PIM2 Expression Induced by Proinflammatory Macrophages Suppresses Immunotherapy Efficacy in Hepatocellular Carcinoma.

Cancer immunotherapy restores or enhances the effector function of T cells in the tumor microenvironment, but the efficacy of immunotherapy has been hindered by therapeutic resistance. Here, we identify the proto-oncogene serine/threonine protein kinase PIM2 as a novel negative feedback regulator of IFNγ-elicited tumor inflammation, thus endowing cancer cells with aggressive features. Mechanistically, IL1ß derived from IFNγ-polarized tumor macrophages triggered PIM2 expression in cancer cells via the p38 MAPK/Erk and NF-κB signaling pathways. PIM2+ cancer cells generated by proinflammatory macrophages acquired the capability to survive, metastasize, and resist T-cell cytotoxicity and immunotherapy. A therapeutic strategy combining immune checkpoint blockade (ICB) with IL1ß blockade or PIM2 kinase inhibition in vivo effectively and successfully elicited tumor regression. These results provide insight into the regulatory and functional features of PIM2+ tumors and suggest that strategies to influence the functional activities of inflammatory cells or PIM2 kinase may improve the efficacy of immunotherapy. SIGNIFICANCE: Cross-talk between T cells and macrophages regulates cancer cell PIM2 expression to promote cancer aggressiveness, revealing translational approaches to improve response to ICB in hepatocellular carcinoma.

EIT Imaging of Intracranial Hemorrhage in Rabbit Models Is Influenced by the Intactness of Cranium.

Electrical impedance tomography (EIT) has been shown to be a promising, bedside imaging method to monitor the progression of intracranial hemorrhage (ICH). However, the observed impedance changes within brain related to ICH differed among groups, and we hypothesized that the cranium intactness (open or closed) may be the one of potential reasons leading to the difference. Therefore, the aim of this study was to investigate this effect of open or closed cranium on impedance changes within brain in the rabbit ICH model. In this study, we first established the ICH model in 12 rabbits with the open cranium and in 12 rabbits with the closed cranium. Simultaneously, EIT measurements on the rabbits' heads were performed to record the impedance changes caused by injecting the autologous nonheparinized blood into cerebral parenchyma. Finally, the regional impedance changes on EIT images and the whole impedance changes were analyzed. It was surprisingly found that when the cranium was open, the impedance of the area where the blood was injected, as well as the whole brain impedance, decreased with the amount of blood being injected; when the cranium was closed, while the impedance of the area where blood was not injected continued to increase, the impedance of the area where blood was injected decreased within 20s of the blood being injected and then remained almost unchanged, and the whole brain impedance had a small fall and then notably increased. The results have validated that the cranium completeness (open or closed) has influences on impedance changes within brain when using EIT to monitor ICH. In future study on application of EIT to monitor ICH, the cranium completeness should be taken into account for establishing an ICH model and analyzing the corresponding EIT results.

Advanced gastrointestinal stromal tumor patients benefit from palliative surgery after tyrosine kinase inhibitors therapy.

The role of palliative surgery is controversial in advanced gastrointestinal stromal tumors (GIST) after tyrosine kinase inhibitors (TKIs) therapy.We evaluated safety and clinical outcomes in a single institution series of advanced GIST patients from January 2002 to December 2008.One hundred and fifty-six patients had been recruited, including 87 patients underwent surgical resection and 69 patients kept on TKIs treatment. Four patients had major surgical complications. Median follow-up was 38.3 months, the overall survival (OS) and progression-free survival (PFS) of the patients in surgical group were longer than the nonsurgical group, PFS: 46.1 versus 33.8 months (P < .01), OS: 54.8 versus 40.4 months. In the subgroup analysis for the patients received surgery, the median PFS for patients with progression disease, stable disease, and partial response was 33.3, 51.5, and 83.0 months, respectively (P < .01). Median OS was 68.0 months in those with only liver or peritoneal metastases, and 45.3 months in those with both metastases. Median PFS of patients underwent R0/R1 resection was 73.6 months compared with 35.8 months in R2 resection patients (P < .01).Patients with advanced GISTs have prolonged OS after debulking procedures. Surgery for patients who have responsive disease after TKIs treatment should be considered.