bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 449: Detection of some selected tumor markers in people from River Nile State - Sudan
Authors: Ali Eltayeb A. , Hassan Osman Mahgoub , Ahmed Mohamed Abdallah
Published: August 2012

This study was designed to use some selected tumor markers (TMs) as screening tool to discover new cancer cases, and to use these TMs as diagnostic tool for early detection of cancer. The study area is the River Nile State with an area of 122100 Km2 and population of 1026000 persons. The national cancer control program was initiated in 1982 with WHO help, and updated in the early 1990s based on the new WHO guidelines. In 2010 the National Cancer Registry was established but still more efforts are needed to register all cancer cases in such a poor country like Sudan. According to Federal Ministry of Health (FMOH) 2008 data; cancer was ranked as the fourth cause of death in hospitals. Five hundred and ten blood samples were collected from healthy people living in River Nile State; 305 samples were males. (PSA) was measured in all males, (CA125) was used for ovarian cancer in females, (CA15-3) was used for breast cancer in females, and (CEA) Carcino Embryonic Antigen was used for colon cancer in both genders. Samples were measured using RIA technique. Written consent was obtained from all volunteers. There was an elevation in blood level of CEA in 26 samples (6.37%), two of them died during the study, 7 (2.29%) males had PSA concentrations above the upper limit, 5 (2.45%) females showed high CA15-3 concentrations, and increase in CA125 in 6 samples (2.94%). Out of the 510 subjects there were 56 samples (10.98%) had family history with cancer, and only 6 of them (10.71%) showed elevated concentrations. Most of these people are very poor and hospitals are not accessible and the diagnosis and treatment services are not affordable. Table 1 shows the concentrations for the selected TMs.The FMOH documented in 2007 that more than 345 cancer patients came from River Nile State, more cases were reported in other studies e.g. 2899 cancer incidences in Northern Sudan in 2006. In the present study, (8.63%) of the studied population showed elevated concentrations of the selected TMs. Table 1: TMs concentrations.

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 449. doi:1538-7445.AM2012-449
Abstract 4492: Colorectal cancer survival by molecular subtypes in a population-based cohort of older women
Authors: Vierkant Robert Alan , Tillmans Lori S. , Wang Alice H. , Samadder Niloy Jewel , Weisenberger Daniel J. , Laird Peter W. , Lynch Charles F. , Anderson Kristin E. , French Amy J. , Haile Robert W. , Harnack Lisa J. , Potter John D. , Slager Susan L. , Smyrk Thomas C. , Thibodeau Stephen N. , Cerhan James R. , Limburg Paul J.
Published: August 2012

Background: Despite recent advances in prevention and therapy, colorectal cancer (CRC) continues to account for nearly 50,000 deaths per year in the US. TNM stage is the current CRC prognostic standard, yet within-stage prognostic heterogeneity is well documented. Microsatellite instability (MSI), CpG island methylation phenotype (CIMP), and BRAF- and KRAS-mutation status represent candidate prognostic markers. However, associations between these markers and CRC survival have not been described in a population-based setting. Methods: Data and tissue resources were obtained from the Iowa Women's Health Study (IWHS), which recruited 41,836 women, ages 55-69 years, at study entry (1986). Incident CRC cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected from 732 representative CRC cases diagnosed through 12/31/2002. Established laboratory methods were used to characterize CRC cases: MSI-H or MSS/MSI-L (by instability in β3 vs. <3 out of 10 markers, respectively); CIMP+ or CIMP− (by promoter hypermethylation in β3 vs. 0-2 out of 5 genes, respectively); BRAFwt or BRAFmut (by fluorescent allele specific PCR to detect the V600E point mutation in exon 15); and KRASwt or KRASmut (by direct sequence analysis of codons 12 and 13 in exon 2). Cox regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for time to death of any cause adjusted for age, stage, grade, and treatment status. Results: CRC cases with informative molecular marker data ranged from 515/732 (70%) for KRAS to 548/732 (75%) for MSI status. Mean follow-up was 4.4 years for deceased individuals and 11.2 years for women alive at last contact. After multivariable adjustment, both MSS/MSI-L (p=0.004) and KRASmut (p=0.048) tumors were associated with poorer survival. Survival did not significantly differ across levels of CIMP and BRAF status. Conclusions: MSI and KRAS status may influence CRC survival among older women.

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 4492. doi:1538-7445.AM2012-4492
Abstract 4496: UBCH10 overexpression in human colorectal cancers
Authors: Piscuoglio Salvatore , Pallante Pierlorenzo , Tornillo Luigi , Fusco Alfredo , Terracciano Luigi Maria
Published: August 2012

Background: Colorectal cancer is the result of the accumulation of different genetic modifications including critical genes involved in the control of cell proliferation. In a large number of carcinomas with worst prognosis, lesions are not diagnosed until the disease is at an advanced stage. To diagnose cancer at an early stage and to establish more effective therapies featuring of key molecules in carcinogenesis is a critical steps. UBCH10 (also known as E2C or UBE2C) is a cell cycle-related protein involved in mitosis completion. UbcH10 participates in proper metaphase to anaphase transition, and abrogation of UbcH10 results in the premature separation of sister chromatids. Thus, UbcH10 is essential for cell cycle progression, and his expression is cell-cycle dependent and related to proliferation Aims: The aim of this study is to investigate the association of UbcH10 gene expression with clinicopathological features and tumor progression of colorectal cancer. Materials and methods: We investigated the expression of the UBCH10 genes in a tissue microarray platform consisting of normal and neoplastic colorectal cancers (CRC) tissues by immunohistochemistry. UBCH10 was detectable in 889 patients. Immunoreactivity was scored semi-quantitatively by evaluating the number of positive tumor cells over the total number of tumor cells. Scores were assigned using 5% intervals and ranged from 0% to 100%. Median protein expression levels were used as cut-off scores to define protein marker positivity and the findings were associated with clinical-pathological parameters. Results: Our results demonstrated that UBCH10 is over-expressed in CRCs tissues compared to normal colon (p<0,001), and more specifically the UBCH10 expression is significant higher in tumor location: left VS. right sided (p=0,005). Moreover we found a significant relationship between overexpression of UBCH10 with T stage (p<0,001), N stage (p=0.022), tumor border configuration: pushing VS. infiltrating (p=0.035) and also UBCH10 over-expression was significantly correlated with shorter patient survival. Conclusion: Our study suggests that the overexpression of UbcH10 gene plays a critical role in the carcinogenesis and tumor progression of colorectal cancer. Also our findings indicate, that in colorectal carcinomas, low expression of UBCH10 may be linked to a more aggressive tumor phenotype.

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 4496. doi:1538-7445.AM2012-4496
Abstract 4499: Loss of ATM (distal chromosome 11q) as a prognostic marker in HPV-negative head and neck squamous cell carcinomas
Authors: Parikh Rahul A. , Lewis Dale W. , Gollin Susanne M.
Published: August 2012

Introduction: HPV-negative head and neck squamous cell carcinomas (HNSCC) represent a subset of head and neck cancers with poor response to treatment and worse prognosis compared to HPV-positive HNSCC. In our prior pre-clinical experiments with HNSCC cell lines, we demonstrated that copy number loss of ATM as a marker for loss of distal chromosome 11q loss leads to defectiveγ-H2AX focus formation, increased chromosomal instability, and reduced sensitivity to ionizing radiation. We hypothesize that in HPV-negative HNSCC, ATM loss is a biomarker for poor outcome. Methods: We performed a single center, retrospective analysis of 42 HNSCC patients to determine if ATM loss is associated with poor overall survival in HPV-negative HNSCC. We performed fluorescence in situ hybridization using probes to cyclin D1 (CCND1) and ATM to assess copy number changes in paraffin sections from HNSCC tumors. Disease-specific survival was defined as time from the date of tissue procurement (surgery or biopsy) until death from disease (HNSCC). Patients who were alive at last follow-up or had died from causes unrelated to their disease were censored. Disease-specific survival by ATM loss status was estimated by the Kaplan-Meier method and tested for a difference by a two-tailed log rank test. Three covariates, age, T stage and N stage were investigated and the effect of ATM loss upon disease-specific survival was assessed with proportional hazards regression by adjusting for these covariates as needed to determine if ATM loss could be considered independently associated with cancer mortality. Results and Conclusions: HPV-negative HNSCC patients with ATM copy number loss have a median disease-specific survival of only 19 months compared to 65 months for patients without ATM loss (log rank p = .0401). We investigated whether the association between ATM loss and disease-specific survival was due to the confounding influence of other clinical variables. Age and T stage were modestly associated with survival, but neither covariate was correlated with ATM loss. We estimated the hazard ratio for ATM loss alone and conditional upon age and T stage was unchanged (.040 alone vs .047 adjusting for age and T stage). Therefore, distal 11q loss, marked by copy number loss of ATM appears to increase the risk of disease-specific mortality independently of age, N stage and T stage. Our results demonstrate that ATM loss in HPV-negative HNSCC may be prognostic of poor outcome and novel therapeutic strategies may be required in this subset of patients. Further studies to elucidate the mechanisms of distal 11q loss and study potential treatment options are underway in our laboratory.

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 4499. doi:1538-7445.AM2012-4499
Abstract 450: Smad interacting protein 1 (SIP1) is associated with peritoneal carcinomatosis in intestinal type gastric cancer
Authors: Okugawa Yoshinaga , Tanaka Koji , Inoue Yasuhiro , Kawamura Mikio , Matsushita Kouhei , Kawamoto Aya , Hiro Junichro , Saigusa Susumu , Toiyama Yuji , Ohi Masaki , Uchida Keiichi , Mohri Yasuhiko , Hori Hiroki , Kusunoki Masato
Published: August 2012

Purpose. Smad interacting protein 1 (SIP1) encodes a transcription factor and is one of the epithelial-mesenchymal transition (EMT)-inducible genes that play a key role in tumor progression in various cancers. The aim of this study is to clarify the clinical significance of SIP1 expression in gastric cancer patients, and to clarify its biological function especially in intestinal type gastric cancer. Methods. We studied one hundred thirty-four patients undergoing surgery for gastric cancer. We analyzed SIP1 mRNA levels by real-time reverse transcription PCR in gastric cancer tissue and adjacent normal mucosa, and in gastric cancer cell lines. SIP1 protein expression in primary cancer and in peritoneal dissemination samples was measured using immunohistochemical analysis. Knockdown of the SIP1 gene by siRNA transfection was performed to evaluate SIP1 function in gastric cancer cell. Results. Expression of the SIP1 gene was significantly higher in cancerous tissue than in adjacent normal mucosa (p<0.05). Increased SIP1 expression was significantly associated with peritoneal dissemination (p<0.05), and was an independent prognostic factor (risk ratio, 2.17; 95% confidence interval, 1.26-3.74; p<0.05). Logistic regression analysis revealed that increased SIP1 expression was an independent risk factor for peritoneal dissemination (odds ratio, 3.43; 95% confidence interval, 1.25-9.43; p<0.05). Especially in intestinal type gastric cancer, elevated SIP1 expression was significantly correlated with peritoneal dissemination and poor prognosis (p<0.05). Immunohistochemical analysis indicated that SIP1 was intensely expressed in both primary cancer and peritoneal dissemination samples. In vitro, cell proliferation, migration and invasion were inhibited by SIP1 knockdown, while resistance to anoikis was decreased after knockdown of SIP1 in the intestinal type gastric cancer cell line MKN7. Conclusion: High SIP1 expression is associated with poor prognosis especially in intestinal type gastric cancer patients and enhanced malignant potential in terms of proliferation, migration, invasion and anoikis inhibition in intestinal type gastric cacner cell. These results indicate that SIP1 plays an important role in progression to peritoneal carcinomatosis in intestinal type gastric cancer.

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 450. doi:1538-7445.AM2012-450
Abstract 4507: Deletion of 9p21.3/p16/CDKN2A is associated with poorer survival in primary central nervous system (PCNSL) lymphoma independent of 6q22 effect. A study facilitated by the Surveillance, Epidemiology and End Results Tissue Repository Program (SEER TRP)
Authors: O'neill Brian Patrick , Decker Paul A. , Macon William R. , McPhail Ellen D. , Law Mark , Cerhan James R.
Published: August 2012

Objective. Molecularly distinct PCNSL signatures with divergent clinical behavior are now recognized. Implied within this heterogeneity are mechanisms for treatment response and pattern of failure. Recent cytogenetic and genomic studies demonstrated influences of select chromosomal regions on outcome to treatment and survival. These included genetic and epigenetic alterations affecting CDKN2A (9p21.3) that distinguished PCNSL from its systemic counterpart. We now report that deletion of 9p21.3/p16 is associated with a negative effect on survival. Methods and Patients. Well-annotated and population-based formalin fixed paraffin embedded (FFPE) patient samples were sourced from the SEER TRP. Specimens were retrieved from the Hawaii, Iowa and Los Angeles County (LA Co) tissue repositories. “Home Brew” fluorescent in situ hybridization (FISH) probes for BCL6, and ptpr-α were prepared according to a standard protocol (Cady et al. J Clin Oncol 2008;26:4814-9). FISH probes for 9p.21 were prepared similarly and then compared to a commercially available probe. Survival was based on the SEER TRP clinical annotations. Results. Thirty five patients were sourced - twelve from Iowa, 13 from Hawaii, and 10 from LA County. The test cohort was 23 from Iowa and Hawaii; the FISH probe failed in 9 and three had insufficient remaining tumor for analysis. For the Iowa and Hawaii registries and for the registries combined the lack of FISH probe detection of 9p.21/p16 correlated with survival (p=0.0159) and was independent of BCL6 (p=0.8788) and ptpr-α (p=0.3724). Conclusion. Deletion of p16 confers a negative effect on survival of PCNSL patients and appears to be independent of treatment, age, BCL6 and ptpr-α status. These results need to be confirmed in a larger sample size. 9p21.3 detection by FISH in feasible in surgical specimens and may aid in the stratification of such patients into different and/or more intensive treatment regimens.

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 4507. doi:1538-7445.AM2012-4507
Abstract 4508: Oxidative protein modifications in serous epithelia ovarian cancer tissues
Authors: Mehrabi Sharifeh , Vatcharapirjon Yupha , Mehreteab Tesfamariam , Adams Gregory , Aikhionbare Felix O.
Published: August 2012

Despite advances in the surgical and chemotherapeutic management of ovarian cancer over the last decade, survival rates remain low, largely due to late diagnosis. Up to now very few candidate biomarkers have been investigated for early detection of ovarian cancer. The implication of ROS in female reproductive system and ovarian cancer are evidenced. Enzymatic antioxidants neutralize excessive ROS in cells. Under special condition, the cellular antioxidants are depleted. The ultimate aim of this study is to identify a biomarker for early detection of ovarian cancer. In this study 155 snap-freeze primary serous epithelial ovarian tissues including, normal, normal surrounding, cystadenoma, borderline and carcinoma with age range of 65±12,(55% Caucasian 45% Africa American), were analyzed. The objectives are: (a) to evaluate the protein expression profiles using two dimension gel electrophoresis (2-D SDS-PAGE) and LC/MS technology, (b) to identify and evaluate the level of oxidative modified protein, using derivatisation of protein carbonyl group with 2,4-dinitrophenylhyrdozine(DNPH) assay and western blot technique. Our results showed that the index of carbonyl protein /total protein increased by onset and progression of the serous ovarian malignancy. The elevation of oxidized protein among African American was 40 % higher than Caucasian in advanced stages of diseases. SDS-PAGE profiles showed a distinct protein pattern among cancerous and non-cancerous tissues. LC/MS analysis for elucidation of molecular changes of selected proteins bands is in 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 4508. doi:1538-7445.AM2012-4508
Abstract 4512: AT rich interactive domain 3A (ARID3A) overexpression correlates with good prognosis in colorectal cancer
Authors: Song Meiying , Shin Chang Hoon , Park Misun , Kim Hoguen , Kim Hyunki
Published: August 2012

AT Rich Interactive Domain 3A (ARID3A) is a member of the ARID family of DNA-binding proteins. Previous studies have shown that ARID3A controls the cell growth through p53-dependent manner, whereas its significance in the prognosis of colorectal cancer (CRC) is not yet fully understood. In this study, formalin-fixed, paraffin-embedded tumors and matched normal mucosae from 690 patients who underwent surgery for CRC were constructed into tissue microarrays. The expression of ARID3A was investigated by immunohistochemistry. We detected a nuclear positive expression of ARID3A in a subset of colorectal cancers, whereas ARID3A was completely negative in all normal mucosae. Of the 690 cases, 195 tumors (28.3%) were strong positive for ARID3A, 187 tumors (27.1%) were weak positive and 308 tumors (44.6%) were negative. We examined p53 expression status by immunohistochemistry simultaneously. Among the 690 tumors, 358 tumors (51.9%) were positive for p53 expression and 332 tumors (48.1%) were negative for p53 expression. Kaplan-Meier method and Cox proportional hazards modeling were used to analyze the overall survival between ARID3A negative or weak expression group and ARID3A strong expression group. The ARID3A expression in CRCs was significantly correlated with age (P=0.003), degree of differentiation (P<0.001), depth of invasion (P=0.001), lymph node metastasis (P=0.008), distant metastasis (P=0.007), TNM stage (P<0.001), status of microsatellite instability (P<0.001), and CEA levels (P=0.003). Moreover, the strong expression of ARID3A and the negativity of p53 were statistically correlated (P=0.045). The survival of CRC patients with ARID3A strong expression was significantly longer than that of patients with ARID3A negative or weak expression (P=0.002), however the effect of ARID3A on the survival rate of CRCs might differ by p53 status. Combined analysis of ARID3A and p53 expression indicated that CRC group with ARID3A-strong positive and p53-negative showed better prognosis compared with the remaining groups (P=0.003). On multivariate analysis, ARID3A overexpression was proven to be an independent predictor for better prognosis in CRC (95% CI: 0.44-0.96; P=0.031). In conclusion, this study strongly suggests the usefulness of ARID3A as a biomarker to predict the prognosis of colorectal cancer.

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 4512. doi:1538-7445.AM2012-4512
Abstract 4515: Low serum levels of a novel anti-inflammatory fatty acid as a new risk factor for colorectal cancer
Authors: Ritchie Shawn A. , Tonita Jon , Alvi Riaz , Lehotay Denis , Elshoni Hoda , McHattie James , Goodenowe Dayan
Published: August 2012

Low serum levels of novel, long-chain, hydroxylated and polyunsaturated fatty acids (GTAs) in colorectal cancer (CRC) patients has been previously reported. This study prospectively investigated the relationship between serum GTA levels and CRC incidence among subjects undergoing colonoscopy. Serum samples and pathology data were collected from 4923 representative subjects undergoing colonoscopy in a typical, non-screening, colonoscopy population and from 964 representative age and geographically-matched subjects from the general population. Serum GTA-446 levels were determined on all subjects using a sensitive tandem mass spectrometric method. A low serum GTA-446 level was defined as a GTA-446 concentration below the tenth percentile of 40-49 year-olds in the general population sampling. Eighty-six percent of newly diagnosed CRC subjects (87% for stage 0-II and 85% for stage III-IV) were observed to have low serum GTA-446 levels, with a PPV of 15% and NPV of 99.7%. CRC incidence was observed to increase significantly with age in all subjects (p<0.05) and in low GTA-446 subjects (p<0.05), but not in subjects with normal serum GTA-446 levels (p=0.86). The CRC incidence rate in subjects with low GTA-446 levels (3.1%) was over six times higher than for subjects with normal GTA-446 levels (0.5%) and approximately twice that of subjects with GI symptoms (2.0%). The results indicate that a low serum GTA-446 level is a significant risk factor for CRC and a sensitive predictor of early-stage disease, and that low-GTA levels could be responsible for the age-associated increase in CRC incidence. Implications for population-wide screening are discussed.

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 4515. doi:1538-7445.AM2012-4515
Abstract 4516: Gene expression analysis as a biomarker study for ACTS-CC trial (TRICC0706), a phase III trial for adjuvant chemotherapy of S-1 and UFT/LV against stage III colon cancer in Japan
Authors: Uetake Hiroyuki , Ishikawa Toshiaki , Matsui Shigeyuki , Sugihara Kenichi
Published: August 2012

Background: The ACTS-CC trial is a phase III trial designed to validate non-inferiority of S-1 to UFT/ LV, a standard treatment in Japan as adjuvant chemotherapy for stage III colon cancer and the initial safety report of the trial was reported in ASCO 2011. In biomarker study of ACTS-CC trial, gene expression levels were studied using formalin fixed and paraffin embedded (FFPE) specimens. Methods: Blocks from resected colorectal cancer specimens were obtained under informed consent for this biomarker study from 892 patients enrolled between Apr.2009 and Jan.2010. Gene expression levels of 11 enzymes (TS, DPD, TP, OPRT, FPGS, GGH, DHFR, MTHFR, MTHFD, FOLRA, GART), that correlate to 5-FU and folic acid metabolism, are studied according to Danenberg Tumor ProfileTM method (Shirota, Y. JCO 2001). Correlation coefficients between gene expressions of the 11 enzymes were computed using Spearman rank correlation test (Rs). Results: Gene expression levels were successfully estimated in 521-808 samples (84.0-90.0%, 89.4% in median). Highest Rs was observed between DPD and TP (0.68. 95% confidence interval; 0.64-0.71). Classifying Rs value into 3 groups (positive (0.5<), week (0.31-0.50) and negative (0.3 or less)), TS and OPRT had positive or week correlation with 4 of 7 metabolic enzymes of folic acid (DHFR, MTHFR, MTHFD, and GART). Conclusions: This is the first and largest gene expression analysis for metabolic enzymes of 5-FU and folic acid. Positive correlation was observed between gene expression level of DPD and TP, which are DNA catabolic enzymes. Gene expression level of TS and OPRT, which are DNA synthetic enzymes, had correlation with metabolic enzymes of folic acid.

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 4516. doi:1538-7445.AM2012-4516
Abstract 4524: Characterization of 28 patient derived colorectal cancer xenografts and analysis for response markers to an antiangiogenic treatment
Authors: Rivera Maria , Becker Michael , Schlag Peter M. , Schwan Alexandra , Merk Johannes , Rosenthal Andre , Hinzmann Bernd , Hoffmann Jens , Fichtner Iduna
Published: August 2012

We have recently described an extended panel of new primary human CRC xenografts and their preclinical chemo-sensitivity to anti-cancer drugs (Poster 1584/3 AACR Annual Meeting 2010). These models consider more thoroughly the heterogeneity and genetic instability of tumors in a way ultimately enabling treatment decisions on an individualized basis. The approach is based on large scale screening for activity in new in vivo models combined with extensive characterization of these models (gene expression and mutations). Bioinformatic methods are used to further evaluate the mechanism of action of new drugs in colorectal cancer, to investigate possible resistance mechanisms and provide a rationale for combination therapies. Here we describe the evaluation of an antiangiogenic treatment in this panel of primary patient derived colorectal cancer models. Primary colon carcinoma tissue samples were collected using a standardized procedure. Tumor pieces were transplanted into immunodeficient mice immediately after surgery. A panel of 28 stably passagable colon cancer xenografts could be established as permanent tumor models. The results obtained so far, show that these patient-derived colon cancer models feature a high coincidence with the original tumor regarding histology and gene expression profiling. Response analysis in a subset of 19 xenografts evaluating the treated-to-control (T/C) ratios of tumor volumes revealed that the human specific VEGF antibody bevacizumab induces a meaningful biological effect (T/C below 50%) in 13 of 19 models. A first comparative genome-wide gene expression analyses of this subset revealed reasonable genes and pathways possibly involved in bevacizumab sensitivity. We will extend this investigation to all 28 tumor models in order to enhance the statistical robustness of the preliminary data. Our approach demonstrates that analysis of drug sensitivity together with bioinformatics correlations can provide candidate markers for further studies. An early implementation of such an approach in the drug development process could be helpful for the identification of predictive markers helping to select tumors likely to benefit from the drug as well as provide a rationale for combinations to be tested in clinical trials. These new strategies may help to better integrate research results in clinical development and may increase the success of new anti-cancer drugs in clinical 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 4524. doi:1538-7445.AM2012-4524
Abstract 453: Prognostic value of 18F-FDG PET/CT in nasopharyngeal carcinoma
Authors: Huang Ying , Xiao WeiWei , Su ShengFa , Chen Yong , Han Fei , Teh Bin S. , Lu TaiXiang
Published: August 2012

Background: To investigate the prognostic value of pretreatment tumor maximal standardized uptake (SUVmax) values of 18F-FDG PET/CT in nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT). Methods: Consecutive biopsy-proven, non-metastatic NPC patients undergoing pretreatment 18F-FDG PET/CT and receiving IMRT from 2002 to 2005 were retrospectively reviewed. SUVmax of primary tumor (SUVmax-T) and regional lymph nodes (SUVmax-N) was measured. Survival was estimated using the Kaplan-Meier method. Prognostic significance was assessed using univariate and multivariate analyses. Results: One hundred sixty-nine eligible patients were enrolled, with 132 male and 37 female. Median age was 42 years. The distribution of stages was 14 for I, 39 for II, 61 for III and 55 for IV. Median SUVmax-T was 4.0 and median SUVmax-N was 3.5. Median follow-up was 71 months. Thirty five patients died and distant metastasis was the main reason of death (71.4%). Among 134 living patients, most patients are disease free (92.6%). In univariate analysis, older age, advanced T stage, advanced N stage, advanced clinical stage, higher SUVmax-T and higher SUVmax-N were all associated with lower OS, DFS and DMFS (Table 1). Remarkably, multivariate analysis found SUVmax-T and SUVmax-N were significant prognostic factors for OS, DFS and DMFS, independent of T and N stage (Table 1). Conclusion: SUVmax-T and SUVmax-N have prognostic value for survivals in IMRT-treated NPC patients. High FDG uptake in primary tumor and regional lymph nodes are useful for the identification of patients at higher risk. Abbreviations: OS, overall survival; DFS, disease-free survival; DMFS, distant metastasis-free survival; uni, univariate analysis; multi, multivariate analysis Table 1.

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 453. doi:1538-7445.AM2012-453
Abstract 4531: Fucosylated haptoglobin is a novel type of cancer biomarker linked to the prognosis after an operation in colorectal cancer
Authors: Shinzaki Shinichiro , Takeda Yuri , Moriwaki Kenta , Murata Kohei , Miyoshi Eiji
Published: August 2012

Background: Fucosylation is a crucial oligosaccharide modification in cancer and inflammation. Total cellular proteins of cancer cells and the sera of patients with cancer both show increased fucosylation levels. Certain kinds of fucosylated proteins can be applied as novel cancer biomarkers in glyco-proteomic analyses. We previously identified fucosylated haptoglobin (Fuc-Hpt) as a serologic marker for pancreatic cancer, and recently developed a lectin-antibody enzyme-linked immunosorbent assay system for quantifying Fuc-Hpt. In the present study, we investigated the clinical outcome of Fuc-Hpt levels in patients with colorectal cancer (CRC), and examined the mechanisms underlying Fut-Hpt production using a murine tumor transplantation model. Methods: The relationship between Fuc-Hpt levels and clinical parameters was investigated in 77 patients with CRC, all of whom underwent primary resection. Serum Fuc-Hpt levels were examined in athymic nude mice injected with colon cancer cell lines that lacked fucosylation. Results: Fuc-Hpt levels were significantly associated with overall and relapse-free survival, distant metastasis, clinical stage, and curability. Multivariate analysis revealed that distant metastasis was an independent factor for increased Fuc-Hpt levels. The combination of Fuc-Hpt and CEA might be a better serologic marker to predict prognosis. Fuc-Hpt levels were higher in mice with direct injection of tumor cells into the spleen than in those injected subcutaneously. Conclusions: Fuc-Hpt might be a useful marker for the prognosis of CRC. Fuc-Hpt could be produced by the tissue surrounding tumor cells, which might be the mechanism underlying Fuc-Hpt elevation associated with distant 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 4531. doi:1538-7445.AM2012-4531
Abstract 4533: Characteristics of HS6ST2 expression in colorectal cancer
Authors: Kimura Hideharu , Hatabe Shigeru , Arao Tokuzo , Hayashi Hidetoshi , Nagai Tomoyuki , Matsumoto Kazuko , Fujita Yoshihiko , Fukushima Masao , Ito Akihiko , Okuno Kiyotaka , Nishio Kazuto
Published: August 2012

Background. We have found that the gene expression of heparin sulfate D-glucosaminyl 6-O-sulfotransferase-2 (HS6ST2) is overexpressed in colorectal cancer in a previous study. Aims of this study are to evaluate the HS6ST2 expression in colorectal cancer tumor samples in relation to the clinicopathological features. Methods. The mRNA expression levels of HS6ST2 were analyzed in various cancer cell lines using real-time RT-PCR. HS6ST2 protein expression was evaluated using immunohistochemistry. Tumor specimens were obtained from 103 colorectal cancer patients operated in Kinki University Hospital. Results. High mRNA expression was observed in 2/15 (13%) of gastric cancer and 3/6 (50%) of colorectal cancer cell lines. In immunohistochemistry analysis, cytoplasm staining was found in cancer cells, not in normal colon cells, and positive staining of HS6ST2 expression was seen in 37 patients (36.3%). There were no relationships between clinicopathological features and HS6ST2 expression in cancer cells. Colon cancer patients with HS6ST2 expression tend to have worse overall survival (p = 0.097, Log-rank test).Conclusion. The cytoplasm expression of HS6ST2 is tumor-specific in colon tissues. HS6ST2 may contribute to be worse 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 4533. doi:1538-7445.AM2012-4533
Abstract 4568: Estrogen receptor and progesterone receptor immunocytochemistry staining in circulating tumor cells as compared to primary tumor or metastatic biopsy
Authors: Mayer Julie Ann , Pircher Tony J. , Pham Tam , Wong Karina , Villarin Eligie , Bischoff Farideh Z.
Published: August 2012

Introduction: Hormone receptor (estrogen receptor (ER) and progesterone receptor (PR)) status in all breast cancer patients is recommended by immunohistochemistry (IHC) and is considered standard practice for selection of treatment options. However, the analytical sensitivity of IHC in detecting low levels of ER/PR is often poor and likely due to methodological variation. Because biopsy is not often feasible in all patients presenting with recurrent and/or metastatic breast disease, circulating tumor cells (CTCs) offer an attractive alternative source of tumor tissue for determining ER/PR status and can be monitored more readily to enable a more effective course of treatment. Experimental Design: Twenty ml of peripheral blood was collected prospectively from 14 patients diagnosed with late stage metastatic/recurrent breast cancer. CTCs were isolated using the microfluidic OncoCEETM platform. A cocktail of antibodies was utilized for CTC capture and detection with an expanded anti-cytokeratin (CK) cocktail mixture and anti-CD45. ER/PR protein expression was assessed by immunocytochemistry (ICC) on the cells captured within the microchannels and compared to IHC performed on the primary tumor or metastatic biopsy. Results: CK+/CD45-/DAPI+ cells were located and assessed for ER/PR immunocytochemistry. Among the 14 cases a high concordance (12/14; 86%) in ER/PR status between primary tumor/metastatic biopsy and CTCs was observed. Two cases were found to be discordant where one was positive by IHC and negative on the CTCs and the other was negative on by IHC on the primary tumor/metastatic biopsy and positive on the CTCs. However, both cases that were discordant had low numbers of CTCs detected. Conclusions: There is significant heterogeneity between ER/PR protein expression in CTCs and primary tumor/metastatic biopsy and this status may change over time due to therapy. ER/PR ICC on CTCs from peripheral blood using the OncoCEETM platform is shown to be feasible with high concordance (86%) in ER/PR status between primary tumor/metastatic biopsy (by IHC) and CTCs (by ICC). The significance of heterogeneity at the ER/PR protein level in CTCs ascertaining to the prognosis and predictive response to anti-estrogen therapy needs further evaluation in larger prospective clinical 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 4568. doi:1538-7445.AM2012-4568
Abstract 457: Significance of angiotensin targeting on treatment of liver metastasis in colorectal cancer patients with diabetes
Authors: Kuniyasu Hiroki , Luo Yi , Chihara Yoshitomo , Ohmori Hitoshi , Fujii Kiyomu , Yoshikawa Motokiyo , Kuwata Masaomi , Fujimoto Kiyohide , Hirao Yoshihiko , Kitadai Yasuhiko
Published: August 2012

We examined the effects of hyperglycemic conditions on liver metastasis of colorectal cancer (CRC). Angiotensin (AT)-II increased growth, invasion, and anti-apoptotic survival in HT29 and CT26 cells. In contrast, angiotensinogen (ATG) increased these features in HT29 cells but not in CT26 cells. HT29 cells expressed AT-II type 1 receptor, chymase, and rennin, whereas CT26 cells did not express renin. Renin expression and ATG-induced cell growth, invasion, and survival induced and increased as glucose concentration increased in HT29 cells and also CT26 cells. An inhibitor of renin or chymase abrogated A-II production in both cells. Reduction of hepatic ATG production by knockdown suppressed liver metastasis of HT29 cells. An examination of 121 CRC patients showed that diabetes in CRC cases was associated with higher blood HbA1c, higher renin and AT-II concentrations in the primary tumors, and higher incidence of liver metastasis than in nondiabetic cases. These results suggest that diabetes-associated AT activation enhances liver metastasis of CRC. We then examined an antimetastatic therapy by anti-AT treatments in CRC. In a streptozotocin-induced BALB/c mouse diabetes model that was fed a high-calorie diet, the blood sugar level increased and was associated with enhanced CT26 liver metastases. In this diabetic mouse model, liver metastasis of CT26 cells was suppressed by anti-AT treatment with a chymase inhibitor, a renin inhibitor, and an AT-II receptor blocker. Moreover, concurrent hypoglycemic and anti-AT treatments showed a synergistic inhibitory effect on CT26 cell liver metastasis. These results suggest that AT activation ability associated with diabetic conditions enhances liver metastasis of colon cancer. Therefore, treatment with anti-AT and hypoglycemic agents might be relevant for suppressing liver metastasis. This scheme should be examined in a clinical setting.

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 457. doi:1538-7445.AM2012-457
Abstract 4572: Frequent MLL3 frameshift mutations in microsatellite-deficient colorectal cancer
Authors: Watanabe Yoshiyuki , Castoro Ryan J. , Kim Hyun Soo , Kleb Brittany , Oikawa Ritsuko , Hiraishi Tetsuya , Ahmed Saira S. , Chung Woonbok , Cho Mee-Yon , Toyota Minoru , Itoh Fumio , Estecio Marcos R. H. , Shen Lanlan , Jelinek Jaroslav , Issa Jean-Pierre J.
Published: August 2012

Background: MLL3 is a histone 3- lysine 4 methyltransferase with tumor-suppressor properties that belongs to a family of chromatin regulator genes potentially altered in neoplasia. Mutations in MLL3 were found in a whole genome analysis of colorectal cancer but have not been confirmed by a separate study. Methods & Results: We analyzed mutations of the coding region and promoter methylation in MLL3 using 126 cases of colorectal cancer. We found two isoforms of MLL3 and DNA sequencing revealed frameshift and other mutations affecting both isoforms of MLL3 in colorectal cancer cell lines and 19 of 134 (14%) primary colorectal samples analyzed. Moreover, frameshift mutations were more common in cases with microsatellite instability (31%) both in CRC cell lines and primary tumors. The largest isoform of MLL3 is transcribed from a CpG island-associated promoter that has highly homology with a pseudo-gene on chromosome 22 (psiTPTE22). Using an assay which measured both loci simultaneously we found prominent age related methylation in normal colon (from 21% in individuals less than 25 years old to 56% in individuals older than 70, R=0.88, p<0.001) and frequent hypermethylation (83%) in both CRC cell lines and primary tumors. We next studied the two loci separately and found that age and cancer related methylation was solely a property of the pseudogene CpG island and that the MLL3 locus was unmethylated. Conclusions: We found that frameshift mutations of MLL3 in both CRC cells and primary tumor that were more common in cases with microsatellite instability. Moreover, we have shown that the CpG island-associated promoter of MLL3 gene has no DNA methylation in CRC cell lines but also primary tumors and normal colon, and this region is highly homologous to a pseudogene (psiTPTE22) that shows age-related DNA methylation.

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 4572. doi:1538-7445.AM2012-4572
Abstract 4575: Three-gene diagnostic classifier for ALK negative ALCL
Authors: Pellegrino Elisa , Mereu Elisabetta , Agnelli Luca , Limongi Tania , Kwee Ivo , Iqbal Javeed , Piccaluga Pier Paolo , Neri Antonino , Chan John C , Pileri Stefano , Bertoni Francesco , Inghirami Giorgio , Piva Roberto
Published: August 2012

Anaplastic Large Cell Lymphomas (ALCL) comprise approximately 12% of all T-cell Non-Hodgkin's lymphomas (T-NHL), representing a heterogeneous group whose definition, origin and relationship with other T-NHL remains controversial. The notion that ALCL strongly express CD30, and display recurrent chromosomal translocations involving the Anaplastic Lymphoma Kinase (ALK) gene, led to recognition of two subsets, according to ALK expression. Although ALK positive ALCL can be readily diagnosed, ALK negative ALCL still lack unique genetic features and their distinction from other CD30 positive Peripheral T-Cell Lymphomas (PTCL) is not trivial. To unravel the regulatory network underlying lymphomagenesis of ALCL, and to discover new genomic classifiers for the recognition of ALK-positive and ALK-negative ALCL patients, we undertook a systematic approach of pathway discovery through a gene expression profiling meta-analysis of 309 cases, using data generated by five sets of experiments. In agreement with previous studies, unsupervised analyses were not able to distinguish ALCL from the other T-NHL categories. However, pathway discovery and prediction analyses defined a minimum set of genes useful for the stratification of ALK negative ALCL and strengthened the hypothesis that ALCL correspond to a distinctive pathological subgroup within T-NHL. Application of RT-qPCR in independent data sets of cryo-preserved and formalin-fixed paraffin embedded samples confirmed the gene expression profiling predictions and validated a simple model based on the measurement of three genes. These data suggest the possibility to translate RT-qPCR protocols to routine clinical settings as a new approach to precisely define T-NHL and to select more appropriate therapeutic protocols.

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 4575. doi:1538-7445.AM2012-4575
Abstract 4583: Comparison of repeated minor liver resection and major resection on lung metastasis growth in mice
Authors: Momiyama Masashi , Hiroshima Yukihiko , Suetsugu Atsushi , Tome Yasunori , Mii Sumiyuki , Yano Shuya , Bouvet Michael , Chishima Takashi , Endo Itaru , Hoffman Robert M.
Published: August 2012

This study examines the effects of types of liver resection on the growth of liver and lung metastasis. Experimental liver metastases were established by spleen injection of the Colon 26 murine adenocarcinoma cell line expressing GFP into transgenic nude mice expressing RFP. Experimental lung metastases were established by tail vein injection with Colon 26-GFP. Three days after cell injection, groups of mice underwent liver resection (35%+35% [repeated minor resection] vs. 70% [major resection]). Metastatic tumor growth was measured by color-coded fluorescence imaging of the GFP-expressing cancer cells and RFP-expressing stroma. Although major and repeated minor resection removed the same volume of liver parenchyma, the two procedures had very different effects on metastatic tumor growth: major resection, stimulated liver and lung metastatic growth as well as recruitment of host-derived stroma compared to repeated minor resection. Repeated minor resection did not stimulate metastasis or stromal recruitment. There was no significant difference in liver regeneration between the two groups. Host-derived stroma density, which is stimulated by major resection compared to repeated minor resection, may stimulate growth in the liver-metastatic tumor. TGF-β is also preferentially stimulated by major resection and may play a role in stroma and metastasis stimulation. The results of this study indicate that when liver resection is necessary, repeated minor liver resection is superior to major liver resection, since major resection, in contrast to repeated minor resection, stimulates metastasis, which should be taken into consideration in clinical situations indicating liver resection.

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 4583. doi:1538-7445.AM2012-4583