Stent placement for the prevention of clinically-relevant postoperative pancreatic fistula following pancreaticojejunostomy: A systematic review and meta-analysis.

OBJECTIVES: There remains a lack of consensus regarding the benefits of stent placement following pancreaticojejunostomy in terms of clinically relevant postoperative pancreatic fistulas (CR-POPFs). This study was aimed at analyzing the effects of stent placement, stent technique (internal and external), stent size, and dilation of the main pancreatic duct on CR-POPFs. METHODS: Our study comprised a systematic review and meta-analysis of randomized controlled trials involving patients undergoing pancreaticojejunostomy. The primary outcome was defined as the incidence of CR-POPFs. Additionally, subgroup analyses were conducted, and pooled analyses were performed to provide comparative references. RESULTS: Twelve randomized controlled trials, including a total of 1117 patients, were included. Compared with no stent placement, stenting did not exhibit a significant association with reduced CR-POPF incidence (odds ratio [OR] â€‹= â€‹0.60, 95% CI: 0.34-1.04, P â€‹= â€‹0.07). Subgroup analysis revealed that only external stents, and not internal stents, were significantly associated with a reduced CR-POPF incidence compared with no stent placement (OR â€‹= â€‹0.53, 95% CI: 0.28-0.99, P â€‹= â€‹0.05 vs. OR â€‹= â€‹0.92, 95% CI: 0.28-3.05, P â€‹= â€‹0.89). Furthermore, stent placement in patients with a main pancreatic duct diameter of ≤3 â€‹mm, and not in those with a main pancreatic duct diameter of >3 â€‹mm, was associated with a significantly reduced CR-POPF incidence compared with no stent placement (OR â€‹= â€‹0.24, 95% CI: 0.07-0.78, P â€‹= â€‹0.02 vs. OR â€‹= â€‹1.58, 95% CI: 0.41-6.06, P â€‹= â€‹0.50). CONCLUSIONS: The findings suggest a potential role for external stent placement in the prevention of CR-POPFs after pancreaticojejunostomy, particularly in patients with undilated pancreatic ducts. The reliability of our findings is constrained by the limited number of studies included. PROSPERO REGISTRATION NUMBER: CRD42022380103.

Preoperative pancreatic stent placement before the enucleation of insulinoma located in the head and neck of the pancreas in proximity to the main pancreatic duct: study protocol for a multicentre randomised clinical trial in Chinese tertiary medical centres.

INTRODUCTION: The surgical intervention approach to insulinomas in proximity to the main pancreatic duct remains controversial. Standard pancreatic resection is recommended by several guidelines; however, enucleation (EN) still attracts surgeons with less risk of late exocrine/endocrine insufficiency, despite a higher postoperative pancreatic fistula (POPF) rate. Recently, the efficacy and safety of preoperative pancreatic stent placement before the EN have been demonstrated. Thus, a multicentre open-label study is being conducted to evaluate the efficacy and safety of stent placement in improving the outcome of EN of insulinomas in proximity to the main pancreatic duct. METHODS AND ANALYSIS: This is a prospective, randomised, open-label, superiority clinical trial conducted at multiple tertiary centres in China. The major eligibility criterion is the presence of insulinoma located in the head and neck of the pancreas in proximity (≤2 mm) to the main pancreatic duct. Blocked randomisation will be performed to allocate patients into the stent EN group and the direct EN group. Patients in the stent EN group will go through stent placement by the endoscopist within 24 hours before the EN surgery, whereas other patients will receive EN surgery directly. The primary outcome is the assessment of the superiority of stent placement in reducing POPF rate measured by the International Study Group of Pancreatic Surgery standard. Both interventions will be performed in an inpatient setting and regular follow-up will be performed. The primary outcome (POPF rate) will be tested for superiority with the Χ2 test. The difference in secondary outcomes between the two groups will be analysed using appropriate tests. ETHICS AND DISSEMINATION: The study has been approved by the Peking Union Medical College Hospital Institutional Review Board (K23C0195), Ruijin Hospital Ethics Committee (2023-314), Peking University First Hospital Ethics Committee (2024033-001), Institutional Review Board of Xuanwu Hospital of Capital Medical University (2023223-002), Ethics Committee of the First Affiliated Hospital of Xi'an Jiaotong University (XJTU1AF2023LSK-473), Institutional Review Board of Tongji Medical College Tongji Hospital (TJ-IRB202402059), Ethics Committee of Tongji Medical College Union Hospital (2023-0929) and Shanghai Cancer Center Institutional Review Board (2309282-16). The results of the study will be published in an international peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05523778.

Laparoscopic necrosectomy for acute necrotizing pancreatitis: mesocolon-preserving approach and outcomes.

The surgical treatment of acute necrotizing pancreatitis has significantly evolved in recent years with the advent of enhanced imaging techniques and minimally invasive surgery. Various minimally invasive techniques, such as video-assisted retroperitoneal debridement (VARD) and endoscopic transmural necrosectomy (ETN), have been employed in the management of acute necrotizing pancreatitis and are often part of step-up approaches. However, almost all reported step-up approaches only employ a fixed minimally invasive technique prior to open surgery. In contrast, we implemented different minimally invasive techniques during the treatment of acute pancreatitis based on the extent of pancreatic necrosis. For acute necrotizing pancreatitis of the pancreatic bed with or without extension into the left retroperitoneum, we performed mesocolon-preserving laparoscopic necrosectomy for debridment. The quantitative indication for pancreatic debridment in our institute has been described previously. For acute necrotizing pancreatitis of the pancreatic bed with or without extension into the left retroperitoneum, mesocolon-preserving laparoscopic necrosectomy was performed for debridment. To safeguard the mesocolon, the pancreatic bed was entered via the gastrocolic ligament, and the left retroperitoneum was accessed via the lateral peritoneal attachments of the descending colon. Of the 77 patients requiring pancreatic debridment, 41 patients were deemed suitable for mesocolon-preserving laparoscopic necrosectomy by multiple disciplinary team and informed consent was acquired. Of these 41 patients, 27 underwent percutaneous drainage, 10 underwent transluminal drainage, and 2 underwent transluminal necrosectomy prior to laparoscopic necrosectomy. Two patients (4.88%) died of sepsis, three patients (7.32%) required further laparotomic necrosectomy, and five patients (12.20%) required additional percutaneous drainage for residual infection. Three patients (7.32%) experienced duodenal fistula, all of which were cured through non-surgical treatments. Nineteen patients (46.34%) developed pancreatic fistula that persisted for over 3 weeks, with 17 being successfully treated non-surgically. The remaining two patients had pancreatic fistulas that lasted over 3 months; an internal drainage procedure has been planned for them. No patient developed colonic fistula. Mesocolon-preserving laparoscopic necrosectomy proved to be safe and effective in selected patients. It can serve as a supplementary procedure for step-up approaches or as an alternative to other debridment procedures such as VARD, ETN, and laparotomic necrosectomy.

Metagenomic next-generation sequencing, instead of procalcitonin, could guide antibiotic usage in patients with febrile acute necrotizing pancreatitis: a multicenter, prospective cohort study.

BACKGROUNDS: The effectiveness of procalcitonin-based algorithms in guiding antibiotic usage for febrile acute necrotizing pancreatitis (ANP) remains controversial. Metagenomic next-generation sequencing (mNGS) has been applied to diagnose infectious diseases. The authors aimed to evaluate the effectiveness of blood mNGS in guiding antibiotic stewardship for febrile ANP. MATERIALS AND METHODS: The prospective multicenter clinical trial was conducted at seven hospitals in China. Blood samples were collected during fever (T ≥38.5°C) from ANP patients. The effectiveness of blood mNGS, procalcitonin, and blood culture in diagnosing pancreatic infection was evaluated and compared. Additionally, the real-world utilization of antibiotics and the potential mNGS-guided antimicrobial strategy in febrile ANP were also analyzed. RESULTS: From May 2023 to October 2023, a total of 78 patients with febrile ANP were enrolled and 30 patients (38.5%) were confirmed infected pancreatic necrosis (IPN). Compared with procalcitonin and blood culture, mNGS showed a significantly higher sensitivity rate (86.7% vs. 56.7% vs. 26.7%, P <0.001). Moreover, mNGS outperformed procalcitonin (89.5 vs. 61.4%, P <0.01) and blood culture (89.5 vs. 69.0%, P <0.01) in terms of negative predictive value. Blood mNGS exhibited the highest accuracy (85.7%) in diagnosing IPN and sterile pancreatic necrosis, significantly superior to both procalcitonin (65.7%) and blood culture (61.4%). In the multivariate analysis, positive blood mNGS (OR=60.2, P <0.001) and lower fibrinogen level (OR=2.0, P <0.05) were identified as independent predictors associated with IPN, whereas procalcitonin was not associated with IPN, but with increased mortality (Odds ratio=11.7, P =0.006). Overall, the rate of correct use of antibiotics in the cohort was only 18.6% (13/70) and would be improved to 81.4% (57/70) if adjusted according to the mNGS results. CONCLUSION: Blood mNGS represents important progress in the early diagnosis of IPN, with particular importance in guiding antibiotic usage for patients with febrile ANP.

USP8 promotes gemcitabine resistance of pancreatic cancer via deubiquitinating and stabilizing Nrf2.

Gemcitabine (Gem) is the first-line chemotherapy drug for pancreatic cancer, but the acquired chemoresistance also hinders its application. Therefore, research about Gem resistance plays a crucial role in enhancing the therapeutic effect of Gem. As a deubiquitinating enzyme, ubiquitin-specific protease 8 (USP8) was shown to play vital roles in the tumorigenesis processes of several cancers; however, the effect of USP8 on Gem resistance of pancreatic cancer still remains largely unknown. In the current study, we observed that the expression of USP8 was increased in pancreatic cancer patients, it is related to the recurrence of Gem chemotherapy, and USP8 expression could be induced by Gem application. Furthermore, USP8 was found to promote Gem resistance both in vivo and in vitro via regulating cell viability and apoptosis. Moreover, USP8 enhanced the activation of Nrf2 signaling which is dependent on its deubiquitinase ability. At last, we illustrated that USP8 interacted with Nrf2 directly and deubiquitinated K48-linked polyubiquitin chains from Nrf2, stabilizing the expression of Nrf2. In summary, the manuscript revealed the role of USP8 in Gem chemoresistance and suggested USP8 as a potential therapeutic target for pancreatic cancer.

miR-222-3p-containing macrophage-derived extracellular vesicles confer gemcitabine resistance via TSC1-mediated mTOR/AKT/PI3K pathway in pancreatic cancer.

Gemcitabine resistance limits the efficacy of chemotherapy and maintains a challenge for treatment outcomes. Therefore, we aimed to clarify the downstream mechanisms underlying the role of miR-222-3p delivered by M2 macrophage-derived extracellular vesicles (M2 MDEs) in the chemoresistance of pancreatic cancer (PCa). We separated the mouse macrophages and polarized them to M2 phenotypes, from which the EVs were derived. miR-222-3p was highly expressed in M2 MDEs. M2 MDEs were internalized by PCa cells. miR-222-3p overexpressing M2 MDEs were treated with gemcitabine and co-cultured with PCa cells for in vitro experiments. Co-culture with M2 MDEs enriched with miR-222-3p suppressed the sensitivity to gemcitabine, accompanied by diminished apoptosis and promoted proliferation. Furthermore, the M2 MDEs and PCa cells were injected to mice with gemcitabine exposure for in vivo substantiation. The delivery of miR-222-3p inhibitor by M2 MDEs suppressed tumor growth and elevated sensitivity of cancer cells to gemcitabine. Moreover, miR-222-3p was indicated to target and suppress TSC1 expression, while miR-222-3p activated the PI3K/AKT/mTOR pathway. Together, miR-222-3p-containing M2 MDEs enhance chemoresistance in PCa through TSC1 inhibition and activation of the PI3K/AKT/mTOR pathway.

Tumor Cell Derived Exosomal GOT1 Suppresses Tumor Cell Ferroptosis to Accelerate Pancreatic Cancer Progression by Activating Nrf2/HO-1 Axis via Upregulating CCR2 Expression.

Recently, evidence has shown that GOT1 expression is upregulated in pancreatic cancer tissues and promotes cancer development, but the specific mechanism remains unclear. We found that GOT1 expression was upregulated in pancreatic cancer cell-derived exosomes. When PANC-1 cells were incubated with exosomes alone or transfected together with si-GOT1, we found that exosomes enhanced cell proliferation, invasion and migration, promoted ferroptosis, and si-GOT1 reversed the effects of exosomes. The results of online bioinformatics database analysis indicated that CCR2 was a potential binding protein of GOT1 and is highly expressed in pancreatic cancer tissues. PANC-1 cells were transfected with pcDNA-CCR2 or si-CCR2, and it was found that pcDNA-CCR2 enhanced cell proliferation, invasion and migration, promoted ferroptosis, and si-CCR2 had an opposite effect. Next, exosome-treated cells were transfected with si-GOT1 alone or together with pcDNA-CCR2, and we found that exosomes promoted CCR2 expression, promoted cell proliferation and invasion, and inhibited ferroptosis, the transfection of si-GOT1 abolished the effect of exosomes, and the transfection of pcDNA-CCR2 again reversed the effect of si-GOT1. Furthermore, when exosome-treated cells were transfected with si-GOT1 alone or co-incubated with Nrf2 activator NK-252, we found that si-GOT1 reversed the promoting effect of exosomes on Nrf2 and HO-1 expression, as well as its inhibitory effect on ferroptosis, but this effect was abrogated by NK-252. In vivo studies showed that knockdown of GOT1 expression inhibited tumor formation compared with tumor tissues formed upon exosome induction, which was mediated by promoting ferroptosis via suppressing the protein expression of GOT1, CCR2, Nrf2 and HO-1 in tumor tissues.

Active drain system with reticulated open-pore foam-surface dressing for postoperative pancreatic fistula in a rat model.

BACKGROUND: Postoperative pancreatic fistula (POPF) is one of the most harmful complications after pancreatic resection. Efficient drainage affects the clinical outcome of POPF. Inefficient drain of the fluid collection should contribute greatly to the need of additional interventional drainage, secondary morbid complications, and death. METHODS: A rat model of POPF was established by distal pancreatosplenectomy. A novel active drain system (ADS) for POPF was developed by wrapping polyvinyl alcohol sponges (PVA) to an end of the drainage tube. Passive drain system (PDS), ADS and ADS with PVA were used for POPF in rat models. The volume and amylase of ascites were measured. CT scan was applied to assess abdominal fluid collection. Rats pancreatic transection stumps were stained by hematoxylin and eosin (H&E). RESULTS: The volume of drainage of ADS with PVA group was less than that of PDS group and ADS group at late stage. CT scan showed obvious abdominal fluid collections in 2/8, 2/8 and 0/8 rats in PDS, ADS and ADS with PVA group separately. Macrofindings showed significant intra-abdominal adhesions and inflammation in PDS and ADS group but not in ADS with PVA group. H&E staining showed less inflammatory cells and destroyed pancreatic glands in ADS with PVA group. CONCLUSION: ADS with PVA drained ascites effectively in the rat model of POPF. The effective drainage of pancreatic juice reduced the inflammation of abdominal organs and pancreatic resection stumps, and might promote the healing of POPF.

Prognostic Analysis of Different Metastatic Patterns in Invasive Intraductal Papillary Mucinous Neoplasm: A Surveillance, Epidemiology, and End Results Database Analysis.

Objective: To evaluate the impacts of different metastatic patterns on the prognosis of patients with invasive intraductal papillary mucinous neoplasm (IPMN). Materials and Methods: All patients who were diagnosed with invasive IPMN in the Surveillance, Epidemiology, and End Results SEER database (2010-2015) were included in this study. They were grouped according to different metastatic patterns. Kaplan-Meier analysis and log-rank test were used for the comparison of their survival rates. The hazard ratio (HR) with 95% confidence interval (CI) was analyzed using the Cox proportional-hazards model. Results: A total of 2264 cases were included in this study. The most common metastatic site was the liver. The patients with the nonorgan metastasis demonstrated the best survival outcomes, while those with multiple metastases showed the worst survival outcomes. As compared to the patients with isolated liver metastasis, those with isolated lung and other organ metastases showed better overall survival rates and tumor-specific survival rates. The patients with liver, lung, multiple, and other organ metastases or of age >60 years were the independent predictors of poor prognosis. Conclusions: The patients with isolated lung and other organ metastases demonstrated better survival outcomes as compared to those with isolated liver metastasis. The patients with nonorgan metastasis demonstrated the best survival outcomes, while those with multiple metastases showed the worst survival outcomes. Further studies are needed to determine a highly selected subset of patients, who might benefit from surgery or chemotherapy.

Overexpression of YBX1 Promotes Pancreatic Ductal Adenocarcinoma Growth via the GSK3B/Cyclin D1/Cyclin E1 Pathway.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers due to frequently late diagnosis and futile treatment. It is a crucial necessity to determine the mechanisms of PDAC. Y-box Binding Protein 1 (YBX1), a highly conserved transcription factor, has been previously reported to play a role in various hallmarks of cancer. We show here that YBX1 is significantly overexpressed in PDAC and correlates with poor prognosis and reduced survival. In PDAC cell lines, YBX1 regulated cell-cycle progression, proliferation, and the expression of glycogen synthase kinase 3 beta (GSK3B) and cell-cycle-related proteins cyclin D1 and E1. Dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays established that YBX1 binds to the promoter of GSK3B, suggesting that YBX1 promotes pancreatic cancer cell growth through induction of GSK3B expression. These findings offer important insights into the mechanisms underlying pathologic proliferation in PDAC.

A Population-Based Study of the Incidence and Survival of Anorectal Gastrointestinal Stromal Tumor.

BACKGROUND Gastrointestinal stromal tumor (GIST) is the most common type of primary gastrointestinal mesenchymal tumor, but GISTs arising in the anus and rectum are rare. This study aimed to undertake a population-based analysis of the incidence, patient demographics, and survival of patients with anorectal GIST compared with patients with GIST arising from other sites based on the Surveillance, Epidemiology, and End Results (SEER) Program database. MATERIAL AND METHODS The SEER database was used to identify all patients diagnosed with GIST and patients diagnosed with anorectal GIST from 2000 to 2015. The incidence of GIST, baseline clinical and demographic data, tumor stage, and patient survival data were analyzed, including overall survival (OS) and cancer-specific survival (CSS). RESULTS A total of 277 patients with anorectal GIST were identified, with an incidence of 0.018 per 100,000. The incidence of GIST arising from other sites was 0.719 per 100,000. The median age at diagnosis for anorectal GIST was 57.5 years (range, 26-92 years), median tumor size was 6.55 cm (range, 0.6-20 cm), and surgery, but not chemotherapy, improved OS and CSS. Patients with anorectal GIST had a mean 1-year, 3-year, 5-year, and 10year OS of 91.1%, 82.5%, 75.2%, and 58.5%, respectively. Patients with GIST arising at other sites had a mean 1-year, 3-year, 5-year, and 10-year OS of 88.3%, 76.4%, 66.5%, and 46.8%, respectively. CONCLUSIONS Anorectal GIST is a rare tumor that has a better outcome compared with GISTs arising at other sites in the gastrointestinal tract.

Prognostic accuracy of the serum lactate level, the SOFA score and the qSOFA score for mortality among adults with Sepsis.

BACKGROUND: Sepsis is a common critical condition caused by the body's overwhelming response to certain infective agents. Many biomarkers, including the serum lactate level, have been used for sepsis diagnosis and guiding treatment. Recently, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) recommended the Sequential Organ Failure Assessment (SOFA) and the quick SOFA (qSOFA) rather than lactate for screening sepsis and assess prognosis. Here, we aim to explore and compare the prognostic accuracy of the lactate level, the SOFA score and the qSOFA score for mortality in septic patients using the public Medical Information Mart for Intensive Care III database (MIMIC III). METHODS: The baseline characteristics, laboratory test results and outcomes for sepsis patients were retrieved from MIMIC III. Survival was analysed by the Kaplan-Meier method. Univariate and multivariate analysis was performed to identify predictors of prognosis. Receiver operating characteristic curve (ROC) analysis was conducted to compare lactate with SOFA and qSOFA scores. RESULTS: A total of 3713 cases were initially identified. The analysis cohort included 1865 patients. The 24-h average lactate levels and the worst scores during the first 24 h of ICU admission were collected. Patients in the higher lactate group had higher mortality than those in the lower lactate group. Lactate was an independent predictor of sepsis prognosis. The AUROC of lactate (AUROC, 0.664 [95% CI, 0.639-0.689]) was significantly higher than that of qSOFA (AUROC, 0.547 [95% CI, 0.521-0.574]), and it was similar to the AUROC of SOFA (AUROC, 0.686 [95% CI, 0.661-0.710]). But the timing of lactate relative to SOFA and qSOFA scores was inconsistent. CONCLUSION: Lactate is an independent prognostic predictor of mortality for patients with sepsis. It has superior discriminative power to qSOFA, and shows discriminative ability similar to that of SOFA.

Overexpression of MIST1 reverses the epithelial-mesenchymal transition and reduces the tumorigenicity of pancreatic cancer cells via the Snail/E-cadherin pathway.

The role of transcription factors in cancer has attracted significant attention. Although genetic models indicate MIST1 functions as a tumor suppressor in mice, its role in human pancreatic cancer is unclear. We explored the expression and function of MIST1 in pancreatic cancer. Analysis of three GEO datasets (GSE16515, GSE15471, and GSE62165) showed MIST1 mRNA was significantly downregulated in human pancreatic cancer compared to normal pancreatic tissues. Moreover, MIST1 protein and mRNA expression were downregulated in pancreatic cancer cell lines compared to normal cells. Immunohistochemistry confirmed MIST1 was downregulated in human pancreatic cancer tissues (n = 47) and associated with differentiation. In vitro, overexpression of MIST1 reduced pancreatic cancer cell growth, migration, and invasion. In vivo, overexpression of MIST1 retarded tumor xenograft growth and decreased tumor cell dissemination to the liver. Furthermore, MIST1 reversed the epithelial-mesenchymal transition by downregulating Snail and upregulating E-cadherin. Knockdown of E-cadherin promoted the migration and invasion of cancer cells overexpressing MIST1. In conclusion, this study indicates restoring the expression of MIST1 reversed the EMT and reduced the tumorigenicity of pancreatic cancer cells partly via the Snail/E-cadherin pathway.

Assessment of the American Joint Commission on Cancer 8th Edition Staging System for Patients with Pancreatic Neuroendocrine Tumors: A Surveillance, Epidemiology, and End Results analysis.

Although several staging systems have been proposed for pancreatic neuroendocrine tumors (pNETs), the optimal staging system remains unclear. Here, we aimed to assess the application of the newly revised 8th edition American Joint Committee on Cancer (AJCC) staging system for exocrine pancreatic carcinoma (EPC) to pNETs, in comparison with that of other staging systems. We identified pNETs patients from the Surveillance, Epidemiology, and End Results (SEER) database (2004-2014). Overall survival was analyzed using Kaplan-Meier curves with the log-rank test. The predictive accuracy of each staging system was assessed by the concordance index (c-index). Cox proportional hazards regression was conducted to calculate the impact of different stages. In total, 2424 patients with pNETs, including 2350 who underwent resection, were identified using SEER data. Patients with different stages were evenly stratified based on the 8th edition AJCC staging system for EPC. Kaplan-Meier curves were well separated in all patients and patients with resection using the 8th edition AJCC staging system for EPC. Moreover, the hazard ratio increased with worsening disease stage. The c-index of the 8th edition AJCC staging system for EPC was similar to that of the other systems. For pNETs patients, the 8th edition AJCC staging system for EPC exhibits good prognostic discrimination among different stages in both all patients and those with resection.

Impact of age on survival of patients with pancreatic cancer after surgery: Analysis of SEER data.

BACKGROUND: To explore the impact of age on all-cause death and cancer-specific death in patients with pancreatic duct adenocarcinoma (PDAC) undergoing surgery. MATERIALS AND METHODS: Individuals with PDAC undergoing surgery between 2004 and 2013 (N = 11,138) were retrospectively studied from the Surveillance, Epidemiology, and End Results (SEER) cancer registry database. The impact of age on all-cause death and cancer-specific death was assessed using Cox regression model and competing risk model respectively. RESULTS: Multivariate Cox regression analysis indicated that the risks of all-cause death increased with age: hazard ratios (95% confidence interval, 95%CI) were 1.10 (1.04-1.17), 1.31 (1.23-1.38), 1.47 (1.35-1.61) for groups 61-70 years, 71-80 years, and >80 years, respectively, compared with ≤60 years. Multivariate competing risk analysis indicated that the risk of cancer-specific death was similar between patients ≤60 years and 61-70 years (subhazard ratio 0.93; 95% confidence interval 0.87-1.00), but decreased in patients 71-80 years (subhazard ratio 0.84; 95%CI 0.79-0.90) and >80 years (subhazard ratio 0.76; 95%CI 0.68-0.85). CONCLUSION: Age at diagnosis appeared to be an independent predictor of prognosis, with reverse impacts on all-cause death and cancer-specific death.

The effect of metformin on survival of patients with pancreatic cancer: a meta-analysis.

We conducted a meta-analysis to analyse the effect of metformin on survival of pancreatic cancer patients at various stages. We performed a systematic search of PubMed, Embase, Cochrane, and Web of Science to identify all relevant studies. Summary hazard ratios (HR) of survival and 95% confidence intervals (95% CI) were calculated with a fixed or random effects model according to inter-study heterogeneity. Nine retrospective cohort studies and two randomized controlled trials (RCTs) were eligible. There was a significant improvement in survival (HR = 0.86, 95% CI 0.76-0.97; P < 0.05) in the metformin group compared with control. Subgroup analysis indicated that metformin improved survival in patients with resection (HR = 0.79, 95% CI 0.69-0.91; P < 0.05) and patients with locally advanced tumors (HR = 0.68, 95% CI 0.55-0.84; P < 0.05) but not in patients with metastatic tumors, even when RCT data were included (HR = 0.99, 95% CI 0.70-1.40; P > 0.05), or were excluded (HR = 0.89, 95% CI 0.61-1.31; P > 0.05). This meta-analysis indicated that the effect of metformin does correlate with tumor stage but should be prudently considered given the limited and variable studies performed to data.

Overexpression of G protein-coupled receptor GPR87 promotes pancreatic cancer aggressiveness and activates NF-κB signaling pathway.

BACKGROUND: Pancreatic cancer is a highly lethal disease and has the worst prognosis of any major malignancy. G protein-coupled receptor GPR87 is reported to be overexpressed in multiple cancers. The clinical significance and biological role of GPR87 in pancreatic cancer, however, remain to be established. METHODS: GPR87 expression in pancreatic cancer cell lines, paired patient tissues were determined using western blotting and Real-time PCR. Ninety-six human pancreatic cancer tissue samples were analyzed by immunochemistry (IHC) to investigate the association between GPR87 expression and the clinicopathological characteristics of pancreatic cancer. Functional assays, such as anchorage-independent growth, chicken chorioallantoic membrane (CAM) assay, transwell matrix penetration assay, and Annexin V-FITC and PI staining and a xenograft tumor model were used to determine the oncogenic role of GPR87 in human pancreatic cancer progression. The effect of GPR87 on NF-κB signaling pathway was further investigated using the luciferase reporter assays, and by detection of the NF-κB signaling downstream genes. RESULTS: Herein, we reported that GPR87 was markedly overexpressed in pancreatic cancer cells and clinical tissues. Immunohistochemical analysis showed that the expression of GPR87 significantly correlated with patients' clinicopathologic features, including clinical stage and tumor-nodule-metastasis (TNM) classification. Pancreatic cancer patients with higher levels of GPR87 expression had shorter overall survival compared to patients with lower GPR87 levels. We gained valuable insights into the mechanism of GPR87 expression in pancreatic cancer cells by demonstrating that overexpressing GPR87 significantly enhanced, whereas silencing endogenous GPR87 inhibited, the proliferation, angiogenesis and increased resistance to gemcitabine-induced apoptosis of pancreatic cancer in vitro and tumorigenicity of pancreatic cancer cells in vivo. Finally, we demonstrated that GPR87 enhanced pancreatic cancer aggressiveness by activating NF-κB signaling pathway. CONCLUSIONS: Taken together, these findings suggest that GPR87 plays a critical oncogenic role in pancreatic cancer progression and highlight its potential as a target for pancreatic cancer therapy. CONCLUSIONS: Our findings suggest that GPR87 plays a critical oncogenic role in pancreatic cancer progression and highlight its potential as a target for pancreatic cancer therapy.

High Mobility Group Box Protein 1 Boosts Endothelial Albumin Transcytosis through the RAGE/Src/Caveolin-1 Pathway.

High-mobility group box protein 1 (HMGB1), an inflammatory mediator, has been reported to destroy cell-cell junctions, resulting in vascular endothelial hyperpermeability. Here, we report that HMGB1 increases the endothelial transcytosis of albumin. In mouse lung vascular endothelial cells (MLVECs), HMGB1 at a concentration of 500 ng/ml or less did not harm cell-cell junctions but rapidly induced endothelial hyperpermeability to (125)I-albumin. HMGB1 induced an increase in (125)I-albumin and AlexaFluor 488-labeled albumin internalization in endocytosis assays. Depletion of receptor for advanced glycation end products (RAGE), but not TLR2 or TLR4, suppressed HMGB1-induced albumin transcytosis and endocytosis. Genetic and pharmacological destruction of lipid rafts significantly inhibited HMGB1-induced albumin endocytosis and transcytosis. HMGB1 induced the rapid phosphorylation of caveolin (Cav)-1 and Src. Either RAGE gene silencing or soluble RAGE suppressed Cav-1 Tyr14 phosphorylation and Src Tyr418 phosphorylation. The Src inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d] pyrimidine (PP2) blocked HMGB1-induced Cav-1 Tyr14 phosphorylation. PP2 and overexpression of Cav-1 with a T14F mutation significantly inhibited HMGB1-induced transcytosis and albumin endocytosis. Our findings suggest that HMGB1 induces the transcytosis of albumin via RAGE-dependent Src phosphorylation and Cav-1 phosphorylation. These studies revealed a new mechanism of HMGB1-induced endothelial hyperpermeability.

High risk factors of pancreatic carcinoma.

Over the past decades, cancer has become one of the toughest challenges for health professionals. The epidemiologists are increasingly directing their research efforts on various malignant tumor worldwide. Of note, incidence of cancers is on the rise more quickly in developed countries. Indeed, great endeavors have to be made in the control of the life-threatening disease. As we know it, pancreatic cancer (PC) is a malignant disease with the worst prognosis. While little is known about the etiology of the PC and measures to prevent the condition, so far, a number of risk factors have been identified. Genetic factors, pre-malignant lesions, predisposing diseases and exogenous factors have been found to be linked to PC. Genetic susceptibility was observed in 10% of PC cases, including inherited PC syndromes and familial PC. However, in the remaining 90%, their PC might be caused by genetic factors in combination with environmental factors. Nonetheless, the exact mechanism of the two kinds of factors, endogenous and exogenous, working together to cause PC remains poorly understood. The fact that most pancreatic neoplasms are diagnosed at an incurable stage of the disease highlights the need to identify risk factors and to understand their contribution to carcinogenesis. This article reviews the high risk factors contributing to the development of PC, to provide information for clinicians and epidemiologists.

Implantation of radioactive (125)I seeds improves the prognosis of locally advanced pancreatic cancer patients: A retrospective study.

Locally advanced pancreatic cancer is associated with a very poor prognosis. This study was performed to evaluate whether patients with locally advanced pancreatic cancer benefit from (125)I seed implantation. This retrospective study included 224 patients with locally advanced pancreatic cancer, with 137 patients (61.2%) in the implantation (IP) group and 87 (38.9%) in the non-implantation (NIP) group. The survival status, complications and objective curative effects were compared between the groups. The average operative time in the IP group was significantly longer than that in the NIP group (243±51 vs. 214±77 min). The tumor response rates were 9.5% and 0 at the 2nd month after surgery in the IP and NIP groups, respectively (P<0.05). The IP group exhibited a trend toward pain relief at the 6th month after surgery. The global health status scores of the IP group were higher than those of the NIP group at the 3rd and 6th month after surgery. The median survival time in the IP group was significantly longer than that in the NIP group. In conclusion, patients with locally advanced pancreatic cancer can benefit from (125)I seed implantation in terms of local tumor control, survival time, pain relief and quality of life.