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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.

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy characterized by a poor prognosis and high mortality rate. Genetic mutations and altered molecular pathways serve as targets in precise therapy. Using next-generation sequencing (NGS), these aberrant alterations can be identified and used to develop strategies that will selectively kill cancerous cells in patients with PDAC. The realization of targeted therapies in patients with PDAC may be summarized by three approaches. First, because oncogenes play a pivotal role in tumorigenesis, inhibition of dysregulated oncogenes is a promising method (Table 3). Numerous researchers are developing strategies to target oncogenes, such as KRAS, NRG1, and NTRK and related molecules, although most of the results are unsatisfactory. Accordingly, emerging strategies are being developed to target these oncogenes, including simultaneously inhibiting multiple molecules or pathways, modification of mutant residues by small molecules, and RNA interference. Second, researchers have attempted to reactivate inactivated tumour suppressors or modulate related molecules. TP53, CDKN2A and SMAD4 are three major tumour suppressors involved in PDAC. Advances have been achieved in clinical and preclinical trials of therapies targeting these three genes, and further investigations are warranted. The TGF-β-SMAD4 signalling pathway plays a dual role in PDAC tumorigenesis and participates in mediating tumour-stroma crosstalk and modulating the tumour microenvironment (TME); thus, molecular subtyping of pancreatic cancer according to the SMAD4 mutation status may be a promising precision oncology technique. Finally, genes such as KDM6A and BRCA have vital roles in maintaining the structural stability and physiological functions of normal chromosomes and are deficient in some patients with PDAC, thus serving as potential targets for correcting these deficiencies and precisely killing these aberrant tumour cells. Recent clinical trials, such as the POLO (Pancreas Cancer Olaparib Ongoing) trial, have reported encouraging outcomes. In addition to genetic event-guided treatment, immunotherapies such as chimeric antigen receptor T cells (CAR-T), antibody-drug conjugates, and immune checkpoint inhibitors also exhibit the potential to target tumours precisely, although the clinical value of immunotherapies as treatments for PDAC is still limited. In this review, we focus on recent preclinical and clinical advances in therapies targeting aberrant genes and pathways and predict the future trend of precision oncology for PDAC.

Yitao Gong,1– 4,* Zhiyao Fan,1– 4,* Guopei Luo,1– 4,* Qiuyi Huang,1– 4 Yunzhen Qian,1– 4 He Cheng,1– 4 Kaizhou Jin,1– 4 Quanxing Ni,1– 4 Xianjun Yu,1– 4 Chen Liu1– 4 1Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China; 3Shanghai Pancreatic Cancer Institute, Shanghai 200032, People’s Republic of China; 4Pancreatic Cancer Institute, Fudan University, Shanghai 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xianjun Yu; Chen LiuDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai 200032, People’s Republic of ChinaTel + 86 21-64175590 ext 1307Fax + 86 21-64031446Email yuxianjun@fudanpci.org; liuchen@fudanpci.orgPurpose: Pancreatic neuroendocrine tumours (panNETs) are rare tumours of pancreas. Lymphocyte subsets in the peripheral blood are reported to reflect tumour prognosis and progression. The objective of the study is to investigate the hypotheses that the levels of peripheral lymphocytes may reflect tumour progression and may predict the prognosis of pancreatic neuroendocrine tumours (panNETs).Patients and Methods: A retrospective cohort study consisting of 73 patients diagnosed with panNETs was conducted. Kaplan–Meier methods and Log rank tests were used to compare the survival rates, and a Cox regression model was used to perform multivariate analyses.Results: panNET patients with distant metastasis were associated with lower peripheral total T cell (p = 0.039) and CD4+ T cell (p = 0.006) counts. Lower peripheral B cells (p = 0.007) and higher peripheral NK cell (p = 0.001) counts indicated worse progression-free survival (PFS) in Log rank tests. In multivariate analyses, low B cell count (hazard ratio (HR): 6.769, 95% confidence interval (CI): 2.158 to 21.228, p = 0.001) and high NK cell count (HR: 3.715, 95% CI: 1.164 to 11.855, p = 0.027) were independent risk factors for progression. NK cells and B cells were also significantly associated with PFS following radical surgical resection.Conclusion: Peripheral total T cell and CD4+ T cell counts may reflect the distant metastasis status in panNET patients. The absolute count of peripheral B cells and NK cells may independently predict the progression of panNET patients, making them promising prognostic indicators and potential targets for treatment of panNETs.Keywords: pancreatic neuroendocrine tumours, panNETs, lymphocyte subsets, progression-free survival, B cells

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.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.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.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.

Patients with distal (body/tail) pancreatic cancer have been found to present worse outcome than patients with head cancer, which is generally attributed to the great proportion of advanced stages for body/tail cancers upon detection. However, differences in prognosis between head and body/tail pancreatic cancers controlled by stage have not been analyzed in-depth. In this study, differences in prognosis between head and body/tail pancreatic cancers were examined using the Surveillance, Epidemiology, and End Results Program (SEER) (1973-2014 registry, 85,715 cases). We found that patients with body/tail pancreatic cancer had worse prognosis than patients with head cancer for all combined stages [adjusted hazard ratio (HR), 1.03, 95% confidence interval (CI), 1.00-1.05, P=0.025]. Compared with patients with head cancer, patients with body/tail cancer had lower mortality for stage I cancers (HR, 0.85, 95% CI, 0.76-0.94, P=0.001), no difference in mortality for stages II or III (stage II, HR, 1.00, 95% CI, 0.95-1.06, P=0.965; stage III, 0.97, 95% CI, 0.91-1.04, P=0.398), and higher mortality for stage IV (HR, 1.07, 95% CI, 1.04-1.10, P

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.

Purpose The CRP/albumin (Alb) ratio, a recently reported predictor, has shown value for prognosis in various human cancers. This study aimed to determine the prognostic value of baseline CRP/Alb and to explore the relevance between postchemotherapy CRP/Alb and the efficacy of chemotherapy in advanced pancreatic cancer patients. Patients and methods Five hundred and ninety-five patients diagnosed with locally advanced or metastatic adenocarcinoma of the pancreas were enrolled. Cut-off Finder was used to calculate the best cut‑off value for baseline CRP/Alb. The primary endpoint was overall survival, which was analyzed by Kaplan-Meier survival curves with 95% confidence intervals. The log rank test and Cox proportional hazard model were used to evaluate the univariate and multivariate analyses. Results The optimal cut-off value for baseline CRP/Alb was determined to be 0.18. Both the baseline CRP/Alb (CRP/Alb≥0.18 vs. CRP/Alb

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 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.

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).The new 8th AJCC staging system for PDAC was released in October, 2016, and will be applied in clinical practice in 2018.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).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).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.

Purpose: The systemic inflammation response index (SIRI), based on peripheral neutrophil, monocyte, and lymphocyte counts, was recently emerged and used as a novel tool in predicting prognosis in different types of cancer. Our aim was to investigate the clinical significance of preoperative SIRI in patients with resectable pancreatic ductal adenocarcinoma (PDAC). Materials and methods: The SIRI was developed in a training cohort of 371 PDAC patients undergoing radical surgery between 2010 and 2013 and validated in a validation cohort of 310 patients from 2014 to 2015. Baseline clinicopathologic characteristics, preoperative laboratory parameters and follow-up information were collected. The optimal cutoff value of SIRI was determined by receiver operating characteristic curve. Univariate and multivariate analysis were performed to analyze the prognostic value of SIRI. Results: The optimal cutoff value of SIRI stratified patients into low SIRI group (≤0.69) and high SIRI group (>0.69). Survival analysis showed that the median overall survival (OS) and recurrence-free survival (RFS) were significantly better in patients with low SIRI. The SIRI was an independent predictor of OS and RFS in multivariate analysis. In addition, SIRI remained its prognostic significance both in patients with early-stage diseases and in patients with normal carbohydrate antigen 19-9 levels. High SIRI indicated poor treatment response for patients who received postoperative adjuvant chemotherapy. Conclusion: Preoperative SIRI was an independent prognostic indicator of poor outcomes in PDAC patients after radical resection. It might assist clinicians to identify high-risk patients and choose the optimal individualized treatment strategy.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with poor prognosis. Many preoperative biomarkers can predict postoperative survival of PDAC patients. In this study, we created a novel ratio index based on preoperative liver function test, γ‐glutamyltransferase‐to‐albumin ratio (GAR), and evaluated its prognostic value in predicting clinical outcomes of PDAC patients following radical surgery. We retrospectively enrolled 833 PDAC patients who had underwent radical surgery at our institution between January 2010 and January 2017. Patients were divided into two groups according to the cut‐off value of GAR. Univariate and multivariate survival analysis between the groups were evaluated. TNM stage, GAR, preoperative serum carbohydrate antigen 19‐9 (CA19‐9) and tumor differentiation were combined to generate a more accurate prognostic model. The optimal cut‐off value of GAR was 0.65. Significant correlations were found between GAR and tumor location, tumor size, vascular invasion, obstructive jaundice, biliary drainage and parameters of liver function test. Univariate and multivariate analysis showed that high level of GAR independently predicted poorer postoperative overall survival (OS, P < 0.001) and recurrence‐free survival (RFS, P < 0.001). Subgroup analysis demonstrated that GAR was predictive of survival in patients without biliary obstruction or severely impaired liver function. In addition, integration of GAR, preoperative serum CA19‐9, and tumor differentiation into TNM staging system could better stratify the prognosis for PDAC patients compared with TNM stage alone. Our study demonstrates that preoperative GAR is an independent prognostic factor for prediction of surgical outcomes in PDAC patients. Combination of TNM stage, GAR, preoperative serum CA19‐9, and tumor differentiation can enhance the prognostic accuracy.

Background Carbohydrate antigen 19-9 (CA19-9) is the best-validated biomarker for pancreatic cancer. The National Comprehensive Cancer Network (NCCN) guideline asserts that “CA19-9 will be undetectable in Lewis antigen-negative individuals”. However, reports of CA19-9 secretion and its significance in Lewis (-) patients with pancreatic cancer have been inconsistent. This study was to examine serum CA19-9 levels in patients with pancreatic cancer according to Lewis status. Methods Patients with pancreatic cancer (1482 cases) were retrieved from a prospectively maintained database. Patients with benign pancreatic disease (210 cases) and normal subjects (315 cases) were used as controls. Lewis genotypes were examined by fucosyltransferase 3 (FUT3) sequencing. Results In patients with pancreatic cancer, 8.4% of subjects were Lewis (-), but only 41.9% of Lewis (-) subjects had CA19-9 values ≤ 2 U/mL. CA19-9 was even elevated (>37 U/mL) in 27.4% of Lewis (-) patients. The area under the receiver operating characteristic (ROC) curve for CA19-9 as a diagnostic biomarker was 0.842 in Lewis (-) patients with pancreatic cancer, which is closing to that of CA19-9 applied in all of patients with pancreatic cancer (0.898). Lewis (-) status was an independent prognostic factor for shorter survival in a multivariable analysis (hazard ratio (HR), 1.30, 95% confidence interval (CI), 1.03–1.64; P = 0.028). Conclusions Not all Lewis (-) patients with pancreatic cancer are non-secretors of CA19-9. Contrary to general understanding, CA19-9 can retain its utility as a biomarker in these patients in spite of Lewis (-) genotype.

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.

Mucinous cystic neoplasms (MCNs) of the pancreas have malignant potential. Carbohydrate antigen 125 (CA125) is a common widely used biomarker for cancers. However, the role of CA125 in predicting the malignant change of MCNs is currently unidentified. Patients with resected and pathologically confirmed MCN were identified from a prospectively maintained database. The predictive role of serum CA125 in assessing malignant change of MCNs was analyzed and compared with serum carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA). This study included 164 patients with MCN (low/moderate grade, 153 cases; high grade and invasive, 11 cases). The serum levels of CA125 in the high grade and invasive group (45.1±42.1 U/ml) was significantly higher than those in the low/moderate grade group (21.0±46.2 U/ml, P=0.006). The area under the receiver operating characteristic (ROC) curve of CA125 (0.75) for predicting malignancy of MCNs was higher than that of CA19-9 (0.68) or CEA (0.72). The prediction value of CA125 was improved when combined with CEA (CA125 alone, sensitivity 36.4%, specificity 90.6%, accuracy 86.6%; combined with CEA, sensitivity 45.5%, specificity 88.2%, accuracy 85.0%). It was concluded that serum CA125 shows value in predicting the malignant change of MCNs, especially when combined with serum CEA.

Objectives Type 2 diabetes mellitus (T2DM) has been associated with several types of cancers, but the role of T2DM in pancreatic neuroendocrine tumors (pNETs) has not been systematically studied. Methods In this study, 299 patients with pNETs were recruited, and the clinicopathologic characteristics and prognosis of the diabetic and nondiabetic patients were compared. The association between metformin use and survival was assessed to examine whether metformin impacts the prognosis of pNETs patients. Results The prevalence of T2DM in the cohort was 20.7% (n = 62). The proportions of grade 3 tumors, distant metastases, and nerve invasion in pNET patients with T2DM were higher than those in patients without T2DM, and as a result, the survival was worse in patients with T2DM. After adjusting for the tumor stage, diabetic status was not associated with poor survival in the univariate analysis. The results of logistic regression showed that pNET patients with T2DM were at high risk for tumor metastasis (odds ratio [OR], 2.81; P = 0.001), nerve invasion (OR, 2.43; P = 0.029), and grade 3 tumors (OR, 4.97; P = 0.010). Conclusions Type 2 diabetes mellitus is associated with pNET metastasis and not an independent risk factor for poor prognosis in pNETs.

Carbohydrate antigen 19-9 (CA19-9) is the best validated biomarker and an indicator of aberrant glycosylation in pancreatic cancer. CA19-9 functions as a biomarker, predictor, and promoter in pancreatic cancer. As a biomarker, the sensitivity is approximately 80%, and the major challenges involve false positives in conditions of inflammation and nonpancreatic cancers and false negatives in Lewis-negative Individuals. Lewis antigen status should be determined when using CA19-9 as a biomarker. CA19-9 has screening potential when combined with symptoms and/or risk factors. As a predictor, CA19-9 could be used to assess stage, prognosis, resectability, recurrence, and therapeutic efficacy. Normal baseline levels of CA19-9 are associated with long-term survival. As a promoter, CA19-9 could be used to evaluate the biology of pancreatic cancer. CA19-9 can accelerate pancreatic cancer progression by glycosylating proteins, binding to E-selectin, strengthening angiogenesis, and mediating the immunological response. CA19-9 is an attractive therapeutic target for cancer, and strategies include therapeutic antibodies and vaccines, CA19-9-guided nanoparticles, and inhibition of CA19-9 biosynthesis.

Hyperglycaemia has been indicated as a pro-tumoural factor; however, the prognostic role of diabetes mellitus (DM) in pancreatic neuroendocrine tumours (panNETs) remains ambiguous, partly due to the effects of anti-diabetic drugs. We hypothesise that the blood sugar level per se affects the outcome of panNETs, and thus, we investigated the prognostic significance of the fasting blood glucose (FBG) level in resected panNET patients with no pre-existing DM. A retrospective cohort study comprising 201 patients with radically resected non-functional panNETs was conducted. A total of 164 patients without pre-existing DM were further studied. An FBG level greater than 5.6 mmol/L was defined as high (otherwise, normal). Survival was evaluated using Kaplan–Meier methods and log-rank tests. Multivariate analyses for survival were performed using the Cox regression model. High FBG levels were significantly associated with poor overall survival (OS; p = 0.019) and recurrence-free survival (RFS; p = 0.011) in resected patients with panNET who had no pre-existing DM. The multivariable-adjusted hazard ratios (HRs) for mortality and recurrence comparing patients with high and normal FBG levels were 12.19 (95% confidence interval (CI) = 1.15–128.78, p = 0.038) and 2.43 (95% CI = 1.03–5.72, p = 0.042), respectively. A pre-operative FBG level greater than 5.6 mmol/L is associated with poor OS and RFS metastasis for patients with panNET who undergo radical surgical resection.

To evaluate the prediction of benefits from adjuvant chemoradiotherapy by postoperative serum CA19-9, CA125 and CEA.The relations between benefits from adjuvant chemoradiotherapy and levels of postoperative serum CA19-9, CA125 and CEA were investigated in 804 pancreatic adenocarcinoma patients who received radical resection.Adjuvant chemoradiotherapy was an independent factor for late recurrence [12.2 vs. 8.5 months, P = 0.001 for recurrence free survival (RFS)] and long survival [23.7 vs. 17.0 months, P 0.001 for overall survival (OS)] in resected pancreatic adenocarcinoma. Postoperative serum CA19-9, CA125 and CEA were independent risk predictors for poor surgical outcome in pancreatic adenocarcinoma (P 0.001 for all). Adjuvant chemradiotherapy (hazard ratio: 0.359, 95% confidence interval: 0.253-0.510, P 0.001 for OS; hazard ratio: 0.522, 95% confidence interval: 0.387-0.705, P 0.001 for RFS) were confirmed to improve the surgical outcome in patients with abnormal levels of any one of the three postoperative markers, but not in patients with normal levels of the three postoperative markers. In the subgroup of patients with negative lymph node, its improvement of surgical outcome was also significant in patients with abnormal levels of any one of postoperative serum CA19-9, CA125 and CEA (hazard ratio: 0.412, 95% confidence interval: 0.244-0.698, P = 0.001 for OS; hazard ratio: 0.546, 95% confidence interval: 0.352-0.847, P = 0.007 for RFS).Postoperative serum CA19-9, CA125 and CEA could serve as predictors of response for adjuvant chemoradiotherapy even if the status of lymph nodes is negative.

Pancreatic cancer remains one of the most lethal malignant diseases worldwide. The majority of patients present with advanced disease and, therefore, need palliative chemotherapy. Some chemotherapeutic regimens have been well established as first-line therapies and have been shown to increase survival; however, almost all patients with advanced pancreatic cancer will experience disease progression after first-line therapy. Nevertheless, many patients who retain good performance status after initial treatment remain good candidates for additional therapy. Historically, few studies have assessed second-line therapy, with most reports representing small phase II trials with variable findings; however, clinical research for second-line treatment has increased in the past decade, and several randomized controlled trials using different regimens have been published. The current literature shows varying results on treatment efficacy and tolerability. Thus, we reviewed the published data on the use of chemotherapy in the second-line setting for the treatment of advanced pancreatic cancer.

Radical surgical resection represents the only hope of cure for pancreatic neuroendocrine tumor (PanNET). Adjuvant therapy is rarely used because there is no evidence to distinguish patients with high recurrence risk. Here we investigated the recurrence feature of resected PanNET and established a novel risk stratification to predict its recurrence. We analyzed 505 PanNET patients who underwent R0 resection at our institute from January 2004 through May 2015. The median follow-up was 71months (range: 12months-143months), 129 patients (25.5%) experienced recurrence with median disease-free survival (mDFS) of 19months. Restricted cubic spline (RCS) functions revealed a positive, linear relationship between Ki-67 index and recurrence. Multivariate analysis showed T stage, N stage, insulinoma and Ki-67 index were independent predictors of recurrence (P

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.

Background Carcinoembryonic antigen (CEA) is one of the most widely used tumor markers and is increased in 30%-60% of patients with pancreatic cancer. Although carbohydrate antigen 19-9 (CA19-9) is the most important serum biomarker in pancreatic cancer, the diagnostic and prognostic value of CEA is gradually being recognized. Materials and methods The MEDLINE, EMBASE, and Web of Science databases were searched for related literature published until January 2017. Diagnostic accuracy variables were pooled using the Meta-Disc software. The pooled hazard ratios (HRs) for prognostic data were calculated and analyzed using Stata software. Results A total of 3,650 participants enrolled in 19 studies met our inclusion criteria. The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of a CEA-based panel were 0.45 (95% confidence interval [CI], 0.41-0.50), 0.89 (95% CI, 0.86-0.91), 5.39 (95% CI, 3.16-9.18), and 0.55 (95% CI, 0.41-0.72), respectively. The area under the curve (AUC, 0.90) and Q-value (0.84) of the CEA-based panel indicated a significantly higher diagnostic accuracy compared with CEA or CA19-9 alone. Moreover, there was also a significant association between high levels of CEA and worse overall survival (HR, 1.43; 95% CI, 1.31-1.56). Conclusion Our meta-analysis indicated that elevated serum CEA level, as a vital supplementary to CA19-9, can play an important role in the clinical diagnosis of pancreatic cancer patients and predict poor prognosis.

Background Previously we have proposed a modified European Neuroendocrine Tumor Society (mENETS) staging system for pNETs, which is more suitable than either the American Joint Committee on Cancer (AJCC) or the European Neuroendocrine Tumor Society (ENETS) systems. However, it is necessary to revise the nodal stage of the mENETS system for the under representation of stage III diseases. Methods Nodal substages of the upper gastrointestinal organs (N0: 0 node, N1: 1–2 nodes; N2: ≥3 nodes) or the lower gastrointestinal organs (0: 0 node, N1: 1–3 nodes, and N2:≥ 4 nodes) were incorporated into the mENETS system and evaluated using the Surveillance, Epidemiology, and End Results (SEER) registry series. Results The mENETS classification with the upper gastrointestinal N-stage revision (stage III, 17.1%) had better proportional distribution than the mENETS classification (stage III, 8.7%) or the lower gastrointestinal N-stage revision (stage III, 14.5%). N-stage revision (N0: 0 node, N1: 1–2 nodes; N2: ≥3 nodes) was incorporated in the mENETS staging definition for further analysis. Survival curves were well separated by nodal substages. HRs of stage IIA (T3N0M0) and IIB (T1-3N1M0) of the mENETS classification with N-stage revision were similar, indicating these two substages should be attributed to stage II. Survival curves were well separated by stage using the mENETS classification with N-stage revision. Conclusions The mENETS classification with N-stage revision (N0: 0 node, N1: 1–2 nodes; N2: ≥3 nodes) had better prognostic value and proportional distribution than the mENETS classification for pNETs and can be used in clinical practice.

The aim of the present study was to investigate the clinical, pathological and prognostic characteristics of Chinese patients with resected pancreatic neuroendocrine neoplasms (p-NENs). Data from patients who were surgically treated and pathologically diagnosed with p-NENs at the Department of Pancreatic Oncology of the Fudan University Shanghai Cancer Center (Shanghai, China), between January 2003 and July 2015, were evaluated using univariate and multivariate analyses. A total of 162 patients with p-NENs met the criteria of the present study and were included in the analysis. Patients with poorly differentiated pancreatic neuroendocrine carcinoma (p-NEC) exhibited a significantly increased rate of lymph node metastasis, as compared with patients with grade (G)1/G2 pancreatic neuroendocrine tumors (p-NETs) (62.5 vs. 20.5%, P=0.003). Univariate analysis identified that the following factors led to decreased overall survival (OS): Lymph node metastasis (P=0.001, vs. the absence of lymph node metastasis); distant metastasis (P=0.043, vs. the absence of distant metastasis); resection margin R1/R2 (P=0.030, vs. R0 resection); NEC G3 (P5–20%; G3, >20%) was more efficient for prognostic stratification compared with the European Neuroendocrine Tumor Society (Berlin, Germany)/World Health Organization (Geneva, Switzerland) 2010 grading classification. The present study indicated that p-NEC was an important predictor of decreased OS in Chinese patients. Furthermore, a Ki-67 staining index of 5% represented a more efficient value for the distinction between G1 and G2.

Cell-free circulating tumor DNA (ctDNA) in plasma has been used as a potential noninvasive biomarker for various tumors. Our study was performed to evaluate the clinical implications of ctDNA detection in patients with metastatic pancreatic cancer. First, we attempted to prospectively screen a panel of 60 genes in cell-free DNA (cfDNA) from ten metastatic pancreatic cancer patients via exome sequencing. Second, droplet digital PCR (ddPCR) was used to identify potential mutations in a cohort of 188 patients with metastatic pancreatic cancer. Finally, to preliminary evaluate the potential role of ctDNA in monitoring tumor responses following chemotherapy, we detected the presence of ctDNA in serial plasma samples from 13 metastatic pancreatic cancer patients (Clinical trial: NCT02017015). The analysis revealed five somatic mutations at BRCA2, EGFR, KDR and ERBB2 gene loci. The frequencies of ctDNA mutation at BRCA2, KDR, EGFR, ERBB2 exon17 and ERBB2 exon27 were 11.7%, 13.8%, 13.3%, 13.3% and 6.4% respectively. Univariate and multivariate analyses identified the ERBB2 exon17 mutation (p = 0.035, HR = 1.61) as an independent factor associated with overall survival among metastatic pancreatic cancer patients. Furthermore, the rate of coincident detection of ctDNA and response to treatment as assessed by CT imaging was 76.9% (10 of 13 cases), and the presence of ctDNA provided the earliest measure of treatment in 6 of 10 patients (60%). ctDNA sequencing may have clinical value for determining metastatic pancreatic cancer treatment and monitoring the tumor response.

Although the prognostic role of neutrophil-lymphocyte ratio (NLR) has been confirmed in a variety of tumors, the prognostic role of NLR in pancreatic neuroendocrine tumors (PNETs) has not been examined. The present study was performed to assess the role of NLR as a prognostic factor in patients with PNETs. Clinical data were retrospectively retrieved from a single institution. The best cut-off value for baseline NLR levels was determined by the receiver operating characteristic (ROC) curve and area under the ROC curve. The primary event was overall survival and event times were assessed by the Kaplan-Meier method. Potential factors associated with the elevation of NLR in PNETs were examined. A total of 165 consecutive patients with pathologically confirmed PNETs were included in this study. The cutoff value of NLR was 2.4 by ROC curve (area under ROC curve, 0.70). NLR >2.4 was found to be a poor prognostic factor in the univariate and multivariate analyses. Patients with a NLR value >2.4 had a higher proportion of tumor size at >3 cm (P=0.001), TNM stage III or IV (P=0.019), and G2/G3 (P=0.003). We concluded that NLR is an independent predictor of overall survival for patients with PNETs. Aberrant elevation of NLR identifies high-risk patients with aggressive characteristics.

Background: Few options besides the avoidance of smoking and obesity are available to prevent pancreatic cancer. The association between aspirin use and risk of pancreatic cancer has been inconsistent across studies. Methods: We performed a population-based study of 761 case and 794 control subjects frequency matched on sex and age during 2006 to 2011 in Shanghai, China. Participants were asked about episodes of regular use of aspirin, tablets per day or week, and ages that the use started and stopped. Data were analyzed by unconditional logistic regression, with adjustments for age, sex, education, body mass index, years of cigarette smoking, cigarettes smoked per day, Helicobacter pylori CagA seropositivity, ABO blood group, and history of diabetes mellitus. Meta-regression was carried out to summarize the literature. Results: Ever-regular use of aspirin was associated with lowered risk of pancreatic cancer: OR = 0.54; 95% confidence interval (CI), 0.40–0.73; P = 10−4.2. Risk decreased 8% per each cumulative year of use: ORtrend = 0.92; 95% CI, 0.87–0.97; P = 0.0034. Across this and 18 published studies of this association, the OR for ever-regular use decreased with increasingly more recent mid-study year, for any aspirin type (Ptrend = 10−5.1), and for low-dose aspirin (Ptrend = 0.0014). Conclusions: Regular use of aspirin thus appears to reduce risk of pancreatic cancer by almost half. Impact: People who take aspirin for prevention of other diseases likely also reduce their risk of pancreatic cancer. Aside from benefits for both cardiovascular disease and certain cancers, long-term aspirin use entails some risks of bleeding complications, which necessitates risk–benefit analysis for individual decisions about use. Cancer Epidemiol Biomarkers Prev; 26(1); 68–74. ©2016 AACR.

Background: Increasing evidence from recent studies has revealed the association of CA125 with the diagnosis of pancreatic cancer, but inconsistent findings have been reported. We aimed to evaluate the diagnostic value of a serum CA125-based diagnostic panel in predicting malignant pancreatic cancer. Materials and Methods: We searched EMBASE, MEDLINE and Web of Science for relevant articles from inception to October 2016. Methodological quality was evaluated using the Quality Assessment of Comparative Diagnostic Accuracy Studies (QUADAS-2) checklist. The performance characteristics were pooled using random-effects models. The statistical analysis was performed using Meta-Disc 1.4 and Stata Version 12.0 software. Results: A total of 1235 participants pooled from 8 eligible studies were included in the meta-analysis to evaluate the accuracy of tumor predictors for the diagnosis of pancreatic cancer. The pooling accuracy analysis of CA125 alone indicated that the pooled sensitivity was 0.59 (95% CI: 0.54-0.62) and the specificity was 0.78 (95% CI: 0.75-0.82), whereas the serum CA125-based diagnostic panel had a pooled sensitivity of 0.47 (95% CI 0.47-0.51) and a specificity of 0.88 (95% CI 0.86-0.90). Furthermore, the AUC and Q-value of the CA125-based diagnostic panel were 0.89 and 0.82, respectively, which indicated that the CA125-based panel is superior to CA125 or CA19-9 alone in diagnosing pancreatic cancer. No obvious publication bias was found. Conclusions: In summary, a CA125-based diagnostic panel is better at diagnosing pancreatic cancer than a test using CA125 or CA19-9 alone. Further studies should be performed to confirm our conclusion.

The incidence of small (≤2 cm), non-functioning pancreatic neuroendocrine tumors (NF-pNETs) increased in the last decades. Before making appropriate strategy for patients with NF-pNETs ≤2 cm, pathological confirmation is vital. Incidentally diagnosed, sporadic small NF-pNETs may bring aggressive behavior and poor prognosis, such as extrapancreatic extension, lymph nodal metastasis, distant metastasis and recurrence, even causing disease-related death. Understanding and formulating an appropriate strategy for the patients with sporadic small, non-functioning pancreatic neuroendocrine tumors have been controversial for some time. Although several studies have reported that patients with NF-pNETs ≤2 cm had less rate of malignant behavior compared with larger ones (>2 cm); and the surgery approach may leading to surgery-related pancreatic complications; but there is still a lack of level I evidence to convince surgeons to abandon all cases with sporadic small NF-pNETs. Based on an updated literature search and review, the members of the Chinese Study Group for Neuroendocrine Tumors (CSNET) from high-volume centers have reached a consensus on the issue of the management strategy for the sporadic small NF-pNETs. We recommend that, except for some selected patients with NF-pNETs

Except pancreatic adenocarcinoma, pancreatic cancer has several uncommon histological subtypes, including invasive intraductal papillary mucinous neoplasm (IPMN), pancreatic neuroendocrine tumor (pNET), adenosquamous carcinoma, invasive mucinous cystic neoplasm (MCN), acinar cell carcinoma (ACC), squamous cell carcinoma (SCC), and invasive solid pseudopapillary tumor (SPT). However, features of theses uncommon subtypes are not systematically analyzed.Subjects with different histological subtypes of pancreatic cancers were retrieved from the Surveillance, Epidemiology, and End Results registry. Characteristics and behaviors of uncommon subtypes were compared.Pancreatic adenocarcinoma (85.8%) represented most primary pancreatic cancers, and other subtypes were rare (14.2%). Features of uncommon subtypes included females with SPT and MCN, located at the pancreatic body/tail of pNET, SPT, and MCN; poor differentiation of adenosquamous carcinoma and SCC; and large size of MCN, SPT, ACC, and SCC. In addition, IPMN, pNET, MCN, ACC, and SPT were indolent. For indolent subtypes, patients with locoregional tumor had prominent prognosis compared with patients with distant disease, especially for invasive IPMN (median survival, localized, 30.0 months; regional, 11.0 months; distant, 4.0 months).The study systematically summarizes characteristics and behaviors of primary pancreatic cancer by histological subtypes, which can facilitate the management of pancreatic cancer.

INTRODUCTION The aim of this study was to determine the optimal number of examined lymph nodes (ELNs) for accurate staging of pancreatic cancer using the nodal staging score model. MATERIALS AND METHODS Clinicopathological data for patients with resected pancreatic cancer were collected from SEER database (development cohort [DC]) and Fudan University Shanghai Cancer Center database (validation cohort [VC]). Multivariable models were constructed to assess how the number of ELNs was associated with stage migration and overall survival (OS). Using the β-binomial distribution, we developed a nodal staging score model from the DC and tested it with the VC. RESULTS Both cohorts exhibited significant proportional increases from node-negative to node-positive disease (DC: odds ratio [OR], 1.047; P

The C-reactive protein/albumin (CRP/Alb) ratio is associated with outcome in septic patients. However, as an inflammation-based score, its prognostic value for cancer has scarcely been investigated. Between February 2010 and January 2015, we enrolled 386 patients with pancreatic ductal adenocarcinoma. Univariate and multivariate survival analysis between the groups were evaluated. Receiver operating characteristics curves were generated and areas under the curve (AUC) were compared to evaluate the discriminatory ability of the inflammation-based prognostic scoring systems, including CRP/Alb ratio, neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR) and modified Glasgow prognostic score (mGPS). The optimal cutoff level of the CRP/Alb ratio was defined as 0.180. The prognosis of patients with CRP/Alb ratio ≥0.180 was significantly worse than CRP/Alb ratio

Background The aim of this study was to assess the immune profile within the microenvironment of pancreatic ductal adenocarcinoma (PDAC), and to investigate the prognostic value of intratumoral infiltrating immune/inflammatory cells (IICs) in patients after surgery. Methods Eighteen phenotypic markers representing 11 types of IIC and the protein products of genes TP53, CDKN2A/p16 and SMAD4/DPC4 were assessed by immunohistochemistry of specimens from patients with pancreatic cancer. The expression of IICs and the mutational status of the genes were correlated with tumour recurrence and survival, and results were validated in an independent cohort. Results CD15+ neutrophils, CD20+ B cells and CD206+ tumour-associated macrophages were seen frequently in tumours, and their presence was associated with reduced survival in a cohort of 79 patients. Expression of CD4+ T helper cells, CD8+ cytotoxic T lymphocytes and CD117+ mast cells was associated with a favourable prognosis. A weighted Cox regression recurrence-predictive model was constructed that showed good correlation of IICs and gene mutations. A combination of CD15, CD206, CD117 and Smad4 expression was independently associated with overall (hazard ratio (HR) 3·63, 95 per cent c.i. 2·18 to 6·04; P < 0·001) and recurrence-free (HR 2·93, 1·81 to 4·75; P < 0·001) survival. These findings were validated in an independent cohort (151 patients) and in 54 tissue samples obtained by preoperative endoscopic ultrasound-guided fine-needle aspiration. Conclusion PDAC has a unique immunosuppressive phenotype that is associated with characteristic gene mutations, disease recurrence and survival after pancreatectomy. Surgical relevanceThe immune microenvironment plays a critical role in the development of pancreatic ductal adenocarcinoma (PDAC). PDAC is associated with mutations in major driver genes, including KRAS, TP53, CDKN2A/p16 and SMAD4/DPC4.This study shows that the microenvironment of PDAC has a unique immunosuppressive phenotype, which may be driven by oncogene mutations. Patients with PDAC with a highly immunosuppressive profile tended to have poor postoperative survival. A model including three intratumoral infiltrating immune markers (CD15+, CD206+ and CD117+) and a SMAD4 mutation can be used to predict recurrence and survival in patients after surgery for PDAC.

In patients with cancer of the pancreatic head, metastasis to para-aortic lymph nodes (LN16) is considered distant metastasis and a poor prognostic marker. However, the incidence of LN16 involvement in pancreatic head cancer is high, and it is unclear whether all such patients have poor surgical outcomes. We investigated the significance of LN16 involvement in resectable pancreatic head cancer by retrospectively analyzing 579 ductal adenocarcinoma patients treated with para-aortic lymph node dissection at two high-volume Chinese centers. Depending upon tumor location, the incidence of LN16 metastasis and the correlation between LN16 involvement and involvement of Group 1 or 2 lymph nodes significantly differed. Metastasis to LN16 indicated a high serum tumor burden and a poor prognosis, though LN16-positive patients with a lymph node ratio (LNR) < 0.25 may still benefit from radical surgery. Survival analysis of LN16-positive patients with resectable pancreatic head cancer revealed that tumor size, tumor differentiation, and tumor location are independent prognostic factors. We also found that preoperative serum CA125 < 18.62 U/ml and the level of JAK2 signaling are both indicators of who may benefit from curative surgical resection for pancreatic head cancer.

Pancreatic cancer is one of the most malignant human tumors. Perineural invasion, whereby a cancer cell invades the perineural spaces surrounding nerves, is acknowledged as a gradual contributor to cancer aggressiveness. Furthermore, perineural invasion is considered one of the root causes of the recurrence and metastasis observed after pancreatic resection, and it is also an independent predictor of prognosis. Advanced research has demonstrated that the neural microenvironment is closely associated with perineural invasion in pancreatic cancer. Therapy targeting the molecular mechanism of perineural invasion may enable the durable clinical treatment of this formidable disease. This review provides an overview of the present status of perineural invasion, the relevant molecular mechanisms of perineural invasion, pain and hyperglycemia associated with perineural invasion in pancreatic cancer, and the targeted therapeutics based on these studies.

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.

To evaluate the effectiveness of nab-paclitaxel plus gemcitabine (NG) as a first-line treatment for advanced pancreatic cancer. A meta-analysis was performed to assess the impact on the objective response rate (ORR), survival rate and grade 3/4 adverse events. Of the 2,056 patients included from 26 studies, the median overall survival ranged from 6.9 months to 24.7 months, with a 1-year survival rate of 45.2% (95%CI: 35.8% -54.5%). The 6-month progression-free survival rate was 41.0% (95%CI: 30.5% - 51.4%), and the ORR was 31.6% (95%CI: 26.7% - 36.6%). Fifty locally advanced pancreatic cancer (LAPC) patients underwent surgery and had an R0 resection rate of 52.0%. No death was caused by toxicity, and 1,329 grade 3/4 adverse events were reported in 1,353 patients. NG has been proven to reduce tumours with an acceptable toxicity profile in metastatic pancreatic cancer. This analysis further demonstrates the efficacy and safety of NG for treating LAPC.

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.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).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).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.

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. 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. 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

Objectives Notable modifications have been made in the American Joint Committee on Cancer (AJCC) Staging eighth edition staging for pancreatic cancer for the consideration of the irreproducible and inapplicable of the AJCC seventh edition staging. However, the new staging classification has not been systemically verified. Methods A comparison was performed to evaluate the application of the AJCC seventh and eighth staging classifications using the Surveillance, Epidemiology, and End Results registry (18,450 patients) and an institutional series (2040 patients). Results For the eighth staging classification, patients with tumor diameter of greater than 4 cm (T3N0M0, IIA) had similar prognosis to patients with 1 to 3 positive nodes (T1-3N1M0, IIB). For patients who underwent tumor resection and without lymph node involvement, survival curves of T1 (≤2 cm), T2 (2-4 cm), and T3 (>4 cm) were well separated. Statistical difference in survival analyses was demonstrated in N0 (0 positive node), N1 (1-3 positive nodes), and N2 (≥4 positive nodes) patients underwent tumor resection. The AJCC eighth edition had better stage distribution than the AJCC seventh edition for pancreatic cancer. Conclusions The eighth edition of AJCC staging is more applicable and accurate than the seventh edition for pancreatic adenocarcinoma.

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. 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). NETs were associated with OS (both, P

Patients with pancreatic ductal adenocarcinoma have much worse prognoses, and much effort has been directed toward understanding the molecular biological aspects of this disease. Accumulated evidence suggests that constitutive activation of the Wnt/β-catenin signalling contributes to the oncogenesis and progression of pancreatic cancer. Transcription factor 7-like2/transcription factor 4 (TCF7L2/TCF4), a β-catenin transcriptional partner, plays a vital role in the Wnt/β-catenin signalling pathway. In the present study, we investigated the clinicopathological significance of TCF7L2 in pancreatic cancer. Our results demonstrated that patients with higher TCF7L2 expression had worse prognosis. Our in vitro studies demonstrated that TCF7L2 positively regulated aerobic glycolysis by suppressing Egl-9 family hypoxia inducible factor 2 (EGLN2), leading to upregulation of hypoxia inducible factor 1 alpha subunit (HIF-1α). The impact of TCF7L2 on aerobic glycolysis was further confirmed in vivo by assessing 18FDG uptake in pancreatic cancer patients and in a subcutaneous xenograft mouse model. In summary, we identified novel predictive markers for prognosis and suggest a previously unrecognized role for TCF7L2 in control of aerobic glycolysis in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer. The 5-year survival rate for PDAC remains low because it is always diagnosed at an advanced stage and it is resistant to therapy. A biomarker, which could detect asymptomatic premalignant or early malignant tumors and predict the response to treatment, will benefit patients with PDAC. However, traditional biopsy has its limitations. There is an urgent need for a tumor biomarker that could easily and repeatedly sample and monitor, in real time, the progress of tumor development. Liquid biopsy could be a tool to assess potential biomarkers. In this review, we focused on the latest discoveries and advancements of liquid biopsy technology in pancreatic cancer research and demonstrated how this technology is being used in clinical applications.

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.

Background Development of a postoperative pancreatic fistula (POPF) is the single most significant complication of pancreatic anastomosis, which is a key procedure in pancreaticoduodenectomy. We previously reported a new papillary-like pancreaticojejunostomy, and a retrospective study showed a benefit in reducing the incidence of grade B/C POPF compared with duct-to-mucosa pancreaticojejunostomy. The aim of this study was to reassess whether the new pancreaticojejunostomy would decrease the POPF rate. Methods A prospective, randomized, controlled trial (NCT01731821 registered at http://ClinicalTrials.gov ) involving 308 patients who underwent pancreaticoduodenectomy was conducted. Results The overall POPF rate was significantly lower in the papillary-like group compared with the duct-to-mucosa group (14/155 [9.0%] vs 31/153 [20.3%]; P = .005), and the grade B/C POPF rate of the papillary-like group was significantly decreased compared with the duct-to-mucosa group. Multivariable analyses identified higher body mass index (odds ratio [OR], 3.520; P = .000), longer operative time (OR, 2.587; P = .041), soft texture and nondilated main pancreatic duct (OR, 0.365; P = .014), and the duct-to-mucosa pancreaticojejunostomy (OR, 0.405; P = .013) as significant risk factors for POPF. Further stratified analyses showed that, for patients with soft texture and nondilated main pancreatic duct, the POPF rate in the papillary-like group (9.6%) was significantly lower than that in the duct-to-mucosa group (27.3%). However, for patients with hard texture or dilated main pancreatic duct, there was no difference between the 2 groups (7.8% vs 8.6%; P > 0.999). Conclusion The new papillary-like pancreaticojejunostomy may provide a better option for patients with soft texture and nondilated main pancreatic duct.

The highly heterozygous nature of pancreatic cancer is partially responsible for its therapeutic ineffectiveness and resistance. Therefore, the ability to identify subgroups of pancreatic cancer with unique biological characteristics and treatment response is urgently needed. In addition to breast and ovarian cancer, pancreatic cancer is the third most common cancer type that is related to the early onset (BRCA) gene mutation in breast cancer. Mounting evidence has demonstrated that BRCA1/2-mutant breast and ovarian cancers are highly sensitive to DNA damage-related treatment, including poly(ADP-ribose) polymerase inhibitors (PARPi) and platinum-based agents. Preliminary evidence also showed promising results for DNA damage-related treatment in BRCA1/2-mutant pancreatic cancer. Importantly, several prospective clinical trials of PARPi-based regimens are underway for BRCA1/2-mutated pancreatic cancer. Pancreatic cancer with a BRCA1/2 mutation is a small subgroup with a promising therapeutic strategy.

Background Incidentally discovered, nonfunctioning pancreatic endocrine tumors (NF-pNETs) are being increasingly diagnosed with the widespread use of imaging examination. The objective of this study was to analyze the different clinicopathologic and imaging features between incidentally discovered and symptomatic NF-pNETs. Methods From March 2010 to October 2014, we retrospectively analyzed 102 patients with pathologically confirmed sporadic NF-pNETs, among which 49 (48.0%) had lesions that were discovered incidentally. Differences in clinicopathologic features and various computerized tomography (CT) and endoscopic ultrasonography (EUS) findings were evaluated between incidental and symptomatic NF-pNETs. Results Among 102 patients with NF-pNETs, 49 (48.0%) had lesions that were discovered incidentally. Incidental NF-pNETs were more highly associated with low tumor grades, stages and lymphatic metastasis compared with symptomatic tumors ( p = 0.007, 0.029 and 0.003, respectively). Moreover, incidental NF-pNETs had a lower rate of hypoenhancement ( p = 0.018), main pancreatic duct dilatation ( p = 0.043), and unclear border ( p = 0.022). In addition, hypoechoic lesion was the most common and had a slightly higher rate in symptomatic tumors ( p = 0.032). Conclusions Incidental NF-pNETs are associated with lower rates of aggressive behaviors of clinicopathologic and imaging features compared with symptomatic tumors.

Pancreatic cancer is currently one of the deadliest solid malignancies and pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. In the past decade, diagnostics and surgical techniques for PDAC have been evolving steadily; however, clinical outcomes of patients with PDAC have shown little, if any, improvement. Subgroup classification based on accurate prediction of prognosis in patients with pancreatic cancer is important for treatment selection and clinical decision-making. The traditional method to evaluate prognosis relies on the TNM staging system, but it may not reflect the true status of every patient due to individual biological differences. Metabolomics is a field of study that involves the identification and quantification of metabolites present in a biological system. Analysis of metabolic differences between cancerous and noncancerous tissues can provide novel insights into tumor biology that are closely associated with disease prognosis and diagnosis. Therefore, evaluation of metabolic tumor burden may improve the accuracy of the clinical decision-making process, thereby facilitating optimization of the treatment strategies for pancreatic cancer.

Purpose The main objectives of this retrospective study were to survey the genetic landscape of PNETs in a clinical cohort by using the high throughput gene sequencing method and to determine cellular signaling networks affected by the uncovered gene mutations. Materials and methods We retrieved the demographics and tumor characteristics of 13 patients. Cellular DNA was extracted from fresh snap frozen tumor tissues and was subject to high throughput gene sequencing analysis using the Illumina NextSeq500 System. Furthermore, the interaction network was constructed from the input gene set by Reactome and performed gene set enrichment analysis was performed with a cutoff FDR of ≤0.01. Results Totally 74 mutated genes and 93 mutations were identified. The median number of mutations was 7 (range 1–20) and that of mutated genes was 6 (range 1–17). Among these mutations, 48 (51.6%) were substitution mutations, nine (9.7%) were duplication mutations, 28 (30.1%) were deletion mutations and eight (8.6%) were deletion/insertion mutations. Gene set enrichment analysis generated a network of 21 interactions, 10 of which were associated with DNA repair like the Fanconi anemia pathway, nucleotide excision repair, and homologous recombination repair, or chromosome maintenance. Moreover, 9 patients had one or more mutations in DNA repair genes including the mismatch repair genes MSH2/MSH6. Conclusions The study has uncovered genetic alterations of genes implicated in DNA damage responses and chromatin remodeling. Our findings will prompt further studies into the role of these mutated genes in the oncogenesis and molecular stratification of PNETs.