Aspirin Nonsteroidal Anti-inflammatory Drugs Research Articles

Aspirin Metabolites and Mammographic Breast Density in Premenopausal Women.

Studies investigating the associations of self-reported aspirin use and mammographic breast density (MBD) have reported conflicting results. We, therefore, investigated the associations of aspirin metabolites, with MBD in premenopausal women. We performed this study on 705 premenopausal women who had fasting blood draw for metabolomic profiling. We performed covariate-adjusted linear regression models to calculate the least squares means of volumetric measures of MBD (volumetric percent density (VPD), dense volume (DV), and non-dense volume (NDV)) by quartiles of aspirin metabolites (salicyluric glucuronide, 2-hydroxyhippurate (salicylurate), salicylate, and 2,6-dihydroxybenzoic acid). Approximately 13% of participants reported taking aspirin in the past 12 months. Aspirin users had higher levels of 2-hydroxyhippurate (salicylurate), salicylate, and salicyluric glucuronide (peak area) than non-users, but only mean peak area of salicyluric glucuronide increased by both dose (1-2 tabs per day=1,140,663.7, and ≥3 tabs per day=1,380,476.0) and frequency (days per week: 1 day=888,129.3, 2-3 days=1,199,897.9 and ≥4 days=1,654,637.0). Aspirin metabolites were not monotonically associated with VPD, DV, or NDV. Given the null results, additional research investigating the associations of aspirin metabolites in breast tissue and MBD is necessary. Elucidating the determinants of MBD, a strong risk factor for breast cancer, can play an important role in breast cancer prevention. Future studies should determine the associations of non-aspirin non-steroidal anti-inflammatory drug metabolites with MBD.

Influence of Low-Density Lipoprotein Cholesterol Levels on NSAID-Associated Cardiovascular Risks After Myocardial Infarction: A Population-Based Cohort Study.

To examine whether low-density lipoprotein cholesterol (LDL-C) levels influence the cardiovascular risk associated with non-aspirin non-steroidal anti-inflammatory drug (NSAID) use after myocardial infarction (MI). Using Danish health registries, we conducted a population-based cohort study of all adult patients with first-time MI during 2010-2020 with an LDL-C value before discharge. Based on the latest LDL-C value, we categorized patients into a low and a high LDL-C group (<3.0 vs ≥3.0 mmol/L). We used time varying Cox regression to compute hazard ratios (HRs) with 95% confidence intervals of the association between NSAID use and a major adverse cardiovascular event (MACE: recurrent MI, ischemic stroke, and all-cause death). We followed 50,573 patients for a median of 3.1 years. While exposed, 521 patients experienced a MACE: 312 in the low LDL-C group and 209 in the high LDL-C group. The HRs for MACE comparing NSAID use with non-use were 1.21 (1.11-1.32) overall, 1.19 (1.06-1.33) in the low LDL-C group, and 1.23 (1.07-1.41) in the high LDL-group. The HRs for recurrent MI and ischemic stroke were comparable between the LDL-C subgroups. The HRs for all-cause death were 1.22 (1.07-1.39) in the low LDL-C group and 1.54 (1.30-1.83) in the high LDL-C group. Changing the cut-off value for LDL-C to 1.8 and 1.4 mmol/L showed consistent results. In patients with MI, LDL-C levels did not influence the increased risk of MACE associated with NSAID use, but might influence the association between NSAID use and all-cause death.

Effect of nonsteroidal anti-inflammatory drugs (aspirin and naproxen) on inflammation-associated proteomic profiles in mouse plasma and prostate during TMPRSS2-ERG (fusion)-driven prostate carcinogenesis.

Recent preclinical studies have shown that the intake of nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin and naproxen could be an effective intervention strategy against TMPRSS2-ERG fusion-driven prostate tumorigenesis. Herein, as a follow-up mechanistic study, employing TMPRSS2-ERG (fusion) positive tumors and plasma from TMPRSS2-ERG. Ptenflox/flox mice, we profiled the stage specific proteomic changes (focused on inflammatory circulating and prostate tissue/tumor-specific cytokines, chemokines, and growth factors/growth signaling-associated molecules) that contribute to prostate cancer (PCa) growth and progression in the TMPRSS2-ERG fusion-driven mouse model of tumorigenesis. In addition, the association of the protective effects of NSAIDs (aspirin 1400 ppm and naproxen 400 ppm) with the modulation of these specific molecular pathways was determined. A sandwich Elisa based membrane array-proteome profiler identifying 111 distinct signaling molecules was employed. Overall, the plasma and prostate tissue sample analyses identified 54 significant and differentially expressed cytokines, chemokines, and growth factors/growth signaling-associated molecules between PCa afflicted mice (TMPRSS2-ERG. Ptenflox/flox, age-matched noncancerous controls, NSAIDs-supplemented and no-drug controls). Bioinformatic analysis of the array outcomes indicated that the protective effect of NSAIDs was associated with reduced expression of (a) tumor promoting inflammatory molecules (M-CSF, IL-33, CCL22, CCL12, CX3CL1, CHI3L1, and CD93),(b) growth factors- growth signaling-associated molecules (Chemerin, FGF acidic, Flt-3 ligand, IGFBP-5, and PEDF), and (c) tumor microenvironment/stromal remodeling proteins MMP2 and MMP9. Overall, our findings corroborate the pathological findings that protective effects of NSAIDs in TMPSS2-ERG fusion-driven prostate tumorigenesis are associated with antiproliferative and anti-inflammatory effects and possible modulation of the immune cell enriched microenvironment.

Abstract A089: Influence of pre-diagnosis aspirin use on epithelial ovarian cancer tumor immune microenvironment markers: results from the Nurses’ Health Study (NHS) and NHSII

Abstract Background: Daily aspirin use versus never use is associated with a 10-20% lower risk of developing epithelial ovarian cancer (EOC). Among women with EOC, aspirin use after diagnosis compared with never use is associated with a 30% improvement in ovarian cancer-specific survival. Inhibition of enzymes in prostaglandin synthesis is a key mechanism responsible for the anti-inflammatory and anti-neoplastic effects of aspirin. Prostaglandins influence immune inflammatory cells in the tumor microenvironment therefore our objective was to evaluate how aspirin use may influence the EOC tumor immune microenvironment. Methods: Tissue microarrays (TMAs) representing EOC tumor tissues from participants in the Nurses’ Health Study (NHS) and NHSII were assessed for total T cells, T cell activation and T cell exhaustion markers within the tumor (epithelium) area using multiplex immunofluorescence. Data on aspirin use and information on EOC risk factors and lifestyle variables were collected by questionnaire every two years. Beta-binomial models were used to estimate odds ratios (ORs) and 95% CIs; these models estimate the odds that a cell was positive for the marker(s) of interest comparing recent regular aspirin use (2+ times per week in the questionnaire cycle prior to diagnosis) versus never use, accounting for the total tumor cells in each core. Former users of aspirin were excluded. Multivariable models were adjusted for cohort, histotype (type 1 versus type 2), age and year of cancer diagnosis, number of CD3+ T cells (in tertiles), hysterectomy, tubal ligation, duration of oral contraceptive use, family history of breast or ovarian cancer, parity and body mass index (as fixed effects) and the participant (random effect) to account for multiple tissue cores per case. Results: We compared tumor tissues from 209 participants with recent pre-diagnosis use of aspirin with 88 participants who never used aspirin. Compared with cases who never used aspirin, recent aspirin users had higher odds of having tumors with recently activated cytotoxic T cells (CD3+CD8+CD69+, OR=1.69, 95% CI: 1.10, 2.59) and T cells expressing exhaustion markers (CD3+Lag-3+, OR=1.63, 95% CI: 1.09, 2.43; CD3+Tim-3+, OR= 1.62, 95% CI: 0.96, 2.72). In contrast, there was no association between recent aspirin use versus never use and odds of a tumor being positive for total T cells (CD3+, OR=1.20, 95% CI: 0.80, 1.79). Conclusions: Our data suggest that recent aspirin use before diagnosis was associated with higher odds of having EOC tumors expressing both recently activated cytotoxic T cells and T cell exhaustion markers. By improving our biological understanding of how aspirin use influences the ovarian tumor immune microenvironment, these results will assist to inform the optimal use of aspirin to improve EOC patient outcomes. Future work will focus on additional immune markers, assess non-aspirin nonsteroidal anti-inflammatory drug (NSAID) use and evaluate associations between aspirin/NSAID use with EOC survival considering the context of tumor immune microenvironment biomarkers. Citation Format: Nicola S. Meagher, Cassandra Hathaway, Mary K. Townsend, Mollie E. Barnard, Jose R. Conejo-Garcia, Brooke L. Fridley, Daryoush Saeed-Vafa, Britton Trabert, Shelley S. Tworoger, Melissa A. Merritt. Influence of pre-diagnosis aspirin use on epithelial ovarian cancer tumor immune microenvironment markers: results from the Nurses’ Health Study (NHS) and NHSII [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A089.

Differential Effect of Non-Steroidal Anti-Inflammatory Drugs Aspirin and Naproxen against TMPRSS2-ERG (Fusion)-Driven and Non-Fusion-Driven Prostate Cancer.

The consumption of the non-steroidal anti-inflammatory drug (NSAID) aspirin is associated with a significant reduction in the risk of developing TMPRSS2-ERG (fusion)-positive prostate cancer (PCa) compared to fusion-negative PCa in population-based case-control studies; however, no extensive preclinical studies have been conducted to investigate and confirm these protective benefits. Thus, the focus of this study was to determine the potential usefulness of aspirin and another NSAID, naproxen, in PCa prevention, employing preclinical models of both TMPRSS2-ERG (fusion)-driven (with conditional deletion of Pten) and non-TMPRSS2-ERG-driven (Hi-Myc+/- mice) PCa. Male mice (n = 25 mice/group) were fed aspirin- (700 and 1400 ppm) and naproxen- (200 and 400 ppm) supplemented diets from (a) 6 weeks until 32 weeks of Hi-Myc+/- mice age; and (b) 1 week until 20 weeks post-Cre induction in the fusion model. In all NSAID-fed groups, compared to no-drug controls, there was a significant decrease in higher-grade adenocarcinoma incidence in the TMPRSS2-ERG (fusion)-driven PCa model. Notably, there were no moderately differentiated (MD) adenocarcinomas in the dorsolateral prostate of naproxen groups, and its incidence also decreased by ~79-91% in the aspirin cohorts. In contrast, NSAIDs showed little protective effect against prostate tumorigenesis in Hi-Myc+/- mice, suggesting that NSAIDs exert a specific protective effect against TMPRSS2-ERG (fusion)-driven PCa.

Association between non-steroidal anti-inflammatory drug use and development of age-related macular degeneration—A 10-year retrospective cohort study

To analyze the associations between development of age-related macular degeneration (AMD) and regular use of aspirin or non-aspirin non-steroidal anti-inflammatory drugs (NA-NSAIDs). We retrospectively recruited individuals who received ≥28-day prescriptions of aspirin or NA-NSAIDs exclusively between 2008 and 2017 in one tertiary center as regular users. Non-regular users were free from regular use of any anti-inflammatory drugs and were matched to regular users in terms of age, sex, and visit date at a ratio of 1-4:1. The aspirin cohort included 36,771 regular users and 110,808 matched non-regular users, while the NA-NSAID cohort included 59,569 regular users and 179,732 matched non-regular users. Stratified multivariate Cox regression analyses with adjustment for systemic confounding factors were performed for the development of AMD and neovascular AMD. In the aspirin cohort, the adjusted hazard ratios of aspirin use for AMD in the whole cohort, individuals without cardiovascular diseases (CVDs), and those with CVDs were 0.664, 0.618, and 0.702, respectively (P<0.0001 for all), while those of aspirin use for neovascular AMD were 0.486, 0.313, and 0.584 (P<0.05 for all), respectively. In the NA-NSAID cohort, regular use of NA-NSAIDs was associated with a decreased risk of AMD (hazard ratio=0.823, P<0.0001) and neovascular AMD (hazard ratio=0.720, P=0.040) only in people without arthritis. Regular use of aspirin or NA-NSAIDs had protective effects on AMD and neovascular AMD. The effect of aspirin was observed in all patients, while the effect of NA-NSAIDs was observed only in people without arthritis.

Non-steroidal anti-inflammatory drug use and markers of Parkinson's disease progression: A retrospective cohort study

BackgroundPrevious studies demonstrated reduced incidence of Parkinson's disease (PD) with regular non-steroidal anti-inflammatory drug (NSAID) exposure, particularly ibuprofen. No studies have investigated the impact of NSAID exposure on markers of disease progression for established PD. MethodsThis is a retrospective observational study using two cohorts. The Deprenyl and Tocopheral Anti-Oxidative Therapy of Parkinsonism (DATATOP) study enrolled 800 drug naïve people with PD with a median follow-up duration of 6.5 years. The DATATOP primary outcome measures were mortality at last study visit. The Parkinson's Progression Markers Initiative (PPMI) cohort was limited to drug naïve PD participants (423 at time of analysis). The PPMI primary outcome measure was annual rate of change in ipsilateral putamen 123I-ioflupane binding ratio at four years study duration. Regular NSAID exposure was defined as any scheduled NSAID use (as needed use was excluded). Analysis was performed separately for recent exposure and cumulative exposure time (CET). ResultsTotal CET median and interquartile range (years) for ibuprofen, non-aspirin NSAID, and aspirin were respectively 0.9 (0.3–2.9), 1.1 (0.3–2.6), and 1.5 (0.4–2.8) for DATATOP and 0.4 (0.01–2.2), 1.4 (0.3–4.4), and 5.5 (2.6–7.1) for PPMI. Exposure was usually discontinuous. Exposure to ibuprofen was low in both cohorts. There was no significant association between NSAID recent exposure or CET and primary outcome measures in either cohort. ConclusionsNSAID exposure in established PD does not appear to provide protective effect although exposure may not have occurred continuously enough in these two cohorts to provide benefit. Statistical power for ibuprofen exposure analyses was limited.

Impact of analgesics on the risk of ovarian cancer; a systematic review and meta-analysis of cohort and case-control studies

Introduction: Ovarian cancer is the sixth leading cancer-related mortality cause in women worldwide. Analgesics may hinder the occurrence of ovarian cancer through inflammation relief. The present study seeks to examine the relationship between analgesic consumption and ovarian cancer risk through a systematic review and meta-analysis. Materials and Methods: PubMed, Scopus, Web of Science, Cochrane databases, and Google Scholar search engines were searched for works published by May 2023 using standard keywords to collect the required data sources. Acquired data were then analyzed in STATA version14, considering a significance level of P &lt; 0.05 in statistical tests. Results: The present meta-analysis comprised 21 studies (14 case-control and 7 cohort studies) performed on 53,755 subjects. Results indicated that taking aspirin reduced the risk of ovarian cancer by 8% (OR: 0.92; 95% CI: 0.87, 0.98), whereas other non-aspirin NSAIDs (non-steroidal anti-inflammatory drugs) did not significantly affect the ovarian cancer risk (OR: 0.91; 95% CI: 0.81, 1.02). Similar results were observed in the case of ibuprofen and acetaminophen, with non-significant relationships between the risk of ovarian cancer and with the consumption of both acetaminophen (OR: 0.95; 95% CI: 0.84, 1.08) and ibuprofen (OR: 0.76; 95% CI: 0.50, 1.14). Furthermore, the duration of analgesic consumption was not significantly linked to the risk of ovarian cancer in the case of all studied drugs. Conclusion: Among aspirin, ibuprofen, acetaminophen, and non-aspirin NSAIDs, only aspirin was found to reduce the risk of ovarian cancer in women while the other studied drugs did not influence the studied risk. However, further research is recommended to confirm the results. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO (CRD42023434730) and Research Registry (UIN: reviewregistry1668) websites.

Aspirin and nonaspirin nonsteroidal antiinflammatory drug use and occurrence of colorectal adenoma in Black American women.

Evidence suggests that aspirin use reduces the occurrence of colorectal neoplasia. Few studies have investigated the association among Black Americans, who are disproportionately burdened by the disease. We assessed aspirin use in relation to colorectal adenoma among Black women. The Black Women's Health Study is a prospective cohort of self-identified Black American women established in 1995. Participants reported regular aspirin use on baseline and follow-up questionnaires. Beginning in 1999, participants reported undergoing a colonoscopy or sigmoidoscopy, the only procedures through which colorectal adenomas can be diagnosed. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between aspirin use and colorectal adenoma among 34 397 women who reported at least 1 colonoscopy or sigmoidoscopy. From 1997 through 2018, 1913 women were diagnosed with an adenoma. Compared to nonaspirin users, regular users had 14% (OR = 0.86, 95% CI: 0.78-0.95) lower odds of adenoma. The odds of adenoma decreased with increasing duration of aspirin use (≥10 years: OR = 0.80, 95% CI: 0.66-0.96). Initiating aspirin at a younger age was associated with a reduced adenoma occurrence (age < 40 years at initiation: OR = 0.69, 95% CI: 0.55-0.86). Regular aspirin use was associated with a decreased odds of colorectal adenoma in our study of Black women. These findings support evidence demonstrating a chemopreventive impact of aspirin on colorectal neoplasia and suggest that aspirin may be a useful prevention strategy among US Black women.

Use of nonsteroidal anti-inflammatory drugs and poor olfaction in women.

It is unclear whether regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with poor olfaction in older adults. We selected 4020 participants, aged 50 to 79years in 2018, from 36,492 eligible participants in the National Institute of Environmental Health Sciences Sister Study, according to their self-reported olfaction status. Of these, 3406 women completed the 12-item Brief Smell Identification Test. We defined poor olfaction as a test score ≤9 in the primary analysis. We then estimated odds ratios (ORs) and 95% confidence intervals (CIs) from weighted logistic models, accounting for the study design, missing exposures/outcomes, and covariates. Overall, NSAID use was not associated with poor olfaction. However, we found evidence for potential multiplicative interactions. Specifically, the OR comparing regular versus never use of aspirin was 1.8 (95% CI, 1.1-3.2) among women who had not regularly used nonaspirin NSAIDs, while the corresponding OR was 0.8 (95% CI, 0.5-1.2) among nonaspirin NSAID users (P for interaction=0.016). Similar results were seen for ibuprofen alone versus ibuprofen with other NSAID use (P for interaction=0.010). Among women using either drug alone, associations with poor olfaction increased with increasing duration and cumulative dose. Post hoc analyses showed that the interactions could not be readily explained by potential biases. Other NSAIDs were not associated with olfaction. Long-term regular use of aspirin or ibuprofen was associated with poor olfaction among women who never regularly used other types of NSAIDs. These preliminary findings warrant independent confirmation.

Low cross-linked terpenes-based porous polymers with reduced content of divinylbenzene: synthesis, physicochemical properties and sorption abilities

The low cross-linked porous polymers were prepared using terpene compounds (citral, limonene and pinene) and divinylbenzene with a suspension method. The prepared materials were characterized by: ATR-FTIR, low temperature nitrogen adsorption–desorption, TGA, swelling ratio and solid phase extraction (SPE) experiments. ATR-FTIR verified the chemical structures of the polymers. All the materials had developed internal structure with SBET in the range of 45–190 m2/g and high thermal stability. Sorption properties of the terpene-based polymers were tested for phenolic compounds (phenol, 2-chlorophenol, 2,4-dichlorophenol and 2,4,6-trichlorophenol) and popular non-steroidal anti-inflammatory drugs (aspirin, paracetamol and ibuprofen) and an antibiotic (ampicillin) with a dynamic solid phase extraction (SPE) method. The recoveries of 2,4-dichlorophenol and 2,4,6-trichlorophenol remained at a level 80–100% for all new materials even for 10–13 concentration cycles. Very high recoveries (70–100%) were also obtained for ibuprofen and aspirin from the citral- and limonene-based polymers using one-component solutions. However, when using ternary component solutions, the maximum recoveries of ibuprofen reached 70%. Paracetamol recoveries did not exceed 20%, while these for ampicillin ranged from 40 to 80%. The performed studies have proven that the process is affected by both chemical nature of adsorbents and adsorbates. Especially in the case of multicomponent solutions, the acid—base balance of solutes in the solution and on the polymer—solution interface should be taken into account as an important factor determining obtained recoveries.

Preventive effects of 13 different drugs on colorectal cancer: a network meta-analysis.

The aim of the study was to evaluate the preventive effect of 13 drugs on colorectal cancer (CRC) and guide the clinical application of these drugs. PubMed, Web of Science, Embase, Cochrane Library, and China National Knowledge Infrastructure were searched for randomized controlled trials (RCTs) and cohort studies. The Cochrane bias risk assessment tool and the Newcastle-Ottawa Scale quality evaluation tool were used to evaluate the quality of the included RCTs and cohort studies. The funnel plot was used to analyze publication bias. A network meta-analysis of the extracted data was conducted using Stata16.0 software. A total of 57 studies (34 RCTs and 23 cohort studies) involving 82719 participants were included. The network meta-analysis revealed that the quality of the included studies was good; the funnel plot showed no obvious publication bias. The network meta-analysis showed that the preventive effect of 13 drugs on CRC was better than that of the placebo. Allopurinol (SUCRA: 97.2%) was found to have the best effect, followed by berberine (SUCRA: 89.9%), non-aspirin NSAIDs (SUCRA: 84.5%), statins (SUCRA: 66.5%), metformin (SUCRA: 66.3%), calcium (SUCRA: 48.9%), mesalazine (SUCRA: 44.5%), ursodeoxycholic acid (SUCRA: 42.6%), vitamin D (SUCRA: 41.4%), mercaptopurine (SUCRA: 39.4%), aspirin (SUCRA: 30.4%), folic acid (SUCRA: 24.9%), and eicosapentaenoic acid (SUCRA: 16.3%). The preventive effect of allopurinol on CRC was better than that of the other 13 drugs. These results can help doctors and patients understand the preventative effects of these drugs more intuitively and provide an evidence-based basis for the clinical application of these drugs.

Hip and Knee Osteoarthritis, Not Nonsteroidal Anti-Inflammatory Drugs, are Linked to Cardiac Disease

BackgroundIn 2005, the Food and Drug Administration placed a black-box warning (the most stringent warning for drugs) on all nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) stating that these agents may cause heart attacks and/or strokes. No level I evidence demonstrates that nonselective NSAIDs increase cardiovascular risk. An alternative hypothesis is that hip and knee osteoarthritis (OA) indirectly causes cardiovascular disease (CVD) through decreased activity and NSAIDs are correlated with CVD as an arthritis treatment. MethodsSystematic reviews were conducted to find observational studies evaluating the association of hip and/or knee OA, CVD, activity, walking, and step counts. The systematic review found studies correlating hip and/or knee OA and CVD morbidity incidence (n = 2); CVD morbidity prevalence (n = 6); odds ratios, relative risks, or hazard ratios of CVD morbidity (n = 11); relative risk, standardized mortality ratios, or hazard ratios of CVD mortality (n = 14); and all-cause mortality hazard ratios associated with NSAID use (n = 3). ResultsHip OA (5 studies), knee OA (9 studies), and hip and knee OA (6 studies) are linked to an increased risk of CVD morbidity and mortality. Cardiac risk increases with validated disability scores, use of walking aids, walking difficulties, longer follow-up times, younger ages of OA onset, numbers of joints involved, and OA severities. No study linked NSAID use to cardiac disease. ConclusionsAll studies with more than 10-year follow-up linked cardiac disease with hip and knee OA. No study linked nonselective NSAID use to CVD. The Food and Drug Administration should reconsider the black-box warnings on naproxen, ibuprofen, and celecoxib.

Common analgesics and ovarian cancer survival: the Ovarian cancer Prognosis And Lifestyle (OPAL) Study.

Most women with ovarian cancer (OC) are diagnosed with advanced disease. They often experience recurrence after primary treatment, and their subsequent prognosis is poor. Our goal was to evaluate the association between use of nonsteroidal antiinflammatory drugs (NSAIDs), including regular and low-dose aspirin, and 5-year cancer-specific survival after an OC diagnosis. The Ovarian cancer Prognosis And Lifestyle study is a prospective population-based cohort of 958 Australian women with OC. Information was gathered through self-completed questionnaires. We classified NSAID use during the year prediagnosis and postdiagnosis as none or occasional (<1 d/wk), infrequent (1-3 d/wk), and frequent (≥4 d/wk) use. We measured survival from the start of primary treatment: surgery or neoadjuvant chemotherapy for analyses of prediagnosis use, or 12 months after starting treatment (postdiagnosis use) until the earliest of date of death from OC (other deaths were censored) or last follow-up to 5 years. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) and applied inverse-probability of treatment weighting to minimize confounding. We also calculated restricted mean survival times. Compared with nonusers and infrequent users, we observed better survival associated with frequent NSAID use prediagnosis (HR = 0.73, 95% CI = 0.55 to 0.97) or postdiagnosis (HR = 0.65, 95% CI = 0.45 to 0.94). Estimates were similar for aspirin and nonaspirin NSAIDs, new and continuous users and in weighted models. These differences would translate to a 2.5-month increase in mean survival by 5 years postdiagnosis. There was no association with acetaminophen. Our findings confirm a previous study suggesting NSAID use might improve OC survival.

Use of Nonsteroidal Anti-Inflammatory Drugs and Risk of Breast Cancer: Evidence from a General Female Population and a Mammographic Screening Cohort in Sweden.

A link has been proposed between the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of breast cancer. There is, however, insufficient data regarding the subtype and stage of breast cancer, and few studies have assessed the interaction between the use of NSAIDs and breast density or previous breast disorders. There is also a lack of data from population-based studies. We first conducted a nested case-control study within the general female population of Sweden, including 56,480 women with newly diagnosed breast cancer during 2006-2015 and five breast cancer-free women per case as controls, to assess the association of NSAID use with the risk of incident breast cancer, focusing on subtype and stage of breast cancer as well as the interaction between NSAID use and previous breast disorders. We then used the Karolinska Mammography Project for Risk Prediction of Breast Cancer (Karma) cohort to assess the interaction between NSAID use and breast density in relation to the risk of breast cancer. Conditional logistic regression was used to estimate the hazard ratio (HR) and a 95% confidence interval (CI) was used for breast cancer in relation to the use of aspirin and non-aspirin NSAIDs. In the nested case-control study of the general population, exclusive use of aspirin was not associated with the risk of breast cancer, whereas exclusive use of non-aspirin NSAIDs was associated with a modestly higher risk of stage 0-2 breast cancer (HR: 1.05; 95% CI: 1.02-1.08) but a lower risk of stage 3-4 breast cancer (HR 0.80; 95% CI: 0.73-0.88). There was also a statistically significant interaction between the exclusive use of NSAIDs and previous breast disorders (p for interaction: <0.001). In the analysis of Karma participants, the exclusive use of non-aspirin NSAIDs was associated with a lower risk of breast cancer among women with a breast dense area of >40 cm2 (HR: 0.72; 95% CI: 0.59-0.89). However, the possibility of finding this by chance cannot be ruled out. Overall, we did not find strong evidence to support an association between the use of NSAIDs and the risk of breast cancer.

Exposure to Commonly Used Drugs and the Risk of Gastric Cancer: An Umbrella Review of Meta-Analyses.

Recently, attention has been paid to some medications and gastric cancer (GC) risk. This review aimed to evaluate associations between commonly used drugs and GC risk and to grade evidence from published systematic reviews and meta-analyses. This umbrella review was registered in PROSPERO (CRD42022320276). The systematic reviews and meta-analyses of observational studies were retrieved by searching Embase, PubMed, and Web of Science. The evidence strength of commonly used drugs and GC risk was categorized into four grades: weak, suggestive, highly suggestive, and strong. Of 19 associations between commonly used drugs and GC risk and its subtypes, none was supported by convincing or highly suggestive evidence. The risk of GC related to non-steroidal anti-inflammatory drugs (NSAIDs), non-aspirin NSAIDs, and acid-suppressive drugs, as well as the risk of non-cardia GC related to NSAIDs and aspirin, was supported by suggestive evidence. The results showed that a reduced GC risk was associated with two drug types (NSAIDs and non-aspirin NSAIDs), and an increased GC risk was associated with acid-suppressing drugs at the suggestive evidence level. Moreover, NSAIDs and aspirin reduced non-cardia GC risk as supported by suggestive evidence. However, the evidence supporting statins or metformin in reducing GC risk was weak, and thus future studies are required to clarify these associations.

Abstract 5893: Analgesic use and renal cell carcinoma incidence and survival: Results from three prospective cohort studies

Abstract Background: Analgesics are the most commonly consumed over-the-counter drugs worldwide. Considerable evidence suggests a beneficial effect of analgesics, and especially aspirin, on cardiovascular disease and colorectal cancer risk. Studies examining whether widely used analgesics - aspirin, non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen - play a role in renal cell carcinoma (RCC) have yielded mixed results. Methods: We examined associations between pre-diagnostic analgesic use and incidence of total and fatal RCC in the Health Professionals Follow-up Study (HPFS; 1986-2016), Nurses’ Health Study (NHS; 1980-2016 for aspirin; 1990-2016 for non-aspirin NSAIDs and acetaminophen), and Nurses’ Health Study 2 (NHS2; 1989-2015; total RCC only). Information on use of aspirin, non-aspirin NSAIDs, and acetaminophen was collected longitudinally on biennial questionnaires. We used Cox proportional hazards models to estimate cohort-specific, multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) according to current use (updated in each questionnaire period) and, separately, duration of use (since study baseline) of each analgesic. Results across cohorts were combined using random-effects meta-analyses. We also used Cox regression to evaluate post-diagnostic analgesic use with respect to RCC-specific mortality among RCC cases in the pooled HPFS and NHS cohorts. Results: Among 259,545 participants, 796 incident RCC cases were diagnosed. Neither current nor duration of pre-diagnostic use of any of the analgesics was associated with the risk of total RCC in meta-analyses of the three study cohorts. For fatal RCC (n=175 cases), however, meta-analyses of the HPFS and NHS suggested covariate-adjusted positive associations with current (HR: 1.37, 95% CI: 0.96-1.96, p-heterogeneity: 0.80) and duration of (HR&amp;gt;10yrs vs. Never: 2.62, 95% CI: 1.23-5.58, p-trend: 0.006, p-heterogeneity: 0.30) pre-diagnostic non-aspirin NSAID use. In addition, in the HPFS only, current (HR: 2.35, 95% CI: 1.33-4.17) and duration of (HR&amp;gt;10yrs vs. Never: 1.83, 95% CI: 0.42-7.93, p-trend: 0.07) pre-diagnostic acetaminophen use indicated positive associations with fatal RCC. Analyses of RCC-specific mortality among participants diagnosed with RCC demonstrated an inverse association with current post-diagnostic aspirin use (HR: 0.68, 95% CI: 0.48-0.97), but not duration of post-diagnostic aspirin use (HR&amp;gt;10yrs vs. Never: 0.89, 95% CI: 0.53-1.51, p-trend: 0.98). Analgesics were not otherwise associated with RCC survival. Conclusions: Our findings support a potential positive association between non-aspirin NSAID use and incident fatal RCC. It remains possible that analgesics may operate differently in the setting of RCC from the context of other chronic diseases. Citation Format: Rebecca E. Graff, Alejandro Sanchez, Toni K. Choueiri, Meir J. Stampfer, Edward L. Giovannucci, Lorelei A. Mucci, Eunyoung Cho, Mark A. Preston. Analgesic use and renal cell carcinoma incidence and survival: Results from three prospective cohort studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5893.

Prediction Factors of Early Postoperative Bleeding after Bariatric Surgery.

Identifying the possible predictors of postoperative bleeding is advantageous to reduce healthcare costs and promote patients' recovery. The aim of this study was to determine early postoperative bleeding predictors after bariatric surgery. This retrospective study was conducted using data from 2260 patients who underwent bariatric surgery. We diagnosed early postoperative bleeding by the following symptoms: abdominal pain, hypotension, tachycardia, hematemesis, melena, decreased hemoglobin level, the need for at least two units of packed red blood cells (PRBCs) transfusion, and reoperation within the first 48h after surgery. Our results showed the odds of early postoperative bleeding in laparoscopic Roux-en-Y gastric bypass (LRYGB) were higher than in laparoscopic sleeve gastrectomy (LSG) (OR 3.49, 95% CI 1.79 to 6.80). In addition, prior intragastric balloon (IGB) (OR 3.14, 95% CI 1.18 to 8.34) and oral non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) (OR 5.91, 95% CI 1.79 to 20.63) were positively associated with the occurrence of postoperative bleeding. In contrast, there was an inverse relationship between staple line oversewing and the odds of postoperative bleeding (OR 0.18, 95% CI 0.04 to 0.81). After stratification data based on the type of the surgery, the positive association between IGB and the odds of bleeding was constant in the LRYGB group. In the LSG group, use of non-aspirin NSAIDs was linked to a higher incidence of postoperative bleeding, while oversewing of the staple line lowered the incidence of this event. Our results demonstrated a positive association between type of procedure, history of IGB, and oral non-aspirin NSIADs use, as well as an inverse relationship between staple line oversewing and the odds of bleeding after bariatric surgery.

Cyclooxygenase Enzyme and Lipid Peroxidation Inhibitory Terpenoids and Steroidal compounds as Major Constituents in Cleome viscosa Leaves

Bioassay guided study of Cleome viscosa Linn. (Cleomaceae) leaves led to the isolation of a new cembrenoid diterpene (1: ) and three known compounds (2: - 4: ) from the hexane extract. The chemical structures of these compounds were elucidated by spectroscopic methods such as NMR (1D and 2D), HRMS and IR and identified and afforded compound 1: , malabaric acid (2: ), stigmast-4-en-3-one (3: ) and stigmast-4-ene-3,6-dione (4: ). This is the first report of compounds 1: and 2: from C.viscosa Linn. Isolates were evaluated for anti-inflammatory activity using in vitro cyclooxygenase enzyme (COX-1 and -2) inhibitory assays. The novel cembrenoid diterpene (1: ) exhibited IC50 values of 8.4 µM for COX-1 enzyme and 45.2 µM for COX-2 enzyme, respectively. Similarly, malabaric acid (2: ) exhibited IC50 values of 11.5 µM for COX-1 enzyme and 46.9 µM for COX-2 enzyme, respectively. Their inhibitory activities were in par with non-steroidal anti-inflammatory drugs aspirin, ibuprofen and naproxen. Sterols 3: and 4: gave IC50 values of 62.6 and 67.9 µM, respectively for COX-1 enzyme while indicating weak COX-2 enzyme inhibition. Lipid peroxidation inhibitory (LPO) and MTT assays were used to determine antioxidant activity of these compounds. Compounds 1: - 4: showed LPO inhibition with IC50 values between 82 and 100 µM and moderate antioxidant activity in the MTT assay. Biological activities reported for these compounds are for the first time and it support anecdotal medicinal claims of C. viscosa Linn.leaves.

Analgesic Use and Circulating Estrogens, Androgens, and Their Metabolites in the Women's Health Initiative Observational Study.

This study explores a potential pathway by which analgesic medications such as aspirin may prevent hormone-related cancers. The findings support a positive association between low-dose aspirin use and endogenous estrogens, indicating that further elucidation of the interplay between low-dose aspirin, estrogen concentrations, and cancer risk is needed.