bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Economic Evaluation of Web- versus Telephone-based Interventions to Simultaneously Increase Colorectal and Breast Cancer Screening Among Women
Authors: Huang Danmeng , Lairson David R. , Chung Tong H. , Monahan Patrick O. , Rawl Susan M. , Champion Victoria L.
Published: April 2023

Abstract
Screening for colorectal and breast cancer is considered cost effective, but limited evidence exists on cost-effectiveness of screening promotion interventions that simultaneously target both cancers. Increasing Colorectal and Breast Cancer Screening (Project COBRA), a randomized controlled trial conducted in the community, examined the cost-effectiveness of an innovative tailored web-based intervention compared with tailored telephone counseling and usual care. Screening status at 6 months was obtained by participant surveys plus medical record reviews. Cost was prospectively measured from the patient and provider perspectives using time logs and project invoices. Relative efficiency of the interventions was quantified by the incremental cost-effectiveness ratios. Nonparametric bootstrapping and net benefit regression analysis were used to assess statistical uncertainty of the results. The average cost per participant to implement the Phone counseling, Web-based, and Web + Phone counseling interventions were $277, $314, and $337, respectively. Comparing Phone counseling with usual care resulted in an additional cost of $300 (95% confidence interval [CI]: $283–$320) per cancer screening test and $421 (95% CI: $400–$441) per additional person screened in the target population. Phone counseling alone was more cost-effective than the Web + Phone intervention. Web-based intervention alone was more costly but less effective than the Phone counseling. When simultaneously promoting screening for both colorectal and breast cancer the Web-based intervention was less cost-effective compared with Phone and Web + Phone strategies. The results suggest that targeting multiple cancer screening may improve the cost-effectiveness of cancer screening interventions.
Prevention Relevance:
This study informs researchers, decision makers, healthcare providers, and payers about the improved cost-effectiveness of targeting multiple cancer screenings for cancer early detection programs.
Data from Effects of Message Framing on Cervical Cancer Screening Knowledge and Intentions Related to Primary HPV Testing
Authors: Ogden Shannon N. , Leskinen Emily A. , Sarma Elizabeth A. , Wainwright Jocelyn V. , Rendle Katharine A.
Published: April 2023

Abstract
Numerous national guidelines now include primary human papillomavirus (HPV) testing as a recommended screening option for cervical cancer in the United States yet little is known regarding screening intentions for this specific screening strategy or interventions that may increase uptake. Gain- and loss-framed messaging can positively impact health behaviors; however, there is mixed evidence on which is more effective for cervical cancer screening, with no published evidence examining HPV testing. To help address this gap, this study compared the effects of message framing on screening knowledge and intentions related to primary HPV testing. We randomized females aged 21–65 (n = 365) to receive brief messaging about cervical cancer screening with either gain- or loss-framing. In January–February 2020, participants completed pretest and posttest measures evaluating cervical cancer knowledge, beliefs, and intentions to be screened using HPV testing. We used generalized estimating equations to model message and framing effects on screening outcomes, controlling for age, education, race, and baseline measures. In comparison to pretest, messaging significantly increased HPV-related screening intentions [adjusted OR (aOR): 2.4 (1–3.5)] and knowledge [aOR: 1.7 (1.2–2.4)], perceived effectiveness of HPV testing [aOR: 4.3 (2.8–6.5)], and preference for primary HPV screening [aOR: 3.2 (1.2–8.5)], regardless of message framing. For all outcomes, no significant interaction by message framing was observed. Brief public health messaging positively impacted HPV-related screening intentions, knowledge, and beliefs, independent of message framing. In conjunction with other strategies, these results suggest that messaging could be an effective tool to increase uptake of primary HPV testing.
Prevention Relevance:
Primary HPV tests are more sensitive and offer greater reassurance than Pap tests alone yet use for routine cervical cancer screening remains low. Brief public health messaging can positively impact awareness, knowledge, and screening intention regarding primary HPV testing. Messaging campaigns paired with other strategies can increase uptake across populations.

See related Spotlight, p. 823
Data from Cyclic-GMP–Elevating Agents Suppress Polyposis in ApcMin Mice by Targeting the Preneoplastic Epithelium
Authors: Sharman Sarah K. , Islam Bianca N. , Hou Yali , Singh Nagendra , Berger Franklin G. , Sridhar Subbaramiah , Yoo Wonsuk , Browning Darren D.
Published: April 2023

Abstract
The cGMP signaling axis has been implicated in the suppression of intestinal cancers, but the inhibitory mechanism and the extent to which this pathway can be targeted remains poorly understood. This study has tested the effect of cGMP-elevating agents on tumorigenesis in the ApcMin/+ mouse model of intestinal cancer. Treatment of ApcMin/+ mice with the receptor guanylyl-cyclase C (GCC) agonist linaclotide, or the phosphodiesterase-5 (PDE5) inhibitor sildenafil, significantly reduced the number of polyps per mouse (67% and 50%, respectively). Neither of the drugs affected mean polyp size, or the rates of apoptosis and proliferation. This was possibly due to increased PDE10 expression, as endogenous GCC ligands were not deficient in established polyps. These results indicated that the ability of these drugs to reduce polyp multiplicity was primarily due to an effect on nonneoplastic tissues. In support of this idea, ApcMin/+ mice exhibited reduced levels of endogenous GCC agonists in the nonneoplastic intestinal mucosa compared with wild-type animals, and this was associated with crypt hyperplasia and a loss of goblet cells. Administration of either sildenafil or linaclotide suppressed proliferation, and increased both goblet cell numbers and luminal apoptosis in the intestinal mucosa. Taken together, the results demonstrate that targeting cGMP with either PDE5 inhibitors or GCC agonists alters epithelial homeostasis in a manner that reduces neoplasia, and suggests that this could be a viable chemoprevention strategy for patients at high risk of developing colorectal cancer. Cancer Prev Res; 11(2); 81–92. ©2018 AACR.
Data from Implementing Strategies at the Workplace Level to Increase Colorectal Cancer Screening Uptake in Argentina: A Controlled Interrupted Time-series Study
Authors: Bardach Ariel Esteban , Pichon-Riviere Andres , Gibbons Luz , Alonso Juan Pedro , Virgilio Sacha Alexis , Belizán María , Comolli Mariana , González Lucas Angel
Published: April 2023

Abstract
Colorectal cancer is the third most common neoplasm. The immunochemical fecal occult blood test (iFOBT) is recommended for screening. The worksite setting has great potential to deliver preventive interventions. We aimed to design and evaluate the feasibility and potential impact of a multicomponent strategy in a workplace [Internal Revenue Agency of the Province of Buenos Aires (ARBA from its acronym in Spanish “Agencia de Recaudación de Buenos Aires”) in Argentina].

We used a quasi-experimental research design, a controlled interrupted time-series (ITS). The study involved: (i) a preintervention period (July 2015–September 2018); and (ii) an intervention period (October 2018–February 2019). We used semi-structured interviews and focus groups to design the intervention and to ensure feasibility and implementability. We fitted segmented linear regression models to evaluate changes in the monthly rates per 10,000 tests done in ARBA employees and controlling for the proportion of tests done in non-ARBA workers. A total of 1,552 ARBA employees aged 50 or more participated. Overall, iFOBT mean uptake rates were 16 times higher in the intervened during the five-month intervention period, remaining statistically significant after adjusting by the proportion of tests done in the control group (P < 0.001). The effect was higher in women aged 50 to 59 years. Activities were suspended due to the COVID-19 pandemic. A multifaceted workplace-based intervention proved to be feasible and acceptable to increase the uptake of colorectal cancer screening in employees of Argentina. Achieving high implementation rates requires building a healthy relationship with the partner organization, adding their values and views, and establishing agreed-upon mechanisms.
Prevention Relevance:
Employee-facing multifaceted worksite cancer screening interventions are a valuable means to increase knowledge and utilization of workers. The controlled ITS showed that colorectal cancer screening mean uptake rates were 16 times higher in the intervened versus the control population during the intervention period, particularly among women aged 50 to 75.
Data from Opium Use and the Risk of Liver Cancer: A Case–Control Study
Authors: Marzban Maryam , Mohebbi Elham , Haghdoost AliAkbar , Aryaie Mohammad , Zahedi Mohammad Javad , Khazaei Zaher , Gholizade Mohamad , Naghibzadeh-Tahami Ahmad
Published: April 2023

Abstract
Limited evidence is available to acknowledge the association between opium use and liver cancer. In a case–control study, we recruited 117 cases of primary liver cancer (PLC) and 234 age and sex-matched neighborhood controls from 2016 to 2018. We calculated odds ratios (OR) for opium use and 95% confidence intervals (95% CI), using conditional logistic regressions. Compared with non-users the adjusted OR (AOR, 95% CI) for opium use was 6.5 (95% CI, 2.87–13.44). Compared with people who had no history of use, a strong dose–response effect of opium use was observed by amount of use (AOR, 10.70; 95% CI, 3.92–28.70). Cumulative use of opium also indicated that using over 30 gr-year could increase the PLC risk dramatically (AOR, 11.0; 95% CI, 3.83–31.58). Those who used opium for more than 21 years were highly at risk of PLC (AOR, 11.66; 95% CI, 4.43–30.67). The observed associations were significant even among never tobacco smokers (including cigarette and water-pipe smoking).
Prevention Relevance:
The results of this study indicate that opium use dramatically increased the risk of liver cancer. Because opioids are increasing for medical and non-medical use globally; accordingly, severe health consequences such as liver cancer have to be investigated widely.
Data from Goblet Cell Ratio in Combination with Differentiation and Stem Cell Markers in Barrett Esophagus Allow Distinction of Patients with and without Esophageal Adenocarcinoma
Authors: Schellnegger Raphael , Quante Anne , Rospleszcz Susanne , Schernhammer Martina , Höhl Bettina , Tobiasch Moritz , Pastula Agnieszka , Brandtner Anna , Abrams Julian A. , Strauch Konstantin , Schmid Roland M. , Vieth Michael , Wang Timothy C. , Quante Michael
Published: April 2023

Abstract
The increasing incidence of esophageal adenocarcinoma (EAC) is mirrored by the increasing prevalence of Barrett esophagus, a precursor lesion resulting in a large number of individuals “at risk” for this lethal malignancy. Among patients with Barrett esophagus, only about 0.3% annually will develop EAC. Because large numbers of patients are followed in endoscopic surveillance, there is a need for risk prediction among a growing population of patients with Barrett esophagus. We identified four potential biomarkers from an inflammation (IL1β)-dependent mouse model of Barrett esophagus and tested them in 189 patients with Barrett esophagus with and without high-grade dysplasia (HGD)/early cancer (T1). The primary goal was to distinguish patients with Barrett esophagus with no evidence of dysplasia from those with dysplasia. Increasing stem cell marker LGR5 and niche cell marker DCLK1 and decreasing differentiation marker (secretory mucus cells, TFF2+ cells) correlated with elevated tumor score in the mouse. Having outlined the origin of those markers in the Barrett esophagus mouse model, we showed the applicability for human Barrett esophagus. We compared 94 patients with nondysplastic Barrett esophagus tissue with 95 patients with Barrett esophagus and HGD or early cancer. Low levels of TFF2 (AUC 87.2%) provided the best discrimination between nondysplastic Barrett esophagus and Barrett esophagus with cancer, followed by high levels of DCLK1 (AUC 83.4%), low goblet cell ratio (AUC 79.4%), and high LGR5 (AUC 71.4%). The goblet cell ratio, rather than the presence of goblet cells per se, was found to be an important discriminator. These findings may be useful in developing future risk prediction models for patients with Barrett esophagus and ultimately to improve EAC surveillance. Cancer Prev Res; 10(1); 55–66. ©2016 AACR.
Data from Risk Stratification System for Oral Cancer Screening
Authors: Pereira Lutécia H. Mateus , Reis Isildinha M. , Reategui Erika P. , Gordon Claudia , Saint-Victor Sandra , Duncan Robert , Gomez Carmen , Bayers Stephanie , Fisher Penelope , Perez Aymee , Goodwin W. Jarrard , Hu Jennifer J. , Franzmann Elizabeth J.
Published: April 2023

Abstract
Oral cavity and oropharyngeal cancer (oral cancer) is a deadly disease that is increasing in incidence. Worldwide 5-year survival is only 50% due to delayed intervention with more than half of the diagnoses at stage III and IV, whereas earlier detection (stage I and II) yields survival rates up to 80% to 90%. Salivary soluble CD44 (CD44), a tumor-initiating marker, and total protein levels may facilitate oral cancer risk assessment and early intervention. This study used a hospital-based design with 150 cases and 150 frequency-matched controls to determine whether CD44 and total protein levels in oral rinses were associated with oral cancer independent of age, gender, race, ethnicity, tobacco and alcohol use, and socioeconomic status (SES). High-risk subjects receiving oral cancer prevention interventions as part of a community-based program (n = 150) were followed over 1 year to determine marker specificity and variation. CD44 ≥5.33 ng/mL was highly associated with case status [adjusted OR 14.489; 95% confidence interval (CI), 5.973–35.145; P < .0001, vs. reference group CD44 <2.22 ng/mL and protein <1.23 mg/mL]. Total protein aided prediction above CD44 alone. Sensitivity and specificity in the frequency-matched study was 80% and 48.7%, respectively. However, controls were not representative of the target screening population due, in part, to a high rate of prior cancer. In contrast, specificity in the high-risk community was 74% and reached 95% after annual retesting. Simple and inexpensive salivary CD44 and total protein measurements may help identify individuals at heightened risk for oral cancer from the millions who partake in risky behaviors. Cancer Prev Res; 9(6); 445–55. ©2016 AACR.
Data from A Calcium-Rich Multimineral Intervention to Modulate Colonic Microbial Communities and Metabolomic Profiles in Humans: Results from a 90-Day Trial
Authors: Aslam Muhammad N. , Bassis Christine M. , Bergin Ingrid L. , Knuver Karsten , Zick Suzanna M. , Sen Ananda , Turgeon D. Kim , Varani James
Published: April 2023

Abstract
Aquamin is a calcium-, magnesium-, and multiple trace element–rich natural product with colon polyp prevention efficacy based on preclinical studies. The goal of this study was to determine the effects of Aquamin on colonic microbial community and attendant metabolomic profile. Thirty healthy human participants were enrolled in a 90-day trial in which Aquamin (delivering 800 mg of calcium per day) was compared with calcium alone or placebo. Before and after the intervention, colonic biopsies and stool specimens were obtained. All 30 participants completed the study without serious adverse event or change in liver and renal function markers. Compared with pretreatment values, intervention with Aquamin led to a reduction in total bacterial DNA (P = 0.0001) and a shift in the microbial community measured by thetaYC (θYC; P = 0.0087). Treatment with calcium also produced a decline in total bacteria, but smaller than seen with Aquamin, whereas no reduction was observed with placebo in the colon. In parallel with microbial changes, a reduction in total bile acid levels (P = 0.0375) and a slight increase in the level of the short-chain fatty acid (SCFA) acetate in stool specimens (P < 0.0001) from Aquamin-treated participants were noted. No change in bile acids or SCFAs was observed with calcium or placebo. We conclude that Aquamin is safe and tolerable in healthy human participants and may produce beneficial alterations in the colonic microbial community and the attendant metabolomic profile. Because the number of participants was small, the findings should be considered preliminary.
Data from Genistein Prevents Development of Spontaneous Ovarian Cancer and Inhibits Tumor Growth in Hen Model
Authors: Sahin Kazim , Yenice Engin , Bilir Birdal , Orhan Cemal , Tuzcu Mehmet , Sahin Nurhan , Ozercan Ibrahim H. , Kabil Nashwa , Ozpolat Bulent , Kucuk Omer
Published: April 2023

Abstract
Genistein, the major isoflavone in soybean, has been reported to exert anticancer effects on various types of cancer including ovarian cancer; however, its chemopreventive effects and mechanisms of action in ovarian cancer have not been fully elucidated in spontaneously developing ovarian cancer models. In this study, we demonstrated the preventive effects and mechanisms of genistein in the laying hen model that develops spontaneous ovarian cancer at high incidence rates. Laying hens were randomized to three groups: control (3.01 mg/hen, n = 100), low (52.48 mg/hen n = 100), and high genistein supplementation (106.26 mg/hen/day; per group). At the end of 78 weeks, hens were euthanized and ovarian tumors were collected and analyzed. We observed that genistein supplementation significantly reduced the ovarian tumor incidence (P = 0.002), as well as the number and size of the tumors (P = 0.0001). Molecular analysis of the ovarian tumors revealed that genistein downregulated serum malondialdehyde, a marker for oxidative stress and the expression of NFκB and Bcl-2, whereas it upregulated Nrf2, HO-1, and Bax expression at protein level in ovarian tissues. Moreover, genistein intake decreased the activity of mTOR pathway as evidenced by reduced phosphorylation of mTOR, p70S6K1, and 4E-BP1. Taken together, our findings strongly support the potential of genistein in the chemoprevention of ovarian cancer and highlight the effects of the genistein on the molecular pathways involved in ovarian tumorigenesis.
Data from Aspirin-Mediated Prevention of Colorectal Adenomas Recurrence is Affected by Blood Biochemistry and Nutritional Intake
Authors: Yoshida Naohisa , Ishikawa Hideki , Otani Takahiro , Goto Chiho , Matsuda Takahisa , Takeuchi Yoji , Sano Yasushi , Itoh Yoshito , Suzuki Sadao , Mutoh Michihiro
Published: April 2023

Abstract
Aspirin has been shown to prevent the onset of colorectal adenoma and cancer. This study aimed to identify patient characteristics and blood chemistry factors related to the effect of aspirin. A total of 231 men and 59 women who participated in our previous randomized clinical study in 2007–2009 using aspirin or placebo (J-CAPP study) were analyzed. Interaction of aspirin with age at entry, body mass index (BMI), alcohol intake, blood biochemistry, and nutrients calculated from a semiquantitative food frequency questionnaire were analyzed on the basis of the presence of adenomas 2 years later. Our study showed that suppression of adenoma by aspirin was not affected by age or BMI. Among men, significant suppression of adenoma by aspirin was seen with triglyceride (TG) <167 mg/dL (P = 0.02), total cholesterol (T-cho) ≥220 mg/dL (P = 0.01), high-density lipoprotein (HDL) ≥60 mg/dL (P < 0.01), and low-density lipoprotein (LDL) ≥140 mg/dL (P = 0.01), aspartate aminotransferase (AST) <30 IU/L (P = 0.01), alanine aminotransferase <30 IU/L (P = 0.04), and gamma-glutamyl transpeptidase <60 IU/L (P = 0.04). In addition, the interaction was significant with TG ≥/<167 mg/dL (P = 0.02), T-cho ≥/<220 mg/dL (P = 0.03), HDL ≥/<60 mg/dL (P = 0.02), LDL ≥/<140 mg/dL (P = 0.03), and AST ≥/<30 IU/L (P = 0.01). Daily nutrient intake associated with aspirin was <2,000 mg sodium (P = 0.06) and ≥850 μg retinol equivalent (P = 0.05) among men, indicating a marginal effect on adenoma suppression. No significant differences were detected among women due to the small sample size. In conclusion, lipid metabolism and liver function were correlated with the suppressive effect of aspirin on the recurrence of colorectal adenoma.
Prevention Relevance:
Aspirin has been shown to prevent the onset of colorectal adenoma and cancer, and its effect modifications have been analyzed. Lipid metabolism and liver function were correlated with the suppressive effect of aspirin on the recurrence of colorectal adenoma.
Data from A Pooled Analysis to Compare the Clinical Characteristics of Human Papillomavirus–positive and -Negative Cervical Precancers
Authors: Castle Philip E. , Pierz Amanda J. , Adcock Rachael , Aslam Shagufta , Basu Partha S. , Belinson Jerome L. , Cuzick Jack , El-Zein Mariam , Ferreccio Catterina , Firnhaber Cynthia , Franco Eduardo L. , Gravitt Patti E. , Isidean Sandra D. , Lin John , Mahmud Salaheddin M. , Monsonego Joseph , Muwonge Richard , Ratnam Samuel , Safaeian Mahboobeh , Schiffman Mark , Smith Jennifer S. , Swarts Avril , Wright Thomas C. , Van De Wyngard Vanessa , Xi Long Fu
Published: April 2023

Abstract
Given that high-risk human papillomavirus (HPV) is the necessary cause of virtually all cervical cancer, the clinical meaning of HPV-negative cervical precancer is unknown. We, therefore, conducted a literature search in Ovid MEDLINE, PubMed Central, and Google Scholar to identify English-language studies in which (i) HPV-negative and -positive, histologically confirmed cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) were detected and (ii) summarized statistics or deidentified individual data were available to summarize proportions of biomarkers indicating risk of cancer. Nineteen studies including 3,089 (91.0%) HPV-positive and 307 (9.0%) HPV-negative CIN2+ were analyzed. HPV-positive CIN2+ (vs. HPV-negative CIN2+) was more likely to test positive for biomarkers linked to cancer risk: a study diagnosis of CIN3+ (vs. CIN2; 18 studies; 0.56 vs. 0.24; P < 0.001) preceding high-grade squamous intraepithelial lesion cytology (15 studies; 0.54 vs. 0.10; P < 0.001); and high-grade colposcopic impression (13 studies; 0.30 vs. 0.18; P = 0.03). HPV-negative CIN2+ was more likely to test positive for low-risk HPV genotypes than HPV-positive CIN2+ (P < 0.001). HPV-negative CIN2+ appears to have lower cancer risk than HPV-positive CIN2+. Clinical studies of human high-risk HPV testing for screening to prevent cervical cancer may refer samples of HPV test–negative women for disease ascertainment to correct verification bias in the estimates of clinical performance. However, verification bias adjustment of the clinical performance of HPV testing may overcorrect/underestimate its clinical performance to detect truly precancerous abnormalities.
Data from Effects of Supplemental Calcium and Vitamin D on Circulating Biomarkers of Gut Barrier Function in Patients with Colon Adenoma: A Randomized Clinical Trial
Authors: Vermandere Kelly , Bostick Roberd M. , Tran Hao Q. , Gewirtz Andrew T. , Barry Elizabeth L. , Rutherford Robin E. , Seabrook March E. , Fedirko Veronika
Published: April 2023

Abstract
Gut barrier dysfunction promotes chronic inflammation, contributing to several gastrointestinal diseases, including colorectal cancer. Preliminary evidence suggests that vitamin D and calcium could prevent colorectal carcinogenesis, in part, by influencing gut barrier function. However, relevant human data are scarce. We tested the effects of supplemental calcium (1,200 mg/day) and/or vitamin D3 (1,000 IU/day) on circulating concentrations of biomarkers of gut permeability (anti-flagellin and anti-lipopolysaccharide IgA and IgG, measured via ELISA) from baseline to 1 and 3 or 5 years postbaseline among 175 patients with colorectal adenoma in a randomized, double-blinded, placebo-controlled clinical trial. We also assessed factors associated with baseline concentrations of these biomarkers. We found no appreciable effects of supplemental vitamin D3 and/or calcium on individual or aggregate biomarkers of gut permeability. At baseline, a combined permeability score (the summed concentrations of all four biomarkers) was 14% lower among women (P = 0.01) and 10% higher among those who consumed >1 serving per day of red or processed meats relative to those who consumed none (Ptrend = 0.03). The permeability score was estimated to be 49% higher among participants with a body mass index (BMI) > 35 kg/m2 relative to those with a BMI < 22.5 kg/m2 (Ptrend = 0.17). Our results suggest that daily supplemental vitamin D3 and/or calcium may not modify circulating concentrations of gut permeability biomarkers within 1 or 3–5 years, but support continued investigation of modifiable factors, such as diet and excess adiposity, that could affect gut permeability.
Prevention Relevance:
Calcium and vitamin D may be involved in regulating and maintaining the integrity of the intestinal mucosal barrier, the dysfunction of which results in exposure of the host to luminal bacteria, endotoxins, and antigens leading to potentially cancer-promoting endotoxemia and chronic colon inflammation. While our results suggest that daily supplementation with these chemopreventive agents does not modify circulating concentrations of gut permeability biomarkers, they support continued investigation of other potential modifiable factors, such as diet and excess adiposity, that could alter gut barrier function, to inform the development of treatable biomarkers of risk for colorectal neoplasms and effective colon cancer preventive strategies.
Data from Chemoprevention of Azoxymethane-induced Colon Carcinogenesis by Delta-Tocotrienol
Authors: Husain Kazim , Zhang Anying , Shivers Steve , Davis-Yadley Ashley , Coppola Domenico , Yang Chung S. , Malafa Mokenge P.
Published: April 2023

Abstract
This study evaluated the preclinical activity of δ-tocotrienol (DT3), a bioactive form of vitamin E, in the inhibition of colorectal cancer growth and development in vitro and in vivo. DT3 is the most bioactive isomer of vitamin E in inhibiting growth of colorectal cancer cells. However, it had little effect on the proliferation of normal colon mucosal cells NCM460. In HCT-116 and SW-620 colorectal cancer cells, DT3 (50 μmol/L) significantly inhibited malignant transformation (P < 0.02, P < 0.001), cell migration (P < 0.02, P < 0.05), and invasion (P < 0.05, P < 0.01) compared with vehicle. DT3 inhibited markers for epithelial (E-cadherin) to mesenchymal (vimentin) transition, metastasis (matrix metalloproteinase 9), angiogenesis VEGF, inflammation (NF-κB), and Wnt signaling (β-catenin) compared with vehicle in colorectal cancer cells. DT3 induced apoptosis selectively in colorectal cancer cells (SW-620 cells, HCT-116 cells, and HT-29) without affecting the normal colon cells. In the azoxymethane-induced colorectal carcinogenesis model in rats, DT3 (200 mg/kg orally twice a day) for 20 weeks significantly inhibited colorectal polyps by 70% and colorectal cancer by almost 99% compared with the vehicle treatment group (P < 0.02, P < 0.001), and the cancer inhibition effect was more potent than sulindac (50%). Taken together, these data demonstrate that DT3 is a potential chemopreventive agent in colorectal cancer, warranting further investigation into its clinical use in the prevention and treatment of colorectal cancer.
Data from The Quality of Pap Smears from the Brazilian Cervical Cancer Screening Program According to the Human Development Index
Authors: Costa Ricardo Filipe Alves , Longatto-Filho Adhemar , de Lima Vazquez Fabiana , Pinheiro Céline , Zeferino Luiz Carlos , Fregnani José Humberto Tavares Guerreiro
Published: April 2023

Abstract
Brazil is a country with strong socioeconomic disparities, which may explain the different rates of cervical cancer incidence and mortality and influence the quality of cervical cancer screening tests. The aim of this study was to perform a trend analysis of some quality indicators of Pap smears according to the Municipal Human Development Index (MHDI). Information about cytopathological exams (approximately 65,000,000) performed from 2006 to 2014 in women ages 25 to 64 years was obtained from the Cervical Cancer Information System (SISCOLO). The average annual percentage change (AAPC) for each indicator was calculated using the Joinpoint Regression Program, according to MHDI levels. Very low frequencies of unsatisfactory cases (<5%) were observed at different MHDI levels. Although the positivity index in the low- and medium-MHDI groups has increased, the values remained below international recommendations (3%–10%). The HSIL (high-grade squamous intraepithelial lesion) percentage remained stationary at all levels of the MHDI. In the low- and medium-MHDI groups, most quality indicators were below the recommendations by Brazilian National Cancer Institute INCA, with no improvement trend; in the high-MHDI group, the majority of the indicators also presented no improvement, although they show slightly better quality indicators. The MHDI should be considered in the definition of the policies of the screening program for cervical cancer in Brazil, and the current program may require adjustments to achieve improved efficiency.
Data from Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden
Authors: Montrose David C. , Zhou Xi Kathy , McNally Erin M. , Sue Erika , Yantiss Rhonda K. , Gross Steven S. , Leve Nitai D. , Karoly Edward D. , Suen Chen S. , Ling Lilan , Benezra Robert , Pamer Eric G. , Dannenberg Andrew J.
Published: April 2023

Abstract
Treatment with celecoxib, a selective COX-2 inhibitor, reduces formation of premalignant adenomatous polyps in the gastrointestinal tracts of humans and mice. In addition to its chemopreventive activity, celecoxib can exhibit antimicrobial activity. Differing bacterial profiles have been found in feces from colon cancer patients compared with those of normal subjects. Moreover, preclinical studies suggest that bacteria can modulate intestinal tumorigenesis by secreting specific metabolites. In the current study, we determined whether celecoxib treatment altered the luminal microbiota and metabolome in association with reducing intestinal polyp burden in mice. Administration of celecoxib for 10 weeks markedly reduced intestinal polyp burden in APCMin/+ mice. Treatment with celecoxib also altered select luminal bacterial populations in both APCMin/+ and wild-type mice, including decreased Lactobacillaceae and Bifidobacteriaceae as well as increased Coriobacteriaceae. Metabolomic analysis demonstrated that celecoxib caused a strong reduction in many fecal metabolites linked to carcinogenesis, including glucose, amino acids, nucleotides, and lipids. Ingenuity Pathway Analysis suggested that these changes in metabolites may contribute to reduced cell proliferation. To this end, we showed that celecoxib reduced cell proliferation in the base of normal appearing ileal and colonic crypts of APCMin/+ mice. Consistent with this finding, lineage tracing indicated that celecoxib treatment reduced the rate at which Lgr5-positive stem cells gave rise to differentiated cell types in the crypts. Taken together, these results demonstrate that celecoxib alters the luminal microbiota and metabolome along with reducing epithelial cell proliferation in mice. We hypothesize that these actions contribute to its chemopreventive activity. Cancer Prev Res; 9(9); 721–31. ©2016 AACR.
Data from Colonoscopy Findings in FIT+ and mt-sDNA+ Patients versus in Colonoscopy-only Patients: New Hampshire Colonoscopy Registry Data
Authors: Anderson Joseph C. , Robinson Christina M. , Hisey William , Limburg Paul J. , Butterly Lynn F.
Published: April 2023

Abstract
Few studies compare fecal immunochemical test (FIT) and multi-target stool DNA (mt-sDNA) outcomes in practice. We compared colonoscopy yield following FIT+ or mt-sDNA+ tests to colonoscopies without preceding stool tests in the comprehensive population-based New Hampshire Colonoscopy Registry (NHCR). Outcomes were any neoplasia and an ordered outcome: adenocarcinoma, advanced neoplasia (adenoma/serrated polyp ≥ 1 cm/villous/high-grade dysplasia), nonadvanced neoplasia, or normal. Our total sample included 306 mt-sDNA+ (average age ± SD 67.0 ± 7.9), 276 FIT+ (66.6 ± 8.7), and 50,990 colonoscopy-only patients (61.8 ± 8.1). Among average-risk patients (N = 240 mt-sDNA+, N = 194 FIT+, N = 26,221 colonoscopy only), mt-sDNA+ patients had a higher risk for any neoplasia (67.1%) compared with FIT+ (54.6%, P = 0.00098) or colonoscopy (40.8%, P < 0.0001). Severity of findings and histology subtypes differed across the three groups (P < 0.0001 for both), with a higher yield of advanced findings in mt-sDNA+ patients. In particular, clinically relevant serrated polyps (hyperplastic polyps ≥10 mm/traditional serrated adenomas/sessile serrated polyps) were detected at a higher frequency in mt-sDNA+ patients as compared with FIT+ or colonoscopy-only patients. Even after adjustment, patients with positive mt-sDNA [OR = 2.82; 95% confidence interval (CI), 2.00–4.02] or FIT+ tests (OR = 1.67; 95% CI, 1.19–2.36) were more likely to have histologically more advanced findings than colonoscopy alone. At follow-up colonoscopy, mt-sDNA+ tests were more likely to predict neoplasia than FIT+, largely due to increased detection of serrated polyps.

Prevention Relevance: Colorectal cancer screening options include colonoscopy and stool-based tests, including the fecal immunochemical test (FIT) and the multi-target stool DNA (mt-sDNA) test which, if positive, must be followed by a colonoscopy. Assessing “real-world” outcomes of colonoscopies following positive stool tests can inform their clinical use.

See related Spotlight, p. 417
Data from In Silico Systems Biology Analysis of Variants of Uncertain Significance in Lynch Syndrome Supports the Prioritization of Functional Molecular Validation
Authors: Borras Ester , Chang Kyle , Pande Mala , Cuddy Amanda , Bosch Jennifer L. , Bannon Sarah A. , Mork Maureen E. , Rodriguez-Bigas Miguel A. , Taggart Melissa W. , Lynch Patrick M. , You Y. Nancy , Vilar Eduardo
Published: April 2023

Abstract
Lynch syndrome (LS) is a genetic condition secondary to germline alterations in the DNA mismatch repair (MMR) genes with 30% of changes being variants of uncertain significance (VUS). Our aim was to perform an in silico reclassification of VUS from a large single institutional cohort that will help prioritizing functional validation. A total of 54 VUS were detected with 33 (61%) novel variants. We integrated family history, pathology, and genetic information along with supporting evidence from eight different in silico tools at the RNA and protein level. Our assessment allowed us to reclassify 54% (29/54) of the VUS as probably damaging, 13% (7/54) as possibly damaging, and 28% (15/54) as probably neutral. There are more than 1,000 VUS reported in MMR genes and our approach facilitates the prioritization of further functional efforts to assess the pathogenicity to those classified as probably damaging. Cancer Prev Res; 10(10); 580–7. ©2017 AACR.
Data from Effect of Exercise or Metformin on Biomarkers of Inflammation in Breast and Colorectal Cancer: A Randomized Trial
Authors: Brown Justin C. , Zhang Sui , Ligibel Jennifer A. , Irwin Melinda L. , Jones Lee W. , Campbell Nancy , Pollak Michael N. , Sorrentino Alexandra , Cartmel Brenda , Harrigan Maura , Tolaney Sara M. , Winer Eric P. , Ng Kimmie , Abrams Thomas A. , Sanft Tara , Douglas Pamela S. , Hu Frank B. , Fuchs Charles S. , Meyerhardt Jeffrey A.
Published: April 2023

Abstract
Observational studies report that physical activity and metformin are associated with improved clinical outcome in patients with cancer. Inflammation is one biological mechanism hypothesized to mediate these associations. In this phase II, multicenter, 2 × 2 factorial trial, 139 patients with breast and colorectal cancer who completed standard therapy were randomized to one of four treatment groups for 12 weeks: exercise alone, metformin alone, exercise and metformin, or control. Inflammation outcomes included high-sensitivity C-reactive protein (hs-CRP), soluble tumor necrosis factor alpha receptor two (sTNFαR2), and IL6. The primary modeling strategy evaluated the trial product estimand that was quantified using a generalized linear mixed model. Compared with control, exercise alone reduced hs-CRP [−30.2%; 95% confidence interval (CI), −50.3, −1.0] and IL6 (−30.9%; 95% CI, −47.3, −9.5) but did not change sTNFαR2 (1.0%; 95% CI, −10.4, 13.9). Compared with control, metformin alone did not change hs-CRP (−13.9%; 95% CI, −40.0, 23.4), sTNFαR2 (−10.4%; 95% CI, −21.3, 2.0), or IL6 (−22.9%; 95% CI, −42.3, 2.0). Compared with control, exercise and metformin reduced sTNFαR2 (−13.1%; 95% CI, −22.9, −1.0) and IL6 (−38.7%; 95% CI, −52.3, −18.9) but did not change hs-CRP (−20.5%; 95% CI, −44.0, 12.7). The combination of exercise and metformin was not synergistic for hs-CRP, sTNFαR2, or IL6. In survivors of breast and colorectal cancer with low baseline physical activity and without type 2 diabetes, exercise and metformin reduced measures of inflammation that are associated with cancer recurrence and mortality.
Data from The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice
Authors: Cao Martine , Royce Darlene B. , Risingsong Renee , Williams Charlotte R. , Sporn Michael B. , Liby Karen T.
Published: April 2023

Abstract
LG101506 was originally synthesized to overcome some of the undesirable side effects of rexinoids. We compared the anticarcinogenic action of LG101506 and LG100268 and for the first time showed that both drugs are useful for prevention of lung cancer in A/J mice. These molecules markedly reduced tumor number, tumor size, and total tumor burden, when chronically administered to A/J mice that had been initiated with the mutagenic carcinogen, vinyl carbamate. Moreover, LG100268 synergized with the histone deacetylase inhibitor, vorinostat, for prevention of experimental lung cancer and enhanced the effect of carboplatin/paclitaxel for treatment of experimental lung cancer. Both rexinoids diminished the percentage of high-grade, highly malignant adenocarcinomas found at autopsy. In cell culture studies, the rexinoids exhibited potent anti-inflammatory properties at nanoMolar concentrations. These drugs suppressed the ability of lipopolysaccharide to stimulate the synthesis and secretion of nitric oxide and inflammatory cytokines and chemokines, such as IL6, IL1β, CXCL2, and CSF3, in macrophage-like RAW264.7 cells. The present results suggest that LG100268, LG101506, or a related rexinoid may have useful clinical applications in the field of oncology. Cancer Prev Res; 9(1); 105–14. ©2015 AACR.
Data from Association Between Aspirin Use and Gastric Adenocarcinoma: A Prospective Cohort Study
Authors: Kwon Sohee , Ma Wenjie , Drew David A. , Klempner Samuel J. , Leonardo Brianna M. , Flynn Jacqueline J. , Cao Yin , Giovannucci Edward L. , Bao Ying , Fuchs Charles S. , Song Mingyang , Chan Andrew T.
Published: April 2023

Abstract
Prospective data examining the association of aspirin use, according to dose and duration, with long-term risk of gastric adenocarcinoma in non-Asian cohorts are lacking. We evaluated the association between aspirin use and risk of gastric adenocarcinoma in two large prospective U.S. cohort studies, the Nurses' Health Study and the Health Professionals Follow-up Study. Cox proportional hazards regression models were used to calculate multivariable adjusted HRs and 95% confidence intervals (CI). Among the 159,116 participants, we documented 316 gastric adenocarcinoma cases (176 women, 140 men) over 34 years encompassing 4.5 million person-years. Among women, regular aspirin use (at least two times or more per week) was significantly associated with lower risk of gastric adenocarcinoma (multivariable HR, 0.52; 95% CI, 0.37–0.73) compared with nonregular use. However, regular aspirin use was not associated with gastric adenocarcinoma risk among men (multivariable HR, 1.08; 95% CI, 0.77–1.52; Pheterogeneity for sex = 0.003). Among women, the lower risk of gastric adenocarcinoma was more apparent with increasing duration of aspirin use (Ptrend < 0.001) and more than five tablets per week (multivariable HR, 0.51; 95% CI, 0.31–0.84). Regular, long-term aspirin use was associated with lower risk of gastric adenocarcinoma among women, but not men. The benefit appeared after at least 10 years of use and was maximized at higher doses among women. The heterogeneity by sex in the association of aspirin use with risk of gastric adenocarcinoma requires further investigation.
Prevention Relevance:
Novel prevention is urgently needed to reduce incidence and mortality of gastric cancer. We found that regular aspirin use was associated with lower risk of gastric adenocarcinoma among women, but not men. The benefit appeared after at least 10 years of use and was maximized at higher doses among women.

See related Spotlight, p. 213
Data from Targeting the Pro-survival Protein BCL-2 to Prevent Breast Cancer
Authors: Young Adelaide , Bu Wen , Jiang Weiyu , Ku Amy , Kapali Jyoti , Dhamne Sagar , Qin Lan , Hilsenbeck Susan G. , Du Yi-Chieh Nancy , Li Yi
Published: April 2023

Abstract
Current chemopreventive strategies require 3–5 years of continuous treatment and have the concerns of significant side effects; therefore, new chemopreventive agents that require shorter and safer treatments are urgently needed. In this study, we developed a new murine model of breast cancer that mimics human breast cancer initiation and is ideal for testing the efficacy of chemopreventive therapeutics. In this model, introduction of lentivirus carrying a PIK3CA gene mutant commonly found in breast cancers infects a small number of the mammary cells, leading to atypia first and then to ductal carcinomas that are positive for both estrogen receptor and progesterone receptor. Venetoclax is a BH3 mimetic that blocks the anti-apoptotic protein BCL-2 and has efficacy in treating breast cancer. We found that venetoclax treatment of atypia-bearing mice delayed the progression to tumors, improved overall survival, and reduced pulmonary metastasis. Therefore, prophylactic treatment to inhibit the pro-survival protein BCL-2 may provide an alternative to the currently available regimens in breast cancer prevention.
Prevention Relevance:
This study demonstrates that prophylactic treatment with the BCL2-specific antagonist venetoclax prevents breast cancer initiated by a mutated and activated PIK3CA, the most common breast oncogene.
Data from Epigenome-Wide Study Identifies Epigenetic Outliers in Normal Mucosa of Patients with Colorectal Cancer
Authors: Ghosh Jayashri , Schultz Bryant M. , Chan Joe , Wultsch Claudia , Singh Rajveer , Shureiqi Imad , Chow Stephanie , Doymaz Ahmet , Varriano Sophia , Driscoll Melissa , Muse Jennifer , Kleiman Frida E. , Krampis Konstantinos , Issa Jean-Pierre J. , Sapienza Carmen
Published: April 2023

Abstract
Nongenetic predisposition to colorectal cancer continues to be difficult to measure precisely, hampering efforts in targeted prevention and screening. Epigenetic changes in the normal mucosa of patients with colorectal cancer can serve as a tool in predicting colorectal cancer outcomes. We identified epigenetic changes affecting the normal mucosa of patients with colorectal cancer. DNA methylation profiling on normal colon mucosa from 77 patients with colorectal cancer and 68 controls identified a distinct subgroup of normally-appearing mucosa with markedly disrupted DNA methylation at a large number of CpGs, termed as “Outlier Methylation Phenotype” (OMP) and are present in 15 of 77 patients with cancer versus 0 of 68 controls (P < 0.001). Similar findings were also seen in publicly available datasets. Comparison of normal colon mucosa transcription profiles of patients with OMP cancer with those of patients with non-OMP cancer indicates genes whose promoters are hypermethylated in the OMP patients are also transcriptionally downregulated, and that many of the genes most affected are involved in interactions between epithelial cells, the mucus layer, and the microbiome. Analysis of 16S rRNA profiles suggests that normal colon mucosa of OMPs are enriched in bacterial genera associated with colorectal cancer risk, advanced tumor stage, chronic intestinal inflammation, malignant transformation, nosocomial infections, and KRAS mutations. In conclusion, our study identifies an epigenetically distinct OMP group in the normal mucosa of patients with colorectal cancer that is characterized by a disrupted methylome, altered gene expression, and microbial dysbiosis. Prospective studies are needed to determine whether OMP could serve as a biomarker for an elevated epigenetic risk for colorectal cancer development.
Prevention Relevance:
Our study identifies an epigenetically distinct OMP group in the normal mucosa of patients with colorectal cancer that is characterized by a disrupted methylome, altered gene expression, and microbial dysbiosis. Identification of OMPs in healthy controls and patients with colorectal cancer will lead to prevention and better prognosis, respectively.
Data from Breastfeeding and Mammographic Breast Density: A Cross-sectional Study
Authors: Getz Kayla R. , Adedokun Babatunde , Xu Shuai , Toriola Adetunji T.
Published: April 2023

Abstract
Breastfeeding is inversely associated with breast cancer risk but the associations of breastfeeding with mammographic breast density (MBD) are not clear. We investigated the association between breastfeeding and volumetric measures of MBD [volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV)] and evaluated whether it differs by race, menopausal status, and body mass index (BMI). The study population was comprised of 964 women (67% non-Hispanic White, 29% non-Hispanic Black) who had screening mammography at Washington University School of Medicine, St. Louis, MO. VPD, DV and NDV were log10 transformed. We performed multivariable linear regression models adjusted for age, BMI, family history of breast cancer, race, and age at menarche among all participants and exclusively in parous women. Mean age was 50.7 years. VPD was 12% lower among women who breastfed 0–6 months, [10β = 0.88, 95% confidence interval (CI; 0.79–0.98)] compared with nulliparous women. Breastfeeding was not associated with VPD among women who breastfed >7 months. Breastfeeding was inversely associated with DV [parous never breastfed: 10β = 0.93; 95% CI (0.83–1.04), breastfed 0–6 months: 10β = 0.91, 95% CI (0.79–1.05), breastfed 7–12 months: 10β = 0.94; 95% CI (0.81–1.10), breastfed >12 months: 10β = 0.87, 95% CI (0.78–0.98), Ptrend = 0.03]. BMI modified the association between breastfeeding and VPD. Women who breastfed for 0–6 months and had a BMI < 25 kg/m2 had lower VPD compared with nulliparous women, but among women with a BMI ≥ 25 kg/m2 there was no association (Pinteraction = 0.04). In this diverse study population, the association of breastfeeding with VPD appears to be modified by BMI, but not by race or menopausal status. Future research exploring the associations of breastfeeding with other mammographic features are needed.
Prevention Relevance:
Breastfeeding for up to 6 months may be associated with lower VPD among women with a BMI < 25 kg/m2. The potential role of MBD in mediating the associations of breastfeeding with breast cancer risk in a select group of women deserves further evaluation.