Survival In Pancreatic Ductal Adenocarcinoma Research Articles

MiR-10b inhibits migration and invasion of pancreatic ductal adenocarcinoma via regulating E2F7.

BackgroundAbnormal microRNAs (miRNAs) expression is closely related to the development and poor prognosis of pancreatic ductal adenocarcinoma (PDAC). We aimed to elucidate the invasive mechanism and clinical significance of miR‐10b in PDAC.MethodsThe RNA sequence data of pancreatic cancer were extracted from the TCGA database. R packages were performed to analyze the differential expression of RNAs. TargetScan, picTar, and miRanda were used to predict the target gene of miRNA. The expression level of the selected candidate was tested by western blot and RT‐PCR in PDAC cells and tissues. Scrape and Transwell assays were determined the effect of candidate molecules on cell migration and invasion. The gain of function and loss of function was achieved by co‐culture with mimics and vector. Luciferase reporters were generated based on the psiCHECK2 vector. The relative luciferase activity was measured with the Dual‐Luciferase Reporter Assay System and Infinate M200 PRO microplate reader.ResultsBased on the TCGA data and bioinformatics analysis, we obtained seven differentially expressed miRNAs. Both TCGA data and our center clinical date indicated that miR‐10b was contributed to the poor survival of PDAC. Based on the target gene prediction database, we found that E2F7 was a target mRNA of miR‐10b. In subsequent experiments in molecular biology, miR‐10b expression was downregulated in PDAC cells and tissues, while E2F7 was upregulated. Scrape and Transwell assay indicated that miR‐10b could inhibit the invasion and migration of PDAC. MiR‐10b was confirmed to be by the E2F7 targeting site by dual‐luciferase report. Moreover, rescue experiments prove that miR‐10b could inhibit the invasion and migration of PDAC cells by regulating E2F7 expression.ConclusionOur results suggest that miR‐10b could inhibit the progression of PDAC by regulating E2F7 expression and acts as an independent prognostic risk factor for PDAC.

Influence of KRAS mutations, persistent organic pollutants, and trace elements on survival from pancreatic ductal adenocarcinoma

Reasons why pancreatic ductal adenocarcinoma (PDAC) continues to have poor survival are only partly known. No previous studies have analyzed the combined influence of KRAS mutations, persistent organic pollutants (POPs), and trace elements upon survival in PDAC or in any other human cancer. To analyze the individual and combined influence of KRAS mutations, POPs, and trace elements upon survival from PDAC. Incident cases of PDAC (n = 185) were prospectively identified in five hospitals in Eastern Spain in 1992-1995 and interviewed face-to-face during hospital admission. KRAS mutational status was determined from tumour tissue through polymerase chain reaction and artificial restriction fragment length polymorphism. Blood and toenail samples were obtained before treatment. Serum concentrations of POPs were analyzed by high-resolution gas chromatography with electron-capture detection. Concentrations of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. Multivariable Cox proportional hazards regression was used to assess prognostic associations. Patients with a KRAS mutated tumor had a 70% higher risk of early death than patients with a KRAS wild-type PDAC (hazard ratio [HR] = 1.7, p = 0.026), adjusting for age, sex, and tumor stage. KRAS mutational status was only modestly and not statistically significantly associated with survival when further adjusting by treatment or by treatment intention. The beneficial effects of treatment remained unaltered when KRAS mutational status was taken into account, and treatment did not appear to be less effective in the subgroup of patients with a KRAS mutated tumor. POPs did not materially influence survival: the adjusted HR of the highest POP tertiles was near unity for all POPs. When considering the joint effect on survival of POPs and KRAS, patients with KRAS mutated tumors had modest and nonsignificant HRs (most HRs around 1.3 to 1.4). Higher concentrations of lead, cadmium, arsenic, vanadium, and aluminium were associated with better survival. When KRAS status, POPs, and trace elements were simultaneously considered along with treatment, only the latter was statistically significantly related to survival. In this study based on molecular, clinical, and environmental epidemiology, KRAS mutational status, POPs, and trace elements were not adversely related to PDAC survival when treatment was simultaneously considered; only treatment was independently related to survival. The lack of adverse prognostic effects of POPs and metals measured at the time of diagnosis provide scientific and clinical reassurance on the effects of such exposures upon survival of patients with PDAC. The weak association with KRAS mutations contributes to the scant knowledge on the clinical implications of a genetic alteration highly frequent in PDAC.

Albumin-to-alkaline phosphatase ratio serves as a prognostic indicator in unresectable pancreatic ductal adenocarcinoma: a propensity score matching analysis

BackgroundRecent evidence suggests that albumin-to-Alkaline Phosphatase Ratio (AAPR) functions as a novel prognostic marker in several malignancies. However, whether it can predict the prognosis of unresectable pancreatic ductal adenocarcinoma (PDAC) remains unclear. Herein, we seek to investigate this possibility by a propensity score matching (PSM) analysis.MethodsThis was a retrospective cohort study in which 419 patients diagnosed with unresectable PDAC and receiving chemotherapy were recruited. Patients were stratified based on the cutoff value of AAPR. The PSM analysis was performed to identify 156 well-balanced patients in each group for overall survival (OS) comparison and subgroup analysis. Univariate and multivariate analyses were carried out to examine the potential of AAPR to indicate the prognosis of unresectable PDAC. The prediction performance of conventional model and combined model including AAPR was compared using the Akaike Information Criterion (AIC) and concordance index (C-index).ResultsWe identified an AAPR of 0.4 to be the optimal cutoff for OS prediction. Patients with AAPR≤0.4 had significantly shorter OS compared with patients with AAPR> 0.4 (6.4 versus 9.3 months; P < 0.001). Based on the PSM cohort and entire cohort, multivariate Cox analysis revealed that high pretreatment for AAPR was an independent marker predicting favorable survival in unresectable PDAC (hazard ratio, 0.556; 95% confidence interval, 0.408 to 0.757; P < 0.001). Significant differences in OS were observed in all subgroups except for the group of patients age ≤ 60. Combined prognostic model including AAPR had lower AIC and higher C-index than conventional prognostic model.ConclusionsPretreatment AAPR servers as an independent prognostic indicator for patients with unresectable PDAC. Inclusion of AAPR improved the prediction performance of conventional prognostic model, potentially helping clinicians to identify patients at high risk and guide individualized treatment.

Restoration of miR-340 controls pancreatic cancer cell CD47 expression to promote macrophage phagocytosis and enhance antitumor immunity

BackgroundImmune checkpoint blockade has emerged as a potential cancer immunotherapy. The “don’t eat me” signal CD47 in cancer cells binds signal regulatory protein-α on macrophages and prevents their phagocytosis. The...

Sa1464 QUANTITATIVE CONTRAST-ENHANCED ENDOSCOPIC ULTRASOUND IN PANCREATIC DUCTAL ADENOCARCINOMA AND PANCREATIC NEUROENDOCRINE TUMORS: CAN WE PREDICT SURVIVAL USING PERFUSION PARAMETERS?

Contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) parameters may be used to predict prognosis of pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (pNET). The perfusion parameters obtained through time intensity curve (TIC) analysis may have different degrees of impact on overall survival (OS). The aim of this study was to investigate the association between several perfusion parameters on CEH-EUS performed before treatment and survival outcome in patients with PDAC or pNET. Patients with PDAC or pNET who underwent CEH-EUS at our institution between 2017-2019 were included in the study. Quantitative analysis of tumor vascularity was performed using TIC analysis-derived parameters, obtained from processing CEH-EUS recordings with a commercially available software. Cox proportional hazards models were used to determine associations with survival outcome Twenty-two patients with PDAC (tumor size on EUS: median, 33 mm; range, 23–45 mm) and eight patients with pNET (tumor size: median, 40mm; range, 18-65mm) were identified. During CEH-EUS, all PDACs were hypoenhanced in all phases, while pNETs appeared as hyperenhancing masses in the arterial phase. Median OS for PDAC patients was 9.61 months (95%CI, 0.1-38.7) while the median OS for pNET patients was 15.81 months (95%CI, 5.8-24.5). In a multivariate model for OS, a lower peak enhancement (HR=1.76, P=0.02) and a lower wash-in area under the curve (HR=1.06, P=0.001) were associated with worse survival outcome for patients with PDAC. CEH-EUS parameters may be used as a surrogate to predict PDAC aggressiveness and survival before treatment. After validation by large-scale studies, CEH-EUS perfusion parameters have the potential to be used in pretreatment risk stratification of patients with PDAC and in evidence-based clinical decision support.

Human equilibrative nucleoside transporter-1 (hENT1) and ribonucleotide reductase regulatory subunit M1 (RRM1) expression; do they have survival impact to pancreatic cancer?

Backgrounds/AimsGemcitabine is still one of adjuvant options in chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC). Integral membrane transporter protein and intracellular enzymes including human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (dCK), ribonucleotide reductase (RR) M1, and M2 are known as important factors for chemosensitivity of gemcitabine. We aimed to investigate the correlation between these key molecules and 5-year actual survival in PDAC patients.MethodsThe expression of intratumoral hENT1, dCK, RRM1, and RRM2 was assessed immunohistochemically in 160 PDAC patients underwent surgical resection. Association between clininopathologic factors, immunohistochemical results, and overall survival were analyzed.ResultsAdjuvant chemotherapy including concurrent chemoradiotherapy was not associated with overall survival (HR, 0.92; 95% CI, 0.65-1.31; p=0.658). High hENT1 expression group did not show statistical survival difference, compared with all others (HR, 1.16; 95% CI, 0.82-1.65, p=0.396). Gemcitabine therapy and high hENT1 group was compared with all other patients, and no difference in overall survival was identified (HR, 0.99; 95% CI, 0.68-1.42; p=0.940). And, gemcitabine therapy and high hENT1 group did not differ statistically from gemcitabine therapy and low hENT1 expression (HR, 0.92; 95% CI, 0.55-1.56; p=0.764). The intensity of dCK, RRM1, and RRM2 expression was not associated with overall survival (p=0.413, p=0.138 and p=0.061) in univariate analysis.ConclusionsThe expression of hENT1, dCK, RRM1 and RRM2 may not be associated with overall survival for patients with pancreatic cancer on gemcitabine adjuvant therapy. These proteins and other factors that may interact with or confound these results should be investigated in the near future.

Fibroblasts as a Biological Marker for Curative Resection in Pancreatic Ductal Adenocarcinoma.

Achievement of microscopic tumor clearance (R0) after pancreatic ductal adenocarcinoma (PDAC) surgery is determined by cancer biology rather than operative technique. Fibroblasts are known to play pro-cancer roles; however, a small subset was recently found to play anti-cancer roles. Therefore, we hypothesized that intratumor fibroblasts contribute to curative resection and a better survival of PDAC. Utilizing a large, publicly available PDAC cohort, we found that fibroblast composition was associated with R0 curative resection. A high amount of fibroblasts in PDACs was significantly associated with a higher amount of mature vessels, but not with blood angiogenesis. A high amount of fibroblasts was also associated with a higher infiltration of anti-cancer immune cells, such as CD8+ T-cells and dendritic cells, together with higher inflammatory signaling, including IL2/STAT5 and IL6/JAK/STAT3 signaling. Further, the fibroblast composition was inversely associated with cancer cell composition in the bulk tumor, along with an inverse association with proliferative characteristics, such as MYC signaling and glycolysis. The patients with high-fibroblast PDACs showed an improved prognosis. In conclusion, we found that PDACs with high fibroblasts were associated with a higher R0 resection rate, resulting in a better prognosis. These findings may be due to less aggressive biology with a higher vascularity and anti-cancer immunity, and a low cancer cell component.

Dietary β-Hydroxy-β-Methylbutyrate Supplementation Promotes PDAC Response to Gemcitabine and Immunotherapy Response in Obese Mice

Abstract Objectives Late diagnosis, aggressive underlying biology, and limited treatment options contribute towards the exceptionally poor survival of pancreatic ductal adenocarcinoma (PDAC). Obesity promotes both incidence and progression of PDAC via chronic systemic inflammation, generation of an immunosuppressive tumor microenvironment, and promotion of tumor fibrosis. β-Hydroxy-β-Methylbutyrate (HMB) reduces cancer associated cachexia and promotes modest reductions in tumor growth in animal models of cancer. The objective of this study was to determine if HMB supplementation would alter therapeutic response to either gemcitabine or anti-PD1 immunotherapy. Methods C57BL/6 mice were fed either a diet induced obesity high fat diet or a matched low fat control. Following PANC02 tumor induction, animals were treated with HMB alone or in combination with gemcitabine or anti-PD1 immunotherapy. Tumor transcriptomic analysis was preformed using Affymetrix microarray, with subsequent gene set enrichment analysis. Immunohistochemistry was performed for CD3 (a T cell marker). C57BL/6 mice were fed either a diet induced obesity high fat diet or a matched low fat control. Following PANC02 tumor induction, animals were treated with HMB alone or in combination with gemcitabine or anti-PD1 immunotherapy. Tumor transcriptomic analysis was preformed using Affymetrix microarray, with subsequent gene set enrichment analysis. Immunohistochemistry was performed for CD3 (a T cell marker). Results DIO-induced immune suppression was partially reversed by HMB, with reduced tumor growth, increased T cell markers and enhanced efficacy of gemcitabine following HMB treatment in obese mice. Separately, HMB enhanced the efficacy of anti-PD1 immunotherapy. Conclusions HMB enhanced PDAC immune surveillance, augmenting both cytotoxic chemotherapy and immunotherapy. HMB-induced suppression of obesity driven PDAC tumor growth, and promotion of immune surveillance may provide extend the therapeutic index of both chemotherapies and immunotherapies in PDAC. Funding Sources This study was supported by a grant from the National Cancer Institute (R35 CA197627) to SDH.

Endoscopic retrograde cholangiopancreatography (ERCP) findings to predict survival in patients with metastatic pancreatic adenocarcinoma.

e16734 Background: Chemotherapy is the primary therapy for patients with metastatic pancreatic ductal adenocarcinoma (PDAC), but response to therapy is variable. Patients with PDAC often develop jaundice and cholangitis and require endoscopic biliary stenting. Here, we investigate the association between ERCP findings, cholangitis, chemotherapy use, and survival in PDAC patients. Methods: We conducted a retrospective chart review of all patients who received metal stents for biliary obstruction with PDAC over a five-year period at the Massachusetts General Hospital. Only patients with metastatic cancer were included. Patients were stratified by whether or not they received chemotherapy, as well as the presence or absence of cholangitis. Associations between chemotherapy use and ERCP findings were investigated. Survival analyses were performed to compare patients by chemotherapy use, presence of cholangitis, and findings at ERCP. Results: A total of 126 patients were included; the average age of patients in our study was 69.9 ± 11.8. The average size of the primary lesion was 38.7 ± 14.4 mm. Sixty-nine percent of patients completed chemotherapy. The average number of stents for all patients was 2.5 ± 2.5, but was significantly higher in patients who experienced cholangitis (3.3 ± 2.8) as expected (p &lt; 0.001). The majority of ERCP reports noted debris or sludge (44%), followed by presence of infiltrating or obstructing tumor (27%), stone (13%), pus or purulence (11%), and blood clot (5%). Patients who did not receive chemotherapy were more likely to have tumor obstruction noted on ERCP compared to those who received chemotherapy (p = 0.024). Patients undergoing chemotherapy were also more likely to have sludge noted on ERCP (p = 0.009) compared to those who did not have chemotherapy. There was no association between chemotherapy use and presence of stones (p = 0.94) or presence of purulence (p = 0.44) noted on ERCP. Among patients who received chemotherapy, those who had sludge or debris noted on their ERCP tended to have better survival compared to those where sludge was not noted on endoscopy (p = 0.038). Conversely, among patients who received chemotherapy, identification of an obstructing tumor on ERCP was prognostic of poorer survival (p = 0.037). Among patients who did not get chemotherapy, there was no survival difference between patients who had sludge or tumor and those who did not. Conclusions: Findings on ERCP may serve as a surrogate for chemotherapy response and be prognostic of survival in metastatic PDAC.

The Main Bottleneck for Non-Metastatic Pancreatic Adenocarcinoma in Past Decades: A Population-Based Analysis.

BackgroundDespite recent advancements in surgical techniques, chemotherapy, and radiotherapy, the 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) remains an unsatisfactory ~8%.Material/MethodsData were extracted to identify patients with non-metastatic pancreatic adenocarcinoma diagnosed in the periods 1988–1996 and 2010–2014 in the Surveillance, Epidemiology, and End Results (SEER) database. The statistical analyses were performed with the log-rank test, Pearson’s chi-square test, propensity score matching, and Cox regression model.ResultsThe hazard ratio (HR) of surgery was reduced from 0.454 to 0.302 in Cox regression modeling, and there was no overlapping about the 95% confidence intervals (CI) of surgery between the 2 periods. The HR values of radiotherapy, which were new prognostic factor for resectable PDAC in 2010–2014, were reduced in both the resectable and unresectable groups. The upgraded chemotherapy regimen reduced the HR values from 0.738 to 0.689 in all PADC patients, and from 0.656 to 0.588 in unresectable PDAC. The log-rank test results showed that advances in surgery significantly improved the median survival from 13 months to 32 months. Radiotherapeutic and chemotherapeutic advancements extended median survival by 12 months and 11 months, respectively, in resectable PDAC. The median survivals were extended by 3 months for both of radiotherapy and chemotherapy in unresectable PDAC.ConclusionsThe development of chemotherapy and radiotherapy has been slow, especially for unresectable PDAC. Although advances in surgery contributed significantly to improved survival for resectable PDAC, lack of early diagnostic tools, which lead to low resection rates, remain a barrier for all PDAC patients.

Response to FOLFIRINOX neoadjuvant chemotherapy is associated with a high prevalence of Tbet expressing T cells in pancreatic cancer patients

Abstract FOLFIRINOX is the first line treatment option for patients with pancreatic ductal adenocarcinoma (PDAC). Neoadjuvant chemotherapy has a beneficial effect on overall survival in PDAC in comparison with upfront surgery and adjuvant therapy. However, chemotherapy has not yet been successfully combined with immune therapy in PDAC. Herein, we characterize the immunologic effect of FOLFIRINOX and thus provide a rationale for future combination with immune therapy in PDAC. Peripheral Blood Mononuclear Cells were obtained from treatment-naïve (n=20) and FOLFIRINOX-treated patients (n=15) with primary PDAC tumors. Immune cell subset composition was assessed by using mass cytometry (CyTOF). Response to FOLFIRINOX was defined as a reduction in tumor size by more than 30%. 8 of 15 patients were considered responders with a range from 32 to 60% reduction in tumor volume. Responders to FOLFIRINOX showed a significantly higher proportion of CD8+ T cells and lower proportion of monocytes in their peripheral blood compared to treatment naïve patients (both p&amp;lt;0.05). Responders to FOLFIRINOX treatment also showed a significantly lower percentage of CD39+ Treg cells and a significantly higher percentage of CXCR3+CCR6+ Th1/Th17 cells compared to treatment naïve patients (both p&amp;lt;0.05). Lastly, FOLFIRINOX responders showed significantly higher proportions of Tbet expressing CD4+ and CD8+ T cells compared to non-responder patients (both p&amp;lt;0.05). Taken together, our study reveals that neoadjuvant chemotherapy with FOLFIRINOX could enhance functional T cells and down-regulate suppressor cells in circulation. Thus, combination neoadjuvant FOLFIRINOX chemotherapy with immunotherapy may improve clinical outcome.

Time intervals to diagnosis and chemotherapy do not influence survival outcome in patients with advanced pancreatic adenocarcinoma.

BackgroundThe effect of treatment delay on survival in pancreatic ductal adenocarcinoma (PDAC) remains unclear. AimsThis study aimed to assess the prognostic impact of time to diagnosis and chemotherapy in advanced PDAC and factors influencing the time intervals. Methodsadvanced PDAC patients receiving chemotherapy in five centers in the decade 2007–2016 were included. Key time points during care pathway from clinical presentation to beginning of chemotherapy were retrospectively collected. Multivariate Cox proportional hazard model was performed. ResultsA total of 409 patients were included (mean age 66.1 ± 10.3 years; 250 metastatic (61%); 139 received FOLFIRINOX chemotherapy (34%). The median overall survival (OS) was 7.2 months. The median times from first symptoms and from first specialist visit to the beginning of chemotherapy were respectively 100 days and 47 days. None of time intervals was significantly associated with OS. Significant prognostic factors were FOLFIRINOX chemotherapy (HR 0.6 [0.5–0.8]; P < 0.001), metastasis (HR 1.6 [1.3–2.0]; P = 0.001), WHO PS ≥ 2 (HR 1.6 [1.2–2.1]; P < 0.001) and acute pancreatitis as first symptom (HR 2.9 [1.7–4.9]; P < 0.001). Jaundice shortened time to diagnosis (P < 0.001). Acute pancreatitis (P < 0.001) and diabetes (P = 0.01) increased time to treatment. ConclusionWait times from clinical presentation to beginning of chemotherapy do not influence survival in advanced PDAC.

Multiparametric Modelling of Survival in Pancreatic Ductal Adenocarcinoma Using Clinical, Histomorphological, Genetic and Image-Derived Parameters.

Rationale: Pancreatic ductal adenocarcinoma (PDAC) remains a tumor entity of exceptionally poor prognosis, and several biomarkers are under current investigation for the prediction of patient prognosis. Many studies focus on promoting newly developed imaging biomarkers without a rigorous comparison to other established parameters. To assess the true value and leverage the potential of all efforts in this field, a multi-parametric evaluation of the available biomarkers for PDAC survival prediction is warranted. Here we present a multiparametric analysis to assess the predictive value of established parameters and the added contribution of newly developed imaging features such as biomarkers for overall PDAC patient survival. Methods: 103 patients with resectable PDAC were retrospectively enrolled. Clinical and histopathological data (age, sex, chemotherapy regimens, tumor size, lymph node status, grading and resection status), morpho-molecular and genetic data (tumor morphology, molecular subtype, tp53, kras, smad4 and p16 genetics), image-derived features and the combination of all parameters were tested for their prognostic strength based on the concordance index (CI) of multivariate Cox proportional hazards survival modelling after unsupervised machine learning preprocessing. Results: The average CIs of the out-of-sample data were: 0.63 for the clinical and histopathological features, 0.53 for the morpho-molecular and genetic features, 0.65 for the imaging features and 0.65 for the combined model including all parameters. Conclusions: Imaging-derived features represent an independent survival predictor in PDAC and enable the multiparametric, machine learning-assisted modelling of postoperative overall survival with a high performance compared to clinical and morpho-molecular/genetic parameters. We propose that future studies systematically include imaging-derived features to benchmark their additive value when evaluating biomarker-based model performance.

Inhibition of stearoyl‐CoA desaturase suppresses growth of pancreatic tumors in vitro and in vivo

Pancreatic ductal adenocarcinoma (PDAC) is a relatively rare cancer type, but is the fourth‐leading cause of cancer death in the US. Although chemotherapy and immunotherapy have been used for patients with PDAC, the overall five‐year survival rate is 8% and there is an urgent need for effective therapies. Stearoyl‐CoA desaturase (SCD) is an enzyme localized in the endoplasmic reticulum and generates monounsaturated fatty acid from saturated fatty acid by introducing a single double bond. In the present study, we examined the role of lipid metabolism regulated by SCD in PDAC growth and survival using Pdx1Cre; LSL‐KrasG12D mice and human PDAC cell lines. We isolated pancreatic tumors expressing epithelial cellular adhesion molecule by magnetic‐activated cell sorting from the Pdx1Cre; LSL‐KrasG12D mouse pancreas and formed tumor organoids in matrigel. We found that a specific SCD inhibitor (A939572) induces degeneration of the tumor organoids. Interestingly, addition of oleic acid (18:1), but not stearic acid (18:0), rescued the inhibitor‐induced degeneration of tumor organoids. Treatment with the SCD inhibitor increased mRNA expression of unfolded protein response (UPR) markers, such as Atf4, Atf6, Ddit3, spliced Xbp1, and Grp78 in organoids. The increased expression of these genes was reversed by addition of oleic acid, but not stearic acid. Similarly, the SCD inhibitor suppressed the proliferation of PANC‐1, a human PDAC cell line. The SCD inhibitor induced the expression of the UPR markers in PANC‐1 and their induction was suppressed by oleic acid, but not by stearic acid. After injection of the SCD inhibitor to Pdx1Cre; LSL‐KrasG12D mice bearing pancreatic tumors, we observed TUNEL+ cells in pancreatic tumors, but not in normal acinar cells. Our data suggest that the inhibition of SCD causes UPR and cell death in pancreatic tumors.Support or Funding InformationPilot project funding from NIH/NIAAA grant P50 AA011999, USC Dean’s pilot project program

Combination of PD-1 Inhibitor and OX40 Agonist Induces Tumor Rejection and Immune Memory in Mouse Models of Pancreatic Cancer

Advanced pancreatic ductal adenocarcinoma (PDAC) is resistant to therapy, including immune checkpoint inhibitors. We evaluated the effects of a neutralizing antibody against programmed cell death 1 (PD-1) and an agonist of OX40 (provides a survival signal to activated T cells) in mice with pancreatic tumors. We performed studies in C57BL/6 mice (controls), KrasG12D/+;Trp53R172H/+;Pdx-1-Cre (KPC) mice, and mice with orthotopic tumors grown from Panc02 cells, KrasG12D;P53flox/flox;PDX-1-Cre;Luciferase (KPC-Luc) cells, or mT4 cells. After tumors developed, mice were given injections of control antibody or anti-OX40 and/or anti-PD-1 antibody. Some mice were then given injections of antibodies against CD8, CD4, or NK1.1 to deplete immune cells, and IL4 or IL7RA to block cytokine signaling. Bioluminescence imaging was used to monitor tumor growth. Tumor tissues collected and single-cell suspensions were analyzed by time of flight mass spectrometry analysis. Mice that were tumor-free 100 days after implantation of orthotopic tumors were rechallenged with PDAC cells (KPC-Luc or mT4) and survival was measured. Median levels of PD-1 and OX40 mRNAs in PDACs were determined from The Cancer Genome Atlas and compared with patient survival times. In mice with orthotopic tumors, all those given control antibody or anti-PD-1 died within 50 days, whereas 43% of mice given anti-OX40 survived for 225 days; almost 100% of mice given the combination of anti-PD-1 and anti-OX40 survived for 225 days, and tumors were no longer detected. KPC mice given control antibody, anti-PD-1, or anti-OX40 had median survival times of 50 days or less, whereas mice given the combination of anti-PD-1 and anti-OX40 survived for a median 88 days. Mice with orthotopic tumors that were given the combination of anti-PD-1 and anti-OX40 and survived 100 days were rechallenged with a second tumor; those rechallenged with mT4 cells survived an additional median 70 days and those rechallenged with KPC-Luc cells survived long term, tumor free. The combination of anti-PD-1 and anti-OX40 did not slow tumor growth in mice with antibody-mediated depletion of CD4+ T cells. Mice with orthotopic tumors given the combination of anti-PD-1 and anti-OX40 that survived after complete tumor rejection were rechallenged with KPC-Luc cells; those with depletion of CD4+ T cells before the rechallenge had uncontrolled tumor growth. Furthermore, KPC orthotopic tumors from mice given the combination contained an increased number of CD4+ T cells that expressed CD127 compared with mice given control antibody. The combination of agents reduced the proportion of T-regulatory and exhausted T cells and decreased T-cell expression of GATA3; tumor size was negatively associated with numbers of infiltrating CD4+ T cells, CD4+CD127+ T cells, and CD8+CD127+ T cells, and positively associated with numbers of CD4+PD-1+ T cells, CD4+CD25+ T cells, and CD8+PD-1+ T cells. PDACs with high levels of OX40 and low levels of PD-1 were associated with longer survival times of patients. Pancreatic tumors appear to evade the immune response by inducing development of immune-suppressive T cells. In mice, the combination of anti-PD-1 inhibitory and anti-OX40 agonist antibodies reduces the proportion of T-regulatory and exhausted T cells in pancreatic tumors and increases numbers of memory CD4+ and CD8+ T cells, eradicating all detectable tumor. This information can be used in development of immune-based combination therapies for PDAC.

An observational study to justify and plan a future phase III randomized controlled trial of metformin in improving overall survival in patients with inoperable pancreatic cancer without liver metastases.

Metformin has plausible direct and indirect anti-cancer properties against pancreatic adenocarcinoma cells. However, metformin may only be efficacious in patients with inoperable pancreatic ductal adenocarcinoma (PDAC) without liver metastases. Absorption may be decreased by gastrointestinal symptoms and proton pump inhibitors (PPIs). We aimed to justify and inform a future phase III trial of metformin versus placebo on survival in inoperable PDAC by documenting prevalence of patients meeting eligibility criteria, gastrointestinal symptoms and PPI use. Patient notes with PDAC were reviewed at a large teaching hospital over 2years. Study variables were obtained from multiple sources of information. 141 participants were identified (51.8% female), of which 37.6% were not prescribed metformin at diagnosis and had no radiological hepatic metastases. Characteristics were similar between non-metformin and metformin users. In eligible patients, 65.2% reported nausea and vomiting and 46.2% were prescribed PPIs. Approximately, a third of all patients with inoperable PDAC are eligible for a future trial of metformin, allowing an estimate of the number of hospitals required for recruitment. Nausea and vomiting are common and should be managed effectively to prevent trial dropouts. PPI use is frequent and their influence on metformin's pharmacodynamic actions needs to be clarified.

Improvement of survival after surgical resection of pancreatic cancer independent of adjuvant chemotherapy in the past two decades – A meta-regression

IntroductionSurgical resection improves survival in pancreatic ductal adenocarcinoma (PDAC) and adjuvant chemotherapy adds an additional survival-benefit. While surgical technique has improved in recent years, it remains unclear whether these improvements translate into a survival benefit independent of adjuvant chemotherapy. Thus, we aimed to clarify whether survival of patients who were treated with either Gemcitabine (GEM) or who were observed only in randomized controlled trials on adjuvant chemotherapy of PDAC improved over time. MethodsA systematic search of MEDLINE/PubMed was performed to identify randomized controlled trials on adjuvant chemotherapy of PDAC. The search was limited to studies with arms on GEM monotherapy or postoperative observation and studies were grouped by the median year of enrolment and the use of GEM. Subsequently, a meta-regression on the effect of the median year of enrolment on patient survival was performed. ResultsA total of 13 studies with 2469 patients was included, with median years of enrollment ranging from 1996 to 2015. While disease-free survival decreased in patients with postoperative observation (18.0 vs. 5.0 months, p = 0.001), median survival improved over time in patients with postoperative observation (15.8 vs. 18.4 months, p = 0.01) and in patients treated with adjuvant GEM (22.8 vs. 35.0 months, p < 0.001). One- (p ≤ 0.01) and two-year survival (p = 0.056) improved in both patients treated with adjuvant GEM and those observed only. ConclusionSurvival after surgical resection of PDAC has improved since 1996, even in patients who did not receive adjuvant chemotherapy. Improved surgical technique and postoperative management are likely to be causative factors.

Upregulated Expression of TUBA1C Predicts Poor Prognosis and Promotes Oncogenesis in Pancreatic Ductal Adenocarcinoma via Regulating the Cell Cycle

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease and has the worst prognosis and survival rate. TUBA1C is a microtubule component implicated in multiple cancers, however, the clinical significance and biological functions of TUBA1C in the progression of PDAC remain unexplored.Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) data were employed to detect the TUBA1C mRNA expression and the relation between TUBA1C expression and overall survival (OS) in PDAC. Then, bioinformatic analysis was employed to determine the potential pathway and genes related to TUBA1C. Human pancreatic cancer tissue and adjacent non-tumor tissues samples were detected by immunochemistry (IHC) staining, and the correlation between TUBA1C expression and the clinicopathological features were investigated. Meanwhile, TUBA1C expression in PDAC cell lines was evaluated by western blotting. Furthermore, functional assays including cell viability, apoptosis, cell cycle, transwell assay, wound healing assay, and a xenograft tumor model were performed to determine the oncogenic role of TUBA1C in PDAC, respectively.Results: TUBA1C was overexpressed in the PDAC tissues and cells. IHC analysis showed that the TUBA1C overexpression was associated with short OS. Bioinformatic analysis indicated that TUBA1C overexpression was mainly associated with cell cycle regulation. The downregulation of TUBA1C significantly suppressed cell proliferation, induced cell apoptosis and cycle arrest, and inhibited invasion and migration in PDAC cells. Furthermore, TUBA1C downregulation also inhibited tumor growth in vivo.Conclusion: These findings suggested that TUBA1C downregulation suppressed PDAC aggressiveness via cell cycle pathway and that TUBA1C may serve as a potential prognostic marker for PDAC therapy.

A pilot study of liposomal irinotecan plus 5-FU/LV combined with paricalcitol in patients with advanced pancreatic cancer progressed on gemcitabine-based therapy.

TPS793 Background: Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second leading cause of cancer-related death by 2030, and is characterized by resistance to chemo- and radiotherapy and a highly fibrotic tumor microenvironment. Front-line therapies for advanced PDAC include FOLFIRINOX and gemcitabine/nab-paclitaxel with median overall survival ranging from 8.5 to 11 months. After progression on gemcitabine-containing therapy, 5-FU/LV/liposomal irinotecan is a standard second-line option, however outcomes are still poor. Retrospective studies demonstrate superior survival of advanced PDAC in patients with high serum levels of 25(OH) vitamin D. Notably, the PDAC tumor microenvironment is enriched in cancer-associated fibroblasts that favorably respond to vitamin D, prolonging survival in combination with chemotherapy in mouse models. Furthermore, vitamin D suppresses catabolism of irinotecan in gastrointestinal cancer cells, potentiating its efficacy. Therefore, we are conducing an investigator-initiated study of 5FU/LV/liposomal irinotecan with paricalcitol as second-line therapy in advanced PDAC. Methods: This is a pilot study of 5FU/LV/liposomal irinotecan combined with paricalcitol in patients with advanced PDAC progressed on gemcitabine-based therapy. All patients receive liposomal irinotecan, LV, 5-FU and paricalcitol. Liposomal irinotecan is given at 70 mg/m2 IV over 90 minutes, LV at 400 mg/m2 IV over 30 minutes, and 5-FU at 2400 mg/m2 continuous IV infusion over 46 hours, on Day 1 of each 14-day cycle. Paricalcitol IV infusion will precede the above, given according to assigned cohort (75 mcg weekly or 7 mcg/kg weekly). The primary objective of this study is to determine the tolerability between two different dose levels of paricalcitol added to the combination regimen of 5-FU/LV/liposomal irinotecan in patients with advanced PDAC. Secondary objectives are measures of efficacy (ORR, PFS, OS, CA19-9 biochemical response rate). Clinical trial information: NCT03883919.

PRELP has prognostic value and regulates cell proliferation and migration in hepatocellular carcinoma.

Purpose: Hepatocellular carcinoma (HCC) is an aggressive and prevalent tumor threatening human health. A previous study suggested low PRELP (proline/arginine-rich end leucine-rich repeat protein) expression was associated with poor patient survival in pancreatic ductal adenocarcinoma (PDAC). However, the role of PRELP in HCC has not yet been illuminated.Methods: PRELP expression analyses were carried out using transcriptomic datasets from the Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB). The correlations between PRELP expression and clinicopathological features, and prognostic analyses were performed with a tissue microarray (TMA) and immunohistochemistry (IHC). The endogenous expression and in vitro roles of PRELP were investigated in cultured HCC cell lines. The potential mechanisms were characterized by a Gene Set Enrichment Analysis (GSEA) and gene-gene correlation analyses.Results: We found that PRELP mRNA expression was dramatically decreased in HCCs in comparison with that in adjacent normal tissues (NTs) or hepatic cirrhosis. IHC staining showed that PRELP was down-regulated in HCCs, which mainly located in cytoplasm, and was also found in nuclei. The correlation analyses revealed that PRELP expression was relevant to later p-stages (p= 0.028) and tumor size (p= 0.001). The overall survival (OS) and relapse free survival (RFS) time was shorter in HCC patients with lower PRELP expression levels than that with higher PRELP expression levels. Overexpression of PRELP inhibited, while knockdown of PRELP promoted proliferation and migration of HCC cells. For potential mechanisms, PRELP may inhibit progression of HCCs by interacting with integrin family members and the extracellular microenvironment.Conclusion: Our findings demonstrated that overexpression of PRELP correlates with better patient survival and inhibits both cell proliferation and migration in HCC. Therefore, PRELP can serve as a potential prognostic biomarker and therapeutic target which deserves further investigation.