ORIGINAL ARTICLE

Dysembryoplastic Neuroepithelial Tumor of the Septum Pellucidum and the Supratentorial Midline Histopathologic, Neuroradiologic, and Molecular Features of 7 Cases Marco Gessi, MD,* Elke Hattingen, MD,w Evelyn Do¨rner,* Tobias Goschzik, PhD,* Verena Dreschmann,* Andreas Waha, PhD,* and Torsten Pietsch, MD*

Abstract: Dysembryoplastic neuroepithelial tumors (DNTs) are one of the most common epilepsy-associated low-grade glioneuronal tumors of the central nervous system. Although most DNTs occur in the cerebral cortex, DNT-like tumors with unusual intraventricular or periventricular localizations have been reported. Most of them involve the septum pellucidum and the foramen of Monro. In this study, we have described the neuroradiologic, histopathologic, and molecular features of 7 cases (4 female and 3 male; patient age range, 3 to 34 y; mean age, 16.7 y). The tumors, all localized near the supratentorial midline structures in proximity to the foramen of Monro and septum pellucidum, appeared in magnetic resonance imaging as welldelimited cystic lesions with cerebrospinal fluid-like signal on T1-weighted and T2-weighted images, some of them with typical fluid-attenuated inversion recovery ring sign. Histologically, they shared features with classic cortical DNTs but did not display aspects of multinodularity. From a molecular point of view the cases investigated did not show KIAA1549-BRAF fusions or FGFR1 mutations, alterations otherwise observed in pilocytic astrocytomas, or MYB and MYBL1 alterations that have been identified in a large group of pediatric low-grade gliomas. Moreover, BRAFV600E mutations, which so far represent the most common molecular alteration found in cortical DNTs, were absent in this group of rare periventricular tumors. Key Words: dysembryoplastic neuroepithelial tumor, DNT, septum pellucidum, BRAF, MLPA, nucleus caudatus, lateral ventricle, midline, foramen of Monro (Am J Surg Pathol 2016;40:806–811)

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ysembryoplastic neuroepithelial tumors (DNTs) are one of the most common low-grade glioneuronal tumors1 of the central nervous system. They are usually From the *Institute of Neuropathology; and wDepartment of Neuroradiology, Institute of Radiology, University of Bonn Medical Center, Bonn, Germany. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Marco Gessi, MD, Institute of Neuropathology, University of Bonn Medical Center, Sigmund-Freud-Strae 25, Bonn 53127, Germany (e-mails: [email protected]; marco.gessi@ ukb.uni-bonn.de). Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.

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intracortical, multinodular lesions affecting young patients and are typically associated with a long-standing history of epilepsy.1 Most DNTs occur in the cerebral cortex, but unusual, rare supratentorial cases with pure periventricular or intraventricular localizations have been described.2–13 These DNT-like neoplams frequently involve the septum pellucidum, as reported by Baisden et al,2 the caudate nucleus, and the foramen of Monro. As cortical DNTs, these tumors show delicate microcystic architecture, “floating neurons,” and are composed of monomorphous tumor cells with rounded nuclei. Despite unequivocal histopathologic similarities with cortical DNTs, the definitive nosological position of these tumors remains undetermined, and data on molecular features of DNTs of the septum pellucidum are unfortunately not available. In recent years many data about the molecular features of the most common glial and glioneuronal tumors have been provided.14 In particular, many reports have shown the high frequency of BRAF mutations in several different low-grade brain tumors, including cortical DNTs.14,15 Besides BRAF mutations, KIAA1549BRAF or SRGAP3/RAF1 fusions and FGFR1 mutations have been identified in pilocytic astrocytomas, and MYB and MYBL1 alterations were observed in a large group of pediatric low-grade gliomas (LGG).14 In this study, we reported the clinical, neuroradiologic, and neuropathologic features of 7 cases of DNTs of the septum pellucidum and the supratentorial midline. Furthermore, their molecular features were investigated using a multiplex ligation-dependent probe amplification (MLPA)-based approach.

MATERIALS AND METHODS Tissues and Neuroradiologic Data Formalin-fixed paraffin-embedded tissue specimens were retrieved from the archive of the Institute of Neuropathology, University of Bonn Medical Center, and the DGNN German Brain Tumor Reference Center, Bonn, Germany. Reports on magnetic resonance imaging (MRI) were available for all patients. In patients with archived and accessible presurgical MRI, an experienced neuroradiologist (E.H.) evaluated them for size, anatomic localization, and signal characteristics on standard Am J Surg Pathol



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T1-weighted and T2-weighted images and on fluid-attenuated inversion recovery (FLAIR) sequences.

tentorial midline or in periventricular structures, most of them adjacent to the foramen of Monro.

Immunohistochemistry

Neuroradiologic Feature

Three-mm-thick sections were stained with hematoxylin and eosin. Reticulin, PAS, and Alcian blue staining studies were performed. Immunohistochemical analysis was carried out on a Ventana Benchmark XT Immunostainer (Roche Ventana, Darmstadt, Germany) with antibodies against Map2c (Sigma, St. Louis, MO), S-100 protein (Dako, Hamburg, Germany), epithelial membrane antigen (Dako), CD34 (Dako), glial fibrillary acidic protein (Dako), synaptophysin (Dako) Olig-2 (RD Systems, Wiesbaden, Germany), neurofilament protein (Dako), NeuN (Millipore, Darmstadt, Germany), vimentin (Dako), and p53 (Dako). The proliferation index was evaluated with an antibody against the Ki67 antigen (MIB-1; Dako).

Presurgical MRI were available and reevaluated in 5 cases. In case 1, MRI showed a cyst-like, sharply delineated lesion (Fig. 1A) with a volume of 19 12 17 mm3, located paramedian in the foramen of Monro of the left ventricle, bulging downward into the third ventricle. The lesion was hyperintense on T2-weighted images and hypointense on T1-weighted images, without contrast enhancement. On FLAIR, it was centrally isointense to white matter, surrounded by a hyperintense rim. There were signs of acute cerebrospinal fluid blockage in the lateral ventricles. In case 2 MRI showed a sharply delineated paramedian cyst-like lesion (Fig. 1B) in the left ventricle with a volume of 24  20  24 mm3, located in the foramen of Monro. The lesion narrowed both foramina of Monro, and the anterior commissure was displaced backwards. The lesion was hyperintense on T2-fast spin-echo– weighted sequences and hypointense on T1-weighted images. On FLAIR, it was centrally isointense to white matter, surrounded by a hyperintense ring. The strongly T2-weighted 3D sequences revealed some small cysts at the margin of the lesion. The lesion did not show contrast enhancement. The lateral ventricles were enlarged but without signs of acute cerebrospinal fluid blockage, indicating a long-standing hydrocephalus. In case 3 MRI revealed a suprasellar midline cystlike lesion (Fig. 1C) with a volume of 19  17  27 mm3, hyperintense on T2-weighted images and hypointense on T1-weighted images. On FLAIR, it was centrally isointense, surrounded by a hyperintense ring. There was a thin rim of enhancement along the caudal margin. The neurohypophysis showed a regular T1 hyperintensity, and the hypophyseal stalk was shortened, ending at the bottom of the lesion. The optic tracts were involved on both sides of the lesion. The apparent diffusion coefficient values within the lesion were approximately 250 mm2/s. In case 4 MRI showed a sharply delineated tumor (Fig. 1D) with a volume of 20 15 11 mm3, with inhomogenous intermediate signal on T2-weighted images and hypointense signal on T1-weighted images, without contrast enhancement. It was located paramedian in the right hemisphere, caudal to the rostrum of the corpus callosum and anteriorly to the fornices, bulging into the third ventricle. In case 7 the MRI scans showed a 25-mm cystic lesion without contrast enhancement in the left lateral ventricle with caudal extension in the foramen of Monro. The lesion was hyperintense in T2-weighted images and hypointense in T1-weighted images. On FLAIR, it was isointense to white matter.

DNA Extraction and FGFR1, BRAFV600E Mutation Analysis Hematoxylin-eosin–stained sections of each case were reviewed carefully before DNA extraction. All samples selected contained at least 80% of viable tumor tissue. DNA from 5 cases was extracted using the QIAamp DNA Mini Tissue Kit (Qiagen GmbH, Du¨sseldorf, Germany) according to the manufacturer’s instructions. We screened the hotspot codon 600 (exon 15) of the BRAF gene and hotspot codons 546 and 656 of the FGFR1 gene for mutations using a pyrosequencing assay as reported in detail elsewhere.16,17 As a positive control for BRAFV600E, DNA from a mutated melanoma brain metastasis was used.

Multiplex Ligation-dependent Probe Amplification KIAA1549/BRAF, FGFR1/TACC1, and SRGAP3/ RAF1 fusions and MYB and MYBL1 alterations were investigated using a MLPA-based approach.18 The P370 MLPA kit (MRC Holland, Amsterdam, the Netherlands) was used. This kit contains multiple specific hybridization probes within and outside the parts of multiple genes that undergo fusion/duplication. The formation of the fusion is associated with the generation of an extra copy that can be detected by a quantitative assessment of regions included and not included in the fusion/duplication. Moreover, the MLPA kit also contains specific probes for recognition of IDH1 and IDH2 mutations. The MLPA analysis of these cases was performed following the manufacturer’s instructions. The results were analyzed using Coffalyser.net software (MRC Holland).

RESULTS Clinical Features The cohort included 7 patients (4 female and 3 male patients; age range, 3 to 34 y; mean age, 16.7 y). Most patients clinically referred to headache or symptoms related to hydrocephalus or increased intracranial pressure. All cases reported here were localized in the supraCopyright

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Histopathologic Features All tumors showed a variable cellularity and delicate microcystic architecture (Figs. 2A, B). The tumor cells were dispersed in a mucoid, alcianophilic matrix (Fig. 2C) and appeared arranged in small groups and in

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FIGURE 1. Neuroradiologic features of the DNT of the septum pellucidum and the supratentorial midline reported in this series. MRI of case 1 displayed a lesion with a hypointense signal in T1-weighted images, without contrast enhancement, located paramedian in the interventricular foramen of Monro of the left ventricle (A). In case 2, the tumor was a sharply delineated cystlike lesion paramedian in the left ventricle located in the foramen of Monro. The lesion was hypointense in T1-weighted images. On FLAIR, it was centrally isointense to white matter, surrounded by a hyperintense ring (B). MRI of case 3 showed a suprasellar midline cyst-like lesion hypointense in T1-weighted images (C). In case 4, MRI showed a sharply delineated tumor with inhomogenous intermediate signal on T2-weighted images (D). It was located paramedian in the right hemisphere caudal to the rostrum of the corpus callosum, anteriorly to the fornices, bulging into the third ventricle.

cord-like structures around capillaries (Figs. 2D, E). Perivascular rosettes were seen in 4 cases (Fig. 2F). Two cases presented elongated microcystic structures vaguely resembling a DNT-like columnar architecture. The tu-

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mors were composed of monomorphous cells, characterized by small or moderately enlarged rounded nuclei. The cells appeared mostly Map2C (Fig. 2G), Olig-2, and S100 positive (Fig. 2H). Glial fibrillary acidic protein Copyright

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FIGURE 2. Histopathologic features of the DNT of the septum pellucidum and the supratentorial midline reported in this series. The tumors mostly displayed a microcystic architecture (A, B: cases 6 and 1, respectively) with an abundant alcianophilic matrix (C: case 1). The tumor cells, which appeared rounded and monomorphic, were disposed to form strands and cords (D, E: cases 5 and 6, respectively). Delicate perivascular rosettes could also be found (F: case 6). The tumors were mostly MAP2C positive (G: case 7) and S100-protein positive (H: case 5). The NeuN immunohistochemistry highlighted the presence of “floating neurons” (arrows) (I: case 1). A, B, D–F: HE staining; C: Alcian-blue-PAS staining.

resulted negative. The MIB-1 (Ki67) index was about 2% to 4%. Floating neurons could be identified in all cases and were positive for NeuN (Fig. 2I) and synaptophysin. Endothelial proliferations were seen in 1 case. No areas of necrosis were evident. The tumors showed neither eosinophilic granular bodies nor Rosenthal fibers. No positivity for epithelial membrane antigen, or CD34 was found.

Molecular Features The mutational screening and MLPA analysis did not reveal BRAFV600E, IDH1R132H, IDHR132C, IDH2R172M, IDH2R172K, and FGFR1 mutations (hotspots N546 and K656). No alterations suggesting the possible presence of KIAA1549/BRAF and SRGAP3/RAF1 fusions or MYB Copyright

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and MYBL1 alterations (gains or deletions with duplication) were identified using MLPA. Notably, a gain at chromosome 8p12 harboring the FGFR1 gene was identified in case 3, but no alterations indicative of a FGFR1 high-copy gain (amplification), a duplication of the tyrosine kinase domain (TKD), or a FGFR1-TACC1 fusion were found. Case 1 showed an allelic loss of CDKN2A, but no evidence of a homozygous deletion was observed.

DISCUSSION Unusual glioneuronal tumors with DNT-like features affecting the lateral ventricles and the surrounding periventricular areas have been described with increasing

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frequency in recent years. These tumors occur in a large spectrum of age but mainly affect young adults. They arise in the periventricular region preferentially affecting the septum pellucidum, caudate nucleus, and foramina of Monro.2,7,11–13 Cases occurring on/in the floor or in the posterior part of the lateral ventricles have also been described.9,13 Although Saito et al4 reported the onset of these tumors in a familial setting, no association with the most common tumor predisposition syndromes, such as neurofibromatoses, have been reported so far. Notably, these tumors appear to be not commonly associated with a clinical history of epilepsy.2 Besides cases incidentally found at autopsy,2 most patients clinically referred to headache, visual disturbances, dizziness, and symptoms related to increased intracranial pressure and hydrocephalus. From a neuroradiologic point of view these lesions showed some common features, including discrete dimensions (mostly 1 to 3 cm), cystic features, and a well-delineated contour. In MRI, they were mostly hypointense to the brain on T1-weighted images and hyperintense on T2-weighted images. Some of our DNTs showed the characteristic bright ring sign on FLAIR.19 Hereby, the bright signal of the cyst-like center is partially suppressed on FLAIR, whereas the margin (ring) remains hyperintense. DNTs appeared uniformly nonenhancing or enhanced only marginally. Calcifications and multinodularity, common features in cortical DNTs, appeared to be rare in such cases. None of our cases had signal changes characteristic of calcifications, and only 1 case showed subtle multinodularity on high-resolution T2weighted images. Clinically, DNTs of the septum pellucidum are characterized by an indolent clinical behavior. The majority of these tumors have been successfully treated by surgery only, without evidence of relapse in the followup.2,12,13 As suggested by the name, the microscopic features are reminiscent of the histology of classical cortical DNTs. They often present with delicate microcystic architecture, floating neurons, and they are characterized by the presence of monomorphous cells with rounded nuclei, embedded in a mucoid matrix and arranged in cords but often with a perivascular disposition. In contrast to classic cortical DNTs they lack histologic aspects of multinodularity. Whereas Rosenthal fibers were usually absent,2,8 eosinophilic granular bodies were rarely described in these tumors.10 In the differential diagnosis, other low-grade glial and glioneuronal tumors must be considered. Although Olig-2 immunohistochemical positivity helps in the distinction from ependymomas and central neurocytoma, the comparison with neuroradiology helps to exclude the possibility of a diffuse glioma (oligodendroglioma) especially in the case of endoscopic biopsies with a small amount of tissue. Data on the molecular profile of these DNT-like neoplasms are very limited,10 and no information about possible molecular similarities with other low-grade gliomas or glioneuronal tumors is available.10 In particular, data regarding the possible presence of BRAF mutations,

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KIAA1549-BRAF fusion, and FGFR1 mutations frequently identified in pilocytic astrocytomas and in other glioneuronal tumors,14,15,17 or MYB and MYBL1 alterations observed in pediatric LGG,14 are to date not available. In our series, we did not observe BRAFV600E mutations, KIAA1549/BRAF fusions, or the more rarely reported SRGAP3/RAF1 fusion.14 Notably, BRAF mutations have been identified in a subgroup of cortical DNT and represent, so far, the most common alteration identified in this tumor entity.15 BRAF, a member of the serine/threonine kinase protein family, is a central component of the MAPK/ ERK signaling pathway, which modulates various intracellular processes, including cell proliferation and survival. Gene fusions and mutations of BRAF lead to constitutive protein phosphorylation and activation.14 Other common alterations considered as highly recurrent and mutually exclusive in pediatric LGG are duplications, fusions, or partial deletions of FGFR1, MYB, and MYBL1,20–22 respectively. Intragenic duplications of FGFR1 TKD and FGFR1-TACC1 fusions have been recently described in a large series of LGG, including a DNT.21 FGFR1 TKD duplication leads to FGFR1 autophosphorylation and activation of both MAPK/ERK and PI3K/AKT/mTOR pathways.21 Although we found a gain of FGFR1 in 1 tumor sample, alterations compatible with FGFR1 TKD duplication or a FGFR1-TACC1 fusion were not evident in our MLPA analysis. Moreover, no FGFR1 high-copy gain (amplification) was found. In contrast, we found neither MYB nor MYBL1 alterations including partial duplication of MYBL1 with truncation of its C-terminal negative-regulatory domain. These rearrangements, which leave the transactivating domain constitutively active20,22 and are a known oncogenic event in leukemia, have been reported in pediatric diffuse LGG. Along with the absence of FGFR1 alterations, we were not able to identify FGFR1 mutations in 2 mutational hotspots (N546 and K656) that have been recently described in pilocytic astrocytomas23 and in Rosette forming glioeneuronal tumors.17 In pilocytic astrocytoma, these mutations are considered to represent a mechanism of MAPK pathway activation alternative to KIAA1549BRAF fusions and BRAF mutations. FGFR1 mutations have been mainly found in midline tumors, which presumably originate from the periventricular white matter. In conclusion, DNTs of the septum pellucidum and of the supratentorial midline represent a rare but distinct group of neoplasms. Despite their similarities with cortical DNT, they are apparently characterized by the absence of molecular alterations, including BRAF mutations, commonly found in the other more common LGG and glioneuronal tumors. REFERENCES 1. Thom M, Toma A, An S, et al. One hundred and one dysembryoplastic neuroepithelial tumors: an adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature. J Neuropathol Exp Neurol. 2011;70:859–878.

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2. Baisden BL, Brat DJ, Melhem ER, et al. Dysembryoplastic neuroepithelial tumor-like neoplasm of the septum pellucidum: a lesion often misdiagnosed as glioma: report of 10 cases. Am J Surg Pathol. 2001;25:494–499. 3. Cataltepe O, Marshall P, Smith TW. Dysembryoplastic neuroepithelial tumor located in pericallosal and intraventricular area in a child. Case report. J Neurosurg Pediatr. 2009;3:456–460. 4. Saito T, Sugiyama K, Yamasaki F, et al. Familial occurrence of dysembryoplastic neuroepithelial tumor-like neoplasm of the septum pellucidum: case report. Neurosurgery. 2008;63:E370–E372. 5. Emmez H, Kale A, Egemen E, et al. Intraventricular dysembryoplastic neuroepithelial tumour: case report. Neurol Neurochir Pol. 2012;46:192–195. 6. Yuan J, Sharma N, Choudhri H, et al. Intraventricular dysembryoplastic neuroepithelial tumor in a pediatric patient: is it the most common extracortical location for DNT? Childs Nerv Syst. 2011;27:485–489. 7. Wang F, Qiao G, Li X, et al. A dysembryoplastic neuroepithelial tumor in the area of the caudate nucleus in a 57-year-old woman: case report. Neurosurgery. 2007;61:E420. 8. Altino¨rs N, Calisaneller T, Gu¨ls¸en S, et al. Intraventricular dysembryoplastic neuroepithelial tumor: case report. Neurosurgery. 2007;61:E1332–E1333. 9. Ongu¨ru¨ O, Deveci S, Sirin S, et al. Dysembryoplastic neuroepithelial tumor in the left lateral ventricle. Minim Invasive Neurosurg. 2003;46:306–309. 10. Xiong J, Liu Y, Chu SG, et al. Dysembryoplastic neuroepithelial tumor-like neoplasm of the septum pellucidum: review of 2 cases with chromosome 1p/19q and IDH1 analysis. Clin Neuropathol. 2012;31:31–38. 11. Guesmi H, Houtteville JP, Courthe´oux P, et al. Dysembryoplastic neuroepithelial tumors. Report of 8 cases including two with unusual localization. Neurochirurgie. 1999;45:190–200. 12. Harter DH, Omeis I, Forman S, et al. Endoscopic resection of an intraventricular dysembryoplastic neuroepithelial tumor of the septum pellucidum. Pediatr Neurosurg. 2006;42:105–107.

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13. Cervera-Pierot P, Varlet P, Chodkiewicz JP, et al. Dysembryoplastic neuroepithelial tumors located in the caudate nucleus area: report of four cases. Neurosurgery. 1997;40:1065–1069. 14. Fontebasso AM, Bechet D, Jabado N. Molecular biomarkers in pediatric glial tumors: a needed wind of change. Curr Opin Oncol. 2013;25:665–673. 15. Chappe´ C, Padovani L, Scavarda D, et al. Dysembryoplastic neuroepithelial tumors share with pleomorphic xanthoastrocytomas and gangliogliomas BRAF(V600E) mutation and expression. Brain Pathol. 2013;23:574–583. 16. Gessi M, Lambert SR, Lauriola L, et al. Absence of KIAA1549BRAF fusion in rosette-forming glioneuronal tumors of the fourth ventricle (RGNT). J Neurooncol. 2012;110:21–25. 17. Gessi M, Moneim YA, Hammes J, et al. FGFR1 mutations in Rosette-forming glioneuronal tumors of the fourth ventricle. J Neuropathol Exp Neurol. 2014;73:580–584. 18. Ho¨mig-Ho¨lzel C, Savola S. Multiplex ligation-dependent probe amplification (MLPA) in tumor diagnostics and prognostics. Diagn Mol Pathol. 2012;21:189–206. 19. Parmar HA, Hawkins C, Ozelame R, et al. Fluid-attenuated inversion recovery ring sign as a marker of dysembryoplastic neuroepithelial tumors. J Comput Assist Tomogr. 2007;31: 348–353. 20. Ramkissoon LA, Horowitz PM, Craig JM, et al. Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. Proc Natl Acad Sci U S A. 2013;110:8188–8193. 21. Zhang J, Wu G, Miller CP, et al. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet. 2013;45:602–612. 22. Tatevossian RG, Tang B, Dalton J, et al. MYB upregulation and genetic aberrations in a subset of pediatric low-grade gliomas. Acta Neuropathol. 2010;120:731–743. 23. Jones DT, Hutter B, Ja¨ger N, et al. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet. 2013;45:927–932.

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Dysembryoplastic Neuroepithelial Tumor of the Septum Pellucidum and the Supratentorial Midline: Histopathologic, Neuroradiologic, and Molecular Features of 7 Cases.

Dysembryoplastic neuroepithelial tumors (DNTs) are one of the most common epilepsy-associated low-grade glioneuronal tumors of the central nervous sys...
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