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1.  A nationwide study of aspirin, other non-steroidal anti-inflammatory drugs, and Hodgkin lymphoma risk in Denmark 
British Journal of Cancer  2011;105(11):1776-1782.
Background:
We recently found an inverse association between low-dose aspirin use and risk of Hodgkin lymphoma (HL) in northern Denmark. To strengthen the evidence for this association, we expanded the study base to include all of Denmark.
Methods:
Between 1997 and 2009, 1659 incident HL cases were identified in nationwide databases and matched with ⩽5 population controls on age, sex, and residence. Use of aspirin, selective cyclooxygenase-2 (sCOX-2) inhibitors, and other non-steroidal anti-inflammatory drugs (NSAIDs) from 1995 through 2008 (⩾1 year before the index date) was ascertained via the Danish National Prescription Database. Odds ratios (ORs) for associations with HL risk were estimated using conditional logistic regression.
Results:
Ever use (>2 prescriptions) vs never/rare use (⩽2 prescriptions) of low-dose aspirin was not associated with HL risk, but the association with long-term use for ⩾7 years vs never/rare use was clearly inverse, although statistically nonsignificantly so (OR=0.65, 95% confidence interval (CI): 0.39–1.09). By contrast, ever use of sCOX-2 inhibitors or other NSAIDs (OR=1.27, 95% CI: 1.10–1.47), especially short-term and low- or medium-intensity use, was associated with elevated HL risk.
Conclusion:
Our results are consistent with the hypothesis that long-term use of low-dose aspirin, but not other NSAIDs, protects against HL development.
doi:10.1038/bjc.2011.443
PMCID: PMC3242601  PMID: 22027707
aspirin; non-steroidal anti-inflammatory drugs; Hodgkin lymphoma; epidemiology; risk; prevention
2.  Prescriptions for selective cyclooxygenase-2 inhibitors, non-selective non-steroidal anti-inflammatory drugs, and risk of breast cancer in a population-based case-control study 
Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs) prevent the growth of mammary tumours in animal models. Two population-based case-control studies suggest a reduced risk of breast cancer associated with selective cyclooxygenase-2 (sCox-2) inhibitor use, but data regarding the association between breast cancer occurrence and use of non-selective NSAIDs are conflicting.
Methods
We conducted a population-based case-control study using Danish healthcare databases to examine if use of NSAIDs, including sCox-2 inhibitors, was associated with a reduced risk of breast cancer. We included 8,195 incident breast cancer cases diagnosed in 1991 through 2006 and 81,950 population controls.
Results
Overall, we found no reduced breast cancer risk in ever users (>2 prescriptions) of sCox-2 inhibitors (odds ratio (OR) = 1.08, 95% confidence interval (95% CI) = 0.99, 1.18), aspirin (OR = 0.98, 95% CI = 0.90-1.07), or non-selective NSAIDs OR = 1.04, (95% CI = 0.98, 1.10)). Recent use (>2 prescriptions within two years of index date) of sCox-2 inhibitors, aspirin, or non-selective NSAIDs was likewise not associated with breast cancer risk (Ors = 1.06 (95% CI = 0.96, 1.18), 0.96 (95% CI = 0.87, 1.06) and 0.99 (95% CI = 0.85, 1.16), respectively). Risk estimates by duration (<10, 10 to 15, 15+ years) or intensity (low/medium/high) of NSAID use were also close to unity. Regardless of intensity, shorter or long-term NSAID use was not significantly associated with breast cancer risk.
Conclusions
Overall, we found no compelling evidence of a reduced risk of breast cancer associated with use of sCox-2 inhibitors, aspirin, or non-selective NSAIDs.
doi:10.1186/bcr2482
PMCID: PMC2879557  PMID: 20193065
3.  Use of low-dose aspirin and non-aspirin nonsteroidal anti-inflammatory drugs and risk of glioma: a case–control study 
British Journal of Cancer  2013;108(5):1189-1194.
Background:
Few studies have examined the association between use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) and risk of glioma and the results have been equivocal. We therefore investigated the influence of NSAID use on glioma risk in a nationwide setting.
Methods:
We used national registries in Denmark to identify all patients aged 20–85 years with a first diagnosis of histologically verified glioma during 2000–2009. Each case was matched on birth year and sex to eight population controls using risk-set sampling. We used prescription data to assess NSAID use and classified exposure to low-dose aspirin or non-aspirin (NA) NSAIDs into ever use or long-term use, defined as continuous use for ⩾5 years. Conditional logistic regression was used to compute odds ratios (ORs), with 95% confidence intervals (CIs), for glioma associated with NSAID use, adjusted for potential confounders.
Results:
A total of 2688 glioma cases and 18 848 population controls were included in the study. Ever use of low-dose aspirin (OR=0.90; 95% CI: 0.77–1.04) or NA-NSAIDs (OR=1.05; 95% CI: 0.96–1.14) was not associated with glioma risk. Compared with never use, long-term use of low-dose aspirin or of NA-NSAIDs was associated with ORs of 0.80 (95% CI: 0.53–1.21) and 1.11 (0.57–2.17), respectively. We observed no clear patterns of risk in stratified analysis according to estimated doses of low-dose aspirin (⩽100 mg, 150 mg).
Conclusion:
We did not find any apparent association between aspirin or NA-NSAID use and risk of glioma, although our results may be consistent with a slight reduction in glioma risk with long-term use of low-dose aspirin.
doi:10.1038/bjc.2013.87
PMCID: PMC3619088  PMID: 23449355
aspirin; non-aspirin NSAIDs; glioma; risk; epidemiology
4.  Effect of Aspirin and other NSAIDs on Postmenopausal Breast Cancer Incidence by Hormone Receptor Status: Results from a Prospective Cohort Study 
Purpose
Aspirin and other non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit aromatase activity and thus could selectively lower incidence of hormone receptor positive tumors. We assessed whether the association of aspirin and other NSAIDs with postmenopausal breast cancer risk differs by estrogen and progesterone receptor (ER, PR) status of the tumor.
Methods
A population-based cohort of 26,580 postmenopausal women was linked to a SEER Cancer Registry to identify incident breast cancers. Regular use of aspirin and other NSAIDs was reported on a self-administered questionnaire mailed in 1992. Cox proportional hazards models were used to estimate multivariate relative risks (RRs) and 95% confidence intervals (CIs) of breast cancer incidence overall and by ER and PR status, adjusting for multiple breast cancer risk factors.
Results
Through 2005, 1,581 incident breast cancer cases were observed. Compared to aspirin never users, women who regularly consumed aspirin had a lower risk of breast cancer (RR=0.80; 95% CI: 0.71–0.90), and there was evidence for lower risk with increasing frequency of use (RR=0.71 for aspirin use 6 or more times/week versus never use; p-trend=0.00001). Inverse associations for regular aspirin use were observed for ER+ (RR=0.77; 95% CI 0.67–0.89), ER− (RR=0.78; 95% CI 0.56–1.08), PR+ (RR=0.79; 95% CI 0.68–0.92), and PR− (RR=0.73; 95% CI 0.56–0.95) breast cancers. In contrast, use of other NSAIDs was not associated with breast cancer incidence overall (RR=0.95, 95% CI: 0.85–1.07), or by ER or PR status.
Conclusions
Aspirin, but not other NSAID use, was associated with about 20% lower risk of postmenopausal breast cancer and did not vary by ER or PR status of the tumor, suggesting that the hypothesized protective effects of aspirin may either be through cellular pathways independent of estrogen or progesterone signaling, or on tumor microenvironment.
doi:10.1007/s10549-010-1074-x
PMCID: PMC2997337  PMID: 20669045
breast cancer; aspirin; NSAIDs; hormone receptors; prevention
5.  Non-steroidal anti-inflammatory drug (NSAID) and acetaminophen use and risk of adult myeloid leukemia 
Background
Little is known about the causes of adult leukemia. A few small studies have reported a reduced risk associated with regular use of non-steroidal anti-inflammatory drugs (NSAIDs).
Methods
In a population-based case-control study, we evaluated analgesic use among 670 newly diagnosed myeloid leukemia cases [including 420 acute myeloid leukemias (AML) and 186 chronic myeloid leukemias (CML)] and 701 controls aged 20–79 years. Prior use of aspirin, ibuprofen, acetaminophen, other NSAIDs, and cyclooxygenase-2 (COX-2) inhibitors was assessed and included frequency, duration, and quantity. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression adjusting for potential confounders.
Results
Regular/extra strength aspirin use was inversely associated with myeloid leukemia in women (OR=0.59, 95%CI=0.37–0.93) but not men (OR=0.85, 95%CI=0.58–1.24). In contrast, acetaminophen use was associated with an increased risk of myeloid leukemia in women only (OR=1.60, 95%CI=1.04–2.47). These relationships were stronger with increasing dose and duration. When stratified by leukemia type, aspirin use was inversely associated with AML and CML in women. No significant overall associations were found with ibuprofen or COX-2 inhibitors for either sex; however, a decreased risk was observed with other anti-inflammatory analgesic use for women with AML or CML (OR=0.47, 95%CI=0.22–0.99; OR=0.31, 95%CI=0.10–0.92, respectively).
Conclusions
Our results provide additional support for the chemopreventive benefits of NSAIDs, at least in women. Since leukemia ranks fifth in person years of life lost due to malignancy, further investigation is warranted.
Impact
NSAIDs may reduce, while acetaminophen may increase, myeloid leukemia risk in women.
doi:10.1158/1055-9965.EPI-11-0411
PMCID: PMC3153558  PMID: 21715605
aspirin; leukemia; NSAIDs; acetaminophen; prevention
6.  Similar reductions in the risk of human colon cancer by selective and nonselective cyclooxygenase-2 (COX-2) inhibitors 
BMC Cancer  2008;8:237.
Background
Epidemiologic and laboratory investigations suggest that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive effects against colon cancer perhaps due at least in part to their activity against cyclooxygenase-2 (COX-2), the rate-limiting enzyme of the prostaglandin cascade.
Methods
We conducted a case control study of colon cancer designed to compare effects of selective and non-selective COX-2 inhibitors. A total of 326 incident colon cancer patients were ascertained from the James Cancer Hospital, Columbus, Ohio, during 2003–2004 and compared with 652 controls with no history of cancer and matched to the cases at a 2:1 ratio on age, race, and county of residence. Data on the past and current use of prescription and over the counter medications and colon cancer risk factors were ascertained using a standardized risk factor questionnaire. Effects of COX-2 inhibiting agents were quantified by calculating odds ratios (OR) and 95% confidence intervals.
Results
Results showed significant risk reductions for selective COX-2 inhibitors (OR = 0.31, 95% CI = 0.16–0.57), regular aspirin (OR = 0.33, 95% CI = 0.20–0.56), and ibuprofen or naproxen (0.28, 95% CI = 0.15–0.54). Acetaminophen, a compound with negligible COX-2 activity and low dose aspirin (81 mg) produced no significant change in the risk of colon cancer.
Conclusion
These results suggest that both non-selective and selective COX-2 inhibitors produce significant reductions in the risk of colon cancer, underscoring their strong potential for colon cancer chemoprevention.
doi:10.1186/1471-2407-8-237
PMCID: PMC2529335  PMID: 18702823
7.  Long-term Use of Aspirin and Nonsteroidal Anti-inflammatory Drugs and Risk of Colorectal Cancer 
Context
Randomized trials of short-term aspirin use for prevention of recurrent colorectal adenoma have provided compelling evidence of a causal relationship between aspirin and colorectal neoplasia. However, data on long-term risk of colorectal cancer according to dose, timing, or duration of therapy with aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) remain limited.
Objective
To examine the influence of aspirin and NSAIDs in prevention of colorectal cancer.
Design, Setting, and Participants
Prospective cohort study of 82 911 women enrolled in the Nurses’ Health Study providing data on medication use biennially since 1980 and followed up through June 1, 2000.
Main Outcome Measure
Incident colorectal cancer.
Results
Over a 20-year period, we documented 962 cases of colorectal cancer. Among women who regularly used aspirin (≥2 standard [325-mg] tablets per week), the multivariate relative risk (RR) for colorectal cancer was 0.77 (95% confidence interval [CI], 0.67–0.88) compared with nonregular users. However, significant risk reduction was not observed until more than 10 years of use (P≤.001 for trend). The benefit appeared related to dose: compared with women who reported no use, the multivariate RRs for cancer were 1.10 (95% CI, 0.92–1.31) for women who used 0.5 to 1.5 standard aspirin tablets per week, 0.89 (95% CI, 0.73–1.10) for 2 to 5 aspirin per week, 0.78 (95% CI, 0.62–0.97) for 6 to 14 aspirin per week, and 0.68 (95% CI, 0.49–0.95) for more than 14 aspirin per week (P<.001 for trend). Notably, women who used more than 14 aspirin per week for longer than 10 years in the past had a multivariate RR for cancer of 0.47 (95% CI, 0.31–0.71). A similar dose-response relationship was found for nonaspirin NSAIDs (P=.007 for trend). The incidence of reported major gastrointestinal bleeding events per 1000 person-years also appeared to be dose-related: 0.77 among women who denied any aspirin use; 1.07 for 0.5 to 1.5 standard aspirin tablets per week; 1.07 for 2 to 5 aspirin per week; 1.40 for 6 to 14 aspirin per week; and 1.57 for more than 14 aspirin per week.
Conclusions
Regular, long-term aspirin use reduces risk of colorectal cancer. Non-aspirin NSAIDs appear to have a similar effect. However, a significant benefit of aspirin is not apparent until more than a decade of use, with maximal risk reduction at doses greater than 14 tablets per week. These results suggest that optimal chemoprevention for colorectal cancer requires long-term use of aspirin doses substantially higher than those recommended for prevention of cardiovascular disease, but the dose-related risk of gastrointestinal bleeding must also be considered.
doi:10.1001/jama.294.8.914
PMCID: PMC1550973  PMID: 16118381
8.  Use of oral glucocorticoids and risk of skin cancer and non-Hodgkin's lymphoma: a population-based case–control study 
British Journal of Cancer  2008;100(1):200-205.
In North Jutland County, Denmark, we investigated whether use of oral glucocorticoids was associated with an increased risk of developing basal cell carcinoma (BCC), squamous cell carcinoma (SCC), malignant melanoma (MM), and non-Hodgkin's lymphoma (NHL). From the Danish Cancer Registry we identified 5422 BCC, 935 SCC, 983 MM, and 481 NHL cases during 1989–2003. Using risk-set sampling we selected four age- and gender-matched population controls for each case from the Civil Registration System. Prescriptions for oral glucocorticoids before diagnosis were obtained from the Prescription Database of North Jutland County on the basis of National Health Service data. We used conditional logistic regression to estimate incidence rate ratios (IRRs), adjusting for chronic medical diseases (information about these were obtained from the National Patient Registry) and use of other immunosuppressants. We found slightly elevated risk estimates for BCC (IRR, 1.15 (95% CI: 1.07–1.25)), SCC (IRR, 1.14 (95% CI: 0.94–1.39)), MM (IRR, 1.15 (95% CI: 0.94–1.41), and NHL (IRR, 1.11 (95% CI: 0.85–1.46)) among users of oral glucocorticoids. Our study supports an overall association between glucocorticoid use and risk of BCC that cannot be explained by the presence of chronic diseases or concomitant use of other immunosuppressants.
doi:10.1038/sj.bjc.6604796
PMCID: PMC2634665  PMID: 19034275
oral glucocorticoids; non-Hodgkin's lymphoma; skin cancer; case–control study; epidemiology
9.  Potential of prescription registries to capture individual-level use of aspirin and other nonsteroidal anti-inflammatory drugs in Denmark: trends in utilization 1999–2012 
Clinical Epidemiology  2014;6:155-168.
Background
Due to over-the-counter availability, no consensus exists on whether adequate information on nonsteroidal anti-inflammatory drug (NSAID) use can be obtained from prescription registries.
Objectives
To examine utilization of aspirin and nonaspirin NSAIDs in Denmark between 1999 and 2012 and to quantify the proportion of total sales that was sold on prescription.
Method
Based on nationwide data from the Danish Serum Institute and the Danish National Prescription Registry, we retrieved sales statistics for the Danish primary health care sector to calculate 1-year prevalences of prescription users of aspirin or nonaspirin NSAIDs, and to estimate the corresponding proportions of total sales dispensed on prescription.
Results
Both low-dose aspirin and nonaspirin NSAIDs were commonly used in the Danish population between 1999 and 2012, particularly among elderly individuals. The 1-year prevalence of prescribed low-dose aspirin increased throughout the study period, notably among men. Nonaspirin NSAID use was frequent in all age groups above 15 years and showed a female preponderance. Overall, the prevalence of prescribed nonaspirin NSAIDs decreased moderately after 2004, but substantial variation according to NSAID subtype was observed; ibuprofen use increased, use of all newer selective cyclooxygenase-2 inhibitors nearly ceased after 2004, diclofenac use decreased by nearly 50% after 2008, and naproxen use remained stable. As of 2012, the prescribed proportion of individual-level NSAID sales was 92% for low-dose aspirin, 66% for ibuprofen, and 100% for all other NSAIDs.
Conclusion
The potential for identifying NSAID use from prescription registries in Denmark is high. Low-dose aspirin and nonaspirin NSAID use varied substantially between 1999 and 2012. Notably, use of cyclooxygenase-2 inhibitors nearly ceased, use of diclofenac decreased markedly, and naproxen use remained unaltered.
doi:10.2147/CLEP.S59156
PMCID: PMC4026552  PMID: 24872722
drug utilization; NSAID; registries; over-the-counter
10.  A Large Cohort Study of Nonsteroidal Anti-inflammatory Drug Use and Melanoma Incidence 
Results of laboratory studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) may have chemopreventive activity and therapeutic efficacy against melanoma. However, few published epidemiological studies have examined the association between NSAID use and melanoma risk. We examined whether NSAID use was associated with melanoma risk among 63 809 men and women in the Vitamins and Lifestyle (VITAL) cohort study. Participants self-reported NSAID use (low-dose aspirin, regular or extra-strength aspirin, and nonaspirin NSAIDs) during the previous 10 years and data related to their melanoma risk factors on a baseline questionnaire. After linkage of the VITAL database to the NCI Surveillance, Epidemiology, and End Results cancer registry, 349 patients with incident melanoma were identified through December 31, 2005. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma by NSAID use as categorized by overall use, duration of use, and dose (expressed as average number of days of use during the past 10 years). All statistical tests were two-sided. After adjusting for melanoma risk factors and indications for NSAID use, no association between NSAID use and melanoma risk was found. When use of at least 4 d/wk was compared with nonuse, no melanoma risk reduction was detected for any NSAID dose (HR = 1.12, 95% CI = 0.84 to 1.48), for any NSAID excluding low-dose aspirin (HR = 1.03, 95% CI = 0.74 to 1.43), for regular- or extra-strength aspirin (HR = 1.10, 95% CI = 0.76 to 1.58), or for nonaspirin NSAIDs (HR = 1.22, 95% CI = 0.75 to 1.99). Moreover, NSAID use was not associated with tumor invasion (Pinteraction = .38), tumor thickness (Ptrend = .98), or risk of metastasis (HR = 1.09, 95% CI = 0.32 to 3.62). NSAIDs do not appear to be good candidates for the chemoprevention of melanoma.
doi:10.1093/jnci/djn154
PMCID: PMC2561247  PMID: 18577752
11.  A Large Cohort Study of Nonsteroidal Anti-inflammatory Drug Use and Melanoma Incidence 
Results of laboratory studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) may have chemopreventive activity and therapeutic efficacy against melanoma. However, few published epidemiological studies have examined the association between NSAID use and melanoma risk. We examined whether NSAID use was associated with melanoma risk among 63 809 men and women in the Vitamins and Lifestyle (VITAL) cohort study. Participants self-reported NSAID use (low-dose aspirin, regular or extra-strength aspirin, and nonaspirin NSAIDs) during the previous 10 years and data related to their melanoma risk factors on a baseline questionnaire. After linkage of the VITAL database to the NCI Surveillance, Epidemiology, and End Results cancer registry, 349 patients with incident melanoma were identified through December 31, 2005. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma by NSAID use as categorized by overall use, duration of use, and dose (expressed as average number of days of use during the past 10 years). All statistical tests were two-sided. After adjusting for melanoma risk factors and indications for NSAID use, no association between NSAID use and melanoma risk was found. When use of at least 4 d/wk was compared with nonuse, no melanoma risk reduction was detected for any NSAID dose (HR = 1.12, 95% CI = 0.84 to 1.48), for any NSAID excluding low-dose aspirin (HR = 1.03, 95% CI = 0.74 to 1.43), for regular- or extra-strength aspirin (HR = 1.10, 95% CI = 0.76 to 1.58), or for nonaspirin NSAIDs (HR = 1.22, 95% CI = 0.75 to 1.99). Moreover, NSAID use was not associated with tumor invasion (Pinteraction = .38), tumor thickness (Ptrend = .98), or risk of metastasis (HR = 1.09, 95% CI = 0.32 to 3.62). NSAIDs do not appear to be good candidates for the chemoprevention of melanoma.
doi:10.1093/jnci/djn154
PMCID: PMC2561247  PMID: 18577752
12.  Use of Aspirin postdiagnosis improves survival for colon cancer patients 
British Journal of Cancer  2012;106(9):1564-1570.
Background:
The preventive role of non-steroid anti-inflammatory drugs (NSAIDs) and aspirin, in particular, on colorectal cancer is well established. More recently, it has been suggested that aspirin may also have a therapeutic role. Aim of the present observational population-based study was to assess the therapeutic effect on overall survival of aspirin/NSAIDs as adjuvant treatment used after the diagnosis of colorectal cancer patients.
Methods:
Data concerning prescriptions were obtained from PHARMO record linkage systems and all patients diagnosed with colorectal cancer (1998–2007) were selected from the Eindhoven Cancer Registry (population-based cancer registry). Aspirin/NSAID use was classified as none, prediagnosis and postdiagnosis and only postdiagnosis. Patients were defined as non-user of aspirin/NSAIDs from the date of diagnosis of the colorectal cancer to the date of first use of aspirin or NSAIDs and user from first use to the end of follow-up. Poisson regression was performed with user status as time-varying exposure.
Results:
In total, 1176 (26%) patients were non-users, 2086 (47%) were prediagnosis and postdiagnosis users and 1219 (27%) were only postdiagnosis users (total n=4481). Compared with non-users, a survival gain was observed for aspirin users; the adjusted rate ratio (RR) was 0.77 (95% confidence interval (CI) 0.63–0.95; P=0.015). Stratified for colon and rectal, the survival gain was only present in colon cancer (adjusted RR 0.65 (95%CI 0.50–0.84; P=0.001)). For frequent users survival gain was larger (adjusted RR 0.61 (95%CI 0.46–0.81; P=0.001). In rectal cancer, aspirin use was not associated with survival (adjusted RR 1.10 (95%CI 0.79–1.54; P=0.6). The NSAIDs use was associated with decreased survival (adjusted RR 1.93 (95%CI 1.70–2.20; P<0.001).
Conclusion:
Aspirin use initiated or continued after diagnosis of colon cancer is associated with a lower risk of overall mortality. These findings strongly support initiation of a placebo-controlled trial that investigates the role of aspirin as adjuvant treatment in colon cancer patients.
doi:10.1038/bjc.2012.101
PMCID: PMC3341868  PMID: 22454078
colorectal cancer; aspirin; NSAIDs; survival; population based
13.  Aspirin and risk for gastric cancer: a population-based case–control study in Sweden 
British Journal of Cancer  2001;84(7):965-968.
While aspirin and other non-steroid anti-inflammatory drugs (NSAIDs) are associated with gastric mucosal damage, they might reduce the risk for gastric cancer. In a population-based case–control study in 5 Swedish counties, we interviewed 567 incident cases of gastric cancer and 1165 controls about their use of pain relievers. The cases were uniformly classified to subsite (cardia/non-cardia) and histological type and information collected on other known risk factors for gastric cancer. Helicobacter pylori serology was tested in a subset of 542 individuals. Users of aspirin had a moderately reduced risk of gastric cancer compared to never users; odds ratio (OR) adjusted for age, gender and socioeconomic status was 0.7 (95% CI = 0.6–1.0). Gastric cancer risk fell with increasing frequency of aspirin use (P for trend = 0.02). The risk reduction was apparent for both cardia and non-cardia tumours but was uncertain for the diffuse histologic type. No clear association was observed between gastric cancer risk and non-aspirin NSAIDs or other studied pain relievers. Our finding lends support to the hypothesis that use of aspirin reduces the risk for gastric cancer. © 2001 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2001.1702
PMCID: PMC2363844  PMID: 11286478
gastric cancer; aspirin; NSAIDs; Helicobacter pylori
14.  Non-Steroidal Anti-Inflammatory Drug Use and the Risk of Parkinson's Disease 
Neuroepidemiology  2011;36(3):155-161.
Background
Experimental evidence supports a preventative role for non-steroidal anti-inflammatory drugs (NSAIDs) in Parkinson's disease (PD).
Methods
We investigated associations between use of aspirin, nonaspirin NSAIDs, and acetaminophen and PD in a large population-based case-control study using Danish health and pharmacy registries. We identified 1,931 PD cases reported in hospital or outpatient clinic records who had received a primary diagnosis of PD between 2001 and 2006, and 9,651 age- and sex-matched controls from the Danish population register. Prescription medication use was documented in a pharmacy database covering all residents of Denmark since 1995.
Results
Adjusting for age, sex, use of cardiovascular disease drugs, diagnosis of chronic pulmonary obstructive disorder, and Charlson comorbidity scores, and excluding prescriptions filled within 5 years before diagnosis, we found no evidence for an association between PD and either aspirin use (OR = 0.97; 95% CI 0.82, 1.14) or nonaspirin NSAID use (OR = 0.97; 95% CI 0.86, 1.09), regardless of intensity of use; further, there was no association between use of ibuprofen or acetaminophen and PD.
Conclusion
Our findings provide no evidence for a protective effect of nonaspirin and aspirin NSAID prescription drug use shortly before PD onset.
doi:10.1159/000325653
PMCID: PMC3095838  PMID: 21508649
Parkinson's disease; Case-control study; Anti-inflammatory drugs
15.  Reduced Risk of Human Lung Cancer by Selective Cyclooxygenase 2 (Cox-2) Blockade: Results of a Case Control Study 
We conducted a case control study of selective cyclooxygenase-2 (COX-2) blocking agents and lung cancer. A total of 492 newly diagnosed lung cancer cases were ascertained during January 1, 2002 to September 30, 2004, at The Ohio State University Medical Center, Columbus, Ohio. All cases were confirmed by examination of the pathology report. Healthy population controls without cancer were ascertained during the same time period. Controls were frequency matched at a rate of 2:1 to the cases by age, gender, and county of residence. We collected information on type, frequency, and duration of use of selective COX-2 inhibitors (primarily celecoxib or rofecoxib) and nonselective NSAIDs such as ibuprofen and aspirin. Estimates of odds ratios (OR) were obtained with adjustment for cigarette smoking, age and other potential confounders using logistic regression analysis. Odds Ratios for selective COX-2 inhibitors were adjusted for past use of other NSAIDs. Use of any selective COX-2 inhibitor for more than one year produced a significant (60%) reduction in the risk of lung cancer (OR=0.40, 95% CI=0.19-0.81). Observed risk reductions were consistent for men (OR=0.26, 95% CI=0.10-0.62) and women (OR=0.52, 95% CI=0.24-1.13) and for individual COX-2 inhibitors (OR=0.28, 95% CI=-0.12-0.67, for celecoxib and OR=0.55, 95% CI=0.19-1.56, for rofecoxib). Intake of ibuprofen or aspirin also produced significant risk reductions (OR=0.40, 95% CI=0.23-0.73 and OR=0.53, 95% CI=0.34-0.82, respectively), whereas acetaminophen, an analgesic with negligible COX-2 activity, had no effect on the risk (OR=1.36, 95% CI=0.53-3.37). This investigation demonstrates for the first time that selective COX-2 blocking agents have strong potential for the chemoprevention of human lung cancer.
PMCID: PMC1893117  PMID: 17589567
Cyclooxygenase-2 (COX-2); lung cancer; Nonsteroidal anti-inflammatory drugs (NSAIDs); chemoprevention
16.  Use of postmenopausal hormone replacement therapy and risk of non-Hodgkin's lymphoma: a Danish Population-based Cohort Study 
British Journal of Cancer  2006;94(9):1339-1341.
Use of postmenopausal hormone replacement therapy (HRT) has been hypothesised to be associated with a reduced risk of non-Hodgkin's lymphoma (NHL), but the epidemiologic evidence is conflicting. To examine the risk of NHL in HRT users aged 40 and older, we conducted a cohort study in the County of North Jutland, Denmark (population 0.5 million) using data from population-based health registries for the period 1989–2002. We computed age-standardised NHL incidence rates and used Cox regression analysis to compute the relative risk (RR) and corresponding 95% confidence intervals (CI) of NHL among HRT users compared with non-users, adjusting for age and calendar period. The number of prescriptions redeemed (1, 2–4, 5–9, 10–19, or 20 or more prescriptions) was used as a proxy for duration of HRT. We identified 40 NHL cases among HRT users during 179 838 person-years of follow-up and 310 NHL cases among non-users during 1 247 302 person-years of follow-up. The age-standardised incidence rates of NHL were 25.7 per 100 000 among HRT users and 24.2 per 100 000 among non-users, yielding an adjusted RR of 0.99 (95% CI: 0.71–1.39). Our data did not support an association between HRT use and risk of NHL.
doi:10.1038/sj.bjc.6603123
PMCID: PMC2361418  PMID: 16670705
postmenopausal hormone replacement therapy; non-Hodgkin's lymphoma; population-based study; risk; cohort study
17.  Polymorphic variation in NFKB1 and other aspirin-related genes and risk of Hodgkin lymphoma 
We found that regular use of aspirin may reduce the risk of Hodgkin lymphoma (HL), a common cancer of adolescents and young adults in the US. To explore possible biological mechanisms underlying this association, we investigated whether polymorphic variation in genes involved in nuclear factor (NF)-κB activation and inhibition, other inflammatory pathways, and aspirin metabolism influences HL risk. Twenty single nucleotide polymorphisms (SNPs) in seven genes were genotyped in DNA from 473 classical HL cases and 373 controls enrolled between 1997 and 2000 in a population-based case-control study in the Boston, Massachusetts, metropolitan area and the state of Connecticut. We selected target genes and SNPs primarily using a candidate-SNP approach and estimated haplotypes using the expectation-maximization algorithm. We used multivariable logistic regression to estimate odds ratios (ORs) for associations with HL risk. HL risk was significantly associated with rs1585215 in NFKB1 (AG vs. AA: OR=2.1, 95% confidence interval [CI]=1.5–2.9; GG vs. AA: OR=3.5, 95% CI=2.2–5.7, Ptrend=1.7×10−8) and with NFKB1 haplotypes (Pglobal=6.0×10−21). Similar associations were apparent across categories of age, sex, tumor Epstein-Barr virus status, tumor histology, and regular aspirin use, although statistical power was limited for stratified analyses. Nominally significant associations with HL risk were detected for SNPs in NFKBIA and CYP2C9. HL risk was not associated with SNPs in IKKA/CHUK, PTGS2/COX2, UDP1A6, or LTC4S. In conclusion, genetic variation in the NF-κB pathway appears to influence risk of HL. Pooled studies are needed to detect any heterogeneity in the association with NF-κB across HL subgroups, including aspirin users and non-users.
doi:10.1158/1055-9965.EPI-08-1130
PMCID: PMC2720066  PMID: 19223558
Hodgkin lymphoma; genetic polymorphism; nuclear factor kappa B; NFKB1 protein; aspirin; case-control
18.  Non-Steroidal Anti-Inflammatory Drugs, Acetaminophen, and Risk of Skin Cancer in the Nurses’ Health Study 
Cancer causes & control : CCC  2012;23(9):1451-1461.
Purpose
Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with lower risk of certain cancers, but data on the effect on skin cancer risk have been limited and contradictory. We prospectively examined whether use of NSAIDS or acetaminophen was associated with a lower risk of skin cancer in women.
Methods
The 92,125 Caucasian women in the Nurses’ Health Study provided information on aspirin use in 1980. Other NSAIDs and acetaminophen were added in 1990. Medication use, frequency, and quantity were reassessed on biennial questionnaires. Through 2008, we confirmed 658 melanoma cases, 1337 squamous cell carcinoma (SCC) cases, and had 15,079 self-reports of basal cell carcinoma (BCC). We used COX proportional hazards models to compute relative risks (RR) adjusted for known skin cancer risk factors.
Results
Neither aspirin nor non-aspirin NSAID use was associated with a lower risk of melanoma, SCC or BCC, even for women with high quantity, frequency, or duration of use. Instead, we observed an increased risk of melanoma among current aspirin users (RR=1.32, 95% CI 1.03–1.70), though an increase of similar magnitude among past users and lack of a dose-response effect did not support a pharmacologic mechanism. We observed a mild reduction in SCC risk in current acetaminophen users (RR=0.88, 95% CI 0.75–1.02), with a linear decrease in risk with greater frequency of use (p=0.04).
Conclusions
Aspirin and other NSAIDs were not associated with a lower risk of melanoma, SCC or BCC in women. Our large, prospective study does not support a chemoprotective effect of NSAIDs against skin cancers.
doi:10.1007/s10552-012-0019-6
PMCID: PMC3416973  PMID: 22763500
skin cancer; melanoma; basal cell carcinoma; (cutaneous) squamous cell carcinoma; aspirin; acetaminophen; non-steroidal anti-inflammatory medications (NSAIDs)
19.  Regular Aspirin Use and Breast Cancer Risk in U.S. Black Women 
Cancer causes & control : CCC  2011;22(11):10.1007/s10552-011-9832-6.
Background
Epidemiologic studies have yet to provide consistent evidence to support a protective effect of aspirin and other non-steroidal anti-inflammatory drugs (NSAID) on the incidence of breast cancer.
Objective
We evaluated the relations of current use of aspirin, non-aspirin NSAIDs, and acetaminophen with breast cancer incidence in the Black Women's Health Study.
Methods
Biennial follow-up of 59,000 study participants began in 1995. During 558,600 person years of follow-up through 2007, 1,275 breast cancer cases were identified. Using Cox proportional hazards regression, we estimated incidence rate ratios (IRR) and 95% confidence intervals (CI) for associations of current and former use of aspirin, other NSAIDs, and acetaminophen with incident breast cancer.
Results
After adjustment for age, education, body mass index at age 18, physical activity, female hormone use, current smoking, and other NSAID use, the IRRs were 0.79 (95%CI=0.66, 0.95) for current aspirin use and 0.68 (95%CI=0.50, 0.92) for ≥ 5 years of aspirin use. Similar associations were observed for acetaminophen use.
Conclusions
Both aspirin and acetaminophen use were inversely associated with breast cancer incidence in the present study. Reasons for the association with acetaminophen use are unclear, given that acetaminophen has very weak anti-inflammatory effects.
doi:10.1007/s10552-011-9832-6
PMCID: PMC3833628  PMID: 21877122
Aspirin; NSAIDs; breast cancer; incidence; epidemiology
20.  Non-Steroidal Anti-Inflammatory Drug Use Reduces Risk for Adenocarcinomas of the Esophagus and Esophagogastric Junction in a Pooled Analysis 
Gastroenterology  2011;142(3):442-e23.
Background & Aims
Regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAID) has been reported to reduce risks for esophageal adenocarcinoma (EAC) and esophagogastric junctional adenocarcinoma (EGJA). However, individual studies have been too small to accurately assess the effects of medication type, frequency, or duration of use. We performed a pooled analysis to investigate these associations.
Methods
We performed a pooled analysis of 6 population-based studies within the Barrett's and Esophageal Adenocarcinoma Consortium to evaluate the association between NSAID use and the risk of EAC and EGJA, using uniform exposure definitions. We collected information from 6 studies (5 case-control and 1 cohort), with a total of 1226 EAC and 1140 EGJA cases, on aspirin and/or NSAID use. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariate adjusted logistic regression models and then pooled using a random effects meta-analysis model.
Results
Compared to non-users, individuals who have used NSAIDs had a statistically significant, reduced risk of EAC (OR=0.68; 95% CI, 0.56–0.82); they also appeared to have a reduced risk of EGJA (OR=0.84; 95% CI, 0.68–1.03). Similar reductions in risk were observed among individuals who took aspirin or non-aspirin NSAIDs. The highest levels of frequency (≥daily) and duration (≥10 years) of NSAID use were associated with an approximately 40% reduction in risk for EAC: OR=0.56 (95% CI, 0.43–0.73; P-trend, <.001) and OR=0.63 (95% CI, 0.45–0.90; P-trend, 0.04), respectively.
Conclusions
Although reverse causation could, in part, explain the inverse association observed between NSAID use and EAC risk, pooled analysis indicates a role for NSAIDs in prevention of adenocarcinomas of the esophagus and esophagogastric junction.
doi:10.1053/j.gastro.2011.11.019
PMCID: PMC3488768  PMID: 22108196
BEACON; Esophageal Neoplasm; Stomach Cancer; Anti-Inflammatory Agent
21.  Regular use of aspirin and pancreatic cancer risk 
BMC Public Health  2002;2:18.
Background
Regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been consistently associated with reduced risk of colorectal cancer and adenoma, and there is some evidence for a protective effect for other types of cancer. As experimental studies reveal a possible role for NSAIDs is reducing the risk of pancreatic cancer, epidemiological studies examining similar associations in human populations become more important.
Methods
In this hospital-based case-control study, 194 patients with pancreatic cancer were compared to 582 age and sex-matched patients with non-neoplastic conditions to examine the association between aspirin use and risk of pancreatic cancer. All participants received medical services at the Roswell Park Cancer Institute in Buffalo, NY and completed a comprehensive epidemiologic questionnaire that included information on demographics, lifestyle factors and medical history as well as frequency and duration of aspirin use. Patients using at least one tablet per week for at least six months were classified as regular aspirin users. Unconditional logistic regression was used to compute crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs).
Results
Pancreatic cancer risk in aspirin users was not changed relative to non-users (adjusted OR = 1.00; 95% CI 0.72–1.39). No significant change in risk was found in relation to greater frequency or prolonged duration of use, in the total sample or in either gender.
Conclusions
These data suggest that regular aspirin use may not be associated with lower risk of pancreatic cancer.
doi:10.1186/1471-2458-2-18
PMCID: PMC126211  PMID: 12213184
22.  Aspirin use after a prostate cancer diagnosis and cancer survival in a prospective cohort 
Experimental and clinical data suggest that aspirin and other non-steroidal inflammatory drugs may delay the progression of prostate cancer through inhibition of the cyclooxygenase (COX) pathway and its effects on cellular proliferation, apoptosis and angiogenesis. Epidemiological data support a reduced risk of prostate cancer incidence with aspirin use, yet no evidence exists regarding whether aspirin after diagnosis influences progression or survival. We conducted a prospective study of 3,986 participants of the Health Professionals Follow-up Study, with a prostate cancer diagnosis between January 1, 1990 and December 31, 2005. We used Cox proportional hazards regression to evaluate the association between aspirin use after diagnosis and the development of metastases or fatal prostate cancer through January 31, 2008, adjusting for risk factors associated with incidence and mortality in this cohort, pre-diagnostic aspirin use, Gleason score, TNM stage and primary treatment. In total, 265 men developed bony or other organ metastases or fatal prostate cancer during the 18 years of follow-up. We observed no association between updated aspirin use after diagnosis and lethal prostate cancer (tablets/week: <2, HR=1.12, 95% CI: 0.72, 1.72; 2-5, HR=1.05, 95% CI: 0.62, 1.80, ≥ 6, HR=1.08, 95% CI: 0.76, 1.54; p-trend=0.99). The results remained unchanged when we examined aspirin use at baseline only (p-trend=0.70) or frequency of use (days/week, p-trend=0.35); or limited the outcome to fatal prostate cancer (p-trend = 0.63). There was no association between aspirin use after a prostate cancer diagnosis and lethal disease in this cohort of prostate cancer survivors.
doi:10.1158/1940-6207.CAPR-12-0171
PMCID: PMC3526345  PMID: 22961777
23.  Association of Use of Nonsteroidal Anti-inflammatory Drugs and Cutaneous Squamous Cell Carcinoma 
Archives of dermatology  2010;146(4):388-395.
OBJECTIVE
To examine the association between non-steroidal anti-inflammatory drug (NSAID) use and cutaneous squamous cell carcinoma (SCC).
DESIGN
Retrospective case-control.
SETTING
Kaiser Permanente Northern California (KPNC), a large population based-health maintenance organization.
PATIENTS
Random sample of 415 KPNC members diagnosed with a pathology-verified SCC in 2004 and 415 age-, sex, and race-matched controls with no history of skin cancer.
MAIN EXPOSURE MEASURE
Self-reported NSAID use in the 10 years prior to baseline. NSAID use was categorized based on type (any NSAIDs, aspirin, ibuprofen, non-aspirin NSAIDs). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression to estimate the association of SCC with regular use, dose and duration of exposure to the different NSAID types. Information on pharmacy-dispensed NSAIDs was also examined to assess its association with SCC risk. Models were adjusted for all ascertained SCC risk factors (fully adjusted model) and only those variables associated with both SCC risk and NSAID use (parsimonious model).
RESULTS
Fully adjusted analyses showed no statistically significant reduction in SCC risk with self-reported regular use of any NSAID (OR=1.32, 95% CI: 0.92–1.89), aspirin (OR=1.38, 95% CI: 0.96–1.97), ibuprofen (OR=0.74, 95% CI: 0.46–1.19), or non-aspirin NSAIDs (OR=0.84, 95% CI: 0.56–1.26). Analyses examining duration, dose, and variables combining duration and dose of NSAID exposure did not appreciably change results. Analysis using the parsimonious model showed similar results. The data on pharmacy dispensed NSAIDs also showed no association with SCC risk.
CONCLUSIONS
Neither self-reported, nor pharmacy-dispensed NSAID exposure was associated with cutaneous SCC risk.
doi:10.1001/archdermatol.2009.374
PMCID: PMC2857681  PMID: 20157019
24.  Aspirin, nonsteroidal anti-inflammatory drugs (NSAID), acetaminophen, and pancreatic cancer risk: A clinic-based case-control study 
Aspirin and other nonsteroidal anti-inflammatory drugs (NSAID) show indisputable promise as cancer chemoprevention agents. However, studies have been inconsistent as to whether aspirin has a protective effect in development of pancreatic cancer. To further evaluate the association between aspirin, NSAID and acetaminophen use with pancreatic cancer risk, we utilized a clinic-based case-control study of 904 rapidly ascertained histologically or clinically documented pancreatic ductal adenocarcinoma cases, and 1,224 age- and sex-matched healthy controls evaluated at Mayo Clinic from April 2004 to September 2010. Overall, there is no relationship between non-aspirin NSAID or acetaminophen use and risk of pancreatic cancer. Aspirin use ≥ 1 day/month was associated with a significantly decreased risk of pancreatic cancer (odds ratio (OR) = 0.74, 95% confidence intervals (CI): 0.60, 0.91, P = 0.005), compared with never or < 1 day/month. Analysis by frequency and frequency-dosage of use categories showed reduced risk (P = 0.007 and 0.022, respectively). This inverse association was also found for those who took low-dose aspirin for heart disease prevention (OR = 0.67, 95% CI: 0.49, 0.92, P = 0.013). In subgroup analyses, the association between aspirin use and pancreatic cancer was not significantly affected by pancreatic cancer stage, smoking status or body mass index. Our data suggest that aspirin use, but not non-aspirin NSAID use, is associated with lowered risk of developing pancreatic cancer.
doi:10.1158/1940-6207.CAPR-11-0146
PMCID: PMC3208748  PMID: 21803981
Aspirin; NSAID; acetaminophen; smoking; pancreatic cancer
25.  Non-steroidal anti-inflammatory drugs and risk of gastric and oesophageal adenocarcinomas: results from a cohort study and a meta-analysis 
British Journal of Cancer  2009;100(3):551-557.
Use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of gastric or oesophageal adenocarcinomas. We examined the association between self-reported use of aspirin or non-aspirin NSAIDs in the earlier 12 months and gastric non-cardia (N=182), gastric cardia (N=178), and oesophageal adenocarcinomas (N=228) in a prospective cohort (N=311 115) followed for 7 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) come from Cox models adjusted for potential confounders. Use of any aspirin (HR, 95% CI: 0.64, 0.47–0.86) or other NSAIDs (0.68, 0.51–0.92) was associated with a significantly lower risk of gastric non-cardia adenocarcinoma. Neither aspirin (0.86, 0.61–1.20) nor other NSAIDs (0.91, 0.67–1.22) had a significant association with gastric cardia cancer. We found no significant association between using aspirin (1.00, 0.73–1.37) or other NSAIDs (0.90, 69–1.17) and oesophageal adenocarcinoma. We also performed a meta-analysis of the association between the use of NSAIDs and risk of gastric and oesophageal adenocarcinoma. In this analysis, aspirin use was inversely associated with both gastric and oesophageal adenocarcinomas, with summary odds ratios (95% CI) for non-cardia, cardia, and oesophageal adenocarcinomas of 0.64 (0.52–0.80), 0.82 (0.65–1.04), and 0.64 (0.52–0.79), respectively. The corresponding numbers for other NSAIDs were 0.68 (0.57–0.81), 0.80 (0.67–0.95), and 0.65 (0.50–0.85), respectively.
doi:10.1038/sj.bjc.6604880
PMCID: PMC2658549  PMID: 19156150
aspirin; NSAIDs; oesophageal cancer; gastric cancer; cohort; meta-analysis

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