bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5295: Detection of VEGFA gene amplification in different neoplastic entities using four different technologies
Authors: Andreozzi MariaCarla , Vuaroqueaux Vincent , Ackermann Andreas , Schneider Sandra , Tornillo Luigi , Ruiz Christian , Fiebig Heinz Herbert , Eppenberger Serenella , Terracciano Luigi Maria
Published: August 2012

Background The VEGFA protein plays an important role in the induction of angiogenesis during tumor initiation and progression. The aims of the study were to investigate the presence of VEGFA gene amplification by FISH analysis on a human multi-tumor tissue microarray (MTMA) and to validate these findings on an independent human multi-tumor tissue in mouse implanted microarray (MTMA) by aCGH, SNP6 microarrays, FISH analysis and real-time PCR. Materials and Methods The VEGFA gene status was evaluated on a human MTMA (n=2,957 tissue samples) including 132 tumor entities and 31 normal tissue types. Furthermore, we reconfirmed the presence of VEGFA gene amplification as detected by FISH analysis on a second independent MTMA including 195 different tissue samples from nude mice xenograft models of 24 different human tumor types using three additional genomic techniques: array-CGH, SNP6 microarrays and real-time PCR. Results VEGFA gene amplification was detected across different tumor types. The following incidences were observed: 5.3% in colorectal carcinoma, 3.2% in endometrial carcinoma, 2.8% in gallbladder adenocarcinoma, 4.2 % in renal carcinoma, 1.5% in hepatocellular carcinoma, 4.5% in pancreas carcinoma and 4.8% in stomach carcinoma samples. Additionally, some tumors were characterized by a high polysomy. In the second independent cohort MTMA VEGFA gene amplification was detected by FISH analysis in four samples, including one non-small cell lung cancer, one sarcoma, one gastric and and breast cancer, previously classified as amplified by aCGH (100%) and SNP6 microarrays. The latter technique also revealed one “supplementary amplified sample”. All results correlated with real-time PCR (p<0.05). Conclusions We detected VEGFA gene amplification in different tumor types, on a human MTMA and we confirmed our findings on an independent MTMA of human tumors implanted in mice. We demonstrated the occurrence of VEGFA gene amplification in several tumor types with an incidence of up to 5% and also we demonstrated the feasibility of four technologies for reliable VEGFA gene copy number detection. Comparison of the four technologies revealed high concordance (p<0.05).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5295. doi:1538-7445.AM2012-5295
Abstract 5299: VEGF receptor-3 interacts with PI3K directly to regulate lymphangiogenesis
Authors: Coso Sanja , Zeng Yiping , Opeskin Kenneth , Williams Elizabeth D.
Published: August 2012

Dissemination of malignant cells into the regional lymph nodes is a common occurrence in many cancers. The vascular endothelial growth factor (VEGF) family is a major regulator spread of cancer to lymph nodes via induction of lymphangiogenesis. We have used primary lymphatic endothelial cells and clinical material to investigate VEGF-C/VEGF receptor (VEGFR)-3 signalling pathways. We found that treatment with VEGF-C induced activation of PI3K/Akt and MEK/Erk in lymphatic endothelial cells. Furthermore, activation of PI3K/Akt by VEGF-C/VEGFR-3 resulted in phosphorylation of P70S6K, eNOS, PLCγ1, and Erk1/2. Importantly, a direct interaction between PI3K and VEGFR-3 in lymphatic endothelial cells was demonstrated both in vitro and in clinical specimens, where it was associated with the presence of lymph node metastases in small cell carcinoma of the lung. Blocking PI3K abolished VEGF-C-stimulated lymphatic endothelial cell tube formation and migration. Our findings demonstrate that specific VEGFR-3 signalling pathways are activated in lymphatic endothelial cells by VEGF-C. The importance of PI3K in VEGF-C/VEGFR-3-mediated lymphangiogenesis provides a potential therapeutic target for tumor lymphatic metastasis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5299. doi:1538-7445.AM2012-5299
Abstract 5302: Characterization the role of leukocyte cell-derived chemotaxin 2 (LECT2) in angiogenesis
Authors: Chi-Kuan Chen , Yang Ching-Yao , Chen Huei-Wen , Kuo Ming-Lian
Published: August 2012

Leukocyte Cell-Derived Chemotaxin 2 (LECT2) protein is expressed preferentially in the liver in a constitutive manner and secreted into bloodstream. Recently studies indicate that LECT2 potentially associated with the liver injury, repair, and regeneration, but other functions are still unknown. Angiogenesis is a process of new blood vessel formation which has essential roles in development, repair, tumor growth, invasion, and metastasis. In our previous studies, we have recently identified LECT2 as a potential tumor suppressor, correlating with decreased vascular invasion in hepatocellular carcinomas (HCC). In this study, we evaluated the function of recombinant LECT2 (rLECT2) proteins on angiogenesis by using human umbilical vein endothelial cells (HUVEC). We demonstrated a selective and significant inhibition of VEGF165-induced angiogenic activity in HUVEC by rLECT2 protein through inhibiting the proliferation, migration, and tube formation. The rLECT2 protein also suppressed VEGF165-induced angiogenesis in CAM assay and matrigel plug assay. Otherwise, we use different stage of HCC to evaluate the density, amounts, and volumes of blood vessels are associated with LECT2 protein level. Furthermore, we also evaluate the association between LECT2 protein level and the maturity of blood vessels. In conclusion, we for the first time found that LECT2 play an important role in anti-angiogenesis. Moreover, the LECT2 might have broad therapeutic applications in diseases characterized by excessive angiogenesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5302. doi:1538-7445.AM2012-5302
Abstract 5311: Transducer of Cdc42-dependent actin assembly-1 (Toca-1) promotes breast cancer invasion and metastasis
Authors: Chander Harish , Meens Jalna A. M , Truesdell Peter F. , Brien Colin D. , Everingham Stephanie L. , Craig Andrew W.B
Published: August 2012

Metastatic breast adenocarcinomas display activation signatures for signaling pathways like Epidermal Growth Factor Receptor (EGFR) that trigger cell motility and tissue invasion. Transducer of Cdc42-dependent actin assembly-1 (Toca-1) is an adaptor protein that promotes recruitment of actin nucleation promoting factors to cellular membranes. Although these actin regulatory proteins have been linked to breast cancer invasion, the role of Toca-1 in this process has not been reported. In this study, breast cancer cell lines with a range of invasive and metastatic properties were used, including human MDA-MB-231 cells, rat MTLn3 cells, and MTLn3-B1 cells expressing human EGFR. To test the role of Toca-1 in these cell lines, we established stable Toca-1 knock-down (KD) using lentiviral delivery of shRNAs specific for human or rat Toca-1. Here, we report that Toca-1 is expressed in highly invasive breast cancers cell lines, and that Toca-1 co-localizes with components of invadopodia. Toca-1 localizes to the filamentous actin-rich core of invadopodial protrusions in breast cancer cells that are actively degrading the extracellular matrix (ECM). In MDA-MB-231 cells, Toca-1 KD led to a significant defect in EGF-induced cell migration and invasion compared to control cells. This correlated with a significant defect in EGF- and Src-induced ECM digestion in Toca-1 KD compared to control MDA-MB-231 cells. Next, control and Toca-1 KD cells were compared in orthotopic mammary tumors that were xenografted in Rag2−/−:[[Unsupported Character - Symbol Font ]]c−/− mice. Although Toca-1 KD remained effective in primary tumors, no defects in tumor growth were observed. However, mice bearing Toca-1 KD cell tumors displayed a significant reduction in spontaneous metastases to the lung. Similar results were obtained for weakly metastatic MDA-MB-231 cells and highly metastatic MTLn3-B1 cells. In contrast, Toca-1 was not required for efficient lung seeding following tail vein injection of MTLn3-B1 cells, suggesting that Toca-1 functions at an early step in the dissemination of metastatic breast tumor cells. Taken together, this investigation identifies Toca-1 as a pro-invasive protein in breast cancer, and a potential therapeutic target to limit tumor metastasis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5311. doi:1538-7445.AM2012-5311
Abstract 5316: GSK3β-dependent phosphorylation of LCRMP-1 is required for filopoda formation and tumor invasion
Authors: Wang Wen-Lung , Pan Szu-Hua , Chang Yih-Leong , Wu Chen-Tu , Chen Yuh-Ling , Hong Tse-Ming , Yang Pan-Chyr
Published: August 2012

LCRMP-1, a novel isoform of CRMP-1, can promote cancer cell migration, invasion and associates with poor clinical outcome in patients with non-small cell lung cancer (NSCLC). However, the underlying mechanisms for regulation of LCRMP-1 in cancer cell invasiveness remain still obscure. Here, we report that GSK-3β can phosphorylate LCRMP-1 at Thr-628 in consensus sequences and this phosphrylation is crucial for function of LCRMP-1 on filopodia formation and cancer cell invasion. Impediment of Thr-628 phosphorylation attenuates the effects of LCRMP-1 to form filopodia and promote cancer invasion; simultaneously, kinase-dead GSK-3β diminishes regulation of LCRMP-1 on cancer cell invasion. Furthermore, we also found that patients with low-level inactive GSK-3β expression and high-level LCRMP-1 expression have worse overall survival than those with high-level inactive GSK-3β expressions and low-level LCRMP-1 expressions (P< 0.0001). Collectively, these results demonstrate that GSK-3β-dependent phosphorylation of LCRMP-1 provides an important mechanism for regulation of LCRMP-1 on cancer cell invasiveness and clinical outcome.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5316. doi:1538-7445.AM2012-5316
Abstract 5381: Activation and frequency of myeloid subsets in peripheral blood is associated with clinical outcome in prostate cancer patients treated with Prostate GVAX and anti-CTLA4
Authors: Stam Anita G.M. , Santegoets Saskia , Scheper Rik , Lougheed Sinéad , Gall Helen , Jooss Karin , Sacks Natalie , Hege Kristen , Lowy Israel , Cuillerot Jean-Marie , Gerritsen Winald , van den Eertwegh Alfons , de Gruijl Tanja
Published: August 2012

Blockade of the CTLA-4 immune checkpoint can enhance anti-tumor responses and prolong survival, but it can also lead to the development of severe and potentially life-threatening immune-related adverse events (IRAE). To avoid unnecessary exposure to this risk, it is essential to identify biomarkers that correlate with clinical activity and can be used to recognize and select patients that will benefit from immune checkpoint blockade. We therefore performed extensive immune monitoring in a phase I/II dose escalation/expansion trial of combined Prostate GVAX (a GM-CSF-secreting allogeneic prostate cancer vaccine) and antiCTLA-4/ipilimumab immunotherapy in patients with Castration Resistant Prostate Cancer (CRPC). Here we report on the effects of the treatment on circulating myeloid cells and the identification of potential myeloid-related biomarkers. The GVAX/ipilimumab combination was clinically active with PSA declines of more than 50% in 5, and PSA stabilizations in 12 of 28 patients. Regressing bone and lymph node metastasis were observed in 2/5 PR patients. Flowcytometric monitoring of myeloid subsets in peripheral blood before and after Prostate GVAX/ipilimumab treatment revealed some striking differences between patients who benefited from therapy and patients who did not. Significant treatment-induced decreases of conventional and plasmacytoid Dendritic Cell subsets (cDC and pDC, respectively) were observed, which were paralleled by increased DC activation and recruitment to the vaccination sites. Treatment-induced activation of BDCA1/CD1c+ cDC and 6-sulfo LacNAc+ inflammatory DC was associated with significantly prolonged over-all survival (OS). In contrast, increased frequencies of CD11b+CD14−CD15+ granulocytic myeloid-derived suppressor cells (MDSC) and high pre-treatment levels of CD14+HLA-DRlo/− monocytic MDSC were associated with reduced OS. Together with similar analyses of T cell subsets, these studies have yielded an immune profile with predictive value for clinical outcome. The profile is characterized by pre- or on-treatment activation of immune effector subsets and low frequencies of regulatory/suppressive subsets. It may thus provide a potentially useful tool for patient selection and should be validated as such in other patient groups treated by antiCTLA-4 blockade.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5381. doi:1538-7445.AM2012-5381
Abstract 539: A preclinical model to evaluate the risk of increased dietary fat consumption and prostate cancer progression
Authors: Kobayashi Yasuyuki , De Velasco Marco A. , Hatanaka Yuji , Yamamoto Yutaka , Tanaka Motoyoshi , Masahiro Nozawa , Shimizu Nobutaka , Yoshimura Kazuhiro , Kodama Mitsuyama , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu
Published: August 2012

Prostate cancer (PCa) is a common disease in older men that is highly associated with various dietary factors including the increased consumption of fats, red and processed meats. Although results from large clinical studies have shown inconsistent findings with regards to obesity and prostate cancer-related mortality, increasing evidence has suggested a link between obesity and an increase in prostate cancer-specific mortality. To better understand the effects of increased dietary fat in prostate carcinogenesis, we developed a preclinical model using prostate-specific PTEN conditional knockout mice. This model is based on the conditional inactivation of PTEN in the prostate to alter PI3K/Akt/mTOR signaling, resulting in a stage-specific development and progression of cancer, with the ability to further develop castrate-refractory prostate cancer in a manner similar to humans. We previously showed that consumption of a high-fat diet (13.6% high fat plus N-nitroso-N-methylurea) for 75 weeks augmented prostate cancer progression in PTEN-mutant mice resulting increased metastases and decreased survival. To determine the molecular mechanisms involved in tumor promotion we randomized PTEN-mutant mice with non-castrate and castrate refractory prostate cancer to a high fat diet for 50 weeks. Chronic consumption of a high-fat diet results in increased tumor growth compared to controls. Mice fed a high fat diet showed increased levels of circulating adipokines and pro-inflammatory cytokines that include leptin, TIMP-1 IL-6, IL-10, IL-11 IGF-II, HGF and LIF. Mice fed the high fat diet also showed increased levels of tumor cell proliferation, transcriptional Stat-3 activation and neovascular angiogenesis. These findings provide evidence for the tumor promoting effects of a high fat diet and establish a preclinical model for the future development of novel chemopreventive strategies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 539. doi:1538-7445.AM2012-539
Abstract 5395: The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation
Authors: Poojary Venuprasad K. , Ahmed Neesar , Zeng Minghui , Polin Lisa , Sinha Indrajit , Wei Wei-Zen , Rathinam Chozha V. , Flavell Richard , Massoumi Ramin
Published: August 2012

Chronic inflammation has been strongly associated with tumor progression, but the underlying mechanisms remain elusive. Our previous studies have achieved important new insights into key regulatory mechanism in the immune system mediated by the ubiquitin ligase, Itch, whose deficiency results in inflammatory disorders and pulmonary inflammation (Venuprasad K et al. Nat. Immunol. 2008, Venuprasad K. et al. J.Clin. Invest. 2004). We demonstrate that E3 ligase Itch and deubiquitinase Cyld formed a complex via interaction through ‘WW-PPXY’ motifs. The Itch-Cyld complex sequentially cleaved K63-linked ubiquitin chains and catalyzed Lys48-linked ubiquitination on TGF-beta activated kinase 1(Tak1) to terminate inflammatory signaling. Itch or Cyld deficiency resulted in sustained Tak1 activation and elevated production of proinflammatory cytokines by bone marrow derived macrophages (BMDMs). Tak1 selective inhibitor, (5Z)-7-Oxozeaenol abrogated Tak1 activation and production of proinflammatory cytokines by Itch-/- and Cyld-/- BMDMs. Similarly, ectopic expression of a catalytically inactive dominant-negative (Tak1-K63W) inhibited elevated cytokine production by Itch-/- and Cyld-/- BMDMs. Reconstitution of wild-type Cyld but not the mutant Cyld(Y485A), which cannot associate with Itch, blocked sustained Tak1 activation and proinflammatory cytokine production by Cyldα/β BMDMs. Deficiency in Itch or Cyld led to chronic production of tumor-promoting cytokines by tumor-associated macrophages and aggressive growth of lung carcinoma. Thus, we have identified an Itch-Cyld-mediated regulatory mechanism in innate inflammatory cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5395. doi:1538-7445.AM2012-5395
Abstract 540: Increased growth and malignant transformation of human prostate epithelial cells by chronic exposure to arsenic and estrogen
Authors: Treas Justin N. , Singh Kamaleshwar P.
Published: August 2012

Both Arsenic and 17β-estradiol have been shown to induce growth and neoplastic formations in prostate epithelial cells. Estrogens are involved in prostate development and function at several stages. Arsenic has mild estrogenic properties. However, the effects of the co-exposure to physiologically relevant doses of these two chemicals on human prostate epithelial cells are not known. We hypothesize that as compared to the individual exposure, the co-exposure to arsenic and estrogen will potentiate the cell growth and transformation in prostate epithelial cells. Therefore, the objective of this study was to examine the effects of chronic exposure to arsenic and estrogen both individually and in combination on neoplastic transformations and increase cell growth. Human prostate epithelial cells, RWPE-1 were treated for 6 months with sodium-meta arsenite and 17β-estradiol both alone and in combination at concentrations of 100 pg/mL and 100 ng/mL. These treated cells were maintained further for 3 months in culture media without arsenic or estrogen supplementation. The effects of these compounds on cell growth were determined by cell count and MTT assay, and malignant transformation of cells was determined by anchorage independent growth assay on soft agar. The mitogenic effects of these chemicals were further confirmed at molecular level by cell cycle analysis using flow cytometry and gene expression analysis by quantitative real time PCR. The result of this study revealed that chronic exposure to arsenic and estrogen causes increased cell proliferation and induces cell transformation as observed in colony formation assay. The combination of these two chemicals had potentiating effects on cell growth and transformation of RWPE-1 cells. The increased percentage of cells in S-phase and increased expression of CyclinD1 as well as the anti-apoptotic gene Bcl2 further confirmed the mitogenic potential of these two chemicals in RWPE-1 cells. The present findings of increased growth and transformation of arsenic and estrogen treated cells and epigenetic changes observed in these cells together suggest that these carcinogenic chemicals induce malignant transformation in prostate epithelial cells at least in part through epigenetic mechanisms.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 540. doi:1538-7445.AM2012-540
Abstract 5468: Transgenic mice ectopically express miR-31 in basal keratinocyte, exhibit high potential for oral tumorigenesis
Authors: Lin Shu-Chun , Tseng Ssu-Hsueh
Published: August 2012

Oral squamous cell carcinoma (OSCC) is one of the leading causes of cancer mortality in the world. Despite that numerous advances have resulted in better control of patient morbidity, overall survival for OSCC has remained low for the past decades due to relapse and metastases. Besides, resistance to conventional therapeutic modalities stands for another important cause of treatment failure. OSCC adopts multiple genetic alterations for pathogenesis including activation of EGFR, AKT and hypoxia pathway, and other oncogenic events. Novel targeting therapy against these alterations in rodent tumors genetically resemble human tumors may confer tremendous abrogation benefits. MiRNAs are small non-coding RNAs mediating the translational repression of target mRNAs. miR-31 is among the most eminently up-regulated miRNAs in OSCC. Our works defined that miR-31 ablated expression of the HIF regulatory factor FIH (factor-inhibiting hypoxia-inducible factor) to activate hypoxia signaling and up-regulate VEGF, which contributed to OSCC pathogenesis. We established K14-GFP-miR-31 transgenic mouse lines in this study. GFP and miR-31 were detected in basal and suprabasal layers of the squamous epithelium of skin, oral cavity and esophagus in these transgenic mice. The transgenic mice exhibited higher potential for tumor induction on oral tongue and esophagus by 4-nitroquinoline 1-oxide treatment than wild type mice. The tumors induced in transgenic mice expressed more abundant K14, miR-31, VEGF and Ki-67 than tumors in wild type mice. The preneoplastic lesions on oral tongues of transgenic mice were also in more advanced stages in contrast to counterparts in wild type mice. Spontaneous occurrences of tumors in transgenic mice are being observed to insight additional oncogenic alterations essential for OSCC pathogenesis. We identified the high sensitivity of this transgenic mouse model for chemical carcinogen-induced oral tumorigenesis, and this model will be developed to select drugs or targeting strategies to facilitate human OSCC interception.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5468. doi:1538-7445.AM2012-5468
Abstract 5475: National survey of malignant mesothelioma and asbestos exposure in Japan
Authors: Fujimoto Nobukazu , Gemba Kenichi , Aoe Keisuke , Kato Katsuya , Takeshima Yukio , Inai Kouki , Kishimoto Takumi
Published: August 2012

A newspaper article published in June 2005 reported that 5 residents who lived near the now-closed asbestos cement pipe plant in Amagasaki developed pleural mesothelioma. The asbestos-related problems that the article described caused much social concern resulting in the so-called ‘Kubota shock.’ Patients who have a history of occupational asbestos exposure and have developed malignant mesothelioma are provided worker's compensation in Japan. However, among 878 cases of death due to mesothelioma in 2003, only 85 cases were actually compensated. Based on this, we initiated this retrospective survey and extracted 6,030 cases of death due to MM between 2003 and 2008 to clarify the clinical features of MM including the association with asbestos exposure (AE). Among them, clinical diagnosis of MM was confirmed in 929 cases. The origin of MM included the pleura in 794 (85.5%) cases, the peritoneum in 123 (13.2%) cases, the pericardium in 7 (0.8%) cases, and the testicular tunica vaginalis in 5(0.5%) cases. The histological subtype of MM included 396 (55.9%) epithelioid, 154(21.7%) sarcomatoid, 126 (17.8%) biphasic, and 33 (4.7%) cases classified as other types. AE was indicated in 76.8% and pleural plaques were detected in 34.2% of all MM cases. Asbestos particles were determined in 103 MM cases. More than 1,000 asbestos particles per gram dried lung tissue were detected in 74.8%, and more than 5,000 particles were detected in 43.7% of the cases. We compared the patient characteristics and the diagnostic procedures of MM before and after the ‘Kubota shock’. Compared to the early phase of this study (2003-2005), the median age at diagnosis of MM was higher, the number of cases without definite diagnosis of MM was lower, the proportion of cases diagnosed by thoracoscopy was higher, and the percentage of the cases in which the occupational history was described in the medical record was significantly higher in the late phase (2006-2008). Our study confirmed that more than 70% of MM cases in Japan are associated with AE. The ‘Kubota shock’ might affect some features pertaining to MM.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5475. doi:1538-7445.AM2012-5475
Abstract 5478: Indoor coal smoke exposure, tobacco use, and lung cancer risk in Xuanwei, China
Authors: Kim Christopher , Chapman Robert , Hu Wei , He Xingzhou , Hosgood H. Dean , Liu Larry Z. , Lai Hong , Tian Linwei , Chen Wei , Rothman Nathaniel , Lan Qing
Published: August 2012

Introduction: Lung cancer rates in Xuanwei County, Yunnan Province are among the highest in China. We have previously reported that indoor combustion of smoky coal for home heating and cooking was associated with increased risk of lung cancer and that this effect varies markedly by coal type. Further, improved stove ventilation is followed by reduction in lung cancer risk. We explored the joint relationship between tobacco use and coal use in Xuanwei men. Methods: We analyzed data from a population-based case-control study of lung cancer in Xuanwei. Cases were identified from four Xuanwei hospitals and controls were selected from the general population by probability sampling. Controls were matched one-to-one with cases on age. In total, 260 cases and 260 controls were analyzed in this study. Tobacco, coal, and solid fuel exposures were tabulated from questionnaires and reported in cigarette pack-years, duration of smoking, and average tons of coal used annually. Odds ratios and 95% confidence intervals were estimated by conditional logistic regression with the main effects of coal, smoking, and coal-smoking interaction terms. Results: Overall, smoking was positively and significantly, although only modestly, associated with lung cancer risk (OR per pack-year: 1.02; 95% CI: 1.01-1.04). The risk of lung cancer per pack-year of smoking decreased as cumulative lifetime use of smoky coal increased (0-50 tons coal: OR: 1.07; 95% CI: 1.01-1.15; >50-150 tons coal: OR: 1.05; 95% CI: 1.01-1.10; >150 tons coal: OR: 1.00; 95% CI: 0.99-1.03; P-interaction: 0.041). Discussion: Our results suggest that the effect of tobacco on lung cancer risk was weaker in men exposed to higher amounts of coal. Results are consistent with previous cohort study findings in Xuanwei. Constituents of coal combustion, such as polycyclic aromatic hydrocarbons, could plausibly act to diminish the carcinogenicity of tobacco through metabolic competition or other possible mechanisms.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5478. doi:1538-7445.AM2012-5478
Abstract 5489: Feasibility study of gut microbiome collection in randomly sampled women
Authors: Feigelson Heather Spencer , Bischoff Kimberly , Ravel Jacques , Gail Mitchell H. , Flores Roberto , Goedert James J.
Published: August 2012

Systemic estrogen level strongly determines risk for postmenopausal breast cancer (BC). We hypothesize that differences in hormone metabolism by the gut microbiota may contribute to BC risk by modulating enterohepatic circulation of estrogens. We conducted a study to determine the feasibility of enrolling healthy postmenopausal members of Kaiser Permanente Colorado (KPCO) in a fecal microbiome study. With electronic medical records, we created a pool of potentially eligible women aged 55-69 who recently had a negative screening mammogram. We excluded those with any hormone prescription in the prior 12 months, an antibiotic prescription in the prior 6 months, or history of cancer, inflammatory bowel disease or other conditions likely to affect fecal microbiota. A packet (invitation letter, informed consent form, information pamphlet, and opt-out postcard) was sent to 250 randomly sampled women. Women who have not returned the postcard are contacted by KPCO research staff to determine interest in participating, verify eligibility, and obtain verbal informed consent. Consented participants were mailed a second packet with a self-administered risk factor questionnaire, link to an on-line diet questionnaire, collection kit for urine (to measure 15 estrogens) and stool specimens, and shipping instructions to the laboratory. Enrollees have spent an estimated 1-2 hours completing all recruitment and data collection components. To date, 60 (24%) have enrolled, 70 (28%) refused (most via the opt-out card), and the remainder are pending phone contact. As shown in the table, the enrolled women are similar to the total sample; slightly more of them are non-Hispanic white, and they are more likely to have a history of breast biopsy. These data demonstrate that we can successfully recruit an apparently representative sample of women into a microbiome study.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5489. doi:1538-7445.AM2012-5489
Abstract 5491: A history of allergies is associated with reduced risk of oral squamous cell carcinoma
Authors: Stott-Miller Marni , Chen Chu , Doody David R. , Schwartz Stephen M.
Published: August 2012

History of any type of allergy is associated with a decreased risk of multiple types of cancers, including colorectal, cervical, esophageal, pancreatic, stomach, leukemia and glioma. It is proposed that having a history of allergies may prevent cancer by enhancing immune surveillance against tumor cells early in disease development and/or against carcinogenic infectious agents. While a few prior studies suggest an inverse relationship between history of allergies and oral squamous cell carcinoma (OSCC); they did not distinguish between oropharyngeal cancer and oral cavity cancers, and did not account for HPV infection. We compared 400 OSCC cases newly diagnosed between 1985-1995 with 613 general population controls from the Seattle-Puget Sound metropolitan areas with respect to self-reported history of allergy to each of the following: dust, pollen, mold, dogs, cats, bee stings, drugs and food. We estimated odds ratios (OR) and 95% confidence intervals (CI), adjusted for age, education level, sex, race, pack years of cigarette smoking, and lifetime average alcoholic drinks per week. We observed a small inverse association between history of any allergy and OSCC (OR=0.81, 95% CI, 0.61-1.08). This inverse association was present only for dust (OR=0.70; 95% CI,0.43-1.13), pollen (OR=0.72; 95% CI,0.51-1.02) and mold (OR=0.34; 95% CI,0.14-0.83). Additional adjustment for HPV-16 seropositivity did not materially affect the estimates. In exploratory analyses, we examined associations with dust, pollen or mold more closely, and observed stronger associations with oropharyngeal cancer (OR=0.56; 95% CI, 0.35-0.90) than with oral cavity cancer (OR=0.71; 95% CI, 0.49-1.05); although a polytomous regression model did not suggest heterogeneity by site (p=0.5). There was no effect modification by sex, cigarette smoking, alcohol consumption, HPV-16 seropositivity (for all sites or oropharynx alone), or herpes simplex virus 1 seropositivity. The inverse association with dust/pollen/mold was near null for 30 cases of oncogenic HPV DNA-positive oropharyngeal cancer (OR=0.86; 95% CI, 0.38-1.94) and stronger for 46 cases of oncogenic HPV DNA-negative oropharyngeal cancer (OR=0.53; 95% CI, 0.24-1.19). These results suggest that a history of allergies to dust, pollen or mold may confer some protection against OSCC. That the inverse association was particularly apparent for oropharyngeal SCC would be consistent with heightened immune surveillance, due to the substantial amount of lymphatic tissue in this organ. Whether the inverse association involves an immune response to HPV or other antigen, or other carcinogenic mechanism, remains to be determined in more definitive studies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5491. doi:1538-7445.AM2012-5491
Abstract 5513: Treatment and mortality in men with localized prostate cancer: A population-based study in California
Authors: Sieh Weiva , Lichtensztajn Daphne Y. , Nelson David O. , Cockburn Myles , West Dee W. , Brooks James D. , Chang Ellen T.
Published: August 2012

Purpose: To provide patients and physicians with population-based estimates of mortality from prostate cancer or other causes depending upon the primary treatment modality, stratified by patient age, tumor stage and grade. Patients and Methods: We conducted a 10-year competing-risk analysis of 45,440 men diagnosed with clinically localized (T1 or T2) prostate cancer in California during 1995-1998. Information on patient demographics, tumor characteristics, primary treatment and causes of death was obtained from the California Cancer Registry. Results: In this population-based observational cohort, the most common primary treatment was surgery (40.4%), followed by radiotherapy (29.1%), active surveillance (20.8%), and androgen deprivation therapy (ADT) monotherapy (9.8%). Prostate cancer mortality differed significantly (p < 0.0001) across treatment groups among patients <80 years at diagnosis with moderately or poorly differentiated disease. In these patients, the 10-year disease-specific mortality rates were generally lowest for men treated with surgery, ranging from 1.2% (95% CI, 0.8-1.7%) to 11.0% (95% CI, 8.4-14.2%); and highest for men treated with ADT monotherapy, ranging from 3.3% (95% CI, 0.8-12.5%) to 53.8% (95% CI, 34.4-72.2%). Conclusion: Use of ADT monotherapy for localized prostate cancer is not uncommon and should be reconsidered in light of the poor outcomes found in this study, lack of supportive evidence from clinical trials, and potential side effects. Although comparisons of treatment effects based on observational data are subject to confounding by indication, the cause-specific mortality estimates provided in this population-based study can help patients and physicians make management decisions based upon expected outcomes and practice patterns in the general population.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5513. doi:1538-7445.AM2012-5513
Abstract 5522: Analysis of recruitment of non small cell lung cancer patients into clinical trials
Authors: Joubert Richard , Bortini Stefanella , Raeth Ulrich , Moehler Thomas
Published: August 2012

Background: Clinical trials are a major step for the assessment of new molecules or novel treatments that may change the medical practice. Accurate estimation of patient recruitment plays a major role when planning clinical trials with new treatment modalities for non-small cell lung cancer (NSCLC) patients. Method: We performed a systematical review of all published results from NSCLC clinical studies in Journal of Clinical Oncology and Journal of Thoracic Oncology between January 2009 and December 2010 by focusing on the parameters considered to be relevant for patient recruitment: number of patients, sites and enrollment period, indication, Phase of trial, type of study sponsor, geographic region, type of drug and line of treatment. Results: Of 104 studies identified within PubMed, data from 51 studies could be integrated into the final analysis. Fifty-three studies were omitted from this analysis as recruitment data were missing. Most of trials were performed in the metastatic or advanced setting. Overall, a mean enrollment of 0.64 Patient/Month/Site (range, 0.02 to 7.14) was estimated and the highest mean recruitment rate estimated was 1.81 Patients/Month/Site corresponding to 9 single-center studies. The mean enrollment rates in Patient/Month/Site were 0.57 for Phase I trials, 0.78 for Phase II trials and 0.33 for Phase III trials. University-sponsored trials were able to enroll patients with the highest mean rate of 1.48 Patient/Month/Site. Trials conducted in only European sites recruited patients with the highest mean rate of 1.40 Patient/Month/Site (8 studies). The majority of the studies evaluated treatments based on targeted therapy alone or combined with cytotoxic chemotherapy. Thirty-five (69%) studies assessed first-line treatment but the highest recruitment rate of 1.02 Patient/Month/Site was estimated for second- and subsequent lines of treatment. The statistically significant differences were mainly found when comparing the mean recruitment rates for (i) the different types of sponsor and (ii) the number of sites involved in the study. These best recruitment rates were found for University driven studies and in single-center trials. Conclusions: Study design aspects as phase I dose escalation and randomization are systematic burden to patient recruitment. Thorough planning of the study to optimize and adapt the treatment concept used in the study and attract the interest of the investigators and patients are key to recruitment. In that respect, phase II trials on targeted agents as single agents or in combination with high potential to impact the standard treatment showed 2-fold higher than mean enrollment rate for multi-center trials.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5522. doi:1538-7445.AM2012-5522
Abstract 5533: Imaging stromal recruitment during liver metastasis formation in the GFP-MUP-uPA mouse
Authors: Suetsugu Atsushi , Ogata Hisanobu , Moriwaki Hisataka , Saji Shigetoyo , Karin Michael , Hoffman Robert M.
Published: August 2012

Major urinary protein-urokinase type plasminogen activator (MUP-uPA) transgenic mice develop liver disease resembling that described for albumin promoter-uPA transgenic mice. We have developed the GFP-MUP-uPA mice, by crossing MUP-uPA mouse with transgenic C57/BL6 mouse expressing GFP. Hepatocyte fluorescence in this model is relatively weak. In contrast, GFP fluorescence of non-parenchymal cells such as stellate cells, Kupper cells and endotherial cells is very bright green more than parenchymal cells enabling the portal vein and sinusoid structure to be clearly visualized Huh7 liver cancer cells expressing red fluorescent protein (RFP) were injected in the spleen of MUP-uPA transgenic mice. By day 7, the Huh7-RFP celsl were visualized in the liver with the Olympus FV1000 conforcal microscope. The hepatoma cells grew around the sinusoids of the host liver. The liver-metastatic Huh7-RFP cells recruited bright GFP-expressing non-parenchymal cells. This model enables imaging the effects of uPA on liver metastasis and stromal recruitment enabling the metastasis to progress.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5533. doi:1538-7445.AM2012-5533
Abstract 5535: Availability of a newly designed technique, triple-combination array analysis: Identification of estrogen receptor 1 gene in hepatocellular carcinoma using this method
Authors: Hishida Mitsuhiro , Nomoto Shuji , Inokawa Yoshikuni , Hayashi Masamichi , Kodera Yasuhiro
Published: August 2012

Background: Hepatocellular carcinoma (HCC) is one of the top five causes of cancer-related deaths worldwide. Recent developments in the treatment of HCC have failed to treat completely or prevent HCC. Genome-wide gene-expression profile analyses can now detect many candidate genes that are modified by HCC. We have developed a new technique to identify suppressor genes of HCC: triple-combination array analysis. Methods: Triple-combination array analysis, which combines gene expression profiles, single nucleotide polymorphism arrays and methylation arrays, was performed on each HCC tissue sample. Subsequently, samples from 48 HCC patients were subjected to quantitative real-time reverse-transcriptase polymerase chain reaction (PCR) and methylation-specific PCR. Results: Using this method, estrogen receptor 1 (ESR1) was detected as a candidate suppressor gene. Of the 48 clinical samples, 40 (83.3%) showed ESR1 promoter hypermethylation. In 24 (50%) HCC samples, the expression level of ESR1 gene was decreased by >90%, which was significantly related to hepatitis B virus, high liver damage score, and pathological invasion of the intrahepatic portal vein. Conclusions: The present study indicates that triple-combination array is an available and convenient technique for detecting the genes with altered expression in disease, and we suggest that the ESR1 gene acts as a suppressor gene in HCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5535. doi:1538-7445.AM2012-5535
Abstract 5540: Non malignant breast cancer tissue identification scoring system
Authors: Eppenberger-Castori Serenella , Sengstag Thierry , Delorenzi Mauro , Gueth Uwe , Wight Edward , Eppenberger Urs , Terracciano Luigi , Obermann Ellen , Obermann Ellen , Vuaroqueaux Vincent , Zanetti-Daellenbach Rosanna
Published: August 2012

Abstract: Introduction. Molecular pathology tools are increasingly important in routine diagnostic. Histological determination remains mandatory, while gene expression profiles (GEP) are successfully classifying breast cancer specimens also when minimal amount of tissue, such as core biopsies (CB), is available. The limit of this application resides however in the fact that the part of material used for RNA extraction could not represent the entire biopsy. To overcome this problem in the present work we calculated an algorithm for the identification of malignant cells in a giving CB. Patients and methods. The quantitative expression levels of 60 selected genes representative for relevant pathways in breast cancer (BC) oncogenesis were assessed by real time PCR in a total of 106 CB samples obtained from patients with neoplasia or invasive BC and in 12 biopsies with known good differentiation grade (Grade 1). The GEP of 48 CBs and of the 12 Grade 1 specimens were used as training set to build the scoring system based on the Welsh variant of t-test and best-fit logistic curves. The remaining GEPs were used as validation set. Results. A 15-genes classifier was built and cross-validated with 1000 iterations of a leave −10% out in which each of the 10 subset is used. The 15 genes were representative for proliferation (thymidine phosphorylase and E2F1), cell matrix degradation (CTSD, MMP1, MMP11, PLAU, PLAUR, SERPINE1), as well as angiogenesis (VEGFA, VEGFD, TGFbeta1). EGFR and GSTP1 were also part of this classifier able to discriminate non-malignant from malignant breast tissue with an accuracy of almost 90%. Discussion. The calculated classifier, which could also be reduced to only six genes, is robust and useful in the discrimination of malignant from non-malignant breast cancer tissue. Such an algorithm identifying normal proliferation rate and inability of invasion should be integrated in the evaluation of GEP data from microarrays before using them for other predictive purposes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5540. doi:1538-7445.AM2012-5540