bluuebunny/crossref_metadata_2025_split huggingface dataset:
Power of fecal DNA methylation analysis: Does it lead to development of a noninvasive screening tool for pancreatic cancer?
Authors: Nagasaka T. , Goel A. , Taniguchi N. , Mori Y. , Sigeyasu K. , Yamada E. , Oka T. , Sun D. , Fujiwara T. 
Published: February 2017

187 Background: The development of noninvasive screening tests is important to reduce mortality from gastrointestinal neoplasia, especially given that there is no noninvasive screening test for pancreatic cancer. We sought to develop such a test by analysis of DNA methylation from exfoliated cancer cells in feces. Methods: We had reported a novel strategy that uses single-step modification of DNA with sodium bisulfite and fluorescence polymerase chain reaction methodology to measure aberrant methylation in fecal DNA. We increased number of biomarkers from 4 to 8 that were analyzed in 144 fecal samples obtained from a variety of patients, including colorectal tumors, hepatic tumors, and pancreatic tumors. Results: The assay successfully identified one or more methylated markers in fecal DNA from patients with colorectal cancer, polyps, hepatocellular carcinoma, metastatic colorectal cancer at liver, and pancreatic cancer. Conclusions: Methylation of 8 biomarkers in fecal DNA is associated with the presence of gastroenterological tumors relative to non-neoplastic conditions. Our fecal DNA methylation assay provides a possible means to noninvasively screen not only for colorectal tumors but also for pancreatic tumors. No significant financial relationships to disclose.
Incidental diagnosis of pancreatic neuroendocrine tumors.
Authors: Cheema A. , Kvols L. K. , Strosberg J. R. 
Published: February 2017

190 Background: Pancreatic neuroendocrine tumors are often discovered incidentally during radiologic or endoscopic examinations. The incidence of incidental detection is unknown. It is also unclear whether patients with incidentally discovered, asymptomatic tumors should be treated similarly to patients who present with tumor-related symptoms. Methods: A database of 425 patients with pancreatic neuroendocrine tumors treated at the H. Lee Moffitt Cancer Center was developed. Patient charts were reviewed to assess whether their diagnosis was incidental or prompted by tumor-related symptoms such as pain, jaundice, or neuroendocrine hormone secretion. The frequency of “incidentalomas” was categorized by TNM stage (AJCC, 7th edition). Overall survival was stratified by “incidental” versus “symptomatic” diagnosis. Results: Among 425 patients with histologically proven pancreatic neuroendocrine tumors, 112 patients (26%) had tumors that were discovered incidentally. The majority of stage I tumors (55%) were incidentally discovered. Among patients with stage IV tumors, 20% were detected incidentally (Table). Median survival of patients with incidentally discovered tumors was 103 months versus 84 months in patients who were symptomatic at diagnosis. Conclusions: A sizeable fraction of patients with pancreatic neuroendocrine tumors are diagnosed incidentally during evaluations for other conditions or unrelated symptoms. The majority of patients with stage I tumors are incidentally diagnosed. The increased incidence of pancreatic neuroendocrine “incidentaloms” may be contributing to improving survival rates in this disease. This study highlights the necessity of developing guidelines for management of patients with incidentally discovered, early-stage tumors. [Table: see text] No significant financial relationships to disclose.
Myeloid-derived suppressor cells as a potential treatment target for pancreas adenocarcinoma.
Authors: Porembka M. R. , Mitchem J. B. , Goedegebuure P. S. , Linehan D. 
Published: February 2017

194 Background: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immunosuppressive cells that are upregulated in cancer. Little is known about the prevalence and importance of MDSC in pancreas adenocarcinoma (PA). Here, we quantify MDSC prevalence in patients with PA and assess the efficacy of MDSC depletion in a murine model of PA. Methods: Peripheral blood and tumor samples were collected from patients with PA, analyzed for MDSC (CD15+11b+) by flow cytometry (FC) and compared to cancer-free controls (CFC). The suppressive capacity of MDSC and the effectiveness of MDSC depletion were assessed in C57BL/6 mice inoculated with Pan02, a murine PA, and treated with placebo or zoledronic acid (ZA), a potent aminobisphosphonate previously shown to target MDSC. Endpoints included tumor size, survival, and MDSC prevalence. Tumor cell infiltrate was analyzed by FC for MDSC (Gr1+CD11b+) and effector T cells; tumor cytokine levels were measured by Luminex assay. Results: Patients with PA demonstrated increased circulating MDSC compared to CFC, which correlated with disease stage (metastatic PA: 68%±3.6% of CD45+ cells, resectable PA: 57%±3.5%, CFC: 37%±3.6%; p<0.0001). Normal pancreas tissue showed no MDSC infiltrate while PA avidly recruited CD11b+15+ cells to the primary tumor. Murine tumors similarly recruited MDSC that actively suppressed CD8+ T cells in vitro measured by CFSE dilution and accelerated tumor growth in vivo by adoptive transfer with Pan02 cells (p<0.001). Treatment with ZA impaired MDSC accumulation in the tumor (Placebo: 78%, ZA: 51%, p<0.05) resulting in delayed tumor growth rate (p<0.0001) and prolonged median survival (Placebo: 59 days, ZA: 73 days, p<0.05). MDSC blockade increased recruitment of T cells to the tumor (CD4: 4.4%±1.1% vs 12.2%±2.0%, p<0.05; CD8: 3.9%±1.3% vs 10.6%±2.2%, p<0.05) and a more robust type 1 response with increased levels of IFN-g (p<0.05) and decreased levels of IL-10 (p<0.05). Conclusions: MDSC are an important mediator of tumor-induced immunosuppression in PA. Treatment with ZA effectively blocks MDSC accumulation improving anti-tumor response in animal studies. Efforts to block MDSC may represent a novel treatment strategy for PA. [Table: see text]
Phase I trial of gene-mediated cytotoxic immunotherapy in combination with chemoradiation for locally advanced pancreatic cancer.
Authors: Bloomston M. , Marsh C. , Walker J. , Coyle W. , Marx H. , Tahiri S. , Moran Cruz C. , Aguilar L. K. , Aguilar-Cordova E. , Chung V. M. 
Published: February 2017

195 Background: More than 80% of patients with pancreatic cancer present with locally advanced or metastatic disease and have a median survival of only 6 months. Immunotherapy approaches may improve outcomes. Gene Mediated Cytotoxic Immunotherapy (GMCI) is an approach that generates a systemic anti-tumor vaccine effect through intra-tumoral delivery of an adenoviral vector expressing the HSV-thymidine kinase gene (AdV-tk) followed by anti-herpetic prodrug and synergy with chemoradiation. The mechanisms of action involve tumor cytotoxicity, activation of antigen presenting cells and stimulation of systemic anti-tumor T-cell immunity. Safety with potential efficacy has been demonstrated in multiple clinical studies. This is the first application of GMCI in pancreatic cancer. Methods: This study evaluated 4 dose levels of AdV-tk (3x1010 to 1x1012 vector particles) injected into locally advanced tumors via EUS or CT-guidance before and during week 3 of standard 5-FU-chemoradiation. Valacyclovir (Valtrex, GSK) prodrug was given for 14 days after each of 2 AdV-tk injections. Results: The study completed accrual with 13 patients enrolled and 12 completing therapy with 3 at each of the 4 dose levels. One patient refused further participation during course 1 after recovering from azotemia. Median age was 64 years (range 55-81) and median baseline CA19-9 was 1634 U/ml. No dose limiting toxicities and no injection related complications occurred. Possibly related grade 3-4 toxicities, all of which were transient, included dehydration, azotemia and worsening elevation of bilirubin and AST. Kaplan-Meier estimated median survival is 12.2 months with 6 patients still alive at 8-20 months. Two patients achieved a partial response by RECIST criteria. One occurred in week 6 despite discontinuing 5-FU/radiation during week 1. The other had gradual decrease of a 7 cm tumor over 11 months. Serum CA19-9 levels decreased in 8/8 evaluable patients by 32-91% at 3 months after treatment initiation. Conclusions: AdV-tk can be safely injected into pancreatic tumors and combined with standard chemoradiation. Early results are highly encouraging and justify further evaluation in a phase II study. [Table: see text]
Molecular pathologic phenotypes and outcome in adenocarcinoma of the ampulla of Vater.
Authors: Chang D. K. , Johns A. , Scarlett C. J. , Pajic M. , Chou A. , Toon C. , Samra J. S. , Sutherland R. , Gill A. J. , Biankin A. V. ,   New South Wales Pancreatic Cancer Network
Published: February 2017

196 Background: Individuals with adenocarcinoma of the ampulla of Vater demonstrate a broad range of outcomes, as they may arise from any of the three epithelia that converge at that location. This variation in outcomes poses specific challenges in clinical decision making concerning the aggressiveness of treatment, and the appropriateness and type of adjuvant therapy. Methods: We assessed the relationship between molecular pathologic phenotypes defined using a combination of histopathology and protein expression (CDX2 [caudal-type homeodomain transcription factor 2] and MUC1), and outcome in 72 patients who underwent operative resection for adenocarcinoma of the ampulla of Vater. Results: Patients with a pancreaticobiliary phenotype (CDX2 negative, MUC1 positive) compared to an intestinal phenotype carcinoma segregated into an independently poor prognostic group (HR = 3.40, 95% CI: 1.71 – 6.76, p = 0.0005). Stratification using lymph node (LN) status (the only other independent poor prognostic factor) (HR = 3.19, 95% CI: 1.54 – 6.58, p = 0.0017) defined three clinically relevant phenotypes: 1) those with a non-pancreaticobiliary (intestinal) phenotype without LN metastases who had an excellent outcome (5-year survival 88.4%, median survival 172.8 months); 2) those that had a pancreaticobiliary phenotype and lymph node metastases that had a poor outcome (5-year survival 20.0%, median survival 7.4 months); and 3) the remainder (intestinal/LN positive or pancreaticobiliary/LN negative) who had an intermediate outcome (5-year survival 46.9%, median survival 57.0 months). Conclusions: A combination of histopathologic and molecular criteria identified three distinct clinically relevant phenotypes of adenocarcinoma of the ampulla of Vater that have significantly different outcomes. This distinction, which requires validation, may be used to refine current therapeutic strategies by guiding aggressiveness of surgery and selection for adjuvant therapy, which would improve overall outcomes. No significant financial relationships to disclose.
Effect of the ultraconserved noncoding RNA uc.338 on cellular growth of hepatocarcinoma.
Authors: Braconi C. , Kogure T. , Valeri N. , Gasparini P. , Huang N. , Nuovo G. , Terracciano L. , Croce C. M. , Patel T. 
Published: February 2017

202 Background: The role of non-protein coding (nc)RNAs in cancer is unknown but emerging evidence suggests that deregulated expression of ncRNA may contribute to cancer pathogenesis. We sought to examine the role of ultraconserved ncRNA (ucRNA) that are 100% conserved across the human, rat and mouse genomes in hepatocellular cancers (HCC). Methods: Whole genome ucRNA expression profiling was performed using a custom microarray, and verified by real time PCR in cell lines and by in situ hybridization in a tissue microarray comprising of 221 human HCC, 72 non cirrhotic (NC) and 97 cirrhotic (C) liver tissues. ucRNA expression was manipulated with siRNA or plasmid-over-expressing ucRNA, and the effects on anchorage-dependent and independent growth, and cell cycle assessed using cell viability, soft agar assays and flow cytometry. Gene ontology analysis was performed by evaluating uc338-dependent changes on mRNA expression using Affymetrix chips. Results: 56 ucRNAs were aberrantly expressed with 33 increased and 23 decreased in HepG2 cells compared to non-malignant hepatocytes. The greatest change was observed with uc.338 (6.9-fold increase). uc.338 expression was significantly increased in several HCC cell lines. uc.338 expression was detected in 170 cases (77%) of HCC, with 62% of these showing a moderate to strong expression. Compared to non- malignant adjacent tissue, uc.338 expression was increased in 97/156 of HCC. The mean % of cells expressing uc.338 was 4% in NC liver, 15% in C and 24% in HCC. Inhibition of uc.338 reduced anchorage dependent and independent growth, and cell cycle progression in both human and murine malignant hepatocytes. Gene annotation enrichment analysis of mRNAs that were altered by inhibition of uc.338 expression identified the top over-represented GenMAPP pathways as: cell cycle, mRNA processing, RNA transcription, G1 to S cell cycle. Moreover, enforced expression of uc.338 increased cell growth in nonmalignant hepatocytes. Conclusions: These data showing that uc.338 is selectively overexpressed in HCC and promotes cell growth provides new insights into the role of RNA genes in HCC. No significant financial relationships to disclose.
The influence of CD44v6, TGF-α, COX-2, MMP-7, and MMP-9 on clinical evolution of patients with gastric cancer.
Authors: Fanelli M. F. , Chinen L. T. , Begnami M. D. , Costa W. L. , Fregnami J. H. , Soares F. A. , Montagnini A. L. 
Published: February 2017

21 Background: Gastric cancer (GC) is the fourth most common tumor worldwide. As palliative chemotherapy is a relevant approach for patients with distant metastasis, determination of prognostic parameters that are predictive of survival may allow better identification of patients who may benefit from current chemotherapy regimens. The process of GC proliferation and metastasis occurs via epithelial-mesenchymal transition (EMT), which consists on gain of motility and invasiveness by epithelial cells via the disassembly of cell-to-cell contacts and significant cytoskeletal reorganization. Molecules involved in each step have been identified, including cell-adhesion molecules, growth factors and matrix degradation enzymes. Objectives: To verify the correlation between tumor progression and the expression of some proteins (CD44v6, TGF-α, COX-2 MMP-7, MMP-9) involved on EMT, by these relation with patient overall survival (OS) and disease stage. Methods: We retrospectively examined the medical records and histopathological biopsy results of 137 patients with GC (stages I to IV), treated at the Department of Medical Oncology at Hospital do Cancer A.C. Camargo between 1998 and 2006. Included patients underwent total or subtotal gastrectomy at our hospital. Expression of proteins related to EMT was evaluated by Tissue Microarray. Results: By the analysis of protein expression according to deep of gastric wall invasion (T), no protein showed to be important. On different levels of lymphonodal commitment (N0, N1, N2, N3) and in relation to presence (M1) or absence (M0) of distant metastasis, only COX-2 expression showed to be determinant with major expression on N2 and N3 and M1 status (p = 0.017 and p = 0.011, respectively). COX-2 was also relevant for clinical stage, where its expression was higher on poor stages (p = 0.011). On 5-year OS, TGF-α (p = 0.017), COX-2 (p < 0.001), MMP-7 (p = 0.020) and MMP-9 (p = 0.015) expressions revealed to be determinant, where the poor expression of these proteins were linked to better OS. Conclusions: This is the first study to correlate proteins involved on EMT with OS. We were able to show that COX-2, TGF-α, MMP-7 and MMP-9 expression on GC were related to poor patient OS. No significant financial relationships to disclose.
The optimal tumor response assessment in patients with HCC after treatment of TACE.
Authors: Jung E. , Kim J. , Yoon E. , Lee H. , Lee Y. , Yeon J. , Byun K. 
Published: February 2017

215 Background: WHO or RECIST has been considered as suboptimal methods for tumor response assessment in HCC, especially receiving locoregional therapies. Recently, new modified methods having concept of viable tumor has been proposed. Herein we compared the efficacy to assess response and to predict prognosis between WHO, RECIST, EASL, mRECIST in HCC patients receiving TACE. Methods: We retrospectively reviewed 141 HCC patients who were newly diagnosed and received TACE between August 2005 and November 2006. Among them, 98 patients who were available for assessing treatment response were analyzed at 1 month after 2nd TACE. We evaluated intermethod aggreement between methods and assessed the efficacy predicting time to progression (TTP) and overall survival (OS). Results: The results of tumor responses (number of CR/ PR/ SD/ PD) by WHO/ RECIST/ EASL/ mRECIST were 1/ 14/ 74/ 9, 1/ 12/ 77/ 8, 34/ 34/ 25/ 5, 34/ 28/ 31/ 5, respectively. The κvalue of intermethod agreement for EASL vs WHO, EASL vs RECIST, mRECIST vs WHO, and mRECIST vs RECIST was 0.102, 0.088, 0.112 and 0.122, respectively. The κvalue for WHO vs RECIST and EASL vs mRECIST was 0.759 and 0.883 (p=0.00). Hazard ratios for TTP in responders compared with nonresponders were 0.313 (95% CI; 0.19-0.52, p=0.00) for EASL and 0.335 (95% CI; 0.21-0.54, p=0.00) for mRECIST. Hazard ratios for survival in responders compared with nonresponders were 0.208 (95% CI; 0.12-0.37, p=0.00) for EASL and 0.269 (95% CI; 0.15-0.48, p=0.00) for mRECIST. In the univariate analysis, tumor size, infiltrative type, PVT, EASL responder, and mRECIST responder were significant risk factors for survival. Multivariate analysis showed EASL responder (HR 0.165, 95% CI 0.056-0.486, p=0.001) and infiltrative type (HR 4.504, 95% CI 1.579-12.848, p=0.005) were independent predictable factors for survival. Conclusions: The recent proposed methods showed different characteristics from preexisting methods in assessing treatment response and furthermore, responder by EASL method was independent predictor for survival in HCC patients receiving TACE. EASL method should be applied as response assessment method for HCC patients receiving TACE. No significant financial relationships to disclose.
Effect of nicotine on chemoresistant phenotype as mediated through Src-dependent Id1 expression in pancreatic adenocarcinoma cells.
Authors: Trevino J. G. , Pillai S. R. , Chellappan S. P. 
Published: February 2017

216 Background: The signaling pathways contributing to DNA-binding protein inhibitor Id1 expression and chemoresistance in pancreatic cancer remain unknown. Id1 plays a role in pancreatic tumor progression with tumor-promoting effects of nicotine regulating protein tyrosine kinase Src activation and Id1 expression, both associated with chemoresistance in other systems. We hypothesize Id1 expression regulates chemoresistance in pancreatic cancer through a nicotine-promoting Src-dependent pathway. Methods: We probed pancreatic cancer cell lines (L3.6pl, PANC-1, Mia-PaCa-2) for innate gemcitabine chemoresistance with cell viability MTT assay and western blot analysis of PARP cleavage programmed cell death. Gemcitabine-sensitive cells were exposed to rising gemcitabine concentrations to establish a resistant subtype, L3.6plGemRes. Protein analysis and mRNA expression were determined by western blot analysis and RT-PCR respectively. Induction of Src phosphorylation or Id1 expression was performed with nicotine (1 μM). Results: Inhibition of c-Src expression was performed with short-interfering RNA (siRNA). Nicotine-induced Src phosphorylation and Id1 expression. Inhibition of Src by siRNA resulted in decreased nicotine-induced Id1 expression. Inhibition of Src and Id1 expression by siRNA in innate or established gemcitabine resistant pancreatic cancer cells resulted in gemcitabine sensitization. To determine if nicotine contributes to gemcitabine chemoresistance, we exposed gemcitabine-sensitive cells to nicotine with subsequent exposure to gemcitabine IC50, 250 ng/ml, and cell viability assays confirmed a 2-fold increase in cell prolilferation and a 4.5-fold reduction in apoptosis. Further, nicotine induced phosphorylation of key signaling enzymes involved in proliferation and apoptosis, Erk1/2 and Akt respectively. Conclusions: In summary, we demonstrate that Id1, through a nicotine-promoting Src-dependent pathway, is necessary for establishment of a chemoresistant phenotype in pancreatic cancer cells. Understanding the signaling pathways involved in pancreatic tumor chemoresistance will lead to therapies resulting in improved tumor responses. No significant financial relationships to disclose.
VEGF receptor 1 and heparanase expression as prognostic factors in cholangiocellular carcinoma.
Authors: Goekkurt E. , Stoehlmacher J. , Aust D. E. , Danenberg P. V. , Danenberg K. D. , Lehmann S. , Mogck U. , Ehninger G. , Hoffmann A. C. 
Published: February 2017

226 Background: Cholangiocellular carcinoma (CCC) remains to be a tumor with very few treatment choices and limited prognosis. In this study, we sought to determine the prognostic role of VEGF receptor 1 (VEGFR1), heparanase (HPSE) and EGF receptor (EGFR) gene expression in patients with resected CCC. Methods: 47 formallin-fixed paraffin embedded FFPE tumor samples from patients with resected CCC were analyzed. FFPE tissues were dissected using laser-captured microdissection and analyzed for VEGFR1, HPSE and EGFR mRNA expression using a quantitative real-time RT-PCR method. Gene expression values (relative mRNA levels) are expressed as ratios between the target gene and internal reference genes (beta-actin, b2mg, rplp2, sdha). Results: VEGFR1 and HPSE expression levels were significantly associated with overall survival (OS). Patients expressing low levels of VEGFR1 displayed a median OS of 23.2 months compared to 5.3 months in patients with high VEGFR1 expression (p=0.006, logrank test). Patients with low HPSE expression had a median OS of 19.8 months compared to 10.0 months in patients with high HPSE expression (p=0.02, logrank test). EGFR and PDGFRα expression were significantly associated with HPSE and VEGFR1 expression (p=0.03 and p<0.0001, respectively). Conclusions: These results suggest that VEGFR1 and HPSE gene expression levels may play a role as prognostic factors in patients with CCC. Further studies are warranted to study these associations. [Table: see text]