Identifying the deficiencies of current diagnostic criteria for neurofibromatosis 2 using databases of 2777 individuals with molecular testing

Purpose We have evaluated deficiencies in existing diagnostic criteria for neurofibromatosis 2 (NF2). Methods Two large databases of individuals fulfilling NF2 criteria (n = 1361) and those tested for NF2 variants with criteria short of diagnosis (n = 1416) were interrogated. We assessed the proportions meeting each diagnostic criterion with constitutional or mosaic NF2 variants and the positive predictive value (PPV) with regard to definite diagnosis. Results There was no evidence for usefulness of old criteria “glioma“ or “neurofibroma.” “Ependymoma” had 100% PPV and high levels of confirmed NF2 diagnosis (67.7%). Those with bilateral vestibular schwannoma (VS) alone aged ≥60 years had the lowest confirmation rate (6.6%) and reduced PPV (80%). Siblings as a first-degree relative, without an affected parent, had 0% PPV. All three individuals with unilateral VS and an affected sibling were proven not to have NF2. The biggest overlap was with LZTR1-associated schwannomatosis. In this category, seven individuals with unilateral VS plus ≥2 nondermal schwannomas reduced PPV to 67%. Conclusions The present study confirms important deficiencies in NF2 diagnostic criteria. The term “glioma” should be dropped and replaced by “ependymoma.” Similarly “neurofibroma” should be removed. Dropping “sibling” from first-degree relatives should be considered and testing of LZTR1 should be recommended for unilateral VS

The microenvironment in sporadic and neurofibromatosis type II–related vestibular schwannoma: The same tumor or different? A comparative imaging and neuropathology study

OBJECTIVE Inflammation and angiogenesis may play a role in the growth of sporadic and neurofibromatosis type 2 (NF2)–related vestibular schwannoma (VS). The similarities in microvascular and inflammatory microenvironment have not been investigated. The authors sought to compare the tumor microenvironment (TME) in sporadic and NF2-related VSs using a combined imaging and tissue analysis approach. METHODS Diffusion MRI and high-temporal-resolution dynamic contrast-enhanced (DCE) MRI data sets were prospectively acquired in 20 NF2-related and 24 size-matched sporadic VSs. Diffusion metrics (mean diffusivity, fractional anisotropy) and DCE-MRI–derived microvascular biomarkers (transfer constant [Ktrans], fractional plasma volume, tissue extravascular-extracellular space [ve], longitudinal relaxation rate, tumoral blood flow) were compared across both VS groups, and regression analysis was used to evaluate the effect of tumor size, pretreatment tumor growth rate, and tumor NF2 status (sporadic vs NF2-related) on each imaging parameter. Tissues from 17 imaged sporadic VSs and a separate cohort of 12 NF2-related VSs were examined with immunohistochemistry markers for vessels (CD31), vessel permeability (fibrinogen), and macrophage density (Iba1). The expression of vascular endothelial growth factor (VEGF) and VEGF receptor 1 was evaluated using immunohistochemistry, Western blotting, and double immunofluorescence. RESULTS Imaging data demonstrated that DCE-MRI–derived microvascular characteristics were similar in sporadic and NF2-related VSs. Ktrans (p 0.05). Tissue analysis confirmed the imaging metrics among resected sporadic VSs and demonstrated that across all VSs studied, there was a close association between vascularity and Iba1+ macrophage density (r = 0.55, p = 0.002). VEGF was expressed by Iba1+ macrophages. CONCLUSIONS The authors present the first in vivo comparative study of microvascular and inflammatory characteristics in sporadic and NF2-related VSs. The imaging and tissue analysis results indicate that inflammation is a key contributor to TME and should be viewed as a therapeutic target in both VS groups

The precambrian mafic magmatic record, including large igneous provinces of the kalahari craton and its constituents : A paleogeographic review

The study of Precambrian dyke swarms, sill provinces and large igneous provinces on the Kalahari craton in southern Africa has expanded greatly since the pioneering work initiated almost four decades ago. The main contributors to this progress have been a large number of precise U–Pb crystallization ages of mafic rocks, published in a number of recent papers. This information is compiled here into a series of maps that provide a nearly 3 billion year intraplate magmatic record of the Kalahari craton and its earlier constituents, the proto-Kalahari, Kaapvaal and Zimbabwe cratons. We also review their possible paleogeographic relations to other cratons or supercontinents. This review provides a more accessible overview of individual magmatic events, and mostly includes precise U–Pb ages of mafic dykes and sills, some of which can be linked to stratigraphically well-constrained volcanic rocks. The extrusion ages of these volcanic units are also starting to be refined by, among others, in situ dating of baddeleyite. Some mafic dyke swarms, previously characterized entirely on similarity in dyke trends within a swarm, are found to be temporally composite and sometimes consist of up to three different generations. Other mafic dyke swarms, with different trends, can now be linked to protracted volcanic events like the stratigraphically well preserved Mesoarchean Nsuze Group (Pongola Supergroup) and Neoarchean Ventersdorp Supergroup. Following upon these Archean events, shorter-lived Proterozoic large igneous provinces also intrude the Transvaal Supergroup, Olifantshoek Supergroup and Umkondo Group, and include the world’s largest layered intrusion, the Bushveld Complex. Longer-lived late Paleoproterozoic magmatic events are also preserved as mafic intrusions and lava units within the Waterberg and Soutpansberg groups as well as the granitic basement. Many gaps in our knowledge of the Precambrian mafic record of the Kalahari craton remain, but further multi-disciplinary studies combining the latest advances in U–Pb geochronology and both paleomagnetism and geochemistry will help solve the Precambrian paleogeographic puzzle