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American Journal of Epidemiology Advance Access originally published online on July 17, 2006
American Journal of Epidemiology 2006 164(6):567-575; doi:10.1093/aje/kwj250
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American Journal of Epidemiology Copyright © 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.

Original Contribution

The Association between Aspirin Use and the Incidence of Colorectal Cancer in Women

Matthew Allison1, Cedric Garland1, Rowan Chlebowski2, Michael Criqui1, Robert Langer3, Lieling Wu4, Hemant Roy5, Anne McTiernan4, Lewis Kuller6 for the Women's Health Initiative Investigators

1 University of California, San Diego, CA
2 Los Angeles Biomedical Research Institute, Torrance, CA
3 Geisinger Health Systems, Danville, PA
4 Fred Hutchinson Cancer Research Center, Seattle, WA
5 Northwestern University, Chicago, IL
6 University of Pittsburgh, Pittsburgh, PA

Correspondence to Dr. Matthew Allison, 3855 Health Sciences Drive, La Jolla, CA 92093-0817 (e-mail: mallison{at}ucsd.edu).

Received for publication December 9, 2005. Accepted for publication March 20, 2006.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The purpose of this study was to test the hypothesis that aspirin use is associated with a decreased risk of incident colorectal cancer. From the Women's Health Initiative, 91,574 participants between the ages of 50 and 79 years at baseline in 1993–1998 provided details on aspirin use via interview using a standardized questionnaire and were subsequently followed annually for incident colorectal cancer during a period of over 6 years. For those persons who reported aspirin use, the type of compound, dose, and duration of use were recorded. Medical histories suggestive of colorectal cancers at the annual update were verified by medical record and pathology report review by trained local physician adjudicators. There were 631 confirmed cases of invasive cancer of the colon or rectum. There was no significant association between any aspirin use and risk for incident colorectal cancer (hazard ratio = 0.96, 95% confidence interval: 0.8, 1.2). Moreover, with no aspirin use as the referent category, there were no significant associations for duration of aspirin intake by category (<1, 1–<2, 2–<3, 3–<4, 4–<5, and ≥5 years) or for daily dosage by category (<165, 165–<300, 300–<495, or ≥495 mg).

aspirin; colonic neoplasms; primary prevention; rectal neoplasms

Abbreviations: CI, confidence interval; HR, hazard ratio; NSAID, nonsteroidal antiinflammatory drug; SEER, Surveillance, Epidemiology, and End Results


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Case-control (1Go–12Go) and prospective (13Go–18Go) epidemiologic studies in a variety of study populations have suggested that regular aspirin or other nonsteroidal antiinflammatory drug (NSAID) use is associated with a reduced risk of both colorectal adenoma and colorectal cancer. Among specific studies of colorectal cancer, case-control and prospective cohort studies have largely supported a risk reduction in those reporting aspirin use. Although even the most carefully conducted and analyzed epidemiologic study can be subject to residual bias, the experimental laboratory data support the biologic plausibility of such an association (19Go–24Go). Unfortunately, results from randomized clinical trials are currently limited. In the Physicians' Health Study with over 22,000 male participants, assignment of 325 mg of aspirin every other day was unrelated to the development of benign or malignant colorectal tumors over a mean follow-up of 5 years (25Go). Notably, results of a recent randomized trial of aspirin and colorectal cancer in women did not reveal any reduction in risk (26Go).

Against this background, we evaluated the association between aspirin use and the incidence of colorectal cancer in 91,574 postmenopausal women in the Women's Health Initiative Observational Study who were followed for an average of 6.4 years.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Subjects
The Women's Health Initiative Observational Study was established to explore the predictors and natural history of major causes of morbidity and mortality in postmenopausal women. Eligibility included being postmenopausal, aged 50–79 years, unlikely to move or die within 3 years, and able to provide informed consent. Women were considered postmenopausal if they were between the ages of 50 and 54 years and had no vaginal bleeding for at least 12 months or were aged 55 through 79 years and had no bleeding in the prior 6 months. The design and reliability of baseline measures have been published in detail previously (27Go). In brief, study participants were enrolled at 40 centers throughout the United States between October 1, 1993, and December 31, 1998. Demographic and exposure information and family and medical history were obtained by use of standardized questionnaires. Certified staff took physical measurements, including blood pressure, height and weight, and blood samples, at the baseline clinic visit. After exclusions during screening for a history of colorectal cancer, 91,574 (97.8 percent) of 93,676 Women's Health Initiative Observational Study participants were eligible for the analysis.

Details on medication usage including aspirin were collected from an interview-administrated questionnaire. Each participant was specifically asked, "Do you take aspirin pills or powders, for example, Anacin, Bufferin, and BC pain reliever? This does not include aspirin-free drugs such as Tylenol or Advil." For those persons who reported aspirin use, the type of compound (tablets, capsules, powder, and so on), strength (milligrams), and duration (number of days, weeks, months, or years) of use were recorded. These medication data were validated by checking pill bottle labels and prescription records during the interview process. Similarly, subjects were queried about their use of nonsteroidal antiinflammatory agents with the following two questions: "Do you take ibuprofen tablets or capsules, for example, Advil, Motrin, or Nuprin?" and "Do you take Naprosyn, Naproxen, Aleve, Indocin, Clinoril, Feldene, or other antiinflammatory pain pills?" (More information about these brand-name medications is available from the corresponding author upon request.)

A standardized written protocol, centralized training of local clinic staff, local quality assurance activities, and periodic quality assurance visits by the Clinical Coordinating Center were used to maintain uniform data collection procedures at all study sites. A human subjects review committee at each participating institution approved the Women's Health Initiative study protocol. All subjects provided written informed consent.

Follow-up and colorectal cancer ascertainment
Medical history was updated annually by mail/telephone questionnaires. Colorectal cancer case ascertainment has been previously described in detail (28Go). Briefly, histories suggestive of colorectal cancers at the annual update were verified by medical record and pathology reports review by trained local physician adjudicators. All colorectal cancers were then confirmed by blinded review at the Women's Health Initiative clinical coordinating center and coded using the Surveillance, Epidemiology, and End Results (SEER) system.

All subjects participated in a clinic visit 3 years after enrollment. During this visit, follow-up information (including changes in medication status) was collected to update that which was collected at baseline. There were no other follow-up clinic visits.

Bowel-screening frequency was not protocol defined. Information on the rectal examination, fecal occult-blood testing, sigmoidoscopy and colonoscopy (asked as one question), and barium enema examination was collected annually throughout the follow-up period by use of self-administered questionnaires or by structured telephone interviews. Clinical decisions regarding colorectal cancer workup were made almost exclusively by local physicians as Women's Health Initiative centers did not provide comprehensive health care.

Statistical analysis
All analyses were performed using SAS System for Windows, version 9 (SAS Institute, Inc., Cary, North Carolina). Differences between baseline categorical variables by cohort group were tested using the chi-square test, while differences for continuous variables were assessed using the F test. Median values of each category were used to conduct tests of trend. The potential associations between known and purported risk factors and colorectal cancer were tested initially by use of Cox proportional hazard regression. In these models, aspirin use was categorized as a specific dose, daily dosage quartile, duration of any aspirin use (in years), or a quartile of cumulative baseline aspirin intake, expressed as the product of daily dosage and months of use. Univariate analyses were used to exclude risk factors that lacked a marginal relation with the development of colorectal cancer. The factors included in the final multivariate models were selected on the basis of clinical judgment and numerical significance by use of a p value of 0.15. Separate models were constructed for risk factor variables that were highly collinear. Multivariate Cox proportional hazard models were developed to evaluate the risk of developing colorectal cancer. The potential interaction between acetylsalicylic acid (aspirin) use and body mass index for incident colorectal cancer was examined. All factors in the multivariate analyses were adjusted simultaneously. Hazard ratios and nominal 95 percent confidence intervals were presented. Person-time for each participant was calculated from enrollment to the date of centrally adjudicated colorectal cancer, death, or February 29, 2004, whichever came first. For site-specific analyses, "right colon" was defined as the cecum/ascending colon/hepatic flexure, while the left colon was composed of the splenic flexure/descending colon/sigmoid colon.

The use of nonsteroidal antiinflammatory agents (other than aspirin) has been associated with a reduced risk for colorectal cancer (5Go, 7Go). To test for the potential interaction between aspirin and other NSAID use, we conducted additional analyses exclusive of those for persons taking any "nonaspirin" NSAIDs. Furthermore, previous research has demonstrated that right- and left-sided colonic lesions are genetically and epidemiologically different (29Go). We therefore conducted analyses specific for tumor location, that is, right versus left colon.

The various survival graphs were examined including the survival function, negative log of survival function, and log negative log of survival functions. A formal test of interaction between time and acetylsalicylic acid was used to test the assumption of proportional hazard. All p values are two sided. Because of the large number of comparisons and the sample size of the study cohort, p < 0.01 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
The characteristics of the entire Women's Health Initiative Observational Study cohort have been described previously by Langer et al. (27Go). Table 1 provides the baseline characteristics of this cohort stratified by aspirin use category. Women who reported taking any aspirin were older, had a higher rate of colon screening by either colonoscopy or sigmoidoscopy, had a higher prevalence of colon polyps, and were more likely to be non-Hispanic White and taking a 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor ("statin"). This group also had higher intakes of a number of vitamins and minerals, as well as different kinds of fiber.


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  		TABLE 1. Baseline cohort characteristics by aspirin use category, Women's Health Initiative Observational Study, 1993–2005*

 
Most women were not taking any aspirin at baseline (71,491; 78 percent). Of those taking any aspirin, the dosage that was most frequently reported was 325 mg (14 percent) followed by 81 mg (6 percent). The mean duration of aspirin use was 1.7 (standard deviation: 6.7) years and ranged from 0 to 59 years. The average duration of use prior to the baseline examination was lower in those with colorectal cancer (552 vs. 629 days), but this difference was not statistically significant (p = 0.4).

As of February 28, 2004, there were 631 confirmed invasive cancers of the colon or rectum. The average time from enrollment in the Women's Health Initiative Observational Study to diagnosis was just over 40 (standard deviation: 23.8) months. Nearly 36.1 percent of the cancers occurred in those who were aged between 70 and 79 years at study enrollment, while 17.1 percent occurred in the group aged 50–59 years. There were 32 deaths due to colorectal cancer.

Just over 32 percent of colorectal cancers occurred between and including the ascending and descending segments of the colon, while 21.2 percent occurred in the cecum, 18.1 percent in the sigmoid colon, and 11.9 percent in the rectum (table 2). According to SEER stage criteria, 256 (40.6 percent) cancers were localized, 238 (37.7 percent) were regional, and 67 (10.6 percent) were distant. SEER staging was unknown or not available for 70 cancers. The majority were histologically classified as adenocarcinoma, while 9 percent were categorized as "carcinoma" or classification was not available. Morphologically, the majority (57.7 percent) were moderately differentiated, while 17.9 percent were poorly differentiated, 6.3 percent were well differentiated, 1.1 percent were anaplastic, and 17 percent were missing/not available.


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  		TABLE 2. Characteristics of incident colorectal cancer cases, Women's Health Initiative Observational Study, 1993–2005

 
The proportion of incident colorectal cancers was identical for those who did and those who did not report any aspirin use at baseline (0.7 percent) (table 2). Among those who reported taking any aspirin at baseline, the majority who developed colorectal cancer, as well as those who did not, took it for more than 5 years. The average daily dose reported was not significantly different (cases: 65 mg; noncases: 59 mg; p = 0.3) while, for both groups and of those who had taken any aspirin, the highest proportion of women were taking between 165 and 300 mg per day.

When considering the time of diagnosis, we found that subjects who developed incident colorectal cancer identified before the third year of the study had a higher mean daily intake of aspirin at baseline (78.3 vs. 53.2 mg, respectively) than did those who did not. Similarly, women who developed colorectal cancer after the year 3 visit had a higher mean daily intake at this visit than did those who did not develop this cancer (61.1 vs. 43.2 mg). These results show a consistent association between higher aspirin use and incident disease during different points of time in the study. Importantly, 68 percent of the women continued on the same dose from baseline to visit 3, while 9 percent increased and 3 percent decreased their daily dose, demonstrating that the majority of subjects remained on the same dose over this time period. Eleven percent started and 10 percent stopped taking aspirin during this time frame. None of these differences, however, was found to be statistically significant by diagnostic category.

Compared with those not taking aspirin, participants who reported any aspirin use did not have a significantly different risk for incident colorectal cancer (hazard ratio (HR) = 0.96, 95 percent confidence interval (CI): 0.8, 1.2). No associations or trends were found for duration of aspirin intake when categorized as 0 (referent), 0.1–0.9, 1–1.9, 2–2.9, 3–3.9, 4–4.9, and ≥5 years or as 0, 1–5, 5.1–10, 10.1–20, and >20 years. Similarly, when daily dosage was categorized as 0 (referent), 1–164, 165–300, 301–494, or ≥495 mg or as 0, 1–324, or ≥325 mg, no significant associations or trends were found. Age and multivariable adjustment did not change the nature of these associations (table 3).


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  		TABLE 3. Hazard ratio for incident colorectal cancer* to aspirin exposure,{dagger} Women's Health Initiative Observational Study, 1993–2005

 
Table 3 also provides the results of cumulative aspirin use expressed as the product of daily dosage and duration of use. With adjustment for age and compared with nonaspirin users (quartile 1), none of the highest three quartiles of cumulative baseline aspirin intake predicted incident colorectal cancer (quartile 2: HR = 0.93, 95 percent CI: 0.7, 1.3; quartile 3: HR = 0.87, 95 percent CI: 0.6, 1.2; quartile 4: HR = 0.96, 95 percent CI: 0.7, 1.3). With further multivariable adjustment, these results were essentially unchanged (quartile 2: HR = 0.99, 95 percent CI: 0.7, 1.4; quartile 3: HR = 0.90, 95 percent CI: 0.6, 1.3; quartile 4: HR = 0.94, 95 percent CI: 0.7, 1.3). For all of these comparisons, there were no significant interactions between aspirin use (cumulative, duration or dose) and body mass index for incident colorectal cancer.

Because of collinearity, we conducted separate analyses that included different types of fiber (soluble and insoluble) and postmenopausal hormone therapy (estrogen alone and estrogen plus progesterone). The results of these analyses were unchanged from those where total dietary fiber and any use of postmenopausal hormone therapy were included. There were also no significant associations found by tumor site (left vs. right colon).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In this prospective cohort study of over 91,000 postmenopausal women recruited from 40 clinical centers across the United States, aspirin use did not significantly affect the risk for incident colorectal cancer after an average of 6.4 years of follow-up and adjustment for significant covariates. This risk remained nonsignificant regardless of the dose or duration of aspirin use prior to study enrollment. Additionally, the proportion of women using any aspirin was not significantly different by diagnostic category.

Five case-control studies have examined the association of aspirin use with colorectal cancer; all found significantly lower risk associated with regular use of aspirin (1Go, 3Go, 30Go–32Go). Five previous cohort studies have examined this same issue (16Go, 17Go, 33Go–36Go). In general, these studies found lower risks for incident colorectal cancer, but only a few reported statistically significant results (table 4). A recently published report from the Nurses' Health Study suggests that the effect of aspirin use on colorectal cancer is dose dependent. In this study, the lowest dose associated with a significant benefit was 2–5 regular-strength pills (93–232 mg) per week (37Go). Paradoxically, older adults who used aspirin regularly in a southern California retirement community cohort had statistically significantly higher incidence of colorectal cancer than did nonusers (33Go, 34Go, 38Go). In summary, the majority of observational evidence to date suggests a benefit for aspirin use on colorectal cancer risk. However, the Physicians' Health Study, a randomized trial of aspirin in male physicians, was intended to determine whether 325 mg taken every other day reduced risk of cardiovascular disease (25Go, 39Go). Aspirin users and nonusers had similar incidence rates of colorectal cancer when the trial was ended after 5 years (25Go) and at the time of a follow-up at 12 years after randomization (39Go).


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  		TABLE 4. Prospective cohort studies of aspirin and colorectal cancer

 
As is evident from the above discussion, there is considerable evidence from most observational studies that persons who took aspirin regularly had a lower risk of colorectal cancer than those who did not. A proposed mechanism that may account for this association includes the established role of aspirin as an inhibitor of cyclooxygenase pathways for formation of inflammatory mediators in the bowel, such as prostaglandin E2 and prostaglandin F (1Go). Sample et al. (40Go) found that 81 mg of aspirin significantly reduced rectal prostaglandin E2 levels compared with placebo and was as effective as higher doses. This pharmacologic role of aspirin is shared with other cyclooxygenase inhibitors including sulindac (41Go) and celecoxib (42Go), which reduce the incidence of new polyps in persons with familial polyposis.

Colon cancer is thought to have a median induction period of approximately 20 years (43Go). There have been mixed findings for aspirin prophylaxis with respect to colorectal cancer and adenomatous polyps (44Go–47Go) that may have a reasonable explanation relating to timing. A stratified analysis of participants in the Nurses' Health Study indicated that there was no reduction in incidence of colorectal cancer according to aspirin use until 20 or more years had passed since the study began, suggesting that the effects of aspirin may occur mainly in the early phases of colon carcinogenesis, at least in women. Additionally, data from the Physicians' Health Study suggest that aspirin may have little or no influence on the later phases of carcinogenesis in the colon and rectum since the Physician's Health Study had 12 years of follow-up, well below 20 years (48Go). Since the average duration of aspirin use was approximately 2 years, the follow-up in the present study (6.4 years) may have been too short to allow detection of an effect of aspirin on risk of clinically apparent cancers in the women we studied. On the other hand, at least one study limited to men found that aspirin was related to lower risk after approximately 7 years (16Go). Although this suggests the possibility of a gender difference in the latency of the effect of aspirin, the clinical trial findings do not support that interpretation (25Go, 39Go).

Simple, nondifferential forgetting or incorrect estimation of usual aspirin intake could have played a role in the findings of our study. Such errors are a form of nondifferential misclassification that tends to make the observed hazard ratio appear closer to the null than is true and could possibly obscure a real association. On the other hand, this cohort study did not rely on very remote recall, suggesting that the probability of this type of misclassification was low.

Although we did not observe an effect of aspirin on the incidence of colorectal cancer, many other associations were present that have been demonstrated in previous studies (data not shown). Furthermore, based on previous research, aspirin use has typically been associated with a 20–30 percent reduction in risk of colorectal cancer. The sample size of our study was more than adequate to detect this magnitude of association. In addition, using the same cohort and similar methodology, Women's Health Initiative investigators have previously reported a dose-dependent relation between aspirin use and breast cancer (49Go), indicating that the approach used in this study was able to detect an aspirin effect on another malignant condition.


   ACKNOWLEDGMENTS
 
This work was supported by contracts with the Women's Health Initiative and in part by the Rebecca and John Moores Cancer Center at the University of California, San Diego.

Women's Health Initiative Investigators. Program Office: National Heart, Lung, and Blood Institute, Bethesda, Maryland: Barbara Alving, Jacques Rossouw, Linda Pottern. Clinical Coordinating Center: Fred Hutchinson Cancer Research Center, Seattle, Washington: Ross Prentice, Garnet Anderson, Andrea LaCroix, Ruth E. Patterson, Anne McTiernan; Wake Forest University School of Medicine, Winston-Salem, North Carolina: Sally Shumaker, Pentti Rautaharju; Medical Research Labs, Highland Heights, Kentucky: Evan Stein; University of California at San Francisco, San Francisco, California: Steven Cummings; University of Minnesota, Minneapolis, Minnesota: John Himes; University of Washington, Seattle, Washington: Bruce Psaty. Clinical Centers: Albert Einstein College of Medicine, Bronx, New York: Sylvia Wassertheil-Smoller; Baylor College of Medicine, Houston, Texas: Jennifer Hays; Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts: JoAnn Manson; Brown University, Providence, Rhode Island: Annlouise R. Assaf; Emory University, Atlanta, Georgia: Lawrence Phillips; Fred Hutchinson Cancer Research Center, Seattle, Washington: Shirley Beresford; George Washington University Medical Center, Washington, DC: Judith Hsia; Harbor-UCLA Research and Education Institute, Torrance, California: Rowan Chlebowski; Kaiser Permanente Center for Health Research, Portland, Oregon: Evelyn Whitlock; Kaiser Permanente Division of Research, Oakland, California: Bette Caan; Medical College of Wisconsin, Milwaukee, Wisconsin: Jane Morley Kotchen; MedStar Research Institute/Howard University, Washington, DC: Barbara V. Howard; Northwestern University, Chicago/Evanston, Illinois: Linda Van Horn; Rush-Presbyterian St. Luke's Medical Center, Chicago, Illinois: Henry Black; Stanford Center for Research in Disease Prevention, Stanford University, Stanford, California: Marcia L. Stefanick; State University of New York at Stony Brook, Stony Brook, New York: Dorothy Lane; The Ohio State University, Columbus, Ohio: Rebecca Jackson; University of Alabama at Birmingham, Birmingham, Alabama: Cora Beth Lewis; University of Arizona, Tucson/Phoenix, Arizona: Tamsen Bassford; University at Buffalo, Buffalo, New York: Jean Wactawski-Wende; University of California at Davis, Sacramento, California: John Robbins; University of California at Irvine, Orange, California: Allan Hubbell; University of California at Los Angeles, Los Angeles, California: Howard Judd; University of California at San Diego, LaJolla/Chula Vista, California: Robert D. Langer; University of Cincinnati, Cincinnati, Ohio: Margery Gass; University of Florida, Gainesville/Jacksonville, Florida: Marian Limacher; University of Hawaii, Honolulu, Hawaii: David Curb; University of Iowa, Iowa City/Davenport, Iowa: Robert Wallace; University of Massachusetts/Fallon Clinic, Worcester, Massachusetts: Judith Ockene; University of Medicine and Dentistry of New Jersey, Newark, New Jersey: Norman Lasser; University of Miami, Miami, Florida: Mary Jo O'Sullivan; University of Minnesota, Minneapolis, Minnesota: Karen Margolis; University of Nevada, Reno, Nevada: Robert Brunner; University of North Carolina, Chapel Hill, North Carolina: Gerardo Heiss; University of Pittsburgh, Pittsburgh, Pennsylvania: Lewis Kuller; University of Tennessee, Memphis, Tennessee: Karen C. Johnson; University of Texas Health Science Center, San Antonio, Texas: Robert Brzyski; University of Wisconsin, Madison, Wisconsin: Gloria Sarto; Wake Forest University School of Medicine, Winston-Salem, North Carolina: Denise Bonds; Wayne State University School of Medicine/Hutzel Hospital, Detroit, Michigan: Susan Hendrix.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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A. Bardia, J. O. Ebbert, R. A. Vierkant, P. J. Limburg, K. Anderson, A. H. Wang, J. E. Olson, C. M. Vachon, and J. R. Cerhan
Association of Aspirin and Nonaspirin Nonsteroidal Anti-inflammatory Drugs With Cancer Incidence and Mortality
J Natl Cancer Inst, June 6, 2007; 99(11): 881 - 889.
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