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Background Utilization of multimodality therapy for clinical stage I-II pancreatic ductal adenocarcinoma is associated with meaningful prolongation of survival. Although the qualitative existence of disparities in treatment utilization by socioeconomic status and race/ethnicity is well documented, the absolute magnitudes of these disparities have not been previously quantified. Methods The exposures in this retrospective cohort study of the 2010–2015 National Cancer Database were a 7-value area-level socioeconomic status index and race/ethnicity. Main outcomes were surgery, chemotherapy, and multimodality therapy (surgery and chemotherapy). Adjusted rate differences were calculated after logistic regression. Models excluded intermediate variables. Overall survival was evaluated in unadjusted and adjusted analyses. Results Of 43,760 patients, 63.4% underwent surgery. Of 39,808 patients without chemotherapy contraindications, refusal, or missing data, 75.1% received chemotherapy and 51.4% received multimodality therapy. Adjusted rate differences for utilization of surgery, chemotherapy, and multimodality therapy in the lowest socioeconomic status patients were –10.0 (95% confidence interval [CI] –12.4 to –7.5), –12.7 (95% CI –16.3 to –9.1), and –15.4 (95% CI –18.8 to –12.0), respectively, versus the highest socioeconomic status patients. Adjusted rate differences for multimodality therapy utilization in non-Hispanic Black and Hispanic patients were –10.1 (95% CI –13.6 to –6.7) and –11.8 (95% CI –14.3 to –9.2), respectively, versus non-Hispanic White patients. Median overall survival increased in a graded fashion from 14.1 (95% CI 13.4–14.8) months in the lowest socioeconomic status patients to 20.2 months (95% CI 19.6–20.8) in the highest socioeconomic status patients. Survival differences were attenuated but not eliminated in multivariable Cox models. Conclusion Socioeconomic status and race/ethnicity are more powerful determinants of whether patients receive treatment for clinical stage I-II pancreatic ductal adenocarcinoma than previously appreciated. Nationwide quality improvement efforts aimed at addressing these inequities are warranted.

To (1) evaluate rates of surgery for clinical stage I-II pancreatic ductal adenocarcinoma (PDAC), (2) identify predictors of not undergoing surgery, (3) quantify the degree to which patient- and hospital-level factors explain differences in hospital surgery rates, and (4) evaluate the association between adjusted hospital-specific surgery rates and overall survival (OS) of patients treated at different hospitals.Curative-intent surgery for potentially resectable PDAC is underutilized in the United States.Retrospective cohort study of patients ≤85 years with clinical stage I-II PDAC in the 2004 to 2014 National Cancer Database. Mixed effects multivariable models were used to characterize hospital-level variation across quintiles of hospital surgery rates. Multivariable Cox proportional hazards models were used to estimate the effect of adjusted hospital surgery rates on OS.Of 58,553 patients without contraindications or refusal of surgery, 63.8% underwent surgery, and the rate decreased from 2299/3528 (65.2%) in 2004 to 4412/7092 (62.2%) in 2014 (P0.001). Adjusted hospital rates of surgery varied 6-fold (11.4%-70.9%). Patients treated at hospitals with higher rates of surgery had better unadjusted OS (median OS 10.2, 13.3, 14.2, 16.5, and 18.4 months in quintiles 1-5, respectively, P0.001, log-rank). Treatment at hospitals in lower surgery rate quintiles 1-3 was independently associated with mortality [Hazard ratio (HR) 1.10 (1.01, 1.21), HR 1.08 (1.02, 1.15), and HR 1.09 (1.04, 1.14) for quintiles 1-3, respectively, compared with quintile 5] after adjusting for patient factors, hospital type, and hospital volume.Quality improvement efforts are needed to help hospitals with low rates of surgery ensure that their patients have access to appropriate surgery.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival rate of 7.7%. Most patients are diagnosed at an advanced stage not amenable to potentially curative resection. A substantial portion of this review is dedicated to reviewing the current literature on carbohydrate antigen (CA 19-9), which is currently the only guideline-recommended biomarker for PDAC. It provides valuable prognostic information, can predict resectability, and is useful in decision making about neoadjuvant therapy. We also discuss carcinoembryonic antigen (CEA), CA 125, serum biomarker panels, circulating tumor cells, and cell-free nucleic acids. Although many biomarkers have now been studied in relation to PDAC, significant work still needs to be done to validate their usefulness in the early detection of PDAC and management of patients with PDAC.

This population-based study investigates the survival and causes of death in patients with pancreatic adenocarcinoma to 21 years after diagnosis.

Background Genes associated with hereditary breast and ovarian cancer (HBOC) and colorectal cancer (CRC) predisposition have been shown to play a role in pancreatic cancer susceptibility. Growing evidence suggests that pancreatic cancer may be useful as a sentinel cancer to identify families that could benefit from HBOC or CRC surveillance, but to date pancreatic cancer is only considered an indication for genetic testing in the context of additional family history. Methods Preliminary data generated at the Huntsman Cancer Hospital (HCH) included variants identified on a custom 34-gene panel or 59-gene panel including both known HBOC and CRC genes for respective sets of 66 and 147 pancreatic cancer cases, unselected for family history. Given the strength of preliminary data and corresponding literature, 61 sequential pancreatic cancer cases underwent a custom 14-gene clinical panel. Sequencing data from HCH pancreatic cancer cases, pancreatic cancer cases of the Cancer Genome Atlas (TCGA), and an unselected pancreatic cancer screen from the Mayo Clinic were combined in a meta-analysis to estimate the proportion of carriers with pathogenic and high probability of pathogenic variants of uncertain significance (HiP-VUS). Results Approximately 8.6% of unselected pancreatic cancer cases at the HCH carried a variant with potential HBOC or CRC screening recommendations. A meta-analysis of unselected pancreatic cancer cases revealed that approximately 11.5% carry a pathogenic variant or HiP-VUS. Conclusion With the inclusion of both HBOC and CRC susceptibility genes in a panel test, unselected pancreatic cancer cases act as a useful sentinel cancer to identify asymptomatic at-risk relatives who could benefit from relevant HBOC and CRC surveillance measures. Electronic supplementary material The online version of this article (10.1186/s12885-018-4573-5) contains supplementary material, which is available to authorized users.

Background Calgranulin C (S100A12) is an innate immune peptide at the air–mucosal interface associated with neutrophil involvement, which when overexpressed has been implicated as a biomarker of inflammatory diseases. Decreased epithelial expression of certain innate immune peptides has been reported in chronic rhinosinusitis (CRS). We hypothesized that S100A12 is differentially expressed in the sinonasal mucosa of patients with CRS compared to controls and that S100A12 is a potential biomarker of CRS-specific quality of life (QOL) and disease severity. Methods A prospective observational study was conducted which included 70 patients: 17 controls, 28 having CRS without (CRSsNP), and 25 with (CRSwNP) nasal polyps. The expression of S100A12 and human neutrophil elastase (HNE) was assessed in the anterior ethmoid tissues from all patients using enzyme-linked immunosorbent assay (ELISA) and immunohistochemical (IHC) analyses. Disease-specific QOL (Rhinosinusitis Disability Index) and disease severity (computed tomography [CT] and endoscopy) were evaluated and correlated to the expression levels of S100A12. Results S100A12 and HNE were significantly elevated in patients with CRSsNP compared to normal controls ( P Conclusions S100A12 is differentially expressed in CRS subtypes and is significantly elevated in patients with CRSsNP and associated with CRS-specific disease severity.

Single-center studies in pancreatic adenocarcinoma have suggested that preoperative chemotherapy (PCT) is associated with higher lymph node ratio (LNR) than preoperative chemoradiation (PCRT). The association of postoperative chemotherapy with overall survival (OS) in patients treated with PCT and PCRT remains unclear. Our objectives were to investigate whether (1) PCT is associated with higher LNR than PCRT and (2) postoperative chemotherapy is associated with longer OS after PCT and PCRT in LNR-stratified cohorts. A retrospective cohort study was performed of patients with pancreatic adenocarcinoma treated with PCT or PCRT followed by resection between 2006 and 2014 in the National Cancer Database. Temporal trends were evaluated with Cuzick’s test. OS was evaluated with multivariable Cox regression and inverse probability weighted (IPW) Cox regression. Of 4187 patients, 1993 (47.6%) received PCT. PCT rates were stable at approximately 30% in 2006–2010 (p = 0.33) but increased to 64.9% by 2014 (p

Background and AimsGenes associated with hereditary breast and ovarian cancer (HBOC) and colorectal cancer (CRC) susceptibility have been shown to play a role in pancreatic cancer susceptibility. Germline genetic testing of pancreatic cancer cases could be beneficial for at-risk relatives with pathogenic variants in established HBOC and CRC genes, but it is unclear what proportion of pancreatic cancer cases harbor pathogenic variants in these genes.Methods66 pancreatic cancer cases, unselected for family history and diagnosed at the Huntsman Cancer Hospital (HCH), were sequenced on a custom 34-gene panel including known HBOC and CRC genes. A second set of 156 unselected HCH pancreatic cancer cases were sequenced on an expanded 59-gene panel (n=95) or with a custom 14-gene clinical panel (n=61). Sequencing data from both sets of pancreatic cancer cases, the pancreatic cancer cases of the Cancer Genome Atlas (TCGA), and an unselected pancreatic cancer screen from the Mayo Clinic were combined in a meta-analysis to estimate the proportion of carriers with pathogenic and variants of uncertain significance.ResultsApproximately 8.9% of unselected pancreatic cancer cases at the HCH carried a variant with potential HBOC or CRC screening recommendations. A meta-analysis of unselected pancreatic cancer cases revealed that approximately 10.5% carry a pathogenic variant or HiP-VUS.ConclusionWith the inclusion of both HBOC and CRC susceptibility genes in a panel test, unselected pancreatic cancer cases have a high enough percentage of carriers to rationalize genetic testing for identification of variants that could be further used in cascade testing of healthy relatives to increase HBOC and CRC surveillance measures.

Many patients with stage I-II pancreatic adenocarcinoma do not undergo resection. We hypothesized that (1) clinical staging underestimates nodal involvement, causing stage IIB to have a greater percent of resected patients and (2) this stage-shift causes discrepancies in observed survival.The Surveillance, Epidemiology, and End Results (SEER) research database was used to evaluate cause-specific survival in patients with pancreatic adenocarcinoma from 2004-2012. Survival was compared using the log-rank test. Single-center data on 105 patients who underwent resection of pancreatic adenocarcinoma without neoadjuvant treatment were used to compare clinical and pathologic nodal staging.In SEER data, medium-term survival in stage IIB was superior to IB and IIA, with median cause-specific survival of 14, 9, and 11 months, respectively (P .001). Seventy-two percent of stage IIB patients underwent resection vs 28% in IB and 36% in IIA (P .001). In our institutional data, 12.4% of patients had clinical evidence of nodal involvement vs 69.5% by pathologic staging (P .001). Among clinical stage IA-IIA patients, 71.6% had nodal involvement by pathologic staging.Both SEER and institutional data support substantial underestimation of nodal involvement by clinical staging. This finding has implications in decisions regarding neoadjuvant therapy and analysis of outcomes in the absence of pathologic staging.

The prognosis for patients with pancreatic cancer is extremely poor, as evidenced by the disease's five-year survival rate of ~5%. New approaches are therefore urgently needed to improve detection, treatment, and monitoring of pancreatic cancer. MRS-detectable metabolic changes provide useful biomarkers for tumor detection and response-monitoring in other cancers. The goal of this study was to identify MRS-detectable biomarkers of pancreatic cancer that could enhance currently available imaging approaches. We used (1) H high-resolution magic angle spinning MRS to probe metabolite levels in pancreatic tissue samples from mouse models and patients. In mice, the levels of lipids dropped significantly in pancreata with lipopolysaccharide-induced inflammation, in pancreata with pre-cancerous metaplasia (4 week old p48-Cre;LSL-Kras(G12D) mice), and in pancreata with pancreatic intraepithelial neoplasia, which precedes invasive pancreatic cancer (8 week old p48-Cre LSL-Kras(G12D) mice), to 26 ± 19% (p = 0.03), 19 ± 16% (p = 0.04), and 26 ± 10% (p = 0.05) of controls, respectively. Lactate and taurine remained unchanged in inflammation and in pre-cancerous metaplasia but increased significantly in pancreatic intraepithelial neoplasia to 266 ± 61% (p = 0.0001) and 999 ± 174% (p < 0.00001) of controls, respectively. Importantly, analysis of patient biopsies was consistent with the mouse findings. Lipids dropped in pancreatitis and in invasive cancer biopsies to 29 ± 15% (p = 0.01) and 26 ± 38% (p = 0.02) of normal tissue. In addition, lactate and taurine levels remained unchanged in inflammation but rose in tumor samples to 244 ± 155% (p = 0.02) and 188 ± 67% (p = 0.02), respectively, compared with normal tissue. Based on these findings, we propose that a drop in lipid levels could serve to inform on pancreatitis and cancer-associated inflammation, whereas elevated lactate and taurine could serve to identify the presence of pancreatic intraepithelial neoplasia and invasive tumor. Our findings may help enhance current imaging methods to improve early pancreatic cancer detection and monitoring.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate of 5%. There is an urgent need for early detection while the tumors are small and surgically resectable. We assessed serum osteopontin (OPN) and tissue inhibitor of metalloproteinase 1 (TIMP-1) as possible diagnostic and prognostic biomarkers in a novel cohort of patients with pancreatic cancer.Osteopontin and TIMP-1 levels were determined in sera from 86 patients with PDAC, 86 healthy control subjects, and 48 patients with chronic pancreatitis. Regression models were used to relate OPN and TIMP-1 to sex, age, stage, class, and treatment. Survival analyses were performed using univariate and multivariate Cox models.The serum levels of both OPN and TIMP-1 distinguished PDAC from chronic pancreatitis (P ≤ 0.0001) and healthy control subjects (P0.0001). The serum levels of both OPN and TIMP-1 also distinguished early-stage resectable PDAC cases from chronic pancreatitis (P0.04) and healthy control subjects (P0.01). High serum levels of OPN were significantly correlated with reduced patient survival.Serum OPN and TIMP-1 have use as diagnostic biomarkers in PDAC. Our data suggest a potential benefit of using OPN, TIMP-1, and CA 19-9 in a panel to improve diagnostic accuracy in PDAC.

Pancreatic cancer is the fourth most common cause of cancer mortality in the United States, with 5 year survival rates for patients with resectable tumors ranging from 15 - 20%. However, most patients present with distant metastases, are not resectable, and have a 5-year survival of close to 0%. This demonstrates a need for improved screening to identify pancreatic cancer while the tumor is localized and amenable to surgical resection. Studies of patients with pancreatic tumors incidentally diagnosed demonstrate longer median survival as compared with tumors discovered only when the patient is symptomatic, suggesting that early detection may improve outcome. Recent evidence from genomic sequencing indicates a 15 year interval for genetic progression of pancreatic cancer from initiation to the metastatic stage, suggesting a sufficient window for early detection. Still, many challenges remain in implementing effective screening. Early diagnosis of pancreatic cancer relies on developing screening methodologies with highly sensitive and specific biomarkers and imaging modalities. It also depends on a better understanding of the risk factors and natural history of the disease in order to accurately identify high risk groups that would be best served by screening. This review summarizes our current understanding of the biology of pancreatic cancer relevant to methods available for screening. At this time, given the lack of proven benefit in this disease, screening efforts should probably be undertaken in the context of prospective trials.

Age-associated decline in antioxidant potential and accumulation of reactive oxygen/nitrogen species are primary causes for multiple health problems, including muscular dystrophy and sarcopenia. The role of the nuclear erythroid-2-p45-related factor-2 (Nrf2) signaling has been implicated in antioxidant gene regulation. Here, we investigated the loss-of-function mechanisms for age-dependent regulation of Nrf2/ARE (Antioxidant Response Element) signaling in skeletal muscle (SM). Under basal physiological conditions, disruption of Nrf2 showed minimal effects on antioxidant defenses in young (2months) Nrf2−/− mice. Interestingly, mRNA and protein levels of NADH Quinone Oxidase-1 were dramatically (*P24months) had a significant increase in ROS along with a decrease in glutathione (GSH) levels and impaired antioxidants in Nrf2−/− when compared to WT SM. Further, disruption of Nrf2 appears to induce oxidative stress (increased ROS, HNE-positive proteins), ubiquitination and pro-apoptotic signals in the aged SM of Nrf2−/− mice. These results indicate a direct role for Nrf2/ARE signaling on impairment of antioxidants, which contribute to muscle degradation pathways upon aging. Our findings conclude that though the loss of Nrf2 is not amenable at younger age; it could severely affect the SM defenses upon aging. Thus, Nrf2 signaling might be a potential therapeutic target to protect the SM from age-dependent accumulation of ROS by rescuing redox homeostasis to prevent age-related muscle disorders such as sarcopenia and myopathy.

Objectives—To assess the relationship between telomere length and adiposity, using dualenergy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI), in addition to conventional anthropometric proxies including body mass index (BMI) and cardiovascular disease risk factors. Methods—A cross-sectional sample of 309 non-Hispanic white participants in the Fels Longitudinal Study aged 8 to 80 yr (52% female) was included. Average telomere length was measured by quantitative PCR. Results—Telomere length was negatively correlated with age (r = −0.32, P < 0.0001) and had numerous significant correlations with established cardiovascular disease risk factors including waist circumference (r = −0.33), apolipoprotein B (r = −0.26), systolic blood pressure (r = −0.28), and fasting serum glucose (r = −0.15); all P < 0.0025. In back-ward selection linear regression models of telomere length, adiposity measures were consistently retained in the best models; BMI, waist circumference, hip circumference, total body fat, and visceral adipose tissue volume were all inversely associated with telomere length at the nominal P < 0.05 level or lower, independent of age, sex, systolic blood pressure, and fasting serum lipid, lipoprotein, and glucose concentrations. The negative association of BMI with telomere length was stronger among younger than older participants (P for interaction, 0.03). Conclusions—Individuals with higher total and abdominal adiposity have lower telomere length, a marker of cellular senescence, suggesting obesity may hasten the aging process. Longitudinal studies are required to establish the causal association of early life adiposity with biological aging. Telomeres are noncoding repeat sequences at the ends of chromosomes [5′-(TTAGGG)n–3′] that function to stabilize the chromosome during mitosis, prevent aberrant recombination, and protect the chromosomes from end-degrading enzymes (Moyzis et al., 1988). In somatic cells, telomere repeats are lost at each cell division due to the inability of DNA polymerase to fully replicate chromosome ends (Levy et al., 1992; Olovnikov, 1973), leading to declines in telomere length with age. When telomere length reaches a critically short length in one or more chromosomes (the “Hayflick limit”), the cell is signaled to arrest replication and

Background: Improved diagnostic, predictive, and prognostic biomarkers for pancreatic ductal adenocarcinoma (PDAC) are urgently needed. Platelet factor 4 (PF4) has been proposed as a diagnostic biomarker for PDAC. We assessed the diagnostic and prognostic potential of serum PF4 levels in PDAC patients. Methods: Serum PF4 levels were determined by enzyme-linked immunosorbent assay in an initial cohort of 62 PDAC patients, 62 healthy control subjects, and 34 chronic pancreatitis patients. A second validation set consisted of 71 PDAC patients. Linear regression models were used to relate PF4 to class, gender, age, stage, platelet count, and diagnosis. Survival analyses were done using univariate and multivariate Cox models. Results: In the initial cohort, serum PF4 levels distinguished PDAC from chronic pancreatitis patients (P = 0.011), but not from healthy control subjects (P = 0.624). In PDAC patients, high serum PF4 level significantly predicted decreased survival independent of all covariates examined (P < 0.01). The prognostic relationship of serum PF4 levels remained significant in the validation set. Venous thromboembolism (VTE) occurred in 20% of the 133 PDAC patients. The VTE risk was higher in subjects with elevated PF4 levels (P = 0.009). Conclusions: Serum PF4 is shown for the first time to be prognostic for survival in PDAC patients. High PF4 is associated with an increased risk for the development of VTE. Impact: Serum PF4 levels may be useful for patient stratification and for directing treatment options in patients with pancreatic cancer including anticoagulation prophylaxis. The relationship between high PF4 levels and poorer outcomes requires further study. Cancer Epidemiol Biomarkers Prev; 19(10); 2605–10. ©2010 AACR.

The dismal prognosis of pancreatic adenocarcinoma is due in part to a lack of molecular information regarding disease development. Established cell lines remain a useful tool for investigating these molecular events. Here we present a review of available information on commonly used pancreatic adenocarcinoma cell lines as a resource to help investigators select the cell lines most appropriate for their particular research needs. Information on clinical history; in vitro and in vivo growth characteristics; phenotypic characteristics, such as adhesion, invasion, migration, and tumorigenesis; and genotypic status of commonly altered genes (KRAS, p53, p16, and SMAD4) was evaluated. Identification of both consensus and discrepant information in the literature suggests careful evaluation before selection of cell lines and attention be given to cell line authentication.

404 Background: Guidelines for adjuvant chemotherapy in patients with resected pancreatic adenocarcinoma (PDAC) who received neoadjuvant chemotherapy are equivocal. A lymph node ratio (LNR) ≥ 0.15 may predict lack of benefit, but conflicting results are reported. Methods: The National Cancer Database was searched to identify patients who were resected after neoadjuvant chemotherapy in 2006-2013. Exclusions: metastases at surgery, 90-day postoperative mortality, adjuvant radiation, and outlier interval from diagnosis to surgery (10 months). The association between adjuvant chemotherapy and overall survival (OS) from diagnosis was examined using multivariable Cox regression and inverse propensity of treatment weighted (IPTW) Cox regression. An IPTW based estimator of the average treatment effect (ATE) was used to quantify the population average survival benefit of treatment. Outcomes were examined in all patients and in those with LNR < 0.15 and ≥ 0.15. Results: 681/2488 patients (27%) received adjuvant chemotherapy. In multivariable Cox regression, adjuvant chemotherapy was associated with improved OS in the overall cohort and in patients with LNR < 0.15. A trend towards improved OS was also observed for those with LNR ≥ 0.15. After accounting for indication bias using IPTW, a significant survival benefit for was observed only for patients with LNR < 0.15. The ATE among LNR < 0.15 patients was 3.3 (95% CI 1.0, 5.7) months, indicating that the average survival of the population would be 3.3 months longer if all received treatment. Conclusions: Adjuvant chemotherapy in resected PDAC patients who received neoadjuvant therapy appears to be beneficial in patients with negative lymph nodes or minimal nodal burden. High LNR after neoadjuvant therapy may be an indicator of adverse tumor biology that is less likely to derive a therapeutic benefit. [Table: see text]

Timely, accurate diagnosis of pancreatic adenocarcinoma (PA) is hampered by the lack of effective circulating biomarkers. No single test has emerged that improves upon the commonly used biomarker cancer antigen 19–9 (CA 19–9) to discriminate PA from benign conditions effectively. The goals of this study were to validate two acute-phase proteins, haptoglobin and serum amyloid A (SAA), as biomarkers for PA and determine if the combination of haptoglobin, SAA, and CA 19–9 would improve PA diagnosis over CA 19–9 alone. Levels of haptoglobin, SAA, and CA 19–9 were measured in pretreatment sera from 75 PA patients, 32 patients with chronic pancreatitis, 42 patients with other benign pancreatic disease or biliary stricture, and 150 healthy control subjects by enzyme-linked immunosorbent assay or colorimetric binding assay. Relative levels of haptoglobin or SAA were compared between groups using analysis of variance. The diagnostic accuracy of serum haptoglobin and SAA levels were investigated using receiver operating characteristics (ROC) analysis. Using classification tree analysis, an algorithm was developed that used haptoglobin, SAA, and CA 19–9 in a diagnostic screening panel. Both haptoglobin and SAA were significantly elevated in sera from PA patients compared to healthy control subjects (p

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Pancreatic cancer (PC) is estimated to become the second leading cause of cancer death in the United States by 2020. Early detection is the key to improving survival in PC. Addressing this urgent need, the Kenner Family Research Fund conducted the inaugural Early Detection of Sporadic Pancreatic Cancer Summit Conference in 2014 in conjunction with the 45th Anniversary Meeting of the American Pancreatic Association and Japan Pancreas Society. This seminal convening of international representatives from science, practice, and clinical research was designed to facilitate challenging interdisciplinary conversations to generate innovative ideas leading to the creation of a defined collaborative strategic pathway for the future of the field. An in-depth summary of current efforts in the field, analysis of gaps in specific areas of expertise, and challenges that exist in early detection is presented within distinct areas of inquiry: Case for Early Detection: Definitions, Detection, Survival, and Challenges; Biomarkers for Early Detection; Imaging; and Collaborative Studies. In addition, an overview of efforts in familial PC is presented in an addendum to this article. It is clear from the summit deliberations that only strategically designed collaboration among investigators, institutions, and funders will lead to significant progress in early detection of sporadic PC.

Crosslinked, chemically modified hyaluronan (HA) hydrogels preloaded with two cytokine growth factors, vascular endothelial growth factor (VEGF) and Angiopoietin-1 (Ang-1), were employed to elicit new microvessel growth in vivo, in both the presence and absence of heparin in the gels. HA hydrogel film samples were surgically implanted in the ear pinnae of mice, and the ears were harvested at 7 or 14 days post implantation. Analysis of neovascularization showed that each of the treatment groups receiving an implant, except for HA/Hp at day 14, demonstrated significantly more microvessel density than control ears undergoing surgery but receiving no implant (p < 0.015). Treatment groups receiving either Ang-1 alone, or aqueous co-delivery of both Ang-1 and VEGF, were statistically unchanged with time. In contrast, film delivery of both growth factors produced continuing increases in vascularization from day 7 to day 14 in the absence of heparin, but decreases in its presence. However, presentation of both VEGF and Ang-1 in crosslinked HA gels containing heparin generated intact microvessel beds with well defined borders. The HA hydrogels containing Ang-1+VEGF produced the greatest angiogenic response of any treatment group tested at day 14 (NI = 7.44 in the absence of heparin and 4.67 in its presence, where NI is a neovascularization index). Even in the presence of heparin, this was 29% greater vessel density than the next largest treatment group, that receiving HA/Hp+VEGF (NI = 3.61, p = 0.04). New therapeutic approaches for numerous pathologies could be notably enhanced by the localized, sustained angiogenic response produced by release of both VEGF and Ang-1 from crosslinked HA films.

Even with improved cancer care generally, the incidence and death rate is increasing for pancreatic cancer. Concern exists that a further increase in deaths caused by pancreatic cancer will be seen as other causes of death, such as heart disease and other cancers, decline. Critical exploration of screening high-risk patients as a tool to reduce deaths from pancreatic cancer should be considered. Technological advances and improved understanding of pancreatic cancer biology provides an opportunity to identify and test a panel of early detection biomarkers easily, accurately, and inexpensively measured in blood, urine, stool, or saliva samples. These biomarkers may have additional usefulness in staging, stratification for treatment, establishing prognosis, and assessing response to therapy in this disease. Screening may prove to be one of several strategies to improve outcomes in a disease that has otherwise been difficult to defeat.

BackgroundIdentification of diagnostic and prognostic biomarkers is a research priority for the improved management of pancreatic ductal adenocarcinoma (PDAC). Insulin-like growth factor binding protein 2 (IGFBP2) and mesothelin (MSLN) have shown potential as serum biomarkers in other cancers, but have not been adequately studied in PDAC.MethodsSerum IGFBP2 and MSLN levels were quantified by enzyme-linked immunosorbent assay (ELISA) in a cohort of 84 PDAC patients, 84 healthy control subjects and 40 chronic pancreatitis (ChPT) patients. Regression models related IGFBP2 and MSLN levels to diagnosis, gender, age, stage and survival.ResultsIGFPB2 and MSLN serum levels were diagnostic for PDAC in age-adjusted models (P = 0.032 and P = 0.002, respectively) when compared with ChPT and healthy control samples. At a 95% specificity threshold, the sensitivity for IGFBP2 was 22% and the sensitivity for MSLN was 17%. Neither protein approached the diagnostic accuracy of CA 19-9. However, IGFBP2 or MSLN or both correctly identified 18 of the 28 samples misidentified by CA 19-9. In age-adjusted models, neither serum IGFBP2 (P = 0.36) nor MSLN (P = 0.29) were significant predictors of survival.DiscussionSerum IGFBP2 and MSLN are weak diagnostic classifiers individually, but may be useful in a diagnostic biomarker panel.

Background: CA19-9, which is currently in clinical use as a pancreatic ductal adenocarcinoma (PDAC) biomarker, has limited performance in detecting early-stage disease. We and others have identified protein biomarker candidates that have the potential to complement CA19-9. We have carried out sequential validations starting with 17 protein biomarker candidates to determine which markers and marker combination would improve detection of early-stage disease compared with CA19-9 alone. Methods: Candidate biomarkers were subjected to enzyme-linked immunosorbent assay based sequential validation using independent multiple sample cohorts consisting of PDAC cases (n = 187), benign pancreatic disease (n = 93), and healthy controls (n = 169). A biomarker panel for early-stage PDAC was developed based on a logistic regression model. All statistical tests for the results presented below were one-sided. Results: Six out of the 17 biomarker candidates and CA19-9 were validated in a sample set consisting of 75 PDAC patients, 27 healthy subjects, and 19 chronic pancreatitis patients. A second independent set of 73 early-stage PDAC patients, 60 healthy subjects, and 74 benign pancreatic disease patients (combined validation set) yielded a model that consisted of TIMP1, LRG1, and CA19-9. Additional blinded testing of the model was done using an independent set of plasma samples from 39 resectable PDAC patients and 82 matched healthy subjects (test set). The model yielded areas under the curve (AUCs) of 0.949 (95% confidence interval [CI] = 0.917 to 0.981) and 0.887 (95% CI = 0.817 to 0.957) with sensitivities of 0.849 and 0.667 at 95% specificity in discriminating early-stage PDAC vs healthy subjects in the combined validation and test sets, respectively. The performance of the biomarker panel was statistically significantly improved compared with CA19-9 alone (P < .001, combined validation set; P = .008, test set). Conclusion: The addition of TIMP1 and LRG1 immunoassays to CA19-9 statistically significantly improves the detection of early-stage PDAC.

Purpose: CA19-9, which is currently in clinical use as a pancreatic ductal adenocarcinoma (PDAC) biomarker, has limited performance in detecting early stage disease. We and others have identified protein biomarker candidates that have the potential to complement CA19.9. We have carried out sequential validations starting with 32 protein biomarker candidates to develop a marker panel to improve detection of early stage disease compared with CA19.9 alone. Patients and Methods: Multiple independent sample sets consisting of PDAC cases, benign pancreatic disease and healthy controls were utilized for immunoassays of candidate markers which after sequential validations yielded a panel of three markers that was further tested in a blinded setting. Results: The 32 biomarker candidates were initially tested in a sample set consisting of 75 PDAC cases, 29 healthy controls, and 19 chronic pancreatitis cases which narrowed the list to seven biomarker candidates. A second independent set of 73 early-stage PDAC cases, 60 healthy controls, and 74 benign pancreatic disease cases (60 chronic pancreatitis cases and 14 benign pancreatic cyst cases) yielded a panel of three markers, including CA19-9, with an AUC (95%CI) of 0.949 (0.917-0.981) and sensitivity of 0.849 at 95% specificity. Additional blinded testing of the model was done using an independent set of plasma samples from 39 resectable PDAC patients and 82 matched healthy controls, yielding an AUC of 0.887. The performance of the biomarker panel was significantly improved compared to CA19-9 alone (P < 0.001) in both plasma sample sets. Conclusion: We validated a protein-based three marker panel with significantly improved performance compared to CA19-9 with the potential to contribute to strategies for detecting early-stage PDAC. Citation Format: Michela Capello, Leonidas E. Bantis, Ghislaine Scelo, Yang Zhao, Dilsher S. Dhillon, Hong Wang, James L. Abbruzzese, Anirban Maitra, Margaret A. Tempero, Randall Brand, Matthew A. Firpo, Sean Mulvihill, Matthew H. Katz, Paul Brennan, Ziding Feng, Samir M. Hanash, Ayumu Taguchi. Sequential validation of blood-based protein biomarker candidates for early-stage pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-134.

SummaryThe size of the pancreas is determined by intrinsic factors, such as the number of progenitor cells, and by extrinsic signals that control the fate and proliferation of those progenitors. Both the exocrine and endocrine compartments of the pancreas undergo dramatic expansion after birth, and are capable of at least partial regeneration following injury. Whether the expansion of these lineages relies on similar mechanisms is unknown. Although we have shown that the Wnt signaling component β-catenin is selectively required for generation of exocrine acinar cells in utero, this gene has been ascribed various functions in the postnatal pancreas including proliferation and regeneration of islet as well as acinar cells. To address whether β-catenin remains important for the maintenance and expansion of mature acinar cells, we have established a system to follow the behavior and fate of β-catenin-deficient cells during postnatal growth and regeneration. We find that β-catenin is continuously required for the establishment and maintenance of acinar cell mass, extending from embryonic specification through juvenile and adult self-renewal and regeneration. This requirement is not shared with islet cells, which proliferate and function normally in the absence of β-catenin. These results make distinct predictions for the relative role of Wnt/β-catenin signaling in the etiology of human endocrine and exocrine disease. We suggest that loss of Wnt/β-catenin activity is unlikely to drive islet dysfunction, as occurs in type 2 diabetes, but that β-catenin is likely to promote human acinar cell proliferation following injury, and may therefore contribute to the resolution of acute or chronic pancreatitis.

Poor survival rates for pancreatic adenocarcinoma (PDAC) are in part due to late presentation. Earlier diagnosis is recognized as a means to improve outcomes by increasing the possibility for potentially curative treatment. Identification of early detection biomarkers is a research priority. The stromal compartment is a potential source for biomarkers as a strong desmoplastic response is a hallmark of PDAC. The interaction of mesenchymal, cancer, and inflammatory cells in the tumor induce secretion of autocrine and paracrine effectors and extracellular matrix remodeling enzymes that contribute to tumor growth, invasion, angiogenesis, and metastasis. Basigin (BSG), a cell surface glycoprotein, plays a role in the interaction of cancer and mesenchymal cells through the stimulation of extracellular matrix remodeling enzymes. Circulating BSG has also been demonstrated as a diagnostic/prognostic biomarker for other cancers. We evaluated the potential utility of plasma BSG as a PDAC diagnostic and prognostic biomarker. BSG levels were measured by ELISA in plasma from 106 healthy control subjects (mean = 3.29 ng/ml, 95% CI =3.0 – 3.6), 77 patients with chronic pancreatitis (3.72 ng/ml, 3.3 – 4.1 CI), and 112 pre-treatment samples from patients with PDAC (4.19 ng/ml, 3.9 – 4.5 CI). Nonparametric analysis revealed a significant difference for the model (P = 0.02, Wilcoxon). By ANOVA and Tukey-Kramer post-hoc tests, the distributions of BSG levels in PDAC and healthy control subjects were significantly different (P = 0.0003), but the comparison of PDAC to chronic pancreatitis cases was not significant (P = 0.147). A striking difference was noted after separating the PDAC cases into early stage (I-II) and late stage (III-IV) groups. ANOVA indicated that early stage disease (N = 70, 4.61 ng/ml, 4.2 – 5.0 CI) had significantly elevated BSG levels compared to healthy controls (P < 0.0001), chronic pancreatitis cases (P = 0.006), and late stage PDAC cases (P = 0.003, N = 42, 3.48 ng/ml, 2.9 – 3.9 CI). Increased plasma BSG levels were also significantly related to decreased survival in univariate Cox proportional hazards models (P = 0.01) indicating a 14% increase in risk per 1 ng/ml. This relationship remained significant in multivariate models adjusting for stage and post-diagnosis treatments. The results suggest that circulating BSG is an early stage phenomenon during PDAC development and would apparently be unique in its ability to specifically identify early stage PDAC cases. If validated, this biomarker should substantially contribute to the accuracy of an early detection biomarker panel. Further investigations are warranted into the usefulness of circulating BSG for early detection, selection of patients for surgical resection, identification of recurrence, screening high-risks groups and/or inclusion in panel screens. Citation Format: Samaa Kamal, Matthew A. Firpo, Courtney L. Scaife, Adler G. Douglas, Kenneth M. Boucher, Sean J. Mulvihill. Plasma basigin as an early detection biomarker for pancreatic adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B23.

Background: Although resectable pancreatic cancers are associated with better survival, only about 10% of pancreatic patients present with localized disease. Imaging modalities, notably endoscopic ultrasound and Magnetic resonance cholangiopancreatography, allow detection of early stage pancreatic cancer or small pancreatic cysts. However, these imaging modalities are not suitable for screening in terms of throughput, cost effectiveness, or invasiveness. Blood-based biomarkers could be ideal for screening of early stage pancreatic cancer. The performance of CA19-9 as a pancreatic cancer biomarker is limited and moreover CA 19-9 is not detectable in 5-10% of subjects with fucosyltransferase deficiency. As a result there is a need for additional markers that complement CA 19-9 for reliable detection of early stage pancreatic cancer. We have previously identified and obtained initial validation data for a set of blood based biomarkers which distinguished cases from control in the pre-diagnostic setting (Faca et al PLoS Medicine, 2008). We have undertaken further validation of this marker panel augmented with novel candidates including autoantibodies to tumor antigens identified by recombinant protein array. Methods: The selected biomarker candidates as well as CA19-9 were further assayed in a training set, consisting of plasmas from 138 pancreatic cancer patients and 81 controls (52 healthy subjects and 29 subjects with chronic pancreatitis) resulting in a combination rule which was tested in an independent cohort consisting of plasmas from 42 early stage pancreatic cancer patients, 50 healthy controls, 29 subjects with chronic pancreatitis, and 14 subjects with benign pancreatic cysts. Results: A logistic regression model was built in the training set using 5 markers. The AUCs of the model and CA19-9 alone were 0.80 (95% CI = 0.71-0.89) and 0.76 (95% CI = 0.67-0.86) (P value for difference in AUC = 0.014) in the training set. In the test set, the AUCs of the model in a comparison of early stage pancreatic cancer vs. (1) healthy controls, (2) subjects with chronic pancreatitis, and (3) subjects with benign pancreatic cysts were 0.91, 0.85, and 0.94 respectively. The marker panel substantially improved the negative predictive values (NPV) at 98% sensitivity in comparison of early stage pancreatic cancer vs. (1) healthy controls and (2) subjects with chronic pancreatitis (NPVs of the panel = (1) 0.96, (2) 0.95, and (3) 0.88; NPVs of CA19-9 alone = (1) 0.83, (2) 0.83, and (3) 0.88). Stratification based on CA19-9 positivity (cut off = 37 units/ml) yielded AUCs of (1) 0.79, (2) 0.72, and (3) 0.90, and NPVs were (1) 0.99, (2) 0.98, and (3) 0.95 in CA19-9 negative subjects. Conclusions: We have validated a marker combination with a potential to differentiate early stage pancreatic cancer from healthy controls, subjects with chronic pancreatitis and subjects with pancreatic cysts. Citation Format: Ayumu Taguchi, Michela Capello, Yang Zhao, Ingrid Babel, Gary Goodman, Margaret A. Tempero, Matthew A. Firpo, Matthew H. Katz, Ziding Feng, Samir Hanash. Development and validation of diagnostic biomarker model for detection of early stage pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B20.

Peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors that regulate cellular energy and lipid metabolism. PPAR-gamma agonists also have potent anti-inflammatory properties through down-regulation of early inflammatory response genes. The role of PPAR-gamma in acute pancreatitis has not been adequately examined. In this study, we determined the effect of PPAR-gamma agonists on the severity of pancreatitis and sought to correlate PPAR-gamma expression in pancreatic acinar cells and the severity of acute pancreatitis in vivo. Acute pancreatitis was induced in mice by hyperstimulation with the cholecystokinin analog, cerulein. PPAR-gamma agonists were administered by intraperitoneal injection 15-30 minutes before induction of pancreatitis (pretreatment) or at various times after induction of pancreatitis (treatment). Pancreata and serum were harvested over the course of 24 hours. Serum amylase activity and glucose levels were measured. Pancreata were used for histological evaluation as well as protein and mRNA analysis. Pretreatment of mice with the PPAR-gamma agonists 15-deoxy-Delta12, 14-prostaglandin J(2), or troglitazone significantly reduced the severity of pancreatitis in a dose-dependent manner. This reduction was indicated by reduced serum amylase activity and histological damage (leukocyte infiltration, vacuolization, and necrosis). Although cerulein decreased PPAR-gamma expression in the pancreas, pretreatment with agonists maintained PPAR-gamma expression early in acute pancreatitis. The expression of PPAR-gamma inversely correlated with pancreatitis severity and expression of the proinflammatory cytokines, interleukin-6, and tumor necrosis factor-alpha. Treatment with troglitazone after the induction of pancreatitis reduced serum amylase activity. The results suggest that PPAR-gamma plays a direct role in the inflammatory cascade during the early events of acute pancreatitis. Our data are the first to demonstrate that PPAR-gamma agonists represent a promising therapeutic strategy for acute pancreatitis.

Crosslinked hyaluronic acid (HA) hydrogels were evaluated for their ability to elicit new microvessel growth in vivo when preloaded with one of two cytokines, vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF). HA film samples were surgically implanted in the ear pinnas of mice, and the ears retrieved 7 or 14 days post implantation. Histologic analysis showed that all groups receiving an implant demonstrated significantly more microvessel density than control ears undergoing surgery but receiving no implant (p0.01). Moreover, aqueous administration of either growth factor produced substantially more vessel growth than an HA implant with no cytokine. However, the most striking result obtained was a dramatic synergistic interaction between HA and VEGF. Presentation of VEGF in crosslinked HA generated vessel density of NI = 6.7 at day 14, where NI is a neovascularization index defined below, more than twice the effect of the sum of HA alone (NI = 1.8) plus VEGF alone (NI=1.3). This was twice the vessel density generated by co-addition of HA and bFGF (NI=3.4, p0.001). New therapeutic approaches for numerous pathologies could be notably enhanced by the localized, synergistic angiogenic response produced by release of VEGF from crosslinked HA films.

Aging promotes accumulation of reactive oxygen/nitrogen species (ROS/RNS) in cardiomyocytes, which leads to contractile dysfunction and cardiac abnormalities. These changes may contribute to increased cardiovascular disease in the elderly. Inducible antioxidant pathways are regulated by nuclear erythroid 2 p45-related factor 2 (Nrf2) through antioxidant response cis-elements (AREs) and are impaired in the aging heart. Whereas acute exercise stress (AES) activates Nrf2 signaling and promotes myocardial antioxidant function in young mice (~2 months), aging mouse (>23 months) hearts exhibit significant oxidative stress as compared to those of the young. The purpose of this study was to investigate age-dependent regulation of Nrf2-antioxidant mechanisms and redox homeostasis in mouse hearts and the impact of exercise. Old mice were highly susceptible to oxidative stress following high endurance exercise stress (EES), but demonstrated increased adaptive redox homeostasis after moderate exercise training (MET; 10m/min, for 45 min/day) for ~6 weeks. Following EES, transcription and protein levels for most of the ARE-antioxidants were increased in young mice but their induction was blunted in aging mice. In contrast, 6-weeks of chronic MET promoted nuclear levels of Nrf2 along with its target antioxidants in the aging heart to near normal levels as seen in young mice. These observations suggest that enhancing Nrf2 function and endogenous cytoprotective mechanisms by MET, may combat age-induced ROS/RNS and protect the myocardium from oxidative stress diseases.

4620 Background: Accurate staging and prognostic information is essential for treatment planning in pancreatic adenocarcinoma (PA). Current methods include endoscopic ultrasound, CT scanning, and serum CA 19–9 levels. Despite these, many patients considered resectable experience early relapse and die from their disease and within this group nodal status correlates with overall survival. For patients metastatic at presentation the prognosis is often variable with limited treatment options. Vascular endothelial growth factor- C (VEGF-C) plays a crucial role in lymphangiogenesis and has been implicated in promoting lymph node metastasis in PA. Prior studies demonstrate diagnostic utility of serum levels of VEGF-C in determining nodal involvement and prognosis in lung, gastric, and cervical cancer. We investigated if serum VEGF-C levels would predict nodal involvement or prognosis in pancreatic cancer. Methods: Pretreatment serum VEGF-C levels were measured in 40 PA patients who were node-negative (N0 =12), n...

Background Gastric ileus is an unsolved clinical problem and current treatment is limited to supportive measures. Models of ileus using anesthetized animals, muscle strips or isolated smooth muscle cells do not adequately reproduce the clinical situation. Thus, previous studies using these techniques have not led to a clear understanding of the pathophysiology of ileus. The feasibility of using food intake and fecal output as simple, clinically relevant endpoints for monitoring ileus in a conscious mouse model was evaluated by assessing the severity and time course of various insults known to cause ileus. Methods Delayed food intake and fecal output associated with ileus was monitored after intraperitoneal injection of endotoxin, laparotomy with bowel manipulation, thermal injury or cerulein induced acute pancreatitis. The correlation of decreased food intake after endotoxin injection with gastric ileus was validated by measuring gastric emptying. The effect of endotoxin on general activity level and feeding behavior was also determined. Small bowel transit was measured using a phenol red marker. Results Each insult resulted in a transient and comparable decrease in food intake and fecal output consistent with the clinical picture of ileus. The endpoints were highly sensitive to small changes in low doses of endotoxin, the extent of bowel manipulation, and cerulein dose. The delay in food intake directly correlated with delayed gastric emptying. Changes in general activity and feeding behavior were insufficient to explain decreased food intake. Intestinal transit remained unchanged at the times measured. Conclusion Food intake and fecal output are sensitive markers of gastric dysfunction in four experimental models of ileus. In the mouse, delayed gastric emptying appears to be the major cause of the anorexic effect associated with ileus. Gastric dysfunction is more important than small bowel dysfunction in this model. Recovery of stomach function appears to be simultaneous to colonic recovery.

Background: Early detection screening of asymptomatic populations for low prevalence cancers requires a highly specific test in order to limit the cost and anxiety produced by falsely positive identifications. Most solid cancers are a heterogeneous collection of diseases as they develop from various combinations of genetic lesions and epigenetic modifications. Therefore, it is unlikely that a single test will discriminate all cases of any particular cancer type. We propose a novel, intuitive biomarker panel design that accommodates disease heterogeneity by allowing for diverse biomarker selection that increases diagnostic accuracy. Methods: Using characteristics of nine pancreatic ductal adenocarcinoma (PDAC) biomarkers measured in human sera, we modeled the behavior of biomarker panels consisting of a sum of indicator variables representing a subset of biomarkers within a larger biomarker data set. We then chose a cutoff for the sum to force specificity to be high and delineated the number of biomarkers required for adequate sensitivity of PDAC in our panel design. Results: The model shows that a panel consisting of 40 non-correlated biomarkers characterized individually by 32% sensitivity at 95% specificity would require any 7 biomarkers to be above their respective thresholds and would result in a panel specificity and sensitivity of 99% each. Conclusions: A highly accurate blood-based diagnostic panel can be developed from a reasonable number of individual serum biomarkers that are relatively weak classifiers when used singly. A panel constructed as described is advantageous in that a high level of specificity can be forced, accomplishing a prerequisite for screening asymptomatic populations for low-prevalence cancers.