bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 53: Tumor-associated macrophage promotes oral cancer progression through activation of Axl signal pathway
Authors: Shieh Yi-Shing , Lee Chien-Hsing , Chen Chi-Kang , Chou Yu-Ting
Published: August 2012

Activation of the receptor tyrosine kinase Axl by its ligand gas6 is implicated in several diseases included inflammation and cancer. Our previous report demonstrated that Axl signal promotes oral squamous cell carcinoma (OSCC) carcinogenesis and progression. Recent studies also suggest that tumor-associated macrophage (TAM) promote tumor growth and metastasis. This study aims to study the potential involvement of Axl signal in the protumoral effect of TAM. We carried out coculture experiment by incubation of oral cancer cells (YD38) and macrophages (THP1). The expression of gas6 and Axl were examined in both cells. Characterized gene expression for M1 and M2 macrophage and EMT gene for cancer were also examined. The effect of Axl signal on cancer cells were further investigated by knockdown Axl expression and neutralized gas6 antibody in coculture system. The association Axl activation (pAxl) and TAM distribution were analyzed by Immunohistochemistry in cancer tissues. Our data indicated that upon coculture with cancer cells, TAM polarized to M2 phenotype with high IL10/low IL12 expression and elevated in gas6 secretion. After coculture with TAM, activation of Axl signal in cancer cells was noted. Furthermore, cancer increased mesenchymal markers expression and invasion/migration ability. While neutralzied gas6 or knockdown Axl, the coculture effects was diminished. In addition our result also demonstrated gas6/Axl signal elevated MMP-2 and -9 through NF-kb pathway to promote tumor invasion/migration, in which coculture of TAM increased NF-kb nuclear translocation and its bonding to MMPs promoter in cancer cells. Finally, in vivo cancer tissues showed significant association between TAM distribution and Axl (phosphorylated) expression. In conclusion, our results showed that TAMs play a protumor role in OSCC. TAM activated Axl signal and promoted tumor progression through NF-kb pathway. Therefore, Gas6/Axl and NF-kb signals in OSCC could be a putative target for therapeutic intervention.

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 53. doi:1538-7445.AM2012-53
Abstract 5306: Overexpression of RAD51 promotes brain metastases from breast cancer
Authors: Woditschka Stephan , Palmieri Diane , Duchnowska Renata , Jassem Jacek , Badve Sunil , Sledge George W. , Steeg Patricia S.
Published: August 2012

Overexpression of the DNA double-strand break (DSB) repair gene RAD51 was identified as part of a 13-gene signature predictive of rapid brain metastasis development (≤3 years vs. >3 years after diagnosis, HR=3.03, p=0.0008) in primary tumors of chemotherapy-naïve HER2+ metastatic breast cancer patients. We also found RAD51 mRNA overexpressed (1.5-fold, p=0.001) in resected brain metastases compared to primary breast tumors from the same patients. In addition, RAD51 expression was significantly higher (1.4-fold, p=0.008,) in brain metastases compared to systemic (bone/lung) metastases. We therefore hypothesize that RAD51 promotes brain metastasis development in breast cancer patients. Given the known role of RAD51 in homologous recombination, important for the repair of DNA DSBs, it was unknown whether RAD51 would promote brain metastasis of breast cancer only in the presence of DNA-damaging chemotherapy or, alternatively, have endogenous biological functions in tumor cells. To functionally evaluate whether RAD51 promotes brain metastases, RAD51 was overexpressed at physiologically relevant levels in a brain-metastatic variants of triple-negative MDA-MB-231 breast carcinoma (231-BR) cells. In vitro, this resulted in a ∼30% increase in clonogenic colony formation (p=0.004), without affecting cell proliferation rates. RAD51 overexpression also conferred chemoresistance to DNA DSB inducing agents such as 25uM carboplatin (p=0.03) and 25nM doxorubicin (p=0.02), but not to agents that do not cause DNA DSBs, such as 2.5nM paclitaxel. In vivo, overexpression of RAD51 in 231-BR cells increased formation of large brain metastases, the equivalent of clinically detectable lesions, (4.0 and 3.3-fold, p=0.01 and p=0.005) and micro-metastases (3.1 and 3.5-fold, p=0.01 and p=0.001) in two independent xenograft experiments. Importantly, this brain-metastasis promoting effect occurred without drugs to induce DSB. This effect was recapitulated in a second animal model based on a brain-metastatic subline of 4T1 murine mammary carcinoma cells (4T1-BR). In this model, RAD51 overexpression increased large brain metastases (3.3-fold, p=0.02) and micro-metastases (2.0-fold, p=0.04) compared to vector control. ShRNA-mediated RAD51 knockdown in 4T1-BR cells resulted in the opposite effect, reducing large brain metastases (1.8-fold, p=0.1) and micro-metastases (2.5-fold, p=0.04). Together these data suggest a driving role for RAD51 in the development of brain metastases from breast 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 5306. doi:1538-7445.AM2012-5306
Abstract 5380: Prophylactic MUC1/Poly-ICLC vaccine in individuals with the history of advanced colorectal adenoma
Authors: Kimura Takashi , McKolanis John R. , Schoen Robert E. , Finn Olivera J.
Published: August 2012

Background MUC1 is aberrantly expressed in a hypoglycosylated form with lack of luminal polarity in variety of human adenocarcinomas including colon cancer. Aberrant MUC1 is also highly expressed in colonic adenomas where it may promote malignant transformation by interacting withβ-catenin known to be an important pathway in colon carcinogenesis. We hypothesized that induction of an immune response against aberrant MUC1 in individuals with a recent history of adenoma may prevent adenoma recurrence and/or their progression to colon cancer. We conducted a clinical study using MUC1 peptide and Poly-ICLC adjuvant vaccine to evaluate the safety and immunogenicity in individuals who are cancer free but at high risk for developing colorectal cancer because of a recent history of advanced adenoma. Method Patients with advanced colorectal adenoma which meets at least one of following criteria: 1) ≥ 1cm in maximal diameter, 2) villous or tubulovillous histology, 3) high-grade dysplasia, were vaccinated with 100μg of 100aa MUC1 peptide (H2N-(GVTSAPDTRPAPGSTAPPAH)5-CONH2) admixed with 500μg of Poly-ICLC (TLR-3 agonist) as adjuvant, on week 0, 2, 10 and one year later. Bloods were collected two weeks after each injection for monitoring of general immunocompetence, development of anti-MUC1 antibody and safety. Results The vaccine was well tolerated without any adverse event grade 2 or higher. Among 36 evaluable patients, anti MUC1 IgG antibody was elicited in 17 patients as measured on week12 (response rate 47.2%). This response rate and the high levels of IgG have never been seen in response to MUC1 vaccines in cancer patients. Antibody titers declined over time but could be boosted to previous or higher levels at 1 year, showing development of immune memory. Vaccine responders were distributed across most HLA-DR and DQ types with similar frequency as in the general population, indicating that the MUC1 peptide could be presented by multiple Class II alleles. Immune competence of colon adenoma patients evaluated by cytokine production of lymphocyte and regulatory T cell frequency was generally equal to healthy individuals, however myeloid derived suppressor cells (MDSCs) were significantly increased in colon adenoma patients. Increase in MDSCs was especially pronounced in non-responders to the vaccine. Conclusion MUC1 poly-ICLC vaccine is highly immunogenic in this prophylactic setting and no significant adverse events have been seen. Vaccine immunogenicity is reduced in individuals with increased numbers of MDSC and this immunosuppressive population might be used as a biomarker to select patients most likely to respond.

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 5380. doi:1538-7445.AM2012-5380
Abstract 5467: Green tea catechin intervention of human breast cell carcinogenesis chronically induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
Authors: Choudhary Shambhunath , Sood Shilpa , Rathore Kusum , Wang Hwa-Chain Robert
Published: August 2012

The purpose of our study was to investigate the mechanism by which dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces breast cell carcinogenesis. More than 85% of breast cancers are sporadic and attributable to long-term exposure to environmental factors, such as carcinogens in the diet, through a multi-step disease process progressing from non-cancerous to premalignant and malignant stages. The dietary carcinogen PhIP is one of the most abundant heterocyclic amines found in high-temperature cooked meats and is recognized as a mammary carcinogen. Here, we demonstrated, for the first time, that cumulative exposures to PhIP at physiologically-achievable, pico- to nano-molar concentrations effectively induced progressive carcinogenesis of human breast epithelial MCF10A cells from a non-cancerous stage to premalignant and malignant stages in a dose- and exposure-dependent manner. Progressive carcinogenesis was measured by increasingly-acquired, cancer-associated properties of reduced dependence on growth factors, anchorage-independent growth, acinar-conformational disruption, proliferation, migration, invasion, tumorigenicity with metastasis, and increased stem-like cell populations. These biological changes were accompanied by biochemical and molecular changes, including upregulated H-Ras gene expression, ERK pathway activation, Nox-1 expression and reactive oxygen species (ROS) elevation. The Ras-ERK-Nox-ROS pathway played an important role in not only initiation but also maintenance of cellular carcinogenesis induced by PhIP. Using biological, biochemical, and molecular changes as targeted endpoints, we identified that the green tea catechin components, at non-cytotoxic doses, were capable of suppressing PhIP-induced cellular carcinogenesis and tumorigenicity.

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 5467. doi:1538-7445.AM2012-5467
Abstract 5481: Mitochondrial DNA copy number and lung cancer risk among Chinese female non-smokers
Authors: Mu Lina , Bonner Matthew , Irla Alyssa , Jin Jiahe , Olson James , Ellison Corie , Zhang Zuo-feng
Published: August 2012

Objectives It has been speculated that mitochondrial DNA copy number is involved in carcinogenesis of several cancers. The purpose of this pilot study was to explore the role of mitochondrial DNA copy number in the development of lung cancer among Chinese female non-smoker. Methods A subset of lung cancer cases (N=95) and healthy controls (N=96) were randomly selected from an original lung cancer case-control study conducted in Taiyuan City, China. mtDNA content was determined with Quantitative Real-time Polymerase Chain Reaction (qRT-PCR). Cases and controls were blindly assayed consecutively. Each sample was done in triplicate. Unconditional logistic regression model was used to calculate the odds ratios (ORs) and 95% confidence intervals after adjusting for age, education level and annual personal income. Spearman correlation coefficient was applied to determine correlation between mtDNA copy number and age or indoor air pollution index. Results Lung cancer cases had a significantly lower median mtDNA copy number of 4.5 as opposed to 7.2 in the controls (p<0.0001). There was an inverse relationship seen between mtDNA copy number and risk of lung cancer. Risk of lung cancer decreased in a dose-response manner with mtDNA copy number (Ptrend=0.0409) in the crude analysis. Those women in the highest quartile of mtDNA have a seventy percent lower risk of lung cancer as opposed to those women in the lowest quartile (aOR=0.3, 95%CI: 0.1-0.7). A significant negative correlation was observed between mtDNA copy number and indoor air pollution index which was developed based on individual's exposure to passive smoking, solid fuel use for heating and cooking, frequency of opening windows and exhaust hood use in the kitchen (p=0.0026). There was not a significant correlation between mtDNA copy number and age (p=0.6672), however a significant inverse relationship seen between mtDNA copy number and risk of lung cancer in those women over the age of 57.1. Conclusion Although the exploratory study showed that mtDNA copy number was negatively associated with indoor air pollution exposure and risk of lung cancer, the small sample size of the study and random selection of the subset from original study has limited the power and generalization of pilot study. Further large sample size studies are needed to verify the findings.

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 5481. doi:1538-7445.AM2012-5481
Abstract 5488: The rate of vertical transmission of human papillomavirus from mothers to infants: Relationship between infection rate and mode of delivery
Authors: Kim Tae Jin , Lee Jae Ho , Jang Hyoung S. , Kim Jun S. , Lee In H. , Cho A R. , Kim Jae W. , Shim Jae W. , Lee Ki H. , Lim Kyung T. , Hong Sung R.
Published: August 2012

Objectives: To assess the prevalence of human papillomavirus(HPV) infection among pregnant women and to evaluate the rate of vertical transmission of HPVs to their infants. Methods: 491 pregnant women and their infants delivered at Cheil General Hospital & Women's Healthcare Center were prospectively recruited for this study between February 2010 and November 2011. Cervical swabs and blood samples were collected from the women at 32-36 weeks of gestation. Neonatal buccal swabs and cord blood were taken immediately after birth. HPV positive neonates were rechecked HPV DNA at 6 months postpartum. HPV genotyping with HPV DNA chip (MyGene Co., Seoul, Korea) was used to detect the HPV of mothers and neonates. Type specific PCR was performed to see HPV DNA in the maternal and cord blood in cases of mother and infant infected same types of HPV DNA. Results: HPV DNA was positive in 16%(80/500) of mothers and 3.5%(17/491) of neonates. The rate of vertical transmission of HPV to their infant was 21.3%(17/80). HPV DNA type-specific maternal/neonate concordance was 100%. 16 HPV positive infants were delivered vaginally and 1 HPV positive infant was delivered by cesarean section with labor. There is no HPV positive infants delivered from cesarean section without labor. All HPV positive neonates were converted HPV negative at 6 months after birth. There was no viremia in maternal and cord blood in cases of mother and infant infected same type of HPV DNA. Conclusions: Prevalence of HPV DNA in neonates born from HPV positive mothers was significantly high. However, these data suggest that neonatal HPV DNA positive is not true vertical infection but contamination during vaginal delivery. Key words: Human papillomavirus, vertical transmission

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 5488. doi:1538-7445.AM2012-5488
Abstract 549: Role of the glucocorticoid receptor in skin carcinogenesis and stem cell maintenance: Implication for the use of selective GR activators (SEGRA) as anti-cancer drugs
Authors: Baida Gleb , Rundhaug Joyce , Bhalla Pankaj , Budunova Irina
Published: August 2012

Glucocorticoids are important physiological and pharmacological regulators of epidermal proliferation, differentiation and skin tumorigenesis. The glucocorticoid effects are mediated via the glucocorticoid receptor (GR), a transcription factor that regulates genes expression by DNA-binding dependent transactivation, and DNA-binding independent transrepression through negative interaction with other transcription factors. Our previous studies demonstrated that keratin5.GR transgenic animals are resistant to skin carcinogenesis. We also found that GR diminishes the number of follicular epithelial stem cells (SC), reduces their proliferative and survival potential and affects the expression of follicular SC “signature” genes. To further explore the tumor suppressor role of GR in skin carcinogenesis we generated skin-specific GR knockout animals by breeding of GRflox/flox animals with Keratin5.Cre recombinase animals in C57Bl genetic background. Skin-specific GR KO (Cre/GRfl/fl) mice do not have gross skin or hair phenotype. However, the detailed analysis of keratinocyte markers revealed decreased expression of some intermediate/late markers of differentiation including Keratin 10 and loricrin. We also found that Cre/GRfl/fl mice are more sensitive to the effects of UV irradiation and tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). The ongoing DMBA/TPA skin carcinogenesis experiment showed that Cre/GRfl/fl mice are more prone to skin carcinogenesis: they have higher tumor incidence and tumor multiplicity compared to GRfl/fl littermates. The analysis of global effect of the GR overexpression and GR silencing on gene expression in follicular epithelial SC, basal keratinocytes, and mouse skin tumors 1) revealed important GR targets in keratinocytes including STAT3 and REDD1 - the major regulator of mTOR; 2) provided an unexpected evidence that gene transrepression by GR plays critical role in the maintenance of SC and in inhibition of skin carcinogenesis. It is well understood that therapeutic effects of glucocorticoids are mediated by GR transreprssion, while many adverse metabolic effects are mediated by GR transactivation. Thus, our findings are important in light of drug discovery programs focused on the development of selective GR acivators (SEGRA) that preferentially induce GR transrepression. Some of SEGRA entered preclinical studies or clinical trials as anti-inflammatory GR ligands with reduced side effects. Our results suggest that SEGRA could be also used for skin cancer prevention/treatment.

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 549. doi:1538-7445.AM2012-549
Abstract 5494: The development and validation of risk predictive models for cervical low-grade and high-grade squamous intraepithelial lesions
Authors: Wu Ming-Tsang
Published: August 2012

Aim To develop and validate a risk predictive model for cervical high-grade squamous intraepithelial lesions (HGSIL; CIN2/CIN3). Materials and Methods Study women were from a community survey network for cervical cytological screening to evaluate and develop a simplified risk-score system (Jan., 2003-Feb., 2009, Kaohsiung county). Two other series of study participants obtained, respectively, from a follow-up of disease-free women in the community (followed from Apr., 2004-Feb., 2010) and from a hospital screening (Nov., 2008-Aug. 2011, KMUH) for cervical lesions were used to validate the risk-score system. Kaplan-Meier failure functions and the Cox proportional hazards model were used to evaluate the cervical precancerous risk for women with high-risk scores. Results Women who have a risk score of ≥5 obtained from the HGSIL model were defined as high risk subjects for the cervical lesion. The sensitivity and specificity of the risk-score system were 76.3% and 88.1%. The results of validation showed that the HGSIL model had high sensitivity and specificity (100% and 89.6%) for the community follow-up samples. We also evaluated the incidences of HGSIL among women with a high risk-score using the community follow-up cohort. The first and second-year cumulative incidences of HGSIL among women with the score of ≥5 were 1.05% and 3.63%, respectively. Conclusion With an acceptable accuracy, our data suggest that the HGSIL risk predictive model can be used to assist the screening of HGSIL.

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 5494. doi:1538-7445.AM2012-5494
Abstract 5495: Does KRAS testing in metastatic colorectal cancer impact overall survival: A comparative effectiveness study in a population-based sample
Authors: Feigelson Heather Spencer ,   The CERGEN Study Team
Published: August 2012

The anti-epidermal growth factor (EGFR) monoclonal antibodies cetuximab and panitumumab are approved for the treatment of metastatic colorectal cancer (mCRC), but have been shown to be ineffective if the tumor has a mutation in KRAS codon 12 or 13. Comparative effectiveness research is intended to create evidence for decision making, and to find out “what works” in health care. This is especially important in scenarios like KRAS testing among patients with mCRC, since there is uncertainty around the significance of rarer mutations, and no proven alternative treatment for those who are found to harbor KRAS mutations in codons 12 or 13. We sought to determine whether recommendations for KRAS testing implemented in mid-2008 impacted survival in mCRC among 1203 mCRC patients from seven integrated health plans that are part of the Cancer Research Network. We included Stage IV cases diagnosed from 2006- 2009 and stage III cases initially diagnosed from 2004- 2008 who progressed to distant metastatic CRC (determined using chart review). We abstracted complete treatment data, pathology reports, survival data and KRAS testing results from electronic medical records. For cases that had not been previously tested for KRAS mutation status, we tested archived pathology specimens from the primary tumor. We used Kaplan-Meier plots and Cox proportional hazards models to examine whether overall survival differed among stage III and IV cases diagnosed before (n=751) and after (n=452) the implementation of KRAS testing. We included 918 stage IV cases and 285 stage III cases with progression. KRAS mutations (codon 12, 13, or 61) were found in 40% of tumors. Mutations were more common among tumors arising in the proximal compared to distal colon (46% mutated in ascending colon versus 33% in sigmoid colon). Median survival among stage III cases with progression was 589 days, compared to 437 days for stage IV cases (p=0.004). EGFR inhibitors were given to 26% of patients in the pre-recommendation period, and 13% of patients in the post-recommendation period. We found no survival differences by mutation status. We also found no statistically significant difference in survival time between the pre- and post- KRAS testing recommendations. Our data suggest that KRAS testing can be used to target anti-EGFR therapies without compromising overall survival time among mCRC patients in a usual care 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 5495. doi:1538-7445.AM2012-5495
Abstract 5506: HPV genotyping of 15,307 Brazilian patients using a microarray based platform.
Authors: Stiepcich Monica M. , Silva Ismael D. , Scarpellini Bruno
Published: August 2012

Introduction: Human papillomavirus (HPV) is the leading cause of cervical cancer and genital lesions in women and men, representing an important global health problem. There are still few data about the prevalence and HPV co-infection in Brazilian patients. Objective: This study aims to describe type specific distribution and co-infection of HPV in patients of a private health clinic using HPV DNA testing. Material and Methods: From April 2010 to October 2011, 15,307 consecutive patients of a private health institution in Sao Paulo, Brazil, were tested using a DNA-array assay, which detects simultaneously 24 HPV types - 19 high risk (HR) and 5 low risk (LR) types (PapilloCheck®). Results: HPV infection was detected in 39% of 13,770 female and 65% of 1,537 male samples. The most common HR-HPV types in women were HPV16, 51, 53, 68, 56 (7.3; 7.2; 7.1; 7.1 and 6.7%) followed by types 39, 66, 52, 31 and 58 (4.7 to 3.9%), which accounted for approximately 56.2% of all detected HPV types. LR-HPV 42 (8.5%) and 44/45 (8.2%) were the most frequent LR types. In males, HR-HPV 16, 51, 56, 68, 53, 39 and 66 (7.8; 7.3; 5.3; 4.6; 4.4 and 4.2%) accounted for 38,7% of all types; HPV 6 (12,8%) and 42 (8%) were the most frequent LR types. HPV 18 accounted for only 1,8% and 2,3% of HPV DNA-positive women and men. Co-infection was observed in 16.3% of female and 36.4% of male samples. 7.1% of women and 22.8% of men showed co-infection with three or more types of HPV. Overall, 59.8% of women and 44% of men had only HR type-infections. 17,6% of women and 23,7% of men had only LR-HPV infections. Co-infection with HR and LR-HPV was observed in 22,6% of female and 32,3% of male samples. Conclusion: Our findings show a high HPV infection prevalence and a high proportion of co-infections in our population. These data can be useful to plan in a more efficient way screening programs and application of prophylactic HPV vaccines in Brazil.

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 5506. doi:1538-7445.AM2012-5506
Abstract 5507: Breast cancer in Jordan: A comprehensive epidemiological analysis 1996-2008
Authors: Salem Ahmed , Almousa Abdelatief , El-Tannir Dania , Salem Abdel-Fattah
Published: August 2012

Background: The epidemiology of breast cancer has been extensively studied in developed countries; however, epidemiological data is scarce in the Middle East. We present an epidemiological analysis of breast cancer in the Jordan in an attempt to aid continuously evolving strategies for cancer surveillance and control. Furthermore, we highlight the temporal changes of cancer care delivery over the period of this study. Material and methods: Data from the national cancer registry addressing the period from January 1996 to December 2008 were reviewed. The Jordanian national cancer registry was established in 1996 and utilizes a passive and active capture system. Tumor stage was classified into local, regional, distant or unknown. Crude incidence rates are expressed per 100,000. Results: Over the study years, 7,813 breast cancer cases were registered. The crude incidence rate of breast cancer ranged from 20 to 29.9 with 28.2% of cases occurring in 40-49, 26.4% of cases occuring in 50-59 and 18% of cases occuring in the 60-69 age groups. The median age was 51 (range, 16-100 years). Ductal carcinoma was found in 7,018 (89.8%), lobular adenocarcinoma in 478 (6.1%) and sarcoma in 139 (1.8%) patients. Overall; 1,412 (17.4%) cases harbored local, 1,504 (19.3%) harbored regional, 1,572 (18.3%) harbored metastatic disease while in 3,306 patients (45.2%) staging data was missing. Over the years; 2,361 (30.2%) cases were treated at academic/ comprehensive cancer centers while 4,760 (60.9%) cases were treated at a primary care/ community and/or private healthcare setting. In 692 (8.9%) patients, the location of healthcare delivery was unknown 1,652 (21.1%). We observed a trend towards referring more patients to academic/ comprehensive cancer centers over the years of the study; only 29 (6.5%) of a total of 449 patients presenting in 1996 were treated at such institutions as opposed to 406 (47.5%) of a total of 855 patients in 2008. Conclusions: This study represents the first comprehensive assessment of the epidemiological features of breast cancer in Jordan basing a framework for enhancing strategic health plans regarding cancer surveillance and control in Jordan and the Middle East.

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 5507. doi:1538-7445.AM2012-5507
Abstract 5518: Clinicopathologic associations with colorectal cancer molecular pathways in a cohort study of older women
Authors: Sammader N Jewel , Vierkant Robert A. , Tillmans Lori S. , Wang Alice H. , 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: Colorectal cancer (CRC) is a molecularly heterogeneous disease. Three molecular pathways (traditional, serrated and alternate) have been recently proposed based on integrated combinations of microsatellite instability (MSI), CpG island methylation phenotype (CIMP), BRAF mutation, and KRAS mutation status (Gastroenterol 2010;138:2088-2100). To our knowledge, clinicopathologic associations with these CRC pathways have not been previously described. Methods: Data and tissue resources were obtained from the population-based Iowa Women's Health Study, which recruited 41,836 randomly selected 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 CRC cases diagnosed through 12/31/2002. Established laboratory methods were used to characterize CRC cases by MSI (MSS/MSI-L or MSI-H), CIMP (neg, low, or high), BRAF mutation (wt or mut), and KRAS mutation (wt or mut) status. Molecular pathways were defined as: traditional (MSS/MSI-L, CIMP-neg, BRAF wt, and KRAS wt); serrated (any MSI, CIMP-high, BRAF mut, and KRAS wt), alternate (MSS/MSI-L, CIMP-low, BRAF wt, and KRAS mut), or other pathway. Chi-square tests and analyses of variance were used to compare clinicopathologic features at CRC presentation (age, anatomic subsite, tumor grade, and SEER stage) across the molecular pathways. Results: Comlete and informative MSI, CIMP, BRAF and KRAS data were obtained for 491/732 (67%) CRC cases. Clinicopathologic associations are shown in the Table. Conclusions: These data suggest that distributions of age at diagnosis, subsite, and tumor grade, but not SEER stage, differ across the traditional, serrated, and alternate carcinogenic pathways, which may have implications for molecularly-targeted CRC prevention and/or therapy 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 5518. doi:1538-7445.AM2012-5518
Abstract 5523: Cost effectiveness of implementing a screening and treatment program for hepatitis C virus infection in Egypt
Authors: Kim David D. , Hutton David W. , Raouf Ahmed A. , Salama Mohsen , Hablas Ahmed , Seifeldin Ibrahim A. , Soliman Amr S.
Published: August 2012

Egypt has one of the highest prevalence rates of hepatitis C virus (HCV) infection in the World. We estimated the cost-effectiveness of implementing a screening and treatment program for HCV infection among Egyptians. We developed a Markov decision analysis model of the natural history of HCV infection and treatment to evaluate cost-effectiveness of screening and treatment for asymptomatic average-risk Egyptian adults. We used HCV age-specific disease progression rates and prevalence for Egyptians. Lifetime costs of screening, treatment, disease progression, and health utilities have been used with 3% annual discounting. We used a societal perspective, local cost estimates, quality-adjusted life years (QALYs) gained, and calculated the incremental cost-effectiveness ratio of a hypothetical program of screening and treating Egyptians for HCV versus no screening. We conducted sensitivity analysis to test uncertainty in the model assumptions. Under base case assumptions, implementing the program for a 40-year-old, asymptomatic Egyptian adult would cost $1,856 for 19.192 QALYs, while non-screening would cost $1,807 for 19.164 QALYs for the 40 year time horizon. The incremental cost-effectiveness ratio (ICER) is $1,750/QALY (equivalent to about 10,392 LE, Egyptian pound/QALY). If applied to the population of 10-60 years old individuals, this program would lead to long-term costs of 2.15 billion dollars, but save one million life-years. Results were the most sensitive to change in disutility by being identified as HCV-positive after screening as well as the probability of receiving treatment after HCV positive diagnosis and probability of successful treatment. Comparing this model to international standards for cost-effectiveness, implementing a screening and treatment program for HCV in Egypt is very cost-effective. Therefore, we recommend implementing this program to reduce the burden of liver disease in Egypt.

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 5523. doi:1538-7445.AM2012-5523
Abstract 5524: Prostate cancer risk assessment model (PCRAM): a scoring model based on the Swedish Family-Cancer Database
Authors: Roudgari Hassan , Hemminki Kari , Brandt Andreas , Sundquist Jan , Fallah Mahdi
Published: August 2012

Background: Many prostate cancer (PC) risk assessment models have been developed, however almost none include familial history. We aimed to produce a risk assessment model for PC based on familial background of related cancers. Method: 976,859 independent index men aged >=30 in year 1998 and their family members in the Swedish Family-Cancer Database (FCD 2010) were randomly divided into the development (60%) and the validation (40%) datasets (follow-up=10 years). The hazard ratio from Cox model for personal and family history was used to extrapolate risk scores. Results: Specified scores were for PC in situ at age<60 years in index man, 5; PC at age<60 in each first-degree relative (FDR), 15; PC at age>=60 in each FDR, 10; PC at age<60 in each second-degree relative, 5; breast cancer in each FDR, 2; oesophageal carcinoma in situ in index man, 2; and oesophagus cancer in each FDR, 2. The curve for score-group 26+ showed a sharp increasing slope from age 60-65 onward. The score-group 21-25 showed 15-40 times higher risk than the general population at age 38-45; ratio decreased to four-folds by age 60, and stayed about 3.5-times thereafter. The score-group 16-20 showed 10-fold increased risk at age<=41; risk ratio 4-6 at age 42-54; and 2.5-3.5-fold thereafter. The curves for score 0-5 and population risk almost overlapped. Based on our findings, if the milestone age for a prostate cancer screening program was 60 years or more, the recommended starting age for the men with the score-group 6-10 would be 54 years; score-group 11-15, 52 years; score-group 16-20, 50 years; score-group 21-25, 44 years; and for the score-group 26+ it should start before age 40. The concordance index in both the development and the validation sets was 0.885 (95% CI=0.883-0.888). No significant difference was found between curves from the development and the validation datasets (internally-validated using two-fold validation and bootstrapping). Conclusion: Familial history of relevant malignancies can be used as risk factors to estimate a man's prior risk of developing prostate cancer. PCRAM could satisfactorily assess risk of developing prostate 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 5524. doi:1538-7445.AM2012-5524
Abstract 5536: TP53 and MED12 mutations in uterine smooth muscle tumors
Authors: Kuhn Elisabetta , Yemelyanova Anna , Wang Tian-Li , Kurman Robert , Shih Ie-Ming
Published: August 2012

Most uterine smooth muscle tumors can be broadly subdivided into two groups: benign leiomyoma (including variant subtypes) and leiomyosarcoma based on cytologic atypia, mitotic activity and coagulative tumor cell necrosis. A small number defies classification into unequivocally benign and unequivocally malignant categories. These tumors, classified as “atypical leiomyoma” and “STUMP” (Smooth muscle Tumors of Uncertain Malignant Potential), generally behave in a benign fashion. Although p53 overexpression, as determined by immunohistochemical staining, has been reported in the atypical group and the leiomyosarcomas, it is uncertain whether they harbor TP53 mutations. In addition, a recent study has reported mutations in the mediator complex 12 (MED12) gene in the majority of benign uterine leiomyomas. We therefore performed a mutational analysis of uterine smooth muscle tumors to determine their TP53 and MED12 mutation status, in order to better understand their molecular genetic characteristics. A total of 9 uterine conventional leiomyomas, 27 atypical leiomyomas and 12 leiomyosarcomas from 40 patients were analyzed. DNA samples were sequenced and TP53 (from exons 4 to 9) and MED12 (exon 2) mutations were analyzed. Clinico-pathological data were collected. TP53 mutations were detected in 17 (63%) of 27 atypical leiomyomas and 8 (67%) of 12 leiomyosarcomas. MED12 mutations were identified in 6 (67%) of 9 conventional leiomyomas, 7 (26%) of 27 atypical leiomyomas and 1 (8%) of 12 leiomyosarcomas. Follow-up was available in 30 patients. None of the patients with atypical leiomyoma had recurrence or died of her disease (average follow-up 23 months). Seven patients with leiomyosarcoma, 4 of whom had TP53 mutations, died of their disease (average follow-up 42 months). The preliminary findings of this study indicate that the presence of TP53 mutations in uterine smooth muscle tumors is not sufficient to drive malignant behavior. Moreover, based on the presence of a MED12 mutation in one case of leiomyosarcoma, we postulate that at least some leiomyosarcomas develop from benign leiomyomas. Future correlated molecular genetic and clinicopathologic studies with a larger number of cases and long-term follow-up information are necessary to confirm this important finding.

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 5536. doi:1538-7445.AM2012-5536
Abstract 5538: Development of RNA quality control methods to improve BCR-ABL measurement in whole blood samples
Authors: Stanoszek Lauren M. , Crawford Erin L. , Blomquist Thomas , Willey Paige , Willey James C.
Published: August 2012

Measurement of BCR-ABL fusion transcripts in whole blood by quantitative, reverse-transcriptase PCR is a clinically validated method to monitor treatment response in patients with chronic myelogenous leukemia. For example, achieving a three-log or greater reduction in BCR-ABL expression from baseline is considered a Maximum Molecular Response (MMR). A 0.5-log increase from MMR signifies treatment failure sufficient to motivate change in treatment. The purpose of this study was to develop a BCR-ABL test with improved analytical performance characteristics including adequate quality control for RNA degradation or reverse transcription interference and reliable comparison of results across testing sites. To test whether RNA degradation could mask a 0.5-log increase in expression, an RNA degradation model was established by incubating whole blood from each of six individuals with K562 cells at room temperature for various times post-venipuncture. When data from six subjects were combined, the BCR-ABL/103 GUSB value trended down at 24h but was not significantly decreased until 48h (51% decrease, p = 0.004). To quantify the amount of whole blood RNA that can be loaded into an RT reaction without reducing RT efficiency, six different amounts of total RNA extracted from whole blood mixed with K562 cells were added into RT reactions. To measure RT efficiency, an RT Standards Mixture (RTSM) containing known copy numbers of External RNA Control Consortium (ERCC) 171 RNA and ERCC 113 cDNA was added to each RT reaction. RT efficiency was measured as the yield of PCR product from ERCC 171 RNA relative to ERCC 113 cDNA. Based on data from three subjects, compared to RT efficiency at reference concentration of 30 ng/µl RNA in RT, there was a 35% decrease (p = 0.043) at 167 ng/μl RNA and 82% reduction at 1000 ng/μl RNA. The maximum yield of BCR-ABL (molecules/μL cDNA) was observed at 300 ng/µl RNA/RT with a 3-fold increase (p=0.003) compared to 30 ng/µl RNA. Greater than 300 ng/µl RNA/RT did not further increase yield of BCR-ABL molecules/μL cDNA, likely due to reduced RT efficiency. We conclude that BCR-ABL/103 GUSB should be measured within 24 hours following blood collection. Because decreasing RT efficiency is associated with increasing RNA input into RT reactions, including 300 ng/µl RNA in RT reactions provides the maximum sensitivity in measuring BCR-ABL expression.

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 5538. doi:1538-7445.AM2012-5538
Abstract 5682: Modeling the pharmacological importance of endoxifen for the treatment of ER-positive breast cancer in premenopausal patients
Authors: Maximov Philipp Y. , McDaniel Russell E. , Jordan V. Craig , Brauch Hiltrud
Published: August 2012

Long term adjuvant tamoxifen therapy for five years is the antiestrogenic standard of care for ER-positive breast cancer in premenopausal patients. The metabolic activation of tamoxifen by CYP2D6 to endoxifen remains controversial to plan the treatment of patients with breast cancer. However, all retrospective studies focus entirely on postmenopausal patients and no studies have been undertaken in the relevant premenopausal treatment population. We have addressed the issue of the pharmacological importance of endoxifen to control the estrogen-stimulated growth of four ER-positive breast cancer cell lines (MCF-7, T47-D, BT-474 and ZR-75). We have modeled the actual estrogen environment in the laboratory (estradiol plus estrone) based on previous data from premenopausal patients taking tamoxifen (Jordan et al, JNCI 2001; 83:1488-91). Our strategy was to evaluate the anti-proliferative actions of actual concentrations of tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen combined, based on the actual measurements reported for these metabolites in patients who were extensive metabolizers (EM), intermediate metabolizers (IM) or poor metabolizers (PM) (Mürdter et al, Clin Pharmacol Ther 2011; 89:708-17). These data were then compared with similar anti-proliferative experiments in the four cell lines, using endoxifen obtained from four sources (Mayo Clinic, University of Indiana, Institut für Klinische Pharmakologie (IKP) and the Fox Chase Cancer Center). Each cell line was evaluated with the clinically relevant circulating levels of estrogen, with and without the inclusion of the different endoxifens at the published concentrations from EM, IM and PM. It is important to note that all synthetic endoxifen currently available is an impure mixture of geometric isomers. Therefore, results obtained are only an estimate of the efficacy of endoxifen in the patient. To address this issue, we have specifically synthesized the appropriate isomer of endoxifen as a fixed ring compound that can no longer isomerize. We have previously used this strategy to discover the actual pharmacology of the two geometric isomers of 4-hydroxytamoxifen (Murphy et al, Mol Pharm 1990; 38:737-43). The results demonstrate the essential requirement with the appropriate concentration of endoxifen necessary to block estrogen-mediated cell replication. Acknowledgements: This work (VCJ) was supported the subcontract under the SU2C (AACR) Grant number SU2C-AACR-DT0409; the Susan G Komen For The Cure Foundation under Award number SAC100009.

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 5682. doi:1538-7445.AM2012-5682
Abstract 5684: Sustained gene silencing by liposomal siRNA incorporated mesoporous silicon particles
Authors: Rodriguez-Aguayo Cristian , Shen Haifa , Deng Xiaoyong , Gonzalez-Villasana Vianey , Sakamoto Jason , Han Hee-Dong , Sood Anil K. , Ferrari Mauro , Lopez-Berestein Gabriel
Published: August 2012

The use of small interfering RNA (siRNA) technology has rapidly become an attractive revolutionary tool in silencing gene expression and holds potential as a therapeutic strategy in cancer and other diseases. However, for siRNA-based therapeutics to become a reality, an efficient method for in vivo systemic delivery is needed. Here, we demonstrate effective and sustained delivery of siRNA using mesoporous silicon particles (MSP). We first developed a novel variant of multistage MSP by tuning the size and shape properties, which can load dioleoyl phosphatidylcholine (DOPC) nanoliposomes containing siRNA. To test this concept, we targeted EphA2 oncoprotein, which is highly overexpressed in most cancers such as breast, lung, pancreas and ovarian carcinoma. MSP incorporated with EphA2 siRNA-DOPC (MSP-siEphA2-DOPC) resulted in effective gene silencing for up to 15 days after single i.v. injection into mice bearing either SKOV3ip1 or HeyA8.MDR ovarian tumors in the peritoneal cavity. In addition, with a single injection of MSP-siEphA2-DOPC given every 15 days during 6 weeks of treatment, there was significant reduction (83%, P** 0.0032, 64%, P* 0.028, 36%, P, ns 0.0032) of tumor weight and number of nodules in a dose dependent manner (15,10 and 5 µg/mice) respectively compared with control groups. Furthermore, when we administrated MSP-siEphA2-DOPC in combination with either paclitaxel or docetaxel, we observed 87% and 91% tumor reduction compared to the control group respectively. Taken together, MSP-siEphA2-DOPC provides a new approach for sustained release of siRNA into disease sites without repetition of injection.

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 5684. doi:1538-7445.AM2012-5684