PMC6757230_01
Gastroscope images of the patients at his first visit. Gastric mucosa was congested, and an enormous ulcer spread from the gastric antrum to the corner of the stomach with irregular upwelling around, ulcerated surface, brittle texture, easy bleeding (biopsy site), and gastroscope could not pass through pylorus in the gastric antrum.
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However, his gastric mucosa was congested, and an enormous ulcer spread from the gastric antrum to the corner of the stomach with irregular upwelling around, ulcerated surface, brittle texture, easy bleeding (biopsy site), and gastroscope could not pass through pylorus in the gastric antrum (Figure 1). The specific treatment schedule was shown in Supplementary figure 1.
Pathologic findings of the gastroscopy biopsy. (A and B) The high-medium differentiated adenocarcinoma showed that some glands were well structured with obvious cell atypia; some glands were cribriform with cell atypia (hematoxylin and eosin, original magnification from left to right was x100, x200). (C) Immunohistochemistry of HER2 demonstrated completely negative staining in tumor cells (immunohistochemistry, original magnification x200).
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Meanwhile, he also underwent gastroscopy biopsy that revealed HER2-negative gastric adenocarcinoma (Figure 2A-C).
Treatment effect images of patients before and after immunotherapy. (A) PET/CT images of the whole body before immunotherapy (-10d). (B) A follow-up PET/CT images after two injections of Nivolumab 200 mg (22 d). (C) A follow-up PET/CT images underwent six doses of Nivolumab (79 d). (D) A follow-up PET/CT images after combination therapy (144 d). We stipulated the starting date for immunotherapy at day 0.
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Follow-up positron emission tomography/computed tomography (PET/CT) depicted that diffuse abnormal thickening of the gastric antrum accompanied by increased metabolism was considered as gastric malignant tumor with extraneous invasion; multiple hypermetabolic enlarged lymph nodes around the pylorus of the gastric antrum, mesenteric root and retroperitoneum were regarded as metastasis, which were divided into IV stages of T4N3M1 (Figure 3A). The PET/CT revealed a partial response (PR, about a 60% decrease in the total diameters of target lesions compared with the first PET/CT results) of the gastric cancer and lymph node, the morphology of the lesion and metabolism was obviously reduced, but tumor activity remained (Figure 3B), which was in accordance with the RECIST guideline (version 1.1). PET/CT examination suggested that PR (the sum of diameters of target lesions decreased by 50% compared with the last PET/CT results), tumor lesions and metabolism were significantly reduced, and the tumor activity was mostly inhibited, while a little tumor activity still left (Figure 3C). PET/CT scan again. PET/CT reported that the metabolism of tumor was in a state of complete repression and no obvious tumor signs were observed (Figure 3D).
Dynamic change curves of tumor markers in peripheral blood during immunotherapy. (A) The curves of CA-125 (carbohydrate antigen-125) showed that an increase in the related quantity at the beginning of immunotherapy, followed by a gradual decrease. (B) The curves of CA-199 (carbohydrate antigen-199) were similar to A. First of all, the gray dashed line represented the normal range in detail. The normal range of tumor markers was below the dashed line. More intuitively, tumor markers had fallen from high to low levels and had remained low, a phenomenon that reflected the effectiveness of combination therapy. In addition, the definition of the normal range is based on our hospital testing methods. Next, if the evaluation of the treatment effect is CR (complete response), the tumor markers are required to continue normally for more than 4 months.
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The hemogram of outpatient reexamination revealed a temporary increase in the tumor markers in the early stage of immunotherapy, possibly due to the death and lysis of tumor cells, and a steady decline in the later stage (Figure 4).
The inflammation of tumor microenvironment. (A) The fluctuation of TNF-a, IL-2, IL-6 and IL-10 in peripheral blood during the immunotherapy. (B) Dynamic changes of immune cells including CD3+T cell, CD4+T cell and CD8+T cell were detected in peripheral blood during immunotherapy. The gray dashed line represented the normal range in detail, the normal range of cytokines was below the dashed line, and the normal range of immune cells was between the two dashed lines.
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On the one hand, TNF-a and IL-6 remained at high levels during immunotherapy, and IL-2 kept a steady rise, while IL-10 showed an exponential decline (Figure 5A). On the other hand, CD3+T cell and CD8+T cell kept a slight decline, but were still at high levels; besides, the level of CD4+T cell consistently increased, which was the same as the rate of CD4+/CD8 (Figure 5B). These phenomena reflected enhancement of overall immune infiltration in tumours and inflammation of tumor microenvironment, which was the proof of the transition of "hot" tumor (Figure 5).