EGFR is a potential therapeutic target for highly glycosylated and aggressive pancreatic neuroendocrine neoplasms.

pNENs are relative indolent tumors with heterogeneous clinical presentation at diagnosis. It is important to establish aggressive subgroups of pNENs and identify potential therapeutic targets. Patients with pNEN (322 cases) were included to examine the association between glycosylation biomarkers and clinical/pathological traits. The molecular and metabolic features stratified by glycosylation status were assessed by RNA-seq/whole exome sequencing and immunohistochemistry. A considerable proportion of patients had elevated glycosylation biomarkers (carbohydrate antigen [CA] 19-9, 11.9%; CA125, 7.5%; carcinoembryonic antigen [CEA], 12.8%). CA19-9 (hazard ratio [HR] = 2.26, P = .019), CA125 (HR = 3.79, P = .004) and CEA (HR = 3.16, P = .002) were each independent prognostic variables for overall survival. High glycosylation group, defined as pNENs with elevated level of circulating CA19-9, CA125 or CEA, accounted for 23.4% of all pNENs. High glycosylation (HR = 3.14, P = .001) was an independent prognostic variable for overall survival and correlated with G3 grade (P < .001), poor differentiation (P = .001), perineural invasion (P = .004) and distant metastasis (P < .001). Epidermal growth factor receptor (EGFR) was enriched in high glycosylation pNENs using RNA-seq. EGFR was expressed in 21.2% of pNENs using immunohistochemistry and associated with poor overall survival (P = .020). A clinical trial focusing on EGFR expressed pNENs was initiated (NCT05316480). Thus, pNEN with aberrant glycosylation correlates with a dismal outcome and suggests potential therapeutic target of EGFR.

Pancreatic Cancer: An Exocrine Tumor with Endocrine Characteristics.

OBJECTIVE: To examine the characteristics of pancreatic cancer patients with long-term survival. BACKGROUND: Although pancreatic cancer is a highly lethal malignancy, a minority of patients experience long-term survival. The characteristics of these patients remain largely unidentified. METHODS: An indolent subgroup was established using carbohydrate antigen 19-9 (CA19-9), which is the best-validated biomarker for pancreatic cancer. Of 1558 patients, 13.9% were included in the CA19-9-normal (≤ 37 U/mL) subgroup. RESULTS: A normal A19-9 level was an independent variable for overall survival (median survival, 18.1 vs. 9.7 months, hazard ratio = 0.53, P < 0.001). The 5-year survival of patients with stage IV CA19-9-normal cancer was higher than that of patients with stage I-IV CA19-9-high cancer (22.4% vs. 6.8%, P = 0.034). The CA19-9-normal subgroup exhibited reduced levels of circulating glucose (P < 0.001) and increased expression of insulin (P < 0.001) compared with the CA19-9-high subgroup. Glucose was a substrate for CA19-9 biosynthesis through the hexosamine biosynthesis pathway. In addition, in pancreatic cancer animal models of diabetes, glucose control decreased CA19-9 levels and improved overall survival. In a clinical trial (NCT05306028) of patients before undergoing major anticancer treatments, glucose control decreased CA19-9 levels in 90.9% of the patients. CONCLUSIONS: CA19-9-normal pancreatic cancer is a strikingly indolent subgroup with low glucose and high insulin. Glucose control is a promising therapeutic strategy for pancreatic cancer.

Glutamine deprivation induces ferroptosis in pancreatic cancer cells.

Ferroptosis is a type of programmed cell death closely related to amino acid metabolism. Pancreatic cancer cells have a strong dependence on glutamine, which serves as a carbon and nitrogen substrate to sustain rapid growth. Glutamine also aids in self-protection mechanisms. However, the effect of glutamine on ferroptosis in pancreatic cancer remains largely unknown. Here, we aim to explore the association between ferroptosis and glutamine deprivation in pancreatic cancer. The growth of pancreatic cancer cells in culture media with or without glutamine is evaluated using Cell Counting Kit-8. Reactive oxygen species (ROS) are measured by 2',7'-dichlorodihydrofluorescein diacetate staining. Ferroptosis is assessed by BODIPY-C11 dye using confocal microscopy and flow cytometry. Amino acid concentrations are measured using ultrahigh-performance liquid chromatography-tandem mass spectrometry. Isotope-labelled metabolic flux analysis is performed to track the metabolic flow of glutamine. Additionally, RNA sequencing is performed to analyse the genetic alterations. Glutamine deprivation inhibits pancreatic cancer growth and induces ferroptosis both in vitro and in vivo. Additionally, glutamine decreases ROS formation via glutathione production in pancreatic cancer cells. Interestingly, glutamine inhibitors (diazooxonorleucine and azaserine) promotes ROS formation and ferroptosis in pancreatic cancer cells. Furthermore, ferrostatin, a ferroptosis inhibitor, rescues ferroptosis in pancreatic cancer cells. Glutamine deprivation leads to changes in molecular pathways, including cytokine-cytokine receptor interaction pathways ( CCL5, CCR4, LTA, CXCR4, IL-6R, and IL-7R). Thus, exogenous glutamine is required for the detoxification of ROS in pancreatic cancer cells, thereby preventing ferroptosis.

Sequential Capecitabine/Temozolomide and Sunitinib Treatment in Patients With Metastatic Well-Differentiated Grade 1/Grade 2 Pancreatic Neuroendocrine Tumors.

OBJECTIVE: The role of alternate sequential administration of sunitinib and capecitabine/temozolomide (CAPTEM) in metastatic pancreatic neuroendocrine tumors (PanNETs) remains unexplored. We thus aimed to analyze the efficacy and tolerability of this strategy in advanced grade 1/grade 2 PanNETs. METHODS: In total, data of 43 patients with metastatic PanNET were collected from a real-world database of a cancer center. Twenty-four patients were treated with sunitinib followed by CAPTEM (group 1), and 19 patients were treated with CAPTEM followed by sunitinib (group 2). RESULTS: Twenty-three patients were treated with first-line sunitinib or CAPTEM, and 20 patients were pretreated with somatostatin analog (SSA) or SSA in combination with transcatheter arterial chemoembolization. The objective response rate with first-line treatment was similar in both groups, whereas that with second-line treatment was higher in group 1 than in group 2, albeit with no significant differences (21.1% vs 5.3%, respectively; P = .205). Median progression-free survival (mPFS) for first-line and second-line treatments did not differ between the 2 groups (11 and 12 months vs 12 and 8 months, respectively). Following subgroup analyses, treatment with first-line sunitinib and sunitinib after pretreated SSA had a longer mPFS than that with second-line sunitinib after CAPTEM (11 months vs 8 months, respectively; P = .046), whereas treatment with first-line CAPTEM and CAPTEM after pretreated SSA had an mPFS similar to that of second-line CAPTEM after sunitinib treatment. CAPTEM and sunitinib had similar tolerability. CONCLUSION: Alternating sunitinib and CAPTEM were well tolerated and associated with similar mPFS in grade 1/grade 2 PanNETs. However, larger prospective studies are required to investigate the efficacy of alternate sequential therapies for metastatic PanNET.

High GFPT1 expression predicts unfavorable outcomes in patients with resectable pancreatic ductal adenocarcinoma.

BACKGROUND: Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the first rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which plays a pivotal role in the progression of pancreatic ductal adenocarcinoma (PDAC). Therefore, we investigated the prognostic significance of GFPT1 expression in patients with resectable PDAC. METHODS: We analyzed public datasets to compare GFPT1 expression in tumor tissues and normal/adjacent pancreatic tissues. We measured the relative GFPT1 expression of 134 resected PDAC specimens in our institution, using real-time polymerase chain reaction (PCR). Survival was compared between high and low GFPT1 expression groups using Kaplan-Meier curves and log-rank tests. Multivariate analyses were estimated using Cox regression and logistic regression models. RESULTS: GFPT1 is generally upregulated in PDAC tissues, according to the analysis of public datasets. The data from our institution shows that high GFPT1 expression was correlated with a high rate of lymph node (LN) metastasis (p = 0.038) and was an independent risk factor for LN metastasis (odds ratio (OR) = 3.14, 95% confidence interval (CI) = 1.42 to 6.90, P = 0.005). High GFPT1 expression was significantly associated with poor overall survival (OS; P = 0.019) in patients with resected PDAC. The multivariable-adjusted hazard ratio (HR) for mortality when comparing patients with high and low GFPT1 expression was 2.54 (95% CI = 1.35 to 4.79, P = 0.004). CONCLUSIONS: GFPT1 is generally upregulated in PDAC tissue and is associated with a high risk of LN metastasis and an unfavorable outcome in patients with resectable PDAC, suggesting its crucial role in PDAC progression.

The Strain Ratio as Obtained by Endoscopic Ultrasonography Elastography Correlates With the Stroma Proportion and the Prognosis of Local Pancreatic Cancer.

OBJECTIVE: The aim of this study was to investigate the association of the strain ratio (SR) with clinicopathologic features and the prognostic value of the SR in local pancreatic cancer. BACKGROUND: The SR as obtained by endoscopic ultrasonography elastography is useful in the differential diagnosis of pancreatic diseases. However, its role in the prognostic prediction of pancreatic cancer remains unknown. METHODS: A total of 78 resected pancreatic cancer patients and 93 locally advanced pancreatic cancer (LAPC) patients were enrolled in this study according to the inclusion criteria. Masson trichrome staining was used to evaluate the stromal proportion. Survival rates were calculated according to the Kaplan-Meier method and were compared using the log rank test. Multivariate analysis was performed with a Cox regression model. RESULTS: The SR was positively associated with the stromal proportion of resected pancreatic cancer (R = 0.768, P < 0.001). High SR was more likely in males (P = 0.039) and was related to perineural invasion (P = 0.022). High SR predicted unfavorable overall survival (OS) relative to low SR (15.4 vs. 25.8 mo, P = 0.017). SR was confirmed as an independent prognostic factor for resected pancreatic cancer based on multivariate analysis (hazard ratio = 1.939, P = 0.020). For LAPC patients who received nab-paclitaxel and gemcitabine, high SR was associated with improved prognosis (OS: 14.9 vs. 11.6 mo, P = 0.045), but this positive association was not observed in patients treated with other gemcitabine-based regimens (OS: 10.7 vs. 12.4 mo, P = 0.478). CONCLUSIONS: A high SR as obtained by endoscopic ultrasonography elastography was associated with poor prognosis of resected pancreatic cancer but predicted improved survival for LAPC patients treated with the nab-paclitaxel and gemcitabine regimen.

Prior history of acute pancreatitis predicts poor survival in patients with resectable pancreatic ductal adenocarcinoma.

BACKGROUND/OBJECTIVES: Mounting evidence has suggested that acute pancreatitis (AP) is a risk factor for pancreatic ductal adenocarcinoma (PDAC), but its role in survival in PDAC patients was rarely investigated. The objective was to investigate the association of a history of AP with survival among PDAC patients who underwent surgical resection. METHODS: A retrospective cohort study comprising 632 patients who were diagnosed with resectable PDAC was conducted. Survival was evaluated by history of AP prior to a diagnosis of PDAC using Kaplan-Meier methods and log-rank tests. Multivariate analyses for mortality were estimated using the Cox proportional hazards model. Propensity score matching methods were used to balance the difference of clinical characteristics between patients with and without AP history. RESULTS: The log-rank tests showed that patients with a history of AP had a worse overall survival than those without a history of AP (p = 0.006). The multivariable-adjusted hazard ratio (HR) for mortality comparing participants with AP to those without AP was 1.808 (95% CI: 1.241-2.632, p = 0.002). Patients with a recent history of AP (<2 years), rather than patients with a remote history of AP (≥2 years), were found to have significantly worse survival (p = 0.014) than those without a history of AP. After adjusted for PSM, history of AP remained an independent survival predictor of PDAC following surgical resection. CONCLUSIONS: Our findings indicate that a history of AP, especially a recent history of AP, is associated with poor survival among patients with resectable pancreatic ductal adenocarcinoma.

Resected Pancreatic Cancer With N2 Node Involvement Is Refractory to Gemcitabine-Based Adjuvant Chemotherapy.

Lymphatic metastasis is a major determinant of the outcome of resected pancreatic cancer. Gemcitabine-based adjuvant chemotherapy can improve the outcome of resected pancreatic cancer. However, the efficacy of gemcitabine against pancreatic cancer stratified by nodal involvement is unclear. In this study, patients who had undergone curative resection of pancreatic adenocarcinoma (612 cases) were included. The efficacy of adjuvant gemcitabine-based regimen, stratified by nodal status (negative, positive) or N substage (N0, no nodal involvement; N1, 1-3-node involvement; N2, ≥4-node involvement), was examined. Both the node-negative (hazard ratio [HR] = 0.62, 95% confidence interval [CI], 0.44-0.87, P = .006) and node-positive subgroups (HR = 0.45, 95% CI, 0.33-0.62, P < .001) benefited from gemcitabine-based adjuvant chemotherapy. Patients with N0 (ie, the node-negative subgroup) or N1 (HR = 0.36, 95% CI, 0.25-0.52, P < .001) disease benefited from gemcitabine-based chemotherapy. However, patients with N2 tumors (HR = 0.95, 95% CI, 0.50-1.78, P = .867) had poor response to gemcitabine-based treatment. Therefore, we postulate that resected pancreatic cancer with N2 node involvement is refractory to gemcitabine-based adjuvant chemotherapy. A more intensive adjuvant regimen may be required for N2 subgroup patients.

The role of necroptosis in cancer biology and therapy.

Apoptosis resistance is to a large extent a major obstacle leading to chemotherapy failure during cancer treatment. Bypassing the apoptotic pathway to induce cancer cell death is considered to be a promising approach to overcoming this problem. Necroptosis is a regulated necrotic cell death modality in a caspase-independent fashion and is mainly mediated by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like (MLKL). Necroptosis serves as an alternative mode of programmed cell death overcoming apoptosis resistance and may trigger and amplify antitumor immunity in cancer therapy.The role of necroptosis in cancer is complicated. The expression of key regulators of the necroptotic pathway is generally downregulated in cancer cells, suggesting that cancer cells may also evade necroptosis to survive; however, in certain types of cancer, the expression level of key mediators is elevated. Necroptosis can elicit strong adaptive immune responses that may defend against tumor progression; however, the recruited inflammatory response may also promote tumorigenesis and cancer metastasis, and necroptosis may generate an immunosuppressive tumor microenvironment. Necroptosis also reportedly promotes oncogenesis and cancer metastasis despite evidence demonstrating its antimetastatic role in cancer. In addition, necroptotic microenvironments can direct lineage commitment to determine cancer subtype development in liver cancer. A plethora of compounds and drugs targeting necroptosis exhibit potential antitumor efficacy, but their clinical feasibility must be validated.Better knowledge of the necroptotic pathway mechanism and its physiological and pathological functions is urgently required to solve the remaining mysteries surrounding the role of necroptosis in cancer. In this review, we briefly introduce the molecular mechanism and characteristics of necroptosis, the interplay between necroptosis and other cell death mechanisms, crosstalk of necroptosis and metabolic signaling and detection methods. We also summarize the intricate role of necroptosis in tumor progression, cancer metastasis, prognosis of cancer patients, cancer immunity regulation, cancer subtype determination and cancer therapeutics.

Angiogenesis in pancreatic cancer: current research status and clinical implications.

Pancreatic cancer is one of the most lethal malignancies worldwide. Although the standard of care in pancreatic cancer has improved, prognoses for patients remain poor with a 5-year survival rate of < 5%. Angiogenesis, namely, the formation of new blood vessels from pre-existing vessels, is an important event in tumor growth and hematogenous metastasis. It is a dynamic and complex process involving multiple mechanisms and is regulated by various molecules. Inhibition of angiogenesis has been an established therapeutic strategy for many solid tumors. However, clinical outcomes are far from satisfying for pancreatic cancer patients receiving anti-angiogenic therapies. In this review, we summarize the current status of angiogenesis in pancreatic cancer research and explore the reasons for the poor efficacy of anti-angiogenic therapies, aiming to identify some potential therapeutic targets that may enhance the effectiveness of anti-angiogenic treatments.

Proposed Modification of the 8th Edition of the AJCC Staging System for Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: The aim of this study was to improve the 8th edition (8th) of the American Joint Committee on Cancer (AJCC) staging system for pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: The new 8th AJCC staging system for PDAC was released in October, 2016, and will be applied in clinical practice in 2018. METHODS: Two large cohorts were included in this analysis. One consisted of 45,856 PDAC patients in the Surveillance, Epidemiology, and End Results (SEER) database (2004-2014), and the other consisted of 3166 PDAC patients in the Fudan University Shanghai Cancer Center (FUSCC) database (2005-2015). RESULTS: Using the 8th AJCC staging system, the median overall survival of the patients in the same stage varied widely among the different substages. We proposed a modified staging system based on median OS in which we maintained the T, N, and M definitions, but regrouped the substages. In the SEER cohort, the concordance index was higher for local disease with the modified staging system [0.637; 95% confidence interval (CI) 0.631-0.642] than with the 8th AJCC staging system (0.620, 95% CI 0.615-0.626). Similar findings were also observed in the FUSCC cohort. In addition, we verified the reliability of the modified staging system in an analysis of patients with different examined lymph node counts (≥15 or 1-14). CONCLUSIONS: The modified 8th AJCC staging system for PDAC proposed in this study provides improvements and may be evaluated for potential adoption in the next edition.

Surgical Resection for Metastatic Tumors in the Pancreas: A Single-Center Experience and Systematic Review.

BACKGROUND: Metastatic lesion to the pancreas accounts for approximately 2% of pancreatic neoplasms. There is no prospective, randomized or case-controlled study evaluating the role of pancreatic metastasectomy. METHODS: The PubMed, EMBASE, and Cochrane Library electronic databases were searched for studies published between January 1, 2001 and December 31, 2017. Studies with five or more patients who received pancreatic metastasectomy and data from our institution (29 patients) were included. The Kaplan-Meier method was used for survival analysis. RESULTS: A total of 414 patients from 20 institutions who underwent pancreatic resections were included. Of the reported 31 kinds of primary neoplasms, renal-cell carcinoma (RCC) comprised the most (54.3%). At the time of diagnosis, although 40.3% patients were asymptomatic, abdominal pain (34.8%) and jaundice (20.6%) were relatively common. As for surgical type, pancreatoduodenectomy, total pancreatectomy, distal pancreatectomy, and enucleation took up 37.9%, 11.4%, 43.5%, and 7.2% respectively. The mortality and morbidity rates were 1.4% and 48.3% respectively. Patients with symptoms at the time of diagnosis had significantly shorter survival compared with asymptomatic patients (p = 0.017). Those with RCC as primary tumor had significantly longer survival compared with non-RCC patients (p < 0.001). Positive margin also predicts worse prognosis (p = 0.035). CONCLUSIONS: Pancreatic metastasectomy is safe and associated with acceptable short- and intermediate-term results. In the conditions of RCC as the primary tumor, being asymptomatic, or negative resection margin, a better prognosis after resection can be achieved.

Tumor-Infiltrating NETs Predict Postsurgical Survival in Patients with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Tumor-infiltrating neutrophils (TINs) indicate poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC). Activated neutrophils can generate neutrophil extracellular traps (NETs). Little is known about the presence and prognostic significance of tumor-infiltrating NETs in PDAC. METHODS: This study enrolled 317 patients, in two independent sets (training and validation), who underwent curative pancreatectomy for PDAC in Shanghai Cancer Center. TINs and NETs were identified by immunohistochemical staining for CD15 and citrullinated histone H3, respectively. The relationship between clinicopathological features and outcomes was analyzed. Accuracy of prognostic prediction models was evaluated using concordance index (C-index) and Akaike information criterion (AIC). RESULTS: NETs were associated with OS (both, P < 0.001) and RFS (both, P < 0.001) in the training and validation sets. Tumor-infiltrating NETs predicted poor postsurgical survival of patients with PDAC. Moreover, multivariate analysis identified NETs and AJCC TNM stage as two independent prognostic factors for OS and RFS. Combination of NETs with the 8th edition TNM staging system (C-index, 0.6994 and 0.6669, respectively; AIC, 1067 and 1126, respectively) generated a novel model that improved the predictive accuracy for survival in both sets (C-index, 0.7254 and 0.7117, respectively; AIC, 1047 and 1102, respectively). The model combining presence of NETs with the 7th edition AJCC TNM staging system also had improved predictive accuracy. CONCLUSIONS: NETs were an independent prognostic factor in PDAC and incorporation of NETs along with the standard TNM stating system refined risk-stratification and predicted survival in PDAC with improved accuracy.

Distinct clinicopathological and prognostic features of insulinoma with synchronous distant metastasis.

BACKGROUND: The clinicopathological and prognostic features of insulinoma with synchronous metastases are unclear. This study aimed to verify the distinct clinicopathological and prognostic features of insulinoma with synchronous distant metastasis. METHODS: Patients with pancreatic neuroendocrine tumor (PanNET) were retrospectively enrolled and divided into cohort 1 (Fudan University Shanghai Cancer Center) and cohort 2 (Surveillance, Epidemiology, and End Results Program database). Both cohorts were further divided into three subgroups: insulinoma, nonfunctioning pancreatic neuroendocrine tumor (NF-PanNET), and non-insulinoma functioning pancreatic neuroendocrine tumor (NiF-PanNET). RESULTS: Cohorts 1 and 2 comprised 505 and 2761 patients (1566 M0 patients and 1195 M1 patients), respectively. In cohort 1 and cohort 2 M0 subgroup, insulinoma showed longer disease-free survival, overall survival (OS), and disease-specific survival (DSS) than NiF-PanNET and NF-PanNET (not reached vs. 48 and 60months, p < 0.001; 183months vs. 87 and 109months, p < 0.001; 247months vs. 121 and 140months, p = 0.002). However, in cohort 2 M1, the mDSS for metastatic insulinoma was shorter than that for NiF-PanNET (31months vs. 61months, p = 0.045), while the mDSS and mOS were similar to those for NF-PanNET. The percentage of T1 and N0 patients was similar between the metastatic insulinoma subgroup and NiF-PanNET and NF-PanNET subgroups. The Ki-67 index and recurrence had a positive linear relationship only for NiF-PanNET and NF-PanNET (p = 0.009). CONCLUSIONS: Insulinoma with synchronous metastasis showed clinicopathological and prognostic characteristics similar to those of NF-PanNET. Metastatic insulinoma had worse prognosis than non-insulinoma F-PanNET. These findings may help in the clinical management of metastatic insulinoma.

PRMT5 enhances tumorigenicity and glycolysis in pancreatic cancer via the FBW7/cMyc axis.

BACKGROUND: The epigenetic factor protein arginine methyltransferase 5 (PRMT5) has been reported to play vital roles in a wide range of cellular processes, such as gene transcription, genomic organization, differentiation and cell cycle control. However, its role in pancreatic cancer remains unclear. Our study aimed to investigate the roles of PRMT5 in pancreatic cancer prognosis and progression and to explore the underlying molecular mechanism. METHODS: Real-time PCR, immunohistochemistry and analysis of a dataset from The Cancer Genome Atlas (TCGA) were performed to study the expression of PRMT5 at the mRNA and protein levels in pancreatic cancer. Cell proliferation assays, including cell viability, colony formation ability and subcutaneous mouse model assays, were utilized to confirm the role of PRMT5 in cell proliferation and tumorigenesis. A Seahorse extracellular flux analyzer, a glucose uptake kit, a lactate level measurement kit and the measurement of 18F-FDG (fluorodeoxyglucose) uptake by PET/CT (positron emission tomography/computed tomography) imaging were used to verify the role of PRMT5 in aerobic glycolysis, which sustains cell proliferation. The regulatory effect of PRMT5 on cMyc, a master regulator of oncogenesis and aerobic glycolysis, was explored by quantitative PCR and protein stability measurements. RESULTS: PRMT5 expression was significantly upregulated in pancreatic cancer tissues compared with that in adjacent normal tissues. Clinically, elevated expression of PRMT5 was positively correlated with worse overall survival in pancreatic cancer patients. Silencing PRMT5 expression inhibited the proliferation of pancreatic cancer cells both in vitro and in vivo. Moreover, PRMT5 regulated aerobic glycolysis in vitro in cell lines, in vivo in pancreatic cancer patients and in a xenograft mouse model used to measure 18F-FDG uptake. We found that mechanistically, PRMT5 posttranslationally regulated cMyc stability via F-box/WD repeat-containing protein 7 (FBW7), an E3 ubiquitin ligase that controls cMyc degradation. Moreover, PRMT5 epigenetically regulated the expression of FBW7 in pancreatic cancer cells. CONCLUSIONS: The present study demonstrated that PRMT5 epigenetically silenced the expression of the tumor suppressor FBW7, leading to increased cMyc levels and the subsequent enhancement of the proliferation of and aerobic glycolysis in pancreatic cancer cells. The PRMT5/FBW7/cMyc axis could be a potential therapeutic target for the treatment of pancreatic cancer.

Do anti-stroma therapies improve extrinsic resistance to increase the efficacy of gemcitabine in pancreatic cancer?

Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating human malignancies, with approximately 20-30% of PDAC patients receiving the surgical resection with curative intent. Although many studies have focused on finding ideal "drug chaperones" that facilitate and/or potentiate the effects of gemcitabine (GEM) in pancreatic cancer, a significant benefit in overall survival could not be demonstrated for any of these combination therapies in PDAC. Given that pancreatic cancer is characterized by desmoplasia and the dual biological roles of stroma in pancreatic cancer, we reassess the importance of stroma in GEM-based therapeutic approaches in light of current findings. This review is focused on understanding the role of stromal components in the extrinsic resistance to GEM and whether anti-stroma therapies have a positive effect on the GEM delivery. This work contributes to the development of novel and promising combination GEM-based regimens that have achieved significant survival benefits for the patients with pancreatic cancer.

AJCC 7th edition staging classification is more applicable than AJCC 8th edition staging classification for invasive IPMN.

BACKGROUND: Both the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) staging systems have been introduced for pancreatic adenocarcinoma. However, the applicability of these classifications for invasive intraductal papillary mucinous neoplasms (IPMN) has not been systematically examined. METHODS: Patients with invasive IPMN were retrieved from a cohort of 18 geographical sites (1973-2014 varying) in the Surveillance, Epidemiology, and End Results (SEER) cancer registry. The 7th and 8th editions of the AJCC staging were compared. Survival rates and multivariate analyses were computed. RESULTS: In total, 1216 patients with resected invasive IPMN were included. A major difference between the 7th and 8th systems is the definition of stage IIA (7th, beyond the pancreas without involvement of major arteries; 8th, maximum tumor diameter > 4 cm). The hazard ratio (HR) of stage IIA disease (versus stage IA, HR = 2.33, P < 0.001) was higher than that of stage IB disease (HR = 1.48, P = 0.087) by the 7th edition classification, whereas the HR of stage IIA disease (HR = 1.26, P = 0.232) was even lower than that of stage IB disease (HR = 1.48, P = 0.040) by the 8th edition classification. In addition, for the 8th edition staging system, tumor size was not a predictor of survival in patients with resectable tumor > 2 cm (size > 4 cm versus > 2 ≤ 4 cm, HR = 0.91, P = 0.420). CONCLUSIONS: The AJCC 7th edition staging classification is more applicable than the 8th edition classification for invasive IPMN.

MiR-29a, targeting caveolin 2 expression, is responsible for limitation of pancreatic cancer metastasis in patients with normal level of serum CA125.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive gastrointestinal tumors, with an overall 5-year survival rate less than 8%. The dismal prognosis is mainly due to aggressive potential for metastasis. Hence, there is an urgent need for a better understanding of the molecular mechanisms underlying pancreatic cancer invasion and metastasis to improve the unfavorable overall survival (OS) of PDAC patients. In this study, we identified microRNA-29a (miR-29a) as an important tumor suppressor, which was downregulated in PDAC tissues. Moreover, miR-29a counteracted MUC16-mediated migration and invasion. In the pancreatic cancer cells, MUC16 upregulated c-Myc expression, which enhanced c-Myc binding to E-box in the miR-29a promoter and inhibited miR-29a transcription. Thus, miR-29a was negatively correlated with both MUC16 expression and serum CA125 levels. Furthermore, caveolin 2 (CAV2) was demonstrated to be the target of miR-29a by bioinformatics and luciferase reporter assays, and high CAV2 expression was responsible for a poor prognosis, especially in the subgroup with normal CA125 levels. Thus, the present study explains why high levels of serum CA125 are correlated with PDAC metastasis, highlighting the predictive value of this marker in PDAC patients.

Intrinsic Contact Between T and N Classifications in Resected Well-Moderately Differentiated Locoregional Pancreatic Neuroendocrine Neoplasms.

BACKGROUND: The role of N classification is controversial in several prognostication systems proposed for pancreatic neuroendocrine neoplasms (pNENs). The widely accepted modified European Neuroendocrine Tumor Society (mENETS) system suggests this contradiction may be related to T classification. METHODS: Data were collected retrospectively from 981 patients in the Surveillance, Epidemiology, and End Results (SEER) database (1973-2012; cohort 1) and 140 patients from the Pancreatic Cancer Institute of Fudan University (2006-2016; cohort 2). All patients had resected well- to moderately differentiated locoregional pNENs, whereby the mENETS system was adopted. Factors related to N1 classification and the association between N and T classifications were analyzed, and N classification prognosis based on T classification was assessed. RESULTS: In cohorts 1 and 2, tumor size (2-4 cm: p < 0.001 and p = 0.037, respectively; > 4 cm: p < 0.001 and p = 0.012, respectively) and tumors extending beyond the pancreas (p < 0.001 and p = 0.016, respectively), which are factors for T classification, affected N1 classification. For tumors limited to the pancreas, the N1 classification was associated with tumor size (p < 0.001 and p = 0.046, respectively) and predicted poor disease-specific survival (DSS), while for tumors extending beyond the pancreas, the N1 classification did not affect patient outcomes. Findings obtained with data from the SEER database were reproducible with our institutional data. CONCLUSIONS: N classification is associated with T classification, limiting the value of N1 classification for the pNENs tumor-node-metastasis system. A new risk model is necessary to predict patient outcomes and guide clinical practice for the prognosis of pNENs.

Tumor-Infiltrating Platelets Predict Postsurgical Survival in Patients with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Platelets are believed to promote tumor growth and metastasis in several tumor types. The prognostic role of blood platelets in pancreatic ductal adenocarcinoma (PDAC) remains controversial, and the prognostic value of tumor-infiltrating platelets (TIPs) remains unknown. METHODS: A total of 303 patients who underwent curative pancreatectomy for PDAC were enrolled from two independent centers in China and divided into three cohorts. Paired preoperative blood samples and surgical specimens from all patients were analyzed. The correlations between patient outcomes and preoperative blood platelet counts and the presence of TIPs, respectively, were analyzed. TIPs were identified by immunohistochemical staining of CD42b. Prognostic accuracy was estimated by concordance index (C-index) and Akaike information criterion (AIC). RESULTS: TIPs, but not preoperative blood platelet counts, were associated with overall survival (OS; all P < 0.001) and recurrence-free survival (RFS; all P < 0.001) in the training, testing, and validation sets. Positive CD42b expression predicted poor postsurgical survival. Incorporation of TIPs improved the predictive accuracy of the 8th edition American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system for OS in each of the three cohorts (C-index: 0.7164, 0.7569, and 0.7050, respectively; AIC: 472, 386, and 1019, respectively). The new predictor system was validated by incorporating TIPs with the 7th edition AJCC TNM staging system (C-index: 0.7052, 0.7623, and 0.7157; AIC: 476, 386, and 1015). CONCLUSION: TIPs were an independent prognostic factor that could be incorporated into the AJCC TNM staging system to refine risk stratification and predict surgical outcomes of patients with PDAC.