bluuebunny/crossref_metadata_2025_split huggingface dataset:
Copy number instability (CNI) combined with CA19-9 as a biomarker for postoperative prognostic prediction of pancreatic cancer.
Authors: Zhan Qian , Ren Dandan , Mao Beibei , Song Xue , Ma Yanna , Zhang Henghui , Shen Baiyong 
Published: May 2019

e15730 Background: Pancreatic cancer is one of the most aggressive human malignancies and has a poor prognosis. Large-scale studies have reported on its initiation, progression, diagnosis and prognosis. However, over the past several decades, the overall 5-year survival rate of pancreatic cancer has remained at less than 5%. Thus, the current major challenge in the postoperative management of pancreatic cancer is to identify high-risk recurrent patients. We retrospectively investigated the clinical, pathological and outcome data for 48 pancreatic cancer patients to clarify the associations of molecular mechanisms and prognosis. Methods: Eligible pancreatic cancer patients were included, and formalin-fixed paraffin-embedded (FFPE) tumor specimens and matched blood samples were collected at Ruijin Hospital, Shanghai Jiao tong University School of Medicine. Genome profiles were analyzed by using a designed 1408-gene panel based on next-generation sequencing (NGS). The copy number instability (CNI) score in primary tumor tissue was calculated to investigate the relationship between molecular features of the primary tumor and prognosis. Results: The CNI score in primary tumor tissue was positively correlated with lymph node metastasis, TP53 mutation, and early recurrence. Moreover, preoperative Carbohydrate antigen 19-9 (CA19-9) levels and CNI scores in primary tumor tissue were significant independent predictors associated with PFS in pancreatic ductal adenocarcinoma (PDAC). Finally, we performed an independent signature that includes CNI score and Carbohydrate antigen 19-9 (CA19-9) level to predict prognosis of pancreatic cancer. Conclusions: These results suggest that CNI score in primary tumor tissue is an independent predictive prognostic biomarker for PDAC. CNI combined with CA19-9 is a better predictor for postoperative prognostic prediction of pancreatic cancer.
Trends in pancreatic cancer chemotherapy treatment in the United States from 2008 through 2016.
Authors: Hui Shirley , Bernstein David , Balachandran Vinod P. , Henk Henry J. 
Published: May 2019

e15734 Background: Pancreatic cancer is the third leading cause of cancer death in the United States. 55% of patients present with advanced disease at diagnosis and are treated with chemotherapy, with gemcitabine and 5FU-backbone based therapies both demonstrating efficacy. However, data on the adoption of these of therapies in academic and non-academic centers is scarce. The goal of this study is to examine the aggregate adoption of these therapeutic regimens in widespread clinical practice from 2008 through 2016 using health plan claims data. Methods: Privately insured and Medicare patients with advanced pancreatic cancer treated with chemotherapy from 2008 through 2016 were identified from the OptumLabs Data Warehouse. First-line treatment regimen and duration were correlated with age, sex, race, Charlson Comorbidiy Index (CCI) score, and opioid use measured by morphine milligram equivalents (MME) (as a proxy for pain) in the 6 months prior to starting chemotherapy. Disease status was classified as advanced, adjuvant or neo-adjuvant. Results: For 14,301 patients treated with chemotherapy primarily, the use of monotherapy has significantly decreased from 73% to 27% (p < 0.001) between 2008 and 2016, while combination therapy using two antineoplastic agents (20% to 41%; p < 0.001) and three or more agents (6% to 32%; p < 0.001) increased. Since 2013, patients receiving combination therapy vs. monotherapy are significantly younger (mean 66 vs. 70; p < 0.001), have higher CCI (6.3 vs. 6.1; p = 0.002), and have similar daily opioid dose prior to chemotherapy (5.2 vs. 3.8 MMEs; p = 0.086). Duration on first-line regimen was greater in patients receiving combined therapy, compared to those on gemcitabine monotherapy (median 130 vs. 119 days; p < 0.001) after adjusting for CCI, disease status, and demographics. Conclusions: The use of combined therapy for the treatment of pancreatic cancer has increased over time, with patients on combined therapy appearing to be younger. [Table: see text]
The peritoneal fluid reflects the effect on pancreatic cancer by intraoperative radiation therapy (IORT).
Authors: Lee Yun Sun , Kim Hyung Sun , Park Joon Seong 
Published: May 2019

e15742 Background: Pancreatic cancer has high aggressive features. Intraoperative radiation therapy (IORT) has advantage to deliver the radiation to the restrictive tumor bed immediately. In breast cancer, a study analyzing the wound fluid in patients underwent IORT found that the curative effect was due to the influence to the remaining cancer cell and tumor microenvironment. However, there is a lack of mechanism study related to the effectiveness of IORT in pancreatic cancer. The aim of this study is to investigate whether IORT influenced the responses of pancreatic cancer with peritoneal fluid in vitro and to evaluate the effect and mechanism of the IORT on pancreatic cancer. Methods: Between Apr 2018 and Jan 2019, 28 patients underwent radical resection for pancreatic cancer at Gangnam Severance Hospital. Peritoneal Fluid were obtained 24 hours immediately after operation by surgical drains. And fluid were treated in the pancreatic cancer cell lines (Miapaca-2, PANC1, AsPC1, BxPC3) in total 28 patients (IORT n = 14, no IORT n = 14). Proliferation of cells were measured by WST-1 manner and matrigel coated chambers were used to analyses the invasiveness. Proteomic analysis of fluid was determined by human cytokine antibody array kit (84 targets). Results: When the fluid from each patient was treated to cells different concentrations, the two-dimensional proliferation was stimulated 48 hours later in common but different reactivity was observed for each cell. In invasion assay, cancer cell attracted more by fluid than FBS and decreased invasiveness of cells was observed when treated the fluid from patient underwent IORT. According to the cytokine array, fluid displayed altered expression of several cytokines in patients underwent IORT (Angiogenin, MCP-1, IL-8, IL-6,ENA-78, p < 0.01). Conclusions: We demonstrated that IORT cause the proteomic difference, thereby inducing a change in the biologic activity to pancreatic cancer cell. These results will help us understand the mechanism related to local tumor control and establish the biological basis of IORT. Through the further analysis and long-term follow-up, it will be possible to establish IORT dependent new molecular therapeutic targets or new treatments.
Retrospective determination of the correlation between the distance of tumor manifestation to peripancreatic arteries and overall survival in primary resected pancreatic ductal adenocarcinoma.
Authors: Wittel Uwe A , Uhl Michael , Makowiec Frank , Hopt Ulrich Theodor , Fichtner-Feigl Stefan , Neubauer Jakob 
Published: May 2019

e15745 Background: Current guidelines determine the resectability of PDAC by evaluating the contact of the tumor to peripancreatic vasculature. We wanted to evaluate the influence of this distance of the tumor to peripancreatic arteries on the overall survival of patients with primary resection of pancreatic ductal adenocarcinoma. Methods: Preoperative radiographs of 208 consecutive patients after distal pancreatectomy and/or pancreatoduodenectomy operated between 2007 and 2014 were included in the analysis. In reconstructions of CT and MRI data 90° planes to the centerline of the celiac trunc (CT), hepatic artery(HA) and superior mesenteric artery(SMA) were computed with Aquarius Intuition Viewer (V4.4.11, Terarecon). The closest distance between the tumor and the CT /HA and SMA was determined by an experienced pancreatic surgeon and radiologist independently and upon a deviation greater than 3 mm consent was reached by additional review in 33,2% (69/208) of the cases. Results: 176 CT and 32 MRI scans of 208 patients were evaluated. 2.4 % (5/208) of the radiographs were excluded due to insufficient quality. Average distance of the tumor to the CT/HA and SMA was 16.3 and 6.5 mm for PD and 12.7 and 11.0 mm for DP. Distance between the artery and the tumor did not influence the R0 resection rates (overall R0 > 1mm resection margin 64%) and median overall survival was 24.0 months after R0 resection and 13.5 months after R1 resection (log-rank test P < 0.05). Borderline resectable patients (n = 57) showed a median survival of 13.4 months, patients with their tumor 1-5mm distant to the closest artery (n = 65) and greater than 5 mm distance (n = 81) showed a median survival of 20.3 and 32.9 months respectively. Patients with 0-5 and greater than 5 mm distance between arteries and tumor showed a survival benefit from R0 resection (R0/R1 0-5mm 20.3/13.5 months; > 5mm 37.3/12.8 months) while R0 resected borderline resectable patients showed a similar survival than R1 resected patients (R0 12.7months, R1 15.1 months). Conclusions: The negative resection margins in borderline resectable patients not increase the survival when compared to R1 resected patients. Patients with primary R0 resection and initially large distance of the tumor to peripancreatic vasculature show a prolonged survival.
Impact of pretreatment serum creatinine on outcomes in pancreatic adenocarcinoma.
Authors: Alrifai Taha , Ali Faisal , Gong Zimu , Myint Phyo Thazin , Nijhawan Karan , Pannu Bibek Singh , Syed Salman , Kozma Kelley Elizabeth 
Published: May 2019

e15749 Background: Pancreatic Adenocarcinoma (PA) is an aggressive malignancy with an estimated 5-year survival of 8.5%. PA was responsible for 7.3% of all cancer deaths in 2018 in the US. We aimed to evaluate the impact of pretreatment serum creatinine (SCr) level on Overall Survival (OS) in patients with PA. Methods: A retrospective review of electronic health records of patients with PA seen at our institution between 01/2014 and 01/2018 was done. We collected patients’ SCr at the time of diagnosis, and excluded patients with a glomerular filtration rate (GFR) below 60 mL/min per 1.73 m2 or SCr > 1.3 mg/dL. Patients were dichotomized around a SCr of 0.5 mg/dL. Kaplan-Meier survival estimate was performed to evaluate statistical significance. Results: A total of 83 patients, including 37 females and 46 males, with a median age at diagnosis of 67 years, were included. SCr of < 0.5 mg/dL was associated with a lower median OS as compared to a SCr of ≥0.5 mg/dL, (253 days versus 364 days; P = 0.035). There were more female patients in the low SCr group (71% vs 39%, P = 0.027). Patients with SCr of < 0.5 mg/dL had a lower mean BMI compared to patients with a SCr of ≥0.5 mg/dL, however this was not statistically significant (BMI = 22.45 versus 25.72; P = 0.49). Conclusions: Low SCr is predictive of a lower median OS in patients with PA. SCr has been suggested as a surrogate marker for muscle mass, which is closely associated with the degree of cancer cachexia. Our finding emphasizes the need for future larger studies to evaluate the utility of SCr as a prognostic indicator, as well as a cost-effective surrogate for measuring cancer cachexia. [Table: see text]
Comparison of the mutation profile between pancreatic head/neck and body/tail cancers.
Authors: Lu Junliang , Liang Zhiyong , Wu Huanwen M. , Pang Junyi , Liang Xiaolong , Guo Junchao , Shao Yang , Zuo Xiaohan 
Published: May 2019

e15752 Background: Carcinomas in the pancreatic head/neck and body/tail represent different clinicopathological characteristics, but little is known about the underlying genetic mechanisms. The present study aims to explore the differences in mutation profile between pancreatic head and body/tail cancers. Methods: Fifty-four patients were retrospectively enrolled in the present study. DNA was purified from qualified formalin-fixed, paraffin-embedded tissue blocks of the tumor and corresponding adjacent normal tissue and subjected to target-capture next generation sequencing (TGS). Somatic mutations were identified, which further underwent gene ontology (GO) and KEGG pathway analysis. Results: The most frequently mutated genes in carcinomas of the pancreatic head were KRAS (61.3%), TP53(38.7%), and CDKN2A (16.1%), while that of the pancreatic body/tail were KRAS (95.7%), TP53(87%), CDKN2A (26.1%), and ARID1A (26.1%). The prevalence of TP53 and KRAS mutations in pancreatic head and body/tail cancers were significantly different from each other (p = 0.0006 and p = 0.0037, respectively). Pancreatic head/neck cancers also preserved a broader KRAS mutation spectrum than their counterparts of the body/tail. Pathway analyses revealed that mutations in cancer of pancreatic head/neck were enriched for genes involved in the protein amino acid phosphorylation, regulation of cell proliferation, transmembrane receptor protein tyrosine kinase signaling pathway, and phosphorylation pathways, while cancers of the pancreatic body/tail were enriched for genes involved in colorectal cancers. Conclusions: Cancer of the pancreatic head/neck and body/tail have distinct mutation profiles.
Effect of tumor cell-derived debris and IgG on metastasis of pancreatic cancer and inflammation through tumor-associated macrophages.
Authors: Zhang Qi , Chen Qi , Bai Xueli , Wang Jianxin , Liang Tingbo 
Published: May 2019

e15764 Background: The progression and metastasis of pancreatic ductal adenocarcinoma (PDAC) is highly dependent on the tumor microenvironment. Most tumor-associated macrophages (TAMs) are M2 phenotypic macrophages, which normally show anti-inflammatory functions in numerous disorders. We previously found that alternatively activated macrophages showed pro-inflammatory characteristics upon stimulation of hepatoma cell-derived debris, but the molecular mechanism was unclear. Methods: Macrophages were induced using tumor cell debris. Xenograft mouse model was established. Immunoblotting and immunochemistry were used to test protein expression. Results: The M2 macrophages-derived inflammation also existed in PDAC. We proved that the necrotic debris of PDAC cells induced potent IL-1β release by M2 macrophages via TLR4/TRIF/NF-κB signaling, and this effect was further boosted by IgG that also derived from PDAC cells. We further revealed that increased IL-1β promoted epithelial-mesenchymal transition (EMT) and consequent metastasis of PDAC cells. Using a selective COX-2 inhibitor celecoxib, we enhanced the anti-tumoral efficacy of gemcitabine. Conclusions: These data revealed a special pro-inflammatory phenomenon and mechanism in PDAC, and indicated that IL-1β and COX-2 can be therapeutic targets of anti-inflammatory strategy in PDAC treatment.
Dynamic assessment of circulating tumor DNA in prediction of response to nab-paclitaxel-based first-line chemotherapy in metastatic pancreatic cancer.
Authors: Shi Yan , Guan Shasha , Han Quanli , Li Jie , Lv Yao , Yan Huan , Dai Guanghai 
Published: May 2019

e15769 Background: Emerging evidence showed circulating tumor DNA (ctDNA) may be used as biomarker for monitoring tumor response to chemotherapy in pancreatic cancer. This pilot study was to evaluate the clinical application of dynamic assessment ctDNA in MPC. Methods: From December 2016 to June 2018 in our center, 29 MPC patients treated with nab-paclitaxel based first-line chemotherapy (NS or N plus Gemcitabine, NG) had at least 2 ctDNA tests were included for analysis. Plasma samples were prospectively collected at baseline and periodical follow-ups until progression, death, or withdrawal of consent. Next-generation sequencing for a panel of 425 genes covering a wide range of cancer-related loci was performed to profile ctDNA. Progression of ctDNA was defined as increased mutation allelic frequency (MAF) of common mutant gene from baseline or nadir, or the presence of new gene alternations. The clinical relevance of the common alteration, and its dynamic changes in ctDNA were analyzed, and compared to conventional imaging response and survival. Results: In our patient cohort, the best overall response of partial response (PR) was 48.3% (14/29). By February 2019, 18 patients passed away with median follow-up of 9.7 months. At baseline, 22 patients (75.9%, N = 29) had at least one common driver gene alterations ( KRAS, TP53, CDKN2A, SMAD4) detected in ctDNA. Mutant KRAS and TP53 were identified in 72.4% and 62.1% patients with a median MAF of 5.8% and 4.7%, respectively. Of 14 patients achieved PR on image, MAF of the mutant driver genes found declined significantly or mutant gene disappeared. At the time of clinical progressive disease (PD), 24 patients had evaluable image and ctDNA results whereas both demonstrated PD in 23 (95.8%), including 9 found earlier progression of ctDNA with median time of 1.93 months compared to image findings. Among 22 patients with any of the above 4 mutant driver genes in ctDNA at baseline, 13 patients demonstrated significant reduction of MAF (reduction to < 1% or undetectable) within 6 weeks, who had a longer progression free survival (PFS, reduction 6.6m vs no reduction 3.4m, P = 0.001) and overall survival (OS, reduction 12.6m vs no reduction 5.4m, P = 0.001), compared to those who had an increased or stable MAF. Conclusions: Our initial findings demonstrated the changes in MAF of 4 common driver genes in ctDNA was well correlated with treatment response to chemotherapy, PFS and OS in MPC. Peripheral ctDNA was a potential reliable alternative biomarker for efficacy and progression prediction in MPC.
Association of pancreatic cancer stem cells with tumor stroma type.
Authors: Sahin Ibrahim Halil , Askan Gokce , Chou Joanne F , Capanu Marinela , Yu Kenneth H. , Basturk Olca , Iacobuzio-Donahue Christine A , O'Reilly Eileen Mary 
Published: May 2019

e15771 Background: Pancreatic ductal adenocarcinoma (PDA) is a heterogeneous disease with distinct stroma features. Cancer stem cells (CSC) in PDA may express CD44 (C) +/- Epithelial Specific Antigen (E). We investigated the relationship of CSC markers with tumor stroma and clinical outcomes in PDA patients (pts) who had surgical resection. Methods: Pts who underwent PDA resection with IRB #00-032/#06-107 consent between 01/2012-06/2014 at Memorial Sloan Kettering were identified. C and E immunohistochemical (IHC) expression scored as follow: 0, none; 1, 1%–10%; 2, 11%–50%; 3, 51%–80%; 4, 81%–100%. Staining intensity was scored as 0, none; 1, weak; 2, moderate; 3, strong. The total scores (0-12) were averaged and was considered positive when average score > median. Stroma was classified as loose, moderate and dense based on fibroblast content using H&E stain. Overall survival (OS) and relapse-free survival (RFS) were estimated using the Kaplan-Meier and compared by log-rank test; association between CSC markers and stroma type was assessed by Fisher`s exact test. Results: N = 93 PDA pts identified. PDA with C(+) E(-) had significantly higher loose stroma and PDA with C(-) E(+) and C(-) E(-) had more moderate and dense stroma (p = 0.0033). The number of PDA pts with dense, moderate, and loose stroma was: 11, 31, and 51 respectively. No local recurrence in pts with dense stroma observed and 8/11 had either lung or liver recurrence. Six of 31pts with loose stroma had a local recurrence and 13/31 pts had either liver or lung recurrence. No statistically significant difference in OS and RFS were observed among subgroups (P = 0.089). Median time from relapse to death was: 2, 11.5, 10,5 and months 7 in C+/E-, C-/E+, C+/E+, and C-/E- groups respectively. Conclusions: PDA CSCs appears to have an association with PDA stroma type. We also observed different recurrence patterns among stroma subgroups. Respecting small sample size, these data indicate CSCs may have an important role in stroma differentiation in PDA. CSC markers do not predict OS and RFS, however, resected PDA with C(+) E(-) may have more aggressive behavior following recurrence. [Table: see text]
Expression level of NRP1 and SMAD2 in correlation to mutational status of RAS (BRAF) in pancreatic cancer.
Authors: Stanek Libor , Tesarova Petra , Gurlich Robert 
Published: May 2019

e15784 Background: Pancreatic cancer is the second leading cause of death in tumor diseases worldwide. Neuropilin-1 (NRP1) is overexpressed in many tumors including the pancreatic cancer. The main goal is to reveal the role of NRP1 in the process of tumorigenesis. The expression of NRP1 and the presence of KRAS point mutation lead to the cell survival by lowering the SMAD2 phosphorylation. On the other hand, the NRP1 inactivation and the wild-type KRAS in tumor cells lead to the tumor growth inhibition. Our aim is to prove correlation between NRP1 level, SMAD2 and the mutational status of KRAS, NRAS in prognosis of patients with pancreatic cancer. Methods: Retrospective study is based on analysis of 50 FFPE bioptical samples (40 resections, 8 punctures, 2 thin-needle biopsies); histology verified all as adenocarcinomas. The expression level of NRP1 and SMAD2 is measured by Imunohistochemistry by mice monoclonal antibodies Anti-Neuropilin 1 and Anti-SMAD2 (Abcan) on the device BenchMark ULTRA (Ventana Medical Systems), Roche. DNA isolation is executed by QIAamp DNA Mini Kit. We used Codon Specific Mutation Detection Kit (Diatech pharmacogenetics) for detection of somatic point mutations in codons 12, 13, 61 and 146 of KRAS and NRAS genes. BRAF mutational status was revealed by direct sequencing on ABI Prism 3130. We monitor the level of expression of NRP1 and SMAD2 and correlate it to the mutational status of RAS and BRAF, and disease prognosis. Results: NRP1 expression was detected in 24 out of 50 cases, SMAD2 expression was detected in 13 of 50 cases, other cases without expression. KRAS gene mutation was detected in 8 cases out of 60, other cases of WT. Mutation in the NRAS gene was detected in 3 of 50 cases. BRAF gene mutation was detected in 1 case out of 50, other WT. NRP1 expression correlated with KRAS gene mutation status in 9 cases and a strong correlation (p = < 0.001) was recorded. One case of mutation in the BRAF gene correlated with KRAS mutation status and NRP1 expression. Due to the small number of samples tested, without statistical significance. Inactivation of NRP1 was detected in 15 cases and was confirmed by the WT status of the KRAS gene. Conclusions: Was demonstrated that causal relationship exists between inactive NRP1 and wild-type KRAS, and that these should cause decrease of the rate of tumor growth. These characteristics, which are achievable simultaneously during the histological verification, may serve as a potential prognostic marker for subsequent decision of how radical surgical resection should be.