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.

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.

Glutamine is a substrate for glycosylation and CA19-9 biosynthesis through hexosamine biosynthetic pathway in pancreatic cancer.

BACKGROUND: Carbohydrate antigen 19-9 (CA19-9) is the most widely used biomarker for pancreatic cancer. Since CA19-9 closely correlates with patient outcome and tumor stage in pancreatic cancer, the deciphering of CA19-9 biosynthesis provides a potential clue for treatment. METHODS: Concentration of amino acids was detected by ultrahigh-performance liquid chromatography tandem mass spectrometry. Metabolic flux of glutamine was examined by isotope tracing untargeted metabolomics. Label-free quantitative N-glycosylation proteomics was used to examine N-glycosylation alterations. RESULTS: Among all amino acids, glutamine was higher in CA19-9-high pancreatic cancers (> 37 U/mL, 66 cases) than in CA19-9-normal clinical specimens (≤ 37 U/mL, 37 cases). The glutamine concentration in clinical specimens was positively correlated with liver metastasis or lymphovascular invasion. Glutamine blockade using diazooxonorleucine suppressed pancreatic cancer growth and intraperitoneal and lymphatic metastasis. Glutamine promotes O-GlcNAcylation, protein glycosylation, and CA19-9 biosynthesis through the hexosamine biosynthetic pathway. UDP-N-acetylglucosamine (UDP-GlcNAc) levels correlated with the glutamine influx through hexosamine biosynthetic pathway and supported CA19-9 biosynthesis. CONCLUSIONS: Glutamine is a substrate for CA19-9 biosynthesis in pancreatic cancer. Glutamine blockade may be a potential therapeutic strategy for pancreatic cancer.

Hyperglycemia predicts adverse prognosis in advanced pancreatic cancer patients.

BACKGROUND: Diabetes mellitus is a prevalent comorbidity in pancreatic cancer. Previous studies have mainly concentrated on the association between diabetes and pancreatic cancer outcomes. However, research on the impact of hyperglycemia on the prognosis of patients with advanced pancreatic cancer is limited. METHODS: Information on patients with advanced pancreatic cancer was collected from a prospectively maintained database, and the patients were divided into the hyperglycemia group (fasting blood glucose ≥7.0 mmol/L) and the normoglycemia group (fasting blood glucose < 7.0 mmol/L). Patients with preexisting diabetes were not included in these groups. The associations between hyperglycemia and clinical variables or prognosis were analyzed. RESULTS: Among 697 patients with advanced pancreatic cancer and no prior history of diabetes, 25.3% were diagnosed with hyperglycemia. Patients older than 65 years had a higher risk of developing hyperglycemia (P = 0.044). Patients with hyperglycemia had a worse prognosis than those with normoglycemia (median survival, 7.5 vs. 8.8 months, P < 0.001). Hyperglycemia was associated with increased mortality (hazard ratio = 1.38; P = 0.003). CONCLUSIONS: Hyperglycemia predicts worse overall survival in patients with advanced pancreatic cancer.

Hyperglycemia is associated with adverse prognosis in patients with pancreatic neuroendocrine neoplasms.

BACKGROUND: Although glucose has a well-recognized protumoral role and the pancreas is a critical organ in adjusting glucose metabolism, the clinical value of hyperglycemia in pancreatic neuroendocrine neoplasms (pNENs) remains largely unidentified. METHODS: A retrospective study including 335 patients with pathologically confirmed pNENs was conducted. A baseline fasting blood glucose concentration ≥5.6 mmol/L was defined as hyperglycemia (otherwise, normal). Survival and regression analyses were performed. RESULTS: Compared with patients with normal glucose, patients with hyperglycemia (47.8%) had a higher proportion of preexisting diabetes mellitus (DM) (36.9% vs. 4.6%, p < 0.001), lymph node involvement (31.0% vs. 14.6%, p = 0.002), distant metastasis (34.4% vs. 22.9%, p = 0.019), and carbohydrate antigen 19-9 (CA19-9) ≥ 37 U/mL (16.6% vs. 7.2%, p = 0.009). Hyperglycemia was associated with CA19-9 ≥ 37 U/mL (Odds Ratio (OR) = 3.19, 95% CI: 1.11-9.17, p = 0.031), lymph node involvement (OR = 2.32, 95% CI: 1.02-5.28, p = 0.045), nonfunctional tumors (OR = 9.90, 95% CI: 2.11-46.34, p = 0.004), and preexisting diabetes (OR = 18.24, 95% CI: 4.06-81.95, p < 0.001). Hyperglycemia was an independent determinant for overall survival in the multivariate analysis (hazard ratio (HR) = 2.65, 95% CI: 1.31-5.34, p = 0.006). CONCLUSION: Hyperglycemia is an independent predictor of overall survival and is associated with preexisting DM or lymphatic metastasis in patients with pNENs. Patients with hyperglycemia and resectable pNENs may benefit from radical resection with dissection of regional lymph nodes.

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.

High pre-operative fasting blood glucose levels predict a poor prognosis in patients with pancreatic neuroendocrine tumour.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Roles of CA19-9 in pancreatic cancer: Biomarker, predictor and promoter.

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.

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma.

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-ß-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.

Clinical implication of serum CA125 for the prediction of malignancy in mucinous cystic neoplasms of the pancreas.

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.

Active surveillance in metastatic pancreatic neuroendocrine tumors: A 20-year single-institutional experience.

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are heterogeneous and indolent; systemic therapy is not essential for every patient with metastatic PanNET. The National Comprehensive Cancer Network guidelines state that delaying treatment is an option for PanNET with distant metastasis, if the patient has stable disease. However, specific factors that influence surveillance were not mentioned. In addition, data regarding the period of active surveillance in patients with metastatic PanNET are lacking. AIM: To specifically determine factors influencing active surveillance in patients with liver metastatic nonfunctioning PanNETs (NF-PanNETs). METHODS: Seventy-six patients with liver metastatic NF-PanNETs who received active surveillance from a high-volume institution were enrolled. Time to disease progression (TTP) and time to initiation of systemic therapy were determined. RESULTS: Thirty-one (40.8%) patients had recurrent liver disease after R0 resection; 45 (59.2%) were diagnosed with liver metastasis. The median follow-up period was 42 mo and 90.7% patients were observed to have disease progression. The median TTP (mTTP) was 10 mo. Multivariate analysis showed that the largest axis of the liver metastasis > 5 mm (P = 0.04), non-resection of the primary tumor (P = 0.024), and T3-4 stage (P = 0.028) were associated with a shorter TTP. The mTTP in patients with no risk factors was 24 mo, which was significantly longer than that in patients with one (10 mo) or more (6 mo) risk factors (P < 0.001). A nomogram with three risk factors showed reasonable calibration, with a C-index of 0.603 (95% confidence interval: 0.47-0.74). CONCLUSION: Active surveillance may only be safe for metastatic NF-PanNET patients with favorable risk factors, and other patients progressed rapidly without treatment. Further studies with a larger sample size and a control group are needed.

Absolute Counts of Peripheral Lymphocyte Subsets Correlate with the Progression-Free Survival and Metastatic Status of Pancreatic Neuroendocrine Tumour Patients.

PURPOSE: 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.

Prognosis of distal pancreatic cancers controlled by stage.

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<0.001). In addition, the proportion of body/tail pancreatic cancer increased from 24.9% in 1973 to 36.3% in 2014. Therefore, tumor location of body/tail is an independent adverse prognostic factor for patients with pancreatic cancer. However, this observation is not applicable when controlled by stage (body/tail versus head pancreatic cancer, better stage I, similar stage II/III, and worse stage IV).

Diabetes Is Associated With the Metastasis of Pancreatic Neuroendocrine Tumors.

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.

Lewis antigen­negative pancreatic cancer: An aggressive subgroup.

Carbohydrate antigen 19­9 (CA19­9) is the most important biomarker for pancreatic cancer. Approximately 5­10% of individuals are Lewis antigen negative with scarce secretion of CA19­9 and fucosylation deficiency. However, the characteristics of Lewis­negative pancreatic cancer are unidentified. Clinicopathological characteristics of 853 patients with pancreatic cancer were examined. Pancreatic cancer cell lines were sequenced for Lewis status. Morphological and molecular features of pancreatic cancer cells were compared. Orthotopic animal modes were established. Lewis­negative patients had poorer outcome (P<0.001), higher metastatic rate (P=0.004), lower CA19­9 expression (P<0.001) and higher MUC16 expression (P<0.001) than Lewis­positive patients. Lewis­negative cells (CaPan­1, MiaPaCa­2 and Panc­1) showed a shuttle shape with scarce pseudopods. Overall, Lewis­negative cells had higher proliferation rate, higher migration ability, lower fucosylation, lower CA19­9 expression and higher MUC16 expression than Lewis­positive cells (BxPC­3, SU8686, SW1990). Lewis­negative cell line MiaPaCa­2 corresponded to larger orthotopic tumor than Lewis­positive cells SU8686. Potential proteoglycans were identified in Lewis­positive cancer, including EGFR, HSPG2, ADAM17, GPC1, ITGA2, CD40, IL6ST and GGT1. Therefore, Lewis­negative pancreatic cancer is an aggressive subgroup with special clinical and molecular features.

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.

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.

Haemoglobin, albumin, lymphocyte and platelet predicts postoperative survival in pancreatic cancer.

BACKGROUND: Systemic inflammation and nutrition status play an important role in cancer metastasis. The combined index of hemoglobin, albumin, lymphocyte, and platelet (HALP), consisting of haemoglobin, albumin, lymphocytes, and platelets, is considered as a novel marker to reflect both systemic inflammation and nutrition status. However, no studies have investigated the relationship between HALP and survival of patients with pancreatic cancer following radical resection. AIM: To evaluate the prognostic value of preoperative HALP in pancreatic cancer patients. METHODS: The preoperative serum levels of hemoglobin, albumin, lymphocyte counts, and platelet counts were routinely detected in 582 pancreatic adenocarcinoma patients who underwent radical resection. The relationship between postoperative survival and the preoperative level of HALP was investigated. RESULTS: Low levels of HALP were significantly associated with lymph node metastasis (P = 0.002), poor tumor differentiation (P = 0.032), high TNM stage (P = 0.008), female patients (P = 0.005) and tumor location in the head of the pancreas (P < 0.001). Low levels of HALP were associated with early recurrence [7.3 mo vs 16.3 mo, P < 0.001 for recurrence-free survival (RFS)] and short survival [11.5 mo vs 23.6 mo, P < 0.001 for overall survival (OS)] in patients with resected pancreatic adenocarcinoma. A low level of HALP was an independent risk factor for early recurrence and short survival irrespective of sex and tumor location. CONCLUSION: Low levels of HALP may be a significant risk factor for RFS and OS in patients with resected pancreatic cancer.