinically tested fluorescent agents for application in fluorescence guided surgery (FGS) for glioma and all preclinically tested agents with the potential for FGS for glioma.
They searched the PubMed and Embase databases for all potentially relevant studies through March 2016.
They assessed fluorescent agents by the following outcomes: rate of gross total resection (GTR), overall and progression free survival, sensitivity and specificity in discriminating tumor and healthy brain tissue, tumor-to-normal ratio of fluorescent signal, and incidence of adverse events.
The search strategy resulted in 2155 articles that were screened by titles and abstracts. After full-text screening, 105 articles fulfilled the inclusion criteria evaluating the following fluorescent agents: 5 aminolevulinic acid (5-ALA) (44 studies, including three randomized control trials), fluorescein (11), indocyanine green (five), hypericin (two), 5-aminofluorescein-human serum albumin (one), endogenous fluorophores (nine) and fluorescent agents in a pre-clinical testing phase (30). Three meta-analyses were also identified.
5-ALA is the only fluorescent agent that has been tested in a randomized controlled trial and results in an improvement of GTR and progression-free survival in high-grade gliomas. Observational cohort studies and case series suggest similar outcomes for FGS using fluorescein. Molecular targeting agents (e.g., fluorophore/nanoparticle labeled with anti-EGFR antibodies) are still in the pre-clinical phase, but offer promising results and may be valuable future alternatives. 4).



Westphal M, Maire CL, Lamszus K. EGFR as a Target for Glioblastoma Treatment: An Unfulfilled Promise. CNS Drugs. 2017 Aug 8. doi: 10.1007/s40263-017-0456-6. [Epub ahead of print] PubMed PMID: 28791656.

Martínez-Sáez E, Peg V, Ortega-Aznar A, Martínez-Ricarte F, Camacho J, Hernández-Losa J, Ferreres Piñas JC, Ramón Y Cajal S. peIF4E as an independent prognostic factor and a potential therapeutic target in diffuse infiltrating astrocytomas. Cancer Med. 2016 Jul 20. doi: 10.1002/cam4.817. [Epub ahead of print] PubMed PMID: 27440383.

Ren Y, Ji N, Kang X, Wang R, Ma W, Hu Z, Liu X, Wang Y. Aberrant ceRNA-mediated regulation of KNG1 contributes to glioblastoma-induced angiogenesis. Oncotarget. 2016 Oct 14. doi: 10.18632/oncotarget.12659. PubMed PMID: 27764797.

Senders JT, Muskens IS, Schnoor R, Karhade AV, Cote DJ, Smith TR, Broekman ML. Agents for fluorescence-guided glioma surgery: a systematic review of preclinical and clinical results. Acta Neurochir (Wien). 2017 Jan;159(1):151-167. doi: 10.1007/s00701-016-3028-5. Review. PubMed PMID: 27878374; PubMed Central PMCID: PMC5177668.
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