bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A124: Genome-wide association identified susceptibility loci as modifiers of colorectal cancer risk in Lynch syndrome
Authors: Pande Mala , Frazier Marsha L. , Lynch Patrick M. , Broaddus Russell , Reuther Jacquelyn , Jiang Wenxiao , Amos Chistopher I.
Published: May 2012

Purpose: The purpose of this study was to determine whether 5 common low-penetrance variants identified in recent genome-wide association studies (GWAS) for colorectal cancer modify colorectal cancer risk in people with Lynch syndrome. People with Lynch syndrome are genetically predisposed to colorectal cancer owing to an inherited DNA mismatch repair (MMR) gene mutation; however, disease expression varies, pointing to the role of modifying factors. A study of Dutch Lynch syndrome families (Wijnen et al., 2009) examined 6 GWAS-identified markers and found that 2 of them—rs16892766 (8q23.3) and rs3802842 (11q23.1)—were associated with colorectal cancer risk. However, other risk variants have yet to be characterized in Lynch syndrome. A replication study of 3 markers in subjects enrolled irrespective of whether they were MMR gene mutation carriers (Poynter et al., 2007) found that 2 risk variants in the 8q24 region (rs10505477 and rs6983267) and 1 variant in the 9p24 region (rs719725) were associated with colorectal cancer risk.

Methods: In a retrospective cohort study, we analyzed 278 people with Lynch syndrome and a confirmed MMR gene mutation from the M. D. Anderson Lynch syndrome registry. We genotyped the 5 aforementioned risk variants—rs16892766, rs3802842, rs10505477, rs6983267, and rs719725—and analyzed the association between each risk variant and colorectal cancer using Cox proportional hazards regression while adjusting for sex, MMR gene mutation status, and familial correlation.

Results: Of the 278 subjects from 128 families with 11,702 person years of follow-up, 146 subjects had colorectal cancer, and the remaining subjects were unaffected. In a codominant model, rs16892766 was significantly associated with colorectal cancer (hazard ratio [HR]: 1.61; 95% confidence interval [CI]: 1.10–2.35). Similarly, rs3802842 exhibited a marginally significant trend in an additive model (Ptrend = 0.07), and the association was most clearly evident among carriers of mutations in the MLH1 MMR gene in a codominant model (HR: 1.98; 95% CI: 1.18–3.33).

Conclusion: Our study replicates the previous finding of an association between 2 GWAS-identified susceptibility loci and risk of colorectal cancer in people with Lynch syndrome. Although people with Lynch syndrome have a strong predisposition to colorectal cancer due to the underlying MMR mutation, these common genetic variants may further modify their colorectal cancer risk, particularly in carriers of multiple risk alleles. These and other low-penetrance susceptibility loci are likely to have future application in personalized risk prediction in identifying individuals who are most susceptible so that they can be provided more rigorous cancer-prevention strategies.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A124.
Abstract A143: Vaccination of a concatenated L2 fusion protein with L1 VLP or capsomeres for broad protection against HPV infection
Authors: Jagu Subhashini , Kwak Kihyuck , Garcea Robert L. , Roden Richard B.S.
Published: May 2012

Background: Immunization with L1 major capsid protein in the form of the pentavalent capsomeres or 360mer virus-like particles (VLPs) generates high and long-lived titers of neutralizing antibodies and protection primarily against the human papillomavirus (HPV) type from which the vaccine was derived. Consequently, multivalent L1 VLP vaccines have been developed to expand the breadth of coverage, e.g. Cervarix which contains L1 VLPs that are derived from HPV16 and HPV18 and formulated in alum and monophosphoryl lipid A (MPL) adjuvant. Vaccination with L2 minor capsid protein induces lower titer, but more broadly neutralizing and protective antibody responses in animals. To enhance cross-protection we generated multi-type L2 proteins by fusing cross-neutralizing epitopes of divergent HPV types, e.g. 11-88×5 that is a concatamer of L2 residues 11–88 of HPV1, HPV5, HPV6, HPV16 and HPV18.

Objectives: A low cost HPV vaccine that yields cross-protective antibodies and broad protection against more than a dozen oncogenic HPV types is urgently needed. We sought to combine the advantages of each protective antigen by immunization with titrated doses of multi-type L2 11-88×5 in alum+MPL, or with either HPV16 L1 capsomeres or Cervarix and to assess the importance of adjuvant for L2 dose sparing.

Methods: Mice were vaccinated three times every alternate week and bled two weeks later. Serum antibody titers were determined by ELISA using HPV16 L1 VLP or L2 11-88×5antigen, as well as in vitro HPV pseudovirion neutralization assays.

Results: The absolute titers and dose response to 11-88×5 were similar in mice vaccinated with 11-88×5 alone or in combination with either L1 capsomeres or VLPs. HPV16 L1 VLP generated significantly higher HPV16 neutralization titers than L1 capsomeres, and the capsomeres induce higher titers than 11-88×5. Importantly, the serum IgG titers specific to HPV16 L1 VLP were not influenced by vaccination with L1 capsomeres or VLP in the presence of L2 11-88×5. The in vitro neutralization titers elicited by vaccination with 11-88×5 in the combinations tested were not significantly different at two weeks after immunization but there was a trend at four months for reduced cross-neutralization when 11-88×5 was combined with L1 VLP but not capsomeres.

Conclusions: There is no evidence of interference between the L1 and L2 serum antibody response to co-administration of L1 capsomeres, but not VLP, with multi-type L2 vaccines based on neutralization titers.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A143.
Abstract A20: Random periareolar fine-needle aspiration is highly reproducible in a CALGB multi-institutional cross-sectional study
Authors: Seewaldt Victoria L. , Ibarra Catherine , Yee Lisa D. , Wilke Lee G. , Kulkarni Swati , Wood Marie , Garber Judy , Ford Anne
Published: May 2012

Background: Biomarkers that vary with risk and response to prevention interventions are referred to as “surrogate endpoint biomarkers”. As outlined by Fabian et al., surrogate endpoint biomarkers should be 1) biologically and statistically significantly associated with cancer development, 2) present in a reasonable proportion of at-risk individuals, 3) obtainable by minimally invasive procedures, and 4) reversible with prevention interventions that have been validated to decrease cancer incidence. Many modalities have been suggested as potential surrogate endpoint biomarkers for breast cancer, including mammographic density, serum biomarkers, and breast tissue biomarkers. Currently, there is no consensus as to the optimal surrogate endpoint biomarker.

Random Periareolar Fine Needle Aspiration (RPFNA) is a research technique developed to assess short-term breast cancer risk in women at increased risk for breast cancer. While there is increasing acceptance of RPFNA, neither the reproducibility nor the inter-institutional compatibility of RPFNA has been established. To address these key limitations, the Cancer and Leukemia Group B (CALGB) Prevention Group tested the reproducibility of RPFNA in a multi-institutional cross-sectional study.

Methods: Sixty-three high-risk women from five CALGB institutions (Duke, Ohio State, Roswell Park, Dana-Farber, and Vermont) underwent RPFNA from July 1, 2007 to June 30, 2008. Duplicate bilateral RPFNA was performed on each woman by a single investigator on a single day. Masood Cytology Index score was assessed by a single blinded cytopathologist.

Results: There was a high degree of statistical agreement in the Masood Cytology Index scores of duplicate RPFNA samples from the same breast, with a Spearman correlation coefficient of 0.8312 (p<0.0001). Importantly, while there was agreement in duplicate samples from the same breast, there was lack of agreement between duplicate samples from the opposite breast.

Conclusions: This multi-institutional study demonstrates that RPFNA is a highly reproducible measure of breast cytology in a cooperative group cross-sectional trial. RPFNA did not demonstrate a high degree of agreement between breasts, suggesting that breast cancer risk and progression may occur at different rates in individual breasts from a single woman.

These data provide important validation of the reproducibility of RPFNA in a multi-institutional cross-sectional study that included cohorts that varied in demographic composition. Important future directions will include a larger RPFNA cohort study and testing for the reproducibility of RPFNA samples with atypia before and after administration of chemoprevention agents.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A20.
Abstract A34: Nonmelanoma skin cancer and the risk of second primary cancers: A systematic review
Authors: Wheless Lee , Black Joshua , Alberg Anthony J.
Published: May 2012

Context: Based on empirical evidence, the hypothesis has been set forth that a personal history of non-melanoma skin cancer (NMSC) may be a marker of a high cancer-risk phenotype. Others hypothesize that NMSC may be a marker of high vitamin D synthesis and therefore inversely associated with risk of other malignancies.

Objective: To reconcile these divergent views, we carried out a systematic review to determine the overall association between nonmelanoma skin cancer and subsequent risk of other cancers.

Data Sources: PubMed and Ovid/MEDLINE databases were searched through March 2009. The formal search was supplemented by hand searches.

Study selection: Articles were included if sufficient information was presented to estimate the risk of developing other cancers following NMSC.

Data extraction: Articles were reviewed and data abstracted independently in duplicate with disagreements decided by consensus.

Results: Of the 21 included articles, 15 presented on NMSC in relation to risk of all other cancers combined. NMSC was associated with a 17% increased future risk of another malignancy (summary random-effects RR (SRR) 1.17, 95% confidence interval (CI) 1.11–1.22). This association held true for both squamous cell carcinoma (SRR 1.21, 95% CI 1.14–1.28) and basal cell carcinoma (SRR 1.15, 95% CI 1.07–1.24), and both men (SRR 1.15, 95% CI 1.09–1.20) and women (SRR 1.10, 95% CI 1.04–1.15).

Conclusions: Strong, consistent evidence indicates that a personal history of NMSC is associated with an increased risk of developing other malignancies. For reasons that are presently unknown, nonmelanoma skin cancer may be a marker of a high cancer-risk phenotype.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A34.
Abstract A4: SNP-SNP interaction and nongenetic risk factors combine to identify lung cancer susceptibility: Validation in a prospective study
Authors: Young Robert , Hopkins Raewyn , Hay Bryan , Gamble Greg
Published: May 2012

Introduction: Key risk indicators for lung cancer include a smoking history, genetic factors, increasing age, family history and impaired lung function (COPD). In a case-control study, 20 genetic markers associated with lung cancer were combined with non-genetic risks to derive a lung cancer susceptibility score (LCSS). The aim of this prospective follow up study was to compare the LCSS in a cohort of very high risk smokers, with and without lung cancer.

Methods: A cohort of 728 high risk individuals (smoker/ex-smokers, >40 yrs old, >20 pack years, with spirometric confirmed COPD) were recruited and followed for a mean of 5 years. All volunteers underwent spirometry, completed a modified ATS respiratory questionnaire and gave blood for DNA. These volunteers were recruited from the community (N=420) and a COPD outpatient clinic (N=308). To date, we have identified 53 cases of lung cancer (histology confirmed) in this cohort (24 community and 28 clinic). The 20 SNP panel was genotyped using the iPLEX system. Each subjects' genotypes were combined, in a predefined algorithm, to derive the lung cancer susceptibility score.

Results: COPD patients subsequently diagnosed with lung caner were comparable to those with no lung cancer for age, gender, smoking exposure. The mean LCSS, was higher in those who developed lung cancer than those who did not (LCSS 7.0 vs 5.7, P=0.06), and significantly higher than those recruited from the community with mild-moderate COPD (LCSS 7.0 vs 4.7, P<0.001). The performance characteristics of the LCSS reported here, confirms its utility in high risk smokers, to target lung cancer screening and/or diagnostic approaches (using molecular, cytological and/or radiological based tools).

Conclusion: We show, in a prospectively recruited high risk cohort, that our LCSS identifies those with mild-moderate COPD at greatest risk of lung cancer. Such a group might benefit from aggressive screening/diagnostic approaches, so that their lung cancer is diagnosed in stage 1 when survival has been shown to be dramatically improved.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A4.
Abstract A41: Regulation of Nrf2-dependent gene expression in aging
Authors: Ma Quan , Han Zheyi , Yu Rong
Published: May 2012

Nrf2 is a transcription factor which controls induction of antioxidant and detoxification enzymes, and, therefore, plays an essential role in protection against chemical carcinogens. Here, we reported that expression of Nrf2 and its dependent genes was affected by age and became compromised in aged mouse livers. Detail analysis revealed that age-dependent Nrf2 expression was regulated primarily at transcriptional level. Accordingly, we cloned and characterized the promoter region of mouse Nrf2 gene. We identified multiple Sp1 binding sites and confirmed their binding activity by gel-shift and chromatin immunoprecipitation assay. We also showed that the identified Sp1 sites were functional since knockdown of Sp1 expression impaired Nrf2 promoter activity as well as expression of Nrf2-dependent genes. We then compared Sp1 expression and its binding activity to Nrf2 promoter in young and aged mouse liver tissues. While no significant change in Sp1 expression was found, Sp1 binding activity was severely impaired in aged tissues. Given that Sp1-binding sites are GC rich elements, we analyzed their methylation status in Nrf2 promoter, and found that Sp1 sites were highly methylated in aged tissues. In support of the role of methylation, treatment of a mouse hepatoma cell line with demethylase inhibitors indeed reduced Sp1 binding to Nrf2 promoter. We also cloned and analyzed human Nrf2 promoter. Multiple Sp1 binding sites were identified and shown to be equally functional as in mouse Nrf2 promoter. Thus, we propose that age-dependent expression of Nrf2 and its downstream genes is regulated by methylation. A strategy that targets methylation would help to restore Nrf2-mediated protection against oxidative stress or chemical carcinogens in aged tissues.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A41.
Abstract A59: Xanthohumol from hops (Humulus lupulus L.) generates superoxide anion radicals via a mitochondria-mediated mechanism
Authors: Strathmann Julia , Klimo Karin , Sauer Sven , Okun Juergen , Prehn Jochen , Gerhauser Clarissa
Published: May 2012

Xanthohumol (XN), a polyphenol from hops (Humulus lupulus L.), exerts a broad spectrum of cancer chemopreventive activities, including the induction of apoptosis in human cancer cell lines. We speculated that apoptosis induction involved pro-oxidant effects at the mitochondrial membrane, leading to uncoupling of the respiratory chain and subsequent membrane collapse. Here, we investigated whether XN has potential to induce reactive oxygen species (ROS). By co-treatment of benign prostate hyperplasia cells (BPH-1) with XN and dihydroethidium (DHE), specifically oxidized by superoxide anion radicals (O2-*), we measured an immediate dose- and time-dependent increase in fluorescence, whereas Amplex Red, specific for hydrogen peroxide (H2O2), was not oxidized, indicating the formation of O2-*. O2-* formation was significantly inhibited by co-treatment with the anti-oxidants ascorbic acid and N-acetyl cysteine or the superoxide dismutase mimetic MnTMPyP. Fluorescence microscopy images of BPH-1 stained with MitoSOX Red, specific for mitochondrial O2-*, suggested a mitochodrial origin of O2-* formation, which was confirmed by XN-mediated induction of O2-* in isolated mitochondria. Furthermore, in BPH-1-ρ0 (rho-zero) cells, harboring non-functional mitochondria, XN-treatment did not induce O2-*. As one mechanism of XN-mediated O2-* formation, we hypothesize that XN is oxidized to its respective phenoxylradical by intracellular oxidases in the presence of glutathione (GSH) and traces of H2O2, which produces O2-* as side poduct. This was supported by the finding that inhibition of oxidases with diphenylene iodonium (DPI) significantly inhibited XN-induced O2-* formation. Additionally, we demonstrated a time- and dose-dependent increase in oxidized glutathione (GSSG) and global GSH depletion upon XN-treatment. Strikingly, within 15min after XN treatment, intracellular ATP production was reduced by 94% and we observed direct inhibition of complexes I – III of the respiratory chain in submitochondrial particles from bovine heart, as well as in BPH-1. In parallel, the mitochondrial membrane potential broke down already after 10min of XN-treatment and as a consequence, release of cytochrome c was observed, leading to the induction of apoptosis.

In this study, we demonstrate cancer chemopreventive activity of XN by the induction of O2-*, which disrupts the cellular redox balance and mitochondrial integrity and subsequently triggers cancer cells into apoptosis.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A59.
Abstract A68: Aromatase inhibition and chemopreventive potential of novel resveratrol derivatives
Authors: Marler Laura E. , Cushman Mark , Sun Bin , Mesecar Andrew D. , Jermihov Katie , van Breemen Richard B. , Pezzuto John M.
Published: May 2012

Resveratrol, a naturally occurring stilbene found in the human diet, has been shown to mediate a host of biological activities. It has been reported to display both estrogenic and anti-estrogenic activities, depending on cell type and conditions, but inhibition of aromatase activity is weak (IC50 = 25 µM). We have conducted a systematic study in which about 60 substituted stilbenes were synthesized and evaluated for biologic potential. Several of these synthetic derivatives were found to inhibit aromatase activity with IC50 values in the sub-micromolar range. Within the series, structure-activity relationships demonstrated substitution of an amine group produced greater inhibition than a nitro group, and the position of these groups was of greater importance than the number and position of methoxy groups. Compound 1 [(E)-4-(3,5-dimethoxystyryl)aniline] was one of the most potent inhibitors, with an IC50 of 0.31 µM, which is comparable to that of aminoglutethimide (IC50 = 0.2 µM). In addition, crystallographic analysis revealed compound 1 binds to quinone reductase 2 in an orientation similar to that of resveratrol, but demonstrates greater inhibitory potency. Compound 1 has been synthesized on a multigram scale, oral administration with laboratory animals indicates excellent absorption and good metabolic stability, and more advanced testing is underway. (Supported by program project P01 CA48112 awarded by the National Cancer Institute)

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A68.
Abstract A76: Curcumin inhibits head and neck squamous cell carcinoma (HNSCC) migration
Authors: Clark Cheryl A. , Rong Joyce , Nathan Cherie-Ann O.
Published: May 2012

Purpose: Curcumin has been shown to inhibit HNSCC cell proliferation through the AKT/MTOR pathway. We wanted to study the biological effects of curcumin-induced AKT/MTOR inhibition in HNSCC.

Procedures: Soluble proteins (pS6, p4EBP1, FGF2 and MMP-9) extracted from cells treated with or without 20µM curcumin overnight were analyzed by western blot. Cell motility with and without 5, 10, and 20µM curcumin was determined by transwell migration assay and compared using one-way ANOVA in four HNSCC cell lines (FaDu, PCI15A, SCC40 and SCC066).

Results: We used the highly invasive SCC cell line PCI15a to investigate the effects of curcumin on the AKT/MTOR pathway in vitro. Phosphorylated S6 (pS6) and p4EBP1 were inhibited in cells treated with 20µM curcumin for 24 hours. Curcumin inhibited the downstream effector FGF2 by 80% in SCC40 and completely abrogated the downstream effector MMP-9 in the PCI15a cell line. Compared to vehicle, curcumin significantly inhibited migration of the HNSCC cell lines in the transwell migration model. A significant dose-response was found among the four curcumin concentrations for all four cell lines compared to vehicle (p<0.001).

Conclusions: Curcumin inhibits migration of HNSCC cell lines trough the AKT/MTOR pathway and its downstream targets. Cancer cell migration is a highly regulated process that permits dissemination from the primary tumor. Concentrations that inhibited cell proliferation through inhibition of AKT/MTOR and its downstream target MMP-9 were sufficient to inhibit the invasion of a variety of HNSCC cell lines in vitro. This sensitivity of HNSCC cells to retardation of cell migration by curcumin further highlights its chemopreventive properties.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A76.
Abstract B107: The association of soy consumption and lung cancer among Japanese women: Analyses stratified by smoking status and reproductive factors
Authors: Okasaka Toshiki , Matsuo Keitaro , Ito Hidemi , Hosono Satoyo , Kawase Takakazu , Tanaka Hideo , Yokoi Kohei , Tajima Kazuo
Published: May 2012

Soybean products intake has been suggested to have protective effects against breast cancer. As for lung cancer, we previously reported that soy consumption showed inverse association with the risk of non-small cell lung cancers (NSCLC) with epidermal growth factor receptor mutations among Japanese. However, other possible heterogeneity of its effect on the etiology of NSCLC by background characteristics is still unclear. In this study, we investigated the impact of soy consumption on the development of NSCLC among larger number of Japanese women, with the association of smoking status, reproductive factors, as well as histology.

We conducted a case-control study with 420 NSCLC women cases and 840 age-sex matched control subjects. Dietary exposures were evaluated based on a semi-quantitative food frequency questionnaire, including items on lifestyles, menstrual and reproductive history. Soy consumption was categorized into two groups: a lower third group, “Low consumption group (LCG)” which intake of soy was less than 30.3 mg/day, and others, “High consumption group (HCG)” which intake of soy were 30.3mg/day or more. We assessed the impact of soy consumption on lung cancer by calculating odds ratios (ORs) and their 95% confidence intervals (CIs) of HCG, relative to LCG with adjustment for potential confounding factors using logistic regression model.

In the overall analysis, we observed inverse association with high consumption of soy products [OR: 0.87, 95%CI: 0.65–1.16]. When stratified by smoking status, HCG in never smokers showed significantly inverse association showed an OR below unity [OR: 0.69, 95%CI: 0.50–0.96] in spite of the increased OR among HCG in ever smokers [OR: 2.02, 95%CI: 1.11–3.68]. As for reproductive factors, ORs of HCG were consistently below unity among women with pre-menopause [OR: 0.55, 95%CI: 0.29–1.04], menopause after 50 years old [OR: 0.57, 95%CI: 0.34–0.94], and no delivery [OR: 0.57, 95%CI: 0.15–1.06]. It is interesting to note that on histology based analysis, we found inverse association between high consumption of soy products and adenocarcinoma [OR: 0.57, 95%CI: 0.34–0.94] among never smokers, despite the increased ORs were seen among ever smokers [OR: 3.35, 95%CI: 0.17–67.7].

In this study, consumption of soybean products generally demonstrated an inverse association with NSCLC. In addition, the results indicated the interaction between soy consumption and smoking status for the impact on the development of NSCLC. We also found associations among soy consumption, reproductive factors and lung cancer, which indicated that female hormonal factors might be involved in the etiology of NSCLC. Further epidemiological evaluation is warranted.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):B107.
Abstract B119: Racial variation in umbilical cord blood leptin concentration in male babies
Authors: Lai Gabriel Y. , Rohrmann Sabine , Agurs-Collins Tanya , Sutcliffe Catherine G. , Bradwin Gary , Rifai Nader , Bienstock Jessica , Platz Elizabeth A.
Published: May 2012

Objective: Because studies have reported that higher birth weight is associated with higher prostate cancer risk later in life, we hypothesized that racial differences in utero affecting birth weight contribute to the racial disparity in prostate cancer risk. Leptin is a candidate for evaluating this hypothesis because it may influence fetal development, and levels in adulthood have been associated with prostate cancer risk in some studies.

Methods: Leptin concentration was measured by ELISA in venous cord blood collected from 70 African-American and 37 white male full-term births. Sex steroid hormones and insulin-like growth factor (IGF) axis concentrations were measured previously. Separately by race, we calculated geometric mean leptin concentrations and estimated adjusted geometric means using linear regression.

Results: Leptin was positively correlated with birth (r=0.34) and placental (r=0.25) weights, IGF-1 (r=0.21), and IGF binding protein (BP)-3 (r=0.29) adjusting for race. Mean (± standard error) birth weight was lower (p=0.0011) in African-American (3,237 ± 342 g) than white (3,477 ± 395 g) male babies. Unadjusted geometric mean leptin did not differ (p=0.92) between African Americans (5,280 pg/mL; 95% CI: 4,322–6,451) and whites (5,187 pg/mL; 95% CI: 3,938–6,832). However, adjusted geometric mean leptin was nonstatistically significantly higher (p=0.15) in African Americans (5,954 pg/mL; 95% CI: 4,725–7,502) than whites (4,133 pg/mL; 95% CI: 2,890–5,910).

Conclusion: We observed a non-significantly higher adjusted cord blood leptin concentration in African-American compared with white male babies, although unadjusted levels were similar. If our hypothesis were correct, we would have expected higher unadjusted leptin levels and birth weight among African-American babies. Funding: NCI grants U54 CA091409, U54 CA091431, T32 CA009314; doctoral research fund, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):B119.
Abstract B129: Use of white blood cell growth factors and risk of acute myeloid leukemia or myelodysplastic syndrome among elderly non-Hodgkin's lymphoma patients
Authors: Gruschkus Stephen K. , Lairson David R. , Dunn J. Kay , Risser Jan M.H. , Du Xianglin
Published: May 2012

Therapy-related myelodysplastic syndromes and acute myeloid leukemia (t-MDS/AML), defined as MDS or AML occurring after myelosuppressive chemotherapy and/or radiation therapy, are devastating long-term complications of cancer therapy. White blood cell growth factors (CSFs) are supportive care agents intended to minimize risk of febrile neutropenia in patients receiving chemotherapy. However, evidence suggests that CSFs may increase risk of t-MDS/AML, possibly due to the observation that CSFs not only stimulate the proliferation and differentiation of hematopoietic stem cells, but also interfere with apoptosis. The purpose of this study was to evaluate the association between CSF use and t-MDS/AML among a large population-based cohort of elderly non-Hodgkin's lymphoma (NHL) patients treated with chemotherapy.

We identified 13,203 NHL patients from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database diagnosed from 1992 to 2002 who received chemotherapy within 12 months of diagnosis. Patients were followed from their initial chemotherapy date until t-MDS/AML development, death, or end of study period (October 31, 2006). Overall, 40% (n=5,266) of patients received CSF. A total of 272 (5.2%) of patients receiving CSF developed t-MDS/AML vs. 230 (2.9%) who did not receive CSF: there was a statistically significant higher incidence of t-MDS/AML among patients receiving CSF compared to patients not receiving CSF (log-rank p<0.0001). In a multivariable Cox regression analysis adjusting for gender, histology, stage, comorbidities, chemotherapy dates, and chemotherapy agent, CSF use was independently associated with a 53% increased risk of t-MDS/AML (HR 1.53; 95% CI 1.26 – 1.84). A dose-response relationship was observed, with t-MDS/AML risk increasing by quartile of CSF claims. In an evaluation of plausible biologic interactions, we found that patients who received both CSF and antimetabolite chemotherapy had a 2.5 fold increased risk of t-MDS/AML (HR 2.49; 95% CI 1.91 – 3.26) vs. patients who received neither agent (p-interaction=0.04). This observation has added clinical significance considering that approximately 10% of the overall population received this therapeutic combination.

To our knowledge, this is the first large population-based study to evaluate the association between CSF use and t-MDS/AML risk among NHL patients. Findings support our hypothesis that the administration of CSF among elderly NHL patients receiving chemotherapy may increase the risk of t-MDS/AML, even though the absolute risk is low in these populations. Future studies are necessary to verify these results and to determine the potential clinical implications of the observed interaction between CSF use and antimetabolite chemotherapy.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):B129.
Abstract B134: Tubal ligation and ovarian cancer: A meta-analysis
Authors: Rice Megan , Hankinson Sue , Tworoger Shelley
Published: May 2012

Background: While several studies have reported varying associations between tubal ligation and ovarian cancer, no recent meta-analysis has been conducted. In addition, past meta-analyses have not examined whether study factors, such as study design, or individual factors, such as age at procedure, modify the relationship between ovarian cancer and tubal ligation.

Methods: We sought to identify all English-language articles in the PubMed database with quantitative data on the effect of tubal ligation and ovarian cancer using the keywords “ovarian cancer” and “tubal ligation” or “tubal sterilization”. We identified 21 articles which provided estimates of the risk of ovarian cancer in relation to tubal ligation and six articles which reported stratum-specific estimates of ovarian cancer risk by age at and years since tubal ligation. The summary relative risk (RR) estimate and the 95% confidence interval (CI) for the summary estimate were calculated using a random-effects model. Tests for homogeneity were used to evaluate the consistency of findings among studies, and Begg's and Egger's tests were used to assess publication bias.

Results: The RRs for ovarian cancer comparing women who had a tubal ligation to those who did not ranged from 0.20 to 2.40 across the studies. The summary RR was 0.68 (95% CI: 0.62–0.75), demonstrating a statistically significant protective effect of tubal ligation on ovarian cancer. We found no evidence of heterogeneity by study design (e.g., cohort versus case-control) or residence of participants (United States vs. non-United States) as well as no evidence of publication bias. In secondary analyses based on four studies, we did not detect a difference in the risk of ovarian cancer between women who had a tubal ligation less than 20 years ago versus 20 or more years ago (p for heterogeneity = 0.65). Similarly, we did not detect effect modification by age (<35 years of age, >35 years of age) at tubal ligation (p for heterogeneity = 0.92). Though data were insufficient to calculate summary RRs by histologic subtype, a qualitative examination of study results demonstrated a stronger protective effect of tubal ligation for endometroid tumors.

Conclusions: Observational epidemiologic evidence strongly suggests that there is a decreased risk of ovarian cancer among women who have had a tubal ligation. We found a 30 percent reduction in ovarian cancer among women who had ever had a tubal ligation compared to women who have never had a tubal ligation. This estimate did not vary by study design or residence of participants. In addition, we did not detect any effect modification by age at tubal ligation or years since tubal ligation. While there is some evidence that the effect of tubal ligation varies by histologic subtype, further research is needed in this area.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):B134.
Abstract B140: Exposure and the risk of pancreatic cancer: Results of the Netherlands Cohort Study
Authors: Heinen Mirjam M. , Verhage Bas A.J. , Goldbohm R. Alexandra , van den Brandt Piet A.
Published: May 2012

Objective: We examined the role of active cigarette smoking, smoking cessation, and environmental tobacco smoking (ETS) as determinants for pancreatic cancer in a large prospective cohort study.

Methods: The Netherlands Cohort Study consisted of 120,852 men and women who completed a baseline questionnaire in 1986. After 16.3 years of follow-up, 520 pancreatic cancer cases were available for analysis.

Results: Compared to never cigarette smokers, both former and current cigarette smokers had an increased pancreatic cancer risk (multivariable-adjusted hazard rate ratio (HR) = 1.34; 95% confidence interval (CI) = 1.02–1.75 and HR = 1.82; 95% CI = 1.40–2.38, respectively). We observed an increased pancreatic cancer risk of 38% (95% CI = 1.01–1.87) with smoking ≥20 cigarettes per day compared to never cigarette smoking. The trend test was significant (P = 0.03), but no clear dose-response relation was present. For duration of smoking, we observed an increased pancreatic cancer risk per increment of 10 years (multivariable-adjusted HR = 1.15; 95% CI = 1.08–1.22), with a clear dose response effect observing a 2-fold increased cancer risk comparing ≥40 years of smoking to never cigarette smoking. Quitting smoking gradually reduced the risk of pancreatic cancer (HR = 1.83, 1.41, and 1.42 for currents smokers, ex-smokers quitted 0.1–<10 yrs, and quitted 10–<20 yrs, respectively) and reached unity after ≥20 years of quitting smoking (multivariable-adjusted HR = 1.17; 95% CI=0.80–1.70). Based on the current study, hypothetically 27% (95% CI = 15–37) of pancreatic cancer cases could be prevented if people would not smoke. We investigated which smoking aspect was most important in pancreatic cancer etiology by including smoking variables simultaneously in the model. Only duration remained significantly associated with pancreatic cancer risk (≥40 years of smoking vs. never cigarette smokers, multivariable-adjusted HR = 1.87; 95% CI = 1.24–2.80); the risk estimates of other smoking variables attenuated and became non-significant. When we investigated the interaction between ethanol intake and cigarette smoking, no significant interaction was found (P = 0.97). However, current smokers who consumed ≥30 g of ethanol daily experienced a significantly increased risk compared to abstainers who never smoked (multivariable-adjusted HR = 2.40; 95% CI = 1.06–5.41). No association was observed for ETS and pancreatic cancer risk in women.

Conclusion: Overall, our findings confirmed that cigarette smoking is an important risk factor for pancreatic cancer, while quitting smoking reduced risk. Therefore from a public health perspective, quitting smoking would benefit the burden on pancreatic cancer incidence and mortality. No association was observed between ETS and pancreatic cancer.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):B140.
Abstract B29: African American men never or rarely screened for prostate cancer
Authors: Williams-Brown Shanita D. , Ross Louie E. , Hinton Lisa
Published: May 2012

Introduction: Prostate cancer is the leading cancer and the second leading cause of cancer deaths among men in the United States. African American (AA) men are at greater risk than Caucasian American (CA) and other men in both incidence and mortality related to prostate cancer. Incidence among AA men is about 60 percent greater and mortality about 240 percent greater than in CA men. AA men also have a greater likelihood of presenting at higher stage and grade with poorer health and other outcomes. Little is known about factors related to AA men who never or are rarely screened for prostate cancer using the DRE and PSA tests. The purpose of this study was to explore prostate cancer screening practices of AA men and to examine demographic characteristics that are associated with AA men who never or are rarely screened.

Methods: AA men age 40 or older were asked questions about their knowledge, awareness, and attitudes regarding prostate cancer and prostate cancer screening using DRE and PSA. The study used a convenience sample of 448 AA men 40 years and older residing in the Southeastern U.S. Data were self-reported survey responses and analyzed using SAS.

Results: The majority of study participants were married (52%), had some college or technical training (78%), and employed (59%). Over 90% of the AA men had prior knowledge of DRE and 77% were aware of the PSA test. The percentage of AA men who had not had prostate cancer screening in over 5 years or not at all (never or rarely screened) was 33% for DRE and 34% for PSA. Demographic factors related to never or rarely screened for DRE were: being single, younger age, no health insurance, and higher levels of education. Factors related to never or rarely screened for PSA were: younger age, no health insurance, and higher levels of education.

Conclusions: Since AA men have greater burden of prostate cancer among men, it is surprising that despite knowledge and awareness of screening and increased levels of education, approximately one-third of the men in this sample had neither a DRE or PSA ever or in 5 or more years. Additional studies are needed to further explore the relationship between prostate cancer knowledge and awareness, education attainment, and prostate cancer screening in AA men.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):B29.
Abstract B5: Psychosocial mechanisms for explaining the relationship between physical activity and fatigue in breast cancer survivors
Authors: White Siobhan M. , McAuley Edward , Rogers Laura Q. , Courneya Kerry S.
Published: May 2012

Fatigue is one of the most commonly reported and enduring symptoms experienced as a result of breast cancer treatment. One important behavior that has been identified as having the potential to reduce breast cancer related fatigue is physical activity. However, few attempts have been made to fully understand this relationship and it is not known whether physical activity directly influences fatigue or operates through other factors. The purpose of this study was to examine the role of psychosocial mechanisms, self-efficacy and depression, as potential pathways from physical activity to fatigue in a cross-sectional sample of breast cancer survivors (N=192). Participants completed measures of health status, physical activity, depression, fatigue, and self-efficacy. Data were analyzed using path analysis within a covariance modeling framework. This model proposed that that physical activity's influence on fatigue is indirect through its direct effect on self-efficacy which, in turn, has both a direct effect on fatigue and an indirect effect through depression. The hypothesized path model provided an excellent fit to the data (Ξ2 = 1.48, df = 2, p =.48; SRMR = 0.02, CFI = 1.00). All of the proposed path coefficients of the hypothesized model were significant. Overall, the model accounted for 45.2% of the variation in fatigue. As a result of the robust relationship between fatigue and depression (β =.51), the analysis was re-run using a depression score which excluded items assessing “somatic and retarded activity” symptoms. The fit of the model was almost identical to the previously described model (Ξ2 = 1.48, df = 2, p =.45; SRMR = 0.03, CFI = 1.00). A final analysis was conducted on the original model to test effects of for demographics (i.e., age, education, employment, income), time since diagnosis, breast cancer stage, current treatment, menopausal status, body mass index, and comorbidities on model fit and path coefficients, as well as the model components themselves. This model also was an excellent fit to the data (Ξ2 = 2.10, df = 2, p =.35; SRMR = 0.01, CFI = 1.00). In general, the magnitude and direction of the hypothesized relationships were unaffected by the inclusion of the covariates in the model. Our findings suggest support for one set of psychosocial pathways from physical activity to fatigue, an important concern in breast cancer survivors. Subsequent work might replicate such associations in other survivor populations and attempt to determine whether model relations change with physical activity interventions, and the extent to which other known correlates of fatigue such as impaired sleep and inflammation can be incorporated into this model.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):B5.
Abstract B54: The anticancer effects of calorie restriction on MC38 colon tumors are associated with decreased macrophage infiltration
Authors: Harvey Alison E. , Otto Glen , Nunez Nomeli P. , Perkins Susan N. , Hursting Stephen D.
Published: May 2012

Obesity is a risk factor for a number of chronic diseases including many types of cancer. The chronic, low-grade inflammation that develops as a result of obesity may be a primary mechanistic target underlying obesity-associated carcinogenesis. While the link between obesity and inflammation is not well understood, increases in adipose tissue macrophages may perpetuate and exacerbate a chronic inflammatory environment through production of inflammatory cytokines such as interleukin (IL)-6. In this study we tested the hypothesis that macrophage infiltration underlies our previously observed anticancer effects of calorie restriction (CR) in a mouse model of colon cancer. Six-week-old female C57BL/6 mice (n=30 per diet) were singly housed and randomized to either a control diet consumed ad libitum (which results in an overweight phenotype) or a 30% calorie-restricted diet regimen (CR) for 22 weeks, at which time 15 mice per group were euthanized and adiposity was measured using dual-energy X-ray absorptiometry (DXA). The remaining 15 mice/diet were then injected subcutaneously (flank) with 50,000 syngeneic mouse colon (MC)-38-adenocarcinoma cells and continued on their diet regimens while tumor growth was monitored for an additional 5 weeks. Excised tumors underwent histological analysis of macrophage infiltration (hematoxylin and eosin staining) and real-time RT-PCR analyses of macrophage (F4/80 and S100A9) and IL-6 gene expression. CR mice had lower body weight (20.3g +/− 0.2 vs. 26.0g +/− 0.5 (mean +/− SEM), p<0.05) and body adiposity (22.9% +/− 1.2 vs. 29% +/− 1.7, p<0.05) after 21 weeks on study compared to control mice. Additionally, CR mice had smaller tumors (100.3 mm^3 +/− 13.2 vs. 242.4 mm^3 +/− 28.3, p<0.05) relative to controls. Tumors from CR mice, relative to controls, exhibited a 3-fold decrease in F4/80 and S100A9 gene expression and a 2.5 fold decrease in IL-6 (p<0.05). Furthermore, HandE staining showed reduced macrophage infiltration in CR tumors compared to control tumors. These findings suggest that the inhibitory effects of CR on MC38 colon tumor growth are associated with reduced tumor infiltration of macrophages, which may lead to new targets for the prevention of colon cancer.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):B54.
Abstract B6: Obesity risk in relation to quality of life: Baseline results from a worksite trial
Authors: Whisnant Stephanie , Beresford Shirley A.A. , Henderson Jo A. , McTiernan Anne , Xiao Liren , Patrick Donald L. , Wang C.Y.
Published: May 2012

Introduction: Obesity, a risk factor for certain cancers, can also be related to reduced health-related quality of life and productivity. We examined eating physical activity behaviors, and body mass index (BMI), as predictors of health-related quality of life and productivity.

Methods: MOVE ‘M is a worksite-randomized trial targeting diet and physical activity to reduce weight gain. Secondary outcomes include Obesity and Weight Loss Quality of Life (OWLQOL) and productivity. Baseline data collection occurred from 2006–2008, and data were analyzed in 2009.

Results: Baseline data were analyzed for individual-level associations using linear mixed models. Since gender was found to be an effect modifier, data were analyzed separately for men (n=288) and women (n=281). BMI was negatively associated with OWLQOL in both women (p<0.001) and men (p<0.001). The linear effect estimate for OWLQOL score associated with one category increase in BMI was 32% (95% CI: 27%, 37%) for women and 12% (95% CI: 8%, 17%) for men. Physical activity was associated (p=0.007) with OWLQOL only in women. Eating while doing another activity was negatively associated with OWLQOL scores only in men (p=0.0003) and with productivity only in women (p=0.004).

Conclusion: Our results suggest obese persons, particularly women, experience diminished OWLQOL. If longitudinal analyses confirm these findings, there may be additional work-related and general health benefits from reducing weight and increasing physical activity.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):B6.
Abstract B61: Ha-RAS mutations in fibroblast of the cervical stroma of squamous neoplasias of the uterine cervix
Authors: Moreno-Acosta Pablo , Serrano Martha , Carrillo Schyrly , Nuñez, Diana , Romero-Rojas Alfredo
Published: May 2012

The stroma is maintained, renovated, and repaired by resident fibroblasts, supports and instructs the epithelium, and is essential for epithelial function. Now recognized that stromal changes are necessary for the establishment of cancer and previously considered as a spectator in front of the clonal expansion and acquisition of malignant characteristics of tumor cells. Most studies on the stroma and t its relationship with the generation, progression and metastasis of cancer in which involve multiple steps of tumorigenesis and the microenvironment, have focused especially on cancers such as breast and others as cancer of prostate, gastric, colorectal and cervical cancer. Reports of cervical cancer specifically address issues such as clonality and genomic features in cervical carcinogenesis. However, the presence of mutations Ha-RAS oncogen in stromal cells and their contribution to the generation and progression of cervical squamous neoplasia has not yet been reported. The aim of this study was detect and determine the frequency of mutations Ha-RAS in stromal fibroblasts from biopsies of the transformation zone of the uterine cervix. We selected eight samples of fresh frozen tissue of patients diagnosed with cervical intraepithelial neoplasia squamous (CIN I, CIN II, CIN III), cancer in situ and invasive squamous cell carcinoma, tissue in which it was represented only the stroma, without evidence of residual tumoral epithelial component, and each of whom had cervical tissue in paraffin-embedded control confirming the presence of cervical squamous neoplasia. The detection of Ha-ras mutations in codon 12 was performed using a nonradioactive PCR-SSCP and restriction enzyme analysis. The mutation found for a substitution of a glycine by a valine at codon 12 of Ha-RAS was detected in alone sample (12.5%), CIN III. The non-detection of the GTC mutation in the remaining seven samples could be due to somatic mutation that this represented only a small fraction (approximately 15%) of total DNA analyzed (33), as well as a topographical heterogeneity likely distribution of these mutations. The presence of a point mutation of Ha-RAS oncogene in the stroma of one case studied, represents an important change, this mutation prevents the conversion of active to inactive form, and suggest an alternative pathway involving stromal genetic instability in the generation of intraepithelial neoplasia and progression of the cervical cancer.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):B61.