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case_images: Pathological and imaging evaluations during the first-line (AG) and second-line (SOXPR) treatment. (A, B) A 2.2cm x 2cm mass at the neck of the pancreas was detected with superior mesenteric artery (SMA) invasion less than 180  on abdominal CT at baseline. (C) Cancer cells were observed in pancreas biopsy (x200) at T0. (D) Ultrasound guided biopsy of the hepatic mass (M2) was concordant with liver metastasis of pancreatic ductal adenocarcinoma (x200) at T1. (E) Pathology of M2 showed inflammatory cells and no residual tumor cells (x200) at T2. (F, G) Abdominal CT during second-line (SOXPR) treatment and the tumor diameter variation. T0, The baseline prior to first-line therapy; T1, The baseline prior to second-line therapy; T2, Obvious relief of TEN symptoms; T3,: Three additional cycles of SOX to end; M1-M4, 4 hepatic metastases; P, primary pancreatic cancer locus.
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case_images: Contrast-enhanced computed tomography (CT) scan showed a 2.2cm x 2cm mass at the neck of the pancreas with distal pancreatic duct dilatation ( Figure 1A ). But after discussion, the Multiple Disciplinary Team (MDT) believed that the patient was also accompanied by superior mesenteric artery (SMA) invasion less than 180  ( Figure 1B ). Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) was performed and subsequently cancer cells were verified pathologically ( Figure 1C ). In addition, CT scan revealed that the size of pancreatic primary tumor had increased remarkably and four new hepatic masses appeared ( Figure 1G-T1 ). Pathology for Ultrasound guided biopsy of the hepatic mass was concordant with liver metastasis of pancreatic ductal adenocarcinoma ( Figure 1D ). CA19-9 decreased to 19.2 U/ml by the TIME. CT scan revealed that the primary pancreatic tumor and hepatic metastases had both shrunk remarkably ( Figure 1G-T2 ). Obvious inflammatory cell infiltration was confirmed by pathology and no cancer cells was found in the biopsy tissues ( Figure 1E ). At the time, CA19-9 decreased to 6.94U/ml and all tumors continued to shrink as CT indicated ( Figure 1G-T3 ). Tumor diameter changes were demonstrated in  Figure 1F .
case_images: Occurrence of TEN after SOXPR. (A) Planning target volume of hepatic metastases radiotherapy. (B) Skin changes during treatment of TEN.
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case_images: In detail, the patient received 3 cycles of S-1 80mg/day on day1-14 plus oxaliplatin 130mg/m2 on day 1 and Sintilimab 200mg on day 1 (21 days for a complete cycle) while 8Gy*3 fractions radiotherapy of liver metastases within PTV was conducted before Cycle2 started ( Figure 2A ). CA19-9 decreased to 19.2 U/ml by the TIME. CT scan revealed that the primary pancreatic tumor and hepatic metastases had both shrunk remarkably ( Figure 1G-T2 ). At the time, CA19-9 decreased to 6.94U/ml and all tumors continued to shrink as CT indicated ( Figure 1G-T3 ).
case_images: Systemic illustrations of clinical therapy flow chart. Broken Line indicates CA19-9 levels of this patient during the treatment.
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case_images: At the time, CA19-9 decreased to 6.94U/ml and all tumors continued to shrink as CT indicated ( Figure 1G-T3 ). The concomitant changes of CA199 and timeline of events were demonstrated in  Figure 3  in details.
case_images: Immunofluorescence and RNA immune-related panel sequencing prior and post second-line treatment. (A) The representative immunofluorescent images of CD8, CD68, CD163, FoxP3 and PD-L1 of tumor tissues prior second-line treatment. (B) The representative immunofluorescent images of CD8, CD68, CD163, FoxP3 and PD-L1 of tumor tissues post second-line treatment. (C) Immune cell-related gene expression prior and after second-line treatment. Black indicates pre-treatment, gray indicates post-treatment; blue indicates decreased expression, red indicates increased expression. (D) Immune signature-related gene expression prior and after second-line treatment. Black indicates pre-treatment, gray indicates post-treatment; blue indicates decreased expression, red indicates increased expression.
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case_images: The spatial immune microenvironments of tumor tissues prior ( Figure 4A ) and post treatment ( Figure 4B ) were shown by mIHC assay. The relative values of CD8+, CD68+, CD163+, Foxp3+, and PD-L1+ were 7.74, 3.9, 1.91, 2.84, and 0.69 respectively, showing a high infiltration of immune cells and low expression of PD-L1 (subtype TIME-3, immune escape type). Figure 4C , and the abundances of all immune cells were elevated to different degrees, and other immune signatures in  Figure 4D . For example, the CD8+ T cell score increased from 4.13 to 7.48, and the Macrophage gene score improved from 6.05 to 8.07, and the Treg gene score improved from 3.32 to 5.36.