bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sarcopenia as a predictor of mortality in advanced pancreatic cancer.
Authors: Baldwin Ashley , Kundranda Madappa N. , Todd Eric , Whitehead Robert P. , Winston Rachel , Weber Jeffery , Weitz David J , Kelly Melinda , Kachaamy Toufic 
Published: February 2017

268 Background: Pancreatic cancer (PC) patients have multiple risk factors for malnutrition including digestive enzyme deficiency, gastric outlet obstruction and post prandial abdominal pain. In order to assess prognosis and triage patients at risk for malnutrition, accurate nutrition assessment is crucial. Overweight (Ow) or obese (Ob) patients pose a particular challenge and weight status should not be the only determining nutritional assessment tool. Sarcopenia (Sp) is defined as muscle mass (MM) two standard deviations below the healthy adult mean. It has been demonstrated in multiple studies to be a more accurate indicator of nutritional status. Sp is associated with poor clinical outcomes and lower survival in other conditions such as cirrhosis. Radiologic assessment of MM can be obtained reliably from computed tomography (CT) scans. Methods: All patients with advanced PC who had baseline CT scans were included in this study. MM assessment was performed using an automated software (SliceOmatic, Tomovision, Montreal) and the skeletal muscle index(SMI) was calculated at level of the 3rd lumbar (L3) vertebrae. Multiple patient characteristics were assessed including demographics, weight, body mass index (BMI), cancer stage, treatment received and survival. Sp was defined as an L3 SMI of less than 38.5 in women and 52.4 in men. Survival analysis was performed using SAS software and Log-rank and Wilcoxon statistics. Results: 167 patients, 49% female, 62% with sarcopenia (S+), 44% Ow/Ob (O+) and 14% sarcopenic and Ow/Ob (S+O+). Patients received a variety of treatments including surgery, chemotherapy and radiation. There was a trend towards lower survival in S+O+ patients while patients who were S-O+ survived the longest. Median survival in months was 6.2 for S+O+, 7.1 for S+O-, 7.8 for S-O- and 10 for S-O+. Conclusions: Patients with sarcopenia appear to have decreased survival especially if overweight/obese. This suggests that overweight/obese pancreatic cancer patients with sarcopenia may derive the most benefit from aggressive nutritional interventions. Well powered prospective studies are needed to confirm this observation and study the effects of aggressive nutritional interventions in this subgroup of patients.
Role of inflammatory monocyte mobilization in growth of liver metastasis in a murine model of metastatic pancreatic cancer.
Authors: Panni Roheena Z. , Nywening Timothy M. , Belt Brian , Sanford Dominic E. , Goedegebuure Peter S. , Linehan David 
Published: February 2017

299 Background: Pancreatic cancer (PC) is currently the fourth leading cause of death and the mortality rate approaches 100% due to early metastatic spread. Liver is the most common site of metastasis in PC. Our group and others have shown that PC induces cellular changes in the liver which include increase in inflammatory monocyte and macrophage population, long before development of metastasis. Based on our preliminary data, we developed a murine model of metastatic PC to study the role of chemotherapy in addition to novel IM blocking agents in established PC metastasis. Methods: We implanted spontaneously derived murine PC cell line (KCKO) orthotopically in the tail of pancreas of WT mice. 10 days after tumor implantation, there was an increase in infiltrating IM and macrophages in the liver by flow-cytometry and IHC. There was also an upregulation of genes associated with development of metastasis and recruitment of myeloid cells i.e. CCL2, CSF1, s100a4, s100a8, CXCL12, LOX, VEGF-A (P<0.01) by RT-PCR. However, there was no evidence of tumor metastasis at this stage in the liver. We removed the primary tumor on day 10. At this time, mice were injected with βluc-KCKO in the inferior pole of the spleen which was removed. Liver metastases were detectable by bioluminescence in 100% mice after 15 days of splenic injection. Results: Mice with established liver metastasis were randomized to treatment with CCR2i, FOLFIRINOX, CCR2i and CCR2i+FOLFIRINOX or vehicle. Mice were treated for 4 weeks and were imaged biweekly in-order to quantify tumor burden in the liver. Mice were sacrificed after 4 weeks and flow-cytometry studies were performed on peripheral blood, bone marrow and liver. The peripheral blood IM were significantly increased in mice bearing liver metastasis. However, CCR2i efficiently blocked the recruitment of IM and macrophages in liver (p<0.01). The burden of liver metastasis was significantly decreased after four weeks of treatment. Interestingly, the lowest tumor burden was found in livers of mice treated with combination of CCR2i and FOLFIRINOX. Conclusions: We demonstrate that CCR2i in combination with FOLFIRINOX decreases macrophages in the liver and impairs growth of liver metastasis.
Coagulation factors in citrated plasma predict for benefit from bevacizumab (B) in patients with advanced pancreatic cancer (APC): Results from CALGB 80303 (Alliance).
Authors: Clarke Jeffrey Melson , Pang Herbert , Starr Mark D. , Hatch Ace Joseph , Kindler Hedy Lee , O'Reilly Eileen Mary , Innocenti Federico , Venook Alan P. , Hurwitz Herbert , Nixon Andrew B. 
Published: February 2017

306 Background: CALGB 80303 evaluated gemcitabine (G) in combination with either B or placebo (P) in 602 patients (pts) with APC. No significant difference in overall survival (OS) between treatment arms was observed. Previously, plasma EDTA samples from CALGB 80303 were analyzed and potential predictive biomarkers for B were identified. This follow-up analysis evaluated citrated plasma samples for circulating proteins related to matrix remodeling and coagulation. Methods: Multiplex ELISA analysis was employed to assess the following circulating factors: E-selectin, matrix metalloprotease (MMP) 2, MMP9, von Willebrand factor (vWF), D-dimer, thrombospondin 1, and tissue factor (TF). Thrombin-antithrombin complex (TAT) was analyzed using a standard enzyme immunoassay. Prognostic characteristics were determined by associating baseline values with OS using a Cox model. Predictive markers were identified with inclusion of a treatment by marker interaction term. Results: Baseline citrated plasma samples from 109 pts were included in this analysis (59 pts G+P; 50 pts G+B). Negative prognostic factors for OS were identified, including E-selectin (p <0.01) for patients receiving G-based therapy, and E-selectin, TF, and vWF (p <0.05) in pts receiving G+P. Potential biomarkers predicting for OS benefit from B were also identified. Pts with low (< median) levels of TAT (interaction p=0.034) exhibited a median OS of 6.0 months (mo) vs. 8.3 mo (HR=0.49; 95%CI 0.28-0.88) when receiving G+P vs. G+B, respectively. Furthermore, pts with elevated levels of TF (>Q3) were found to benefit from B (interaction p=0.021), with median OS of 4.3 mo vs 4.8 mo (HR=0.44;95%CI 0.18-1.08), respectively. Longitudinal analysis of samples collected at baseline and at cycle 3 indicated that only vWF changed in pts receiving G+P, with an increase in vWF (p<0.05). Conclusions: In patients with APC, baseline levels of TAT and TF were identified as potential predictors of benefit from B. These data emphasize the importance of coagulation factors in modulating tumor angiogenesis. The potential predictive value of these factors warrants further validation.
Impact of STAT4 expression on cellular immunity and prognosis in hepatocellular carcinoma.
Authors: Yoshimoto Toshiaki , Ishikawa Daichi , Yoshikawa Masato , Teraoku Hiroki , Yamada Shinichiro , Saito Yu , Iwahashi Shuichi , Arakawa Yusuke , Ikemoto Tetsuya , Imura Satoru , Morine Yuji , Shimada Mitsuo 
Published: February 2017

307 Background: Signal transducer and activator of transcription 4 (STAT4) mediates the intracellular effects of IL-12, leading to the production of IFN-γ and cytotoxicity. However, the significance of STAT4 expression in patients with hepatocellular carcinoma (HCC) remains unknown. Herein, we investigated the association of STAT4 expression with cellular immunity and clinicopathological factors in HCC. Methods: A total of 66 HCC patients who underwent hepatic resection were enrolled. RT-PCR was performed to determine STAT4 mRNA and IFN gamma mRNA expression. Immunohistochemistry was performed to examine CD8+ T cells. Results: STAT4 was differentially expressed in tumor and non-tumor tissues (p < 0.01), and positively correlated with IFN gamma and CD8+ T-cell infiltration (p < 0.01). Significant correlations were observed between STAT4 expression and tumor TNM stage, hepatic venous invasion, tumor size, and tumor differentiation. Patients with high STAT4 expression had significantly better disease-free survival (p < 0.01). In addition, low STAT4 expression (p < 0.03) were independent risk factors for tumor recurrence. Conclusions: Down-regulation of STAT4 in HCC indicated aggressive tumor behavior and predicted worse clinical outcome. STAT4 might be a useful biomarker to identify patients with high risk of tumor recurrence after hepatic resection.
Family members’ perspectives of caring for patients with terminal hepatocellular carcinoma.
Authors: Hansen Lissi , Rosenkranz Susan J. , Wherity Kathleen , Sasaki Anna 
Published: February 2017

323 Background: Hepatocellular carcinoma (HCC) is a growing problem worldwide and accounts for more than 700,000 deaths annually. There is no curative treatment for those diagnosed with terminal HCC. This group of patients differs from other populations with liver disease or cancer due to the combined disease processes of cancer and liver failure. Although family members often play an integral role in providing care, no study was found specifically examining family member experiences of caring for patients with terminal HCC. The aim of this study was to describe family members’ experiences and perceptions of providing care for patients with HCC as they near the end of life. Methods: This longitudinal, prospective pilot study described here presents the qualitative results of semi-structured in-person interviews with a convenience sub-sample of 13 family members conducted once a month for up to a 6-month period. The interview guide included questions about family member experiences of providing care for patients living with HCC and any current concerns of significance. Interview data were analyzed using conventional content analysis. Results: Analysis included a total of 39 family member interviews. Ten family members were female and three were male (mean age = 56 years, range = 22-68 years). Family members’ relationships to patients varied and included: spouses, siblings, adult children, parents, and ex-spouses. The analysis resulted in four major themes: perception of and response to terminal HCC diagnosis, HCC progression, symptom assessment and interpretation, and challenges of providing care. Findings were colored by complex relationships between family members and patients that changed or did not change as the disease progressed. Conclusions: This study contributes new knowledge to begin developing interventions that address family members’ need for support, help, and information as the disease progresses and at the end of life. Future research should include a larger sample size that is more ethnically and racially diverse, includes more male family members, and focuses on how care provided by family members may vary based on kinship, and relationship dynamics.
Preclinical immunotherapy studies using an orthotopic pancreatic cancer mouse model.
Authors: Siolas Despina , Aristizabal Orlando , Byrne Kate , Leichman Lawrence P. , Vonderheide Robert H. , Bar-Sagi Dafna 
Published: February 2017

324 Background: Pancreatic cancer is well known for its aggressive clinical course and resistance to chemotherapy. The advent of new mouse models of pancreatic cancer have accelerated our understanding of tumorigenesis and enabled preclinical testing of experimental therapeutics with a desire to translate these findings into meaningful clinical treatments. Methods: We have developed a model where pancreatic cells obtained from a KrasG12D;Trp53R172H genetically engineered mouse can be cultivated in two dimensional cell culture and implanted into the pancreas of a immunocompetent syngeneic mouse allowing for tumor formation in situ. In addition, we are using this model to study the effectiveness of new drug combination therapy such as gemcitabine, albumin-bound paclitaxel and CD40 agonist immunotherapy using overall survival as a primary endpoint. Results: These cells generate tumors of five millimeter diameter within two weeks of implantation with 100% efficiency. Because cancer cells are seeded in the context of normal surrounding pancreatic tissue, this model is not hampered by the genetic field effect of expressing cancer mutations in the entire pancreatic organ, allowing for the study of the tumor microenviroment. Responses to therapeutic interventions can be non-invasively monitored through small animal high resolution ultrasound. Conclusions: Our orthotopic pancreatic cancer mouse system is an effective model for pre-clinical studies of tumorigenesis, immunotherapy and examination of the tumor microenvironment. Future experiments will focus on exploiting this system for identifying potent immunotherapy and chemotherapy combinations and for detecting biomarkers of efficiency.
In vitro synergistic cellular proliferation inhibition in pancreatic cancer cells Su86 and Mia-PaCa-2 with fluvastatin and nab-paclitaxel.
Authors: Feinsilber Doron , Whatcott Cliff , Matrana Marc Ryan , Cole John T. , Munoz Ruben , Luo Qingyang , Fuloria Jyotsna , Satti Suma 
Published: February 2017

331 Background: Statins have been shown to possess antiproliferative activity in-vitro. Synergism with multiple drug combinations has been of great interest in pancreatic cancer. We examined 2 in-vitro cell models for synergism using a combination of fluvastatin and nab-paclitaxel. Methods: Pancreatic cancer cell lines Mia-Paca-2 (MP2) and Su86 were cultivated and seeded to 25,000 cells/mL and subsequently grown in 96 well plates for 24 hours. The cells were then treated with a fixed concentration of fluvastatin in 9 rows, 8 receiving serial 1:2 dilutions 16 times in triplicate of nab-paclitaxel, 1 fluvastatin only row, and 1 untreated. Upon dosing cells were incubated for 72 hrs. Cellular proliferation was determined by sulforhodamine B proliferation assays and read at 570 nm. A nab-paclitaxel only assay was done as well for comparison. Results: The lowest inhibitory concentration of fluvastatin in combination with nab-paclitaxel was between 500-600 micro mole (mm). Fluvastatin alone at these concentrations attenuated cellular proliferation. Synergism was seen on IC50 curves that are available. Anti-proliferative effects were reduced by 1:256 dilution. Conclusions: Preliminary studies show fluvastatin has an in-vitro anti proliferative effect on Su86 and MP2 cells and synergism in combination with nab-paclitaxel. Fluvastatin is more cytotoxic in Su86 than MP2. Future experimental design will focus on in-vivo models.
Effect of gemcitabine-ALK-014 combination on MMP9 expression in primary pancreatic adenocarcinoma CELL cultures (PCCs).
Authors: Funel Niccola , Genova Giuseppe , Perrone Vittorio , Caniglia Fabio , Boggi Ugo 
Published: February 2017

332 Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth highest cause of death in the western world. The adjuvant chemotherapy can increase the overall survivor (OS) of PDAC patients. The Gemcitabine (GEM) and alkaloids mixture (ALK-014) combination shows the increase two time the OS non resectable in PDAC patients with respect to gemcitabine treatment alone. Indeed the Alkaoids compound modulated the Matrix MetalloProteinase 9 (MMP9) in PDAC cell clines. AIM: Our goal was to investigate the MMP 9 protein modulation in primary cell cultures (PCCs) of PDAC by Gem and ALK-014 combination treatment. Methods: Two PCCs (LPc006 and LPc028) were seeded in 4 multi-well chamber slids (8,000 each/well) for cytotoxicity study by Gem [10 Nm], ALk-014 [1µm]and their combination. After 48 h of treatment the cells were stained Immunocytochemistry (IHC) using polyclonal antibody for MMP9. We used no-treated cells to evaluate basic level of MMP9 protein. No–stained cells were used as negative control. All experiments were done in triplicates. We evaluated protein expression and cellular morphology by computer for imaging analysis (D-Sight, Menarini, Italy). The expression differences was evaluated by ANOVA and t-test analyses. Results: We found a significant reduction of MMP9 expression in both cell lines treated with Gem/ALK-014 combination with respect to their controls ( p<0.01). The same drug combination reduced significantly the number of proliferating cells and showed the modification of the structure of nuclei with respect to untreated cells (p<0.001). Conclusions: New therapeutic approaches are warranted to reduce the metastatic behavior of PDAC. The present drug combination seems to be a promising tool for PDAC treatment in vitro. The new computerized approach for MMP9 evaluation could be a first quantitative attempt for protein quantification in preclinical model.
A randomized phase II open label multi-institution study of the combination of bevacizumab (B) and erlotinib (E) compared to sorafenib (S) in the first-line treatment of patients (pts) with advanced hepatocellular carcinoma (HCC).
Authors: Thomas Melanie B. , Garrett-Mayer Elizabeth , Anis Munazza , Anderton Kate Robertson , Bentz Tricia A , Adelman Andie Ray , Brisendine Alan , Duddalwar Vinay , Weiss Geoffrey R. , Siegel Abby B. , Bendell Johanna C. , Baron Ari David , El-Khoueiry Anthony B. 
Published: February 2017

337 Background: HCC is the 2nd most common cancer worldwide. Most pts present with advanced disease and require systemic therapy. S, a multi-targeted tyrosine kinase inhibitor (TKI) is the only approved drug for HCC. B is a mAb that binds circulating ligand of the transmembrane VEGF receptor; E is a TKI that inhibits EGFR signal transduction. Published single-arm trial data suggest clinical benefit from B+E in HCC. Methods: The study was designed to estimate the HR for OS of B+E vs S with its 95% confidence interval for a sample size of 90 evaluable pts. A difference in OS favoring the B+E arm with a HR of 0.67 was expected and of interest, based on median OS for B+E and S of 15 and 11 mos. seen in previous trials.Secondary endpoints include event-free survival (EFS), toxicity, and RR. Eligible pts had advanced HCC, Childs-Pugh Class A-B7, no prior systemic therapy, preserved organ function, ECOG PS 0-2. Patients were randomized 1:1 to receive S 400 mg orally twice daily, continuously, or B 10 mg/kg IV every 14 days and E 150 mg orally daily. Treatment cycles were 28 days, restaging every 2 cycles by investigator-assessed RR per RECIST 1.1 and subsequent independent radiologic review. Results: A total of 95 pts were registered, 43 in the S arm and 47 in the B+E arm. Pts who received at least 1 dose of study drug(s) were evaluable. Data are summarized in the table. Conclusions: Based on initial data analysis, the OS of advanced HCC pts treated with B+E is consistent with that of S, and the toxicity profile and EFS of B+E compare favorably to S. Clinical trial information: NCT00881751. [Table: see text]
The clinicopathological characteristics of understaging and overstaging of the preoperative assessment for gastric cancer by endoscopic ultrasonography and computed tomography.
Authors: Lee Ae-Ra , Lee Dong Ho , Hwang Jae Jin , Shin Cheol Min , Yoon Hyuk , Park Young Soo , Kim Nayoung 
Published: February 2017

34 Background: Despite the development of EUS and CT technology, there are no clinically relevant imaging tools to detect accurate preoperative staging such as lymph node (LN) metastases. The aim of this study was to elucidate of the clinicopathological characteristics of understaging and overstaging of the preoperative assessment for the gastric cancer by EUS and CT. Methods: In total, 180 patients who underwent EUS and CT, followed by gastrectomy at Bundang Hospital, Seoul National University, from July 2012 to June 2014, were analyzed. The results from the preoperative EUS and CT were compared to the postoperative pathological findings. Results: For T staging, a total of 180 patients who underwent CT and EUS have been recruited and 99 patients with visualized primary lesions on CT were analyzed. For N staging, 180 patients who underwent EUS and CT were analyzed. The overall accuracy of EUS and CT for T staging was 63.7% and 69%, respectively. The overall accuracy for N staging was 74.3% and 69.6%, respectively. Compared with variables of under and over staging group with accurate staging group, Accuracy of T staging for lesions at the cardia (36.4% vs. 63.6%, P = 0.021), advanced gastric cancer group (55% vs. 90.9%, P = 0.005) and advanced T stage group (24.4% vs. 5.2 %, P = 0.001) was higher than that non-cardia lesions and EGC group. Ulcerative lesion (38.5% vs. 61.5%, P < 0.001) and histologically undifferentiated type (3.8% vs. 93.8%, P = 0.002) had significantly lower accuracy in N staging than non-ulcerative lesions and the differentiated cancer. Conclusions: Caution is required in interpreting the T staging of the advanced T stage (T3 and T4) lesions, lesions at the cardia and advanced gastric cancer lesions. The ulcerative and undifferentiated lesions needed careful interpretation for N staging. However, there seemed to be no significant differences of clinicopathological characteristics between EUS and CT. The accuracy of CT was close to that of EUS and both modalities were useful and complementary for the locoregional staging of gastric cancer.