Increased staple loading pressures and reduced staple heights in laparoscopic sleeve gastrectomy reduce intraoperative bleeding.

BACKGROUND: In laparoscopic sleeve gastrectomy, tissue thickness and closed staple height of the staple cartridge determine the pressure applied to the tissue. Prior studies have suggested 8 g/mm2 to be ideal to minimize leaks or bleeding. METHODS: We evaluated the relationship between staple loading pressure applied to gastric tissue and bleeding rate prospectively with a novel tissue measuring device and video-recorded operative findings for 116 patients undergoing laparoscopic sleeve gastrectomy performed by 2 surgeons at a single institution. Stapling protocol 1 was used for 64 cases, defined as standard practice, typically using green-blue-blue-blue Ethicon staple cartridges. Stapling protocol 2 was defined as blue-blue-white-white or gold-blue-white-white. RESULTS: Tissue thickness measurements from 39 cases and staple load selection showed that surgeons preferred a median staple loading pressure of 15 g/mm2. Tissue thickness measurements at 15 g/mm2 had a mean of 1.86 mm at the antrum, 1.71 mm at the body, and 1.15 mm at the fundus, all significantly thinner than tissue thickness at 8 g/mm2. For each 10 g/mm2 increase in minimum pressure and maximum pressure value within each cartridge zone, there was a reduction in bleeding rate by 59.8% and 38.7%, respectively. Compared with stapling protocol 1, stapling protocol 2 had a lower intraoperative bleeding rate (90.2% vs 70.7%; P < .0001), usage of preventive hemostatic techniques (100% vs 10%; P < .0001), and hemostatic treatments (66% vs 46%; P = .04). In the 30-day postoperative period, there was 1 bleed in stapling protocol 1; there were no leaks. CONCLUSION: Our data suggest using shorter closed staple heights to exert higher staple loading pressures decreases intraoperative bleeding rates in laparoscopic sleeve gastrectomy.

Wnt-mediated endothelial transformation into mesenchymal stem cell-like cells induces chemoresistance in glioblastoma.

Therapeutic resistance remains a persistent challenge for patients with malignant tumors. Here, we reveal that endothelial cells (ECs) acquire transformation into mesenchymal stem cell (MSC)-like cells in glioblastoma (GBM), driving tumor resistance to cytotoxic treatment. Transcriptome analysis by RNA sequencing (RNA-seq) revealed that ECs undergo mesenchymal transformation and stemness-like activation in GBM microenvironment. Furthermore, we identified a c-Met-mediated axis that induces ß-catenin phosphorylation at Ser675 and Wnt signaling activation, inducing multidrug resistance-associated protein-1(MRP-1) expression and leading to EC stemness-like activation and chemoresistance. Last, genetic ablation of ß-catenin in ECs overcome GBM tumor resistance to temozolomide (TMZ) chemotherapy in vivo. Combination of Wnt inhibition and TMZ chemotherapy eliminated tumor-associated ECs, inhibited GBM growth, and increased mouse survival. These findings identified a cell plasticity-based, microenvironment-dependent mechanism that controls tumor chemoresistance, and suggest that targeting Wnt/ß-catenin-mediated EC transformation and stemness activation may overcome therapeutic resistance in GBM.

c-Met-mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma.

Aberrant vascularization is a hallmark of cancer progression and treatment resistance. Here, we have shown that endothelial cell (EC) plasticity drives aberrant vascularization and chemoresistance in glioblastoma multiforme (GBM). By utilizing human patient specimens, as well as allograft and genetic murine GBM models, we revealed that a robust endothelial plasticity in GBM allows acquisition of fibroblast transformation (also known as endothelial mesenchymal transition [Endo-MT]), which is characterized by EC expression of fibroblast markers, and determined that a prominent population of GBM-associated fibroblast-like cells have EC origin. Tumor ECs acquired the mesenchymal gene signature without the loss of EC functions, leading to enhanced cell proliferation and migration, as well as vessel permeability. Furthermore, we identified a c-Met/ETS-1/matrix metalloproteinase-14 (MMP-14) axis that controls VE-cadherin degradation, Endo-MT, and vascular abnormality. Pharmacological c-Met inhibition induced vessel normalization in patient tumor-derived ECs. Finally, EC-specific KO of Met inhibited vascular transformation, normalized blood vessels, and reduced intratumoral hypoxia, culminating in suppressed tumor growth and prolonged survival in GBM-bearing mice after temozolomide treatment. Together, these findings illustrate a mechanism that controls aberrant tumor vascularization and suggest that targeting Endo-MT may offer selective and efficient strategies for antivascular and vessel normalization therapies in GBM, and possibly other malignant tumors.