bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A107: Polymorphisms in nucleotide excision repair pathway and acute myeloid leukemia outcome
Authors: Strom Sara , Gokhale Sameer , Estey Elihu
Published: May 2012

A107

Acute myeloid leukemia (AML), the most common leukemia in adults is frequently associated with genetic abnormalities. Based on pre-treatment cytogenetics, AML patients are classified into favorable, intermediate and poor subgroups. Cytogenetics are good predictors of treatment outcome for the favorable and poor subgroups. However, for patients with intermediate cytogenetics, optimal treatment is uncertain. For these patients incorporating genetic markers to the existing prognostic factors might be helpful to identify subgroups of patients. Variants in genes within the nucleotide excision repair (NER) pathway may lead to inter-individual differences in DNA repair capacity which could eventually influence AML outcome. We studied the role of 5 polymorphisms (ERCC1 Gln504Lys, XPD Lys751Gln, XPC Ala499Val, XPC Lys939Gln, and CCNH Val270Ala) within this pathway on overall and disease-free survival among 170 adult de-novo AML patients with intermediate cytogenetics [diploid karyotypes (n = 117) and non-diploid karyotypes (n = 53)], treated with induction chemotherapy. Kaplan-Meier methods and Cox proportional hazards models were performed. After a median follow-up of 16 months, 56% of diploid patients died compared to 71% among the non-diploid group (Log Rank p= 0.03). Among patients with diploid karyotypes, after adjusting for clinical and socio-demographic characteristics (age, sex, ethnicity, WBC, performance status, and smoking), XPD Lys751Gln and XPC Ala499Val were found to be independently associated with overall survival. Patients with the XPD Lys751Gln/Gln751Gln genotype were twice more likely to have died than those with the wild genotype (HR: 1.97; 95% CI: 1.09 - 3.55). XPC Ala499Val/Val499Val patients had a 75% increased mortality compared to those with the wild genotype (HR: 1.75; 95% CI: 1.02 - 2.98). Patients carrying both (XPD Lys751Gln/Gln751Gln and XPC Ala499Val/Val499Val) had significantly shorter survival compared to those with the wild genotype (HR: 3.49; 95% CI: 1.58 - 7.68). 21% of the AML patients with diploid cytogenetics carried both risk variants. No significant associations were observed for disease-free survival in AML patients. Our results suggest that polymorphic variants in NER repair enzymes may modulate AML outcome in patients with diploid cytogenetics. Patients with the high risk genotype combination could have diminished DNA repair capacity, which in turn, could result in greater susceptibility to genotoxic effects of treatment decreasing overall survival. These findings could in the future be used in selecting treatment strategies for patients with normal cytogenetics.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A107.
Abstract A118: Tea drinking habits and esophageal cancer in a high risk area in Northern Iran
Authors: Islami Farhad , Kamangar Farin , Pourshams Akram , Nasrollahzadeh Dariush , Fahimi Saman , Abnet Christian , Moller Henrik , Dawsey Sanford , Malekzadeh Reza , Boffetta Paolo
Published: May 2012

A118

Golestan Province in northern Iran is a high incidence area for oesophageal squamous cell carcinoma (ESCC). We investigated the association between tea drinking habits and risk of ESCC in a population-based case-control study conducted between 2003 and 2007 in Golestan, with 300 histologically-proven ESCC cases and 571 matched neighborhood controls. In addition, we measured tea temperature and tea drinking patterns among 48582 healthy participants in a cohort study in the same region. Nearly all (98%) of the cohort participants drank black tea regularly, with a mean volume of over one liter/day, and over 60% drank their tea at temperatures over 60°C. The results of the case-control study showed that compared to drinking lukewarm or warm tea, the OR (95% CI) for drinking hot tea was 2.07 (1.28-3.35) and for drinking very hot tea was 8.16 (3.93-16.9). Likewise, compared to drinking tea four or more minutes after pouring it, the ORs (95% CIs) for drinking tea 2-3 minutes and less than 2 minutes after pouring were 2.49 (1.62 - 3.83) and 5.41 (2.63 - 11.1), respectively. There was a strong agreement between responses to questions on temperature of tea drinking and time interval from pouring tea to drinking it (weighted kappa = 0.68). In conclusion, drinking hot tea, a habit commonly seen in Golestan Province, was strongly associated with higher risk of ESCC.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A118.
Abstract A134: Honokiol targets STAT3 in head and neck squamous cell carcinoma
Authors: Leeman Neill Rebecca , Cai Quan , Arbiser Jack , Grandis Jennifer
Published: May 2012

A134

Head and neck squamous cell carcinoma (HNSCC) is a commonly occurring malignancy associated with severe morbidity, persistently high mortality rates, frequent recurrence, and the appearance of second primary tumors. Honokiol, a naturally occurring compound that is derived from the plant, Magnolia officinalis, which has been used in traditional Chinese medicine, has been shown to have anticancer activity in various models and to inhibit nuclear factor kappa B (NFκB), an oncogenic transcription factor. Crosstalk between NFκB and another transcription factor, signal transducer and activator of transcription (STAT)-3, has been demonstrated in HNSCC. Furthermore, NFκB and STAT3 have been found to directly interact in certain cell lines and to have various target genes, including proteins that regulate apoptosis, the cell cycle, and tumor angiogenesis, in common. Therefore, we hypothesized that honokiol might be useful in targeting STAT3, a protein that is known to promote growth, invasion, metastasis, and tumor angiogenesis in HNSCC and that shows promise as an important therapeutic target in the treatment of HNSCC. In the current study, 72-hour honokiol treatments inhibited the growth of HNSCC cell lines, Cal-33, UM-22b and 1483 with IC50’s ranging from 3.90-7.44 μM, as shown through trypan blue dye exclusion assays. Honokiol treatment also decreased expression levels of phosphotyrosine STAT3 in these same cell lines. The growth inhibitory activity of honokiol is associated with apoptosis, as demonstrated by staining for annexin-V. Because clinical data indicates that currently available HNSCC therapies have been inadequate in improving mortality rates over the last three decades, it is of interest that honokiol enhances the activity of the small-molecule receptor tyrosine kinase inhibitor, erlotinib, in HNSCC cells. Finally, honokiol was found to modestly inhibit the growth of tumors in HNSCC xenograft models. These results suggest that honokiol inhibits HNSCC growth in conjunction with downregulation of phosphotyrosine STAT3 in HNSCC.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A134.
Abstract A16: External Qi of Yan Xin Qigong induces apoptosis in estrogen-independent breast cancer cells through inhibition of the Akt/NF-κB pathway
Authors: Yan Xin , Shen Hua , Jiang Hongjian , Hu Dan , Zhang Chengsheng , Wang Jun , Wu Xinqi
Published: May 2012

A16

The concept External Qi of Qigong refers to the technology and ability of the “Qi deployment” therapy and health preservation in traditional Chinese medicine (TCM). External Qi therapy of TCM has long been one of the medical practices and under the management of the health authorities in China. Studies have shown substantial beneficial effects of Yan Xin Qigong (YXQ) that originated from TCM on disease management, weight control, and optimizing caloric intake and diet habit. The external Qi of Yan Xin Qigong (YXQ-EQ) has previously been shown to have potent antioxidative properties. In the present study we have investigated the effect of YXQ-EQ on the Akt/NF-κB signaling pathway that is crucial for tumor growth and progression in estrogen-independent breast cancer MDA-MB-231 cells. YXQ-EQ significantly inhibited constitutive and EGF-stimulated Akt phosphorylation. Furthermore, YXQ-EQ substantially inhibited constitutive NF-κB activity and downregulated the expression of NF-κB target genes Bcl-2, Bcl-xL, XIAP and survivin. YXQ-EQ treatment caused a dramatic reduction in the viability of MDA-MB-231 cells, accompanied by DNA fragmentation, cleavage of PARP, and activation of caspase-3 and caspase-9. These findings suggest that YXQ-EQ might induce apoptosis in MDA-MB-231 cells through inactivation of Akt/NF-κB signaling. YXQ-EQ could potentially be a novel approach for breast cancer prevention and therapy.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A16.
Abstract A2: Dauricine inhibits IGF-I-induced HIF-1α protein accumulation and VEGF expression
Authors: Tang Xudong , Li Gang , Zhou Keyuan
Published: May 2012

A2

Dauricine (Dau), a bisbenzylisoquinoline alkaloid derivative isolated from the rhizome of Menispermum dauricum DC, has been found to have anticancer activities. However, the effect of Dau on tumor angiogenesis is still unclear. A growing body of evidence has demonstrated that hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) play an important role in tumor angiogenesis. In this study, we investigated the effect of Dau on HIF-1α and VEGF expression induced by insulin-like growth factor-I (IGF-I) in human breast cancer cells (MCF-7). Our results showed that Dau significantly inhibited IGF-I-induced HIF-1α protein accumulation, but had no effect on HIF-1α mRNA expression. Meanwhile, Dau also remarkably suppressed VEGF expression at both protein and mRNA levels in response to IGF-I. Mechanistically, we found that Dau suppressed IGF-I-induced HIF-1α and VEGF protein expression mainly via blocking the activation of PI-3K/AKT/mTOR signaling pathway. Functionally, we found that Dau dramatically abrogated IGF-I-stimulated formation of capillary tube-like structures in vitro. Taken together, our results suggested that Dau may be a promising antiangiogenic agent for human breast cancer. Supported by National Natural Science Foundation of China (No. 30872944) and Guangdong Administration of Traditional Chinese Medicine (No.2008166).

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A2.
Abstract A20: Deacetylation of histone H3 at lysine 9 with ethanol in human colonic epithelial cells
Authors: Jang Hyeran , Moyer Mary , Choi Sang-Woon
Published: May 2012

A20

Epidemiologic observations have implicated chronic excess ethanol consumption as a risk factor for various cancers including colon cancer. Recent epigenetic studies demonstrated that ethanol causes selective acetylation of histone H3 at lysine 9 (H3K9) in the liver, lung, spleen and testes, indicating that ethanol may inhibit histone deacetylase activity, or enhance histone acetyltransferase activity in those tissues. We therefore investigated the effect of ethanol on histone H3 modifications in colonic epithelial cells. NCM460, human colonic epithelial cells were incubated with 100mM of ethanol for 24, 48, or 72 hr and then the acetylation and methylation states of histone H3K9 were measured by immunoblot analysis using site-specific antibodies. We found that ethanol decreased acetylation of histone H3K9 in a time-dependent manner (71, 21, 17%, respectively, P<0.0001), while the histone deacetylase inhibitor, trichostatin A, which was used as a positive control, increased H3K9 acetylation. However, both ethanol and trichostatin A had little effect on histone H3K9 methylation. This is the first report of the colon-specific post-translational deacetylation of histone H3 with ethanol.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A20.
Abstract A24: Endothelial cell aging and possible role in angioprevention: increased expression of TGFβ and other antiangiogenic factors
Authors: Albini Adriana , Generoso Luca , Mirisola Valentina , Romeo Francesco , Pfeffer Ulrich
Published: May 2012

A24

Alterations of endothelium are associated with increased risk in cardiovascular diseases; they are also involved in tumor angiogenesis, one of the main “rate limiting step” in tumor progression and spreading. For this reason in the last years several agents have been patented for the cancer therapy thanks to their ability to inhibit tumor angiogenesis and now angiogenesis is considered also a target prevention.

Since senescence is considered an “anti-cancer” phenomenon we are evaluating the molecular changes that occur during aging in endothelial cells. We conducted this study on endothelial cells derived from Human Umbilical Vein (HUVECs) of ealry and late passages, fromboth masculin and feminin origin and we have analyzed the expression profile at different stages of in culture aging.

Several genes are regulated during this process; among these there is a significant reduction of the expression of genes such as E-selectin and CCL2 from cells of both male or female origin. This reduction could correlate with a decrease of the ability of endothelial cells to recruit inflammatory cells, and may have implications for metastatic spread of cancer. Angiopoietin 2 (ANG2) also seem to decrease during the endothelial cell senescence; this could be related to a potential impairment of the capacity to undergo remodeling in “aged” vessels. Interestingly, all three genes show a 2-fold higher expression in females as compared to males and the rate of decrease is different although the trend is the same. These data could suggest that there may be important gender-specific differences in gene expression of endothelial cells, and that these may have an effect on the senescence process.

Finally we have evidence that TGFβI, a molecule related to TGFβinduction, is increased with passages in culture and is very high in aged endothelial cells. Probably it could clarify the pro-apoptotic and antiangiogenic activity of TGFβ.

Taken together, these data confirm that physiological endothelial cell senescence could be associated with a reduction in anti-angiogenic potential; this property suggests that some tumors could be less angiogenic in the elderly.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A24.
Abstract A26: IL-1β dependent epithelial-mesenchymal transition in non-small cell lung cancer
Authors: Heinrich Eileen , Charuworn Burt , Dohadwala Miriam , Dubinett Steven
Published: May 2012

A26

Pulmonary diseases associated with a heightened risk of lung cancer, such as emphysema and pulmonary fibrosis, show both increased and deregulated inflammation. Tobacco smoke exposure is associated with chronic airway inflammation and is a strong risk factor for the development of lung cancer. Inflammatory mediators and inflammatory cells are over expressed in the pulmonary microenvironment of both smokers and patients with non-small cell lung cancer (NSCLC). Expression of interleukin 1β (IL-1β) is increased in a number of cancers, including lung cancer and is associated with tumor aggressiveness and poor patient outcomes. A chronic increase in inflammatory mediators in the lung tumor microenvironment can lead to increased tumor promotion, invasion, angiogenesis and metastasis; however the mechanism by which this occurs has yet to be elucidated.

We have found that IL-1β exposure leads to the down regulation of E-cadherin in NSCLC cell lines. Loss of E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT) in which epithelial cells lose cell-cell junctions, undergo cytoskeletal reorganization and basement membrane degradation and switch from cadherin to integrin mediated adhesion. This transformation results in cells with a mesenchymal phenotype. An important feature of mesenchymal cells is their ability to migrate independently and invade locally - prerequisites for metastasis. Following IL-1β exposure we see, along with the loss of E-cadherin, changes in cellular morphology, down regulation of cytokeratin 18 and an up regulation of mesenchymal markers, particularly N-cadherin, vimentin and SNAI2 (Slug) - a transcriptional repressor of E-cadherin. Slug expression is increased at both the mRNA and protein levels and is found via chromatin immunoprecipitation to be bound to the E-cadherin promoter following IL-1β exposure. Further, in NSCLC cell lines which do not express E-cadherin, Slug expression is elevated. Blocking Slug expression using siRNA inhibits IL-1β mediated down regulation of E-cadherin

IL-1β has many well-characterized effects on signaling pathways and protein expression, including the up regulation of COX-2 which has been shown previously to decrease E-cadherin expression. However, the IL-1β mediated effects on E-cadherin expression are COX-2 independent. Blocking COX-2 activity with celecoxib does not abrogate the E-cadherin down regulation seen here. Additionally, others have found that loss of E-cadherin is associated with resistance to epidermal growth factor receptor tyrosine kinase inhibitors which are currently in use as treatment and have been suggested as prevention agents for NSCLC. Thus, the presence of inflammatory mediators in the pulmonary microenvironment may play a specific role in promoting resistance to targeted prevention and therapy.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A26.
Abstract A32: Proteomic signatures of deoxycholic acid and ursodeoxycholic acid treated human colon cancer cells
Authors: Nakanishi Masako , Menoret Antoine , Vella Anthony , Rosenberg Daniel
Published: May 2012

A32

Dietary factors play an important role in the pathogenesis of colorectal cancer (CRC), due in part to the influence of the bile acids. While the secondary bile acid, deoxycholic acid (DCA), has been associated with tumor promotion, one tertiary bile acid in particular, ursodeoxycholic acid (UDCA), has been demonstrated to exert chemopreventive properties in the colon. Although its efficacy against high-grade adenomas has already been demonstrated in phase III clinical trials, mechanisms by which UDCA suppresses colon tumorigenesis remain unclear. In order to gain further insight into the tumor modifying properties of the bile acids, we compared the effects of DCA and UDCA on human colon tumor cells (CaCo-2) using proteomic analyses. In the following study, CaCo-2 cells grown at 70% confluence were treated with either 10 µM deoxycholic acid (DCA) or 1 mM ursodeoxycholic acid (UDCA) for 72 hours. For the proteomic analysis, protein was first fractionated by PF2D isochromatofocusing on a Beckman Coulter ProteomeLab PF2D platform. Fractions corresponding to a linear gradient between pH 8.0 and 4.0 were collected and processed through an automated autoloader for further separation by HPRP-PF2D reverse phase chromatography. Two dimensional protein expression maps displaying isoelectric point (pI) versus hydrophobicity were generated by the ProteoView/DeltaVue software package. Pairwise analysis of these complex protein chromatograms demonstrated common peak profiles (signatures) as well as unique peaks (fingerprints) characteristic of UDCA or DCA treatment. One of these protein peaks that exhibited a differential expression pattern between the two drug treatments was identified by MALDI and tandem mass spectrometry sequencing as heat-shock protein 60 (Hsp60). Furthermore, this protein was found to be less oxidized upon treatment with UDCA, suggesting the attenuation of oxidative stress present in cancer cells. Further analyses on the role of Hsp60 as well as resultant diminished oxidative stress will enable the discovery of potential mechanisms by which DCA and UDCA control cellular pathways.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A32.
Abstract A36: Combinatorial attack on radiation-induced neoplastic transformation by phenylbutyrate: Involvement of Hsp90 molecular chaperone and histone deacetylase
Authors: Miller Alexandra
Published: May 2012

A36

Phenyl fatty acids like phenylacetate (PA) and phenylbutyrate (PB) have shown anti-cancer efficacy in clinical trials and in both in vitro and in vivo models. The mechanism of action of these agents is not fully understood however. In vitro studies have demonstrated that PB treatment induces apoptosis and growth rate effects in a time- and dose- dependent manner in the p21ras-expressing hematopoietic cells, Ras-DC and the human chronic myeloid leukemia blast crisis cells, (CML-BC) K562 cells. Both leukemia cell types are characterized by deregulated activity of the oncoprotein tyrosine kinase known as Bcr-Abl frequently observed in radiation-associated leukemias. Molecular studies are underway to characterize the effect of PB on Bcr-Abl expression in these leukemia cells since Bcr-Abl is a well known client protein for Hsp90. Furthermore, gene expression profile analysis of PB treatment of leukemia cells and human osteoblast cells (HOS) demonstrated that PB down-regulated Hsp90 suggesting that PB may affect molecular chaperoning. The anti-leukemic activity of PB was investigated using the cobalt radiation-induced neoplastic transformation model, HOS cells. HOS cells were exposed to a total of 2 Gy (60Co, 50 cGy/exposure) and transformed foci were formed within 35 days. Cellular incubation with PB either pre- or post-radiation significantly suppressed the radiation-induced transformation. Molecular studies also showed that PB induced acetylation of histones H3 and H4 and apoptosis in this cell model. A radiation leukemia rodent model is currently being employed to evaluate PB’s anti-leukemia efficacy. Although preliminary, these data suggest that PB involvement in both Hsp90 molecular chaperoning and inhibition of histone deacetylase is mechanistically related to its anti-leukemia efficacy.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A36.
Abstract A43: Hops (humulus lupulus) induce detoxification enzymes in vivo
Authors: Dietz Birgit , Hagos Ghenet , Guo Jian , Main Matthew , Lantvit Daniel , Farnsworth Norman , Pauli Guido , van Breemen Richard , Bolton Judy
Published: May 2012

A43

Extracts of hop strobiles, the female parts of Humulus lupulus L., are popular botanical dietary supplements as alternative treatment for menopausal symptoms (1). Cancer preventive properties of hops, which are in part mediated through the induction of detoxification enzymes, have frequently been reported (2). This effect has been mainly attributed to one of its major constituents, xanthohumol (XN) (3). However, the chemopreventive effects have so far only been demonstrated in vitro and have not been confirmed in vivo. Therefore, we conducted an in vivo study in adult female rats and analyzed the effect of oral administration of a standardized hop extract (7.5 g extract/kg BW per day, containing 2% XN) or s.c. injection of XN (20 mg/day) on detoxification enzymes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione-S-transferase (GST). Analysis of various tissues revealed that while pure XN and oral hops significantly induced NQO1 activity in liver and colon tissue, only oral hops and not pure xanthohumol induced NQO1 activity in the uterus. Interestingly, hops but not xanthohumol significantly induced GST activity in the liver and mammary gland suggesting that other hop constituents and/or an additional mechanism might be responsible for these effects. Transcription of many detoxification enzymes is regulated through the antioxidant response element (ARE) and its transcription factor Nrf2, which is repressed under basal conditions by Keap1 (4). It has been shown that XN alkylates Keap1 and therefore enhances the concentration of free Nrf2 in the nucleus which results in ARE activation (5). Another pathway leading to ARE activation is mediated by protein kinase C (PKC) that phosphorylates Nrf2 leading to accumulation of Nrf2 in the nucleus (6). To investigate whether this pathway is involved in the observations described above, additional experiments with HepG2-ARE-luciferase C8 cells were performed. The cells were treated with hop extract or XN with or without the selective PKC inhbitor, Ro-32-0432, and the ARE-luciferase induction was determined. The results revealed that hops- but not XN-regulated ARE induction is in part mediated by PKC. Possible active compounds are under investigation. These results suggest that hop dietary supplements have the potential as preventive agents against cancer through induction of detoxifying enzymes.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A43.
Abstract A47: Drinking water with red beetroot food dye antagonizes esophageal carcinogenesis in NMBA-treated rats
Authors: Lechner John , Wang Li-Shu , Schwartz Steven , Stoner Gary
Published: May 2012

A47

This study was undertaken to determine if the oral consumption of red beetroot dye would result in an inhibition of N-nitrosomethylbenzylamine (NMBA)-induced tumors in the rat esophagus. Rats were treated with NMBA and given either regular water ad libitum or water containing 78 µg/ml of commercial red beetroot dye, E162. The number of NMBA-induced esophageal papillomas was reduced by 45% (p<0.001) in animals that received the dye when compared to controls. Dye treatment also resulted in reduced rates of cell proliferation in both precancerous esophageal lesions and in papillomas of NMBA-treated rats, as measured by immunohistochemical staining of Ki-67 in esophageal tissue specimens. The effects of beetroot dye on angiogenesis (microvessel density by CD34 immunostaining), inflammation (by CD45 immunostaining), and apoptosis (by TUNEL staining) in esophageal tissue specimens were also determined. When compared to rats treated with NMBA only, the levels of angiogenesis and inflammation in the beetroot dye-consuming animals was reduced and the apoptotic rate was increased. Thus, the mechanism(s) of chemoprevention by the active constituents of red beetroot dye include reducing cell proliferation, angiogenesis and inflammation, and stimulating apoptosis. Importantly, consumption of the dye in the drinking water for a period of 35 weeks did not appear to induce any overt toxicity. Based on the fact that red beetroot dye contains betacyanins, which have strong anti-oxidant activity, it is postulated that these effects are mediated through inhibition of oxygen radical-induced signal transduction.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A47.
Abstract A58: Breast cancer risk estimates from the CARE and GAIL models among black women: Howard University Cancer Center experience
Authors: Adams-Campbell Lucile , Makambi Kepher , Frederick Wayne , McCaskill -Stevens Worta
Published: May 2012

A58

The Gail model has been used to predict invasive breast cancer risk in women using the following risk factors: age, age at menarche, age at first live birth, number of first degree relatives with breast cancer, and number of previous benign breast biopsy examinations. However, this model underestimates breast cancer risk in black women. The Contraceptive and Reproductive Experience (CARE) model has been developed to replace the Gail model in predicting breast cancer risk in black women. Using a sample of 883 black women who were screened for the STAR chemoprevention trial, we compared breast cancer risk estimates from the Gail and CARE models. The mean 5- year breast cancer risk was 0.88% for the Gail model and 1.29% for the CARE model. Using the usual cut-point of 1.67% or above for elevated risk, there is significant difference in the proportion of women with elevated breast cancer risk between the Gail and the CARE models (McNemar’s test, p < 0.0001). Among those with a family history of breast cancer, the mean risk was 1.57% for the Gail model and 1.88% for the CARE model. For both models, there was a significant mean risk difference between those with and without a family history of breast cancer (Wilcoxon rank-sum test, p<0.0001).

Conclusion

The CARE model is an improvement of the Gail model for estimating the risk of invasive breast cancer among black women and will improve counseling, risk assessment, prescribing of chemoprevention agents and eligibility for chemoprevention trials

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A58.
Abstract A61: Pilot study of difluoromethylornithine (DFMO) in patients with Barrett's esophagus and dysplasia
Authors: Sinicrope Frank , Broaddus Russell , Joshi Nina , Morlan Bruce , Kirsch Ilan , Gerner Eugene , Hong Waun
Published: May 2012

A61

Background

Patients with Barrett's esophagus (BE) and dysplasia are ideal candidates for chemopreventive strategies to reduce cancer risk. Difluoromethylornithine (DMFO) is a promising chemopreventive agent that inhibits polyamine synthesis involved in the regulation of cell growth and differentiation. We conducted a pilot study to examine the effects of DFMO on esophageal histopathology, mucosal polyamine content, and gene expression.

Materials and Methods

Patients (n=10) with histologically confirmed BE and low grade dysplasia were enrolled in a single-arm study of DFMO (0.5 g/m2/d) given continuously for 6 months. Esophagoscopy with biopsies (4 quadrants every 1 cm) was performed at baseline, 3 and 6 months, and at 12 months (where available). Grading of dysplasia was performed by a GI pathologist blinded to clinical/biomarker data. Audiology was also performed. Mucosal polyamine content was measured by high-performance liquid chromatography, and analyzed using paired t-tests. Gene expression profiling was performed using a cDNA two-color chip, and was compared between baseline and 6 months. Expression data was normalized using the two-channel fastlo routine and differential expression was computed using a Wilcoxon signed-rank test.

Results

After 6 months of DFMO treatment, histopathological response data demonstrate regression of dysplasia (n= 1), stable disease (n= 8), and progression of dysplasia (n= 1). Within the stable category, 2 patients with extensive low grade dysplasia showed only focal dysplasia based upon 4 or more biopsies at 6 months. Histolopathological improvements seen at 6 months were maintained at 12 months. Overall, DFMO was well tolerated. One patient had subclinical, unilateral ototoxicity. Modulation of polyamines (spermine, spermidine, putrescine, histamine) was shown only for putrescine which decreased with treatment (6 mo., p=0.07) and showed recovery to baseline at 12 months (p= 0.01). Gene expression profiling revealed modulated genes of potential biological importance (KLF5, KAL1, RFC5, TIMM8a, TC10) and of these, Krüppel-like factor 5 (KLF5) was downregulated whereas the others were upregulated.

Conclusion

>Further study of the chemopreventive effect of DFMO upon BE with dysplasia is suggested. DFMO treatment suppressed mucosal putrescine levels and downregulated KLF5, an important mediator of cell proliferation.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A61.
Abstract A76: Nuclear androgen receptor expression is linked to two SNPs in prostate tumor tissue
Authors: Judson Gregory , Sinnott Jennifer , Stark Jennifer , Penny Kathryn , Stampfer Meir , Hunter David , Loda Massimo , Fiorentino Michelangelo , Finn Stephen , Schumacher Fredrick , Giovannucci Edward , Mucci Lorelei
Published: May 2012

A76

Introduction

The androgen receptor (AR) plays a critical role in the pathogenesis of prostate cancer (PCa), and down-regulated expression in prostatic epithelium is linked to decreased differentiation and increased proliferation of tumors cells. Genetic variation in the AR gene, located on the X-chromosome, has previously been linked with PCa risk. Whether the effect of AR variants on cancer risk is explained through regulation of prostate AR expression is not well understood. This study examines whether six SNPs located in AR, as well as the CAG repeat, are related to expression of cytoplasmic and nuclear AR in prostate tumor tissue.

Methods

We genotyped 6 SNPs with minor allele frequencies greater than 5% located in a 310 kb region overlapping the AR gene and the CAG repeat in 270 PCa cases diagnosed among participants in the Health Professionals Follow-up Study and the Physicians Health Study. AR expression was assessed by immunohistochemistry in tumor tissue obtained from archival prostatectomy blocks. To determine if expression levels varied by genotype, we conducted an ANOVA analysis with AR expression modeled as the dependent variable.

Results

We found two SNPs that were significantly associated with AR nuclear expression. Men who carried the rs1337082 variant allele (18.2% of men) had reduced AR nuclear expression (p= 0.03) compared to wild-type in the non-adjusted analysis. In addition, men with the rs6152 variant allele (13.6% of men) also had decreased AR expression (p= 0.04) when adjusted for age at diagnosis. When adjusting for age, the association between rs1337082 and AR expression also became stronger (p= 0.02). The linkage disequilibrium R2 value was 0.63. Approximately 2% of the variation in AR expression can be explained by these two SNPs. The four other SNPs examined were weakly but not significantly associated with AR expression. CAG repeat length was not correlated with expression of AR.

Discussion

rs1337082 (approximately 40 kb downstream of AR) is an A/G polymorphism while rs6152 (exon 1) is a silent G/A polymorphism. The link between nuclear AR expression and these two non-coding SNPs provides evidence of novel genetic factors that may influence AR expression.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A76.
Abstract A81: Cutaneous lymphoma incidence patterns in the United States: A population-based study of 3,884cases
Authors: Bradford Porcia , Devesa Susan , Toro Jorge
Published: May 2012

A81

Background

Primary cutaneous lymphomas (CL) represent 27 % of all non-Hodgkin lymphoma (NHL) and are a diverse group of lymphoid neoplasms manifesting heterogeneous clinical, histologic, immunophenotypic, cytogenetic, and molecular features. Given their rarity and heterogeneity, cutaneous lymphomas present substantial diagnostic and therapeutic challenges. There have been no prior large population-based descriptive studies focusing on CL in the United States.

Methods

Using the Surveillance, Epidemiology and End Results (SEER) program, we analyzed CL incidence rates (IR) and patient relative survival rates according to race, gender, and histologic type using the 2005 criteria of the World Health Organization/European Organization for Research and Treatment of Cancer (WHO/EORTC) classification. Age-adjusted (2000 US standard) IR were calculated using the SEER*Stat software public use program version 6.4.4 (Surveillance Research Program); IR were expressed as new cases per 1,000,000 person-years and were analyzed by age, gender, race, ethnicity, and year of diagnosis.

Results

3,884 CL were diagnosed in 16 SEER registries during 2001 to 2005. Cutaneous T-cell lymphomas (CTCLs) were the most common group of cutaneous lymphomas (72%), while cutaneous B-cell lymphomas (CBCLs) accounted for 28% of all cutaneous lymphomas. IR for both cell types of CL and their histologic subtypes were all higher among males than females. Overall age-adjusted CL IR were highest among Non-Hispanic Whites and Blacks (11.5/1,000,000 person-years), intermediate in Hispanic Whites (7.9), and lowest among Asian/Pacific Islanders (7.2). CTCL IR were highest among Blacks, whereas the IR of CBCL overall and subtypes were highest among Non-Hispanic Whites and lowest among Blacks. The 5-year relative survival rates for patients with CTCL and CBCL were 87% and 89%, respectively. Patients with primary cutaneous diffuse large B-cell lymphoma-leg type had the poorest survival rates (50%).

Conclusion

CL incidence rates vary markedly by race, gender, and histological type, supporting the notion that the histologic variants of CL represent distinct clinical entities. Further investigations using large populations and molecular tools are warranted to elucidate the etiology of the diverse spectrum of cutaneous lymphomas.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A81.
Abstract A84: Grade- and stage-specific age incidence patterns of serous ovarian epithelial cancer among different racial and ethnic groups in the United States
Authors: Matsuno Rayna , Popovici Raluca , Grimley Philip , Anderson William , Visvanathan Kala
Published: May 2012

A84

Background

Molecular and epidemiologic studies suggest that low- and high-grade serous ovarian epithelial cancers (sOEC) have distinct etiological pathways. However little is known about patterns in tumor grade and stage among different racial and ethnic groups in the US.

Methods

Data on sOEC (ICD-O-3 codes 8441, 8460-1) were obtained from the Surveillance, Epidemiology, and End Results 17-registry database (SEER17) for non-Hispanic Whites (NHW), Hispanic Whites (HW), African Americans (AA), and Asian Pacific Islanders (API), ages 20-84 years, for the period 2000-2005. Tumor stage was based on the American Joint Committee on Cancer Classification (AJCC) 6th edition, and was categorized as early (Stage I-II) and late (Stage III-IV). Tumor grade was categorized as low (well or moderately differentiated) and high (poorly differentiated or undifferentiated). Overall age-adjusted and age-specific rates of sOEC were calculated and stratified by race/ethnicity, stage, and/or grade using Poisson regression. Likelihood ratio tests were used to assess age interactions; age-specific incidence rate curves were smoothed using regression splines.

Results

There were a total of n=11,569 cases of sOEC; of which 79.8% were NHW, 9.2% HW, 5.4% AA, and 5.3% API. The age-adjusted rate for high-grade sOEC was nearly three times the rate for low-grade sOEC (IRR=2.85). Within low-grade sOEC, the IRR=2.62 for late- to early-stage; within high grade sOEC, the IRR=6.67 for late- to early-stage. Age-specific rates were similar for all groups except HW. There was significant age interaction with tumor grade (p<0.001 for both early and late stage), though within early-stage, the main effect of grade was non-significant (p=0.078). When age-specific rates were stratified by stage and grade, there was a highly significant age interaction in WH compared to WNH (reference group) in the late-stage/high-grade stratum (p=2.37x10-05).

Conclusion

Grade appears to play an important role in late-stage sOEC, particularly among WH. Though age incidence patterns by grade were generally similar among race/ethnicity groups in late-stage sOEC, the age incidence pattern for high-grade sOEC within late-stage was distinct for WH.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A84.
Abstract A92: Oxidative stress, obesity, and breast cancer risk: results from the Shanghai women health study (SWHS).
Authors: Dai Qi , Gao Yu-Tang , Shu Xiao-Ou , Yang Gong , Milne Ginger , Cai Qiuyin , Wen Wanqing , Rothman Nathaniel , Cai Hui , Li Honglan , Xiang Yongbing , Chow Wong-Ho , Zheng Wei
Published: May 2012

A92

Background

Increased reactive oxygen species may exhaust the antioxidant capability of human defense systems, leading to oxidative stress and cancer development. Urinary F2-isoprostanes, secondary end products of lipid peroxidation, are more accurate markers of oxidative stress than other available biomarkers. No prospective study has investigated whether levels of 15-F2t-Isop and its metabolite (15-F2t-IsopM) are related to breast cancer risk.

Methods

We conducted a nested case-control study within the Shanghai Women’s Health Study, a population-based cohort study of 74,942 Chinese women between 40 and 70 years of age. Prediagnostic urinary 15-F2t-Isop and 15-F2t-IsopM were measured by gas chromatography-mass spectrometry for 436 breast cancer cases and 852 individually matched controls.

Results

Urinary excretion of isoprostanes was not significantly different between cases and controls. However, among overweight women, levels of isoprostanes were positively associated with breast cancer risk, which became stronger with increasing BMI. Among women with a BMI≥29, the odds ratio (OR) increased to10.27 (2.41-43.80) for the highest compared to the lowest tertile of 15-F2t-IsopM (p for trend, 0.003; p for interaction, 0.0004). In contrast, 15-F2t-Isop and 15-F2t-IsopM were inversely associated with breast cancer risk among non-overweight women. Among women with a BMI≤23, breast cancer risk was reduced with increasing 15-F2t-Isop levels in a dose-response manner (p for trend, 0.006), with an OR of 0.46 (95%CI: 0.26-0.80) for the highest tertile versus the lowest (p for interaction, 0.006).

Conclusion

Our results suggest that the role of oxidative stress in breast cancer development may depend on adiposity and menopausal status.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A92.
Abstract A97: Obesity in relation to serum folates, plasma B12 and homocysteine in premenopausal African American women
Authors: Mahabir Somdat , Forman Michele , Hajek Richard , Shete Sanjay , Dong Yong , Brewster Abenaa , Gor Beverley , Pfeiffer Christine , Jones Lovell
Published: May 2012

A97

Background

Lower folate status is a risk factor for cardiovascular disease and certain cancers. Since pre-menopausal African American women have high rates of obesity, breast and colorectal cancers, understanding the link between obesity and folate metabolic status offers a mechanistic insight into the obesity-cancer connection.

Objective

We assessed the associations between serum total folate, 5-methyltetrahydrofolic acid (5MeTHF), pteroylmonoglutamic acid (PGA), 5-formyltetrahydrofolic acid (5FoTHF), tetrahydrofolic acid (THF]), plasma vitamin B12, and total homocysteine concentrations and obesity in pre-menopausal AA women (n=113).

Design

This was a cross sectional study conducted at the baseline segment of a dietary intervention study in which fasting samples were used for folate, vitamin B12, and homocysteine measurements.

Results

In multivariable analysis, serum total folate concentrations were 14.5% lower in the overweight (BMI 25-29.9) and obese (BMI 30-39.9) women, and 25% lower in the extremely obese (BMI >40) compared to normal weight (BMI <24.9) women (p-trend=0.08). For 5MeTHF, the major form of folate in circulation, overweight women had 15.2% lower, obese women 15.7% lower, and extreme obese women 26.9% lower concentrations than normal weight women (p-trend=0.06). Also, the overweight and obese women were more likely to be in the lower 50th percentile of serum total folate (p-trend=0.03) and 5MeTHF (p-trend=0.08) concentrations compared to the normal weight women. There were no significant associations between BMI and the minor folate species, plasma B12, and homocysteine.

Conclusions

With obesity at epidemic levels, these data, if confirmed by prospective or randomized controlled studies, have important public health implications.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A97.
Abstract B14: Howard University Cancer Center's Mammoday yields results in the fight against breast cancer
Authors: Regis Deon , Higginbotham Kimberly , Gaskins Melvin , Adams-Campbell Lucile , Dewitty Robert , Frederick Wayne , Spencer Cherie , Heyison Marc
Published: May 2012

B14

Background

Washington D.C. has one of the highest breast cancer mortality rates in the country(30.3 per 100,000)*. In June 2003, Howard University Cancer Center started Mammoday, a free breast cancer screening program for women in the Washington, D.C. area to help remedy this egregious public health disparity. Mammograms, in conjunction with clinical breast exams, are provided to low income, underinsured or uninsured women who are at least 40 years of age.

Methods

All participants complete a survey that takes into account all of the major breast cancer risk factors before being examined by a physician. The women then receive a clinical breast examination and mammogram. If the results warrant further investigation, an ultrasound and biopsy is offered at no cost to the patient. If the findings are positive, the patient will receive assistance from a patient navigator to obtain the health coverage needed for treatment. The survey data, the clinical breast examination, and radiologic results are all recorded for analysis.

Results

Using a pure frequency analysis, with a sample size of 243 patients, 17.0% resulted in an abnormal clinical breast exam and 12.9% resulted in an abnormal mammogram. Over the four years that the program has been in existence, 304 women have received breast cancer screening and 10 women have been diagnosed with breast cancer.

Conclusion

The results prove the necessity for a screening program such as Mammoday, by discovering breast cancers that otherwise would have gone unnoticed . The importance of this program registers with the patients and leads to a follow-up rate of 19.4%.Due to its success, the program plans to expand by increasing the number of screenings per year in order to further impact the glaring statistics of breast cancer mortality in the District of Columbia.

*American Cancer Society, Surveillance Research , 2007

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B14.
Abstract B18: Pain, depression, and fatigue symptom cluster as a predictor of physical quality of life in advanced and recurrent cancer
Authors: Morrison Eleshia , Andersen Barbara
Published: May 2012

B18

Pain, depression, and fatigue are common symptoms affecting quality of life (QoL) in cancer patients and survivors. Recent research has suggested the existence of a pain, depression, and fatigue (PDF) symptom cluster. The present study examined whether the PDF symptom cluster predicts physical QoL in cancer patients with advanced disease, an underrepresented group in this area of research. Method: Patients (N=121) with newly diagnosed advanced breast cancer (i.e. metastatic or recurrent disease) were accrued. Women were consecutive cases at a university-affiliated National Cancer Institute-designated Comprehensive Cancer Center or self- and physician-referred cases from the community. The Brief Pain Questionnaire (BPQ), Center for Epidemiological Studies Depression Scale (CES-D), and Fatigue Symptom Inventory (FSI) were used to measure pain, depression, and fatigue, respectively. The Karnofsky Performance Status Scale (KPS) assessed functional status, which was used as a proxy for QoL. Patients were assessed at baseline, and 4, 8, and 12 month follow-ups. A composite score for pain, depression, and fatigue was calculated for each participant by adding the individual scores from each symptom scale. Hierarchical linear regressions were conducted to examine whether PDF predicted physical functioning over time, controlling for relevant disease and demographic variables. Results: Correlation analyses revealed strong positive intercorrelations between pain, depression, and fatigue at all time points. Analyses revealed that a lower PDF composite score at 4 months predicted greater physical functioning both at 8 months and 12 months (p<0.05). Discussion: Results suggest that there may be a longitudinal effect of PDF symptom clustering on quality of life in these patients. Symptom management interventions may need to treat all three symptoms to be maximally effective. Future research could investigate mechanisms for the relationships among symptoms, or generate effective treatment strategies.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B18.