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Background: A significant challenge to overcome in pancreatic ductal adenocarcinoma (PDAC) is the profound systemic immunosuppression that renders this disease non-responsive to immunotherapy. Our supporting data provide evidence that CD200, a regulator of myeloid cell activity, is expressed in the PDAC microenvironment. Additionally, myeloid-derived suppressor cells (MDSC) isolated from patients with PDAC express elevated levels of the CD200 receptor (CD200R). Thus, we hypothesize that CD200 expression in the PDAC microenvironment limits responses to immunotherapy by promoting expansion and activity of MDSC., Methods: Immunofluorescent staining was used to determine expression of CD200 in murine and human PDAC tissue. Flow cytometry was utilized to test for CD200R expression by immune populations in patient blood samples. In vivo antibody blocking of CD200 was conducted in subcutaneous MT-5 tumor-bearing mice and in a genetically engineered PDAC model (KPC-Brca2 mice). Peripheral blood mononuclear cells (PBMC) from patients with PDAC were analyzed by single-cell RNA sequencing. MDSC expansion assays were completed using healthy donor PBMC stimulated with IL-6/GM-CSF in the presence of recombinant CD200 protein., Results: We found expression of CD200 by human pancreatic cell lines (BxPC3, MiaPaca2, and PANC-1) as well as on primary epithelial pancreatic tumor cells and smooth muscle actin+ stromal cells. CD200R expression was found to be elevated on CD11b+CD33+HLA-DR lo/- MDSC immune populations from patients with PDAC (p=0.0106). Higher expression levels of CD200R were observed in CD15+ MDSC compared with CD14+ MDSC (p<0.001). In vivo studies demonstrated that CD200 antibody blockade limited tumor progression in MT-5 subcutaneous tumor-bearing and in KPC-Brca2 mice (p<0.05). The percentage of intratumoral MDSC was significantly reduced in anti-CD200 treated mice compared with controls. Additionally, in vivo blockade of CD200 can also significantly enhance the efficacy of PD-1 checkpoint antibodies compared with single antibody therapies (p<0.05). Single-cell RNA sequencing of PBMC from patients revealed that CD200R+ MDSC expressed genes involved in cytokine signaling and MDSC expansion. Further, in vitro cytokine-driven expansion and the suppressive activity of human MDSC was enhanced when cocultured with recombinant CD200 protein., Conclusions: These results indicate that CD200 expression in the PDAC microenvironment may regulate MDSC expansion and that targeting CD200 may enhance activity of checkpoint immunotherapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To assess the value of intraoperative radiotherapy (IORT) in the combined treatment of locally advanced pancreatic cancer., Methods: All patients with locally advanced pancreatic cancer at our hospital from January 2007 to December 2009, judged as unresectable and confirmed by histology or cytology, were recruited into this prospective study. They were randomly assigned into the IORT group (n=31) and control group (n=34). The IORT group received IORT plus internal drainage or laparotomy. The control group had internal drainage or laparotomy only. The evaluation of adverse results of two groups included: intraoperative and postoperative adverse events, recent post-operative side effects, analgesic effect, the level of tumor marker such as CA19-9 and the long-term survival., Results: There was no difference in operation duration, intraoperative hemorrhage and postoperative recovery. Significant differences were found in hematotoxicology, analgesic effect, tumor marker decreasing and long-term survival., Conclusion: IORT is a safe, reliable and easy-to-master technique without any obvious side effect. Its analgesic effect is better than the control group. Also IORT can retard the tumor growth and improve the patient survival.

Objective: To study the role of slow-release 5-fluorouracil implantation in treatment of unresectable pancreatic cancer., Methods: 85 cases of untreated patients with locally advanced pancreatic cancer (LAPC) were randomized into two groups: Trial group: slow-release 5-fluorouracil implantation (50 patients) and control group (35 patients). Observing the objective tumor response, clinical benefit response, toxicity, complications and survival of patients of the two groups., Results: In the trial group the overall response rate (PR + NC) was 76.0%, and the clinical benefit response rate was 52.0%. No toxicity was observed. Pancreatic fistula occurred in 2 patients. The median survival time of the two groups was 9.0 months and 4.0 months, respectively. The survival rates of 6- and 12-month were 56.8% vs. 31.4% and 22.9% vs. 2.9% in the two groups, respectively (P = 0.012)., Conclusion: Slow-release 5-fluorouracil implantation is a simple, safe and effective method in treatment of LAPC.

Objective: To study the role of (125)I seed implantation in the treatment of unresectable pancreatic cancer., Methods: From April 2004 to march 2006, 66 untreated patients with locally advanced pancreatic cancer (LAPC) were randomized into two groups: Group A: (125)I seeds implantation (n = 31) and Group B: control (n = 34). The objective tumor response, clinical benefit response, toxicity, complications and survival of two groups were observed., Results: In Group A, the overall response rate (PR + NC) was 80.6%. Clinical benefit response rate was 54.8%. No toxicity was observed. Gastrointestinal hemorrhage and pancreatic fistula occurred in 1 patient respectively in Group A. The survival rates of 6 and 12 months were 56.0% vs 31.4% and 16.8% vs 2.9% respectively in two groups (P < 0.05). The median survival time of two groups was 8.0 months vs 4.0 months (P < 0.05)., Conclusion: (125)I seed implantation is a simple, safe and effective method in the treatment of locally advanced pancreatic cancer.

Objective: To assess the risk factors of stress-related ulcer and gastrointestinal hemorrhage after pancreaticoduodenectomy., Methods: From May 1999 to July 2007, 285 periampullary cancer patients underwent pancreaticoduodenectomy in our hospital. The clinical data, pathological results, type of operation, and postoperative treatment were retrospectively analyzed. Patients with stress-related ulcer and gastrointestinal hemorrhage were selected for risk factor analysis, and other patients were taken as control group., Results: 35 patients (12.3%) developed stress-related ulcer and gastrointestinal hemorrhage following pancreaticoduodenectomy. Pathological examination showed pancreatic cancer in 5 cases, duodenal cancer in 8, common bile duct cancer in 10, ampullary carcinoma in 11, and solid-pseudopapillary tumors in 1. Single variate analysis demonstrated that alcohol, preoperative bilirubin level, operation time, lymph node metastasis, prealbumin decrease after operation and other complication were significantly associated with the stress-related ulcer and gastrointestinal hemorrhage. Logistic regression in multivariate analysis revealed that preoperative bilirubin level, operation time, other complication, prealbumin decrease after surgery were independent risk factors., Conclusion: Stress-related ulcer and gastrointestinal hemorrhage are one of the most common complications after pancreaticoduodenectomy. Preoperative bilirubin level, operation time, other complications, and prealbumin decrease after operation are four independently risk factors.

Objective: To investigate the method and value of tru-cut biopsy (TCB) combined with fine needle aspiration biopsy (FNAB) in the pathological diagnosis of pancreatic carcinoma during operation., Methods: From April 2007 to October 2008, 22 cases who were suspected to suffer from pancreatic carcinoma were enrolled into this prospective study. All of them underwent a tru-cut biopsy combined with fine needle aspiration biopsy for the pathological diagnosis during operation., Results: Of the 22 patients, 20 were finally diagnosed as having pancreatic carcinoma, while 2 having pancreatitis. The diagnosis of pancreatic carcinoma was confirmed in 19 by tru-cut biopsy combined with fine needle aspiration biopsy, while other 3 cases were not confirmed as pancreatic carcinoma. Among those 3 cases, one was diagnosed as having pancreatic carcinoma with hepatic metastasis by liver nodular biopsy, one as suffering from autoimmune pancreatitis, and another case as having chronic pancreatitis confirmed by follow-up for 9 months without any changes after the operation. The accuracy of FNA, TCB and FNA combined with TCB in the diagnosis for suspected pancreatic cancer were 86.4%, 90.9%, and 95.5%, respectively. No pancreatic fistula and bleeding developed after operation., Conclusion: Tru-cut biopsy is more accurate in diagnosis for the suspected pancreatic cancer than fine needle aspiration biopsy during operation. Tru-cut biopsy combined with fine needle aspiration biopsy can improve the accuracy of diagnosis, and is a safe and effective diagnostic method.

Objective: To investigate the factors influencing recurrence and metastasis following curative resection of pancreatic ductal adenocarcinoma and analyze the prognosis., Methods: The clinicopathological and follow-up data of 56 patients who underwent curative resection for pancreatic ductal adenocarcinoma between Jan. 1997 and Dec. 2006 in this hospital were analyzed retrospectively., Results: The recurrence rate after curative resection was 73.2% (41/56). The recurrence rate after operation at the time of 3 months, half year, 1 year and 2 years was 26.8% (15/56), 51.8% (29/56), 64.3% (36/56) and 69.6% (39/56), respectively. Hepatic metastasis and local recurrence accounted for 36.6% and 31.7% of the cases, respectively. The 3-year accumulated survival of this group was 22.7%. The symptom presenting time, back pain, preoperative level of CA19-9, tumor size, AJCC stage and T stage were correlated with metastasis/recurrence. Univariate analysis revealed that the preoperative level of CA19-9, T stage and the tumor size were prognostic factors. Cox regression analysis revealed that only tumor size was an independent prognostic factor., Conclusion: The metastasis or recurrence mostly occurs within 2 years after curative resection, and the liver is the most common site of metastasis. High recurrence rate is the major reason causing the failure of curative resection and short survival time after operation. The symptom presenting time, back pain, preoperative level of CA19-9, tumor size, AJCC stage and T stage are correlated with metastasis/recurrence. The tumor size is an independent prognostic factor.

A well-known observation with respect to cancer biology is that transformed cells display a disturbed cytoskeleton. The underlying mechanisms, however, remain only partly understood. In an effort to identify possible mechanisms, we compared the proteome of pancreatic cancer with matched normal pancreas and observed diminished protein levels of gelsolin--an actin filament severing and capping protein of crucial importance for maintaining cytoskeletal integrity--in pancreatic cancer. Additionally, pancreatic ductal adenocarcinomas displayed substantially decreased levels of gelsolin as judged by Western blot and immunohistochemical analyses of tissue micoarrays, when compared with cancerous and untransformed tissue from the same patients (P < 0.05). Importantly, no marked downregulation of gelsolin mRNA was observed (P > 0.05), suggesting that post-transcriptional mechanisms mediate low gelsolin protein levels. In apparent agreement, high activity ubiquitin-proteasome pathway in both patient samples and the BxPC-3 pancreatic cancer cell line was detected, and inhibition of the 26s proteasome system quickly restored gelsolin protein levels in the latter cell line. The status of ubiquitinated gelsolin is related to lymph node metastasis of pancreatic cancer. In conclusion, gelsolin levels are actively downregulated in pancreatic cancer and enhanced targeting of gelsolin to the ubiquitin-proteasome pathway is an important contributing factor for this effect.

Objective: To investigate the expression of annexin in human pancreatic cancer and to elucidate its role in oncogenesis of pancreatic cancer., Methods: A pancreatic carcinoma cell line Suit-II with high-expression of annexin I gene was adopted. Three subtypes of annexin I -siRNA sequences and a non-related fragment were combined, and the eukaryotic expression vectors bearing siRNA fragments were constructed. Then they were transfected into pancreatic carcinoma cells to knock down the expression of annexin I by RNAi. After knocking down the expression of annexin I , the growth speed, cell cycling, morphological features and apoptosis of pancreatic carcinoma cells were examined by RT-PCR and MTT test., Results: When the expression of annexin I was blocked, the growth speed of pancreatic carcinoma cells was significantly decreased, the morphological features were changed and pronounced apoptosis occurred., Conclusion: Annexin I can modulate pancreatic carcinoma cell cycle, promote the cell proliferation, increasingly stimulate the cell growth, and suppress the process of apoptosis in pancreatic carcinoma cells.

Objective: To explore diagnosis and surgery therapy and factors influencing the prognosis of tumor of body and tail of the pancreas., Methods: The clinical data of 117 cases of tumor of tail and body of pancreas who underwent operation were analysed., Results: Imaging and tumor marker detection can give exact diagnosis to cases with tumors of body and tail of pancreas. The medial survival time of radical resection, palliative resection and exploratory laparotomy were 18, 8 and 3.5 months., Conclusions: Atypical signs should be noticed, combined imaging and serum detection can diagnose the cases exactly, radical resection is the unique method for long survival, the diameter of the tumor and degree of infiltration to major vessels and organs is important.

Aim: Serum tumour markers carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9) and CA242 were investigated to evaluate the values of single and combined test in the diagnosis and prognosis of pancreatic cancer., Methods: Pre-operative serum CEA, CA19-9 and CA242 were measured in 105 pancreatic cancers, 70 non-pancreatic malignancies and 30 benign pancreatic diseases., Results: The sensitivity of CA19-9 alone was the highest in pancreatic cancer patients (80%), but the specificity was significantly lower than that of CEA and CA242 (P<0.01). The combination of CEA and CA242 could increase the specificity to 92%. In serum CA242 positive patients, the survival time was remarkably shorter than that of patients with negative result (P<0.01). The survival time in patients with more than two markers positive expression of CEA, CA19-9 and CA242 was obviously shorter than that of only one or no marker positive expression (P<0.05)., Conclusion: The diagnostic rate of CA19-9 in pancreatic cancer is better than that of CEA and CA242. Combined detection of CEA and CA242 can improve the diagnostic specificity obviously. High levels of serum markers are associated with advanced stage of the disease. Patients with two or three markers positive expression of CEA, CA19-9, and CA242 simultaneously had a shorter survival time.

Aim: To investigate the expression of annexin I in pancreatic cancer and its relationship with the clinicopathologic factors, and to evaluate its potential clinical significance., Methods: Annexin I expression was analyzed by Western blot and immunohistochemical staining in pancreatic adenocarcinoma and multi-tissue microarrays (MTAs)., Results: Western blot analysis showed that annexin I was overexpressed in 84.6% (11/13) pancreatic ductal adenocarcinomas. Immunohistochemistry analysis of pancreatic cancer in MTAs showed that annexin I protein was 71.4%(30/42) positive which was markedly increased compared with that in the tumor matched normal pancreas tissues 18.4%(7/38) (P<0.01). In the meantime, the high expression of annexin 1 was correlated with the poor differentiation of pancreatic adenocarcinoma., Conclusion: Annexin 1 overexpression is a frequent biological marker and correlates with the differentiation of pancreatic cancer during tumorigenesis.