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Article ; Online: Perinatal hypoxic-ischemic brain injury: What's behind the "ribbon effect"?

Viaene, Angela N / Nelson, Ernest J / Santi, Mariarita

Journal of neuropathology and experimental neurology

2023 Volume 82, Issue 10, Page(s) 865–875

Abstract: Ribbon effect describes a perceived macroscopic color reversal of the gray and white matter, characterized by a pale cortex and diffusely dusky underlying white matter. This finding is thought to be unique to the perinatal period and indicative of ... ...

Abstract	Ribbon effect describes a perceived macroscopic color reversal of the gray and white matter, characterized by a pale cortex and diffusely dusky underlying white matter. This finding is thought to be unique to the perinatal period and indicative of hypoxic-ischemic injury. However, the clinical and microscopic correlates of this macroscopic finding have not been clearly defined. A 21-year retrospective study of autopsies was performed. Ribbon effect was seen in 190 subjects, ages 20 weeks gestation to 9.5 months adjusted age. Clinical associations and radiographic findings were similar in ribbon effect cases and controls. A variety of histologic findings were observed including acute neuronal injury, diffuse white matter gliosis, and white matter necrosis. Only white matter vascular congestion was significantly correlated to the macroscopic severity of ribbon effect; the severity of white matter injury and acute neuronal injury were not significantly correlated to ribbon effect. While hypoxic-ischemic changes were present in nearly all cases of ribbon effect, the location, severity, and chronicity of these changes varied considerably, and similar findings were observed in controls. The presence of ribbon effect therefore does not predict microscopic findings apart from vascular congestion, highlighting the importance of microscopic examination in perinatal brain autopsies.
MeSH term(s)	Pregnancy ; Female ; Humans ; Retrospective Studies ; Hypoxia-Ischemia, Brain/complications ; Hypoxia-Ischemia, Brain/diagnostic imaging ; Hypoxia-Ischemia, Brain/pathology ; Brain/diagnostic imaging ; Brain/pathology ; White Matter/pathology ; Brain Injuries/pathology
Language	English
Publishing date	2023-08-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3088-0
ISSN	1554-6578 ; 0022-3069
ISSN (online)	1554-6578
ISSN	0022-3069
DOI	10.1093/jnen/nlad067
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Article ; Online: Ependymal Tumors.

Santi, Mariarita / Viaene, Angela N / Hawkins, Cynthia

Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society

2022 Volume 25, Issue 1, Page(s) 59–67

Abstract: Ependymomas (EPN) are commonly encountered brain tumors in the pediatric population. They may arise in the supratentorial compartment, posterior fossa and spinal cord. Histopathologic grading of EPN has always been challenging with poor interobserver ... ...

Abstract	Ependymomas (EPN) are commonly encountered brain tumors in the pediatric population. They may arise in the supratentorial compartment, posterior fossa and spinal cord. Histopathologic grading of EPN has always been challenging with poor interobserver reproducibility and lack of correlation between histologic grade and patient outcomes. Recent studies have highlighted that, despite histopathological similarities among variants of EPN at different anatomical sites, they possess site-specific genetic and epigenetic alterations, transcriptional profiles and DNA copy number variations. This has led to a molecular and location-based classification for EPN which has been adopted by the World Health Organization Classification of Central Nervous System Tumors and more accurately risk-stratifies patients than histopathologic grading alone. Given the complexity of this evolving field, the purpose of this paper is to offer a practical approach to the diagnosis of EPN, including the selection of the most appropriate molecular surrogate immunohistochemical stains, basic molecular studies and more sophisticated techniques if needed. The goal is to reach a rapid, sound diagnosis, providing essential information regarding prognosis and guiding clinical decision-making.
MeSH term(s)	Brain Neoplasms/diagnosis ; Brain Neoplasms/genetics ; Child ; DNA Copy Number Variations ; Ependymoma/diagnosis ; Ependymoma/genetics ; Humans ; Prognosis ; Reproducibility of Results
Language	English
Publishing date	2022-01-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	1463498-3
ISSN	1615-5742 ; 1093-5266
ISSN (online)	1615-5742
ISSN	1093-5266
DOI	10.1177/10935266211018928
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Article ; Online: Pediatric Glial Tumors.

Viaene, Angela N / Santi, Mariarita / Hawkins, Cynthia

Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society

2021 Volume 25, Issue 1, Page(s) 46–58

Abstract: Pediatric glial tumors are unique from their adult counterparts. This important distinction is recognized and incorporated into the World Health Organization classification of central nervous system tumors and applies to both high- and low-grade gliomas, ...

Abstract	Pediatric glial tumors are unique from their adult counterparts. This important distinction is recognized and incorporated into the World Health Organization classification of central nervous system tumors and applies to both high- and low-grade gliomas, incorporating their specific molecular profiles. Molecular alterations in pediatric high-grade gliomas provide important prognostic information, for example in H3 K27M-mutant tumors. The integration of molecular information is also important for pediatric low-grade gliomas due to their overlapping morphologies and the prognostic and therapeutic implications of these molecular alterations. In this paper, we cover a variety of glial tumors, encompassing neoplasms with predominantly glial histology, astrocytic tumors, oligodendroglial tumors, and mixed glioneuronal tumors. Considering the complexity of this evolving field, the purpose of this article is to offer a practical approach to the diagnosis of pediatric gliomas, including the selection of the most appropriate molecular surrogate immunohistochemical stains, basic molecular studies, and more sophisticated techniques if needed. The goal is to reach a rapid, sound diagnosis, helping guide clinical decision-making regarding prognosis and potential therapies.
MeSH term(s)	Adult ; Brain Neoplasms/diagnosis ; Brain Neoplasms/genetics ; Brain Neoplasms/therapy ; Child ; Glioma/diagnosis ; Glioma/genetics ; Glioma/therapy ; Humans ; Mutation ; Neuroglia ; Prognosis
Language	English
Publishing date	2021-04-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	1463498-3
ISSN	1615-5742 ; 1093-5266
ISSN (online)	1615-5742
ISSN	1093-5266
DOI	10.1177/10935266211009101
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Article ; Online: First-time identification of a KIF5B-NTRK2 fusion in extraventricular neurocytoma.

Gubbiotti, Maria A / Santi, Mariarita / Storm, Philip B / Li, Marilyn / Xu, Feng / Abdullaev, Zied / Aldape, Kenneth / Viaene, Angela N

Journal of neuropathology and experimental neurology

2023 Volume 82, Issue 3, Page(s) 272–275

MeSH term(s)	Humans ; Brain Neoplasms/genetics ; Magnetic Resonance Imaging ; Neurocytoma/genetics
Chemical Substances	KIF5B protein, human ; tropomyosin-related kinase-B, human (EC 2.7.10.1)
Language	English
Publishing date	2023-02-07
Publishing country	England
Document type	Letter
ZDB-ID	3088-0
ISSN	1554-6578 ; 0022-3069
ISSN (online)	1554-6578
ISSN	0022-3069
DOI	10.1093/jnen/nlad002
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Article ; Online: A Practical Approach to the Evaluation and Diagnosis of Pediatric CNS Tumors.

Cotter, Jennifer A / Viaene, Angela N / Santi, Mariarita / Hawkins, Cynthia / Judkins, Alexander R

Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society

2021 Volume 25, Issue 1, Page(s) 6–9

Abstract: Tumor classification in neuropathology is a dynamic and complex topic, with many changes emerging in the past 5 years, up to and including the 2021 publication of the 5th edition of the World Health Organization Classification of Tumours of the Central ... ...

Abstract	Tumor classification in neuropathology is a dynamic and complex topic, with many changes emerging in the past 5 years, up to and including the 2021 publication of the 5th edition of the World Health Organization Classification of Tumours of the Central Nervous System (CNS). For pediatric pathologists who will encounter brain tumors with varying frequency, it is important to understand the principles of these classification updates, particularly the inclusion of molecular genetic features and development of a layered, or integrated, diagnosis. This issue of Perspectives in Pediatric Pathology is dedicated to the examination of pediatric brain tumors, and features articles on intraoperative diagnosis and updated information on molecular-based classification for pediatric glial, glioneuronal, ependymal, and embryonal tumors of the CNS.
MeSH term(s)	Brain Neoplasms/diagnosis ; Brain Neoplasms/genetics ; Central Nervous System ; Central Nervous System Neoplasms/diagnosis ; Child ; Humans ; Neoplasms, Germ Cell and Embryonal ; World Health Organization
Language	English
Publishing date	2021-04-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	1463498-3
ISSN	1615-5742 ; 1093-5266
ISSN (online)	1615-5742
ISSN	1093-5266
DOI	10.1177/10935266211007022
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Article ; Online: Pro-inflammatory cytokines mediate the epithelial-to-mesenchymal-like transition of pediatric posterior fossa ependymoma.

Aubin, Rachael G / Troisi, Emma C / Montelongo, Javier / Alghalith, Adam N / Nasrallah, Maclean P / Santi, Mariarita / Camara, Pablo G

Nature communications

2022 Volume 13, Issue 1, Page(s) 3936

Abstract: Pediatric ependymoma is a devastating brain cancer marked by its relapsing pattern and lack of effective chemotherapies. This shortage of treatments is due to limited knowledge about ependymoma tumorigenic mechanisms. By means of single-nucleus chromatin ...

Abstract	Pediatric ependymoma is a devastating brain cancer marked by its relapsing pattern and lack of effective chemotherapies. This shortage of treatments is due to limited knowledge about ependymoma tumorigenic mechanisms. By means of single-nucleus chromatin accessibility and gene expression profiling of posterior fossa primary tumors and distal metastases, we reveal key transcription factors and enhancers associated with the differentiation of ependymoma tumor cells into tumor-derived cell lineages and their transition into a mesenchymal-like state. We identify NFκB, AP-1, and MYC as mediators of this transition, and show that the gene expression profiles of tumor cells and infiltrating microglia are consistent with abundant pro-inflammatory signaling between these populations. In line with these results, both TGF-β1 and TNF-α induce the expression of mesenchymal genes on a patient-derived cell model, and TGF-β1 leads to an invasive phenotype. Altogether, these data suggest that tumor gliosis induced by inflammatory cytokines and oxidative stress underlies the mesenchymal phenotype of posterior fossa ependymoma.
MeSH term(s)	Cytokines/genetics ; Cytokines/pharmacology ; Ependymoma/genetics ; Epithelial-Mesenchymal Transition/genetics ; Humans ; Neoplasm Recurrence, Local ; Transforming Growth Factor beta1/metabolism
Chemical Substances	Cytokines ; Transforming Growth Factor beta1
Language	English
Publishing date	2022-07-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-31683-9
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Article ; Online: Diffuse leptomeningeal glioneuronal tumor in a child masquerading as an intramedullary spinal pilocytic astrocytoma.

Madsen, Peter J / Hollawell, Madison L / Santi, Mariarita / Surrey, Lea F / Vossough, Arastoo / Orr, Brent A / Hill-Kayser, Christine / Tucker, Alexander M / Storm, Phillip B / Foster, Jessica B

Neuro-oncology advances

2023 Volume 5, Issue 1, Page(s) vdad049

Abstract: Diffuse leptomeningeal glioneuronal tumor (DLGNT) occurs predominantly in children and is typically characterized by diffuse leptomeningeal lesions throughout the neuroaxis with focal segments of parenchymal involvement. Recent reports have identified ... ...

Abstract	Diffuse leptomeningeal glioneuronal tumor (DLGNT) occurs predominantly in children and is typically characterized by diffuse leptomeningeal lesions throughout the neuroaxis with focal segments of parenchymal involvement. Recent reports have identified cases without diffuse leptomeningeal involvement that retain classic glioneuronal features on histology. In this report, we present a case of a 4-year-old boy with a large cystic-solid intramedullary spinal cord lesion that on surgical biopsy revealed a biphasic astrocytic tumor with sparsely distributed eosinophilic granular bodies and Rosenthal fibers. Next-generation sequencing revealed a
Language	English
Publishing date	2023-04-19
Publishing country	England
Document type	Journal Article
ZDB-ID	3009682-0
ISSN	2632-2498 ; 2632-2498
ISSN (online)	2632-2498
ISSN	2632-2498
DOI	10.1093/noajnl/vdad049
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Article ; Online: Thrombosis of the Renal Vein and Inferior Vena Cava Associated With Placental Fetal Vascular Malperfusion in a Neonate Exposed to Methadone Maintenance Therapy In Utero.

Guerrero, J C / Kim, Joseph / Santi, Mariarita / Ruchelli, Eduardo / Carreon, Chrystalle Katte

Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society

2020 Volume 24, Issue 1, Page(s) 56–61

Abstract: Methadone, an opioid agonist, is the recommended treatment for pregnant women with opioid use disorder (OUD). Fetal/neonatal autopsy findings as well as placental changes in the setting of maternal OUD or methadone maintenance therapy (MMT) are not well- ... ...

Abstract	Methadone, an opioid agonist, is the recommended treatment for pregnant women with opioid use disorder (OUD). Fetal/neonatal autopsy findings as well as placental changes in the setting of maternal OUD or methadone maintenance therapy (MMT) are not well-characterized. Here we present a case of a neonate who had exposure to MMT while in utero and died shortly after birth and was subsequently found to have multifocal calcified renal vein thrombosis, a recent inferior vena cava thrombus, and placental features of fetal vascular malperfusion at autopsy.
MeSH term(s)	Analgesics, Opioid/adverse effects ; Autopsy ; Female ; Fetal Death/etiology ; Fetus/blood supply ; Humans ; Methadone/adverse effects ; Opiate Substitution Treatment/adverse effects ; Opioid-Related Disorders/diagnosis ; Opioid-Related Disorders/drug therapy ; Pregnancy ; Renal Veins/pathology ; Vena Cava, Inferior/pathology ; Venous Thrombosis/chemically induced ; Venous Thrombosis/pathology
Chemical Substances	Analgesics, Opioid ; Methadone (UC6VBE7V1Z)
Language	English
Publishing date	2020-09-24
Publishing country	United States
Document type	Case Reports
ZDB-ID	1463498-3
ISSN	1615-5742 ; 1093-5266
ISSN (online)	1615-5742
ISSN	1093-5266
DOI	10.1177/1093526620962062
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Article ; Online: ZFTA-fused supratentorial ependymoma with a novel fusion partner, DUX4.

Gubbiotti, Maria A / Madsen, Peter J / Tucker, Alexander M / Abdullaev, Zied / Aldape, Kenneth / Shekdar, Karuna / Yang, Adeline / Minturn, Jane E / Santi, Mariarita / Viaene, Angela N

Journal of neuropathology and experimental neurology

2023 Volume 82, Issue 7, Page(s) 668–671

MeSH term(s)	Humans ; Supratentorial Neoplasms/genetics ; Brain Neoplasms ; Ependymoma/genetics
Language	English
Publishing date	2023-05-22
Publishing country	England
Document type	Letter
ZDB-ID	3088-0
ISSN	1554-6578 ; 0022-3069
ISSN (online)	1554-6578
ISSN	0022-3069
DOI	10.1093/jnen/nlad038
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Article ; Online: Pediatric phase 2 trial of a WEE1 inhibitor, adavosertib (AZD1775), and irinotecan for relapsed neuroblastoma, medulloblastoma, and rhabdomyosarcoma.

Cole, Kristina A / Ijaz, Heba / Surrey, Lea F / Santi, Mariarita / Liu, Xiaowei / Minard, Charles G / Maris, John M / Voss, Stephan / Reid, Joel M / Fox, Elizabeth / Weigel, Brenda J

Cancer

2023 Volume 129, Issue 14, Page(s) 2245–2255

Abstract: Background: Inhibition of the WEE1 kinase by adavosertib (AZD1775) potentiates replicative stress from genomic instability or chemotherapy. This study reports the pediatric solid tumor phase 2 results of the ADVL1312 trial combining irinotecan and ... ...

Abstract	Background: Inhibition of the WEE1 kinase by adavosertib (AZD1775) potentiates replicative stress from genomic instability or chemotherapy. This study reports the pediatric solid tumor phase 2 results of the ADVL1312 trial combining irinotecan and adavosertib. Methods: Pediatric patients with recurrent neuroblastoma (part B), medulloblastoma/central nervous system embryonal tumors (part C), or rhabdomyosarcoma (part D) were treated with irinotecan and adavosertib orally for 5 days every 21 days. The combination was considered effective if there were at least three of 20 responses in parts B and D or six of 19 responses in part C. Tumor tissue was analyzed for alternative lengthening of telomeres and ATRX. Patient's prior tumor genomic analyses were provided. Results: The 20 patients with neuroblastoma (part B) had a median of three prior regimens and 95% had a history of prior irinotecan. There were three objective responses (9, 11, and 18 cycles) meeting the protocol defined efficacy end point. Two of the three patients with objective responses had tumors with alternative lengthening of telomeres. One patient with pineoblastoma had a partial response (11 cycles), but parts C and D did not meet the protocol defined efficacy end point. The combination was well tolerated and there were no dose limiting toxicities at cycle 1 or beyond in any parts of ADVL1312 at the recommended phase 2 dose. Conclusion: This is first phase 2 clinical trial of adavosertib in pediatrics and the first with irinotecan. The combination may be of sufficient activity to consider further study of adavosertib in neuroblastoma.
MeSH term(s)	Child ; Humans ; Irinotecan/therapeutic use ; Medulloblastoma ; Neuroblastoma/drug therapy ; Neuroblastoma/genetics ; Rhabdomyosarcoma/drug therapy ; Cerebellar Neoplasms/drug therapy ; Cerebellar Neoplasms/etiology ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Protein-Tyrosine Kinases ; Cell Cycle Proteins
Chemical Substances	Irinotecan (7673326042) ; adavosertib (K2T6HJX3I3) ; WEE1 protein, human (EC 2.7.10.2) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Cell Cycle Proteins
Language	English
Publishing date	2023-04-20
Publishing country	United States
Document type	Clinical Trial, Phase II ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1429-1
ISSN	1097-0142 ; 0008-543X ; 1934-662X
ISSN (online)	1097-0142
ISSN	0008-543X ; 1934-662X
DOI	10.1002/cncr.34786
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