Dataset Information

Cognitive Implications of Ototoxicity in Pediatric Patients With Embryonal Brain Tumors.

ABSTRACT:

Purpose

Sensorineural hearing loss (SNHL) is associated with intellectual and academic declines in children treated for embryonal brain tumors. This study expands upon existing research by examining core neurocognitive processes that may result in reading difficulties in children with treatment-related ototoxicity.

Patients and methods

Prospectively gathered, serial, neuropsychological and audiology data for 260 children and young adults age 3 to 21 years (mean, 9.15 years) enrolled in a multisite research and treatment protocol, which included surgery, risk-adapted craniospinal irradiation (average risk, n = 186; high risk, n = 74), and chemotherapy, were analyzed using linear mixed models. Participants were assessed at baseline and up to 5 years after diagnosis and grouped according to degree of SNHL. Included were 196 children with intact hearing or mild to moderate SNHL (Chang grade 0, 1a, 1b, or 2a) and 64 children with severe SNHL (Chang grade 2b or greater). Performance on eight neurocognitive variables targeting reading outcomes (eg, phonemics, fluency, comprehension) and contributory cognitive processes (eg, working memory, processing speed) was analyzed.

Results

Participants with severe SNHL performed significantly worse on all variables compared with children with normal or mild to moderate SNHL (P ? .05), except for tasks assessing awareness of sounds and working memory. Controlling for age at diagnosis and risk-adapted craniospinal irradiation dose, performance on the following four variables remained significantly lower for children with severe SNHL: phonemic skills, phonetic decoding, reading comprehension, and speed of information processing (P ? .05).

Conclusion

Children with severe SNHL exhibit greater reading difficulties over time. Specifically, they seem to struggle most with phonological skills and processing speed, which affect higher level skills such as reading comprehension.

SUBMITTER: Olivier TW

PROVIDER: S-EPMC6599406 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

Cognitive Implications of Ototoxicity in Pediatric Patients With Embryonal Brain Tumors.

Olivier Traci W TW Bass Johnnie K JK Ashford Jason M JM Beaulieu Rebecca R Scott Sarah M SM Schreiber Jane E JE Palmer Shawna S Mabbott Donald J DJ Swain Michelle A MA Bonner Melanie M Boyle Robyn R Chapeiski Mary Lynn ML Evankovich Karen D KD Armstrong Carol L CL Knight Sarah J SJ Wu Shengjie S Onar-Thomas Arzu A Gajjar Amar A Conklin Heather M HM

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20190502 18

<h4>Purpose</h4>Sensorineural hearing loss (SNHL) is associated with intellectual and academic declines in children treated for embryonal brain tumors. This study expands upon existing research by examining core neurocognitive processes that may result in reading difficulties in children with treatment-related ototoxicity.<h4>Patients and methods</h4>Prospectively gathered, serial, neuropsychological and audiology data for 260 children and young adults age 3 to 21 years (mean, 9.15 years) enroll ...[more]

PMID: 31046551

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Project description:Abstract BACKGROUND: In previous work we established that PLK4 is overexpressed and essential for proliferation and survival of pediatric embryonal brain tumors. PLK4 is a cell cycle-regulated protein recruited at the centrosome in dividing cells. Its overexpression triggers centrosome amplification, which is associated with genetic instability and carcinogenesis. We demonstrated that PLK4 inhibition exerts a potent cytostatic effect in EBT. We also established the synergism of the PLK4 inhibitor CFI-400945 with cytotoxic drugs and other signal transduction modulators. METHODS: We studied protein kinase inhibitors (PKI) with PLK4 cross-over potential (CFI-400945, CFI-400437, centrinone, centrinone-B, R-1530, axitinib, alisertib and KW-2449) by assessing their chemical profiles through docking simulations over PLK4 (PDB entry: 3COK) using Gold 5.4 software; evaluating their potential to penetrate the BBB (via logBB calculation by Clark equation), performing LanthaScreen EU Kinase Binding assays (ThermoFisher Scientific) and cell based studies (viability and proliferation) in multiple embryonal tumor cell lines (MON, BT-12, BT-16, DAOY, D283). RESULTS: Kinase binding assays and cell based studies showed that CFI-400437 was the most effective compound, yielding an IC50 <5nM in the binding assay and requiring <100nM of drug to significantly inhibit proliferation in multiple cell lines. However, docking simulations using the PLK4 catalytic cavity and each of the various PKIs demonstrated that all of the inhibitors tested exhibit similar interactions within the binding cavity, engaging in H-bonding with backbone residues Glu-89 and Cys-91. Additional polar and hydrophobic (?-stacking) interactions were also identified for each of the PKIs. LogBB calculations revealed that compound R-1530 has the greatest likelihood to enter the brain (LogBB+0.130). CONCLUSION: Although CFI-400945 is the most effective PLK4 inhibitor among those assayed, it has low potential for BBB exposure. Molecular docking results indicate the potential to develop new chemical entities with higher BBB exposure potential using a similar binding mode to that of CFI-400945.

Project description:Pediatric embryonal brain tumors (PEBTs), which encompass medulloblastoma (MB), primitive neuroectodermal tumor (PNET) and atypical teratoid/rhabdoid tumor (AT/RT), are the second most prevalent pediatric brain tumor type. AT/RT is highly malignant and is often misdiagnosed as MB or PNET. The distinction of AT/RT from PNET/MB is of clinical significance because the survival rate of patients with AT/RT is substantially lower. The diagnosis of AT/RT relies primarily on morphologic assessment and immunohistochemical (IHC) staining for a few known markers such as the lack of INI1 protein expression. However, in our clinical practice we have observed several AT/RT-like tumors, that fulfilled histopathological and all other biomarker criteria for a diagnosis of AT/RT, yet retained INI1 immunoreactivity. Recent studies have also reported preserved INI1 immunoreactivity among certain diagnosed AT/RTs. It is therefore necessary to re-evaluate INI1(+), AT/RT-like cases.Sanger sequencing, array CGH and mRNA microarray analyses were performed on PEBT samples to investigate their genomic landscapes.Patients with AT/RT and those with INI(+) AT/RT-like tumors showed a similar survival rate, and global array CGH analysis and INI1 gene sequencing showed no differential chromosomal aberration markers between INI1(-) AT/RT and INI(+) AT/RT-like cases. We did not misdiagnose MBs or PNETs as AT/RT-like tumors because transcriptome profiling revealed that not only did AT/RT and INI(+) AT/RT-like cases express distinct mRNA and microRNA profiles, their gene expression patterns were different from those of MBs and PNETs. The most similar transcriptome profile to that of AT/RTs was the profile of embryonic stem cells. However; the transcriptome profile of INI1(+) AT/RT-like tumors was more similar to that of somatic neural stem cells, while the profile of MBs was closer to that of fetal brain tissue. Novel biomarkers were identified that can be used to distinguish INI1(-) AT/RTs, INI1(+) AT/RT-like cases and MBs.Our studies revealed a novel INI1(+) ATRT-like subtype among Taiwanese pediatric patients. New diagnostic biomarkers, as well as new therapeutic tactics, can be developed according to the transcriptome data that were unveiled in this work.

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Dataset Information

Cognitive Implications of Ototoxicity in Pediatric Patients With Embryonal Brain Tumors.

Purpose

Patients and methods

Results

Conclusion

Publications

Cognitive Implications of Ototoxicity in Pediatric Patients With Embryonal Brain Tumors.

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