A retrospective comparative study on the treatment of non-metastatic pancreatic cancer using high-intensity focused ultrasound versus radical surgery.

OBJECTIVE: To compare the efficacy and safety of high-intensity focused ultrasound (HIFU) and radical surgery for non-metastatic pancreatic cancer (PC). MATERIALS AND METHODS: We retrospectively analyzed 89 stage I/II/III PC patients who underwent HIFU (n = 43) or surgery (n = 46) at the Third Xiangya Hospital from January 2020 to December 2021. Pain relief, Karnofsky Performance Scale (KPS), overall survival (OS), treatment-related complications and risk factors for OS were assessed. RESULTS: There was no significant difference in the pain relief rate at 30 days post-treatment between the two groups. However, compared with the surgery group, the HIFU group showed significantly lower post-treatment VAS scores (p = 0.019). In the surgery group, the KPS at 30 days post-treatment was lower than pretreatment KPS (70 vs 80; p = 0.015). This relationship was reversed in the HIFU group (80 vs 70; p = 0.024). Median OS favored surgery over HIFU (23 vs 10 months; p < 0.001), with a higher 1-year OS rate (69.57% vs 32.6%; p < 0.001). However, there was no significant difference in OS between the two groups for stage III patients (p = 0.177). Complications rated ≥ grade III were 2.33% in the HIFU group and 32.6% in the surgery group. Multivariate analyses showed that age, KPS, and treatment methods were independent prognostic factors for OS. CONCLUSION: HIFU demonstrates advantages over surgery in terms of early KPS, VAS improvements, and safety for pancreatic cancer; however, long-term outcomes favor surgery. For III-stage disease, HIFU was noninferior to surgery in overall survival.

MLKL signaling regulates macrophage polarization in acute pancreatitis through CXCL10.

Acute pancreatitis (AP) is a disease characterized by local and systemic inflammation with an increasing incidence worldwide. Receptor-interacting serine/threonine protein kinase 3 (RIPK3), mixed-lineage kinase domain-like protein (MLKL), and innate immune cell macrophages have been reported to be involved in the pathogenesis of AP. However, the mechanisms by which RIPK3 and MLKL regulate pancreatic injury, as well as the interactions between injured pancreatic acinar cells and infiltrating macrophages in AP, remain poorly defined. In the present study, experimental pancreatitis was induced in C57BL/6J, Ripk3-/- and Mlkl-/- mice by cerulein plus lipopolysaccharide in vivo, and primary pancreatic acinar cells were also isolated to uncover cellular mechanisms during cerulein stimulation in vitro. The results showed that MLKL and its phosphorylated protein p-MLKL were upregulated in the pancreas of the mouse AP model and cerulein-treated pancreatic acinar cells, independent of its canonical upstream molecule Ripk3, and appeared to function in a cell death-independent manner. Knockout of Mlkl attenuated AP in mice by reducing the polarization of pancreatic macrophages toward the M1 phenotype, and this protective effect was partly achieved by reducing the secretion of CXCL10 from pancreatic acinar cells, whereas knockout of Ripk3 did not. In vitro neutralization of CXCL10 impaired the pro-M1 ability of the conditioned medium of cerulein-treated pancreatic acinar cells, whereas in vivo neutralization of CXCL10 reduced the polarization of pancreatic macrophages toward M1 and the severity of AP in mice. These findings suggested that targeting the MLKL-CXCL10-macrophage axis might be a promising strategy for the treatment of AP.

Murine Chronic Pancreatitis Model Induced by Partial Ligation of the Pancreatic Duct Encapsulates the Profile of Macrophage in Human Chronic Pancreatitis.

Immune responses are an integral part of the pathogenesis of pancreatitis. Studies applying the mouse model of pancreatitis induced by partial ligation of the pancreatic duct to explore the pancreatic immune microenvironment are still lacking. The aim of the present study is to explore the macrophage profile and associated regulatory mechanisms in mouse pancreatitis, as well as the correlation with human chronic pancreatitis (CP). In the present study, the mouse model of pancreatitis was induced by partial ligation of the pancreatic duct. Mice in the acute phase were sacrificed at 0, 4, 8, 16, 32, 72 h after ligation, while mice in the chronic phase were sacrificed at 7, 14, 21, 28 days after ligation. We found that the pancreatic pathological score, expression of TNF-α and IL-6 were elevated over time and peaked at 72h in the acute phase, while in the chronic phase, the degree of pancreatic fibrosis peaked at day 21 after ligation. Pancreatic M1 macrophages and pyroptotic macrophages showed a decreasing trend over time, whereas M2 macrophages gradually rose and peaked at day 21. IL-4 is involved in the development of CP and is mainly derived from pancreatic stellate cells (PSCs). The murine pancreatitis model constructed by partial ligation of the pancreatic duct, especially the CP model, can ideally simulate human CP caused by obstructive etiologies in terms of morphological alterations and immune microenvironment characteristics.

CircHIPK3 Promotes Pyroptosis in Acinar Cells Through Regulation of the miR-193a-5p/GSDMD Axis.

Acute pancreatitis (AP), especially severe acute pancreatitis (SAP), is an extremely dangerous illness with a high mortality rate. Pyroptotic cells release their cellular contents and inflammatory factors, aggravating the inflammatory response. Pyroptosis may be the main mode of acinar cell death during AP. The circular RNA circHIPK3 is expressed in pancreatic tissue and is associated with inflammatory response. In this study, we focused on the role and underlying mechanism of circHIPK3 in AP. We found that the expression of circHIPK3 was significantly elevated in serum of patients with AP and in caerulein-stimulated AR42J cells and was associated with caspase-1 and caspase-11 activation. circHIPK3 silencing ameliorated caerulein-induced cell damage and reduced the release of inflammatory factors IL-1ß, IL-6, IL-8, and TNF-α and inhibited the activation of caspase-1 and caspase-11. In addition, circHIPK3 bound to miR-193a-5p and negatively regulated its expression. Inhibition of miR-193a-5p increased the release of IL-1ß, IL-6, IL-8, and TNF-α and activated caspase-1 and caspase-11, thereby counteracting the effect of circHIPK3 silencing on caerulein-induced cell damage. Furthermore, we identified GSDMD as a target gene of miR-193a-5p, which is the key gene for pyroptosis. Interfering with the expression of GSDMD can increase cell viability, reduce the secretion of inflammatory cytokines, and suppress the activation of cleaved caspase-1 and caspase-11. Silencing GSDMD reversed the effects of miR-193a-5p inhibitors on caerulein-induced damage. In conclusion, circHIPK3 promotes pyroptosis in acinar cells through regulation of the miR-193a-5p/GSDMD axis, which eventually aggravates AP disease.