| Pancreatic cancer is one of the most challenging gastrointestinal cancer and is associated with poor prognosis. It is characterized by rapid progression, high incidence and mortality. Surgery remains the only opportunity for long-term survival for patients with resectable pancreatic cancer. With the development of laparoscopic instruments and skills, LDP has become widely accepted by surgeons for benign and low-grade tumors of the pancreas. Recent comparative studies showed that LDP has the advantage of less blood loss and fewer hospital stay days as well as fewer postoperative complications compared with open distal pancreatectomy. However, application of laparoscopic approach has been restricted for malignant pancreatic lesions, especially pancreatic ductal adenocarcinoma (PDAC), due to concerns over oncologic safety. Until now only a few studies has been reported and total cases were less. We designed a case-control study to analysis the short- and long-term outcomes of the patients undergoing either Laparoscopic distal pancreatectomy or open distal pancreatectomy for PDAC. Also we systematically review the surgical and oncologic outcomes of laparoscopic distal pancreatectomy (LDP) versus open distal pancreatectomy (ODP) for pancreatic ductal adenocarcinoma (PDAC).Tumor biology of pancreatic cancer is prone to early recurrence and metastasis postoperation. Even after curative resection, the 5-year survival remains at 25%, so chemotherapy plays an important role for patients postoperation or with local advancement or metastasis. But traditional chemotherapy has limited efficiency for pancreatic cancer. Recently with the development of molecular targeted therapy and nanotechnology, it supplies better chemotherapy effect and could reduce systemic toxicity and multidrug resistance (MDR). Autophagy acts as both tumor suppressor and tumor inducer through different mechanism, now regulation of autophagy become an important targeted therapy for cancer. Autophagy is required for tumorigenic growth of pancreaitc cancer and is one of the strategy for chemotherapy-resistant of pancreatic caner. We designed a cancer targeted micellar nanocarrier using Pluronics123 (P123) as main body which could co-delivery of Docetaxel (DTX) and Atg7 siRNA-P123P600iRGD/DTX/Atg7 siRNA(PP6iRGD/DTX/Atg7) complex. Using this PP6iRGD/DTX/Atg7 complex we studied the the release of DTX and Atg 7 siRNA in vivo and in vitro. Knockout of Atg7 by Atg7 siRNA could inhibite autophagy and induce cellular apoptosis.Part 1:Laparoscopic Versus Open Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma:A case-control studyObjective:Laparoscopic distal pancreatectomy (LDP) showed advantage of perioperation outcomes for benign and low-grade tumor of the pancreas. The application of LDP for pancreatic ductal adenocarcinoma (PDAC) didn’t gain popular acceptance and the number of LDP for PDAC remains low. We designed a case-control study to analysis the short- and long-term outcomes of the patients undergoing either Laparoscopic distal pancreatectomy or open distal pancreatectomy for PDAC.Methods:From April 2003 to October 2015,29patients were underwent LDP and 48 patients were underwent ODP for PDAC. The two groups’demographic information, perioperative outcomes and survival data were compared.Results:Baseline characteristics were comparable between the LDP and ODP groups. The mean operation time, intraoperative blood loss, first flatus, first oral intake and postoperative hospital stay were significantly less in LDP group than ODP group (180min vs270min, P=0.003; 50ml vs400ml, P=0.000; 3d vs 4d, P=0.001; 3d vs 4d, P=0.003; 13d vs 15.5d, P=0.022). The ration of R0 resection, overall postoperative morbidity and postoperative pancreatic fistula rates were similar in the two groups. There were no significant differences in tumor sizes (3.5cm vs 3.9cm, P=0.987) and number of harvested lymph nodes (11 vs 9, P=0.072). The median overall survival for LDP and ODP groups were 16.0 months and 15.0 months. Cox proportional hazards analysis showed, R1 resection and rejection of adjuvant treatment were associated with worse survival.Conclusion:The results in our study validated that LDP was technically feasible and safe for PDAC in selected patients and the short-term oncologic outcomes were not inferior to ODP in this small sample study. However the long-term oncologic safety of LDP for PDAC has to be further evaluated by multicenter or randomized controlled trials.Part 2:Laparoscopic Versus Open Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma:A Systematic Review and Meta-AnalysisObjective:To systematically review the surgical and oncologic outcomes of laparoscopic distal pancreatectomy (LDP) versus open distal pancreatectomy (ODP) for pancreatic ductal adenocarcinoma (PDAC).Methods:A systematic search of PubMed, Embase, Cochrane Library, and Web of Science was conducted from Jan 1996 to Feb 2016. All original studies comparing LDP versus ODP were included for critical appraisal. Data synthesis and statistical analysis were carried out using RevMan 5.2 software.Results:7 studies were involved in this research. The rate of R0 resection was similar in both LDP and ODP groups(P=0.23). LDP was associated with less intraoperation blood loss, postoperative hospital stay and less tumor size (P<0.01, P<0.01, P=0.04). After sensitivity analyses using propensity score analysis, tumor size was similar in both groups (P=0.07). The mean operation time, overall postoperative morbidity, mortality, number of harvested lymph nodes, ration of N1 and postoperative pancreatic fistula rates were similar in LDP and ODP. The ration of adjuvant treatment and the ration of recurrences were also similar in both groups.Conclusion:The results in this study validated that LDP was technically feasible and safe for PDAC. The oncologic outcomes were similar between LDP and ODP with less blood loss and postoperative hospital stay in LDP group. However, further randomized, controlled studies would be required to evaluate the laparoscopic approach in PDAC.Part 3:Targeted micellar nanocarriers co-delivery of DTX and Atg7 siRNA for Pancreatic cancerObjective:1. To design a tumor-targeted micellar nanocarrier using pluronic123 as main body which could co-delivery gene and drug and to evaluate the ability of drug loading and gene condense.2. To study the synergistic effect of autophagy inhibition and apoptosis induction by PP6iRGD/DTX/Atg7 nanocomplexes as well as antitumor Laparoscopic distal pancreatectomy or open distal pancreatectomy for PDAC.Methods:From April 2003 to October 2015,29patients were underwent LDP and 48 patients were underwent ODP for PDAC. The two groups’demographic information, perioperative outcomes and survival data were compared.Results:Baseline characteristics were comparable between the LDP and ODP groups. The mean operation time, intraoperative blood loss, first flatus, first oral intake and postoperative hospital stay were significantly less in LDP group than ODP group (180min vs270min, P=0.003; 50ml vs400ml, P=0.000; 3d vs 4d, P=0.001; 3d vs 4d, P=0.003; 13d vs 15.5d, P=0.022). The ration of R0 resection, overall postoperative morbidity and postoperative pancreatic fistula rates were similar in the two groups. There were no significant differences in tumor sizes (3.5cm vs 3.9cm, P=0.987) and number of harvested lymph nodes (11 vs 9, P=0.072). The median overall survival for LDP and ODP groups were 16.0 months and 15.0 months. Cox proportional hazards analysis showed, R1 resection and rejection of adjuvant treatment were associated with worse survival.Conclusion:The results in our study validated that LDP was technically feasible and safe for PDAC in selected patients and the short-term oncologic outcomes were not inferior to ODP in this small sample study. However the long-term oncologic safety of LDP for PDAC has to be further evaluated by multicenter or randomized controlled trials.Part 2:Laparoscopic Versus Open Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma:A Systematic Review and Meta-AnalysisObjective:To systematically review the surgical and oncologic outcomes of laparoscopic distal pancreatectomy (LDP) versus open distal pancreatectomy (ODP) for pancreatic ductal adenocarcinoma (PDAC).Methods:A systematic search of PubMed, Embase, Cochrane Library, and Web of Science was conducted from Jan 1996 to Feb 2016. All original studies comparing LDP versus ODP were included for critical appraisal. Data synthesis and statistical analysis were carried out using RevMan 5.2 software.Results:7 studies were involved in this research. The rate of R0 resection was similar in both LDP and ODP groups(P=0.23). LDP was associated with less intraoperation blood loss, postoperative hospital stay and less tumor size (P<0.01, P<0.01, P=0.04). After sensitivity analyses using propensity score analysis, tumor size was similar in both groups (P=0.07). The mean operation time, overall postoperative morbidity, mortality, number of harvested lymph nodes, ration of N1 and postoperative pancreatic fistula rates were similar in LDP and ODP. The ration of adjuvant treatment and the ration of recurrences were also similar in both groups.Conclusion:The results in this study validated that LDP was technically feasible and safe for PDAC. The oncologic outcomes were similar between LDP and ODP with less blood loss and postoperative hospital stay in LDP group. However, further randomized, controlled studies would be required to evaluate the laparoscopic approach in PDAC.Part 3:Targeted micellar nanocarriers co-delivery of DTX and Atg7 siRNA for Pancreatic cancerObjective:1. To design a tumor-targeted micellar nanocarrier using pluronic123 as main body which could co-delivery gene and drug and to evaluate the ability of drug loading and gene condense.2. To study the synergistic effect of autophagy inhibition and apoptosis induction by PP6iRGD/DTX/Atg7 nanocomplexes as well as antitumor effect for pancreatic cancer.Methods:PP6iRGD/DTX/Atg7 nanocomplexes was synthesized and the struture, drug loading and gene condense ability were examined. In virto and in vivo studies were carried out to evaluate the synergistic effect of autophagy inhibition and apoptosis induction by PP6iRGD/DTX/Atg7 nanocomplexes.Results:A novel tumor-targeted micellar nanocarrier was synthesized using P123 as main body and could co-delivery DTX and Atg7 siRNA through hydrophobic core and hydrophilic shell. The nanocomplexes could self-assembly in fluid.In vitro studies PP6iRGD/DTX/Atg7 nanocomplexes showed controlled release and knockout of Atg7 which inhibiting autophagy and inducing apoptosis in Panc-1 cell through MTT, Western Blotting and qPCR. In vivo studies PP6iRGD/DTX/Atg7 nanocomplexes showed inhibition of autophagy and inhibiting of the tumor growth as well as induction of apoptosis through immunohistochemical, tunned, Western Blotting and qPCR. The targeted therapy effect was obvious in vivo study.Conclusion:1. PP6iRGD/DTX/Atg7 nanocomplexes could co-delivery DTX and Atg7 siRNA and functioned the synergistic effect.2. In vitro studies PP6iRGD/DTX/Atg7 nanocomplexes showed controlled release of DTX. The release of Atg7 siRNA silenced Atg7 expression and inhibited autophagy and induced apoptosis.3. In vivo studies PP6iRGD/DTX/Atg7 nanocomplexes showed inhibition of autophagy and inhibiting of the tumor growth as well as induction of apoptosis. The targeted therapy effect was obvious in vivo study. |
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