PMC8776642_01
Response to therapy with larotrectinib: 18FDG-PET/CT scan evaluation. (A) Baseline FDG PET/CT study showing coronal fused PET/CT image with abnormal FDG uptake in multiple liver metastases, left rib and left femor. (B) Progressive metabolic response to larotrectinib after 7 days, four months, eight months and after almost one year of treatment. (C) Maximum intensity projection (MIP) PET/CT images: pre-therapy PET/CT scan again showed FDG-avid metastases occupying virtually the entire liver, left rib and left femor, all demonstrating high FDG avidity. (D) Seven days after the start of larotrectinib, PET/CT scan showed early tumor shrinkage with a reduction in FDG avidity in all previously described lesions.
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Room of a local hospital following a diagnosis of bone metastases in the left acetabulum, with pathological fracture. A 18FDG-PET/CT scan revealed multiple bone metastases in the hip bone, bilateral ribs and left femur, multiple bilateral lung lesions, multiple liver metastases, muscle metastases, and one lesion in the left kidney suspicious for metastasis ( Figure 1A ). Radiotherapy was performed for the bone pathological fracture (20 Gy). Larotrectinib was administered orally in capsules on a continuous 28-day schedule, at a dose of 100 mg twice daily ( Figure 1B ). Subsequent evaluations confirmed tumor regression in disease sites ( Figures 1C, D ).
Histological features of NTRK rearranged spindle cell neoplasm. (A) Hematoxylin & Eosin (H&E) staining of the surgically resected recurrence tumor of the thoracic wall. (B) H&E staining of the surgically resected liver metastasis. (C) p53 positivity by immunohistochemistry (IHC) in the surgically resected liver metastasis. (D) S100 positivity by IHC in the surgically resected liver metastasis. (E) CD34 positivity by IHC in the surgically resected liver metastasis. (F) Ki-67 by IHC in the surgically resected liver metastasis (1% positivity).
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Figure 2A ). Following a multidisciplinary evaluation of the case, a biopsy of the hepatic metastasis was performed, revealing the presence of spindle cells arranged in a clearly fascicular pattern ( Figure 2B ). The sections of the tumor were incubated with antibodies and analyzed, revealing the expression of CD34, S100 and p53 at immunohistochemistry (IHC), Ki-67 1% ( Figures 2C   -F ).
Representative graphical output of next-generation sequencing analysis using Oncomine Focus Assay showing TPM4-NTRK1 rearrangement in the liver metastasis.
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Next generation sequencing (NGS) analysis was performed with the Oncomine Focus Assay on the histologic slides of the 2015 surgery to remove the subcutaneous nodule, highlighting the presence of the TPM4 (exon 7)-NTRK1 (exon 12) fusion gene ( Figure 3 ).
Microsatellite instability analysis. Representative melt curves of target gene analyzed for microsatellite instability status in patient tumor sample (Pt, red curve) compared to stable positive control (C-, blue curve).
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Microsatellite instability status (MSI) was also evaluated, but microsatellite stability was confirmed ( Figure 4 ).