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PubMed2026

A 3D in vitro co-culture model to investigate tumor-endothelial interactions in Neurofibromatosis type 2-associated meningiomas.

BACKGROUND: Neurofibromatosis type 2 (NF2)-associated meningiomas and schwannomas are vascular tumors, and while vascular endothelial growth factor (VEGF) inhibition with bevacizumab has benefited some NF2-related schwannomas, most NF2-associated meningiomas remain nonresponsive. METHODS: Leveraging our transcriptomic data, we performed Gene Ontology (GO) analysis comparing NF2-deficient meningioma cells with NF2-expressing arachnoid cells (ACs). We then established a 3D in vitro angiogenesis model by co-culturing NF2-null meningioma cells with human umbilical vein endothelial cells (HUVECs). Endothelial sprouting was assessed by CD31/PECAM immunostaining. Effects of third-generation mechanistic target of rapamycin complex 1 (mTORC1)-selective inhibitor RMC-6272 as well as APLN knock-out using CRISPR-Cas9 gene editing were also examined. RESULTS: GO analysis identified vascular development among the top significantly upregulated pathways in NF2-deficient cells. In 3D co-culture, ECs formed radially sprouting tube-like networks from the spheroid surface, and our data supports an angiogenesis phenotype driven by meningioma cells. Given these results along with hyperactivation of mTORC1 upon NF2-deficiency, we examined whether RMC-6272 disrupts meningioma-driven angiogenesis. RMC-6272 potently suppressed EC sprouting. Cross-referencing baseline transcriptomic data, we identified Apelin (APLN), the ligand for APLN receptor (APLNR), as a basally upregulated angiogenic factor in NF2-deficient meningiomas. Quantitative RT-PCR (qRT-PCR) confirmed increased APLN expression in NF2-null immortalized and patient-derived meningioma lines, with reduced expression upon mTORC1 inhibition. Apelin-13 stimulation enhanced sprouting, whereas APLN deletion reduced endothelial sprouting. CONCLUSIONS: Here we establish a 3D-tumoroid model and implicate tumor-derived Apelin as an important contributor to NF2-associated meningioma angiogenesis. Our data also suggest that APLN expression is regulated, at least in part, by mTORC1. Together, these results provide a preclinical platform for investigating angiogenic vulnerabilities beyond VEGF in NF2-deficient meningiomas.

3D tumoroid model↗

PubMed2025

History and clinical epidemiology of NF2-related schwannomatosis.

NF2-related schwanomatosis (NF2-SWN) (previously Neurofibromatosis 2) as characterised by bilateral vestibular schwannomas (VS) was first described in 1822. However, due to the erroneous conflation of individuals with bilateral eighth nerve tumours with von Recklinghausen disease (currently Neurofibromatosis 1, NF1) in 1917 the literature was confusing for much of the 20th century. Even when the conditions were separated officially in 1987 (with separate localisation of the genes), NF2-SWN remained classified as a neurofibromatosis despite the tumours pathognomonic for NF1, neurofibromas, not being a feature of NF2-schwannomatosis. It is only in 2022 that NF2-SWN was correctly delineated as a schwannomatosis. The epidemiology of NF2-SWN has only been possible to delineate after the separation of NF2-SWN from the much more frequent nerve sheath predisposing tumour condition NF1. Two research groups have published on the birth prevalence and population prevalence of NF2-SWN in the UK and Finland. The most highly ascertained assessment of NF2-SWN cases from the Manchester region of England (population 4.8 million) gave a diagnostic prevalence of 1 in 50,500 and calculated birth prevalences of 1 in 27,956 respectively. However, an updated prevalence across England in 2024 (population 55 million) gave a prevalence of at least 1 in 58,000. NF2-SWN usually presents with bilateral vestibular schwannoma, but can present with meningioma or spinal tumour or ophthalmic features before a VS diagnosis or with a unilateral VS and other tumours and rarely with a unilateral VS alone. Molecular testing is now extremely helpful in confirming the diagnosis of mosaic (present in up to 50% of de novo cases) versus germline NF2 and distinguishing from other tumour predisposition conditions especially in childhood or cases with less common presentation. This chapter summarises the clinical epidemiology of NF2-SWN differentiating the condition from the overlapping non NF2-SWN.

Humans↗

PubMed1979

Localization of pheochromocytoma by selective venous catheterization and assay of plasma catecholamines.

The diagnosis of pheochromocytoma rests primarily on determination of the 24-hour urinary excretion of catecholamines and their metabolites. In most cases nephrotomography and selective arteriography or venography, or both, are sufficient to localize the tumour. Selective venous catheterization and the assay of plasma catecholamines should be considered for pheochromocytoma localization in: (a) patients in whom standard techniques fail to localize the tumour; (b) patients who exhibit idiosyncratic reactions to the angiographic contrast materials; (c) young patients or patients with familial pheochromocytoma, including those with multiple neurofibromatosis or multiple endocrine adenomatosis, type 2; (d) patients with recurrent, malignant, or suspected multicentric or extra-adrenal tumours; and (e) patients excreting only norepinephrine in the urine. The validity of the results is particularly dependent on the skill with which venous catheterization is carried out.

Adrenal Gland Neoplasms↗

PubMed1977

Chromosome complement and SV40 transformation of cells from patients susceptible to malignant disease.

A comparative study has been made of fibroblasts obtained from patients with differing susceptibilities to malignant disease, both with respect to their chromosome complements and their transformation with SV40 virus. Fibroblasts from 2 Bloom's syndrome patients were found not to have raised SV40 transformation rates and no correlation was found between chromosome abnormality per se and transformation. Of 2 cell types with greatly increased rates, one was derived from a neurofibromatosis patient and the other from an A-T heterozygote. When SV40 DNA was employed as the transforming agent for the latter, the transformation rate was no longer raised.

Antigens, Viral↗

PubMed1979

The association of neurofibromatosis and hyperparathyroidism.

Two patients with coexisting neurofibromatosis and hyperparathyroidism are described, bringing the total number of such cases in the world literature to seven. Other more classic examples of the association of tumorous conditions of neuroectodermal and entodermal origin are discussed to support the suggestion that the association of these two diseases may be another variant of multiple endocrine neoplasia type 2 (MEN2b). It may be clinically profitable to investigate all patients with either disease in order to uncover their coexistence.

Adenoma↗

PubMed2026

Combination of EZH2 and MEK inhibitors as an effective therapy for neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.

BACKGROUND: Neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with poor outcomes and limited therapeutic options. Although mitogen-activated protein kinase kinase (MEK) inhibitors are active in benign plexiform neurofibromas, their efficacy in MPNST treatment is modest. Enhancer of zeste homolog 2 (EZH2) inhibitors are preclinically efficacious in MPNST treatment, but their mechanisms of action remain unclear. We evaluated the therapeutic potential and molecular mechanism of combined EZH2 and MEK inhibitors in NF1-associated MPNST. METHODS: Five human NF1-associated MPNST cell lines were exposed to EZH2 and/or MEK inhibitors. Cell growth and apoptosis were quantified over time. Therapeutic efficacy was tested in a subcutaneous xenograft model. Proliferation and apoptosis in tumors were assessed using standard histologic markers, and intracellular localization of phosphorylated extracellular signal-regulated kinase (pERK) was examined using fluorescent immunohistochemistry. RESULTS: Monotherapy with EZH2 or MEK inhibitors reduced proliferation and increased apoptosis across all MPNST lines. Combination therapy produced greater tumor cell growth suppression and marked increases in apoptosis. In vivo, the combination significantly delayed tumor progression compared with monotherapy, with concomitant reductions in proliferative indices and increases in apoptotic indices. EZH2 inhibitor limited nuclear pERK entry. CONCLUSIONS: Dual EZH2 and MEK inhibitors yield additive antitumor activity in NF1-associated MPNST. Although the molecular mechanism could not be elucidated, our findings suggest that EZH2 inhibitors exhibited a polycomb repressive complex 2-independent, noncanonical mechanism characterized by pERK nuclear translocation restriction, providing a strong rationale for clinical evaluation of this combination in NF1-associated MPNST.

EZH2 inhibitor↗

PubMed1976

[Studies on neurinomas and neurofibromas in tissue culture (author's transl)].

10 acoustic neurinomas, 2 spinal cord neurinomas and 3 neurofibromas of von Recklinghausen's disease were elaborately studied by monolayer tissue culture method and Gelfoam organ culture method. Four morphological types were found in the acoustic and spinal cord neurinoma. (1) multinucleated cells (type I), dividing into bipolar spindle-shaped cells. (2) bipolar spindle-shaped cells (type II), forming of palisade fashion in the monolayer tissue culture method. (3) fibroblastic cells (type III), tending to predominate in the long-term cultures. (4) round cells (type IV), gathering to the Gelfoam mesh in the organ culture method. Neurofibroma of von Recklinghausen's disease was divided into cells of two types in the tissue culture. (1) spindle-shaped cells, rarely observed, and have been thinking that the cells originated from schwann cells. (2) round cells, having the macrophagic character, are predominant in the long-term culture.

Culture Techniques↗

PubMed1976

Multiple endocrine adenomatosis of mixed type.

A case of multiple endocrine adenomatosis (MEA) of mixed type is presented. The syndrome, observed in a 65 year-old female, consisted of multiple neurofibroadenomatosis, medullary thyroid carcinoma, multiple adenomata of the parathyroids, adrenal cortical adenoma and small cell anaplastic bronchogenic carcinoma. Thus, it was composed of type 1 as well as of type 2 MEA. On the basis of another seven cases, collected from the literature, the MEA syndrome of mixed type is reviewed with special reference to the phylogenetic origin of the cells of the APUD system.

Adenoma↗

PubMed1979

Primary malignant peripheral nerve tumors (malignant schwannomas). A clinicopathologic and electron microscopic study.

A clinicopath-logic and electron microscopic study was performed on 35 cases of primary malignant peripheral nerve tumors, among which 12 developed in association with neurofibromatosis (von Recklinghausen's disease) and further 11 in keeping with anatomically discernible nerves in patients without neurofibromatosis. Depending upon the histologically predominant pattern, these tumors were subdivided into three groups: 23 compact spindle cell, 6 myxoid, and 6 epithelioid varieties of the tumor. The common ultrastructures in three of the 35 tumors were as follows: 1) The cell membranes manifested characteristic infoldings and lamellar configuation. 2) The tumor cell surfaces were coated by occasional basal lamina or homogeneously electron-dense membranous material. 3) The cytoplasms contained well-developed organelles and a few neurosecretory-type granules. Differential points from other soft-tissue sarcomas were briefly discussed on the histologic basis.

Adolescent↗

PubMed1977

Multiple primary neoplasms and the nervous system.

Studies of multiple primary neoplasms and their relation to the nervous system should consider two important principles: 1) neoplasms of the nervous system have certain unusual features that distinguish them from tumors occurring elsewhere in the body; and 2) there is good evidence that the various histologic types of nervous system tumors should be regarded as separate diseases. The association of nervous system neoplasms and tumors of other sites may occur in patients with phacomatoses or particular genetic syndromes. In addition, certain nervous system neoplasms may be multicentric in origin. Retinoblastoma and osteosarcoma occur together in the same patient more often than expected by chance, as do meningioma and breast cancer. These relationships are important in that they serve to identify the high risk patient, may provide etiologic clues, may point to the presence of genetic syndromes, and may highlight sites in which subsequent tumors are most likely to develop.

Brain Neoplasms↗

PubMed2026

NF2-related Schwannomatosis Diagnosed Before and After 30 Years of Age: Differences in Disease Presentation and Rates of Positive Genetic Testing.

OBJECTIVE: Characterize pathogenic variants, rates of mosaicism, genetic testing yield, and disease severity among patients with NF2-related schwannomatosis dichotomized by diagnosis before or after the age of 30. STUDY DESIGN: Retrospective analysis. SETTING: Tertiary referral center multidisciplinary NF2 clinic from 2021 to 2024. PATIENTS: Patients with NF2-related schwannomatosis. INTERVENTION: Next-generation sequencing. MAIN OUTCOME MEASURE: Rates of mosaicism, genetic testing rates and yield, and overall disease severity by tumor burden. RESULTS: From 2021 to 2024, there were 32 patients ≥30 years of age and 39 patients diagnosed at younger ages. Patients diagnosed ≥30 years exhibited decreased likelihood of receiving genetic testing (53% vs. 85%; P =0.009) and decreased genetic yield (defined as identification of a pathogenic genetic variant in those undergoing testing; 65% vs. 85%; P =0.20). Both age groups demonstrated similar rates of pathogenic variant type with loss-of-function being the predominant variant detected in 73% vs. 67%, for ≥30 vs. <30 years of age; P =0.90. Those ≥30 years harbored fewer number of average anatomic regions involved by tumor (2.3 vs. 3.4; P <0.001) and decreased total number of tumors (7 vs. 12; P <0.001). CONCLUSIONS: Patients diagnosed with NF2-related schwannomatosis at age ≥30 years exhibited reduced disease severity compared with those diagnosed at a younger age despite harboring similar distributions of genetic pathogenic variants inclusive of loss-of-function pathogenic variants. These observations emphasize the importance of considering patient age in addition to genetic testing for diagnostic framing tailored to patients' biology and clinical context to optimize care in the setting of NF2-related schwannomatosis.

Humans↗