bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A111: Sweetened beverages, sweetened foods, glycemic load, and breast cancer recurrence
Authors: Thomson Cynthia A. , Rock Cheryl R. , Patterson Ruth E. , Flatt Shirley W. , Ritenbaugh Cheryl , Newman Vicky A. , Cussler Ellen , Pierce John P.
Published: May 2012

Background: The role of sweetened food and beverage intake in breast cancer recurrence has been largely unexplored despite mechanistic evidence that these dietary factors may be associated with elevated glycemic load, insulin levels and proinflammatory response.

Objective: To assess risk for recurrent or a new primary breast cancer event among 2832 breast cancer survivors enrolled in the Women's Healthy Eating and Living (WHEL) Study in relation to baseline sweetened beverage and sweetened food intakes and glycemic index/glycemic load. Design: Prospective sub-group analysis of dietary GI, GL, white bread/rolls/crackers, sweet food and sweetened beverage intakes, as assessed using the Arizona Food Frequency Questionnaire (AFFQ), and new breast cancer events (N=471). Descriptive statistics and Cox regression analysis, adjusted for confounding variables, were performed to assess hazard ratio for recurrence risk by dietary exposure.

Results: Study subjects consumed, on average, 281.7±111.4 g/d carbohydrate (CHO) and 25.2±12.3 g/d of dietary fiber and had an estimated GL of 129.5±52.2.While GI and GL were not significantly associated with breast cancer events, postmenopausal women who reported a higher intake of sweetened beverages demonstrated a significant elevation in risk for recurrent disease (HR 1.46; 95% CI,1.07–1.98). Intake of sweetened beverages was greater among minority women and was associated with higher body mass index and lower reported physical activity suggesting sweetened beverage intake may be a surrogate of other risk factors.

Conclusions: High intake of sweetened beverages, including carbonated beverages and sweetened fruit drinks, is associated with an increased risk for breast cancer recurrence among postmenopausal women previously treated for early stage disease.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A111.
Abstract A113: Toenail selenium and the risk of esophageal and gastric cancer subtypes: The Netherlands Cohort Study
Authors: Steevens Jessie , van den Brandt Piet A. , Alexandra Goldbohm R. , Schouten Leo J.
Published: May 2012

Purpose: Selenium may protect against the development of esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC) and gastric cardia adenocarcinoma (GCA). Only in very few studies have the associations with ESCC and GCA been investigated, and no epidemiologic studies exist on EAC.

Methods: We studied the association between selenium and risk of ESCC, EAC, and GCA within the prospective Netherlands Cohort Study, conducted among 120,852 men and women aged 55–69 years at baseline. In September 1986, the cohort members completed a questionnaire on risk factors for cancer and provided toenail clippings for determination of baseline selenium status. After 16.3 years of follow-up, 64 ESCC, 112 EAC, and 114 GCA cases and 2072 subcohort members with toenail selenium data were available for case-cohort analysis. Incidence rate ratios (RR) were calculated using Cox proportional hazards models.

Results: In multivariable analyses of selenium status, we found an inverse association with ESCC (RR quartile 4 versus quartile 1 0.37, 95% confidence intervals (CI) 0.16–0.86), and a borderline significant inverse association with GCA (RR 0.52, 95% CI 0.27–1.02). No overall association was observed for EAC (RR 0.76, 95% CI 0.41–1.40), although results suggested an inverse association in women. Stratified analyses showed stronger associations in never smokers, and (only for EAC) in subjects with a low antioxidant intake.

Conclusions: This prospective study supports an inverse association between toenail selenium and risk of ESCC and GCA and suggests an inverse association with risk of EAC in subgroups (women, never smokers, and low antioxidant consumers). These associations need confirmation.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A113.
Abstract A119: Effect of weight-bearing exercise on circulating biomarkers in breast cancer survivors
Authors: Bea Jennifer W. , Thomson Cynthia , May Melissa , Nardi Emily , Frey Georgette , Stopeck Alison , Thompson Patricia
Published: May 2012

Breast cancer patients generally demonstrate a gain in body fat mass accompanied by loss of lean mass (i.e. muscle) during cancer therapy (Demark-Wahnefried et al, J. Clin Oncol, 2001). These changes may lead to adverse metabolic and inflammatory phenotypes. The objective of this pilot study was to evaluate changes in metabolic, inflammatory, and growth factor biomarkers among breast cancer survivors following 8 weeks of supervised resistance training combined with self-reported cardiovascular training. No diet or weight loss component was included in the intervention.

Twenty-seven breast cancer survivors (78.3% Caucasian, mean age 56.5 ± 8.1 yrs, mean BMI 29.8 ± 4.4kg/m2) who were on average 5 years post-cancer treatment were recruited to participate in a prospective behavioral intervention trial to test the hypothesis that weight bearing activity including stretching, resistance, balance, and aerobic training would improve select metabolic and inflammatory indicators over an 8 week period. Height, weight, body composition (dual X-ray absorptiometry), fasting plasma glucose, insulin, IL-6, CRP, IL-1Ra, and IGF-1 were measured at baseline and 8 weeks. IL-6, IL-1Ra and IGF-1 were analyzed using high sensitivity ELISA and glucose was measured by a glucose oxidase-peroxide reaction; insulin and CRP testing were performed by the local hospital clinical laboratory. The homeostasis model of insulin resistance was computed (HOMA-IR) from glucose and insulin values.

Eighty-one percent of the sample completed the 8-week intervention. Among completers (n=22) there was no significant change in body weight. Inflammatory response, as assessed using IL-1Ra, was improved (76.75 ± 161.39, p<0.05), however, there was no significant change in IL-6 or CRP. IGF-1 and HOMA-IR also remained unchanged.

Breast cancer survivors participating in a pilot, short-term structured physical activity intervention targeting resistance training, in the absence of diet or weight change, demonstrated a significant improvement in the anti-inflammatory biomarker IL-1Ra without concomitant increases in pro-inflammatory biomarkers, IL-6 and CRP. Larger studies with sufficient sample size to detect statistically significant differences should be pursued; combining structured exercise with diet to support weight reduction may also be superior and should be evaluated.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A119.
Abstract A122: Genetic variation in selenoprotein P, selenium levels, and prostate cancer risk and survival
Authors: Penney Kathryn L. , Li Haojie , Mucci Lorelei A. , Morris J. Steven , Sesso Howard D. , Stampfer Meir J. , Ma Jing
Published: May 2012

Background: Selenoprotein P (SelP) is the most common selenoprotein in serum and delivers selenium around the body, carrying up to ten selenocysteine residues per polypeptide. Antioxidants such as selenium may decrease the risk of developing prostate cancer (PCa). One study observed that serum SelP levels were lower in PCa cases than in controls while another found the expression of the gene, SEPP1, decreased with progression from normal prostate tissue to carcinoma to metastatic disease. Genetic variation in SEPP1 may also influence PCa risk or progression, or may modify the effects of selenium. We examined the association of single nucleotide polymorphisms (SNPs) in SEPP1 with PCa risk and survival, and tested for interactions with plasma selenium levels.

Methods: The Physicians' Health Study (PHS) is a prospective cohort of 22,071 US physicians, of whom 2,584 were diagnosed with PCa between 1982 and 2005. Blood was collected from 68% of participants at baseline. We used a nested case-control study of 1,352 PCa cases and 1,382 controls matched on age, smoking status, and follow-up time; analyses were restricted to Caucasians. Using the HapMap database, we selected 5 SNPs to capture variation with a minor allele frequency >5% within SEPP1 and 5 kb up- and downstream. Four SNPs had high genotyping success (92–97%); the other failed genotyping, however, it tagged only itself so did not reduce the coverage. The incidence analysis used unconditional logistic regression, adjusting for matching factors. For survival analysis, individuals were censored at death or the end of follow-up; PCa deaths or metastases were considered lethal events (n=191). Plasma selenium levels were measured on 805 cases and 549 controls.

Results: Two of the four SNPs were significantly associated with risk of incident PCa. For rs11959466, each additional T allele significantly increased the risk of PCa (odds ratio (OR)=1.31; 95% confidence interval (CI): 1.02, 1.69; ptrend=0.03), while for rs13168440, the minor allele homozygote genotype (CC) was associated with a decreased risk compared to the homozygote TT referent (OR=0.56, 95% CI: 0.33, 0.96). Moreover, there was a significant interaction of rs13168440 with quartiles of plasma selenium; increasing levels were associated with a decreased risk of PCa only among men with the minor allele (OR=0.76; 95% CI: 0.62, 0.93; pinteraction=0.02). None of the four SNPs was associated with PCa survival among the cases.

Conclusions: Genetic variation within SEPP1 was associated with PCa incidence and may modify the association of selenium. Considering the multiple hypotheses tested, replication of these findings in an independent data set is needed to confirm or refute these results.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A122.
Abstract A127: Comparison of discriminatory power and accuracy of three lung cancer risk models
Authors: D'Amelio Anthony M. , Cassidy Adrian , Asomaning Kofi , Raji Olaide Y. , Duffy Stephen W. , Field John K. , Spitz Margaret R. , Christiani David , Etzel Carol J.
Published: May 2012

Background: Since lung cancer only occurs in a small fraction of long-term smokers, there is a need to develop risk prediction models to identify high-risk subgroups. Three lung cancer models, constructed using clinical and epidemiological variables, predicted absolute risk of lung cancer: one based on a cohort of patients recruited for the CARET study, and two constructed from case-control studies conducted in Houston, Texas and Liverpool, England. Given their potential application to primary chemo-prevention strategies and screening trials, it is important to compare the accuracy of these three models in an independent population.

Methods: We used data for 3197 lung cancer patients and 1703 cancer-free controls recruited to an ongoing case-control study of lung cancer at Harvard School of Public Health and Massachusetts General Hospital (Boston, MA). We estimated 5-year lung cancer risk for each risk model and compared the discriminatory power, as measured by the area under the the receiver-operator characteristic curve, accuracy, as measured by the positive predictive value and negative predictive value, and clinical utility of these models, as measured with scaled rectangles.

Results: Overall, the discriminatory power for the Liverpool Lung Project (LLP) (AUC = 0.69, 95% CI = 0.67–0.71) and Spitz models (AUC = 0.69, 95%CI = 0.66–0.71) were comparable, while the Bach model had significantly lower power (AUC =0.66, 95% CI = 0.64–0.69; P=0.02). Positive predictive values were highest with the Spitz model (0.882) compared to 0.809 for the Bach model and 0.759 for the LLP model. In contrast, the negative predictive values were highest for the LLP model (0.560) compared to 0.450 for the Spitz model and 0.447 for the Bach. The Spitz and Bach models had lower sensitivity but higher specificity compared to the LLP model. For instance, 26.6% of all lung cancer cases have a five-year absolute risk of lung cancer ≥ 2.5% for the Spitz model compared to 66.7% of all cases for the LLP model. However, only 5.6% of all healthy controls have a five-year absolute risk of lung cancer ≥ 2.5% with the Spitz model compared to 33.4% of all controls for the LLP model.

Conclusion: We observed modest differences in discriminatory among the three lung cancer risk models. The level of the discriminatory powers of these three lung cancer risk models was moderate at best, which highlights the difficulty in developing effective risk models. There is considerable room for improvement in model performance by incorporating additional risk factors, such as genetic risk factors, to increase discriminatory power and accuracy, while still maintaining clinical utility.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A127.
Abstract A129: Declining incidence of breast cancer since 2002 in the United States: How much is explained by the decrease in postmenopausal hormone use?
Authors: Sprague Brian L. , Trentham-Dietz Amy , Remington Patrick L.
Published: May 2012

The striking decline in breast cancer incidence since 2002 in the United States has been widely attributed to discontinuation of postmenopausal hormone use following the results of the Women's Health Initiative (WHI) randomized trial. However, very little analysis has been conducted to quantify the contribution of cessation of hormone use to the observed decline in breast cancer incidence. We used literature-based estimates of the change in the prevalence of hormone use and the relative risk associated with hormone use to estimate the impact of cessation of hormone use on the observed decline in breast cancer incidence between 2002 and 2003 among women aged 40–79 years old. For the base case of a 46% decline in hormone use and a relative risk for current use of 1.5, we estimate that 42% of the decline in incidence was attributable to cessation of hormone use. By exploring a range of parameter values we found that high, unlikely values of the relative risk (i.e., ≥2.25) and/or the percent decline in hormone use (i.e., ≥75%) would be required to account for 100% of the observed decline in breast cancer incidence. We conclude that cessation of postmenopausal hormone use following the announcement of the results of the WHI is unlikely to account for more than half of the observed decline in breast cancer incidence among women aged 40–79 years old. The potential contributions of other factors should be examined in future studies, especially the role of the recent plateau in screening utilization.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A129.
Abstract A134: Prediagnostic NSAID use and colorectal cancer mortality in the Seattle Colon Cancer Family Registry
Authors: Coghill Anna E.
Published: May 2012

Introduction: Research has demonstrated that use of non-steroidal anti-inflammatory drugs (NSAIDs) decreases the risk of developing colorectal cancer as well as the recurrence of the disease among those with prior colorectal cancer. Limited prior studies investigating the association with colorectal cancer (CRC) survival have also observed a beneficial effect of NSAID use, specifically aspirin, against colorectal cancer mortality. We examined the role of pre-diagnostic aspirin and non-aspirin NSAID use on colorectal cancer-specific mortality in a population-based study.

Methods: We investigated the effect of NSAID use on CRC mortality after diagnosis among 1,737 incident colorectal cancer cases identified from the Seattle Colon Cancer Family Registry. Type of medication, duration, and timing of use relative to diagnosis were collected for NSAIDs, including aspirin and ibuprofen. Cases were followed up for mortality through linkages to the National Death Index records to obtain date and cause of death. Cox proportional hazards regression models were used to assess the relationship between pre-diagnostic NSAID use and colorectal cancer-specific mortality and to estimate hazard ratios and 95% confidence intervals.

Results: Regular, pre-diagnostic use of NSAID medications was associated with a 21% decrease in CRC mortality (HR: 0.79; 95% CI 0.65–0.97); current use was associated with a 25% decreased risk of CRC mortality (HR: 0.75; 95% CI 0.58–0.96); former use was not associated with a significant survival benefit. Among cases with advanced disease, regular use of NSAID medications was not observed to significantly alter CRC mortality. However, regular and current pre-diagnostic use of NSAID medications was associated with a 31% and 37% decrease, respectively, in CRC mortality (95% CI: 0.53– 0.90; 0.46–0.87) among cases with non-advanced disease. Although cases with distal and rectal tumors did not experience a survival benefit from NSAID use, regular pre-diagnostic NSAID use was associated with a 32% decreased risk of CRC mortality among cases with proximal tumors (HR: 0.68; 95% CI 0.51–0.92).

Conclusion: Our results demonstrate that regular pre-diagnostic use of NSAIDs, including aspirin, is associated with improved colorectal cancer survival, particularly if the medications are taken recently prior to diagnosis. This improvement in survival may be mediated through alteration in disease progression, resulting in lower stage of disease at presentation, among those with regular NSAID use. The survival benefit was not explained by increased screening among NSAID users, and the improvement appears to be particularly strong among patients diagnosed with proximal tumors and with non-advanced disease.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A134.
Abstract A136: Immunohistologic and clinicopathologic profile of thymic epithelial tumors: A 30-year experience in the Philippine Heart Center
Authors: Asuncion Bernadette R.
Published: May 2012

The thymus, said to be the “organ of mystery” throughout the 2000-year history of medicine, demonstrates a variety of clinical and pathologic manifestations that require comprehensive understanding of its entity. In this study, we discuss the profile of patients with thymic epithelial tumors seen in the Philippine Heart Center, including the variable clinical, pathologic, immunohistochemical and prognostic features.

For the last 30 years, surgically resected cases of thymic epithelial tumors were reviewed. We used descriptive statistics and quanititative variables are expressed as mean, range and standard deviation whereas qualitative variables are expressed as proportion.

A comprehensive review of the tumor registry in our center revealed majority of mediastinal masses, 75% occured at the anterior compartment, 4% in the posterior compartment and 1% from the superior compartment. Thymomas are most common among the adult age group with an average mean age of 42 years. Other thymic tumors encountered were thymic carcinoma, lymphoma, cysts, and carcinoid. In recent years, several variants of thymic epithelial tumors have been observed, some with unique biological behavior, high malignant potential, frequent metastases, and tumor recurrence. Such cases as primary neuroendocrine carcinoma with oncocytic differentiation, composite Hodgkins and Non-Hodgkins lymphoma arising from the thymus and thymic carcinoma arising from a thymoma has definitely challenged the Pathologist. In such cases, several battery of immunohistochemical studies were done, such as Cytokeratin 7 and 20, Chromogranin, Synaptophysin, Neuron Specific Enolase, CD 3, CD 15, CD 20, CD 30, CD 68, and LCA.

The series of neoplasm presented varies in clinical and histopathologic presentation. Its histologic variants and spectrum of differentiation are necessary to be defined, the soonest possible time. This will eventually lead the pathway towards treatment options. The World Health Organization histologic classification for thymic tumors paved the way to a better phase in the prognostication of thymic epithelial tumors. A greater challenge for the Pathologist is to prove the existence of synchronous, concurrent and composite tumors in the thymus. Most of these tumors are far advanced upon diagnosis, and therefore requires more aggressive treatment.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A136.
Abstract A138: Association of HER2/neu with extracapsular extension of axillary lymph node metastasis in T1 to T3 breast cancer
Authors: Maksimovic Sinisa
Published: May 2012

Background: Amplification of the protein product of the HER2/neu oncogene in primary breast cancer specimens is associated with an adverse prognosis. Studies on the association of HER-2/neu with the axillary lymph node metastasis are controversial.

Methods: From January 2000 to January 2009, 504 breast cancer patients operated in General hospital “Sveti Vracevi” in Bijeljina. We selected 253 (50,2%) patients with breast cancer who had metastases to axillary lymph nodes.

Results: Extracapsular extension (ECM) was found in 103 (40,7%). The patients were identified and divided into two groups: patients in the HER-2 positive group (38 patients) and HER-2 negative group (65 patients). In the HER-2 positive group ECM was seen in 62.5% patients compared with 37.4% in the HER-2 negative group (P = 0,059). 41 patients (39,8%) were identified with three or less lymph nodes involved, 30 patients (29,1%) patients four to six, 20 patients (19,4%) seven to nine, and 11 patients (10,6%) ten or more nodes, respectively. Total number of lymph nodes showing ECM were also significantly more in the HER-2 positive group (48 of 81, 59.25%) vs. (13 of 60, 21.66%) in the HER-2 negative group (P < 0,001). With a median follow-up of 96 months factors with independent prognostic value for disease-free survival by multivariate analysis included HER-2/neu overexpression with extracapsular extension (P < 0.005), pN category (P < 0.01), presence of lymphovascular invasion (LVI; P < 0.005), and ECM (P < 0.001). An independent negative prognostic effect on overall survival was observed for HER-2/neu overexpression with extracapsular extension (P < 0.05), pN category (P < 0.05), and presence of LVI (P < 0.005) and ECM (P < 0.001).

Conclusions: In patients whose tumors expressed HER-2/neu who had positive lymph nodes and extracapsular extension prognosis was significantly worse compared with those who were HER-2/neu negative and lymph node positive with extracapsular extension. These findings have led to the conclusion that HER-2/neu overexpression is associated with a more aggressive subtype of cancer.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A138.
Abstract A141: Chemopreventive properties of omeprazole against azoxymethane-induced colonic aberrant crypt foci formation in fats
Authors: Patlolla Jagan Mohan R. , Zhang Yuting , Qian Li , Steele Vernon E. , Rao Chinthalapally V.
Published: May 2012

Omeprazole is a proton-pump inhibitor which is widely used to treat ulcers and gastroesophageal reflux diseases (GERD). Previous studies show that omeprazole exhibits possible anti-tumorigenic properties in preclinical models of colon cancer. However, no systematic studies were carried to establish the potential anti-carcinogenic potential of omeprazole using established animal models of colon cancer. In the present study, omeprazole was evaluated for its colon cancer chemopreventive properties using azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) as a efficacy endpoint in F344 rats. In addition, we analyzed the growth inhibitory effects and induction of apoptosis in human colon cancer HCA-7 cells. We also studied its possible anti-inflammatory properties in Raw 264.7 macrophage cell line. Prior to efficacy studies we evaluated the maximum tolerated dose (MTD) of omeprazole. For MTD assay, seven week-old rats were fed either control AIN-76 diet, diets containing 5 different dose levels of omeprazole (100, 200, 400, 600 and 800 ppm) for six weeks. Based on body weight gain and toxicity symptoms, the MTD of Omeprazole is found to be ∼600 ppm. To evaluate the inhibitory properties of omeprazole on colonic ACF, seven-week-old male F344 rats were fed experimental diets containing 0, 200, and 400 ppm of omeprazole. One week later, rats received s.c. injections of azoxymethane (AOM) (15 mg/kg body wt., once weekly for two weeks) or equal volume of normal saline (vehicle). Rats were continued on experimental diets for seven weeks before being sacrificed. Colons were evaluated histopathologically for ACF and immunohistochemistry for PCNA marker to assess the crypt cell proliferation. Administration of omeprazole at 400 ppm significantly suppressed total colonic ACF formation (∼30%, p<0.001) when compared to the control diet group. Rats fed with 200 ppm and 400 ppm of Omeprazole showed significantly lower numbers (∼30–50%, p<0.05–0.001) of multi-crypt foci (≥4 or more). Overall, omeprazole produced significant dose-response effect in preventing colonic ACF formation. In in vitro assays, Omeprazole inhibited phorbol-12-myristate 13-acetate -induced iNOS expression in macrophages in a dose dependent manner. Furthermore, omeprazole induced apoptosis by suppressing survivin in HCA-7 colon cancer cells. The results from this study provides evidence for the first time that omeprazole, a proton-pump inhibitor may be used as a chemopreventive agent against colon carcinogenesis. (Supported by NOI-N01-CN-53300).

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A141.
Abstract A142: Radiation-induced acute toxicity in head and neck cancers: Nutritional status as a special parameter
Authors: Dastidar Aloke Ghosh , Dastidar Anjana Basu Ghosh , Chakroborty Indranil
Published: May 2012

Introduction: Acute radiation toxicity is a limiting factor of radiotherapy for head and neck cancers. This acute toxicity depends on number of factors like dose of radiation, dose per fraction, total dose, treatment portals, machines used etc. Nutritional status (NS) of the patient is also an important factor of head and neck cancer so far, development of acute toxicity and tolerance is concerned. Keeping other variables unchanged, how NS affects radiation induced toxicity was the main object of the study.

Patients and Methods: Total 280 patients of squamous cell carcinoma of upper aero-digestive tract were selected for the study. NS of all patients were calculated. The degree of acute toxicity during the course of radiation and 3 weeks after completion of external radiation were noted. The acute toxicity was recorded as per RTOG acute toxicity criteria.

NS is assessed by 1. clinical examination, 2. anthropometric measurement, 3. biochemical investigations, 4. hematological examinations, 5. dietetic assessment.

Anthropometric measurement done by: 1. weight (kg), 2. height (cm), 3. wrist circumference, 4. waist circumference, 5. waist: hip ratio, 6. body mass index = weight (kg) height2 (m2), 7. triceps skin fold thickness. Biochemical Estimation is done by: 1. serum albumin, 2. serum transferrin, 3. serum ceruloplasmin.

Immunologicalparameters are: 1. total circulating lymphocyte count (more than 2000 cells / cu mm normal value, 1200 – 2000 cells / cu mm mild malnutrition, 800 – 1200 cells / cu mm moderate malnutrition, less than 800 cells / cu mm severe malnutrition), 2. delayed cutaneous hypersensitivity (DCH) test, 3. DNCB challenge test, 4. Mantoux test

Acute radiation morbidity scoring was done as per criteria (RTOG).

Result Analysis: There was significantly increased toxicity in patients who were poorly nutritious (n=135) as compared to those who were normally nourished (n=88). Those patients who were under nutritious also showed poor standard of oral hygiene. Rest 57 patients NS were undetermined and were excluded from evaluation. In under nutritious group, acute radiation toxicity grading was: Gr.1 (0%), Gr.2 (42.96%), Gr.3 (55.55%), & Gr.4 (1.48%) respectively. On the contrary, the normal nutritious group acute toxicity developed Gr.1 (11.36%), Gr.2 (81.81%), Gr.3 (6.81%) & Gr.4 (0%) respectively. Oral hygiene of poor standard was 12.5% in under nutritious patients and 4.5% in normal nutritious patients.

Conclusion: Aim of this paper lies in its attempt to explore the acceptability of “Nutritional Status” as a variable in development of radiation induced toxicity, as far as acute morbidity is concerned. In that sense it is a successful phase I trial. One can conclude that there exists some correlation between radiation morbidity and NS of the patients. Therefore correction of NS before onset of radiation provides better tolerance to radiotherapy.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A142.
Abstract A145: Atorvastatin (Lipitor) delays progression of PanINs to pancreatic carcinoma through AKT pathway in a conditional LSL-K-rasG12D transgenic mice
Authors: Mohammed Altaf , Qian Li , Lightfoot Stan , Vernon Steele E. , Rao Chinthalapally V.
Published: May 2012

Pancreatic ductal adenocarcinoma (PDAC) a devastating disease with a dismal prognosis is the most common pancreatic malignancy and is the fourth leading cause of deaths in the U.S. with a 5-year survival rate of less than 5%. Thus, developing novel strategies to prevent or delay the progression of pancreatic cancer is of intense interest. In the present study, we studied chemopreventive efficacy of atorvastatin on pancreatic intraepithelial neoplasms (PanINs) and adenocarcinoma in conditional LSL-K-RasG12D transgenic mice. LSL-K-RasG12D and P48Cre mice were bred and offspring of activated K-rasG12D were generated. Six-week old male KrasG12D (20/group) and wild-type (12/group) mice were fed (AIN-76A) diets containing 0, 200, and 400 ppm Atorvastatin for 35 weeks. At the end of experimental feeding, pancreas were collected, weighed, and evaluated histopathologically for PanINs and adenocarcinomas. To understand the mechanisms, expression levels of PCNA, p21, Akt-1, cdK2, Cav1, cyclin E, survivin, Rho A and p2X7 were determined by IHC, Western blotting or RT-PCR. Results suggest that control diet fed mice showed 100% incidence of pancreatic ductal adenocarcinomas; whereas, mice fed with 200 and 400 ppm atorvastatin had significantly reduced (p<0.0001) ductal adenocarcinomas. Importantly, significant reduction of pancreatic ducts with carcinoma (56–94%, p< 0.0001) was observed in mice fed 200 and 400 ppm Atorvastatin. Similarly, significant suppression of PanIN 3 (22.63%) was observed in mice fed 400 ppm Atorvastatin. However, we did not find any statistically significant inhibition of PanIN 2 lesions between control and atorvastatin fed groups. Whereas, mice fed high dose Atorvastatin showed a significant increase in PanIN 1 lesions compared to mice fed with control diet. Also, mice fed Atorvastatin showed reduced pancreatic tumor weights (∼50%) compared to control diet fed mice. Furthermore, treated mice showed ∼75% of pancreas free from carcinoma. The pancreas of mice fed Atorvastatin diets showed significantly reduced expressions of PCNA, survivin, Akt-1, cyclin E, cdK2 and Cav1 with a significant increase in p21 (p<0.005) levels compared to pancreas of control diet fed mice. In summary, our results suggest that Atorvastatin delays the progression of pancreatic cancer precursor lesions in PanIN 1 and 2 stages from further progressing to adenocarcinoma in a preclinical model. These data highlight the promise of chemoprevention in pancreatic cancer and administration of statins represents an important strategy to prevent pancreatic cancer in high-risk patients. {Supported by NCI-NO1-CN53300}

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A145.
Abstract A146: Meloxicam inhibits prostate tumor growth and progression in prostate specific-PTEN conditional gene targeting knockout mice
Authors: De Velasco Marco A. , Tanaka Motoyoshi , Shimada Keiji , Nishio Kazuto , Uemura Hirotsugu
Published: May 2012

A high incidence of prostate cancer in older men suggests that agents that inhibit or delay the disease process could be beneficial in reducing cancer mortality and morbidity. Increased expression of COX-2 has been found in most of the cancers and compelling evidence from genetic and clinical studies indicates that COX-2 upregulation is one of the key steps in carcinogenesis. There is a strong body of evidence pointing out the role of COX-2 early in the prostate carcinogenesis process, particularly in the progression of prostatic intraepithelial neoplasia (PIN) lesions to prostate carcinoma. Epidemiological data suggests that treatments with non-steroidal anti-inflammatory drugs (NSAIDs) were associated with reduced risk in a number of malignancies. We evaluated the chemopreventive efficacy of meloxicam, a selective COX-2 inhibitor, against prostate cancer in prostate-specific PTEN knockout mice. In our mouse model, homozygous inactivation of PTEN leads to PIN at 8 weeks of age with 50% of the mice progressing to prostate cancer by the age of 10 weeks and 100% by 20 weeks of age. Mice were fed meloxicam (3.0 mg/l ad libitum) in drinking water beginning at 4 or 11 weeks of age for 5 to 28 weeks in stage-specific manners. There were no bodyweight differences were seen between treatment groups. Our data showed a significant reduction (19–23%, p<0.05) of genitourinary tract weights in meloxicam-fed mice. There was a strong reduction in the incidence and extent of adenocarcinoma and increases in PIN in meloxicam-fed mice. Significant differences in tumor differentiation scores were also noted in the treatment groups (p<0.05). Immunohistochemical analysis revealed that meloxicam treatment did in fact reduce COX-2 expression without inhibiting COX-1. Furthermore, meloxicam-fed mice also showed reduced proliferation rates as well as increases in apoptotic rates. Moreover, a reduction of VEGF expression in tumors and tumor stroma was also observed in mice treated with meloxicam. These results suggest that meloxicam safely inhibited tumor growth and progression in the PTEN knockout mouse model by antiproliferative, pro-apoptotic and anti-angiogenic effects and may thus be a suitable candidate for use in human chemoprevention trials.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A146.
Abstract A16: DNA microarray analysis of the UPII-SV40Tag model for invasive bladder TCC: Identification of markers for bladder premalignancy
Authors: Stone Randolph , Sabichi Anita L. , Gill Jennifer , Lee I-ling , Cvek Urska , Trutschl Marjan , Loganantharaj Rasiah , Clifford John L.
Published: May 2012

Transitional cell carcinoma of the bladder (TCC) ranks 4th in incidence of all cancers in the developed world, yet the mechanisms of its origin and progression remain poorly understood. There are a few commercially available urine-based tests for screening and surveillance for bladder cancer, but none of these can detect premalignancy. We have combined a transgenic mouse model for invasive bladder cancer (UPII-SV40Tag mice) with DNA microarray technology, in order to determine molecular mechanisms involved in early TCC development and to identify new biomarkers for detection, diagnosis and prognosis of TCC. We have identified genes that are differentially expressed between the bladders of UPII-SV40Tag mice and their age-matched wild type (WT) littermates at 3, 6, 20 and 30 weeks of age. These are ages which correspond to premalignant, carcinoma in-situ, and early and later stage papillary TCC, respectively. There were approximately 1,900 unique genes differentially expressed (>= 3-fold difference at one or more time points) between WT and UPII-SV40Tag urothelium during the time course of tumor development. Among these, there were a high proportion of cell cycle regulatory genes and proliferation signaling genes that are more strongly expressed in the UPII-SV40Tag bladder urothelium. We have tested several of the genes upregulated in UPII-SV40Tag urothelium, including autocrine motility factor (AMFR), hyaluronan-mediated motility receptor (Hmmr), proliferating cell nuclear antigen (PCNA), Rac GTPase activating protein 1 (RacGAP 1) and others as biomarkers for premalignancy, in urine samples from a recently completed Phase II, randomized, placebo controlled chemoprevention trial (N01 CN85186, PI: A. Sabichi) that was designed to test whether celecoxib can prevent recurrence in patients successfully treated by TUR for non-muscle invasive bladder cancer.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A16.
Abstract A18: Spatial dynamics of cellular proliferation in preneoplastic lesions: Comparison between bronchial, oral, and cervical epithelium
Authors: Guillaud Martial D. , van Niekerk Dirk , Khojasteh Mehrnoush , Carraro Anita , Korbelik Jagoda , Frung Priscilla , Kamalov Rassim , Rosin Miriam P. , Follen Michele , Lam Stephen , MacAulay Calum
Published: May 2012

Introduction: Uncontrolled proliferation is a hallmark of cancer and a biologically plausible risk biomarker for preneoplastic epithelium. The expression Ki-67 has been widely used as a marker of cellular proliferation even though it does not specifically elucidate the complexity of clonal growth that eventually drives a normal homeostatic epithelium towards carcinoma in situ. Our objective is to quantify the spatial dynamics of cellular proliferation in pre-neoplastic lesions of three different tissue types; bronchial, oral and cervical epithelium.

Materials and Methods: Five hundred sixty-two bronchial lesions, seventy nine oral mucosa lesions, and two hundred sixty five cervical lesions were reviewed by at least two pathologists. Expression of Ki-67 was studied by Mib-1 immunohistochemistry. Using an in-house imaging system, a mapping of the regions of interest were performed; nuclei positions were registered; Mib-1 positive cells were manually marked, the basal membrane and the external surface delineated. Using graph-theory tools, the spatial arrangements of all nuclei, in addition to the spatial distribution of Mib-1 positive nuclei were measured. The percentage of Mib-1 positive nuclei within each layer - from the basal layer to the superficial layer - was a study focus.

Results: On average, proliferation increased with pathology grade. Nevertheless, the amplitude and the patterns of cellular proliferation within the different layers differ among the different tissue types. The propotions of Mib-1 positive cells in the bronchial, oral, and cervical normal epithelium were respectively: 19.8%, 6.3%, and 6.1% in the basal layer; 18.7%, 28.5% and 33.2 in the layer 1; 8.0%, 18.7% and 31.1% in the layer 2. For specimens classified as mild dysplasia, the proportion of Mib-1 positive cells in bronchial, oral and cervical dysplastic epithelium were respectively: 42.0%, 19.3%, and 21.5% in the basal layer; 63,2%, 19.3%, and 43.5% in layer 1; 61.8%, 9.9% and 50.0% in layer 2. Furthermore, we observed a high variability of the proliferation patterns (along the different layers) in each tissue within each pathology grade. The significance of these findings and their correlation with other biomarkers (quantitative nuclear phenotype, p16 staining, LOH, etc.) and with clinical parameters (age, sex, HPV status, cancer progression, etc..) will be shown.

Conclusions: Quantitative analysis of spatial patterns and arrangement of proliferating cells squamous dysplastic lesions provide additional insights in the dynamic nature of these early neoplastic changes.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A18.
Abstract A19: S100A7, a prognosticator and early predictive marker for head and neck/oral squamous cell carcinoma
Authors: Tripathi Satyendra C. , Matta Ajay , Kaur Jatinder , Chauhan Shyam S. , Shukla Nootan K. , Duggal Ritu , Gupta Siddhartha D. , Ralhan Ranju , Siu K.W. Michael
Published: May 2012

Recently using multidimensional LC-MS/MS with iTRAQ-tagging, we identified a panel of potential Head and Neck/Oral Squamous cell carcinoma (HNOSCC) biomarkers. S100A7 was one of the promising candidate biomarkers in this panel. S100A7 is 11.4 kDa calcium-binding protein of S100 protein family, found to be highly expressed in pre-invasive ductal carcinoma in situ of the breast. Here, we firstly report its potential as a prognostic biomarker for HNOSCC. The present study also further explores the clinical significance of S100A7 in identification of oral leukoplakic lesions in early stages.

Ninety-nine HNOSCCs, 100 leukoplakias and 50 non-malignant archived tissues were retrieved from the research tissue bank to determine the expression of psoriasin using immunohistochemistry. The immunohistochemical data were subjected to statistical analyses using the SPSS 13.0 software (Chicago). Sensitivity and specificity were calculated and quantified using receiver operating characteristic (ROC) analysis. The expression of S100A7 in oral lesions was further validated by immunoblotting and RT-PCR analyses in the same tissue samples as used for immunohistochemical analysis.

S100A7 expression was found to be significantly increased from normal mucosa to leukoplakia with or without dysplasia to HNOSCC (ptrend<0.001). Receiver Operating Characteristic (ROC) analysis was used to determine the potential of S100A7 as a biomarker for diagnosis of leukoplakia and OSCC. The area-under-the-curve (AUC) value was 0.732 and 0.843 for leukoplakia and OSCC respectively. S100A7 overexpression was significantly associated with dedifferentiation of tumors also. Cytoplasmic S100A7 was significantly associated with tumor size (p=0.015) and stage (p=0.023) of HNOSCC patients. In univariate analysis, nuclear localization of S100A7 was found to be associated poor survival (p < 0.014), while multivariate analysis revealed nuclear S100A7 as independent indicator of disease free survival (hazard ratio, 2.7; 95% confidence interval, 1.4–5.3; p < 0.004).

This is the first large-scale study that suggests overexpression of S100A7 to be an early event and a poor prognostic factor in HNOSCC progression. On the basis of our current findings, S100A7 may serve as a potential biomarker in diagnosis and prognosis of HNOSCCs.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A19.
Abstract A2: Genetic variation in estrogen receptor genes and mammographic breast density
Authors: Lloyd Stacy M. , Diergaarde Brenda
Published: May 2012

Mammographic density is one of the strongest, independent risk factors in the development of breast cancer. Women with mammographically dense breasts, those with greater than or equal to 75% dense tissue, are at a four to six-fold greater risk of developing breast cancer when compared to those with “no measurable dense tissue,” in which the breasts are composed entirely of fat. Many of the established risk factors for breast cancer have been shown to be associated with variations in breast density (i.e., age, menopausal status, parity, BMI, and postmenopausal hormone use). Additionally, twin studies have also shown that heritability accounts for approximately 60% of the variance in mammographic density. Given the established role of estrogens in the development and progression of breast cancer, we have evaluated the role of 17 single-nucleotide polymorphisms (SNPs) in the estrogen receptor 1 and 2 genes (ESR1 and ESR2), and the recently identified G-Protein Coupled Estrogen Receptor 1 (GPER) gene, which has been demonstrated to regulate physiologic responses to estrogens independent of the traditional estrogen receptors.

This study population consisted of 370 cancer-free (excluding cancers of the skin) Caucasian, postmenopausal women enrolled in the Mammograms and Masses Study (MAMS). Three different measures of mammographic density were computed: dense breast area, total breast area, and percent breast density, using the classification system developed by Wolfe in 1976, and a compensating polar planimeter, wax pencil, and transparent overlay. Breast density was calculated as the proportion of visibly dense breast to total breast area, expressed as a percentage. DNA was extracted from buffy coat samples, and genotyping was done using the Sequenom iPLEX Gold Assay. Heterozygote and homozygous variant genotypes were collapsed and compared to the common allele genotype for all statistical analyses. General linear models and χ2 analyses were conducted. We arranged our percent density variable into tertiles for further analysis.

We observed that three SNPs in ESR2 (rs12435857, rs1256044, and rs1256031) were significantly associated with percent mammographic density. For ESR2 rs1256044 and rs1256031, mean percent mammographic density was significantly higher among women with at least one rare allele compared to women homozygous for the common allele (respectively, P=0.02 and P=0.03). Conversely, mean percent mammographic density was significantly higher among women with ESR2 rs12435857 GG genotype compared to those with GA/AA genotypes, 29.0 and 23.7, respectively (P=0.03).

Our results suggest that common genetic variation in ESR2 is associated with percent mammographic density. Since estrogen receptor genes are highly expressed in breast tissue, functional SNPs in these genes may alter breast cancer risk, by altering mammographic density.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A2.
Abstract A21: Lung cancer surveillance with CT scan and autofluorescence bronchoscopy
Authors: Jayaprakash Vijayvel , Loewen Gregory , Mahoney Martin , Moysich Kirsten , Yendamuri Saikrishna , Hutson Alan , Hogarth Kyle , Menezes Ravi , Mary Reid
Published: May 2012

Background: More than 75% of lung cancer patients are diagnosed at an advanced stage, when the survival rate is less than 15%. Sputum cytology, x-ray and CT scan have been evaluated as screening tools for early lung cancers, without much success. Auto-fluorescence bronchoscopy (AFB) has been recently shown to be effective in diagnosing central bronchial cancers. Combined surveillance with both spiral CT scan and AFB might help to increase the detection rate of the both central and peripheral lung cancers.

Methods: The study included 205 patients who were enrolled in the High Risk Lung Cancer Surveillance Cohort at Roswell Park Cancer Institute (RPCI) with at least 2 of the following risk factors: (1) radiographically documented pulmonary asbestosis or; (2) a history of previously treated aero-digestive cancer or; (3) > 20 pack years smoking history or; (4) COPD with an FEV1 < 70% of predicted. Patients underwent spirometry testing, chest X-ray, sputum cytology, non-enhanced low dose spiral CT scan of the chest, and conventional white light/AF bronchoscopy with biopsy.

Results: A total of 20 invasive cancers/CIS were diagnosed in the 205 patients. Seven were diagnosed at baseline, 4 within 1 year of enrollment and 9 on follow up of more than 1 year. Between them, AFB and CT scan diagnosed all baseline cancers. Only 3/7 cancers were detected on x-ray screening and only 1/7 patients demonstrated atypia on sputum cytology. Overall, 17 invasive cancers and 3 CIS were diagnosed during the surveillance study. All the 3 CIS were identified only on AFB. Of the 17 invasive cancers, CT scan detected 15 cancers (88%) and AFB detected 5 of these cancers (30%). CT scan showed a 67% relative increase in sensitivity for detecting prevalent cancers and 3 times greater sensitivity for incident and prevalent cancers compared to x-ray screening. CT scan and AFB detected 19 of the 20 CIS/cancers (95%), whereas x-ray and sputum cytology together detected only 5/20 CIS/cancers (25%). The sensitivity of CT scan and AFB in diagnosing pre-malignant lesions and cancers improved by almost two and half times relative to x-ray and sputum.

Conclusion: The addition of AFB exam to yearly spiral CT scan of the chest could be a more efficient surveillance tool to identify early stage lung cancers, both in the central and peripheral lung. A greater efficiency and cost effectiveness can be achieved by limiting the use of the combination of AFB and CT scan in very high risk patients, selected based on their exposures and risk factors.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A21.