bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of feasibility and survival in repeated cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in appendiceal cancer with peritoneal dissemination.
Authors: Karpes Josh , Parikh Roneil , Shamavonian Raphael , Alzahrani Nayef , Morris David L.
Published: May 2019

e15702

Background: CRS/HIPEC has been established as the method of choice for the management of peritoneal dissemination from appendiceal cancer. With recurrence rates after first surgery as high as 44%, re-do CRS/HIPEC is evolving as an effective recurrent treatment regime. This analysis examines the feasibility of repeated CRS/HIPEC for patients with appendiceal cancer with peritoneal dissemination and evaluates the survival outcomes. Methods: A retrospective cohort study of 1074 patients who had CRS/HIPEC procedures and had a recorded tumour grade from 1996 to 2017 was performed. Morbidity and mortality as well as the survival effect was analysed. Tumour grade was divided into low grade: diffuse peritoneal adenomucinosis (DPAM); and high grade: peritoneal mucinous carcinomatosis (PMCA). Results: Initial CRS/HIPEC comprised of 991 patients, with 148 of those undergoing repeated CRS/HIPEC for appendiceal cancer with peritoneal dissemination. The overall survival for patients with DPAM who had only one CRS/HIPEC was 248 months with a five-year survival of 80%, compared to an overall survival of 75 months and five-year survival of 54% in those who had repeated CRS/HIPEC. For patients with PMCA, the overall survival of those who only had one CRS/HIPEC was 63 months with a five-year survival of 47%, compared to an overall survival of 52 months and five-year survival of 44% in those who had repeated CRS/HIPEC. There was no statistically significant difference in the morbidity and mortality for patients who had repeated CRS/HIPEC for management of appendiceal cancer with peritoneal metastases when compared to those who only had one. Conclusions: This study suggests that re-do CRS/HIPEC is a feasible and effective treatment regime in the management of tumour recurrence in appendiceal cancer with peritoneal dissemination, with no difference in the morbidity and mortality of patients who had repeated CRS/HIPEC compared to only one procedure.
Identifying mechanisms of macrophage-induced metastasis in pancreatic ductal adenocarcinoma.
Authors: Wu Tony James
Published: May 2019

e15705

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal, incurable disease. Macrophages are one of the most abundant, multifunctional immune cell populations in the tumor microenvironment and a major component of the immune infiltrate in many solid tumors. Methods: Employing a multi-omics approach, PDAC cell lines and primary macrophages were CTAP (cell-type specific labelling using amino acid precursors)-labelled and admixed together for a prolonged period of time. To identify cell-of-origin of novel RNA and proteins, these mixed co-cultures were FACS sorted for downstream RNA-sequencing analysis or harvested in bulk for downstream proteome and secretome analysis. Results: Here, we provide new insight into the dichotomous relationship between epithelial and mesenchymal phenotypes of PDAC cells in 3D culture. We report the ability of PDAC mesenchymal cells to form vascular mimicry-like structures in a 3D in vitro assay of invasion. Additionally, we demonstrate that macrophages have the ability to impart a pro-invasive phenotype to PDAC cells when co-cultured in 3D, regardless of EMT (epithelial-to-mesenchymal transition) status. Preliminary integration of cell culture transcriptomes with CTAP-TMT proteomes and secretomes implicates several key epithelial- and macrophage-derived signalling molecules as principal instructing signals for mediating the observed pro-invasive phenotype. Conclusions: Blockade of these signalling molecules or their receptors disrupted the crosstalk between PDAC cells and macrophages within the tumor microenvironment and impaired the ability of macrophages to induce a pro-invasive phenotype to PDAC cells.
Prognostic factors associated with short-term survival (STS) in advanced pancreatic cancer (APC): A Canadian multicenter analysis from the CHORD Consortium.
Authors: Cardoso Miguel , Mehta Sakshi , Kim Christina , Armstrong Dawn Elizabeth , Ramjeesingh Ravi , Renouf Daniel John , Ahmed Shahid , Ko Yoo-Joung , Harb Mohammed , Kong Shiying , Cheung Winson Y. , Meyers Brandon M. ,   on behalf of the CHORD Consortium
Published: May 2019

e15717

Background: The survival of patients (pts) with APC (locally advanced/metastatic) is slowly improving; however in some pts it remains extremely short. Few studies have evaluated the clinical, pathologic and treatment characteristics associated with STS in APC. Methods: Pts with APC (between 2011-2017) were included in the analysis. Descriptive analyses were conducted for demographic, tumor and treatment characteristics between pts who survived ≤ and > 90 days using Wilcoxon rank-sum test and Chi-square test for continuous and categorical variables respectively. Multivariable logistic regression was performed to identify association between pts’ characteristics and STS. Results: A total of 580 pts were included in the analysis: median age 68, 53% male, 92% metastatic and 53% ECOG 0/1. STS ≤90 days occurred in 152 pts (26.2%), with 65.1% not receiving any chemotherapy. Median overall survival for STS was 49 days vs. 276 for non-STS. At least 1 cycle of chemotherapy was administered to 358 pts; mean duration of 1st line chemotherapy for pts with STS ≤90 was 1.5(SD 2.5) cycles (N = 53), compared to 7.6(SD 11.1) cycles (N = 305) for pts surviving > 90 days. Prognostic factors associated with STS ≤90 days were neutrophil:lymphocyte ratio, LDH, metastatic disease, ECOG and not receiving chemotherapy (Table). Other clinical factors (BMI, smoking history, diabetes) and laboratory values (platelet, baseline CA19-9, estimated GFR) were not prognostic. Conclusions: In a multicenter database of Canadian academic centers, < 2/3 of pts received at least 1 cycle of chemotherapy. STS ≤90 days occurred most often in pts who did not receive chemotherapy. Prognostic factors associated with STS include routine laboratory values, receipt of chemotherapy, ECOG and the presence of metastatic disease. Further analyses of these factors may help improve survival in APC. [Table: see text]
Predictors of neoadjuvant chemotherapy efficacy in localized pancreatic head cancer: A 15-year experience at a high volume pancreatic cancer center.
Authors: Al Abbas Amr I. , Hodges Jacob , Varley Patrick , Buchholz Connor , Bellon Johanna E , Bahary Nathan , Singhi Aatur D. , Hogg Melissa , Zeh Herbert , Zureikat Amer H.
Published: May 2019

e15724

Background: Surgery followed by adjuvant chemotherapy (SF) is the standard approach for localized pancreatic adenocarcinoma (PC). Although neoadjuvant chemotherapy (NC) is being increasingly used, its efficacy remains debatable. This study aims to identify baseline factors associated with benefit from NC as compared to SF for PC. Methods: Review of a prospectively maintained database of resected localized head PC undergoing NC or SF at a tertiary referral hospital from 2002 to 2018. Baseline factors investigated included clinical stage by EUS (7th edition AJCC), CT vessel involvement, and serum CA19-9. Baseline CA19-9 levels were grouped into mild (37-200), moderate (200-900), and marked elevations (≥ 900). Patients with baseline serum CA19-9 < 37 IU/dL were excluded from the analysis. Results: In total, 269 patients were evaluated: 165 (61%) received NC and 104 (39%) had SF. Mean patient age was 68.3 years and 50% were females. Of these, 42% had stage IIB, 44% had N1 disease, and 38% had vascular involvement. Compared to SF approach, NC was associated with improved median survival for CA19-9 of < 200 IU/dL (30 vs 21 months, p = 0.08), 200-900 IU/dL (32 vs 17 months, p < 0.01), and the ≥900 IU/dL (33 vs 12 months, p < 0.01) groups. On Cox regression, NC was the only baseline factor predictive of improved survival in the groups with moderate (HR:0.35,[95% CI:0.20-0.62];p < 0.01) and marked (HR:0.36,[95% CI:0.18-0.71];p < 0.01) pretreatment CA19-9 elevation. Notably, NC was not predictive of improved survival in the cohort with mild CA19-9 elevation. Conclusions: This study identifies a cohort of patients that benefits from neoadjuvant chemotherapy over a surgery first approach for localized pancreatic head cancer. Elevation in baseline CA19-9 may serve as the strongest indicator for chemotherapy before resection.
Prediction of response to pelareorep plus pembrolizumab in pancreatic ductal adenocarcinoma (PDAC).
Authors: Fountzilas Christos , Wilkinson Grey A , Eng Kevin H. , Fields Paul , Arora Sukeshi Patel , Kalinski Pawel , Raber Patrick , Nuovo Gerard , Coffey Matthew C. , Mahalingam Devalingam
Published: May 2019

e15726

Background: Pelareorep is an oncolytic reovirus that can induce an inflamed T-cell-infiltrated (hot) phenotype in PDAC. In a phase Ib trial, pelareorep was administered in combination with pembrolizumab and chemotherapy in patients (pts) with advanced, pre-treated PDAC. The safety profile was acceptable and efficacy results were encouraging (Mahalingam ASCO GI 2018). Here we present the results of immune analysis in peripheral blood. Methods: Peripheral blood mononuclear cells (PBMCs) were collected on cycle 1 day 1 (C1D1, pre-pelareorep), C1D8 (pre-pembrolizumab) and C2D1 (pre-pelareorep). RNA from PBMCs was analyzed using a customized Nanostring panel. The research-use only immunoSEQ Assay (Adaptive Biotechnologies, Seattle, WA) was used to characterize T-cell receptors from PBMCs. Results: Eleven pts were enrolled. Disease control was achieved in 50% of the 6 efficacy-evaluable pts. One pt achieved PR that lasted 17.4m. Two additional pts achieved SD, lasting 277 and 126 days. Downregulation (relative change < -1.5) of CD1b (C1D1), HLA-C, MAPK14 (C1D8), CD63, LY96, LTF, TXK, TNFSF13, IL25, C1QB (C2D1) and upregulation ( > 1.5) of IL17F (C1D1), MAGEA4, CCL7 (C1D8), CSF1, ICOS, LILRA4, TICAM2 (C2D1) was observed in pts with clinical benefit vs. no clinical benefit (raw p < 0.05). Increase in clonal diversity was noted during therapy overall (Table). C2D1 had significantly more clonal expansion than C1D8; ~30% of expanded clones from C1D8 were also expanded at C2D1 (durable). High numbers of early expanded (C1D8 only) and durable clones were associated with longer survival. Conclusions: Pts with disease control had higher baseline IL17F compared to non-responders. On-treatment relative decrease in IL25 (Th2), increase in LILRA4, TICAM2 (antiviral response) and ICOS were noted in these pts. There was new clone expansion after treatment overall; ~30% of expanded clones at C1D8 were durable. Early and durable clonal expansion correlated with survival. A phase II trial with pelareorep plus pembrolizumab in advanced PDAC is ongoing. Clinical trial information: NCT02620423. [Table: see text]
The prevalence of hereditary pancreatitis mutations in families with pancreatic cancer.
Authors: Seedor Rino S. , Savage Michelle J. , Iqbal Waleed , Arora Sanjeevani , Rainey Kim , Forman Andrea , Lincoln Steven , Garcia John , Truty Rebecca , Esplin Edward D. , Handorf Elizabeth A. , Hall Michael J.
Published: May 2019

e15728

Background: Germline pathogenic variants (PV) in hereditary cancer risk genes are found in ~10-15% of pancreatic adenocarcinomas/cancers (PC), but most cases of familial PC have no identifiable genetic cause. Chronic pancreatitis is an established risk factor for PC, with a lifetime risk of PC of 10-30%, and has been associated with germline mutations in several genes: PRSS1, SPINK1, CASR, CTRC, and CFTR. Few studies have examined the prevalence of PV in the pancreatitis risk genes among patients reporting a personal or family history (FHx) of PC. Methods: The FCCC Risk Assessment Program (RAP) database was queried to identify patients tested for PRSS1, SPINK1, CASR, CTRC, and CFTR as part of risk assessment. Pedigrees, demographic and cancer history data were reviewed. De-identified data from Invitae on patients found to be CFTR+ on hereditary pancreatitis testing were also reviewed for personal/FHx of PC. Results: 26 patients with PC and 48 patients with a FHx of PC underwent germline testing for the pancreatitis genes at FCCC. 7 of 26 (26.9%) patients with PC carried at least one CFTR mutation, while 3 of 48 (6.3%) patients with a FHx of PC carried a CFTR mutation. Interestingly, 8 patients carried an intronic variant in the CFTR gene. No patients with PC and 2 of 48 (4.2%) patients with a FHx of PC carried a SPINK1 mutation. The CFTR mutation rate in PC patients exceeded the expected carrier rate (2.6-3.6%)(p < 0.001). The SPINK1 mutation rate in PC patients also exceeded the expected carrier rate but was not statistically significant (1.9%)(p = 0.23). CaSR, PRSS1, and CTRC mutations were not identified in our population. Personal/FHx data were available to review for 175 of the 496 CFTR+ patients tested through Invitae. 49 of 175 (28%) had a personal history of PC and 105 of 175 (60%) had a reported FHx of PC. Strikingly, 23% of CFTR+ patients carried pathogenic mutations in other genes (most commonly SPINK1). Conclusions: In our select sample, CFTR mutations, and in particular a known intronic variant, were highly enriched in a population of patients undergoing risk assessment for hereditary PC. Commercial data suggest a substantial minority of CFTR+ carriers with a personal/FHx of PC may also carry SPINK1 mutations.
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.
Relationship between cholangitis, initial chemotherapy regimen, and overall survival in patients with unresectable pancreatic adenocarcinoma.
Authors: Lumish Melissa , Wang Thomas , Darnell Elijah , Hernandez-Barco Yasmin , Krishnan Kumar
Published: May 2019

e15788

Background: Chemotherapy remains the primary therapy for patients with unresectable pancreatic adenocarcinoma, though response to therapy is variable. Patients with pancreatic adenocarcinoma frequently develop jaundice and cholangitis and require endoscopic biliary stenting. Here, we investigate the association between cholangitis, initial chemotherapy regimen, and one-year survival in patients with unresectable pancreatic adenocarcinoma. Methods: We conducted a retrospective chart review of all patients who received metal stents for biliary obstruction with pancreatic adenocarcinoma over a five-year period at the Massachusetts General Hospital. Only patients with unresectable cancer were included. We compared the association between survival and cholangitis within four subgroups: no chemotherapy, gemcitabine alone or in combination, FOLFOX combination and FOLFIRINOX. The statistical methods used were the chi-squared test for categorical variables, regular ANOVA for continuous variables, and log-rank (Mantel-Cox) test for survival analysis. Results: In total, we identified 74 patients who did not develop cholangitis and 52 patients who developed at least one episode of cholangitis. Among patients undergoing chemotherapy, cholangitis was associated with decreased survival within each subgroup (p-value = < 0.001). At one year from diagnosis, there was an association between cholangitis and decreased survival among patients receiving chemotherapy, independent of the number of episodes of cholangitis. Among those who were not receiving chemotherapy, cholangitis was not associated with survival outcome (p-value = 0.60). Conclusions: In conclusion, the development of cholangitis in patients receiving chemotherapy for metastatic pancreatic cancer is associated with decreased survival. This association is not affected by the number of episodes of cholangitis or by chemotherapy regimen. These data suggest that the development of cholangitis among patients receiving chemotherapy for pancreatic cancer may be a predictor of poor clinical outcomes. Further studies are needed to understand the impact of the local tumor microbial environment and to determine whether cholangitis is a surrogate for a more aggressive disease phenotype.
Efficacy and tolerability of adjuvant gemcitabine and capecitabine in patients with resected pancreatic cancer in US population: A single network experience.
Authors: Kaur Gurveen , Jahangiri Vida , Park Seon Jo , Wegner Rodney E , Monga Dulabh K.
Published: May 2019

e15789

Background: Adjuvant chemotherapy with combination of gemcitabine and capecitabine improved overall survival (OS) with an acceptable toxicity profile in the European patient population. However, limited data is available for tolerability and efficacy of the combination regimen in the adjuvant setting in the US population. Herein, we report a single network experience with the combination regimen. Methods: We retrospectively evaluated 45 patients with pancreatic cancer who were treated at our institution from 1/1/2017 – 12/31/2018. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas. These patients received adjuvant combination chemotherapy with gemcitabine (1000 mg/m2) and capecitabine (1660 mg/m2). Electronic medical record was reviewed to collect patient data. Medcalc software was used for statistical analysis including Kaplan Meier analyses. Results: Median age of patients was 64.6 years (range 47-87). Majority of patients had stage II disease (73.5%). Seventy-one percent of patients were able to receive 6 cycles of chemotherapy. Median OS for all patients was 20.2 months (95% CI 11.7-22.7). Median OS for patients who received < 6 vs 6 cycles was 14.9 months (95% CI 6.6-14.9) vs 21.5 months (95% CI 11.9-22.9) (p = 0.21). Median progression free survival (PFS) for all patients was 19.3months (95% CI 13.1-25.7). Median PFS for patients with < 6 vs 6 cycles was 7.3 months versus 22.2 months (p = 0.0002). Overall, 31.1% of patients developed disease progression. Of note, 33.3% and 71.1% of patients required dose reductions for gemcitabine and capecitabine respectively. Fifteen grade 3-4 adverse events were reported of which 11 were hematologic and 4 non-hematologic. Conclusions: This single institution analysis shows a trend in improvement for PFS for patients able to complete adjuvant therapy with gemcitabine and capecitabine following pancreatic resection. It is worth noting, however, that dose reductions were required in the majority of patients. Therefore, we propose investigating a modified regimen of gemcitabine and capecitabine in the US population.
Influence of post-resection time to chemotherapy in pancreatic adenocarcinoma on overall survival.
Authors: Abel Stephen , White Richard , Schiffman Suzanne , Williams Kenneth , Thakkar Shyam , Monga Dulabh K. , Finley Gene Grant , Islam Mohammed , Kirichenko Alexander V. , Wegner Rodney E
Published: May 2019

e15791

Background: Pancreatic adenocarcinoma is an aggressive malignancy with a high propensity for distant spread. To date, surgery remains the only potentially curative treatment option; which has traditionally been followed by adjuvant chemotherapy. Past research from the pancreatic literature as well as other disease sites has shown conflicting outcomes as it relates to timely delivery of adjuvant chemotherapy. We thus used the National Cancer Database (NCDB) to evaluate time to initiation of chemotherapy following pancreatic resection and if there was any correlate with outcome. Methods: We identified patients diagnosed with stage 1-3 pancreatic adenocarcinoma in the NCDB, excluding those with stage IV disease, those treated nonoperatively, with adjuvant or neoadjuvant chemotherapy or radiotherapy and those with unknown or inadequate ( < 3 months) follow-up. Receiver operator curve analysis identified an interval of 66 days as associated with outcome. Multivariable logistic regression analysis identified variables associated with increased time to chemotherapy postoperatively ( > 66 days). Propensity matching was done to account for indication bias. Overall survival (OS) was compared between both propensity-matched groups receiving earlier and postponed chemotherapy post-resection, with an additional breakdown by stage. Results: In total, 6,873 and 3,348 patients received chemotherapy before and after the 66 day cutoff, respectively. Predictors of expedited chemotherapy included lower comorbidity, treatment outside a community program in an urban location, having insurance, Caucasian race and treatment after 2009. Median overall survival was 21.8 months for all patients and of these, 6462 were stage 1. 5-year OS was 20% in patients receiving chemotherapy within 66 days and 18% in those not (p = 0.0266). In stage 1 patients, 5-year OS was 23% versus 21% (p = 0.0116) in favor of expedited chemotherapy. In stage 2 patients, 5-year OS was 16% in both arms (p = 0.7231). Higher stage and comorbidity score, treatment at a community cancer program, lower salary, increased time from surgical resection to chemotherapy, higher grade, positive margins, and more distant year of treatment were associated with worse prognosis. Conclusions: The present propensity-matched analysis showed a significant benefit to earlier delivery of chemotherapy in the adjuvant setting, with the largest benefit seen in stage 1 patients.
Hospitalization cost and length of stay in pancreatic cancer population: A national inpatient database study.
Authors: Enofe Ikponmwosa , Rai Manoj P. , Nemakayala Divyesh Reddy , Tatineni Shilpa , Aluko Atinuke , Bedi Prabhjot Singh , Yam Julie , Khan Nazia Naz S , Laird-Fick Heather
Published: May 2019

e15793

Background: Pancreatic cancer accounts for 7% of all cancer deaths in the U.S. It contributes to burgeoning health care cost and is associated with poor prognosis. The aim of this study was to describe the disease burden, pattern of resource utilization, hospital cost and outcomes among hospitalized pancreatic cancer patients based on the location of disease. Methods: We conducted a retrospective study utilizing the 2014 national inpatient sample database. Adult records with a primary discharge diagnosis of pancreatic cancer were included. Records with no specification on cancer location were excluded. Regression models (logistic and linear) were used to estimate adjusted odds ratios (OR), mean length of stay (LOS) and hospital charges (HC). Covariates included sociodemographic factors, co-morbidities and therapeutic surgical procedures received during hospitalization. Results: A total of 4,799 discharge records met the inclusion criteria. Overall, 74.3% had cancer in the pancreatic head and 25.6% had cancer in the body and tail. Pancreatic head cancers were more common in whites (73%). Patients with cancer in the body and tail more commonly experienced metastasis than patients with pancreatic head cancer (23.8% versus 20.4% p = 0.02). Compared to pancreatic head cancers, patients with body and tail cancers were more likely to have a pancreatectomy during index hospitalization (OR 45, 95% CI 27.8 - 65.2). Alternatively, cancers of the pancreatic head were more likely to have an endoscopic pancreatic procedure during index hospitalization compared to body and tail (OR 7.39, 95% CI 3.9 -13.9). Pancreatic head cancers were associated with a significantly longer mean hospital LOS (8.1 versus 6.4 days, mean difference 1.66, p < 0.001) and higher mean cost of hospitalization (Mean HC $85,263.40 versus $56,156.60 p < 0.001) compared to cancer in the body and tail. Conclusions: Despite lower rate of metastasis and pancreatectomy, patients hospitalized for pancreatic head cancers have longer hospital LOS and higher healthcare cost burden. Our findings may inform physicians, patients, and policymakers and may help channel resources toward specific patient population to reduce healthcare cost and improve outcomes for individuals and healthcare organizations.