Risk factors and managements of hemorrhage associated with pancreatic fistula after pancreaticoduodenectomy.

BACKGROUND: Post-pancreaticoduodenectomy pancreatic fistula associated hemorrhage (PPFH) is one of the leading lethal complications. Our study was to analyze the risk factors and managements of hemorrhage associated with pancreatic fistula after pancreaticoduodenectomy, and to evaluate treatment options. METHOD: We analyzed 445 patients who underwent pancreaticoduodenectomy or pylorus-preserving pancreaticoduodenectomy and evaluated the relevance between clinical data and PPFH. RESULTS: The incidence of postoperative pancreatic fistula (POPF) was 27.42% (122/445), and the incidence of PPFH was 4.49% (20/445). Among the 20 patients with PPFH, 7 died and 13 were cured. Interventional angiographic therapy was performed for 10 patients and 5 were successfully treated. Relaparotomy was performed for 5 patients and 2 were successfully cured. Univariate logistic regression analysis indicated that several risk factors were related to PPFH: the nature of tumor (carcinoid/low-grade or high-grade malignancy), preoperative day 1 serum prealbumin, preoperative day 1 total bilirubin (TBIL), operative time, blood loss in the operation, operative method (vascular resection and revascularization), postoperative day 3 TBIL, biliary fistula, and the grade of POPF. The multivariate stepwise logistic regression analysis demonstrated that the nature of tumor and the grade of POPF were independently risk factors of PPFH. Receiver operating characteristic curve indicated that preoperative day 1 serum prealbumin level <173 mg/L and postoperative day 3 TBIL level ≥168 µmol/L were the risk factors of PPFH. CONCLUSIONS: The risk of PPFH was found to be increased with high potential malignancy and high grade of POPF. Angiography-embolization is one of the major and effective therapies for PPFH. Extraluminal-intraluminal PPFH is more serious and needs more aggressive treatments.

Downregulation of ASPP2 in pancreatic cancer cells contributes to increased resistance to gemcitabine through autophagy activation.

BACKGROUND: Apoptosis-stimulating of p53 protein 2 (ASPP2) is one of the ASPP family members and it has been reported to be associated with human cancer. However, the role of it in pancreatic cancer is still not clear. METHODS: We analyzed the expression level of ASPP2 in cancer tissue samples with RT-qPCR, Western Blotting assay and immunohistochemistry staining. We studied the biological function of ASPP2 and its mechanism with gene overexpression and gene silencing technologies. We determined the sensitivity of pancreatic cells with differential ASPP2 level to gemcitabine and whether autophagy inhibition affected the gemcitabine resistance, both in vitro and in vivo. RESULTS: Expression of ASPP2 was downregulated in cancerous tissues in comparison with para-cancerous tissues. ASPP2 expression was linked to clinical outcomes in patients and down-regulation of ASPP2 increased cell proliferation, autophagic flux, the activity of AMP Kinase of pancreatic cancer cells and vice versa. Knockdown of ASPP2 results in increased resistance to gemcitabine, which was attributed to the enhanced autophagy. CONCLUSIONS: ASSP2 expression is lower in cancerous tissues and decreased ASPP2 lead to higher cancer cells proliferation and autophagic flux, which contribute to the gemcitabine resistance.

TSG101 Silencing Suppresses Hepatocellular Carcinoma Cell Growth by Inducing Cell Cycle Arrest and Autophagic Cell Death.

BACKGROUND: The tumor susceptibility gene 101 (TSG101) was originally identified as a tumor-suppressor gene that mediates many molecular and biological processes, such as ubiquitination, endosomal trafficking, cell survival, and virus budding, but its role in hepatocellular carcinoma (HCC) is currently unknown. MATERIAL AND METHODS: We assessed the expression of TSG101 in HCC and paracancerous tissues using qPCR. Then, we used the TSG101-specific siRNA mix to disrupt the expression of TSG101 to investigate the subsequent effect on human hepatoma-7 (Huh7) cells. Western blot was used to detect the protein expression of TSG101 and other molecules. Cell growth assay was performed using CCK8. Transwell assay was used to investigate the migration and invasion ability of Huh7 cells after transfection with of TSG101 siRNA. Flow cytometry was used to estimate the effect of TSG101 knockdown on cell cycle and apoptosis. Confocal laser scanning microscopy was used to observe the actin filaments change and the formation of autophagy. RESULTS: TSG101 was over-expressed in HCC tissues. TSG101 silence was able to suppress Huh7 cell proliferation, migration, and invasion. Furthermore, silencing of TSG101 could induce cell cycle arrest at G1 phase and inhibit the expression of cyclin A and cyclin D, while up-regulating the expression of CDK2. The mechanism might be induction of autophagic cell death and inactivation of Akt and ERK1/2. CONCLUSIONS: TSG101 plays an important role in the development of HCC and may be a target for molecular therapy.

Decreased TIP30 expression predicts poor prognosis in pancreatic cancer patients.

Pancreatic ductal adenocarcinoma (PDAC) is known for its aggressive growth, and is characterized by early tissue invasion and metastasis with poor prognosis. Identifying prognostic markers and delineating the underlying mechanisms that promote progression of PDAC are important for the treatment of pancreatic cancer. TIP30, a newly identified tumor suppressor, appears to be involved in multiple processes during tumor development and metastasis. Here, we investigated the expression of TIP30 in PDAC and its prognostic value in PDAC patients. We examined the expression of TIP30 by immunohistochemistry in tissue microarrays containing 106 surgically resected PDAC. Kaplan-Meier analysis and Cox proportional hazards regression modeling analysis showed that TIP30 expression independently predicted better survival in pancreatectomy patients (p < 0.01). Moreover, decreased TIP30 expression was associated with lymph node metastasis (p < 0.05) and loss of E-cadherin expression (r = 0.329, p < 0.01). Suppression of TIP30 resulted in upregulation of Snail and subsequent downregulation of E-cadherin in SW1990 cells containing high-level of endogenous TIP30. However, in the PANC-1 cells containing low level of endogenous TIP30, suppressing TIP30 caused upregulation of Slug instead of Snail, followed by upregulation of MMP9 rather than E-cadherin. Taken together, our work reveals that decreased TIP30 expression is able to enhance invasion and metastasis of pancreatic cancer cells through upregulation of the Snail family members and may serve as an independent predictor for poor outcomes in PDAC patients.

Downregulation of CPE regulates cell proliferation and chemosensitivity in pancreatic cancer.

Pancreatic cancer (PC) is one of the most common cancers worldwide and a leading cause of cancer-related death. Discovering novel targets is a key for its therapy. Carboxypeptidase E (CPE), a subtype of the pro-protein convertases, has been shown to be upregulated in many types of cancer, yet its function in PC remains elusive. The expressions of CPE in PC cell lines and cancer patients were investigated by Western blot and qRT-PCR. In PC cell line BX-pc-3, CPE was downregulated and its effect on cancer cell proliferation, migration, cisplatin chemosensitivity, and in vivo tumor growth was analyzed by Western blot, proliferation assay, invasion assay, and in vivo transplantation, respectively. The expression of nuclear factor-kappaB (NF-κB), a possible downstream target of CPE was examined by Western blot upon CPE regulation in PC cells, and the effects of inhibiting NF-κB on PC cell invasion and proliferation were examined. CPE was significantly upregulated in PC cell lines and tumor tissues. Proliferation and invasion assays indicated that downregulation of CPE inhibited cancer cell growth and migration and increased chemosensitivity to cisplatin. Inoculation of small interfering RNA (siRNA) transfected BX-pc-3 cells into null mice demonstrated that downregulation of CPE prevented tumor growth in vivo. NF-κB was directly regulated by CPE in pancreatic cancer, and siRNA-mediated inhibition of NF-κB exerted similar anti-tumor effect as downregulating CPE. Taken together, our results demonstrate that CPE plays an important role in pancreatic cancer. Inhibition of CPE may serve as a potential target for PC therapeutics.

[A clinical series of 80 patients with adenosquamous carcinoma of pancreas].

OBJECTIVE: To raise the awareness of adenosquamous carcinoma of pancreas and discuss the treatment of it. METHODS: Clinical data of 80 cases of pancreas adenosquamous carcinoma patients in the Department of Pancreas Surgery of Changhai Hospital of Second Military Medical University from December 2003 to October 2011 were analyzed. The diagnose and treatment methods were discussed. There were 61 male cases and 19 female cases who aged from 28 to 81 years, with an average age of 60 years. The primary symptoms included 46 cases (57.5%) of abdominal malaise, 6 cases (7.5%) of low back pain, 4 cases (5.0%) of abdominal swelling pain with low back pain, 15 cases (18.8%) of abdominal swelling pain with jaundice, 5 cases (6.3%) of painless jaundice, 3 cases (3.8%) of significantly decreased body-weight and 1 case (1.3%) of no symptom. All the patients had been identified as pancreas tumor suffers by ultrasound, enhanced CT scan or MRI. Totally there were 43 cases of head/unciform process tumors, 15 cases of pancreas body tumors and 22 pancreas tail cases.Health situation of all cases were follow-up observed in the outpatient department or telephoned every 3 months till 24 months after the surgery. RESULTS: Among the 80 patients, 19 patients underwent pancreaticoduodenectomy (PD) , 19 patients received pylorus-preserving PD, with 4 cases of palliative resection and 1 case of total pancreatectomy. The volume of bleeding during the surgery varied from 50 to 3 500 ml with a blood transfusion volume varied from 0 to 4 000 ml. Consumed time for PD procedures was 90 to 260 min with 60 to 150 min for body and (or) tail resection with or without lienectomy. The mean diameter of tumor was (4.9 ± 2.2) cm. Pathological tests showed 35 cases of positive lymph nodes, adjacent organ invasion happened in 35 patients, however, nerve invasion were found in 68 cases.Eighteen cases occurred postoperative complications, including bleeding, pancreatic fistula, gastric emptying, incision fat liquefaction and infection, pleural effusion, ascites and nervous diarrhea. There were only 48 effective follow-up patients, with a loss ratio of follow-up by 40.0%, reasons for the loss includes change of contact information, refuse or unable to provide useful information by the relatives of the patients.Sixteen patients received chemotherapy, and 8 patients received radiotherapy after operation. All patients were dead in the effective follow-ups. The postoperative median survival time was 6 months (0.1 to 23.0 months). CONCLUSIONS: Adenosquamous carcinoma of pancreas is a rare kind of malignant tumor, nerve invasion can be found in almost all the cases. Patients with adenosquamous carcinoma of pancreas have an unfavorable prognosis. The principle treatments are surgery, radiotherapy and chemotherapy.

Distal pancreatectomy with en bloc celiac axis resection for the treatment of locally advanced pancreatic body and tail cancer.

BACKGROUND/AIMS: Pancreatic body and tail carcinoma (PBTC) is an aggressive disease with a low resectability rate. Celiac axis infiltration usually contraindicates resection. Extended distal pancreatectomy with combined en bloc celiac axis resection (DP-CAR, also named Appleby operation) was described as a new concept for the curative treatment of these tumors. The aim of this study was to analyze the results of DP-CAR in PBTC. METHODOLOGY: Analyze by summarizing the 24 cases of PBTC during October 2005 to August 2010 in the pancreatic surgery of our hospital and analyzing the clinical manifestations, surgical processing, pathological effects and survival rate of the patients. RESULTS: The postoperative mortality rate was 0%, despite a high morbidity rate (54%). Preoperative intractable abdominal and/or back pain in all the patients was completely alleviated immediately after surgery. During the follow-up survey among all the patients of 2 to 37 months (with an average follow-up survey of 12.67 months), no patient was still alive, with the median survival of 9.25 months. Estimated overall 1- and 3-year survival rates were 46% and 4%, respectively. CONCLUSIONS: DP-CAR offers a high resectability rate without increasing the mortality rate given skilled surgical technique.

The clinical efficacy and safety of modified Miwa's augmented regional pancreatoduodenectomy in the treatment of ductal adenocarcinoma of the pancreas in the uncinate process.

BACKGROUND/AIMS: En bloc resection of a tumor located in the uncinate process of the pancreas is a challenging problem. The aim of this study was to analyze outcomes of modified Miwa's augmented regional pancreatoduodenectomy for patients with pancreatic cancer in the uncinate process involving the root of the mesentery. METHODOLOGY: We analyzed by summarizing the 48 cases of ductal adenocarcinoma in the uncinate process of the pancreas during January 2004 to December 2010 with Miwa's augmented regional pancreatoduodenectomy in our hospital and examined the clinical effect and safety of this procedure. RESULTS: We performed extended pancreaticoduodenectomy combined with isolation of full-length superior mesentery artery (SMA) for 48 patients. Sixteen of the forty-eight patients were combined with PV/SMV resection and reconstruction. There was no operative death and 20 cases developed complications, including mild to severe diarrhea in 17 cases. During follow-up survey among all patients of 6 to 45 months (median 20 months), 9 died of liver metastasis, 10 died of local recurrence, and 5 died of non-tumor causes. The 1-, 2- and 3-year accumulated survival rates were 69.1%, 35.1% and 20.2%, respectively. CONCLUSIONS: Full-length SMA isolation and involved mesentery resection with extended pancreaticoduodenectomy is safe and effective.

Analysis of tumor-induced lymphangiogenesis and lymphatic vessel invasion of pancreatic carcinoma in the peripheral nerve plexus.

Cancer cells can metastasize throughout the body by various mechanisms, including the lymphatic system, resulting in tumor-induced lymphangiogenesis that can profoundly affect patient survival. The aim of the present study was to examine the role of lymphangiogenesis in the metastasis of pancreatic cancer to the peripheral nerve plexus. Immunohistochemistry was performed to analyze specimens obtained from 70 ductal adenocarcinoma patients. The markers used included lymphangiogenic factor vascular endothelial growth factor (VEGF)-C, the lymphatic-specific marker D2-40, and cytokeratin 19, an independent prognostic factor for pancreatic tumors. The relationship between survival rate and invasion of both the lymphatic vessels and peripancreatic nerve plexus (PNP) was evaluated, with clearly elevated lymphatic vessel density (LVD) in tissues adjacent to the cancer tissues. In fact, LVD levels were higher in adjacent tissues than in localized cancer tissues, and lymphatic vessel invasion into tissues adjacent to the tumor was significantly correlated with both PNP invasion (P = 0.005) and lymph node metastasis (P = 0.010). Correspondingly, LVD in tissues adjacent to the tumor was correlated with both invasion of lymphatic vessels surrounding the tumor (P = 0.024) and VEGF-C expression (P = 0.031); in addition, VEGF-C expression was correlated with invasion of lymphatic vessels around the tumor (P = 0.004). Survival rates were significantly lower in patients in whom there was peritumor lymphatic vessel invasion (P < 0.001), extrapancreatic nerve plexus invasion (P = 0.001), and/or lymph node metastasis (P < 0.001). Based on these results, lymphatic invasion associated with adjacent tumor growth likely contributes to the development of metastatic tumors that invade the PNP.

Systemic therapy and perioperative management improve the prognosis of pancreatic ductal adenocarcinoma: A retrospective cohort study of 2000 consecutive cases.

OBJECTIVE: This study aimed to explore patterns of the treatment strategies of pancreatic ductal adenocarcinoma based on 2000 consecutive cases of a prospective database since 2012 to obtain new insights for future directions. METHODS: Among 2000 patients enrolled in this study, 210 patients were excluded, and 710, 521, and 559 patients were treated between 2012 and 2015 (group 1), between 2016 and 2017 (group 2), and between 2018 and 2019 (group 3), respectively. Patient clinicopathologic and biological factors, and perioperative outcomes were used to assess the prognostic factors. RESULTS: The median survival for all patients with pancreatic ductal adenocarcinoma was 21.7 months (1-year survival, 75.0%; 2-year survival, 43.7%; 5-year survival, 19.7%). Group 3 had a better survival outcome than groups 1 and 2 (median survival time: 23 versus 20.5 and 21.1 months). The proportion of patients younger than 65 gradually increased over time, as did the use of systemic chemotherapy and postoperative adjuvant radiotherapy. The tendency for early diagnosis (lower CA19-9 and CEA levels, smaller size, and earlier N stage), use of chemotherapy and radiotherapy, early recovery (lesser hospital stay and Clavien-Dindo grade <3), absence of abdominal pain, younger age, length of operation ≤3 h, and pathological factors (absence of lymphovascular invasion, peripancreatic fat infiltration and neural invasion, higher differentiation) were related to patients' survival. Multivariable analysis for prognosis revealed that tumor biological factors (increased preoperative serum CA19-9 level, tumor size, tumor differentiation, N stage, and presence of lymphovascular invasion and neural invasion), chemotherapy, radiotherapy, abdomen pain, operation period, length of stay, and length of operation correlated with patients' survival. CONCLUSIONS: Systemic therapy, including chemotherapy and radiotherapy, has gradually improved the prognosis after operative resection for pancreatic ductal adenocarcinoma. Neoadjuvant therapy is also beneficial to improve the prognosis to a certain extent. The enhanced recovery after surgery (ERAS) policies and the specific assessment of postoperative pancreatic fistula (POPF) risk may be related to reduced hospital stays and the reduction of serious complications. These advancements show that the concept of systemic therapy has been accepted and actively applied by Chinese medical institutions.

Nomogram predicts CR-POPF in open central pancreatectomy patients with benign or low-grade malignant pancreatic neoplasms.

Introduction: Central pancreatectomy (CP) is a standard surgical procedure for benign and low-grade malignant pancreatic neoplasms in the body and neck of the pancreas. Higher incidence of clinically relevant postoperative pancreatic fistula (CR-POPF) after CP than after pancreaticoduodenectomy (PD) or distal pancreatectomy (DP) has been reported, but no nomogram for prediction of CR-POPF after open CP has been previously established. Methods: Patients undergoing open CP for benign or low-grade malignant pancreatic neoplasms in the department of Hepatobiliary and Pancreatic (HBP) surgery of Shanghai Changhai Hospital affiliated to Naval Medical University between January 01, 2009 and December 31,2020 were enrolled. Pre-, intra- and post-operative parameters were analyzed retrospectively. Results: A total of 194 patients, including 60 men and 134 women, were enrolled with median age of 52 years (21~85 years). 84 patients (43.3%) were overweight (BMI>23.0 Kg/m2) and 14 (7.2%) were obese (BMI>28.0 Kg/m2). Pathological diagnoses ranged from serous cystic neoplasm (32.5%), solid pseudopapillary neoplasm (22.2%), pancreatic neuroendocrine tumor (20.1%), intraductal papillary mucinous neoplasm (18.0%) to mucinous cystic neoplasm (5.2%). All patients had soft pancreatic texture. Main pancreatic duct diameters were ≤0.3cm for 158 patients (81.4%) and were ≥0.5cm in only 12 patients (6.2%). A stapler (57.7%) or hand-sewn closure (42.3%) were used to close the pancreatic remnant. The pancreatic anastomosis techniques used were duct to mucosa pancreaticojejunostomy (PJ)-interrupted suture (47.4%), duct to mucosa PJ-continuous suture (43.3%), duct to mucosa "HO" half-purse binding PJ (5.2%) and invaginating pancreaticogastrostomy (4.1%). Post-surgical incidences of CR-POPF of 45.9%, surgical site infection of 28.9%, postpancreatectomy hemorrhage of 7.7% and delayed gastric emptying of 2.1% were found. Obesity and pancreatic anastomosis technique were independent risk factors of CR-POPF, with a concordance index of 0.675 and an Area Under the Curve of 0.678. Discussion: This novel nomogram constructed according to obesity and pancreatic anastomosis technique showed moderate predictive performance of CR-POPF after open CP.

Incidence of bifid pancreatic duct in pancreaticoduodenectomy and its impact on clinically relevant postoperative pancreatic fistula.

Objectives: This study aimed to examine the incidence of bifid pancreatic duct (BPD) in pancreaticoduodenectomy (PD) and clarify its impact on clinically relevant postoperative pancreatic fistula (CR-POPF). Background: Until now, all the literature about BPD during PD are published as case reports, and the incidence of BPD in PD and its impact on CR-POPF remain unknown. Results: A total of 438 consecutive PDs were divided into two groups: the former year group and the latter year group. The former year group included 215 consecutive PDs, while the latter year group included 223. In the latter year group, we found 16 BPDs during PD (O-BPD); the incidence of O-BPD is 7.17%. Of them, there were eight patients who had BPD in the preoperative imaging (I-BPD). All the I-BPDs are O-BPDs; which means that 50% of O-BPDs were a single pancreatic duct in the preoperative imaging (I-SPD). There were 17 I-BPDs in the 438 consecutive PDs; the incidence of I-BPD is 3.88%. In the former year group, the rate of severe complications of I-BPD and I-SPD is 77.78% and 27.18%, respectively (p = 0.003); the rate of CR-POPF of I-BPD is higher than I-SPD, 55.56% vs. 27.18%, but there were no statistically significant differences. In the latter year group, the rate of severe complications of O-BPD and O-SPD is 50% and 18.36%, and the rate of CR-POPF of O-BPD and O-SPD is 37.5% and 22.22%, respectively; both of them have statistically significant differences, and the p-value is 0.003 and 0.006, respectively. In the subgroup analysis, both the rate of severe complications and the rate of CR-POPF of I-BPD were higher than O-BPD, 77.78% vs. 50%, and 55.56% vs. 37.5%, but there were no statistically significant differences in both of them; the p-value is 0.174 and 0.434, respectively. Univariate and multivariate analyses showed that BPD was an independent risk factor of CR-POPF. Conclusions: The incidence of O-BPD in PD is 7.17%, 50% of O-BPDs were I-SPD, and the incidence of I-BPD is 3.88%. BPD is an independent risk factor of CR-POPF. The suture closure method may be a simple, safe, and effective method in dealing with BPD in PD.

Downregulation of miR-132 by promoter methylation contributes to pancreatic cancer development.

MicroRNAs (miRNAs), which regulate gene expression by partial complementarity to the 3' untranslated region of their target genes, have been implicated in cancer initiation and progression. However, the molecular mechanism underlying the regulation of miRNA expression during pancreatic tumorigenesis has not been extensively reported. In this study, we first compared the miRNA expression in human pancreatic cancers and adjacent normal tissues by miRNA array and identified 12 differentially expressed miRNAs. miR-132, which is downregulated in tumors, was further studied in greater detail. Decreased expression of miR-132 was confirmed in 16 of 20 pancreatic carcinomas (P < 0.0001), compared with their respective benign tissues by TaqMan miRNA assays. miR-132 expression was remarkably influenced by promoter methylation in PANC1 and SW1990 cells. Promoter hypermethylation was observed in tumor samples but not in the normal counterparts, and the expression of miR-132 negatively correlated with its methylation status (P = 0.013). miR-132 was transcribed by RNA polymerase II, and Sp1 played a major role in miR-132 transcription. The expression of Sp1 correlated with that of miR-132 in tissues. Moreover, cancerous tissues showed significantly lower Sp1-binding affinity to the miR-132 promoter, relative to non-tumor samples. Proliferation and colony formation of pancreatic cancer cells were suppressed in cells transfected with miR-132 mimics and enhanced in cells transfected with miR-132 inhibitor by negatively regulating the Akt-signaling pathway. Our present findings illustrate the mechanism driving miR-132 downregulation and the important role of miR-132 in pancreatic cancer development.

MicroRNA 421 suppresses DPC4/Smad4 in pancreatic cancer.

MicroRNAs (miRNAs) have emerged as important regulators in the development of pancreatic cancer and may be a valuable therapeutic application. DPC4/Smad4 is a critical tumor suppressor involved in the progression of pancreatic cancer, but few studies have been conducted to determine its relationship with miRNAs. In this study, we identify miR-421 as a potential regulator of DPC4/Smad4. We find that in human clinical specimens of pancreatic cancer miR-421 is aberrantly upregulated while DPC4/Smad4 is strongly repressed, and their levels of expression are inversely correlated. Moreover, ectopic expression of miR-421 significantly decreases DPC4/Smad4 protein level in pancreatic cancer cell lines and simultaneously promotes cell proliferation and colony formation in vitro. Our findings identify miR-421 as a potent regulator of DPC4/Smad4, which may provide a novel therapeutic strategy for treatment of DPC4/Smad4-driven pancreatic cancer.

MiR-499a-5p promotes 5-FU resistance and the cell proliferation and migration through activating PI3K/Akt signaling by targeting PTEN in pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) can be considered a representative cancer type of the human body. As demonstrated by some studies, microRNA (miR)-499 is dysregulated in various cancer types including PC, for which chemotherapy involving 5-fluorouracil (5-FU) has long been considered the first-line therapy. However, there are complex and comprehensive mechanisms related to 5-FU, which have not been fully elucidated. This study thus aimed to examine the molecular mechanisms of 5-FU resistance through miR-499a-5p in PC. METHODS: The expression of miR-499a-5p in PC was measured using quantitative polymerase chain reaction (PCR). MiR-499a-5p was examined in-vivo for its effects on the malignant phenotypes of PC cells. RESULTS: The results of the present study demonstrated miR-499a-5p to be upregulated in PC and 5-FU resistant PC tissues. According to in vitro assays in PC cells (PANC1/FR), miR-499a-5p was found to affect adenosine triphosphate (ATP) binding cassette subfamily B member 1 (P-gp), ATP binding cassette subfamily C member 1 (MRP1), and ATP binding cassette subfamily G member 2 (BCRP), thereby facilitating 5-FU resistance in PC cells. Functions assays indicated that suppressed miR-499a-5p expression inhibited the proliferation and migration of cells but facilitated apoptosis in the PC cell line; by contrast, miR-499a-5p overexpression triggered the inverse phenotypic changes of cells. Concerning the mechanisms involved, miR-499a-5p increased PI3K/Akt signaling by targeting phosphatase and tensin homolog (PTEN). CONCLUSIONS: Taken together, these findings demonstrate that miR-499a-5p can be potentially applied to PC therapy.

Radical antegrade modular pancreatosplenectomy versus standard distal pancreatosplenectomy for pancreatic cancer, a dual-institutional analysis.

BACKGROUND: Radical antegrade modular pancreatosplenectomy (RAMPS) has been adopted by some surgeons in the treatment of left-sided pancreatic cancer (PDAC). Low disease incidence and heterogenous disease biology make robust prospective comparison of RAMPS and standard distal pancreatosplenectomy (DPS) difficult. METHODS: Consecutive cases of chemo-naïve patients undergoing open RAMPS and DPS for PDAC between 2010-2017 at two international high-volume pancreatectomy centers were compared. Cox proportional hazard modeling was utilized for multivariate analysis. RESULTS: We identified 193 DPS and 253 RAMPS during the study period. DPS was associated with higher rates of median estimated blood loss (500 vs. 300 cc, P<0.001), median total harvested lymph nodes (18 vs. 12, P<0.001) and R0 resection (94.3% vs. 88.9%, P=0.013). There were no differences in rates of postoperative pancreatic fistula (16.5% vs. 17.8%, P=1) or postoperative hemorrhage (5.9% vs. 3.6%, P=0.385) (DPS vs. RAMPS). After controlling for significant clinical pathological parameters, RAMPS was associated with non-superior recurrence-free survival (RFS) (HR 0.29; 95% CI, 0.07-1.27, P=0.101) and overall-survival (HR 1.03; 95% CI, 0.71-1.49, P=0.895) compared with DPS. Similar results were observed in node-positive patients. CONCLUSIONS: RAMPS is safe and effective in the treatment of PDAC, but is not associated with an improvement in either RFS or overall-survival over DPS.

[The role of full length superior mesenteric artery isolation in extended pancreaticoduodenectomy in the treatment of ductal adenocarcinoma of the pancreas in the uncinate process].

OBJECTIVE: To improve the prognosis and safety of extended pancreaticoduodenectomy for patients with pancreatic cancer in the uncinate process of pancreas. METHODS: From January 2004 to March 2008, 26 extended pancreaticoduodenectomies with full length superior mesenteric artery (SMA) isolation and mesentery root resection were performed for the ductal adenocarcinomas in the uncinate process of pancreas. There were 16 males and 10 females aging from 30 to 75 years old [medium age (55.0 +/- 13.0) years old]. Eleven of 26 patients were combined with portal vein-superior mesenteric vein resection. The effect and safety of this procedure were analyzed retrospectively. RESULTS: There was no operative mortality in all patients. The pathological examination showed that all the incisal margins were negative. After a follow-up of 7 to 45 months, the pain relief was occurred in all patients. The 1-year, 2-year accumulated survival rates were 72.2%, and 48.1%, respectively. CONCLUSIONS: Full length SMA isolation and the mesentery resection in extended pancreaticoduodenectomy are safe and effective. The procedure is also benefit for the patients in improving the survival rate and quality of life.

Long non-coding RNA CUDR promotes malignant phenotypes in pancreatic ductal adenocarcinoma via activating AKT and ERK signaling pathways.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with a marked potential for invasion and metastasis. Emerging evidence has suggested that dysregulation of long non-coding RNAs (lncRNAs) is associated with the development of multiple types of cancer. However, the function of lncRNAs in PDAC is poorly known. In the present study, a microarray assay was used to screen for differently expressed lncRNAs in PDAC and it was identified that cancer upregulated drug resistance (CUDR) was upregulated in PDAC. CUDR increased PDAC cell proliferation, migration and invasion, inhibited apoptosis, and promoted drug resistance; it also regulated the PDAC cell epithelial-mesenchymal transition. The CUDR-induced PDAC malignant phenotypes is via the protein kinase B and extracellular-signal-regulated kinase signaling pathways. Downregulation of CUDR may be a novel therapeutic strategy to prevent PDAC development and drug resistance in the future.

Primary pancreatic lymphoma: report of six cases.

AIM: To heighten recognition of primary pancreatic lymphoma (PPL) in clinical practice. METHODS: A retrospective review of the clinical presentation, imaging characteristics and pathological features of PPL patients were presented, as well as their diagnosis and treatment, in combination with literature review. RESULTS: Histological diagnosis was made in four patients by surgery and in two patients by EUS-FNA. The six PPL patients (5 males and 1 female; age range, 16-65 years; mean age, 46 years) had the duration of symptoms for two weeks to three months. The primary presenting symptoms, though not characteristic, were abdominal pain, abdominal masses, weight loss, jaundice, nausea and vomiting. One of the patients developed acute pancreatitis. In one patient, the level of serum CA19-9 was 76.3 microg/L. Abdominal CT scan showed that three of the six tumors were located in the head of pancreas, two in the body and tail, and one throughout the pancreas. Diameter of the tumors in the pancreas in four cases was more than 6 cm, with homogeneous density and unclear borders. Enhanced CT scan showed that only the tumor edges were slightly enhanced. The pancreatic duct was irregularly narrowed in two cases whose tumors were located in the pancreatic head and body, in which endoscopic retrograde cholangiopancreatography (ERCP) showed that the proximal segment was slightly dilated. Two patients underwent Whipple operation, one patient underwent pancreatectomy, and another patient underwent operative biliary decompression. PPL was in stage I E in 2 patients and in stage II E in 4 patients according to the Ann Arbor classification system. The diagnosis of B-cell non-Hodgkin's lymphoma was made in all patients histopathologically. All six patients underwent systemic chemotherapy, one of whom was also treated with gamma radiometry. One patient died two weeks after diagnosis, two patients lost follow-up, two patients who received chemotherapy survived 49 and 37 mo, and the remaining patient is still alive 21 mo, after diagnosis and treatment. CONCLUSION: PPL is a rare form of extranodal lymphoma originating from the pancreatic parenchyma. Clinical and imaging findings are otherwise not specific in the differentiation of pancreatic lymphoma and pancreatic cancer, which deserves attention. EUS-guided fine-needle aspiration (EUS-FNA) of the pancreas requires experienced cytopathologists as well as advanced immunohistochemical assays to obtain a final diagnosis on a small amount of tissue. Surgery and adjuvant chemotherapy or radiotherapy can produce fairly good outcomes.

Interplay between menin and Dnmt1 reversibly regulates pancreatic cancer cell growth downstream of the Hedgehog signaling pathway.

Menin, the product of the Men1 gene, which is frequently mutated in pancreatic neuroendocrine tumors, acts as a chromatin-remodeling factor to modulate the transcription of cell cycle regulators by interacting with histone modification factors. However, the function of menin and its underlying mechanisms in pancreatic ductal adenocarcinoma remain unknown. Here, we found that menin inhibited pancreatic cancer cell growth in vitro and in vivo and that its expression was gradually lost during pancreatic carcinogenesis. Menin overexpression significantly activated the expression of the cyclin-dependent kinase (CDK) inhibitors p18 and p27, accompanied with a decrease in DNA methylation levels of p18 and p27 promoters. Mechanistically, we found that interaction of menin with DNA methyltransferase 1 (Dnmt1) competitively pulled down Dnmt1 from p18 and p27 promoters, leading to the downregulation of DNA methylation levels. Moreover, menin expression was suppressed by Dnmt1 downstream of the Hedgehog signaling pathway, and menin overexpression strongly antagonized the promotion effect of hedgehog signaling on pancreatic cancer cell proliferation. Taken together, the interaction between menin and Dnmt1 reversibly regulates pancreatic cancer cell growth downstream of Hedgehog pathways with complex mutual modulation networks, suggesting that the Hedgehog/Dnmt1/menin axis is a potential molecular target for pancreatic cancer therapy.