The aim of this study was to investigate the long-term natural history of nontraumatic angiogram-negative subarachnoid hemorrhage with typical pretruncal (P-SAH) and diffuse (D-SAH) pattern of hemorrhage. A retrospective review of 102 patients who experienced angiographically negative SAH at our institution was undertaken (11.6% of 882 spontaneous SAH). Follow-ups were obtained at 7.9 to 16 years. In the D-SAH group, 11 patients (13.9%) out of 79 had an aneurysm, and four (5.1%) had rebleeding episodes. In the P-SAH group, the second angiography was negative in all of the 23 cases, and no rebleeding episodes were recorded. The long-term follow-up confirms that P-SAH is a benign disease. A second angiography could not be necessary. D-SAH is probably due to an aneurysm that thrombose early after the bleeding. At short-term follow-up, the sack could frequently recanalize and rebleed, whereas a late follow-up shows that rebleeding is very rare.
The cIMPACT-NOW Update 7 has replaced the WHO nosology of “ependymoma, RELA fusion positive” by “Supratentorial-ependymoma, C11orf95-fusion positive”. This modification reinforces the idea that supratentorial-ependymomas exhibiting fusion that implicates the C11orf95 (now called ZFTA) gene with or without the RELA gene, represent the same histomolecular entity. A hot off the press molecular study has identified distinct clusters of the DNA methylation class of ZFTA fusion-positive tumors. Interestingly, clusters 2 and 4 comprised tumors of different morphologies, with various ZFTA fusions without involvement of RELA. In this paper, we present a detailed series of thirteen cases of non-RELA ZFTA-fused supratentorial tumors with extensive clinical, radiological, histopathological, immunohistochemical, genetic and epigenetic (DNA methylation profiling) characterization. Contrary to the age of onset and MRI aspects similar to RELA fusion-positive EPN, we noted significant histopathological heterogeneity (pleomorphic xanthoastrocytoma-like, astroblastoma-like, ependymoma-like, and even sarcoma-like patterns) in this cohort. Immunophenotypically, these NFκB immunonegative tumors expressed GFAP variably, but EMA constantly and L1CAM frequently. Different gene partners were fused with ZFTA: NCOA1/2, MAML2 and for the first time MN1. These tumors had epigenetic homologies within the DNA methylation class of ependymomas-RELA and were classified as satellite clusters 2 and 4. Cluster 2 (n = 9) corresponded to tumors with classic ependymal histological features (n = 4) but also had astroblastic features (n = 5). Various types of ZFTA fusions were associated with cluster 2, but as in the original report, ZFTA:MAML2 fusion was frequent. Cluster 4 was enriched with sarcoma-like tumors. Moreover, we reported a novel anatomy of three ZFTA:NCOA1/2 fusions with only 1 ZFTA zinc finger domain in the putative fusion protein, whereas all previously reported non-RELA ZFTA fusions have 4 ZFTA zinc fingers. All three cases presented a sarcoma-like morphology. This genotype/phenotype association requires further studies for confirmation. Our series is the first to extensively characterize this new subset of supratentorial ZFTA-fused ependymomas and highlights the usefulness of ZFTA FISH analysis to confirm the existence of a rearrangement without RELA abnormality.
FET:CREB fusions have been described in a variety of tumors from various phenotypes. Recently, these fusion transcripts were reported in intracranial tumors, variably named intracranial mesenchymal myxoid tumors or angiomatoid fibrous histiocytomas. Controversy remains concerning the terminology for these tumors. Here, we report 11 cases of central nervous system mesenchymal tumors with proven FET:CREB fusion. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor or Sarcoma Classifier (v11b4/v12.2). However, by using unsupervised t-SNE and hierarchical clustering analyses, six of the cases constituted a distinct cluster. The remaining four tumors showed no obvious relation to any of the other referenced classes but were close to the clusters of extra-CNS angiomatoid fibrous histiocytomas (n = 1), clear cell sarcomas (n = 1), or solitary fibrous tumors (n = 2). Our findings confirm that intracranial FET:CREB-fused tumors do not represent a single molecular tumor entity, although most samples clustered close to each other, indicating the existence of a distinct epigenetic group that could potentially be partially masked by the low number of cases included.Further analyses are needed to characterize intracranial FET:CREB fuseddefined tumors in more detail.
Our study did not confirm the association between functionally active polymorphisms in the IL6 gene and the risk of aneurysmal SAH in an Italian population. Additional studies in different populations are warranted to clarify the role of the IL6 gene in the pathogenesis of aneurysmal SAH.
Our results do not support the hypothesis that genetic variation in select polymorphisms of the IL-1 cluster genes is associated with aneurysmal subarachnoid cerebral hemorrhage. However, the IL-1beta gene may modify disease severity and may be regarded as disease severity gene.
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