Imaging Skeletal Muscle Mitochondrial OXPHOS Activity In Acute Lymphoblastic Leukemia Survivors
Trial Snapshot
- Phase
- Not Applicable
- Status
- Recruiting
- Enrollment
- 60
- Locations
- 1
- Primary Endpoint
- To explore feasibility of CrCEST MRI to measure OXPHOS capacity
Study Overview
Brief Summary
The participants are being asked to take part in this trial, because the participant is a survivor of childhood cancer or agreed to be part of a volunteer group to understand the relation between cancer and cancer treatment and muscle weakness in survivors of Acute Lymphoblastic Leukemia (ALL). ALL is cancer of the blood and bone marrow.
Primary Objective
• To compare muscle mtOXPHOS activity and satellite cell content among ALL survivors and controls.
Secondary Objective
- To evaluate the association between muscle mtOXPHOS, muscle satellite cell content and physical performance in ALL survivors.
- To evaluate the association of muscle morphology and epigenetics with muscle mtOXPHOS in ALL survivors.
Detailed Description
This study hypothesizes that sarcopenia (low lean mass and muscle weakness), the central components of frailty, result from cancer- and or treatment-related impairment of cellular function within skeletal myocytes. Impaired mitochondrial oxidative phosphorylation (mtOXPHOS) is a hallmark of aging and implicated in skeletal muscle (muscle) weakness and lowered physical performance with normal aging. There is a lack of understanding of how the dysfunctional mitochondrial capacity affects the individual muscle groups in the lower extremities of the survivors.
This pilot study will explore the feasibility of non-invasive metabolic imaging to measure the major muscle groups in the calf muscle mtOXPHOS in childhood survivors of Acute Lymphoblastic Leukemia (ALL) in SJLIFE cohort by incorporating magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in survivors and age/sex-matched healthy volunteers (Controls). Control participants will be recruited from SJLIFE control cohort and may be recruited from new SJLIFE controls; The MRI/MRS findings will be correlated with clinically ascertained muscle phenotype; and will explore and describe differences in muscle morphology, epigenetics, mtDNA-CN between survivors and controls using peripheral blood and muscle biopsies, and their association with MRI/MRS findings.
Survivor and Control participants will be asked to have two MRI sessions; a physical function, and a muscle ultrasound assessment done during SJLIFE Human Performance Lab (HPL). Participants will be asked to give a peripheral blood sample and muscle sample. MR imaging will be performed in two appointments.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Screening
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Survivor- or Control-Participant is age 18 years old or older at time of consent and enrolled in SJLIFE.
- •Survivor- Participant is childhood ALL survivor
- •Survivor- or Control Participant has low muscle mass as defined by relative lean mass z-score of less than or equal to -0.5 SD (lean mass divided by height in meters squared).
- •Survivor - Participant is able and willing to give informed consent
Exclusion Criteria
- •Survivor-Participant has history of cranial radiation.
- •Survivor- or Control-Participant has implanted medical devices or metal that would interfere with MRI or MRS
- •Female Survivor- or Control-Participant is pregnant.
- •Survivor- or Control-Participant is taking anticoagulants (e.g. aspirin, apixaban, coumadin, edoxaban, rivaroxaban)
- •Survivor- or Control-Participant weighs more than 300 pounds.
- •Survivor- or Control-Participant is allergic to local anesthetic (i.e., lidocaine, bupivacaine).
- •Survivor- or Control-Participant cannot lie flat on his/her back for 90 minutes or longer
- •Survivor- or Control-Participant has a current history of peripheral motor neuropathy.
Arms & Interventions
Survivors
Adult survivor of acute lymphoblastic leukemia (ALL) enrolled in St. Jude Life Cohort (SJLIFE).
Intervention: Muscle Ultrasound (Diagnostic Test)
Control
Control participants are not a close relative of someone who has received treatment for childhood cancer or a similar illness; age/sex-matched healthy volunteers and recruited from SJLIFE Control cohort and may be recruited from new SJLIFE Controls.
Intervention: Skeletal muscle biopsy (Other)
Survivors
Adult survivor of acute lymphoblastic leukemia (ALL) enrolled in St. Jude Life Cohort (SJLIFE).
Intervention: Physical function assessment (Other)
Survivors
Adult survivor of acute lymphoblastic leukemia (ALL) enrolled in St. Jude Life Cohort (SJLIFE).
Intervention: Peripheral blood sample (Other)
Control
Control participants are not a close relative of someone who has received treatment for childhood cancer or a similar illness; age/sex-matched healthy volunteers and recruited from SJLIFE Control cohort and may be recruited from new SJLIFE Controls.
Intervention: Magnetic Resonance Imaging (Diagnostic Test)
Control
Control participants are not a close relative of someone who has received treatment for childhood cancer or a similar illness; age/sex-matched healthy volunteers and recruited from SJLIFE Control cohort and may be recruited from new SJLIFE Controls.
Intervention: Magnetic Resonance Spectroscopy (Diagnostic Test)
Control
Control participants are not a close relative of someone who has received treatment for childhood cancer or a similar illness; age/sex-matched healthy volunteers and recruited from SJLIFE Control cohort and may be recruited from new SJLIFE Controls.
Intervention: Physical function assessment (Other)
Control
Control participants are not a close relative of someone who has received treatment for childhood cancer or a similar illness; age/sex-matched healthy volunteers and recruited from SJLIFE Control cohort and may be recruited from new SJLIFE Controls.
Intervention: Peripheral blood sample (Other)
Control
Control participants are not a close relative of someone who has received treatment for childhood cancer or a similar illness; age/sex-matched healthy volunteers and recruited from SJLIFE Control cohort and may be recruited from new SJLIFE Controls.
Intervention: Muscle Ultrasound (Diagnostic Test)
Survivors
Adult survivor of acute lymphoblastic leukemia (ALL) enrolled in St. Jude Life Cohort (SJLIFE).
Intervention: Skeletal muscle biopsy (Other)
Survivors
Adult survivor of acute lymphoblastic leukemia (ALL) enrolled in St. Jude Life Cohort (SJLIFE).
Intervention: Magnetic Resonance Imaging (Diagnostic Test)
Survivors
Adult survivor of acute lymphoblastic leukemia (ALL) enrolled in St. Jude Life Cohort (SJLIFE).
Intervention: Magnetic Resonance Spectroscopy (Diagnostic Test)
Outcomes
Primary Outcomes
To explore feasibility of CrCEST MRI to measure OXPHOS capacity
Time Frame: Baseline
We will perform CrCEST MRI to map calf muscle Cr recovery kinetics (TCrCEST) following plantar flexion exercise (sec).
To explore feasibility of 31P-MRS to measure OXPHOS capacity
Time Frame: Baseline
This will be performed with a 7-cm diameter 1H/31P dual-tuned surface/volume coil using an unlocalized free induction decay (FID) sequence: number of points = 512, averages = 2-5, and TR = 2.4-5 seconds, with 4 dummy scans. TPCr is determined by fitting the signal intensity of PCr following plantar flexion exercise to a mono-exponential function. Additionally, we will acquire a steady state 31P-MR spectra for phosphorylated metabolite quantification (sec).
To explore feasibility of 1H-MRS to measure OXPHOS capacity
Time Frame: Baseline
This will be performed on a Siemens 3T scanner using Point RESolved Spectroscopy (PRESS) 31 sequence. A water-suppressed 1H MR spectrum will be acquired from a voxel positioned in gastrocnemius and soleus muscles. 1H MRS data will be processed using LCModel providing the metabolite levels (mM).
To explore feasibility of Fat Fraction MRI to measure OXPHOS capacity
Time Frame: Baseline
We will perform Dixon MRI to quantify intramuscular fat fraction (IFF %) in the calf.
To explore feasibility of Muscle Ultrasound to measure OXPHOS capacity
Time Frame: Baseline
Participants will lay supine with legs fully extended with their ankles stabilized in neutral. Customized templates will be strapped on the thigh and consist of five to eight 2-cm slices with a 1-cm gap between slices. Using transmission gel, a continuous, single view will be measured by transversely moving the probe across the thigh in approximately four seconds to acquire images of the rectus femoris (RF) and the vastus lateralis (VL), ensuring minimal pressure is applied to the skin to avoid muscle compression. Bilateral calf muscle CSA will be assessed in the same manner.
To explore feasibility of Muscle Biopsy to measure OXPHOS capacity
Time Frame: Baseline
A vacuum-assisted biopsy device and ultrasound guidance will be used to obtain skeletal muscle samples. The procedure is performed under local anesthesia with the patient in supine position. The needle will be inserted into the vastus lateralis, accessed through a 2-3 mm incision, under local anesthesia. When the needle is removed, a small section of muscle will remain with the needle. Two samples will be obtained during the procedure. One sample will be analyzed for satellite cell content and morphology. The second sample will be analyzed for mtDNA-CN and epigenetic profile.
To explore feasibility of mtDNA-CN to measure OXPHOS capacity
Time Frame: Baseline
Peripheral blood samples will be drawn and analyzed for mtDNA-CN, metabolic and epigenetic profile and compared to the muscle sample.
To explore feasibility of MRI/MRS to measure OXPHOS capacity
Time Frame: Baseline
Multimodal MR imaging will be performed in two appointments. The first appointment will consist of Part 1 (approximately 1 hour) and Part 2 (approximately 30 minutes). There will be a 5-10 minute break between the two parts. The second appointment will consist of Part 1 (approximately 1 hour).
Secondary Outcomes
- Evaluate muscle strength to measure physical performance(Baseline)
- Evaluate physical function to measure physical performance(Baseline)