CSIMEMPHIS: Long-term Follow-up of Medulloblastoma Survivors That Received Craniospinal Irradiation

In the SJLIFE study Survivors will undergo the SJLIFE core battery of testing with a focus on outcomes for which early evidence has demonstrated the potential association between proton therapy and reduced late-effect burden. Testing includes neuromuscular function, laboratory testing, neurocognitive assessments, physiologic assessments, and outcome questionnaires.

Subjects selected for the Brainatomy2 study will undergo a one-time investigational MRI/fMRI study designed to target working memory and processing speed. The investigational MRI/fMRI exam includes Axial T2 weighted imaging for post-surgical and post-radiotherapy assessment of brain parenchymal changes, and 3D isometric voxel T1 volume imaging for structural analysis of the whole brain. It also employs pulsed ASL technique for voxel-based cerebral blood flow assessment and diffusion imaging to generate ADC and FA maps, normalizing anatomical connectivity maps to the T1 volume. Additionally, resting-state functional MRI (fMRI) provides whole brain coverage for analyzing temporal co-activation in BOLD fMRI maps in relation to cognitive testing results.

Subjects selected for Brainatomy2 will undergo a one-time investigational MRI/fMRI exam for post-surgical and post-radiotherapy assessment of brain parenchymal changes, and structural analysis of the whole brain. The exploratory endpoints focus on imaging assessments: Perfusion imaging with median regional cerebral blood flow map registration to T1 MPRAGE structural brain imaging, Diffusion and Diffusion Tensor Imaging with median Apparent Diffusion Coefficient map registration to structural brain imaging, including the generation of whole-brain anatomic connectivity maps, and Resting state fMRI with whole brain coverage, analyzing differences in functional connectivity between processing speed groups through voxel-by-voxel comparisons.

fMRI maps brain activity associated with cognitive functions such as memory, attention, language, and executive function. It can reveal patterns of brain reorganization corresponding with cognitive test scores and declines in performance. By integrating fMRI findings with cognitive testing and other measures, we can study differences in treatment such as craniospinal dose and better understand the neural mechanisms underlying cognitive disorders and related complications. fMRI findings can be mapped to the spatial distribution of radiation dose using conventional and voxel-based analysis.

To determine impact of speech and language, hearing is evaluated with tympanometry, pure-tone audiometry at 250, 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz, and speech audiometry in quiet. Speech-in-noise tests measure the ability to hear and understand speech in background noise.

We will utilize these instruments in addition to the SJLIFE Comprehensive Health Form to evaluate quality of life. This 23-item questionnaire encompasses physical functioning, emotional functioning, social functioning, and school functioning. Items are scored to create a Psychosocial Health Summary Score (0 to 100 scale), with a higher score indicating better health-related quality of life (HRQOL). Self-report measures are available for children and adolescents aged 5 to 18 years, and parent proxy-report measures are available for those aged 2 to 18 years.

Subjects will be given processing speed tasks performed together while in the scanner. The N-back task, they are required to respond, using the response button, when they see the same stimulus repeated after N intervening stimuli. The stimuli used will be line drawings of everyday objects. The task will last 5 minutes. Object snap task and Silly sentence task are two processing speed tasks using pictures and sentences. For the Object snap task, they are required to respond yes when two object pictures, presented at the same time, are identical. Subjects are required to respond quickly, but accurately. The fMRI paradigm will use NordicNeuro Lab software.

This will be evaluated using the Family Environment Scale to assess the environmental characteristics of the family. A Brief Symptom Inventory-18 will be administered to measure parental/caregiver emotional distress. The Parent Protection Scale will be administered to evaluate parental protective behavior. The census tract-based Social Vulnerability Index (SVI) will be used to evaluate neighborhood adversity per the patient's residential address. Collectively these surveys will show interplay between socioeconomic status and environmental factors that influence health outcome disparities.

Sleep will be assessed to determine the effects from surgery, treatment, and complications using polysomnography evaluation and various sleep surveys assessing quality of sleep, sleep patterns, drowsiness during the day, and insomnia.

The following lab measures will be collected LH, AMH, FSH, inhibin B, and testosterone in males aged ≥ 9 years and LH, FSH, estradiol, and AMH in females aged ≥ 8 years. Additional endocrine lab assessments will include hemoglobin A1c, insulin, lipid panel, vitamin D 25-OH, morning cortisol, IGF-1, TSH, and free T4. Tanner staging will be performed as part of the clinical exam regardless of age until fully developed (Tanner stage 5). A bone radiograph will be obtained for participants < 18 to assess skeletal maturation in relation to chronological age to assess growth and pubertal development. Thyroid ultrasound will assess thyroid nodules. Dual x-ray absorptiometry (DXA) scan obtained will be used to estimate total and specific regional relative lean mass values, visceral fat, subcutaneous adipose tissue, and appendicular lean mass.

Neurocognitive outcomes will be evaluated with age-appropriate measures using a battery of standardized tests. The core battery of cognitive tests will ensure that long-term neurocognitive and learning sequelae of treatment are captured.

Electrocardiogram will be used to evaluate for rhythm and conduction abnormalities. Pulmonary function will be measured with pulmonary function tests (PFTs). For patients under 5 years of age or those that cannot perform adequate testing, pulse oximetry will be the primary measure of pulmonary function. Cardiorespiratory fitness will be evaluated with maximal cardiopulmonary exercise testing (CPET) on a treadmill using a modified Bruce protocol, or with an arm or leg ergometer for participants with impairments that prohibit walking on a treadmill. Heart Rate Variability (HRV) will be assessed remotely using photoplethysmogram (PPG) data collected using the LEAP® wrist biosensor. Stool self-collection will occur and overall diversity and microbiome compositional attributes will be compared.

Stool self-collection will occur, and composition will be assessed using DNA extracted from frozen aliquots. The extraction will be conducted using the Chemagic 360 system, followed by 16S rRNA gene amplification by touchdown PCR and sequencing at St Jude Hartwell Center. Overall diversity and microbiome compositional attributes will be compared.

Growth velocity, the change in height and weight over time, is a more sensitive measure of growth than a single height or weight. Spinal MRI of the spine will be used to assess for scoliosis, kyphosis, vertebral body wedging, spinal height loss, degenerative disc, and degenerative bone changes. Sitting height will also be obtained to evaluate for skeletal dysplasia or impaired spinal growth.