Clusterin is upregulated by erastin, a ferroptosis inducer and exerts cytoprotective effects in pancreatic adenocarcinoma cells.

Ferroptosis is a novel form of cell death, which is distinguished from apoptosis and necrosis, and characterized by accumulation of lipid-based reactive oxygen species (ROS) in an iron-dependent manner. Erastin, a small molecule, was widely reported to trigger ferroptosis in various kinds of cancer cells, including pancreatic cancer cells by inducing ROS accumulation. However, how erastin treatment exerts cytotoxicity is not still fully understood. In this study, the effects of erastin in causing pancreatic cancer cell death via inducing ferroptosis and apoptosis are investigated. As expected, erastin treatment caused ROS accumulation, increase in iron concentration and non-apoptotic cell death, which is different from that of induced by apoptosis inducer, staurosporine. Interestingly, erastin treatment caused the upregulation of clusterin, which contributes to the regulation of malignant behaviors of pancreatic cancer, including preventing apoptosis and inducing chemoresistance. Without erastin treatment, overexpressed clusterin significantly promoted cell proliferation, which is consistent with its cytoprotective roles. After erastin treatment, overexpressed clusterin decreased erastin-induced ROS accumulation and cell death. By measuring iron concentration, reduced glutathione (GSH) and glutathione peroxidase 4 (GPX4), it is revealed that clusterin caused resistance to erastin-induced ferroptosis potentially via maintaining the enzymatic activity of GPX4, without disturbing GSH amount. Thus, ferroptosis inducer, erastin, may crosstalk with apoptotic cell death via regulating clusterin, indicating a more complex regulatory network between ferroptosis and apoptosis.

Dinaciclib exerts a tumor-suppressing effect via ß-catenin/YAP axis in pancreatic ductal adenocarcinoma.

Dinaciclib, a cyclin-dependent kinase-5 (CDK5) inhibitor, has significant anti-tumor properties. However, the precise mechanism of dinaciclib requires further investigation. Herein, we investigated the anti-tumor functions and molecular basis of dinaciclib in pancreatic ductal adenocarcinoma (PDAC). PDAC and matched para-carcinoma specimens were collected from the patients who underwent radical resection. Immunohistochemistry was performed to assess CDK5 expression. Cell proliferation ability, migration, and invasion were measured using Cell Counting Kit-8, wound healing, and transwell assay, respectively. The cell cycle and apoptosis were assessed using flow cytometry. Gene expression was examined using RNA-seq and quantitative real-time PCR. Protein expression of proteins was measured by western blot analysis and immunofluorescence microscopy. Tumor-bearing mice were intraperitoneally injected with dinaciclib. CDK5 is highly expressed in PDAC. The expression level of CDK5 was significantly related to tumor size, T stage, and the American Joint Committee on Cancer stage. High CDK5 expression can predict poor survival in PDAC patients. In addition, the expression level of CDK5 might be an independent prognostic factor for PDAC patients. Dinaciclib inhibits the growth and motility of PDAC cells and induces apoptosis and cell cycle arrest in the G2/M phase. Mechanistically, dinaciclib down-regulated yes-associated protein (YAP) mRNA and protein expression by reducing ß-catenin expression. Moreover, dinaciclib significantly inhibited PDAC cell growth in vivo . Our findings reveal a novel anti-tumor mechanism of dinaciclib in which it decreases YAP expression by down-regulating ß-catenin at the transcriptional level rather than by activating Hippo pathway-mediated phosphorylation-dependent degradation.

Preoperative acute pancreatitis and hyperenzymemia are associated with poor prognosis in patients with nonfunctional pancreatic neuroendocrine tumors.

BACKGROUND: We aimed to investigate the prevalence of acute pancreatitis (AP) and hyperenzymemia as well as their clinical impact on postoperative survival outcomes in patients with pancreatic neuroendocrine tumors (PNETs). METHODS: A retrospective cohort study of 218 patients who underwent radical surgical resection for nonfunctional PNETs (NF-PNETs) was conducted. Multivariate survival analysis was performed by the Cox proportional hazard model, with results expressed as hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Of the 151 patients who met the inclusion criteria, the incidences of preoperative AP and hyperenzymemia were 7.9% (12/152) and 23.2% (35/151), respectively. The mean recurrence-free survival (RFS, 95% CI) for patients in control, AP, and hyperenzymemia groups was 136 (127-144), 88 (74-103), and 90 (61-122) months, with a 5-year RFS rate of 86.5%, 58.3%, and 68.9%, respectively. In the multivariable-adjusted Cox hazard model that included tumor grade and lymph node status, the adjusted HR of AP and hyperenzymemia for recurrence was 2.58 (95% CI: 1.47-7.86, p = 0.008) and 2.43 (95% CI: 1.08-7.06, p = 0.040). CONCLUSION: Preoperative AP and hyperenzymemia are associated with poor RFS following radical surgical resection in NF-PNETs patients.

Beyond successful hemostasis: CT findings and organ failure predict postoperative death in patients suffering from post-pancreatoduodenectomy hemorrhage.

BACKGROUND: To predict postoperative death even after successful hemostasis in patients with post pancreatoduodenectomy pancreatic fistula-associated hemorrhage (PPFH). METHODS: Patients who underwent pancreatoduodenectomy (PD) between September 2011 and August 2020 were identified. PPFH patients were enrolled in this retrospective case-control study and divided into the Cured and Death groups. Perioperative variables were analyzed, especially the characteristics of PPFH and CT image findings. RESULTS: Among the 2732 consecutive pancreaticoduodenectomies, 63 patients (2.3%) were confirmed to have PPFH. The mortality rate of patients following PPFH was 50.8% (32/63). After univariate and multivariate analysis, organ failure 24 h before initial hemorrhage (P = 0.039, OR = 11.53, 95% CI: 1.14-117.00), CT imaging findings of the operative area bubble sign (P = 0.021, OR = 5.15, 95% CI: 1.28-20.79) and PJ dehiscence (P = 0.016, OR = 8.95, 95% CI: 1.50-53.38) were remained as significant predictive factors of postoperative death for PPFH patients. CONCLUSIONS: Patients following PPFH showed a high mortality rate. Organ failure and CT evidence of pancreaticojejunostomy (PJ) dehiscence and operative area bubble signs before initial hemorrhage may allow early prediction of postoperative death in PPFH patients.

Surgical strategies for duodenal gastrointestinal stromal tumors.

PURPOSE: Duodenal gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors of the gastrointestinal tract. For localized or potentially resectable GISTs, surgery is the first choice. But the important and complex anatomical structure adjacent to the duodenum makes surgical management for duodenal GISTs challenging and few comprehensive surgical strategies have been described. This study aims to provide new comprehensive surgical strategies for duodenal GISTs by summarizing the surgical approaches and outcomes of duodenal GISTs in different locations in our center in the past 11 years. METHODS: Information from patients who underwent surgical resection for duodenal GISTs at our facility during the past 11 years was retrospectively analyzed. RESULTS: Ninety-two patients have received surgical procedures in the facility. Twenty-three, 31, 3, and 35 patients underwent wedge resection, segmental resection, pancreatic head-preserving duodenectomy, and pancreaticoduodenectomy, respectively. The mean operative times were 212.6 (150-270), 260 (180-370), 323 (300-350), and 354.9 (290-490) min; the mean blood loss was 226.1 (100-400), 303.2 (100-600), 500 (400-600), and 582.9 (200-1300) ml, respectively. R0 margins were obtained in 21, 29, 3, and 32 patients, respectively. CONCLUSIONS: For duodenal GISTs without invasion of the ampulla of Vater or the pancreatic head, a limited resection (such as wedge resection, segmental resection, or pancreatic head-preserving duodenectomy) is feasible. For duodenal GISTs with an invasion of the ampulla of Vater or the pancreatic head, a pancreaticoduodenectomy is still necessary.

Diabetes mellitus induced by immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) are widely used in oncology for their favourable antitumor efficacy. ICI therapy is associated with a unique toxicity profile known as immune-related adverse events (irAEs). One such irAE is ICI-related diabetes mellitus (DM), which is relatively uncommon but can become extremely severe, leading to irreversible impairment of ß-cells, and even lead to death if not promptly recognised and properly managed. The precise mechanisms of ICI-related DM are not well understood. In this review, we summarise the clinical characteristics, pathophysiology, and management of this adverse effect caused by ICI therapy. Deeper investigation of ICI-related DM may contribute to elucidate the molecular mechanisms of classical type 1 DM.

MEX3A knockdown inhibits the development of pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is one of the most serious causes of death in the world due to its high mortality and inefficacy treatments. MEX3A was first identified in nematodes and was associated with tumor formation and may promote cell proliferation and tumor metastasis. So far, nothing is known about the relationship between MEX3A and PDA. METHODS: In this study, the expression level of MEX3A in PDA tissues was measured by immunohistochemistry. The qRT-PCR and western blot were used to identify the constructed MEX3A knockdown cell lines, which was further used to construct mouse xenotransplantation models. Cell proliferation, colony formation, cell apoptosis and migration were detected by MTT, colony formation, flow cytometry and Transwell. RESULTS: This study showed that MEX3A expression is significantly upregulated in PDA and associated with tumor grade. Loss-of-function studies showed that downregulation of MEX3A could inhibit cell growth in vitro and in vivo. Moreover, it was demonstrated that knockdown of MEX3A in PDA cells promotes apoptosis by regulating apoptosis-related factors, and inhibits migration through influencing EMT. At the same time, the regulation of PDA progression by MEX3A involves changes in downstream signaling pathways including Akt, p-Akt, PIK3CA, CDK6 and MAPK9. CONCLUSIONS: We proposed that MEX3A is associated with the prognosis and progression of PDA,which can be used as a potential therapeutic target.

World Health Organization grading classification for pancreatic neuroendocrine neoplasms: a comprehensive analysis from a large Chinese institution.

BACKGROUND: Pancreatic neuroendocrine neoplasms (p-NENs) are a group of highly heterogeneous tumors with distinct clinicopathological features and long-term prognosis. In 2017, in order to better stratify patients into prognostic groups and predicting their outcomes, World Health Organization (WHO) officially updated its grading system for p-NENs which distinguished these neoplasms among Grading 1 (G1) pancreatic neuroendocrine tumors (p-NETs), G2 p-NETs, G3 p-NETs and G3 pancreatic neuroendocrine carcinomas (p-NECs). However, this new grading classification for p-NENs has not yet been rigorously validated. METHODS: Data of patients who were surgically treated and histopathologically diagnosed as p-NENs at West China Hospital of Sichuan University from January 2002 to December 2018 were retrospectively collected and analyzed according the novel WHO 2017 grading classification. RESULTS: We eventually enrolled 480 eligible patients with p-NENs in our present study, in which 150 patients with WHO 2017 G1 p-NETs, 158 with G2 p-NETs, 64 with G3 p-NETs and 108 with G3 p-NECs were identified. The estimated 5-year overall survival for patients with G1 p-NETs, G2 p-NETs, G3 p-NETs and G3 p-NECs was 75.8, 58.4, 35.1 and 11.1%, with a median survival time of 85.3mons, 67.4mons, 51.3mons and 26.8mons, respectively. Patients with G2 p-NETs present notably worse survival than those with G1 p-NETs (P = 0.03). Survival of G3 p-NETs were significantly worse than that of G1 p-NETs or G2 p-NETs (P < 0.001, P = 0.023, respectively), as well as that when comparing G3 p-NECs with G1 p-NETs or G2 p-NETs (P < 0.001, P < 0.001, respectively). Patients with G3 p-NECs showed statistically shorter survival than those with G3 p-NETs (P < 0.001). Both WHO 2017 and 2010 grading criteria could be independent predictor for the OS of p-NENs (P = 0.016, P = 0.022; respectively). The 95% confidence intervals of WHO 2017 grading classification (0.983-9.454) was slightly smaller than that of WHO 2010 criteria (0.201-13.374), indicating a relatively more accurate predicting ability for the prognosis of p-NENs. CONCLUSION: The WHO 2017 grading classification for p-NENs could successfully allocate patients into four groups with distinct clinical features and significant survival differences, which might be superior to the WHO 2010 criteria for its better prognostic stratification and more accurate predicting ability.

Unusual metastasis of papillary thyroid cancer to the pancreas, liver, and diaphragm: a case report with review of literature.

BACKGROUND: Papillary thyroid cancer (PTC) is the most common form of well-differentiated endocrine malignancy. Distant metastases of PTC are rare and usually occur in the bones, lungs, and thoracic lymph nodes despite the common locoregional metastases to the lymph nodes of the neck. The metastasis of PTC to the pancreas is extremely rare. Here, we present a patient with PTC that had simultaneously metastasized to the pancreas, liver, and diaphragm. CASE PRESENTATION: A 47-year-old male patient suffering from mild abdominal pain for 2 months was admitted to our hospital. The ultrasound (US) and computed tomography (CT) scan of the abdomen revealed a pancreatic space-occupying lesion and pancreatic duct dilatation, and the patient underwent exploratory laparotomy. Intraoperative examination identified a hard mass (approximately 4.0 cm × 3.0 cm) in the body and tail of the pancreas and a mass (1.5 cm in diameter) in the diaphragm. Three light masses were also noted on the surface of his liver. The patient underwent radical distal pancreatectomy, splenectomy, diaphragm, and liver mass resection. After surgery, the pathological report revealed that the masses resected from the pancreas, liver, and diaphragm were PTC metastases. Then, the patient had a thyroid US and an endoscopic US-guided fine needle aspiration biopsy of the thyroid mass. Pathology showed papillary cancer. Subsequently, the patient received a complete thyroidectomy, a cervical lymphadenectomy, bilateral parotidectomy, and bilateral submandibular gland resection. CONCLUSIONS: Aggressive surgeries, such as pancreaticoduodenectomy (PD), should be considered for selected patients with metastatic diseases from PTC to alleviate the symptoms and prolong their survival.

Exosomes play roles in sequential processes of tumor metastasis.

Overwhelming evidence demonstrates that exosomes, a series of biologically functional small vesicles of endocytic origin carrying a variety of active constituents, especially tumor-derived exosomes, contribute to tumor progression and metastasis. This review focuses on the specific multifaceted roles of exosomes in affecting sequenced four crucial processes of metastasis, through which cancer cells spread from primary to secondary organs and finally form macroscopic metastatic lesions. First, exosomes modulate the primary tumor sites to assist cancer growth and dissemination. In this part, five main biological events are reviewed, including the transfer of oncogenic constituents, the recruitment and activation of fibroblasts, the induction of angiogenesis, immunosuppression and epithelial-mesenchymal transition (EMT) promotion. In Step 2, we list two recently disclosed mechanisms during the organ-specific homing process: the exosomal integrin model and exosomal epidermal growth factor receptor (EGFR)/miR-26/hepatocyte growth factor (HGF) model. Subsequently, Step 3 focuses on the interactions between exosomes and pre-metastatic niche, in which we highlight the specific functions of exosomes in angiogenesis, lymphangiogenesis, immune modulation and metabolic, epigenetic and stromal reprogramming of pre-metastatic niche. Finally, we summarize the mechanisms of exosomes in helping the metastatic circulating tumor cells escape from immunologic surveillance, survive in the blood circulation and proliferate in host organs.

Risk of pancreatic cancer in patients undergoing surgery for chronic pancreatitis.

BACKGROUND: Chronic pancreatitis (CP) is considered to be a risk factor for pancreatic cancer. A retrospective study was conducted to evaluate the incidence of pancreatic cancer after surgery for CP and to determine the risk factors. METHODS: The patients who underwent surgery for histologically documented CP between January 2009 and December 2017 were reviewed. The baseline characteristics, operative data, postoperative complications, and follow-up information were analysed. We calculated standardized incidence ratio on the base of the incidence of pancreatic cancer in the standard population in China. The risk factor for pancreatic cancer was assessed using Cox regression. RESULTS: Among 650 patients, pancreatic cancer was detected in 12 patients (1.8%) after a median follow-up of 4.4 years. The standardized incidence ratio of pancreatic cancer was 68.12 (95% CI, 35.20-118.99). Two independent risk factors for the development of pancreatic cancer in patients with chronic pancreatitis after surgery were identified: time interval to surgery [HR 1.005, 95% CI (1.002-1.008), P = 0.002] and de novo endocrine insufficiency [HR 10.672, 95% CI (2.567-44.372), P = 0.001]. CONCLUSIONS: Patients who require surgery for CP are at a very high risk of developing pancreatic cancer. Early surgical intervention plays a protective role in the development of pancreatic cancer from CP. A high index of suspicion for pancreatic cancer should be maintained in CP patients with de novo postoperative diabetes after surgery.

Short-term outcomes and risk factors for pancreatic fistula after pancreatic enucleation: A single-center experience of 142 patients.

BACKGROUND: Enucleation is increasingly used for benign or low-grade pancreatic neoplasms. Enucleation preserves the pancreatic parenchyma as well as decreases the risk of long-term endocrine and exocrine dysfunction, but may be associated with a higher rate of postoperative pancreatic fistula (POPF). The aim of this study was to assess short-term outcomes, in particular, POPF. METHODS: Data were collected retrospectively from all 142 patients who underwent pancreatic enucleation between 2009 and 2014 in our institution were analyzed. RESULTS: Lesions were most frequently located in the head and uncinate process of the pancreas (60.6%), and the most common types were neuroendocrine neoplasms (52.1%). Overall morbidity was 66%, mainly due to POPF (53.5%), and severe morbidity was only 8.4%, including one death (0.7%). Clinical POPF (Grade B or C) occurred in 22 patients (15.5%). Independent risk factors for clinical POPF were age ≥60 years, an episode of acute pancreatitis, and cystic morphology. Tumor size, coverage, histological differentiation, and prolonged operative time were not associated with the risk of POPF. CONCLUSIONS: Enucleation is a safe and feasible procedure for benign or low-grade pancreatic neoplasms. The rate of clinical POPF is acceptable, and clinical POPF occurs more frequently in elderly patients (≥60 years of age), patients with cystic neoplasms, or patients with an episode of acute pancreatitis.

Deregulated expression of miR-107 inhibits metastasis of PDAC through inhibition PI3K/Akt signaling via caveolin-1 and PTEN.

Pancreatic ductal adenocarcinoma (PDAC) displays a highly aggressive malignancy and is considered to be an incurable and rapidly lethal disease. MicroRNAs (miRNAs) are small non-coding RNAs of approximately nucleotides that regulate several aspects of tumors pathogenesis, including migration, invasion, metastasis and epithelial-mesenchymal transition. We have found that miR-107 was significantly high expression in PDAC tissues and cells. High miR-107 expression is associated with poor clinicopathological parameters and prognosis in PDAC patients. Deregulated expression of miR-107 in PDAC cells (AsPC-1 and Panc-1) is sufficient to reduce cell migration and invasion, and to induce upregulation of epithelial markers (ß-catenin, ZO-1 and E-cadherin) and a decrease of mesenchymal marker expression (ZEB-1 and vimentin). We also found that the caveolin-1, PTEN and p-Akt expression are modulated by miR-107 in PDAC cells. Moreover, our study clearly demonstrated that deregulated expression of miR-107 inhibited cell migration and invasion and EMT by up-regulation of caveolin-1 and PTEN, and inhibition of PI3K/Akt signaling in PDAC cells. Our study suggested that miR­107 expression might both be a useful indicator of the metastatic potential and provided a new potential therapeutic target in PDAC.

Circular RNAs: a new frontier in the study of human diseases.

Circular RNAs (circRNAs) are recently discovered new endogenous non-coding RNAs and an area of much research activity. In addition to their potential as major gene regulators, reports are linking heterogeneous circRNA groups with many different human disorders, especially cancer. In this review, we focus on the rapidly advancing field of circRNAs that play a part in human diseases. We list tools (eg, public databases) that scan genome spans of interest to identify known circRNAs; describe the relationship between dysregulated circRNAs and human disease, highlighting their specific roles; and consider the possible use of current and potential circRNA research applications in treating human diseases. Specifically, we review the role of circRNAs as biomarkers, drug targets and therapeutic agents.

[Circular RNA in human disease and their potential clinic significance].

Circular RNAs (circ RNAs) are a novel type of RNA that, unlike linear RNAs, form a covalently closed continuous loop and are highly represented in the eukaryotic transcriptome. They share a stable structure, high expression and often exhibit tissue/developmental-stage-specific expression. Emerging evidence indicates that circRNAs might play important roles in human disease, such as cancer, neurological disorders and atherosclerotic vascular disease risk. The huge potentials of circRNAs are recently being discovered from the laboratory to the clinic. CircRNAs might be developed as a potential novel and stable biomarker and potential drugs used in disease diagnosis and treatment. Here, we review the current understanding of the roles of circRNAs in human disease and their potential clinic significance in disease.

Plasma miRNAs Effectively Distinguish Patients With Pancreatic Cancer From Controls: A Multicenter Study.

OBJECTIVES: To identify plasma microRNA (miRNA) markers of pancreatic cancer (PC). BACKGROUND: Accurate pretreatment diagnosis of PC remains challenging, whether plasma miRNAs could be used as biomarkers in PC remains unknown. METHODS: In this multiphase multicenter study, peripheral blood samples were obtained preoperatively in 3 phases: the discovery phase [7 patients with PC, 6 patients with chronic pancreatitis (CP), and 5 healthy volunteers (N)], the preliminary validation phase (29 patients with PC, 16 patients with CP, and 31 N), and the large sample validation phase (156 patients with PC, 65 N, 57 patients with CP, 27 patients with pancreatic neuroendocrine tumors, and 58 patients with other pancreatic tumors). The diagnostic values of the miRNAs were assessed and compared with cancer antigen 19-9 (CA19-9). RESULTS: The discovery phase demonstrated that 29 miRNAs were dysregulated in the patients with PC compared with the controls. In the preliminary validation phase, 13 miRNAs were shown to be dysregulated in the patients with PC and were selected for validation in a multicenter trial. MiR-486-5p exhibited diagnostic value in discriminating patients with PC from normal subjects or patients with CP, with area under the curve values of 0.861 and 0.707, respectively. MiR-938 exhibited diagnostic value in differentiating patients with PC from those with CP, pancreatic neuroendocrine tumors, and patients with other pancreatic tumors, with area under the curve values of 0.693, 0.660, and 0.618, respectively. In addition, we demonstrated that the value of miR-486-5p in discriminating patients with PC from normal subjects or patients with CP was comparable with that of CA19-9 (P = 0.602 and P = 0.230). CONCLUSIONS: This study identified several plasma miRNAs potentially suitable for distinguishing patients with PC from normal subjects or patients with other pancreatic tumors.

Major hepatectomy in Bismuth types I and II hilar cholangiocarcinoma.

BACKGROUND: Historically, hilar bile duct resection (HBDR) has been regarded as the choice of treatment for Bismuth types I and II hilar cholangiocarcinoma (HCCA). The present study aimed to evaluate the advantages of major liver resection (MLR) in the treatment of patients with Bismuth types I and II HCCA when compared with HBDR. MATERIALS AND METHODS: Between January 2005 and September 2012, in total, 52 patients with Bismuth types I and II HCCA who underwent HBDR alone or MLR were included for retrospective analysis. The intraoperative outcomes, postoperative complications, and oncological outcomes including recurrence and overall or disease-free survival rate were compared. RESULTS: The MLR group had significantly higher curative resection rates compared with the HBDR group (95% versus 62.5%, P = 0.021) and lower tumor recurrence (28% versus 63%, P = 0.049), albeit with longer operating time (395.5 ± 112.7 versus 270.9 ± 98.8, P < 0.001), and higher blood transfusion requirements (70% versus 16%, P < 0.001). MLR resulted in significantly higher overall postoperative morbidity (70% versus 34.4%, P = 0.012), compared with HBDR alone. When restricted to R0 resections for all the procedures, MLR significantly increased the overall postoperative survival rate compared with the HBDR group (P = 0.016); the overall survival rate at 1, 3 y was 68.4% and 60.8% for MLR group and 59.6% and 21.9% for HBDR group, respectively. Also, the disease-free survival rate was significantly higher in patients who underwent MLR, as compared with those who underwent HBDR (53.2% versus 0% at 3 y, P = 0.005). CONCLUSIONS: Our study has shown that MLR results in higher curative resections, fewer recurrences, and increased postoperative survival rate for Bismuth types I and II HCCA as compared with HBDR alone. However, there is a need for well-designed, multicenter studies to be undertaken to better inform a decision on the standard treatment for Bismuth types I and II HCCA.