Xianbao Zhan

Importance: Standard first-line therapy for advanced or metastatic esophageal carcinoma is chemotherapy, but the prognosis remains poor. Camrelizumab (an anti-programmed death receptor 1 [PD-1] antibody) showed antitumor activity in previously treated advanced or metastatic esophageal squamous cell carcinoma. Objective: To evaluate the efficacy and adverse events of camrelizumab plus chemotherapy vs placebo plus chemotherapy as a first-line treatment in advanced or metastatic esophageal squamous cell carcinoma. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled, multicenter, phase 3 trial (ESCORT-1st study) enrolled patients from 60 hospitals in China between December 3, 2018, and May 12, 2020 (final follow-up, October 30, 2020). A total of 751 patients were screened and 596 eligible patients with untreated advanced or metastatic esophageal squamous cell carcinoma were randomized. Interventions: Patients were randomized 1:1 to receive either camrelizumab 200 mg (n = 298) or placebo (n = 298), combined with up to 6 cycles of paclitaxel (175 mg/m2) and cisplatin (75 mg/m2). All treatments were given intravenously every 3 weeks. Main Outcomes and Measures: Coprimary end points were overall survival (significance threshold, 1-sided P < .02) and progression-free survival (significance threshold, 1-sided P < .005). Results: Of the 596 patients randomized (median age, 62 years [interquartile range, 56-67 years]; 523 men [87.8%]), 1 patient in the placebo-chemotherapy group did not receive planned treatment. A total of 490 patients (82.2%) had discontinued the study treatment. The median follow-up was 10.8 months. The overall survival for the camrelizumab-chemotherapy group was a median of 15.3 months (95% CI, 12.8-17.3; 135 deaths) vs a median of 12.0 months (95% CI, 11.0-13.3; 174 deaths) for the placebo-chemotherapy group (hazard ratio [HR] for death, 0.70 [95% CI, 0.56-0.88]; 1-sided P = .001). Progression-free survival for camrelizumab plus chemotherapy was a median of 6.9 months (95% CI, 5.8-7.4; 199 progression or deaths) vs 5.6 months (95% CI, 5.5-5.7; 229 progression or deaths) for the placebo-chemotherapy group (HR for progression or death, 0.56 [95% CI, 0.46-0.68]; 1-sided P < .001). Treatment-related adverse events of grade 3 or higher occurred in 189 patients (63.4%) in the camrelizumab-chemotherapy group and 201 (67.7%) in the placebo-chemotherapy group, including treatment-related deaths among 9 patients (3.0%) and 11 patients (3.7%), respectively. Conclusions and Relevance: Among patients with advanced or metastatic esophageal squamous cell carcinoma, the addition of camrelizumab to chemotherapy, compared with placebo and chemotherapy, significantly improved overall survival and progression-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03691090.

Figure 2. Transgenic expression of human PRSS1 R122H caused severe AP. (A) Schema of cerulein-induced AP protocol. (B) Representative photos of pancreata from transgenic human PRSS1 R122H mice and C57BL/6J mice 24 hours after cerulein induction (n = 8). (C) Significant increase in pancreatic edema (pancreas-to-body weight ratio) in PRSS1 R122H mice 24 hours after cerulein induction. Mean SEM (n = 8). *P < 0.05; ***P < 0.001; 2-way ANOVA with Tukey's test. (D) Serum amylase levels after 24 hours of cerulein induction. Mean SEM (n = 8). ***P < 0.001; 2-way ANOVA with Tukey's test. (E) Representative images of H&E staining of the pancreata (n = 8). Scale bars: 300 m. (F) Histology score evaluation of AP. Mean SEM (n = 8). ***P < 0.001; 2-way ANOVA with Tukey's test. (G) Representative immunohistochemical staining for CD11b (pan leukocytes), F4/80 (macrophage), and Gr-1 (neutrophil) positive inflammatory cells (brown signal with hematoxylin purple counterstain) on sections from transgenic PRSS1 R122H mice and C57BL/6J mice 24 hours after cerulein induction (n = 8). Scale bars: 200 m. (H) Immunohistochemical staining for analysis of p65 nuclear translocation, an indicator of NF-B activation in the pancreata of PRSS1 R122H mice and C57BL/6J mice (n = 8). Scale bars: 200 m. (I) Quantification of p65 nuclear translocation in the pancreata of PRSS1 R122H mice and C57BL/6J mice. Mean SEM (n = 8). ***P < 0.001; 2-way ANOVA with Tukey's test. (J) Pancreatic mRNA expression levels of monocyte chemoattractant protein-1 (Mcp1), tumor necrosis factor alpha (Tnfa), interleukin 1 (Il1b), and Il6 in PRSS1 R122H mice and C57BL/6J mice were measured by real-time RT-PCR. Mean SEM (n = 4). *P < 0.05; ***P < 0.001; 2-way ANOVA with Tukey's test.

Animal models of pancreatitis are useful for elucidating the pathogenesis of pancreatitis and developing and testing novel interventions. In this review, we aim to summarize the most commonly used animal models, overview their pathophysiology, and discuss their strengths and limitations. We will also briefly describe common animal study procedures and refer readers to more detailed protocols in the literature. Although animal models include pigs, dogs, opossums, and other animals, we will mainly focus on rodent models because of their popularity. Autoimmune pancreatitis and genetically engineered animal models will be reviewed elsewhere.