Introduction:The pancreas often interferes with the surgical field during laparoscopic gastrectomy (LG) and its disorders cause severe postoperative complications. This study aimed to evaluate the association between the anatomical location of the pancreas and surgical outcome and to investigate the optimal surgical position in LG.Methods: We newly defined the angle formed between the supra-pancreatic region and the root of the left gastric artery (LGA) as the pancreas-LGA angle (PLA). The association between PLA and surgical outcomes in 107 consecutive patients who underwent laparoscopic distal gastrectomy (LDG) was investigated. Then, the change in PLA before and after insertion of the back pillow in 30 patients with gastric cancer was examined. Results: The median PLA was 62 (range, 2 -157 ). No differences were found in the patient background between patients with small PLA (PLA < 62 ; n = 53) and those with large PLA (PLA ≧ 62 ; n = 54). The postoperative inflammation response (white blood cells, neutrophils, and C-reactive protein) and amylase concentration in the drainage fluid (D-AMY) were significantly higher in the small PLA group than large PLA group. Multivariable analyses demonstrated that small PLA was an independent risk factor for high D-AMY. After insertion of a back pillow, PLA was noninvasively increased in all patients, and the median PLA was changed to 92 (range, 8 -151 ) from 61 (range, 2 -140 ). Of 17 patients with small PLA, nine developed large PLA.
Despite the effectiveness of imatinib, most gastrointestinal stromal tumors (GISTs) develop resistance to the treatment, mainly due to the reactivation of KIT tyrosine kinase activity. Sunitinib, which inhibits the phosphorylation of KIT and vascular endothelial growth factor (VEGF) receptor, has been established as second‐line therapy for GISTs. The recently‐developed heat shock protein 90 (HSP90) inhibitor pimitespib (PIM; TAS‐116) demonstrated clinical benefits in some clinical trials; however, the effects were limited. The aim of our study was therefore to clarify the effectiveness and mechanism of the combination of PIM with sunitinib for imatinib‐resistant GISTs. We evaluated the efficacy and mechanism of the combination of PIM with sunitinib against imatinib‐resistant GIST using imatinib‐resistant GIST cell lines and murine xenograft models. In vitro analysis demonstrated that PIM and sunitinib combination therapy strongly inhibited growth and induced apoptosis in imatinib‐resistant GIST cell lines by inhibiting KIT signaling and decreasing auto‐phosphorylated KIT in the Golgi apparatus. In addition, PIM and sunitinib combination therapy enhanced antitumor responses in the murine xenograft models compared to individual therapies. Further analysis of the xenograft models showed that the combination therapy not only downregulated the KIT signaling pathway but also decreased the tumor microvessel density. Furthermore, we found that PIM suppressed VEGF expression in GIST cells by suppressing protein kinase D2 and hypoxia‐inducible factor‐1 alpha, which are both HSP90 client proteins. In conclusion, the combination of PIM and sunitinib is effective against imatinib‐resistant GIST via the downregulation of KIT signaling and angiogenic signaling pathways.
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