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Pediatric midline H3K27M-mutant tumor with disseminated leptomeningeal disease and glioneuronal features: case report and literature review
Navarro, Ralph E; Golub, Danielle; Hill, Travis; McQuinn, Michelle W; William, Christopher; Zagzag, David; Hidalgo, Eveline Teresa
BACKGROUND:H3K27M-mutant midline lesions were recently reclassified by the World Health Organization (WHO) as "diffuse midline glioma" (DMG) based entirely on their molecular signature. DMG is one of the most common and most lethal pediatric brain tumors; terminal progression is typically caused by local midbrain or brainstem progression, or secondary leptomeningeal dissemination. H3K27M mutations have also been infrequently associated with a histologically and prognostically diverse set of lesions, particularly spinal masses with early leptomeningeal spread. CASE PRESENTATION/METHODS:A 15-year-old girl after 1Â week of symptoms was found to have a T2/FLAIR-hyperintense and contrast-enhancing thalamic mass accompanied by leptomeningeal enhancement along the entire neuraxis. Initial infectious workup was negative, and intracranial biopsy was inconclusive. Spinal arachnoid biopsy revealed an H3K27M-mutant lesion with glioneuronal features, classified thereafter as DMG. She received craniospinal irradiation with a boost to the thalamic lesion. Imaging 1-month post-radiation demonstrated significant treatment response with residual enhancement at the conus. CONCLUSIONS:This case report describes the unique presentation of an H3K27M-mutant midline lesion with significant craniospinal leptomeningeal spread on admission and atypical glioneuronal histopathological markers. With such florid leptomeningeal disease, spinal dural biopsy should be considered earlier given its diagnostic yield in classifying the lesion as DMG. Consistent with similar prior reports, this lesion additionally demonstrated synaptophysin positivity-also potentially consistent with a diagnosis of diffuse leptomeningeal glioneuronal tumor (DLGNT). In atypical DMG cases, particularly with leptomeningeal spread, further consideration of clinical and histopathological context is necessary for accurate diagnosis and prognostication.
PMID: 32989496
ISSN: 1433-0350
CID: 4651682
Hemispherectomy Outcome Prediction Scale: Development and validation of a seizure freedom prediction tool
Weil, Alexander G; Lewis, Evan C; Ibrahim, George M; Kola, Olivia; Tseng, Chi-Hong; Zhou, Xinkai; Lin, Kao-Min; Cai, Li-Xin; Liu, Qing-Zhu; Lin, Jiu-Luan; Zhou, Wen-Jing; Mathern, Gary W; Smyth, Matthew D; O'Neill, Brent R; Dudley, Roy; Ragheb, John; Bhatia, Sanjiv; Delev, Daniel; Ramantani, Georgia; Zentner, Josef; Ojemann, Jeffrey; Wang, Anthony C; Dorfer, Christian; Feucht, Martha; Czech, Thomas; Bollo, Robert J; Issabekov, Galymzhan; Zhu, Hongwei; Connelly, Mary; Steinbok, Paul; Zhang, Jian-Guo; Zhang, Kai; Hidalgo, Eveline Teresa; Weiner, Howard L; Wong-Kisiel, Lily; Lapalme-Remis, Samuel; Tripathi, Manjari; Sarat Chandra, Poodipedi; Hader, Walter; Wang, Feng-Peng; Yao, Yi; Olivier Champagne, Pierre; Guo, Qiang; Li, Shao-Chun; Budke, Marcelo; Pérez-Jiménez, Maria Angeles; Raftapoulos, Christian; Finet, Patrice; Michel, Pauline; Schaller, Karl; Stienen, Martin N; Baro, Valentina; Cantillano Malone, Christian; Pociecha, Juan; Chamorro, Noelia; Muro, Valeria L; von Lehe, Marec; Vieker, Silvia; Oluigbo, Chima; Gaillard, William D; Al Khateeb, Mashael; Al Otaibi, Faisal; Krayenbühl, Niklaus; Bolton, Jeffrey; Pearl, Phillip L; Fallah, Aria
OBJECTIVE:To develop and validate a model to predict seizure freedom in children undergoing cerebral hemispheric surgery for the treatment of drug-resistant epilepsy. METHODS:We analyzed 1267 hemispheric surgeries performed in pediatric participants across 32 centers and 12 countries to identify predictors of seizure freedom at 3 months after surgery. A multivariate logistic regression model was developed based on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). Missing data were handled using multiple imputation techniques. RESULTS:Overall, 817 of 1237 (66%) hemispheric surgeries led to seizure freedom (median follow-up = 24Â months), and 1050 of 1237 (85%) were seizure-free at 12Â months after surgery. A simple regression model containing age at seizure onset, presence of generalized seizure semiology, presence of contralateral 18-fluoro-2-deoxyglucose-positron emission tomography hypometabolism, etiologic substrate, and previous nonhemispheric resective surgery is predictive of seizure freedom (area under the curve = .72). A Hemispheric Surgery Outcome Prediction Scale (HOPS) score was devised that can be used to predict seizure freedom. SIGNIFICANCE/CONCLUSIONS:Children most likely to benefit from hemispheric surgery can be selected and counseled through the implementation of a scale derived from a multiple regression model. Importantly, children who are unlikely to experience seizure control can be spared from the complications and deficits associated with this surgery. The HOPS score is likely to help physicians in clinical decision-making.
PMID: 33713438
ISSN: 1528-1167
CID: 4836542
Somatic Focal Copy Number Gains of Noncoding Regions of Receptor Tyrosine Kinase Genes in Treatment-Resistant Epilepsy
Vasudevaraja, Varshini; Rodriguez, Javier Hernaez; Pelorosso, Cristiana; Zhu, Kaicen; Buccoliero, Anna Maria; Onozato, Maristela; Mohamed, Hussein; Serrano, Jonathan; Tredwin, Lily; Garonzi, Marianna; Forcato, Claudio; Zeck, Briana; Ramaswami, Sitharam; Stafford, James; Faustin, Arline; Friedman, Daniel; Hidalgo, Eveline Teresa; Zagzag, David; Skok, Jane; Heguy, Adriana; Chiriboga, Luis; Conti, Valerio; Guerrini, Renzo; Iafrate, A John; Devinsky, Orrin; Tsirigos, Aristotelis; Golfinos, John G; Snuderl, Matija
Epilepsy is a heterogenous group of disorders defined by recurrent seizure activity due to abnormal synchronized activity of neurons. A growing number of epilepsy cases are believed to be caused by genetic factors and copy number variants (CNV) contribute to up to 5% of epilepsy cases. However, CNVs in epilepsy are usually large deletions or duplications involving multiple neurodevelopmental genes. In patients who underwent seizure focus resection for treatment-resistant epilepsy, whole genome DNA methylation profiling identified 3 main clusters of which one showed strong association with receptor tyrosine kinase (RTK) genes. We identified focal copy number gains involving epidermal growth factor receptor (EGFR) and PDGFRA loci. The dysplastic neurons of cases with amplifications showed marked overexpression of EGFR and PDGFRA, while glial and endothelial cells were negative. Targeted sequencing of regulatory regions and DNA methylation analysis revealed that only enhancer regions of EGFR and gene promoter of PDGFRA were amplified, while coding regions did not show copy number abnormalities or somatic mutations. Somatic focal copy number gains of noncoding regulatory represent a previously unrecognized genetic driver in epilepsy and a mechanism of abnormal activation of RTK genes. Upregulated RTKs provide a potential avenue for therapy in seizure disorders.
PMID: 33274363
ISSN: 1554-6578
CID: 4694512
Treatment Options for Hydrocephalus Following Foramen Magnum Decompression for Chiari I Malformation: A Multicenter Study
Bartoli, Andrea; Soleman, Jehuda; Berger, Assaf; Wisoff, Jeffrey H; Hidalgo, Eveline Teresa; Mangano, Francesco T; Keating, Robert F; Thomale, Ulrich W; Boop, Frederick; Roth, Jonathan; Constantini, Shlomi
BACKGROUND:New-onset hydrocephalus following foramen magnum decompression (FMD) for Chiari I malformation (CM-I) is rare; its natural history and pathophysiology are poorly understood. OBJECTIVE:To describe a series of patients who developed hydrocephalus following FMD for CM-I, provide possible explanations of this phenomenon, and outline treatment options. METHODS:Out of patients undergoing FMD for CM-I from 6 different tertiary centers, we evaluated patients presenting with new-onset hydrocephalus following FMD. The retrospectively collected data included demographics, clinical, and radiological findings of the CM-I and hydrocephalus patients. Time from FMD and hydrocephalus onset, treatment, and surgical techniques were assessed. RESULTS:Of 549 patients who underwent FMD for CM-I, 28 (5.1%) subsequently developed hydrocephalus (18 females, 10 males), with a mean age of 11.7 ± 11.9 yr (range 6 mo to 52 yr). Hydrocephalus occurred on average 2.2 ± 2.6 mo after FMD (range 1 wk to 8 mo). Four patients did not have a violation of the arachnoid during the FMD surgery. Main presenting symptoms of hydrocephalus were headaches (17, 41%), vomiting (10, 24.4%), and cerebrospinal fluid (CSF) leak or pseudomeningocele (7, 17%).Overall, 23 patients (82.1%) underwent CSF shunting, 1 patient (3.5%) had an endoscopic third ventriculostomy, 3 patients (10.7%) temporary CSF diversion only, and 1 patient (3.5%) was treated with acetazolamide. CONCLUSION/CONCLUSIONS:Hydrocephalus following FMD for CM-I is uncommon, but important. Based on our series and literature review, its incidence is about 5% to 7% and most likely will require further surgery. Shunting appears to be the favored treatment option.
PMID: 31232427
ISSN: 1524-4040
CID: 3955052
Quality of life, hypothalamic obesity, and sexual function in adulthood two decades after primary gross-total resection for childhood craniopharyngioma
Hidalgo, Eveline Teresa; Orillac, Cordelia; Kvint, Svetlana; McQuinn, Michelle W; Dastagirzada, Yosef; Phillips, Sophie; Wisoff, Jeffrey H
PURPOSE/OBJECTIVE:All treatments for childhood craniopharyngioma are associated with complications that potentially affect quality of life. This study was designed to investigate the impact of gross total resection on long-term quality of life and sexual functioning in adulthood. METHODS:Adults treated with primary gross total resection for childhood craniopharyngioma and ≥ 10 years of follow-up were included in this retrospective cohort study. The Short Form 36 Health Survey Questionnaire Version 2 (SF-36v2), Medical Outcomes Study (MOS) sexual functioning survey, and a sociodemographic/health questionnaire were administered. RESULTS:). Preoperative hypothalamic involvement correlated with a significantly higher BMI, although the proportion of participants with class 3 obesity (BMI ≥ 40) did not differ significantly from that of the general population (9% and 7%, respectively). CONCLUSIONS:Young adults with gross total resection of childhood craniopharyngioma report similar quality of life and sexual functioning compared to the general population, but appear to be less sexually active. Hypothalamic involvement on preoperative imaging was associated with a higher BMI in long-term follow-up.
PMID: 31222446
ISSN: 1433-0350
CID: 3939402
Subgroup-specific outcomes of children with malignant childhood brain tumors treated with an irradiation-sparing protocol
Hidalgo, Eveline Teresa; Snuderl, Matija; Orillac, Cordelia; Kvint, Svetlana; Serrano, Jonathan; Wu, Peter; Karajannis, Matthias A; Gardner, Sharon L
PURPOSE/OBJECTIVE:Molecular subgroups of pediatric brain tumors associated with divergent biological, clinical, and prognostic features have been identified. However, data regarding the impact of subgroup affiliation on the outcome of children with malignant brain tumors treated with radiation-sparing protocol is limited. We report long-term clinical outcomes and the molecular subgroups of malignant brain tumors in young children whose first-line treatment was high-dose chemotherapy without irradiation. METHODS:Tumor subclassification was performed using the Illumina HumanMethylation450 BeadChip (450k) genome-wide methylation array profiling platform. Clinical information was obtained from chart review. RESULTS:Methylation array profiling yielded information on molecular subgroups in 22 children. Median age at surgery was 26 months (range 1-119 months). Among medulloblastomas (MB), all 6 children in the infant sonic hedgehog (SHH) subgroup were long-term survivors, whereas all 4 children in subgroup 3 MB died. There was one long-term survivor in subgroup 4 MB. One out of five children with ependymoma was a long-term survivor (RELPOS). Both children with primitive neuroectodermal tumors died. One child with ATRT TYR and one child with choroid plexus carcinoma were long-term survivors. CONCLUSIONS:The efficacy of high-dose chemotherapy radiation-sparing treatment appears to be confined to favorable molecular subgroups of pediatric brain tumors, such as infant SHH MB. Identification of molecular subgroups that benefit from radiation-sparing therapy will aid in the design of prospective, "precision medicine"-driven clinical trials.
PMID: 31375903
ISSN: 1433-0350
CID: 4015542
AN UNUSUAL PRESENTATION OF A PEDIATRIC MIDLINE H3K27M-MUTANT TUMOR WITH DISSEMINATED CRANIOSPINAL LEPTOMENINGEAL DISEASE [Meeting Abstract]
Navarro, Ralph; Golub, Danielle; Hill, Travis; McQuinn, Michelle; Kim, Nora; Tang, Karen; Livingston, Stephanie; Cooper, Benjamin; Gardner, Sharon; Nicolaides, Theodore; William, Christopher; Zagzag, David; Hidalgo, E. Teresa
ISI:000590061300725
ISSN: 1522-8517
CID: 4688202
Intra-reservoir administration of alteplase to treat a distal ventriculo-atrial shunt obstruction
Delavari, Nader; Mureb, Monica C; Yaun, Amanda; Wisoff, Jeffrey H; Harter, David H; Hidalgo, E Teresa
BACKGROUND:Ventriculoatrial shunts can be afflicted with distal malfunctions due to thrombus formation at the distal tip. Distal tip thrombus formation may occur more commonly in oncologic patients who are predisposed to hypercoagulability. CASE DESCRIPTION/METHODS:A patient who had a ventriculo-atrial shunt placed for leptomeningeal carcinomatosis presented with headaches and confusion and was found to have a partial distal shunt obstruction. Intra-reservoir administration of alteplase resulted in resolution of her symptoms. Nuclear medicine shunt patency test demonstrated restoration of distal flow. CONCLUSIONS:Intra-reservoir administration of alteplase can be a useful non-operative treatment strategy for ventriculo-atrial shunt malfunction. This strategy may be particularly useful in cases with higher peri-operative risk, such as patients with advanced metastatic cancer.
PMID: 31715416
ISSN: 1878-8769
CID: 4185252
Long-term clinical and visual outcomes after surgical resection of pediatric pilocytic/pilomyxoid optic pathway gliomas
Hidalgo, Eveline Teresa; Kvint, Svetlana; Orillac, Cordelia; North, Emily; Dastagirzada, Yosef; Chang, Jamie Chiapei; Addae, Gifty; Jennings, Tara S; Snuderl, Matija; Wisoff, Jeffrey H
OBJECTIVEThe choice of treatment modality for optic pathway gliomas (OPGs) is controversial. Chemotherapy is widely regarded as first-line therapy; however, subtotal resections have been reported for decompression or salvage therapy as first- and second-line treatment. The goal of this study was to further investigate the role and efficacy of resection for OPGs.METHODSA retrospective chart review was performed on 83 children who underwent surgical treatment for OPGs between 1986 and 2014. Pathology was reviewed by a neuropathologist. Clinical outcomes, including progression-free survival (PFS), overall survival (OS), and complications, were analyzed.RESULTSThe 5- and 10-year PFS rates were 55% and 46%, respectively. The 5- and 10-year OS rates were 87% and 78%, respectively. The median extent of resection was 80% (range 30%-98%). Age less than 2 years at surgery and pilomyxoid features of the tumor were found to be associated with significantly lower 5-year OS. No difference was seen in PFS or OS of children treated with surgery as a first-line treatment compared with children with surgery as a second- or third-line treatment. Severe complications included new disabling visual deficit in 5%, focal neurological deficit in 8%, and infection in 2%. New hormone deficiency occurred in 22% of the children.CONCLUSIONSApproximately half of all children experience a long-term benefit from resection both as primary treatment and as a second-line therapy after failure of primary treatment. Primary surgery does not appear to have a significant benefit for children younger than 2 years or tumors with pilomyxoid features. Given the risks associated with surgery, an interdisciplinary approach is needed to tailor the treatment plan to the individual characteristics of each child.
PMID: 31100719
ISSN: 1933-0715
CID: 3920122
JOURNAL OF NEUROSURGERY-PEDIATRICS
Hidalgo, Eveline Teresa; Kvint, Svetlana; Orillac, Cordelia; North, Emily; Dastagirzada, Yosef; Chang, Jamie Chiapei; Addae, Gifty; Jennings, Tara S.; Snuderl, Matija; Wisoff, Jeffrey H.
ISI:000478646300009
ISSN: 1933-0707
CID: 5883582