Biomarkers may identify which children with optic glioma will need chemotherapy to preserve vision

Peter de Blank, M.D.

Cincinnati Children’s Hospital

Funded in April, 2017: $100000 for 2 years
LAY SUMMARY . ABSTRACT .

LAY SUMMARY

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Biomarkers may identify which children with optic glioma will need chemotherapy to preserve vision

This second phase study in 52 children with optic glioma will see whether two imaging techniques provide a reliable brain biomarker that differentiates those children who are at high risk of future vision loss from those who are not. An imaging biomarker would enable physicians to initiate chemotherapy early and only in the at-risk children.

 

Optic gliomas are low grade tumors that occur in early childhood. Although rarely fatal, the tumors cause permanent and uncorrectable vision loss in up to 50 percent of affected children. A brain biomarker of future vision loss would serve two vital purposes. First, it would enable clinicians to initiate chemotherapy in the at-risk children early, when treatment is most likely to help control the tumor and prevent or minimize future vision problems. Second, it would spare non-high risk children from undergoing chemotherapy and its harmful side effects unnecessarily.

 

The investigators will determine if OCT (optical coherence tomography) and DTI (diffusion tensor imaging) can identify signs that serve as a valid and reliable biomarker. OCT measures whether the thickness of retinal nerve fiber layers in the visual pathway is reduced as an indication of cell loss. DTI measures retinal nerve fiber arrangements in the optic pathway, where alterations may be may be correlated with future vision loss.

 

While DTI is non-invasive, relatively fast (about four minutes), and does not require children to pay attention, they must be still or sedated. A Phase I study to assess whether DTI is feasible in children aged 12 and younger was awarded in 2013.  Initial data show that DTI of the optic radiations is associated with visual acuity in children with optic gliomas. DTI may be a reliable and valid biomarker of future visual acuity loss. A total of 70 children will be enrolled in the study to determine whether OCT and DTI can distinguish normal from abnormal vision and predict future visual acuity loss.

 

Significance: Imaging in young children with optic glioma is anticipated to lead to improved methods to prevent or minimize future vision loss and to enable researchers to assess the effectiveness of various experimental therapeutic interventions.

ABSTRACT

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Biomarkers may identify which children with optic glioma will need chemotherapy to preserve vision

Development of non-invasive biomarkers of functional outcomes in pediatric brain tumors offers the prospect of early identification, allowing for subsequent preemptive intervention in subclinical disease to improve clinical outcomes. This is particularly evident in optic pathway gliomas (OPGs), where the traditional endpoint of progression-free survival does not correlate with the functional outcome of vision. Although preserving vision is the primary objective in treating OPGs, visual deficits measured by ophthalmologic examination can be difficult to measure accurately due to young age, fatigue or lack of cooperation, and challenging to compare longitudinally due to the variety of measurements (visual acuity, visual field defects) and testing methods (preferential looking tests, recognition acuity). A reliable, quantifiable surrogate measure of vision would help identify subjects with early vision loss who may benefit from early intervention, stratify risk of subsequent vision loss to identify individuals who require therapy, and provide an accessible longitudinal measure of vision for future clinical trials. In this proposal, we hypothesize that diffusion tensor imaging (DTI) of the optic pathway will serve as a non-invasive imaging biomarker of visual acuity in children with OPGs. By measuring the diffusion of water preferentially along and not across hydrophobic myelin, DTI can identify specific pathways, quantify white matter microstructure, and assess tract integrity. Fractional anisotropy (FA) assesses the uniformity of the direction of diffusion and is sensitive to damage within white matter tracts. We will study white matter tract microstructure and integrity in the optic radiations to investigate the correlation between tract damage and functional outcomes. In the first phase of this study, we will conduct a multi-institutional study of DTI and concurrent ophthalmology evaluations among children with OPGs to validate FA of the optic pathways as a non-invasive biomarker of best-corrected visual acuity. In the second phase of the project, we will prospectively gather longitudinal DTI and ophthalmology evaluations in this cohort to assess whether FA corresponds with changes in visual acuity or predicts future visual acuity changes. We will also investigate a combined biomarker of DTI of the optic radiations and optical coherence tomography (OCT) of the retinal nerve fiber layer to assess microstructural damage and neuronal loss in both the pre-synaptic (OCT) and post-synaptic (DTI) portions of the visual pathway and their association with visual acuity loss. Through the proposed studies we will investigate the connection between structural damage and functional outcomes in pediatric brain tumors. We will validate and describe a vitally needed biomarker of visual acuity that may be superior to traditional vision assessments in the identification of subclinical visual acuity loss, the measurement of visual deficits and the prediction of future risk of visual acuity loss. This proposal will characterize DTI for future use in clinical trials and investigate a unique combined biomarker to evaluate damage both anterior and posterior portions of the visual pathway.

INVESTIGATOR BIOGRAPHIES

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Peter de Blank, M.D.

Dr. de Blank graduated from Stanford University with a B.S. in chemistry, a B.A. in English and an M.A. in English and American Literature.  He taught high school chemistry and English for four years before entering medical school at the University of California, San Francisco where he completed a concentration in Medical Education.  In medical school, Dr. de Blank was inducted into the Gold Headed Cane Society, an honor given to the top three graduates in the medical school class.  Dr. de Blank completed his residency in Pediatrics, and fellowships in Pediatric Hematology & Oncology and Pediatric Neuro-Oncology at the Children’s Hospital of Philadelphia.  During his fellowship, he was awarded a T32 training grant from the NIH/NCI to support his training in clinical research.  He completed a Masters of Science in Clinical Epidemiology and Biostatistics at the University of Pennsylvania during his fellowship training.  During his fellowship in Pediatric Neuro-Oncology, Dr. de Blank worked with Dr. Michael Fisher on investigating diffusion tensor imaging and visual acuity in children with optic pathway gliomas.  From 2012-2016, Dr. de Blank was a member of the faculty at Case Western Reserve University School of Medicine, where he directed the program in cancer survivorship and was Scientific Director of the Neurocutaneous Syndromes Clinic.  In 2017, Dr. de Blank joined the faculty at Cincinnati Children’s Hospital Medical Center.  He is an Associate Professor of Pediatrics in the Cancer and Blood Diseases Institute and a member of the neuro-oncology team.  Dr. de Blank is a pediatric neuro-oncologist whose research focuses on the development of early radiographic biomarkers of functional complications of brain tumors and brain tumor therapy. Functional, non-invasive biomarkers of important clinical outcomes may improve clinical outcomes, guide early intervention efforts and direct support for children with brain tumors.

KEYWORDS


Anatomy: Optic nerve
Retina
Visual cortex
White matter
Conditions: Blindness
Neurofibromatosis
Function: Vision
Technology: Diffusion tensor imaging

MRI