ObjectiveInnate immunity plays important roles in pancreatic ductal adenocarcinoma (PDAC), as non-T-cell-enriched tumour. Neutrophils are major players in innate immune system. Here, we aimed to explore the heterogeneity and pro-tumour mechanisms of neutrophils in PDAC.DesignWe analysed single-cell transcriptomes of peripheral blood polymorphonuclear leucocytes (PMNs) and tumour-infiltrating immune cells from five patients with PDAC, and performed immunofluorescence/immunohistochemistry staining, multi-omics analysis and in vitro experiments to validate the discoveries of bioinformatics analysis.ResultsExploration of the heterogeneity of tumour-associated neutrophils (TANs) revealed a terminally differentiated pro-tumour subpopulation (TAN-1) associated with poor prognosis, an inflammatory subpopulation (TAN-2), a population of transitional stage that have just migrated to tumour microenvironment (TAN-3) and a subpopulation preferentially expressing interferon-stimulated genes (TAN-4). Glycolysis signature was upregulated along neutrophil transition trajectory, and TAN-1 was featured with hyperactivated glycolytic activity. The glycolytic switch of TANs was validated by integrative multi-omics approach of transcriptomics, proteomics and metabolomics analysis. Activation of glycolytic activity by LDHA overexpression induced immunosuppression and pro-tumour functions in neutrophil-like differentiated HL-60 (dHL-60) cells. Mechanistic studies revealed BHLHE40, downstream to hypoxia and endoplasmic reticulum stress, was a key regulator in polarisation of neutrophils towards TAN-1 phenotype, and direct transcriptional regulation of BHLHE40 on TAN-1 marker genes was demonstrated by chromatin immunoprecipitation assay. Pro-tumour and immunosuppression functions were observed in dHL-60 cells overexpressing BHLHE40. Importantly, immunohistochemistry analysis of PDAC tissues revealed the unfavourable prognostic value of BHLHE40+ neutrophils.ConclusionThe dynamic properties of TANs revealed by this study will be helpful in advancing PDAC therapy targeting innate immunity.
Aim: The goal of this retrospective study was to analyze the strategy for the surgical management of insulinomas. Methods: From May 2000 to October 2006, the medical records of 52 patients with insulinomas were retrospectively studied. Results: All tumors were localized precisely by imaging techniques combined with intraoperative palpation. Forty-eight patients with benign lesions underwent surgical treatment: 41 patients open and 7 patients laparoscopic procedures. Four patients with malignant insulinomas underwent tumor resection; 3 of them underwent metastatic lesion and/or lymph node dissection. There were no discrepancies regarding operation time, blood loss, and complication rate between open enucleation and laparoscopic surgery. The mean hospital stay was 11.8 ± 3.4 days after laparoscopic surgery, shorter than the 17.0 ± 6.0 days after the open approach. Twenty-two complications occurred in 17 patients (32%) following resection. On follow-up, 86% of the patients were free from symptoms, and surgical cure was achieved in 95% of the patients with benign insulinomas. Conclusions: The choice of the surgical strategy for the treatment of pancreatic insulinomas depends on size and location of the tumor and the risk of malignancy. The optimal surgical procedure is key to prevent postoperative complications. The laparoscopic approach is safe and feasible for patients with benign tumors located in body or tail of the pancreas.
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