Childhood cancer survivors experience premature declines in muscle mass, strength, and physical function that contribute to morbidity and early mortality. The biological mechanisms driving these impairments are heterogeneous and poorly understood. This observational study aims to characterize distinct muscle health endotypes in adult survivors of childhood cancer using advanced imaging, neuromuscular testing, and functional assessment. Survivors with reduced muscle health and community controls will undergo multimodal magnetic resonance imaging and spectroscopy, nerve conduction studies, surface electromyography, body composition assessment, and physical performance testing during a single study visit integrated into an ongoing cohort evaluation. Identifying mechanistic endotypes of impaired muscle health will support development of targeted interventions to preserve function and improve long-term outcomes in childhood cancer survivors.

Primary Objective:

- Characterize reduced muscle health endotypes in childhood cancer survivors.

Secondary Objective:

- Identify specific treatment and lifestyle related risk factors for each reduced muscle health endotype.

Exploratory Objective:

- Host germline genetics will be associated with specific muscle endotypes.

Survivors of childhood cancer are at increased risk for early-onset frailty characterized by low lean mass, muscle weakness, and impaired physical function. Prior studies in the St. Jude Lifetime Cohort (SJLIFE) demonstrate that the prevalence of these impairments increases with age and is associated with a significantly higher risk of mortality. Traditional lifestyle and resistance training interventions have yielded only modest benefits, suggesting that superficially similar muscle phenotypes may be driven by distinct biological mechanisms.

Potential contributors to impaired muscle health in this population include peripheral nervous system dysfunction, altered motor unit activation, mitochondrial dysfunction, and muscle fat infiltration, resulting from cancer therapies, chronic health conditions, and lifestyle factors. Advanced imaging and neuromuscular phenotyping provide an opportunity to define distinct mechanistic "endotypes" that underlie reduced muscle health and to inform future precision interventions.

Inclusion Criteria:

• Age 18 years old or older at time of consent and enrolled in SJLIFE.
• Participant (100 per group for a total of 400) is/has:
• Group 1: No cancer history
• Group 2: Age and sex specific relative lean mass z-score of less than -0.5 OR age and sex specific hand grip or isokinetic (60 degrees/sec) quadriceps strength z-score of <-0.5 AND exposure to a peripheral neurotoxin.
• Group 3: Age and sex specific relative lean mass z-score of less than -0.5 OR age and sex specific hand grip or isokinetic (60 degrees/sec) quadriceps strength z-score of <-0.5 AND NOT exposed to a peripheral neurotoxin.
• Group 4: Age and sex specific relative lean mass z-score of less than -0.5 AND age and sex specific hand grip strength or isokinetic (60 degrees/sec) quadriceps strength z-score of <-0.5 REGARDLESS of exposure status.
• Participant or legal guardian is able and willing to give informed consent.

Exclusion Criteria:

• Presence of implanted medical devices or metal that would interfere with MRI or MRS.
• Female Participant is pregnant.
• Body weight exceeding 300 pounds, due to MRI restrictions.
• Inability to lie flat on his/her back for 90 minutes or longer for MRI.
• Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.

The study population includes adults aged 18 years or older enrolled in the St. Jude Lifetime Cohort (SJLIFE) who are childhood cancer survivors and community control participants without a cancer history. Eligible survivors are at least five years from primary cancer diagnosis and have reduced muscle mass and/or muscle strength based on age- and sex-specific z-scores. Survivors are categorized by prior exposure to peripheral neurotoxic cancer therapies. Community controls are frequency-matched by age and sex. All participants complete neuromuscular, imaging, and physical function assessments during a single study visit.

Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.

Data will be made available at the time of article publication.

Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.