bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4644: PDGFRα/β and VEGFR2 SNPs incolorectal cancer.
Authors: Estevez-Garcia Purificacion , Castaño A , Martin Ana , Lopez-Rios Fernando , Iglesias J , Muñoz-Galvan Sandra , Lopez-Calderero Iker , Molina-Pinelo Sonia , Pastor Maria D. , Carnero Amancio , Pa-Ares Luis , Garcia-Carbonero Rocio 
Published: August 2014

Abstract
Angiogenesis plays an essential role in tumor growth and metastasis, and is a major target in cancer therapy. VEGFR and PDGFR are key players involved in this process. The purpose of this study was to assess the incidence of genetic variants in these receptors and its potential clinical implications in colorectal cancer (CRC). VEGFR2, PDGFRα and PDGFRβ mutations were evaluated by sequencing their tyrosine kinase domains in 8 CRC cell lines and in 92 samples of patients with CRC. Correlations with clinicopathological features and survival were analyzed. Four SNPs were identified, three in PDGFRα [exon 12 (A12): c.1701A&gt;G; exon13 (A13): c.1809G&gt;A; and exon 17 (A17): c.2439+58C&gt;A) and one in PDGFRβ (exon19 (B19): c.2601A&gt;G) (figure 1). SNP B19 was present in 58% of tumor samples and in 4 cell lines (LS174T, LS180, SW48, COLO205), and this was associated with higher PDGFR and pPDGFR protein levels. 5-year survival was greater for patients with PDGFR B19 wild type tumors (AA) than for those harboring the G-allele genotype (GA or GG) (51%vs17%; P=0.073). Multivariate analysis confirmed SNP B19 (P=0.029) was a significant prognostic factor for survival, independent of age (P=0.060) or TNM stage (P&lt;0.001). In conclusion, PDGFRβ exon 19 c.2601A&gt;G SNP is commonly encountered in CRC patients and is associated with increased pathway activation and poorer survival. Implications regarding its potential influence in response to PDGFR targeted agents remain to be ellucidated.
Citation Format: Purificacion Estevez-Garcia, A Castaño, Ana Martin, Fernando Lopez-Rios, J Iglesias, Sandra Muñoz-Galvan, Iker Lopez-Calderero, Sonia Molina-Pinelo, Maria D. Pastor, Amancio Carnero, Luis Pa-Ares, Rocio Garcia-Carbonero. PDGFRα/β and VEGFR2 SNPs incolorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4644. doi:10.1158/1538-7445.AM2013-4644
Abstract 4646: Notch and DLL4 expression in bevacizumab-treated colon cancer patients.
Authors: Negri Francesca , Bozzetti Cecilia , Crafa Pellegrino , Lagrasta Costanza , Cavalli Stefano , Pedrazzi Giuseppe , Gardini Giorgio , Tamagnini Ione , Porzio Rosa , Cavanna Luigi , Paties Carlo , Romano Ida , Musolino Antonino , Tomasello Gianluca , Petronini Pier Giorgio , Ardizzoni Andrea 
Published: August 2014

Abstract
Background: In order to investigate mechanisms of resistance to angiogenesis inhibitors, Notch and Delta-like 4 ligand (DLL4) expression was correlated with response and survival in a series of bevacizumab treated advanced colon cancer patients. DLL4-mediated Notch signalling has recently emerged as an attractive target for angiogenesis-based cancer therapies, given that DLL4 is an important component of Notch-mediated stem cell self-renewal and vascular development. DLL4-induced Notch signalling mediates tumour-resistance to anti-VEGF therapy by inducing the formation of large vessels and activating multiple pathways in preclinical models. Method: Notch and DLL4 expression was evaluated by immunohistochemistry (IHC) on 65 primary colon cancer patients enrolled within randomized clinical trials assessing first-line bevacizumab plus chemotherapy. Results: Notch positivity was localized to the cytoplasm of malignant epithelial cells. In all, 10/60 (17%) evaluable primary tumours had a high Notch expression. Five of the 10 cases (50%) with high Notch expression experienced progressive disease compared with 5/49 (10%) Notch negative cases (p=0.008). Median progression-free survival (PFS) was 2.8 months for Notch positive cases compared with 13.07 months for Notch negative cases (p=0.045). Membranous and/or cytoplasmic DLL4 immunoreactivity of tumour vessels was observed in 30/56 (54%) evaluable colon cancers. No correlation was found between DLL4 expression and clinical outcome. Conclusion: Clinical trials investigating the therapeutic efficacy of bevacizumab in colon cancer did not explore the impact of DLL4-Notch pathway on response and clinical outcome. Our results seem to suggest that high Notch expression might be involved in tumour resistance in colon cancer patients treated with bevacizumab.
Citation Format: Francesca Negri, Cecilia Bozzetti, Pellegrino Crafa, Costanza Lagrasta, Stefano Cavalli, Giuseppe Pedrazzi, Giorgio Gardini, Ione Tamagnini, Rosa Porzio, Luigi Cavanna, Carlo Paties, Ida Romano, Antonino Musolino, Gianluca Tomasello, Pier Giorgio Petronini, Andrea Ardizzoni. Notch and DLL4 expression in bevacizumab-treated colon cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4646. doi:10.1158/1538-7445.AM2013-4646
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 4654: Genomic and proteomic profiling of signaling pathways targeted by a multi-kinase inhibitor, sorafenib.
Authors: Masuda Mari , Honda Kazufumi , Yamada Tesshi 
Published: August 2014

Abstract
Background: Deregulation of intracellular signaling by various genetic alterations is a hallmark of cancer. Therapeutics targeting such activated signaling pathways have achieved significant progress, but the precise pathway(s) targeted by sorafenib has remained unclear.
Methods: Using high-density reverse-phase protein arrays, we profiled the phosphorylation status of 180 signaling molecules in the 120 pathways registered on the NCI-Nature curated database in 23 hepatocellular carcinoma (HCC) cell lines showing different sensitivities to sorafenib. We also sequenced the entire coding regions of 518 protein kinase genes in 20 overlapping HCC cell lines.
Results: We identified 25 non-synomymous alterations in the 4 mTOR and MAPK pathway genes (RPS6KA1, RPS6KA6, RPS6KB2, and BRAF) in HCC cell lines 1 to 11. We also found that the levels of phosphorylated S6 ribosomal protein and c-Raf were associated with the sensitivity of the HCC cell lines to sorafenib. A mTOR inhibitor, AZD8055, exerted growth-inhibitory activity against sorafenib-resistant HCC cell lines.
Discussion: Although a recent phase III clinical trial has demonstrated the effectiveness of sorafenib in patients with unresectable HCC, only a small proportion of the patients achieved the anticipated therapeutic benefits. The present results indicate cross-talk between the mTOR and MAPK signaling pathways in sorafenib-resistant HCC cell lines. Use of a combination of mTOR and MAPK inhibitors may improve the efficacy of molecular targeting therapy against HCC.
Citation Format: Mari Masuda, Kazufumi Honda, Tesshi Yamada. Genomic and proteomic profiling of signaling pathways targeted by a multi-kinase inhibitor, sorafenib. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4654. doi:10.1158/1538-7445.AM2013-4654
Abstract 4659: Phase II study of a weekly liposomal paclitaxel formulation (Genexol®-PM) and gemcitabine® combination chemotherapy in patients with advanced biliary cancer.
Authors: Keon Uk Keon UK , Kim Jin Young , Do Young Rok , Song Hong Suk , Jeon Young June , Ryoo Hun Mo , Bae Sung Hwa , Kim Jong Gwang , Baek Jin Ho , Chae Yee Soo , Kim Min Kyoung , Lee Kyung Hee , Cho Yoon Young 
Published: August 2014

Abstract
OBJECTIVE: Advanced biliary cancer is associated with a poor prognosis due to wide resistance to chemotherapeutic agents. This phase II clinical trial was conducted to determine the efficacy and safety of weekly gemcitabine and liposomal paclitaxel in patients with unresectable of metastatic biliary cancer.
METHODS: The eligibility criteria were patients 1) with pathologically proven biliary cancer, 2) with an ECOG performance status 0 to 2, 3) aged more than 18, 4) with measurable lesions, 5) with adequate hematologic, renal and liver functions, and 6) who provided written informed consent. Each treatment cycle was consisted of gemcitabine 1000 mg/m² and liposomal paclitaxel (Genexol-PM)100 mg/m² on days 1, 8 followed by rest perioid of 14 days. It was repeated until the appearance of disease progression or unacceptable toxicity up to maximal 10 cycles. The primary end point of this study was reponse rate, and secondary end points included toxicity, progression free survival and overall survival.
RESULTS: Forty five patients were enrolled; median age was 63 years; male (n=33) and female (n=12). The median number of cycles administered was 4.0 (range,1-10). Thirty nine patients were assessable for efficacy. Ten partial responses and 18 stable diseases were confirmed. Giving an overall response rate was 25.6% and disease control rate was 71.8% in per-protocol population. The median time to progression and median overall survival was 4.0 (95% CI; 3.17∼4.83) months and 8.13 (95% CI; 4.76∼11.51) months, respectively. MUC4 expression was not significantly correlated with overall survival and progression free survival (p=0.391).
CONCLUSION: Weekly gemcitabine combined with Genexol-PM® appears to be effective against advanced biliary cancers. Further randomized trials are needed to confirm this finding.
Citation Format: Keon Uk Keon Uk, Jin Young Kim, Young Rok Do, Hong Suk Song, Young June Jeon, Hun Mo Ryoo, Sung Hwa Bae, Jong Gwang Kim, Jin Ho Baek, Yee Soo Chae, Min Kyoung Kim, Kyung Hee Lee, Yoon Young Cho. Phase II study of a weekly liposomal paclitaxel formulation (Genexol®-PM) and gemcitabine® combination chemotherapy in patients with advanced biliary cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4659. doi:10.1158/1538-7445.AM2013-4659
Abstract 466: Tumor-induced fibrocytes mediate immune suppression via Indoleamine Oxidase.
Authors: Zhang Hua , Mackall Crystal L. 
Published: August 2014

Abstract
Fibrocytes are hematopoietic stem cell-derived, fibroblast precursors implicated in chronic inflammation, fibrosis and wound healing, whereas human myeloid derived suppressor cells (MDSC) have been described as CD14-CD11b+CD33+HLADR- cells that exert T cell suppression via ROS, ARG1 and iNOS2. Here we report that patients with metastatic pediatric sarcomas have abnormal expansions of myeloid cells within elutriated mononuclear apheresis samples of pediatric cancer patients. Like myeloid derived suppressor cells, these cells are CD14-CD11b+, but they also cells bear markers of classical fibrocytes, including surface α smooth muscle actin, fibroblast activation protein, collagen I/V, and HLA-DR, but are PM2K negative. They also mediate angiogenesis and are CD33lo/-CD34+CD15+CD16+CD66b+CD68+PDL1+ and IL4Rα+. While classical fibrocytes serve as antigen presenting cells and augment immune reactivity, fibrocytes from cancer patients suppressed anti-CD3 mediated T cell proliferation, primarily via indoleamine oxidase (IDO). Interestingly the degree of fibrocyte expansion observed in individual patients directly correlated with the frequency of circulating GATA3+CD4+ cells (R=0.80) and monocytes from healthy donors cultured with IL-4 differentiated into fibrocytes with the same phenotypic profile and immunosuppressive properties as those observed in patients with cancer. We conclude that fibrocytes are a subset of myeloid derived suppressor cells expanded in cancer patients likely in response to Th2 immune deviation. These cells may contribute to tumor progression via both immune evasion and angiogenesis.
Citation Format: Hua Zhang, Crystal L. Mackall. Tumor-induced fibrocytes mediate immune suppression via Indoleamine Oxidase. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 466. doi:10.1158/1538-7445.AM2013-466
Abstract 4691: Class III beta tubulin is a strong predictive marker for taxane-based first-line palliative chemotherapy in recurrent or metastatic gastric cancer.
Authors: Hwang Jun-Eul , Kim Dae-Eun , Shim Hyun-Jeong , Bae Woo-Kyun , Oh In-Jae , Cho Sang-Hee , Chung Ik-Joo 
Published: August 2014

Abstract
Backgrounds. Class III β tubulin (TUBB3) is a prognostic marker in various tumors and role of TUBB3 in advanced gastric cancer is not clearly defined yet. We analyzed the significance of TUBB3 expression along with ERCC1 in recurrent or metastatic gastric cancer patients receiving taxane based first-line palliative chemotherapy.
Methods. We reviewed 146 patients with advanced gastric adenocarcinoma who received taxane based first-line palliative chemotherapy between 2004 and 2010 at Chonnam National University Hwasun hospital. Immunohistochemical stain of TUBB3 and ERCC1 was done in paraffin-embedded tumor tissue. We evaluated response to chemotherapy, progression-free survival (PFS), and overall survival (OS).
Results. A total of 146 patients with advanced gastric cancer received docetaxel and cisplatin (n=15), or paclitaxel and cisplatin (n=131). The median PFS was significantly shorter for patients with TUBB3 high expression than patients with TUBB3 low expression (3.63 versus 6.67 months, p=0.001). OS was not associated with TUBB3 expression status (12.9 versus 13.1 months, p=0.769). In multivariate analysis, only TUBB3 was related to shorter PFS (HR 2.74, 95% CI 1.91-3.91, p=0.001). Patients with ERCC1 high expression showed lower response rate than patients with ERCC1 low expression (24% versus 63.2%, p=0.001), however ERCC1 showed no clinical influence on PFS and OS.
Conclusions. TUBB3 is a strong predictive marker in recurrent or metastatic gastric cancer patients receiving taxane based first-line palliative chemotherapy. Clinical impact of ERCC1 is not evident in this setting.
Citation Format: Jun-Eul Hwang, Dae-Eun Kim, Hyun-Jeong Shim, Woo-Kyun Bae, In-Jae Oh, Sang-Hee Cho, Ik-Joo Chung. Class III beta tubulin is a strong predictive marker for taxane-based first-line palliative chemotherapy in recurrent or metastatic gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4691. doi:10.1158/1538-7445.AM2013-4691
Abstract 4694: Nuclear expression of IL23p19 shows indolent tumor features and favorable outcome in patients with colorectal cancer.
Authors: Zlobec Inti , Helbling Melina , Diamantis-Karamitopoulou Eva , Koelzer Viktor H. , Dawson Heather , Lugli Alessandro 
Published: August 2014

Abstract
Background: The IL23 signaling pathway is involved in chronic inflammation and autoimmune disorders but its role in cancer progression is not fully elucidated. The aim of this study was to characterize the expression of IL23 subunits p40 and p19 as well as IL23R in the normal-adenoma-carcinoma-metastasis cascade of colorectal cancers and investigate the relationship between these proteins and clinicopathological, molecular and clinical outcome data in colorectal cancer patients.
Methods: Immunohistochemistry for IL12p40 (p40 subunit shared between IL12 and IL23), IL23 (polyclonal), IL23p19 (monoclonal) and IL23R was performed on a multiple-punch tissue microarray of 213 colorectal cancers from patients with full clinicopathological and follow-up information. Normal tissues, matched adenomas and lymph node metastases were assessed as well as microsatellite instability (MSI), KRAS and BRAF mutations.
Results: IL12p40, IL23, IL23p19 and IL23R expression were significantly increased in colorectal cancers in comparison to all other tissue types (p&lt;0.001; all). Cytoplasmic and/or membranous expression of all proteins was unrelated to clinicopathological or molecular features. Unexpectedly, 45 cases (23.1%) showed distinct nuclear IL23p19+ expression associated with smaller tumor diameter (p=0.0333), early TNM stage (p=0.0186), absence of venous (p=0.0124) and lymphatic invasion (p=0.0493), lymph node negativity (p=0.0621) and MSI (p=0.0032). IL23p19+ patients had more favorable overall survival (p=0.0634); none had distant metastatic disease (p=0.0146). No relationship with KRAS or BRAF was observed.
Conclusion: Our results of a more indolent, less aggressive cancer expressing nuclear IL23p19 support a more “protective” role of this protein in colorectal cancer progression. These findings add to the current controversy regarding the pro- or anti-tumor effects of IL23 signaling in cancer.
Citation Format: Inti Zlobec, Melina Helbling, Eva Diamantis-Karamitopoulou, Viktor H. Koelzer, Heather Dawson, Alessandro Lugli. Nuclear expression of IL23p19 shows indolent tumor features and favorable outcome in patients with colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4694. doi:10.1158/1538-7445.AM2013-4694
Abstract 4701: Cancer-specific genomic rearrangements used to quantify disease burden in plasma from patients with colorectal cancer.
Authors: Schøler Lone V. , Thomsen Rune , Tobiasen Heidi , Vang Søren , Nielsen Hans Jørgen , Laurberg Søren , Ørntoft Torben F. , Andersen Claus L. 
Published: August 2014

Abstract
Tumor-specific chromosomal rearrangements have the potential to serve as highly sensitive biomarkers for tumor detection. Such alterations are not present in normal cells and should be exquisitely specific. It is well recognized that some colorectal cancers (CRC) release small amounts of DNA into plasma. Accordingly, sensitive and specific assays targeting these tumor-specific rearrangements should enable quantification of changes in disease burden if applied to serial plasma samples. Here we report the establishment of efficient procedures for 1) identification of tumor-specific genomic rearrangements, 2) development of sensitive and specific assays to these, 3) quantification of these rearrangements in plasma, and 4) results from applying these procedures to quantify disease burden in serial plasma samples from CRC patients. The tumor-specific genomic rearrangements were identified using a combination of next generation paired-end sequencing of large-insert libraries and SNP array based DNA copy number analysis. Nested real-time PCR assays targeting the rearrangements were applied to plasma samples in order to quantify disease burden. Initially the approach was tested using the CRC cell line SW620 as a tumor model, and serial dilutions of SW620 DNA and normal human plasma DNA as models of patient plasma. Multiple cell line specific rearrangements were identified and nested real-time PCR analysis of these in the serial dilutions revealed an excellent linearity, recovery across three log scales. Also the sensitivity was very good. As little as 6.4 pg cell line DNA could be detected in a background 20 ng of normal plasma DNA, corresponding to DNA from 1-2 tumor cells circulating in 2 ml plasma. We are currently in the process of analyzing 25 CRC patients from which we have more than three years of follow-up and serial plasma samples collected every third month, starting the day before surgery and until month 36. The results from these analyses will be presented. In conclusion: We have shown that the combination of large insert paired end sequencing and copy number analysis readily identifies multiple tumor-specific rearrangements that can be targeted by sensitive and specific nested real-time PCR assays to quantify disease burden in plasma samples.
Citation Format: Lone V. Schøler, Rune Thomsen, Heidi Tobiasen, Søren Vang, Hans Jørgen Nielsen, Søren Laurberg, Torben F. Ørntoft, Claus L. Andersen. Cancer-specific genomic rearrangements used to quantify disease burden in plasma from patients with colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4701. doi:10.1158/1538-7445.AM2013-4701
Abstract 4708: Anti-tumor phenotype of tumor-associated macrophages are induced by COX-2 inhibition via the up-regulation of IFN-γ.
Authors: Nakanishi Yuki , Nakatsuji Masato , Seno Hiroshi , Chiba Tsutomu 
Published: August 2014

Abstract
BACKGROUNDS AND AIMS
Macrophages are a major constituent in tumor stroma, and macrophages infiltrating tumors are called tumor-associated macrophages (TAMs). Macrophages have a functional plasticity depending on the stimuli from microenvironment. M1 macrophages are induced by Th1 cytokines, and exerted anti-tumor function. On the contrary, M2 macrophages are induced by Th2 cytokines, and showed pro-tumor phenotype. TAMs are considered to shift from M1 to M2 during tumor progression. However, the mechanism for this M1/M2 switch is poorly understood. Cyclooxygenase-2 (COX-2)/PGE2 pathway is up-regulated in a variety of cancers including colorectal cancers, and promotes the cancer progression. COX-2 inhibition shows anti-tumor effect in familial adenomatous polyposis patients and in Apc knockout mice. Although COX-2 inhibition affects cytokine expression profiles and tumor microenvironments, the relationship between COX-2/PGE2 pathway and TAM phenotypes remains unclear.
The aim of this study is to uncover the effects of COX-2 inhibition on TAM phenotypes and cytokine expression.
METHODS
Cytokine expression and the phenotypes of TAMs infiltrating the stroma of ApcMin/+ mouse polyps were examined by qRT-PCR and immunohistochemistry in terms of M1 and M2 dichotomy. Selective COX-2 inhibitor was administered to ApcMin/+ mice, and the effects of COX-2 inhibition on cytokine expression and TAM phenotypes were evaluated. Furthermore, by using mouse peritoneal macrophages, the direct effects of COX-2 inhibitor on Th1- or Th2-related cytokines on macrophage phenotypes were examined.
RESULTS
Th2 cytokines were predominant in ApcMin/+ mouse polyps, and TAMs were polarized to M2. Selective COX-2 inhibitor skewed TAM phenotypes from M2 to M1, accompanied by tumor regression in ApcMin/+ mice. Concomitantly, the expression of M1-related cytokine IFN-γ was significantly up-regulated by COX-2 inhibition, although that of M2-related cytokines IL-4, IL-13, and IL-10 was not significantly altered. Administration of COX-2 inhibitor alone was insufficient to alter the phenotypes of mouse peritoneal macrophages from M2 to M1. However, IFN-γ treatment polarized the macrophage phenotypes from M2 to M1 even in the presence of M2-related cytokines IL-4, IL-13, and IL10.
CONCLUSIONS
Our results suggest that COX-2 inhibition induced anti-tumor (M1) phenotype of TAMs via the up-regulation of IFN-γ, and subsequently, may suppress intestinal tumor progression in ApcMin/+ mouse polyps.
Citation Format: Yuki Nakanishi, Masato Nakatsuji, Hiroshi Seno, Tsutomu Chiba. Anti-tumor phenotype of tumor-associated macrophages are induced by COX-2 inhibition via the up-regulation of IFN-γ. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4708. doi:10.1158/1538-7445.AM2013-4708