bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Breast Hormone Concentrations in Random Fine-Needle Aspirates of Healthy Women Associate with Cytological Atypia and Gene Methylation
Authors: Lee Oukseub , Heinz Richard E. , Ivancic David , Muzzio Miguel , Chatterton Robert T. , Zalles Carola M. , Keeney Kara , Phan Belinda , Liu Dachao , Scholtens Denise , Fackler Mary Jo , Stearns Vered , Sukumar Saraswati , Khan Seema A.
Published: March 2024

Abstract
Sex steroid hormones contribute to breast cancer development, but data on concentrations of these within breast tissue are limited. We performed simultaneous multiparameter measurement of breast sex steroids, breast epithelial cytology, and DNA methylation in 119 healthy women (54 pre- and 65 postmenopausal) without a history of breast cancer. Random fine-needle aspiration (rFNA) of the breast was performed simultaneously with blood collection. Breast samples were analyzed by LC/MS-MS for estrone, estradiol, progesterone, androstenedione, and testosterone. Blood samples were assayed for estradiol and progesterone by immunoassay. Cytomorphology was classified using the Masood Score, and DNA methylation of eight genes was analyzed using quantitative multiplexed methylation-specific PCR, and expressed as the cumulative methylation index (CMI). Serum and breast concentrations of estradiol and progesterone showed significant correlation (Spearman r = 0.34, Padj = 0.001 and r = 0.69, Padj < 0.0006, respectively). Progesterone concentration was significantly higher in the premenopausal breast (Padj < 0.0008), and showed a luteal surge. Breast estrone and estradiol concentrations did not differ significantly by menopause, but androstenedione concentration was higher in the breasts of postmenopausal women (P = 0.026 and Padj = 0.208). Breast androgens were significantly correlated with breast density (Spearman r = 0.27, Padj = 0.02 for testosterone) and CMI (Spearman r = 0.3, Padj = 0.038 for androstenedione). Our data indicate that future larger studies of breast steroid hormones along with other parameters are feasible. Significant associations of breast androgen concentrations with breast density and gene methylation warrant future study. Cancer Prev Res; 11(9); 557–68. ©2018 AACR.
Data from Plasma and Urine Metabolite Profiles Impacted by Increased Dietary Navy Bean Intake in Colorectal Cancer Survivors: A Randomized-Controlled Trial
Authors: Zarei Iman , Baxter Bridget A. , Oppel Renee C. , Borresen Erica C. , Brown Regina J. , Ryan Elizabeth P.
Published: March 2024

Abstract
Navy beans contain bioactive phytochemicals with colon cancer prevention properties as demonstrated in carcinogen-induced animal models. Human studies support that dietary navy bean intake modulates metabolism by the gut microbiome. This study investigated the effect of navy bean ingestion on plasma and urine metabolite profiles of overweight and obese colorectal cancer survivors. Twenty participants completed a single-blinded, randomized-controlled dietary intervention with precooked navy beans (35 g bean powder/day) or control (0 g/day) for 4 weeks. Plasma and urine were collected at baseline, 2 weeks, and 4 weeks following consumption. Nontargeted metabolomics was applied to study meals and snacks, navy beans, plasma, and urine. Increased navy bean consumption was hypothesized to (i) delineate dietary biomarkers and (ii) promote metabolic shifts relevant for cancer protection in the plasma and urine metabolome. At 4 weeks, 16 plasma and 16 urine metabolites were significantly different in the navy bean intervention group compared with placebo control (P < 0.05). Increased plasma 2,3-dihydroxy-2-methylbutyrate (1.34-fold), S-methylcysteine (1.92-fold), and pipecolate (3.89-fold), and urine S-adenosylhomocysteine (2.09-fold) and cysteine (1.60-fold) represent metabolites with cancer-protective actions following navy bean consumption. Diet-derived metabolites were detected in plasma or urine and confirmed for presence in the navy bean intervention meals and snacks. These included 3-(4-hydroxyphenyl)propionate, betaine, pipecolate, S-methylcysteine, choline, eicosapentaenoate (20:5n3), benzoate, S-adenosylhomocysteine, N-delta-acetylornithine, cysteine, 3-(4-hydroxyphenyl)lactate, gentisate, hippurate, 4-hydroxyhippurate, and salicylate. The navy bean dietary intervention for 4 weeks showed changes to pathways of metabolic importance to colorectal cancer prevention and merit continued attention for dietary modulation in future high-risk cohort investigations.
Prevention Relevance:
This clinical study suggests that increased consumption of navy beans would deliver bioactive metabolites to individuals at high risk for colorectal cancer recurrence and produce metabolic shifts in plasma and urine profiles.
Data from Clinical Trial of 2-Phenethyl Isothiocyanate as an Inhibitor of Metabolic Activation of a Tobacco-Specific Lung Carcinogen in Cigarette Smokers
Authors: Yuan Jian-Min , Stepanov Irina , Murphy Sharon E. , Wang Renwei , Allen Sharon , Jensen Joni , Strayer Lori , Adams-Haduch Jennifer , Upadhyaya Pramod , Le Chap , Kurzer Mindy S. , Nelson Heather H. , Yu Mimi C. , Hatsukami Dorothy , Hecht Stephen S.
Published: March 2024

Abstract
2-Phenethyl isothiocyanate (PEITC), a natural product found as a conjugate in watercress and other cruciferous vegetables, is an inhibitor of the metabolic activation and lung carcinogenicity of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in F344 rats and A/J mice. We carried out a clinical trial to determine whether PEITC also inhibits the metabolic activation of NNK in smokers. Cigarette smokers were recruited and asked to smoke cigarettes containing deuterium-labeled [pyridine-D4]NNK for an acclimation period of at least 1 week. Then subjects were randomly assigned to one of two arms: PEITC followed by placebo, or placebo followed by PEITC. During the 1-week treatment period, each subject took PEITC (10 mg in 1 mL of olive oil, 4 times per day). There was a 1-week washout period between the PEITC and placebo periods. The NNK metabolic activation ratio [pyridine-D4]hydroxy acid/total [pyridine-D4]NNAL was measured in urine samples to test the hypothesis that PEITC treatment modified NNK metabolism. Eighty-two smokers completed the study and were included in the analysis. Overall, the NNK metabolic activation ratio was reduced by 7.7% with PEITC treatment (P = 0.023). The results of this trial, while modest in effect size, provide a basis for further investigation of PEITC as an inhibitor of lung carcinogenesis by NNK in smokers. Cancer Prev Res; 9(5); 396–405. ©2016 AACR.
Data from The Costs and Benefits of Risk Stratification for Colorectal Cancer Screening Based On Phenotypic and Genetic Risk: A Health Economic Analysis
Authors: Thomas Chloe , Mandrik Olena , Saunders Catherine L. , Thompson Deborah , Whyte Sophie , Griffin Simon , Usher-Smith Juliet A.
Published: March 2024

Abstract
Population-based screening for colorectal cancer is an effective and cost-effective way of reducing colorectal cancer incidence and mortality. Many genetic and phenotypic risk factors for colorectal cancer have been identified, leading to development of colorectal cancer risk scores with varying discrimination. However, these are not currently used by population screening programs. We performed an economic analysis to assess the cost-effectiveness, clinical outcomes, and resource impact of using risk-stratification based on phenotypic and genetic risk, taking a UK National Health Service perspective. Biennial fecal immunochemical test (FIT), starting at an age determined through risk-assessment at age 40, was compared with FIT screening starting at a fixed age for all individuals. Compared with inviting everyone from age 60, using a risk score with area under the receiver operating characteristic curve of 0.721 to determine FIT screening start age, produces 418 QALYs, costs £247,000, and results in 218 fewer colorectal cancer cases and 156 fewer colorectal cancer deaths per 100,000 people, with similar FIT screening invites. There is 96% probability that risk-stratification is cost-effective, with net monetary benefit (based on £20,000 per QALY threshold) estimated at £8.1 million per 100,000 people. The maximum that could be spent on risk-assessment and still be cost-effective is £114 per person. Lower benefits are produced with lower discrimination risk scores, lower mean screening start age, or higher FIT thresholds. Risk-stratified screening benefits men more than women. Using risk to determine FIT screening start age could improve the clinical outcomes and cost effectiveness of colorectal cancer screening without using significant additional screening resources.
Prevention Relevance:
Colorectal cancer screening is essential for early detection and prevention of colorectal cancer, but implementation is often limited by resource constraints. This work shows that risk-stratification using genetic and phenotypic risk could improve the effectiveness and cost-effectiveness of screening programs, without using substantially more screening resources than are currently available.
Data from Aspirin Suppresses PGE2 and Activates AMP Kinase to Inhibit Melanoma Cell Motility, Pigmentation, and Selective Tumor Growth In Vivo
Authors: Kumar Dileep , Rahman Hafeez , Tyagi Ethika , Liu Tong , Li Chelsea , Lu Ran , Lum David , Holmen Sheri L. , Maschek J. Alan , Cox James E. , VanBrocklin Matthew W. , Grossman Douglas
Published: March 2024

Abstract
There are conflicting epidemiologic data on whether chronic aspirin (ASA) use may reduce melanoma risk in humans. Potential anticancer effects of ASA may be mediated by its ability to suppress prostaglandin E2 (PGE2) production and activate 5′-adenosine monophosphate–activated protein kinase (AMPK). We investigated the inhibitory effects of ASA in a panel of melanoma and transformed melanocyte cell lines, and on tumor growth in a preclinical model. ASA and the COX-2 inhibitor celecoxib did not affect melanoma cell viability, but significantly reduced colony formation, cell motility, and pigmentation (melanin production) in vitro at concentrations of 1 mmol/L and 20 μmol/L, respectively. ASA-mediated inhibition of cell migration and pigmentation was rescued by exogenous PGE2 or Compound C, which inhibits AMPK activation. Levels of tyrosinase, MITF, and p-ERK were unaffected by ASA exposure. Following a single oral dose of 0.4 mg ASA to NOD/SCID mice, salicylate was detected in plasma and skin at 4 hours and PGE2 levels were reduced up to 24 hours. Some human melanoma tumors xenografted into NOD/SCID mice were sensitive to chronic daily ASA administration, exhibiting reduced growth and proliferation. ASA-treated mice bearing sensitive and resistant tumors exhibited both decreased PGE2 in plasma and tumors and increased phosphorylated AMPK in tumors. We conclude that ASA inhibits colony formation, cell motility, and pigmentation through suppression of PGE2 and activation of AMPK and reduces growth of some melanoma tumors in vivo. This preclinical model could be used for further tumor and biomarker studies to support future melanoma chemoprevention trials in humans. Cancer Prev Res; 11(10); 629–42. ©2018 AACR.
Data from Common Analgesic Use for Menstrual Pain and Ovarian Cancer Risk
Authors: Sasamoto Naoko , Babic Ana , Vitonis Allison F. , Titus Linda , Cramer Daniel W. , Trabert Britton , Tworoger Shelley S. , Terry Kathryn L.
Published: March 2024

Abstract
Menstrual pain has been associated with increased ovarian cancer risk, presumably through increased inflammation, which is known to play a critical role in ovarian carcinogenesis. Analgesic medications are frequently used to treat menstrual pain, some of which lower ovarian cancer risk. In this study, we examined the association between analgesic use for menstrual pain during the premenopausal period and ovarian cancer risk among women with history of menstrual pain. We used data from the New England Case-Control Study, including 1,187 epithelial ovarian cancer cases and 1,225 population-based controls enrolled between 1998 and 2008 with detailed information on analgesic use for their menstrual pain. We used unconditional logistic regression to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between analgesic use (i.e., aspirin, ibuprofen, acetaminophen) for menstrual pain and ovarian cancer risk. We further conducted a stratified analysis by intensity of menstrual pain (mild/moderate, severe). Among women with menstrual pain during their 20s and 30s, ever use of analgesics for menstrual pain was not significantly associated with ovarian cancer risk. However, among women with severe menstrual pain, ever use of aspirin or acetaminophen for menstrual pain was inversely associated with risk (OR, 0.41; 95% CI, 0.18–0.94 and OR, 0.43; 95% CI, 0.21–0.88 compared with never users, respectively). No significant association was observed between analgesic use and ovarian cancer risk among women with mild/moderate menstrual pain (Pinteraction ≤ 0.03). Our results suggest that use of aspirin or acetaminophen for severe menstrual pain may be associated with lower risk of ovarian cancer.
Prevention Relevance:
This study investigates whether analgesic use specifically for menstrual pain during the premenopausal period influences ovarian cancer risk. Our results suggest use of aspirin or acetaminophen for severe menstrual pain may be associated with lower risk of ovarian cancer among women with severe menstrual pain.
Data from Implementation of HPV-based Cervical Cancer Screening Combined with Self-sampling Using a Midwifery Network Across Rural Greece: The GRECOSELF Study
Authors: Agorastos Theodoros , Chatzistamatiou Kimon , Tsertanidou Athena , Mouchtaropoulou Evangelia , Pasentsis Konstantinos , Kitsou Anastasia , Moysiadis Theodoros , Moschaki Viktoria , Skenderi Alkmini , Katsiki Evangelia , Aggelidou Stamatia , Venizelos Ioannis , Ntoula Maria , Daponte Alexandros , Vanakara Polyxeni , Garas Antonios , Stefos Theodoros , Vrekoussis Thomas , Lymberis Vasilis , Kontomanolis Emmanuel N. , Makrigiannakis Antonis , Manidakis George , Deligeoroglou Efthimios , Panoskaltsis Theodoros , Decavalas George O. , Michail George , Kalogiannidis Ioannis , Koukoulis George , Zempili Paraskevi , Halatsi Despina , Truva Theoni , Piha Vaia , Agelena Georgia , Chronopoulou Athanasia , Vaitsi Violetta , Chatzaki Ekaterini , Paschopoulos Minas , Adonakis George , Kaufmann Andreas M. , Hadzidimitriou Anastasia , Stamatopoulos Kostas
Published: March 2024

Abstract
Self-sampling for human papillomavirus (HPV) testing is an alternative to physician sampling particularly for cervical cancer screening nonattenders. The GRECOSELF study is a nationwide observational cross-sectional study aiming to suggest a way to implement HPV-DNA testing in conjunction with self-sampling for cervical cancer screening in Greece, utilizing a midwifery network. Women residing in remote areas of Greece were approached by midwives, of a nationwide network, and were provided with a self-collection kit (dry swab) for cervicovaginal sampling and asked to answer a questionnaire about their cervical cancer screening history. Each sample was tested for high-risk (hr) HPV with the Cobas HPV test. HrHPV-Positive women were referred to undergo colposcopy and, if needed, treatment according to colposcopy/biopsy results. Between May 2016 and November 2018, 13,111 women were recruited. Of these, 12,787 women gave valid answers in the study questionnaire and had valid HPV-DNA results; hrHPV prevalence was 8.3%; high-grade cervical/vaginal disease or cancer prevalence was 0.6%. HrHPV positivity rate decreased with age from 20.7% for women aged 25–29 years to 5.1% for women aged 50–60 years. Positive predictive value for hrHPV testing and for HPV16/18 genotyping ranged from 5.0% to 11.6% and from 11.8% to 27.0%, respectively, in different age groups. Compliance to colposcopy referral rate ranged from 68.6% (for women 25–29) to 76.3% (for women 40–49). For women residing in remote areas of Greece, the detection of hrHPV DNA with the Cobas HPV test, on self-collected cervicovaginal samples using dry cotton swabs, which are provided by visiting midwives, is a promising method for cervical cancer secondary prevention.
Data from A BET Bromodomain Inhibitor Suppresses Adiposity-Associated Malignant Transformation
Authors: Chakraborty Debrup , Benham Vanessa , Jdanov Vladislav , Bullard Blair , Leal Ana S. , Liby Karen T. , Bernard Jamie J.
Published: March 2024

Abstract
Almost half a million of all new cancers have been attributed to obesity and epidemiologic evidence implicates visceral adipose tissue (VAT) and high-fat diets (HFD) in increasing cancer risk. We demonstrated that VAT-derived fibroblast growth factor 2 (FGF2) from mice fed an HFD or obese individuals stimulates the malignant transformation of epithelial cells. Mechanism-based strategies to prevent this VAT-enhanced tumorigenesis have not been explored. Clinical studies have indicated that bromodomain inhibitors have considerable potential as therapeutic agents for cancer by inhibiting the activity of several oncogenes, including c-Myc; however, their chemopreventive activity is unknown. We show herein that mice with visceral adiposity have elevated nuclear c-Myc expression in their epidermis. We hypothesized that the bromodomain inhibitor I-BET-762 (I-BET) would have efficacy in the prevention of malignant transformation by VAT and FGF2. We tested this hypothesis using our novel models of VAT-stimulated transformation in vitro and FGF2- stimulated tumor formation in vivo. We found that I-BET significantly attenuates VAT and FGF2-stimulated transformation and inhibits VAT-induced c-Myc protein expression in several skin and breast epithelial cell lines. Moreover, I-BET attenuated tumor growth significantly in FGF2-treated nude mice. Work is ongoing to determine the role of visceral adiposity in c-Myc activity in several tissues and determine the inhibitory effect of I-BET on VAT-promoted tumors in vivo. Cancer Prev Res; 11(3); 129–42. ©2017 AACR.

See related editorial by Berger and Scacheri, p. 125
Data from Circulating Osteopontin and Prediction of Hepatocellular Carcinoma Development in a Large European Population
Authors: Duarte-Salles Talita , Misra Sandeep , Stepien Magdalena , Plymoth Amelie , Muller David , Overvad Kim , Olsen Anja , Tjønneland Anne , Baglietto Laura , Severi Gianluca , Boutron-Ruault Marie-Christine , Turzanski-Fortner Renee , Kaaks Rudolf , Boeing Heiner , Aleksandrova Krasimira , Trichopoulou Antonia , Lagiou Pagona , Bamia Christina , Pala Valeria , Palli Domenico , Mattiello Amalia , Tumino Rosario , Naccarati Alessio , Bueno-de-Mesquita H.B(as). , Peeters Petra H. , Weiderpass Elisabete , Quirós J. Ramón , Agudo Antonio , Sánchez-Cantalejo Emilio , Ardanaz Eva , Gavrila Diana , Dorronsoro Miren , Werner Mårten , Hemmingsson Oskar , Ohlsson Bodil , Sjöberg Klas , Wareham Nicholas J. , Khaw Kay-Tee , Bradbury Kathryn E. , Gunter Marc J. , Cross Amanda J. , Riboli Elio , Jenab Mazda , Hainaut Pierre , Beretta Laura
Published: March 2024

Abstract
We previously identified osteopontin (OPN) as a promising marker for the early detection of hepatocellular carcinoma (HCC). In this study, we investigated the association between prediagnostic circulating OPN levels and HCC incidence in a large population-based cohort. A nested case–control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. During a mean follow-up of 4.8 years, 100 HCC cases were identified. Each case was matched to two controls and OPN levels were measured in baseline plasma samples. Viral hepatitis, liver function, and α-fetoprotein (AFP) tests were also conducted. Conditional logistic regression models were used to calculate multivariable odds ratio (OR) and 95% confidence intervals (95% CI) for OPN levels in relation to HCC. Receiver operating characteristics curves were constructed to determine the discriminatory accuracy of OPN alone or in combination with other liver biomarkers in the prediction of HCC. OPN levels were positively associated with HCC risk (per 10% increment, ORmultivariable = 1.30; 95% CI, 1.14–1.48). The association was stronger among cases diagnosed within 2 years of follow-up. Adding liver function tests to OPN improved the discriminatory performance for subjects who developed HCC (AUC = 0.86). For cases diagnosed within 2 years, the combination of OPN and AFP was best able to predict HCC risk (AUC = 0.88). The best predictive model for HCC in this low-risk population is OPN in combination with liver function tests. Within 2 years of diagnosis, the combination of OPN and AFP best predicted HCC development, suggesting that measuring OPN and AFP could identify high-risk groups independently of a liver disease diagnosis. Cancer Prev Res; 9(9); 758–65. ©2016 AACR.
Data from Interception Targets of Angelica Gigas Nakai Root Extract versus Pyranocoumarins in Prostate Early Lesions and Neuroendocrine Carcinomas in TRAMP Mice
Authors: Tang Su-Ni , Jiang Peixin , Kim Sangyub , Zhang Jinhui , Jiang Cheng , Lü Junxuan
Published: March 2024

Abstract
We reported efficacy of Angelica gigas Nakai (AGN) root ethanol extract and equimolar decursin (D)/decursinol angelate (DA) through daily gavage starting at 8 weeks of age (WOA) to male transgenic adenocarcinoma of mouse prostate (TRAMP) mice such that these modalities suppressed precancerous epithelial lesions in their dorsolateral prostate (DLP) to similar extent, but AGN extract was better than the D/DA mixture at promoting the survival of mice bearing prostate neuroendocrine carcinomas to 28 WOA. Here, we compared by microarray hybridization the mRNA levels in pooled DLP tissues and individual neuroendocrine carcinomas to characterize potential molecular targets of AGN extract and D/DA. Clustering and principal component analyses supported distinct gene expression profiles of TRAMP DLP versus neuroendocrine carcinomas. Pathway Enrichment, Gene Ontology, and Ingenuity Pathway Analyses of differential genes indicated that AGN and D/DA affected chiefly processes of lipid and mitochondrial energy metabolism and oxidation-reduction in TRAMP DLP, while AGN affected neuronal signaling, immune systems and cell cycling in neuroendocrine carcinomas. Protein–Protein Interaction Network analysis predicted and reverse transcription-PCR verified multiple hub genes common in the DLP of AGN- and D/DA-treated TRAMP mice at 28 WOA and select hub genes attributable to the non-D/DA AGN components. The vast majority of hub genes in the AGN-treated neuroendocrine carcinomas differed from those in TRAMP DLP. In summary, the transcriptomic approach illuminated vastly different signaling pathways and networks, cellular processes, and hub genes of two TRAMP prostate malignancy lineages and their associations with the interception efficacy of AGN and D/DA.
Prevention Relevance:
This study explores potential molecular targets associated with in vivo activity of AGN root alcoholic extract and its major pyranocoumarins to intercept precancerous epithelial lesions and early malignancies of the prostate. Without an ethically-acceptable, clearly defined cancer initiation risk reduction strategy available for the prostate, using natural products like AGN to delay formation of malignant tumors could be a plausible approach for prostate cancer prevention.
Data from Estimating the Breast Cancer Burden in Germany and Implications for Risk-based Screening
Authors: Quante Anne S. , Hüsing Anika , Chang-Claude Jenny , Kiechle Marion , Kaaks Rudolf , Pfeiffer Ruth M.
Published: March 2024

Abstract
In Germany, it is currently recommended that women start mammographic breast cancer screening at age 50. However, recently updated guidelines state that for women younger than 50 and older than 70 years of age, screening decisions should be based on individual risk. International clinical guidelines recommend starting screening when a woman's 5-year risk of breast cancer exceeds 1.7%. We thus compared the performance of the current age-based screening practice with an alternative risk-adapted approach using data from a German population representative survey. We found that 10,498,000 German women ages 50–69 years are eligible for mammographic screening based on age alone. Applying the 5-year risk threshold of 1.7% to individual breast cancer risk estimated from a model that considers a woman's reproductive and personal characteristics, 39,000 German women ages 40–49 years would additionally be eligible. Among those women, the number needed to screen to detect one breast cancer case, NNS, was 282, which was close to the NNS = 292 among all 50- to 69-year-old women. In contrast, NNS = 703 for the 113,000 German women ages 50–69 years old with 5-year breast cancer risk <0.8%, the median 5-year breast cancer risk for German women ages 45–49 years, which we used as a low-risk threshold. For these low-risk women, longer screening intervals might be considered to avoid unnecessary diagnostic procedures. In conclusion, we show that risk-adapted mammographic screening could benefit German women ages 40–49 years who are at elevated breast cancer risk and reduce cost and burden among low-risk women ages 50–69 years.
Prevention Relevance:
We show that a risk-based approach to mammography screening for German women can help detect breast cancer in women ages 40–49 years with increased risk and reduce screening costs and burdens for low-risk women ages 50–69 years. However, before recommending a particular implementation of a risk-based mammographic screening approach, further investigations of models and thresholds used are needed.
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: March 2024

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 Endoscopic History and Provider Characteristics Influence Gastric Cancer Survival in Asian Americans
Authors: Jeon Christie Y. , Lin Yu-Chen , Klempner Samuel J. , Wu Bechien U. , Kim Sungjin , Waters Kevin M. , Haile Robert W.
Published: March 2024

Abstract
Gastric carcinoma (GC) disproportionately affects Asian Americans. We examined whether history of upper gastrointestinal (GI) endoscopy was associated with lower stage at GC diagnosis among Asian Americans and whether origin of providers influenced referral for endoscopy. We employed Surveillance Epidemiology and End Results–Medicare data on Asian Americans diagnosed with GC in 2004–2013 (n = 1,554). Stage distribution, GI conditions at diagnosis, and history of endoscopy were compared between Asian ethnic groups. Multivariate logistic regression adjusting for age, sex, poverty level, tumor location, and histology was used to examine the association of ethnicity and endoscopic history with stage I disease at diagnosis of GC. Koreans were more likely to be diagnosed with stage I, T1a GC and have prior history of endoscopy, compared with other Asian ethnicities (24% vs. 8% for stage I, T1a; 40% vs. 15% for endoscopy). Patients with primary care providers of concordant ethnic origin were more likely to have history of endoscopy. Asian American patients with GC with history of endoscopy were more likely to be diagnosed with GC at stage I disease (adjusted OR, 3.07; 95% confidence interval, 2.34–4.02). Compared with other Asian Americans, Koreans were diagnosed with GC at earlier stages owing to common history of endoscopy, which was more often undergone by patients with primary care providers of concordant ethnic origin. Overall, upper GI endoscopy was associated with early detection of GC in Asian Americans. Novelty and Impact. It is well-established that Asian Americans in the United States are disproportionately affected by gastric cancer. In our study we found that Asian American patients treated by physicians of similar ethnic background are more likely to undergo upper GI endoscopy in the United States, leading to early detection of gastric cancer and longer survival. Given this, targeted endoscopic screening in Asian Americans should be considered for early detection of GC.
Data from A Randomized Phase IIb Trial of myo-Inositol in Smokers with Bronchial Dysplasia
Authors: Lam Stephen , Mandrekar Sumithra J. , Gesthalter Yaron , Allen Ziegler Katie L. , Seisler Drew K. , Midthun David E. , Mao Jenny T. , Aubry Marie Christine , McWilliams Annette , Sin Don D. , Shaipanich Tawimas , Liu Gang , Johnson Evan , Bild Andrea , Lenburg Marc E. , Ionescu Diana N. , Mayo John , Yi Joanne (Eunhee) , Tazelaar Henry , Harmsen William S. , Smith Judith , Spira Avrum E. , Beane Jennifer , Limburg Paul J. , Szabo Eva
Published: March 2024

Abstract
Previous preclinical studies and a phase I clinical trial suggested that myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia. Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once a day for 2 weeks, and then twice a day for 6 months. The primary endpoint was change in dysplasia rate after 6 months of intervention on a per-participant basis. Other trial endpoints reported herein include Ki-67 labeling index, blood and bronchoalveolar lavage fluid (BAL) levels of proinflammatory, oxidant/antioxidant biomarkers, and an airway epithelial gene expression signature for PI3K activity. Seventy-four (n = 38 myo-inositol and n = 36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (P = 0.76). Compared with placebo, myo-inositol intervention significantly reduced IL6 levels in BAL over 6 months (P = 0.03). Among those with a complete response in the myo-inositol arm, there was a significant decrease in a gene expression signature reflective of PI3K activation within the cytologically normal bronchial airway epithelium (P = 0.002). The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent. Cancer Prev Res; 9(12); 906–14. ©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: March 2024

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 Proton Pump Inhibitor Omeprazole Suppresses Carcinogen-induced Colonic Adenoma Progression to Adenocarcinoma in F344 Rat
Authors: Madka Venkateshwar , Kumar Gaurav , Pathuri Gopal , Panneerselvam Janani , Zhang Yuting , Ganta Vishal , Lightfoot Stanley , Lubet Ronald , Suen Chen S. , Steele Vernon E. , Janakiram Naveena B. , Mohammed Altaf , Rao Chinthalapally V.
Published: March 2024

Abstract
Colorectal cancer causes over 53,000 deaths annually in the United States. Its rising incidences worldwide and particularly in young adults is a major concern. Here, we evaluated the efficacy of omeprazole that is clinically approved for treating acid reflux, to enable its repurposing for colorectal cancer prevention. In the azoxymethane-induced rat colorectal cancer model, dietary omeprazole (250 and 500 ppm) was administered at early adenoma stage (8 weeks after azoxymethane) to assess the progression of early lesions to adenocarcinoma. Administration of omeprazole at 250 or 500 ppm doses led to suppression of total colon adenocarcinoma incidence by 15.7% and 32% (P < 0.01), respectively. Importantly, invasive carcinoma incidence was reduced by 59% (P < 0.0005) and 90% (P < 0.0001) in omeprazole-administered rats in a dose-dependent manner. There was also a strong and dose-dependent inhibition in the adenocarcinoma multiplicity in rats exposed to omeprazole. Administration of 250 and 500 ppm omeprazole inhibited total colon adenocarcinoma multiplicity by approximately 49% and approximately 65% (P < 0.0001), respectively. While noninvasive adenocarcinomas multiplicity was suppressed by approximately 34% to approximately 48% (P < 0.02), the invasive carcinomas multiplicity was reduced by approximately 74% to approximately 94% (P < 0.0001) in omeprazole-exposed rats in comparison with the untreated rats. Biomarker analysis results showed a decrease in cell proliferation and anti-apoptotic/pro-survival proteins with an increase in apoptosis. Transcriptome analysis of treated tumors revealed a significant increase in adenocarcinoma inhibitory genes (Olmf4; Spink4) expression and downregulation of progression promoting genes (SerpinA1, MMP21, IL6). In summary, omeprazole showed significant protection against the progression of adenoma to adenocarcinoma.
Prevention Relevance:
Preventing colon cancer is urgently needed because of its high incidence and mortality rates worldwide. Toward this end, preventive efficacy of omeprazole, a common medication, was evaluated in animal model of colorectal cancer and was found to suppress colonic adenoma progression to carcinoma. These findings warrant its further evaluation in humans.
Data from Isorhapontigenin (ISO) Inhibits Invasive Bladder Cancer Formation In Vivo and Human Bladder Cancer Invasion In Vitro by Targeting STAT1/FOXO1 Axis
Authors: Jiang Guosong , Wu Amy D. , Huang Chao , Gu Jiayan , Zhang Liping , Huang Haishan , Liao Xin , Li Jingxia , Zhang Dongyun , Zeng Xingruo , Jin Honglei , Huang Haojie , Huang Chuanshu
Published: March 2024

Abstract
Although our most recent studies have identified Isorhapontigenin (ISO), a novel derivative of stilbene that isolated from a Chinese herb Gnetum cleistostachyum, for its inhibition of human bladder cancer growth, nothing is known whether ISO possesses an inhibitory effect on bladder cancer invasion. Thus, we addressed this important question in current study and discovered that ISO treatment could inhibit mouse-invasive bladder cancer development following bladder carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) exposure in vivo. We also found that ISO suppressed human bladder cancer cell invasion accompanied by upregulation of the forkhead box class O 1 (FOXO1) mRNA transcription in vitro. Accordingly, FOXO1 was profoundly downregulated in human bladder cancer tissues and was negatively correlated with bladder cancer invasion. Forced expression of FOXO1 specifically suppressed high-grade human bladder cancer cell invasion, whereas knockdown of FOXO1 promoted noninvasive bladder cancer cells becoming invasive bladder cancer cells. Moreover, knockout of FOXO1 significantly increased bladder cancer cell invasion and abolished the ISO inhibition of invasion in human bladder cancer cells. Further studies showed that the inhibition of Signal transducer and activator of transcription 1 (STAT1) phosphorylation at Tyr701 was crucial for ISO upregulation of FOXO1 transcription. Furthermore, this study revealed that metalloproteinase-2 (MMP-2) was a FOXO1 downstream effector, which was also supported by data obtained from mouse model of ISO inhibition BBN-induced mouse-invasive bladder cancer formation. These findings not only provide a novel insight into the understanding of mechanism of bladder cancer's propensity to invasion, but also identify a new role and mechanisms underlying the natural compound ISO that specifically suppresses such bladder cancer invasion through targeting the STAT1–FOXO1–MMP-2 axis. Cancer Prev Res; 9(7); 567–80. ©2016 AACR.
Data from Long-Term Glucocorticoid Use and Cancer Risk: A Population-Based Cohort Study in South Korea
Authors: Oh Tak Kyu , Song In-Ae
Published: March 2024

Abstract
Long-term glucocorticoid (GC) exposure causes immunosuppression; therefore, the risk of cancer may be increased in long-term GC users. We investigated whether long-term GC use is associated with a higher risk of cancer in the population without cancer. A population-based cohort study using data from the National Health Insurance Service was conducted among the South Korean adult population in 2010. Long-term GC users were defined as those who were prescribed a continuous supply of oral GC for ≥30 days. The primary endpoint was a new cancer diagnosis from January 1, 2011, to December 31, 2015. Among 770,880 individuals included in the analysis, 1,602 (0.2%) were long-term GC users and 36,157 (4.7%) were newly diagnosed with cancer from January 2011 to December 2015. In the multivariable Cox regression analysis, the risk of cancer among long-term GC users was 1.23-fold higher than that of the unexposed individuals [95% confidence interval (CI), 1.06–1.43; P = 0.007]. In the competing risk analyses, the risks of liver cancer and lung cancer were 1.46-fold (95% CI, 1.03–2.07; P = 0.034) and 1.52-fold (95% CI, 1.04–2.21; P = 0.029) higher in the long-term GC users than that of the unexposed individuals, respectively. We found that long-term GC exposure might be associated with a higher risk of overall cancer, and this association was more evident for lung and liver cancer risk. However, because there might be unmeasured and potential confounders in this study, the results should be interpreted carefully, and future studies should be performed to confirm these findings.
Impact:
Long-term glucocorticoid therapy might be associated with a higher cancer risk. This association was more evident for lung and liver cancer risk. Our findings suggest that long-term prescriptions of glucocorticoids should be administered carefully considering the risk of cancer.
Data from Low Colorectal Cancer Screening Uptake and Persistent Disparities in an Underserved Urban Population
Authors: Ni Katherine , O'Connell Kelli , Anand Sanya , Yakoubovitch Stephanie C. , Kwon Simona C. , de Latour Rabia Ali , Wallach Andrew B. , Sherman Scott E. , Du Mengmeng , Liang Peter S.
Published: March 2024

Abstract
Colorectal cancer screening has increased substantially in New York City in recent years. However, screening uptake measured by telephone surveys may not fully capture rates among underserved populations. We measured screening completion within 1 year of a primary care visit among previously unscreened patients in a large urban safety-net hospital and identified sociodemographic and health-related predictors of screening.

We identified 21,256 patients ages 50 to 75 who were seen by primary care providers (PCP) in 2014, of whom 14,425 (67.9%) were not up-to-date with screening. Because PCPs facilitate the majority of screening, we compared patients who received screening within 1 year of an initial PCP visit to those who remained unscreened using multivariable logistic regression.

Among patients not up-to-date with screening at study outset, 11.5% (1,658 patients) completed screening within 1 year of a PCP visit. Asian race, more PCP visits, and higher area-level income were associated with higher screening completion. Factors associated with remaining unscreened included morbid obesity, ever smoking, Elixhauser comorbidity index of 0, and having Medicaid/Medicare insurance. Age, sex, language, and travel time to the hospital were not associated with screening status. Overall, 39.9% of patients were up-to-date with screening by 2015.

In an underserved urban population, colorectal cancer screening disparities remain, and overall screening uptake was low. Because more PCP visits were associated with modestly higher screening completion at 1 year, additional community-level education and outreach may be crucial to increase colorectal cancer screening in underserved populations.
Data from Periodontal Disease, Tooth Loss, and Risk of Serrated Polyps and Conventional Adenomas
Authors: Lo Chun-Han , Nguyen Long H. , Wu Kana , Ogino Shuji , Chan Andrew T. , Giovannucci Edward L. , Song Mingyang
Published: March 2024

Abstract
Growing data indicate an association between periodontal disease and the development of cancer. However, the evidence for colorectal cancer has been inconsistent and longitudinal study examining its precursor lesions is lacking. We prospectively collected information on periodontal disease and number of tooth loss in the Nurses' Health Study (1992–2002) and the Health Professionals Follow-up Study (1992–2010). Polyp diagnosis was acquired via self-reported questionnaires and confirmed through review of medical records. We used logistic regression to calculate the multivariate-adjusted ORs and 95% confidence intervals (CI) with adjustment for smoking and other known risk factors for periodontal disease and colorectal cancer. In this study, we included 17,904 women and 24,582 men. We documented 2,336 cases of serrated polyps and 4,102 cases of conventional adenomas among 84,714 person-endoscopies throughout follow-up. The ORs of serrated polyps and conventional adenomas comparing individuals with and without periodontal disease were 1.17 (95% CI, 1.06–1.29) and 1.11 (95% CI, 1.02–1.19), respectively. Compared with participants without tooth loss, those who lost ≥4 teeth had 20% (OR, 1.20; 95% CI, 1.03–1.39) greater risk of serrated polyps (Ptrend 0.01). Among never smokers, similar associations with periodontal disease were observed for both serrated polyps (OR, 1.20; 95% CI, 1.02–1.41) and conventional adenomas (OR, 1.12; 95% CI, 1.00–1.26). History of periodontal disease and possibly higher number of tooth loss may modestly increase the risk of developing colorectal precursor lesions. Our findings advance our understanding of the interplay between oral health, microbiome, and early colorectal carcinogenesis.
Data from Using Digital Pathology to Understand Epithelial Characteristics of Benign Breast Disease among Women Undergoing Diagnostic Image-Guided Breast Biopsy
Authors: Mullooly Maeve , Puvanesarajah Samantha , Fan Shaoqi , Pfeiffer Ruth M. , Olsson Linnea T. , Hada Manila , Kirk Erin L. , Vacek Pamela M. , Weaver Donald L. , Shepherd John , Mahmoudzadeh Amir , Wang Jeff , Malkov Serghei , Johnson Jason M. , Hewitt Stephen M. , Herschorn Sally D. , Sherman Mark E. , Troester Melissa A. , Gierach Gretchen L.
Published: March 2024

Abstract
Delayed terminal duct lobular unit (TDLU) involution is associated with elevated mammographic breast density (MD). Both are independent breast cancer risk factors among women with benign breast disease (BBD). Prior digital analyses of normal breast tissues revealed that epithelial nuclear density (END) and TDLU involution are inversely correlated. Accordingly, we examined associations of END, TDLU involution, and MD in BBD clinical biopsies. This study included digitized images of 262 representative image-guided hematoxylin and eosin–stained biopsies from 224 women diagnosed with BBD, enrolled within the cross-sectional BREAST-Stamp project that were visually assessed for TDLU involution (TDLU count/100 mm2, median TDLU span and median acini count per TDLU). A digital algorithm estimated nuclei count per unit epithelial area, or END. Single X-ray absorptiometry of prebiopsy ipsilateral craniocaudal digital mammograms measured global and localized MD surrounding the biopsy region. Adjusted ordinal logistic regression models assessed relationships between tertiles of TDLU and END measures. Analysis of covariance examined mean differences in MD across END tertiles. TDLU measures were positively associated with increasing END tertiles [TDLU count/100 mm2, ORT3vsT1: 3.42, 95% confidence interval (CI), 1.87–6.28; acini count/TDLUT3vsT1, OR: 2.40, 95% CI, 1.39–4.15]. END was significantly associated with localized, but not, global MD. Relationships were most apparent among patients with nonproliferative BBD. These findings suggest that quantitative END reflects different but complementary information to the histologic information captured by visual TDLU and radiologic MD measures and merits continued evaluation in assessing cellularity of breast parenchyma to understand the etiology of BBD.