PMC8226071_01
(A) The baseline CT scan of the patient's chest in June 2016. (B) CT scan of the chest before and after the seeds implantation. (C) The baseline MRI scan of the patient's brain in July 2017. (D) MRI scan of the brain after 2 months of whole brain radiotherapy treatment in September 2017. (E) Contrast-enhanced CT scan of the new lesions in abdomen in December 2017. (F1-8) CT scan of the abdomen (F1-2), chest (F3) and MRI scan of the brain (F4-8) after 6 months of dabrafenib combined with trametinib therapy in June 2018. (G1-8) CT scan of the patient's abdomen (G1-2), chest (G3) and MRI scan of the brain (G4-8) after 9 months of dabrafenib combined with trametinib therapy in September 2018. (H) MRI scan of the brain after a month of dabrafenib with bevacizumab therapy in November 2018. (I) MRI scan of the brain after 3 months of vemurafenib with bevacizumab therapy in March 2019.
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A subsequent chest computed tomography (CT) scan revealed consolidation in the upper lobe of the right lung ( Figure 1A ). To achieve better results, radioactive seed implantation was performed in the lesion of the right lung, by percutaneous puncture under the guidance of CT scan, 28 seeds were implanted, with the radiation dose 140 Gy, seeds activity 0.6 and the half-life 2.5 months, and the lesions again remained stable, with the curative effect SD and the PFS 9 months ( Figures 1B1 ,  2 ). Head magnetic resonance imaging (MRI) revealed lesions in the right parietal lobe, bilateral frontal lobes, and the right cerebellar hemisphere ( Figures 1C1, 2 ). After the radiotherapy, the lesions regressed with the curative effect evaluation was PR (partly response, PR) ( Figures 1D1, 2 ). Three months later, chest CT again showed stable lesions, but an abdominal contrast-enhanced CT revealed multiple lesions in the liver, and a mass in the pancreas metastases ( Figures 1E1, 2 ). Dabrafenib and trametinib were given orally daily, and the lesions in chest, abdomen and brain all regressed within the first 6 months, with the curative effect evaluation regressed SD ( Figures 1F1-8 ), but became enlarged 3 months later ( Figures 1G1-8 ), with the curative effect enlarged SD and the PFS 6 months. The BRAFS365L mutation indicates resistance to trametinib, so dabrafenib and bevacizumab were given as new therapy, but the lesions in the brain became enlarged, and evaluated as enlarged SD ( Figure 1H ). Therefore, vemurafenib was given with bevacizumab, and the lesions in brain regressed and others remained stable within the first 3 months, with the curative effect evaluation SD ( Figures 1I1-3 ).
(A-C) Positive detection of papillary carcinoma cells in needle biopsy sample of the superficial lymph node biopsy. Magnification; x100, x200, x400.
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A pathological examination of the superficial lymph node biopsy was conducted, and lung papillary carcinoma was diagnosed ( Figures 2A-C ). To achieve better results, radioactive seed implantation was performed in the lesion of the right lung, by percutaneous puncture under the guidance of CT scan, 28 seeds were implanted, with the radiation dose 140 Gy, seeds activity 0.6 and the half-life 2.5 months, and the lesions again remained stable, with the curative effect SD and the PFS 9 months ( Figures 1B1 ,  2 ). Head magnetic resonance imaging (MRI) revealed lesions in the right parietal lobe, bilateral frontal lobes, and the right cerebellar hemisphere ( Figures 1C1, 2 ). After the radiotherapy, the lesions regressed with the curative effect evaluation was PR (partly response, PR) ( Figures 1D1, 2 ). Three months later, chest CT again showed stable lesions, but an abdominal contrast-enhanced CT revealed multiple lesions in the liver, and a mass in the pancreas metastases ( Figures 1E1, 2 ). A BRAFV600E mutation was identified both in the tissue (allele fraction [AF], 11.8%) and the plasma (AF, 4.3%) ctDNA ( Figures 3A1, 2 ). Dabrafenib and trametinib were given orally daily, and the lesions in chest, abdomen and brain all regressed within the first 6 months, with the curative effect evaluation regressed SD ( Figures 1F1-8 ), but became enlarged 3 months later ( Figures 1G1-8 ), with the curative effect enlarged SD and the PFS 6 months. To explore potential resistance mechanisms, targeted NGS of both CSF ctDNA obtained by lumbar puncture and plasma ctDNA was conducted: NGS revealed the presence of the BRAFV600E mutation in the CSF (AF, 37.8%) and in the plasma (AF, 0.4%) ctDNA ( Figures 3B1, 2 ), as well as a newly acquired BRAFS365L mutation in the CSF (AF, 25.5%) ( Figures 3B3 ). Therefore, vemurafenib was given with bevacizumab, and the lesions in brain regressed and others remained stable within the first 3 months, with the curative effect evaluation SD ( Figures 1I1-3 ). Targeted NGS of both the CSF cell-free DNA obtained by lumbar puncture and the plasma ctDNA revealed the presence of the BRAFV600E mutation in the CSF (AF, 25.8%) and in the plasma (AF, 2.3%) ctDNA ( Figures 3C1, 2 ), but the BRAFS365L mutation in the CSF decreased substantially (AF, 0.5%) ( Figures 3C3 ).
(A1-2) NGS reads showing the BRAFV600E mutation in both tumor tissue BRAFV600E mutation in both tumor tissue and ctDNA from the plasma were visualized using the Integrated Genomics Viewer before dabrafenib combined with trametinib therapy. (B1-3) NGS reads showing the BRAFV600E and BRAFS365L mutation in both CSF and ctDNA from the plasma were visualized using the Integrated Genomics Viewer when the resistance of dabrafenib combined with trametinib therapy occurred. (C1-3) NGS reads showing the BRAFV600E and BRAFS365L mutation in both CSF and ctDNA from the plasma were visualized using the Integrated Genomics Viewer when the resistance of vemurafenib therapy occurred.
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A BRAFV600E mutation was identified both in the tissue (allele fraction [AF], 11.8%) and the plasma (AF, 4.3%) ctDNA ( Figures 3A1, 2 ). Dabrafenib and trametinib were given orally daily, and the lesions in chest, abdomen and brain all regressed within the first 6 months, with the curative effect evaluation regressed SD ( Figures 1F1-8 ), but became enlarged 3 months later ( Figures 1G1-8 ), with the curative effect enlarged SD and the PFS 6 months. To explore potential resistance mechanisms, targeted NGS of both CSF ctDNA obtained by lumbar puncture and plasma ctDNA was conducted: NGS revealed the presence of the BRAFV600E mutation in the CSF (AF, 37.8%) and in the plasma (AF, 0.4%) ctDNA ( Figures 3B1, 2 ), as well as a newly acquired BRAFS365L mutation in the CSF (AF, 25.5%) ( Figures 3B3 ). Therefore, vemurafenib was given with bevacizumab, and the lesions in brain regressed and others remained stable within the first 3 months, with the curative effect evaluation SD ( Figures 1I1-3 ). Targeted NGS of both the CSF cell-free DNA obtained by lumbar puncture and the plasma ctDNA revealed the presence of the BRAFV600E mutation in the CSF (AF, 25.8%) and in the plasma (AF, 2.3%) ctDNA ( Figures 3C1, 2 ), but the BRAFS365L mutation in the CSF decreased substantially (AF, 0.5%) ( Figures 3C3 ).