PMC9424992_01
The treatment timeline of the patient. The patient was diagnosed with glioblastoma in March 2014. He underwent surgery, followed by standard adjuvant treatment with Temozolomide (TMZ) and radiotherapy (RT). The tumor recurred intracranially in November 2015, and he received RT and Bevacizumab (Bev) treatment, the response evaluation of the brain lesion was a partial response (PR). In November 2017, lung metastases were detected, the patient accepted Bev and TMZ, but the lung lesion progressed. Two months (M) later, Keytruda was added because of a positive PD-L1 expression and a partial response (PR) was achieved for the metastatic lesion while the brain lesion was a stable disease (SD). Then TMZ was discontinued to relieve the symptoms of fatigue and due to the unmethylation of the MGMT promoter (May 2018). The patients received five months of Bev plus Keytruda. In October 2018, bone metastases were identified. The patient continued treatment with Bev and Keytruda for two months because no other treatment could be used. Dorsal metastasis was found in December 2018 and due to no other suitable treatment, and the patient continued to receive Bev and Keytruda for another nine months before pulmonary lesion progression. Five months later, the patient discontinued all treatment and died from a pulmonary infection.
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March 2014, complaining of left fingertip numbness for more than two months, intermittent dizziness and left limb weakness for half a month ( Figure 1 ). Magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) of the brain revealed multiple lesions in the right lobe ( Figure S1A ). A follow-up MRI in April 2015 showed the absence of new lesions ( Figure S1B ). PET/CT showed that the brain lesion ( Figure 2A ) was stable when compared with the brain lesion in November 2015 ( Figure S1D ), but multiple nodules were observed in the right lung ( Figure 2B , November 2017). There was a total of 11 months (November 2017 to October 2018) of remission from lung to bone metastases, during which bevacizumab and pembrolizumab were used ( Figure 1 ). Nearly two months later (December 2018), a left posterior dorsal mass was found during routine follow-up ( Figure 1 ).
PET-CT/MRI images of the brain and lung at the time of lung metastasis, during and after treatment. (A, B) The brain lesion was stable and the lung metastasis was found in November 2017. (C, D) After two months of Bevacizumab (Bev)+TMZ treatment, the brain lesion was stable and the lung lesions progressed (January 2018). (E, F) After Keytruda was added for three months (April 2018), the brain lesion was stable, and the response evaluation of lung lesion was PR. (G, H) After Keytruda was added for five months (June 2018), the brain lesion was kept on SD and the lung lesion was kept on PR. The white arrow represents the lesion. M, month.
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PET/CT showed that the brain lesion ( Figure 2A ) was stable when compared with the brain lesion in November 2015 ( Figure S1D ), but multiple nodules were observed in the right lung ( Figure 2B , November 2017). The NGS results from Onco PanScan  (GenetronHealth) revealed KRAS mutation ( Figure S2A ), TP53 mutation ( Figures S2B, C ) and FGFR3 fusion ( Figure S2D ) but the absence of IDH1/2 mutation, H3F3A/HIST1H3B mutation and RELA mutation ( Table 1 ). Figures 2C, D , January 2018 vs. November 2017). Fortunately, the lung lesion had positive expression of PD-L1; therefore, we decided to add pembrolizumab with bevacizumab and During this treatment, we reassessed the patient in April 2018, and the MRI scan revealed an effective response of the lung lesion, with a RECIST criteria PR, while the brain lesion was stable ( Figures 2E, F , April 2018 vs. Interestingly, the lung lesion decreased further in size while the brain lesion remained stable ( Figures 2G, H , June 2018 vs.
Histopathology and immunostaining of metastatic lung lesions. Hematoxylin-Eosin (HE) staining showed that the lung lesion was neoplastic. Immunohistochemistry (IHC) showed positive GFAP, OLIG2 and S-100. Magnification: 40X and 400X.
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Lung biopsy was performed, and we confirmed that the lung lesion was, in fact, a neoplastic metastasis of GBM by pathological analysis and IHC ( Figure 3 ).