bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of hypophosphatemia-occurring sorafenib with prognosis and hepatic impairment in patients with advanced hepatocellular carcinoma.
Authors: Aizawa M. , Mitsunaga S. , Okuyama H. , Nakachi K. , Ohno I. , Shimizu S. , Takahashi H. , Okusaka T. , Ochiai A. , Ikeda M. 
Published: February 2017

188 Background: Hypophosphatemia is observed during sorafenib treatment. At the increased metabolic demand of the liver, hypophosphatemia is considered to be associated with a good clinical course. Hypophosphatemia associated with sorafenib treatment may also be a favorable event, but this has not yet been elucidated. The aim of this study was to evaluate the clinical significance of hypophosphatemia developing during sorafenib treatment for advanced hepatocellular carcinoma (HCC). Methods: The data of 41 advanced HCC patients (median age: 68 years, female/male: 4/37, HBs-Ag(+)/HCV-Ab(+):10/22) who received sorafenib treatment (800 mg, daily) for more than 30 days were reviewed. There were 27 and 14 patients with Child-Pugh class A and B. UICC stage II/III/IV was observed in 13/10 /18 patients. Clinical data, including those on the serum level of inorganic phosphate (IP), were collected before and after 30 days of sorafenib treatment. Overall survival time (OS) was calculated from the start of sorafenib treatment. The significance level was set at p<0.05. Results: Mean serum IP level before sorafenib treatment was 3.2mg/dL (range 2.4-4.5). After 30 days treatment, IP level was decreased (mean 2.6mg/dL, range 1.3-3.9), compared to that at pre-treatment (p<0.001). The patients in whom the serum IP was less than 2.4mg/dL at 30 days was assigned to the decreased IP group (N=14, mean IP 2.1mg/dL, range1.3-2.3). The decreased IP group showed a better prognosis (no event of death during the observation time) than the nondecreased IP group (MST 286 days, p=0.024). In the non-decreased IP group, the serum Alb (mean 3.6g/dL) and T.Bil (mean 0.8mg/dL) were worse after 30 days treatment (Alb 3.4g/dL p=0.007, T.Bil 1.1mg/dL p=0.037). However, deterioration of Alb (mean 3.7 vs. 3.6g/dL p=0.505) and T.Bil (mean 0.7 vs. 0.8mg/dL p=0.404) could be avoided in the decrease IP group. Conclusions: Hypophosphatemia occurring during sorafenib treatment for advanced HCC was associated with a favorable prognosis. The serum Alb and T.Bil levels were indicators of liver function and were preserved in patients with decreased serum levels of phosphate. No significant financial relationships to disclose.
The Virginia Mason Pancreatic Cancer Database.
Authors: Picozzi V. J. , Nguyen M. , Traverso L. W. , Kozarek R. A. 
Published: February 2017

191 Background: Pancreatic cancer (PC) is associated with poor overall survival (OS);1-year PC OS PC is only 24% (ACS Facts and Figures 2010). We created a database (DB) intended to analyze clinical outcomes for the composite PC population treated at our institution. Methods: Inclusion of patients (pts) in the DB required: 1) identification by ICD code 157.9, and 2) all active therapy elements (surgery, radiotherapy, and/or at least 1 cycle chemotherapy) executed at our institution. Among DB datafields are pt age, sex, and performance status, tumor stage, tumor size, node and margin status (resected pts), staging laparoscopy results (if performed), liver involvement (metastatic pts), anticancer therapies administered, time and site of disease progression (if applicable), cause of death and clinical trial participation. Data is updated quarterly; patients are censored for OS if care is transferred or death occurs.The DB can interface with other clinical/administrative databases within our system. Results: From 1/1/2008 to 6/30/2010, 491 pts with ICD code 157.9 were identified. 307/491 (63%) pts did not meet DB inclusion criteria. Reasons included consultation only (n=211), palliative care only (n=52), therapy shared with other institutions (n=42), unknown (n=2). Of the remaining 184 pts, 38 pts (21%) were resected, 27pts (15%) were borderline resectable per institutional criteria, 44 pts (24%) were locally advanced/nonresectable and 75 pts (40%) had metastatic disease. 65% of pts wre >60 years old (median age 65 yrs) 30/184 pts (16%) were ECOG PS 2 or higher. 5/184 (3%) transferred care or were lost to c; thus 179 pts were fully evaluable for OS. Current median follow-up of all pts is 13.6 mo. 101/179 (61%) pts are presently alive; 1-yr OS of the entire patient population is 69% (Kaplan-Meier). 1-yr OS by disease category includes 94% resected, 81% borderline resectable, 78% locally advanced/nonresectable, and 44% metastatic disease. The DB will be continuously updated and developed. Conclusions: 1) The general characteristics of pts in our DB are comparable to literature expectations. 2) The DB provides guidance as to the effectiveness of institutional therapy for our entire PC population. 3) A variety of potential DB applications exist. We anticipate continued DB development. No significant financial relationships to disclose.
1H NMR–based metabolic profiling of serum for the detection of pancreatic cancer.
Authors: Owusu-Sarfo K. , Asiago V. , Gowda N. , Shanaiah N. , Xi B. , Chiorean E. G. , Raftery D. 
Published: February 2017

193 Background: Pancreatic cancer (PC) is one of the leading causes of cancer deaths with a 5-yr mortality rate of 95%, and the lack of a suitable early detection method contributes to its poor prognosis. Metabolomics, the analysis of the metabolic profiles in biological samples such as serum and urine is emerging as an important tool to complement other “omic” techniques. In an effort to identify potential biomarkers for PC, we analyzed serum from PC patients (pts) focusing on altered metabolic profiles using 1H nuclear magnetic resonance (NMR). Methods: The metabolite profiles from serum samples consisting of 55 PC pts and 32 healthy controls were analyzed using NMR combined with advanced supervised and unsupervised multivariate statistical methods such as partial least squares discriminant analysis (PLSDA) and principal component analysis (PCA). A number of metabolite markers selected based on p values and logistic regression rank the importance of each potential marker. Statistically significant metabolites between cancer and controls were used to build a prediction model. Results: Based on multivariate logistic regression analysis of 20 targeted metabolites, 10 metabolite markers were selected from the variable selection process and used to build a regression model with high accuracy (AUROC >0.99), a sensitivity of 95% and specificity of 95% using a training set of samples. When the model was tested on an independent set of patient samples, it yielded a sensitivity of 95% and a specificity of 100% (AUROC >0.98). Box and whisker plots for individual markers verified the high performance of all 10 markers. Conclusions: The high sensitivity of the metabolic profile that distinguishes PC pts from controls indicates the potential utility of 1H NMR metabolic profiling for the early detection of PC. The investigation has identified perturbations in several pathways such as glycolysis and amino acid metabolism, highlighting their contribution to disease onset. This study demonstrates the potential of metabolite profiling as an important tool toward detecting PC development. Future studies will involve metabolite validation on high risk pts, and additional mass spectrometry based metabolic discovery efforts. No significant financial relationships to disclose.
Effect of raloxifene on human pancreatic adenocarcinoma growth in vitro and in vivo.
Authors: Seeliger H. , Seel N. , Camaj P. , Ischenko I. , Jauch K. , Bruns C. J. 
Published: February 2017

207 Background: The role of estrogen receptor (ER) signaling in pancreatic cancer is unknown. Recently, we demonstated that expression of the isoform ER beta correlates with an adverse prognosis in patients with pancreatic cancer. Here, we show that raloxifene, a specific estrogen receptor modulator (SERM), suppresses in vitro and in vivo tumor growth by interfering with ER beta signaling in human pancreatic adenocarcinoma. Methods: The human pancreatic adenocarcinoma cell line L3.6pl was cultured and exposed to raloxifene in vitro, and cell proliferation was determined by the BrdU assay. To analyze the specificity of raloxifene induced effects, ER knockdown was performed using siRNA specific for ER alpha and ER beta. In an in vivo model of orthotopic tumor xenografts in nude mice, raloxifene was administered daily, and tumor growth was monitored. Expression of ER beta and the proliferation marker Ki-67 were determined by immunohistochemistry. Results: Raloxifene treatment resulted in a potent, dose dependent reduction of proliferation in vitro over a nanomolar dose range. This effect was completely reversed by siRNA knockdown of ER beta, but not ER alpha, indicating an ER isotype specific signaling. In vivo, orthotopic tumor growth, as well as lymph node and liver metastases, was significantly suppressed in raloxifene treated mice. Analogous to the in vitro data, Ki-67 expression in vivo was significantly reduced in raloxifene treated mice, while ER beta expression was not changed in vivo. Conclusions: Inhibition of ER beta signaling by raloxifene results in a potent reduction of human pancreatic adenocarcinoma growth in vitro and in vivo. Treatment with SERMs may be an attractive therapeutic option in subjects expressing the ER beta isotype. No significant financial relationships to disclose.
Relative value of serum cytokines and clinical factors in predicting weight loss in advanced pancreatic cancer (PC).
Authors: Fogelman D. R. , Wang X. S. , Hassan M. , Li D. , Javle M. M. , Varadhachary G. R. , Shroff R. T. , Overman M. J. , Wolff R. A. , Abbruzzese J. L. 
Published: February 2017

208 Background: The identification of PC patients at high risk for cachexia may allow for early intervention to prevent this outcome. Symptoms such as pain, nausea, and anorexia might predict weight loss. Likewise, inflammatory cytokines are also associated with cachexia. We evaluated the ability of each to predict weight loss in patients beginning treatment for PC. Methods: We evaluated 44 newly diagnosed advanced or metastatic PC patients for baseline symptomatology via the M. D. Anderson Symptom Inventory (MDASI). This survey assesses symptom severity, such as nausea, vomiting, fatigue, pain, diarrhea, and constipation, on a 1-10 scale. Baseline serum levels of IL-1a, IL-1b, IGF-1, CXCL-12, CXCL-16, CRP, IL-6, IL-8, VEGF, CEA, and CA 19-9 were assessed. Logistic regression analysis was performed to determine the odds ratio (OR) and confidence interval (CI) for the association of different parameters with 10% weight loss at 60 days from treatment initiation. Student t-test was used to compare the mean values across different strata. Results: A weight loss of >10% was observed in 15 patients (34%). Only the use of mild (but not strong) opioids was associated with weight loss; estimated OR = 6.2 (C.I. 1.2-31.9, p=.03). No association was observed for the MDASI parameters. Baseline levels of cytokines were available for 23 patients. We observed significant differences in the mean values of CXCL-16 (p=.05) and IL-6 (p=.045) in patients with weight loss as compared to those without weight loss. Moreover, serum level of erythropoietin may be negatively associated with weight loss (p=0.06). Conclusions: Alterations in serum cytokine levels may correlate more strongly with cachexia than clinical symptoms and underscore the importance of cytokine analysis in identifying PC patients at high risk for cachexia. [Table: see text]
Use of DPC-4 immunostaining of diagnostic cytology specimens to predict the pattern of tumor progression in locally advanced pancreatic cancer patients (LAPC).
Authors: Crane C. H. , Yordy J. S. , Varadhachary G. R. , Haque W. , Wolff R. A. , Das P. , Krishnan S. , Fleming J. B. , Abbruzzese J. L. , Staerkel G. A. 
Published: February 2017

209 Background: An autopsy study has identified DPC-4 as a potential biomarker of the pattern of disease spread in pancreatic cancer patients (Iacobuzio-Donahue et al, JCO, 2009). We sought to determine whether DPC-4 expression determined by immunohistochemistry (IHC) staining of primary tumor cytology specimens correlates with the clinical pattern of progression in patients with locally advanced pancreatic cancer (LAPC). Methods: LAPC patients with ECOG 0-1 PS were treated with gemcitabine (1000 mg/m2), oxaliplatin (100 mg/m2), and cetuximab for (500mg/m2) q2wks for 4 doses followed by XRT (50.4 Gy to the gross tumor only) with capecitabine (825 mg/m2 twice daily, days of radiation) and cetuximab on a multiinstitutional trial. Forty-one of 58 patients treated at our institution had cytology specimens suitable for IHC staining. The patterns of progression were determined based on radiographic studies and clinical symptoms. Findings were blinded from the IHC results. Patients were categorized as 1) local disease dominant, 2) distant disease dominant, 3) indeterminate pattern, and 4) no progression. The IHC scoring of DPC-4 was determined by an experienced cytopathologist who was blinded from the clinical data. Results: Median, 1yr and 3yr actuarial OS are 18.2 months, 67.2% and 18.5%. Dominant progression pattern was local (n=15), distant (n=14), indeterminate (n=8), and no progression (n=4). Intact DPC expression correlated with local dominant progression (11/15) and DPC-4 loss correlated with distant dominant progression (10/14), p=0.016. The median DM free survival rate was 18.0 for intact DPC-4 versus 12.5 mo for DPC-4 loss patients (p=NS). There was no significant difference in overall survival based on DPC-4 status. Conclusions: Determination of DPC-4 expression from cytology specimens is feasible. DPC-4 expression correlated with the pattern of progression and is consistent with previous autopsy data. DPC-4 expression does not appear to be predictive or prognostic. Prospective validation of DPC-4 as a biomarker of disease progression is warranted and may lead to personalized treatment strategies for patients with LAPC. [Table: see text]
Effect of transplantation of pro-angiogenic monocytes to pancreatic cancer-bearing mice on resistance to chemotherapy/radiotherapy.
Authors: Mizukami Y. , Kawamoto T. , Sugiyama Y. , Sasajima J. , Koizumi K. , Moriichi K. , Fujiya M. , Bardeesy N. , Chung D. C. , Kohgo Y. 
Published: February 2017

212 Background: Hypoxic tumors are usually resistant to conventional chemotherapy and radiotherapies, which typically target actively dividing cells. The tumor vasculatures are unorganized and lack adequate pericyte coverage, which compromises delivery of drugs to tumors. How best to normalize the aberrant tumor vasculature to maximize anticancer drug delivery comprises an area of intensive investigation. Methods: We tested out hypothesize that bone marrow (BM) cells may be able to restore appropriate vessel function in tumor vasculature using nude mice bearing pancreatic cancer xenografts and genetically engineered mice that develop pancreatic adenocarcinoma. Results: Culturing BM mononuclear cells with endothelial growth medium resulted in the early outgrowth of spindle-shaped attached monocytic cells expressing CD11b/CXCR4 with a significant vessel stabilizing activity. Intravenous administration of these cultured pro- angiogenic cells into mice bearing pancreatic cancer significantly reduced areas of hypoxia without enhancing tumor growth. The resulting vasculature structurally mimicked normal vessels with intensive pericyte coverage. Consistent with a marked reduction in gene expressions involved in drug resistance such as MDR1 and ABCG2 in monocytes-injected tumors, a combination of the transplantation and chemotherapeutic agents reduced tumor size and significantly increased areas of necrosis as compared to chemotherapy alone. Conclusions: Our findings offer an alternate approach to improve delivery and efficacy of anticancer drugs to hypoxic tumors through a remodeling of the abnormal tumor vessels. No significant financial relationships to disclose.
A novel p53-based strategy for protection of gastrointestinal track and bone marrow (BM) from 5-fluorouracil (5-FU).
Authors: Ha C. S. , Ganapathy S. , Yuan Z. 
Published: February 2017

213 Background: Acute toxicity from DNA damaging agents such as radiation and chemotherapy is mainly mediated by p53 which, upon activation, induces massive apoptotic cell death in sensitive tissues such as GI track and BM. Expanding from our recent finding that low-dose arsenic can temporarily and reversibly suppress p53 activation and subsequent tissue damages in normal tissues but not in carcinomas due to distinct differences in p53 status, we used a mouse tumor xenograft model to test the potential of arsenic in protecting the GI track and BM from one of the most commonly used chemotherapeutic agents for GI malignancies, 5-FU, without compromising tumor control. Methods: Arsenic pretreatment was done by feeding sex-matched mice (4-6 weeks old) with water with or without 1.0 mg/L sodium arsenic for 3 days. Mice were randomized into 4 groups: A. control; B. arsenic only; C. 5-FU (30 mg/kg body weight i.v. for 5 days) only; D. arsenic and 5-FU. 5- FU-induced GI track and BM damages were analyzed histologically with H&E staining 4 weeks after last treatment. Body weight was monitored as a measure of toxicity. Lung carcinoma NCI-H358 was used to generate a mouse xenograft model. Treatments were initiated 3 weeks after implantation when the lung carcinomas reached an average volume of 100 mm3. Tumor volumes were measured periodically. Two independent experiments were done with10 mice per group. Results: Tumor sizes at 9 weeks were (mean±SE in mm3): 528.1±62.81, 504.04±55.19, 133.02±35.74, 114.47±17.49 for groups A,B,C and D respectively (p=ns, C vs. D). The corresponding body weights were (in gm): 34.6±1.5, 36.4±2.1, 31±1.2, and 35.4±1.8 (p=0.0001, t-test, C vs D). 5-FU treatment was associated with severe damages to small intestine and BM, and such damages were significantly reduced by low-dose arsenic pretreatment by histological examination. Conclusions: Our data demonstrate that a brief treatment with low-dose arsenic is associated with a marked protection of GI track and BM without compromising the ability of 5-FU to kill carcinoma cells.Our data have provided proof-of- principle for the use of low-dose arsenic to protect GI track and BM from toxicity of 5-FU, and for potential 5-FU dose intensification in clinical settings. No significant financial relationships to disclose.
Effect of apricoxib, a novel COX-2 inhibitor, on the efficacy of standard therapy in human pancreatic cancer cell lines in vitro and in vivo.
Authors: Kirane A. R. 
Published: February 2017

227 Background: Gemcitabine-erlotinib is standard of care (SOC) for pancreatic cancer, but this regimen can still be improved upon with regard to prolonging patient survival. Cyclo-oxygenase-2 (COX-2) is overexpressed in pancreatic cancer and implicated in pancreatic tumor progression. Inhibition of COX-2 decreases tumor growth, augments the activity of both gemcitabine and EGFR inhibition, and may play a role in preventing or reversing EMT. This study characterized the effects of COX-2 inhibition on pancreatic cancer cell lines and determined if the addition of apricoxib enhances sensitivity to chemotherapy. Methods: Baseline EGFR and COX-2 expression were determined in 7 human pancreatic cancer cell lines and functional responses measured by changes in phospho-EGFR (p-EGFR) and prostaglandin E2 (PGE2) production by ELISA. Cytotoxicity was determined for gemcitabine, erlotinib, and apricoxib independently and in combination by MTS assay. The effect of SOC therapy alone or in combination with 10 or 30 mg/kg apricoxib PO on AsPC-1 and Colo357 tumors in vivo was determined in SCID mice bearing established orthotopic xenografts. Tissue was analyzed by IHC and VEGF levels were determined by ELISA. Results: All lines expressed EGFR and COX-2, but expression alone was not predictive of p-EGFR level, PGE2 production, or response to drug therapy. In vitro, AsPC-1 cells had negligible COX-2 activity, whereas Colo357 cells displayed high levels of COX-2 and PGE2 production. Cell growth and COX-2 activity decreased in all cell lines in the presence of apricoxib and addition of apricoxib improved response to chemotherapy. In vivo, addition of apricoxib to SOC significantly reduced primary tumor growth and almost eradicated metastases in mice bearing Colo357 but not AsPC-1 xenografts. Plasma VEGF levels were unaltered by apricoxib treatment in AsPC-1-bearing animals but were suppressed to undetectable levels in Colo357-bearing animals. Markers of EMT were significantly decreased in animals treated with apricoxib. Conclusions: Apricoxib enhances the efficacy of gemcitabine and erlotinib in vitro and in vivo and warrants clinical evaluation in patients with pancreatic cancer. A phase II study is ongoing. No significant financial relationships to disclose.
Effect of AZD0530 (saracatinib) on biliary cancer cell motility and invasion.
Authors: Leone F. , Peraldo-Neia C. , Cavalloni G. , Colombi F. , Aglietta M. 
Published: February 2017

231 Background: Biliary carcinoma (BC) has a poor prognosis and limited therapeutic options. The identification of new targets is essential. Among candidates we have studied the tyrosine kinase Src, which is involved in proliferation, invasion, and migration in many tumors.It has been demonstrated that the inhibition of Src significantly reduces proliferation and metastasis development in different solid tumors, such as pancreatic and head and neck cancers. Targeting Src tyrosine kinase may be therapeuticallyuseful in cholangiocarcinoma. We explored the antitumor activity of Src inhibitor saracatinib (AZD-0530) in BC preclinical models. Methods: Four cholangiocarcinoma cell lines, TFK1, EGI-1, HuH28, and TGBC1-TKB, were treated with saracatinib and analyzed by western blot for the expression of Src and its downstream principal transducer FAK. The inhibition of proliferation was evaluated by cell titer glo assay after treatment with scalar doses of saracatinib alone or in combination with gemcitabine for 72 hours. The effect on migration of BC cells was tested by wound healing assay. Finally, we investigated the antitumor activity in EGI-1 xenografts in NOD/Shi-scidIL2rgnull mice treated with saracatinib at 10 mg/kg/die. Results: Activation of Src pathaway was shown in all cell lines and saracatinib was able to inhibit its downstream molecules. Saracatinib inhibited BC cell proliferation in standard monolayer liquid culture only at very high concentration (median doses from 2.5 to 15 μM) and did not enhance the antiproliferative effect of gemcitabine. Evidence of anti-tumor activity of saracatinib was obtained in terms of migration inhibition: quantitation of the wound closure over time revealed a significant and dose-dependent inhibitory effect of saracatinib on BC cell motility. In the in vivo model, no reduction of tumor volumes was evidenced up to 14 days of treatment. Assays with prolonged treatments are ongoing. Conclusions: These results suggest that inhibition of Src kinase by saracatinib impairs the invasiveness of bile duct carcinoma. Further in vivo studies will provide information about the effect on metastasis inhibition by saracatinib. No significant financial relationships to disclose.