PMC9713015_01
Timeline and imaging of case 1. (A) Anterior volume-rendered maximum activity-projection FDG-PET images show intense FDG uptake in the bones, lung, and liver prior to starting immunotherapy (ICI). (B) PET demonstrates complete response after three cycles of ICI. (C-E) PET demonstrates persistent 2.8 x 1 cm right external iliac lymph node with interval increase in FDG uptake with a maximum SUV of 6. (F) PET shows resolution of external iliac lymph node. (G) Timeline of administered systemic therapy and ctDNA changes during surveillance.
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Figure 1A ). Further staging workup with a brain MRI did not demonstrate intracranial metastases. ICI regimen ( Figure 1B ). Ipilimumab was permanently discontinued, and maintenance nivolumab (480 mg, IV every 4 weeks) was continued after resolution of IRAE symptoms. However, 10 months after ICI initiation, a restaging PET-CT scan showed increased metabolic activity in the right external iliac lymph node, concerning for disease recurrence ( Figure 1C ). Repeat imaging 2 months later showed interval stability of the size and metabolic activity of an inguinal lymph node ( Figure 1D ). ctDNA analysis at this time was once again negative. A repeat scan 6 months after the initial concern for progression showed resolution of the metabolic activity of the right iliac lymph node ( Figure 1E ). Subsequent scans have demonstrated a complete metabolic response ( Figure 1F ).
PMC9713015_02
Timeline and imaging of case 2. (A) Cross-sectional CT demonstrates progression of infiltrative lesions in a left level 2B lymph node prior to starting imatinib. (B) CT demonstrates a decrease in the size of the lesion after starting imatinib. (C) CT demonstrates progressive disease. (D) Timeline of administered systemic therapy and ctDNA changes (no ctDNA is available beyond day 450 as the patient opted not to have the test).
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After 5 months, the patient developed three pigmented cutaneous nodules around the surgical graft site, which demonstrated involvement with metastatic melanoma on biopsy. ctDNA testing results were obtained at this time, which indicated low values but detectable at 8.73 MTM/ml ( Figure 2D ). Brain MRI was negative for intracranial disease but a left retroauricular soft tissue lesion was observed ( Figure 2A ). At this time, ctDNA was significantly elevated at 389 MTM/ml ( Figure 2D ). After 1 week, his ctDNA decreased to 45.96 MTM/ml, and at 2 months follow-up, there was notable reduction in the size of the retroauricular lesion ( Figure 2B ). Restaging images at 5 months showed disease progression, which prompted discontinuation of imatinib therapy ( Figure 2C ).
PMC9713015_03
Timeline and imaging of case 3. (A, B) PET demonstrates an aortocaval lymph node with a maximum SUV of 21.8. (C) PET demonstrates resolution of the aortocaval lymph node after radiation therapy. (D) Timeline of case 3 and ctDNA changes.
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Sequential PET-CT showed disease progression in a single aortocaval lymph node measuring 17 x 16 mm with standardized uptake value (SUV) of 21.8 that was not amenable for biopsy ( Figures 3A, B ). At this time, the patient also underwent ctDNA testing, which returned positive, at 20.92 MTM/ml ( Figure 3D ). However, subsequent ctDNA measurements after completion of SBRT returned undetectable at 0 MTM/ml, and surveillance imaging showed no evidence of disease ( Figure 3C ).
PMC9713015_04
Timeline and imaging of case 4. (A) PET scan demonstrates metastatic disease in the bones and lymph nodes. (B) Axial section of brain MRI in T1 post contrast phase showing an enhancing parietal lesion. (C, D) MRI demonstrates persistent increase in size of enhancing lesions in the brain. (E) Timeline of case 4 and clinical course representing treatment sequence and ctDNA changes.
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After 10 months, imaging demonstrated multiple metastases in the thoracic spine, femur, lung, and left axilla ( Figure 4A ). However, after 4 months of ICI, an MRI of the brain revealed several new intracranial metastases (not all metastases shown on imaging) ( Figure 4B ). MTM/ml ( Figure 4E ). Maintenance nivolumab was added to the therapeutic regimen, and repeat imaging after 2 months demonstrated near-complete response in extracranial disease and partial response in the brain metastases ( Figure 4C ). Longitudinal ctDNA monitoring after 4 weeks demonstrated undetectable levels during the treatment period despite continued progression of intracranial metastases ( Figure 4D ).