Modulating effect of the PI3-kinase inhibitor LY294002 on cisplatin in human pancreatic cancer cells

<p>Abstract</p> <p>Background</p> <p>Chemoresistance is a serious problem in pancreatic cancer, but the mechanism of resistance and strategies against the resistance have not been elucidated. We examined the potential of the phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor LY294002 to enhance the anti-tumor effect of cisplatin and investigated the mechanism of chemoresistance in pancreatic cancer cells using a combination therapy of cisplatin and LY294002, both <it>in vitro </it>and <it>in vivo</it>.</p> <p>Methods</p> <p>Cisplatin and LY294002, individually or in combination, were given to AsPC-1 and PANC-1 cell lines. Tumor growth, DNA fragments, and Akt phosphorylation were examined <it>in vitro</it>. To examine the therapeutic effect of cisplatin and LY294002, individually or combination an AsPC-1 tumor xenograft model was prepared for <it>in vivo </it>study.</p> <p>Results</p> <p>Cisplatin induced growth inhibition and Akt phosphorylation in pancreatic cancer cells. LY294002 also inhibited cell proliferation but without showing Akt phosphorylation. However, the combination therapy markedly increased cleavage of caspase-3 and cytoplasmic histone-associated DNA fragments compared to the results with cisplatin alone. In the <it>in vivo </it>study, blocking the PI3K/Akt cascade with LY294002 increased the efficacy of cisplatin-induced inhibition of tumor growth in nude mice, suppressing half the tumor growth with cisplatin alone. There were no detectable side effects in mice treated with combination therapy.</p> <p>Conclusion</p> <p>Our studies suggest that the PI3K/Akt pathway plays an important role in cisplatin resistance of pancreatic cancer cells. The augmentation of cisplatin with PI3K/Akt inhibitor may resolve the chemoresistance problem of cisplatin, and this might be a plausible strategy for achieving tolerance for chemotherapeutic agents in pancreatic cancer therapy.</p

Comparison of Postoperative Complications after Endoscopic Submucosal Dissection: Differences of Insufflations and Anesthesias

Endoscopic submucosal dissection (ESD) has enabled the collective resection and increased the accuracy of pathological diagnosis. However, ESD requires a long operation time, which results in increased doses of analgesics/sedatives, and causes worsening of respiratory and hemodynamic statuses. To reduce postoperative complications, we have applied ESD with CO2 insufflation and general anesthesia. This study included 50 patients who underwent ESD for early gastric cancer, 25 with air insufflation and intravenous anesthesia (Air/IV group), and the remaining 25 with CO2 insufflation and general anesthesia (CO2/GA group). Postoperative enlarged feeling of the abdomen was observed only in 1 of 25 patients in the CO2/GA group (P = 0.0416). Postoperative severe unrest was observed in none of the patients in the CO2/GA group and in 4 of 25 (16%) patients in the Air/IV group (P = 0.0371). CO2 insufflation and general anesthesia are useful in stabilizing intraoperative conditions and reducing postoperative complications

Role of 18F-fluorodeoxyglucose positron emission tomography imaging in surgery for pancreatic cancer

AIM: To evaluate the role of positron emission tomo-graphy using 18F-fluorodeoxyglucose (FDG-PET) in the surgical management of patients with pancreatic cancer, including the diagnosis, staging, and selection of patients for the subsequent surgical treatment

Effectiveness of CO₂-insufflated endoscopic submucosal dissection with the duodenal balloon occlusion method for early esophageal or gastric cancer: a randomized case control prospective study

<p>Abstract</p> <p>Background</p> <p>Endoscopic submucosal dissection (ESD) has typically been performed using air insufflation. Recently, however, insufflation of CO₂ has been increasingly used to avoid complications. This prospective study was designed to compare the CO₂ concentration, intestinal volume, and acid–base balance using the duodenal balloon procedure.</p> <p>Methods</p> <p>From June 2010 to February 2011, we enrolled 44 patients with esophageal or gastric cancer and randomly allocated them into two groups. We compared 22 patients undergoing CO₂-insufflated ESD with a balloon placed into the duodenal bulb (duodenal balloon group) and 22 patients undergoing regular CO₂-insufflated ESD (regular group). Three-dimensional computed tomography was performed before and after the procedure to measure intestinal volume. CO₂ concentrations were measured every 10 minutes. The visual analogue system (VAS) scores for postoperative symptoms were recorded, and pH was measured immediately after the procedure. This was a prospective case control study randomized by the sealed envelope method.</p> <p>Results</p> <p>Intestinal CO₂ gas volume before and after ESD was lower in the duodenal balloon group than in the regular group (<it>P</it> = 0.00027). The end-tidal CO₂ level was significantly lower in the duodenal balloon group than in the regular group (<it>P</it> = 0.0001). No significant differences in blood ΔpH were found between the two groups. The VAS score for the occurrence of nausea due to abdominal distension after ESD indicated a significant difference (<it>P</it> = 0.031).</p> <p>Conclusions</p> <p>ESD using the duodenal balloon occlusion method is effective for reduction of post-ESD intestinal CO₂ gas volume, resulting in a lower total amount of CO₂ insufflation during ESD and reducing harmful influences on the human body to some extent.</p

Current Innovations in Endoscopic Therapy for the Management of Colorectal Cancer: From Endoscopic Submucosal Dissection to Endoscopic Full-Thickness Resection

Endoscopic submucosal dissection (ESD) is accepted as a minimally invasive treatment for colorectal cancer. However, due to technical difficulties and an increased rate of complications, ESD is not widely used in the colorectum. In some cases, endoscopic treatment alone is insufficient for disease control, and laparoscopic surgery is required. The combination of laparoscopic surgery and endoscopic resection represents a new frontier in cancer treatment. Recent developments in advanced polypectomy and minimally invasive surgical techniques will enable surgeons and endoscopists to challenge current practice in colorectal cancer treatment. Endoscopic full-thickness resection (EFTR) of the colon offers the potential to decrease the postoperative morbidity and mortality associated with segmental colectomy while enhancing the diagnostic yield compared to current endoscopic techniques. However, closure is necessary after EFTR and natural transluminal endoscopic surgery (NOTES). Innovative methods and new devices for EFTR and suturing are being developed and may potentially change traditional paradigms to achieve minimally invasive surgery for colorectal cancer. The present paper aims to discuss the complementary role of ESD and the future development of EFTR. We focus on the possibility of achieving EFTR using the ESD method and closing devices

Protective effect of lipopolysaccharide preconditioning in hepatic ischaemia reperfusion injury

AbstractBackgroundPreconditioning using lipopolysaccharide (LPS), a toll-like receptor4 (TLR4) ligand, has been demonstrated to reduce ischaemia/reperfusion injury (IRI) in some organs, but its effect in the liver has not been elucidated. We examined the liver protective mechanism and correlated signalling pathway of LPS preconditioning in mice.MethodsBALB/c and TLR4 mutant mice underwent 90min of 70% hepatic ischaemia. Lipopolysaccharide (100µg/kg) was injected intraperitoneally 20h or 30min before ischaemia. Liver damage after reperfusion was examined using serum samples and liver specimens. To analyse the mechanism of preconditioning in detail, phosphorylation of representative signalling mediators to nuclear factor-κB (NF-κB) activation, Akt and interleukin-1 receptor-associated kinase-1 (IRAK-1), and expression of a negative feedback inhibitor, suppressor of cytokine signalling-1 (SOCS-1), were evaluated by Western blotting.ResultsPretreatment with LPS only 20h before ischaemia elicited a preconditioning effect; however, preconditioning was absent in TLR4 mutant mice. Lipopolysaccharide significantly decreased serum alanine aminotransferase, tumour necrosis factor-α, hepatocyte necrosis and NF-κB activity after reperfusion. Phosphorylated IRAK-1 was suppressed by LPS, whereas no difference was observed in phosphorylated Akt. Pre-ischaemic LPS provided early induction of SOCS-1.DiscussionLate-phase LPS preconditioning provided liver protection against IRI through the downregulation of the TLR4 cascade derived from early induction of SOCS-1 during ischaemia/reperfusion