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Anonymous 2A 2013

Created By: Sarah Nguyen
http://www.britishskinfoundation.org.uk/SkinInformation/AtoZofSkindisease/Melanoma.aspx

Melanoma

What is a melanoma?

Cutaneous malignant melanoma is a cancer of the pigment cells of the skin.  If it is treated early, the outlook is usually good.  It is not contagious.

The word ‘melanoma’ comes from the Greek word ‘melas’, meaning black.  Melanin is the dark pigment that gives the skin its natural colour.  Melanin is made in the skin by pigment cells called melanocytes.  After our skin is exposed to sunlight, the melanocytes make more melanin, and so the skin becomes darker.

[1] Melanocytes sometimes grow together in harmless groups or clusters, which are known as moles.  Most people have between 10 and 50 moles and often they are darker than the surrounding skin. Melanomas can come up in or near to a mole, but can also appear on skin that looks quite normal. They develop when the skin pigment cells (melanocytes) become cancerous and multiply in an uncontrolled way. They can then invade the skin around them and may also spread to other areas such as the lymph nodes, liver and lungs.

What causes melanoma?

The most important preventable cause is exposure to too much ultraviolet light in sunlight, especially during the first 20 years of life.  There is lots of evidence linking melanoma to this, and melanomas are especially common in white-skinned people who live in sunny countries.  The use of artificial sources of ultraviolet light, such as sun beds, also raises the risk of getting a melanoma.

Some people are more likely to get a melanoma than others:

[2] People who burn easily in the sun are particularly at risk.  Melanoma occurs most often in fair-skinned people who tan poorly.  Often they have blond or red hair, blue or green eyes, and freckle easily.  Melanomas are less common in dark-skinned people.  
Past episodes of severe sunburn, often with blisters, and particularly in childhood, increase the risk of developing a melanoma. However, not all melanomas are due to sun exposure, and some appear in areas that are normally kept covered.  
People with many (more than 50) ordinary moles, or with a very large dark hairy birthmark, have a higher than average chance of getting a melanoma. 
Some people have many unusual (atypical) moles (known as ‘dysplastic naevi’).  They tend to be larger than ordinary moles, to be present in large numbers, and to have irregular edges or colour patterns.  The tendency to have these ‘dysplastic naevi’ can run in families and carries an increased risk of getting a melanoma. 
The risk is raised if another family member has had a melanoma. 
People who have already had one melanoma are at an increased risk of getting another one. 
People with a damaged immune system (e.g. as a result of an HIV infection or taking immunosuppressive drugs, perhaps after an organ transplant) have an increased chance of getting a melanoma
.  


Are melanomas hereditary?

About 1 in 10 of people with a melanoma have family members who have also had one.  There are several reasons for this.  Fair skin is inherited; dysplastic naevi can run in families, as can a tendency to have large numbers of ordinary moles.

What are the symptoms of melanoma?

Melanomas may not cause any symptoms at all, but tingling or itching may occur at an early stage.  Some melanomas start as minor changes in the size, shape or colour of an existing mole (see below): others begin as a dark area that can look like a new mole.  Later on a melanoma may feel hard and lumpy, and bleed, ooze or crust up.

 [3] What does a melanoma look like?
All melanomas do not look the same, and there are several different types.  The ABCD system (below) tells you some of the things to look out for. 
A melanoma may show one or more of the following features:
Asymmetry – the two halves of the area differ in their shape.
Border – the edges of the area may be irregular or blurred, and sometimes show notches. 
Colour – this may be uneven. Different shades of black, brown and pink may be seen. 
Diameter - most melanomas are at least 6 mm. in diameter.
Melanomas can appear on any part of the skin but they are most common in men on the body, and in women on the legs.


How is a melanoma diagnosed?

If you are at all worried about changes in a mole, or about a new area of pigmentation appearing on your skin, you should see your family doctor.  The ABCD changes listed above can sometimes be found in completely harmless conditions, and your doctor will often be able to put your mind at rest quickly.   However, if there is still any doubt, your doctor will usually refer you to a specialist (a dermatologist or a surgeon with a special interest in pigmented lesions) who will examine the area, perhaps with a special instrument (a dermatoscope), and decide whether it needs to be removed.  The only way in which the diagnosis of a melanoma can be made firmly is by looking at the suspected area under microscope in the laboratory.  

If the mole needs to be examined further, the whole of the suspicious area will then be removed under a local anaesthetic (an excision biopsy) and sent to the laboratory to be examined. If the area is too large to remove easily, a sample of it (a biopsy) will be taken.  If a melanoma is found, the biopsy specimen will provide valuable information about its type and depth that will help to plan the next step in treatment.

Can a melanoma be cured?

Yes: three quarters of the people who have a melanoma removed will have no further problems.  However it is crucial for a melanoma to be removed as early as possible - before it has had time to spread deep into the skin or to other parts of the body. The thinner the melanoma is when it is removed; the better is the survival rate.  This is why a doctor should examine anyone with a suspicious mole or blemish as soon as possible.  In a small minority of people the melanoma may have spread but further surgery or chemotherapy can often help to control this. 

For information about available treatments please visit this page on the website of the British Association of Dermatologists

 
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Anonymous 2013 2B

Created By: Sarah Nguyen
http://www.cancer.net/cancer-types/familial-malignant-melanoma


What is familial malignant melanoma?

Cancer begins when normal cells begin to change and grow uncontrollably forming a lesion called a tumor. A tumor can be benign (noncancerous) or malignant (cancerous, meaning it can spread to other parts of the body).

 [1] Familial malignant melanoma is a term usually referring to families in which two or more first-degree relatives (parent, sibling, or child) have a type of skin cancer called melanoma. Overall, about 8% of people newly diagnosed with melanoma have a first-degree relative with melanoma. A much smaller percentage, about 1%, have three or more close relatives with melanoma.Familial melanoma is a genetic condition. This means that the risk of melanoma can be passed from generation to generation in a family. To date, two genes have been linked to familial melanoma; 

Dysplastic nevi are large, flat, irregular, asymmetric, variably pigmented moles. They occur primarily on sun-exposed skin, but they also occur in areas that are not exposed to the sun. Individuals in melanoma-prone families frequently have these moles. The moles must be monitored very carefully for any change in size, shape, and color to watch for cancer. In the United States, the average age when melanoma is diagnosed in people with familial melanoma is in the 30s; the average age when melanoma is diagnosed in the general population is in the 50s.

What causes familial melanoma?

they are called CDKN2A and CDK4. A mutation (alteration) in one of these genes gives a person an increased risk of melanoma. However, alterations in these two genes only account for a small percentage of familial melanoma.

CDKN2A is unusual because it affects two separate proteins that have different functions; one is called p16, and one is called p14ARF. Both CDKN2A and CDK4 play important roles in controlling when cells divide. Studies of families with mutations in CDKN2A from Europe, North America, and Australia have shown that the risk of melanoma varies by geographic area. The reasons for these differences are not fully understood. There may be differences in the amount of sun they receive, other individual or genetic differences, or a combination of these factors.

Within melanoma-prone families with known genetic mutations dysplastic nevi and sun exposure are independent risk factors for melanoma. There is also growing evidence that variations in another gene, MC1R, alter the risk of melanoma, both in individuals with CDKN2A mutations and in individuals without CDKN2A mutations. MC1R is important in regulating pigment; variations have been associated with freckling and red hair.

Other inherited genes are associated with an increased risk of melanoma. For instance, Xeroderma pigmentosum (XP) is a rare disorder in which patients have a defect in a gene needed for repair of ultraviolet radiation (sunlight) induced DNA damage. Patients with XP have an extremely high rate of skin cancer, including melanoma. The hereditary breast cancer gene, BRCA2, is also associated with a risk of melanoma. Scientists believe that there are other genes not yet identified that also increase the risk of melanoma. Learn more about the genetics of melanoma. Research is ongoing to learn more about familial melanoma.

How is familial melanoma susceptibility inherited?

Normally, every cell has two copies of each gene: one inherited from the mother and one inherited from the father. Familial melanoma susceptibility follows an autosomal dominant inheritance pattern, in which case a mutation happens in only one copy of the gene. This means that a parent with a gene mutation may pass along a copy of his or her normal gene or a copy of the gene with the mutation. Therefore, a child who has a parent with a mutation has a 50% chance of inheriting that mutation. A brother, sister, or parent of a person who has a mutation also has a 50% chance of having the same mutation.

How common is familial melanoma?

Most cases of melanoma are sporadic (occur by chance). The number of people who have an inherited risk of melanoma is unknown, but the number is thought to be low. It is estimated that about 8% of people with melanoma have a first-degree relative with melanoma and that only 1% to 2% of people with melanoma have two or more close relatives with melanoma.

How is familial melanoma diagnosed?

Familial melanoma is suspected when two or more close relatives have invasive melanomas (melanoma that has spread). In areas of higher sun exposure, like the southern United States or Australia, the frequency of sporadic melanoma is higher, so familial melanoma is not diagnosed unless three or more close relatives have invasive melanoma. Familial melanoma may also be suspected if a single family member has multiple melanomas.
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Uong A 2010

Created By: Sarah Nguyen
http://www.ncbi.nlm.nih.gov/pubmed/19795394


Abstract
 [1] Melanocytes are pigment-producing cells in the skin of humans and other vertebrates. A number of genes involved in melanocyte development and vertebrate pigmentation have been characterized, largely through studies of a diversity of pigment mutations in a variety of species. Embryonic development of the melanocyte initiates with cell fate specification in the neural crest, which is then followed by cell migration and niche localization. Many genes involved in melanocyte development have also been implicated in the development of melanoma, an aggressive and fatal form of skin cancer that originates in the melanocyte. [2] Although early stage melanomas that have not spread to the lymph nodes can be excised with little risk of recurrence, patients diagnosed with metastatic melanoma have a high mortality rate due to the resistance of most tumors to radiotherapy and chemotherapy. Transformed melanocytes that develop into melanomas proliferate abnormally and often begin to grow radially in the skin. Vertical growth can then follow this radial growth, leading to an invasion through the basement membrane into the underlying dermis and subsequent metastasis. It is still unclear, however, how a normal melanocyte becomes a melanoma cell, and how melanoma utilizes the properties of the normal melanocyte and its progenitors in its progression. The goal of this mini-review is to highlight the role of melanocyte developmental pathways in melanoma, and to discuss recent studies and tools being used to illuminate this connection
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Anonymous 2013

Created By: Sarah Nguyen
http://www.cancercompass.com/melanoma-information.htm


Melanoma Information
What is Melanoma?
 [1] Melanoma is a type of skin cancer. It begins in cells in the skin called melanocytes. To understand melanoma, it is helpful to know about the skin and about melanocytes—what they do, how they grow, and what happens when they become cancerous.
The Skin

The skin is the body’s largest organ. It protects against heat, sunlight, injury, and infection. It helps regulate body temperature, stores water and fat, and produces vitamin D.
The skin has two main layers: the outer epidermis and the inner dermis:
The epidermis is mostly made up of flat, scalelike cells called squamous cells. Round cells called basal cells lie under the squamous cells in the epidermis. The lower part of the epidermis also contains melanocytes.
The dermis contains blood vessels, lymph vessels, hair follicles, and glands. Some of these glands produce sweat, which helps regulate body temperature. Other glands produce sebum, an oily substance that helps keep the skin from drying out. Sweat and sebum reach the skin’s surface through tiny openings called pores.
Melanocytes and Moles

Melanocytes produce melanin, the pigment that gives skin its natural color. When skin is exposed to the sun, melanocytes produce more pigment, causing the skin to tan, or darken.
Sometimes, clusters of melanocytes and surrounding tissue form noncancerous growths called moles. (Doctors also call a mole a nevus; the plural is nevi.) Moles are very common. Most people have between 10 and 40 moles. Moles may be pink, tan, brown, or a color that is very close to the person’s normal skin tone. People who have dark skin tend to have dark moles. Moles can be flat or raised. They are usually round or oval and smaller than a pencil eraser. They may be present at birth or may appear later on—usually before age 40. They tend to fade away in older people. When moles are surgically removed, they normally do not return.
Understanding Cancer

Cancer begins in cells, the building blocks that make up tissues. Tissues make up the organs of the body. Normally, cells grow and divide to form new cells as the body needs them. When cells grow old, they die, and new cells take their place.
Sometimes this orderly process goes wrong. New cells form when the body does not need them, and old cells do not die when they should. These extra cells can form a mass of tissue called a growth or tumor. Not all tumors are cancer.
Tumors can be benign or malignant:
Benign tumors are not cancer:
They are rarely life threatening.
Usually, benign tumors can be removed, and they seldom grow back.
Cells from benign tumors do not spread to tissues around them or to other parts of the body.
Malignant tumors are cancer:
They are generally more serious and may be life threatening.
Malignant tumors usually can be removed, but they can grow back.
Cells from malignant tumors can invade and damage nearby tissues and organs. Also, cancer cells can break away from a malignant tumor and enter the bloodstream or lymphatic system. That is how cancer cells spread from the original cancer (the primary tumor) to form new tumors in other organs. The spread of cancer is called metastasis. Different types of cancer tend to spread to different parts of the body.
Melanoma
Q. Can melanoma be cured?
A.[2] When detected in its earliest stages, melanoma is highly curable. The average five-year survival rate for individuals whose melanoma is detected and treated before it spreads to the lymph nodes is 99 percent.1

Early detection is essential; there is a direct correlation between the thickness of the melanoma and survival rate. Dermatologists recommend a regular self-examination of the skin to detect changes in its appearance. Additionally, patients with risk factors should have a complete skin examination by a dermatologist annually. Anyone with a changing, suspicious or unusual mole or blemish should be examined as soon as possible. Individuals with a history of melanoma should have a full-body exam at least annually and perform monthly self-exams for new and changing moles.12


Q. Can melanoma be prevented?
A. [3] Sun exposure is the most preventable risk factor for all skin cancers, including melanoma.1,13 You can have fun in the sun and decrease your risk of skin cancer. Here's how to Be Sun Smart®:
Generously apply a broad-spectrum, water-resistant sunscreen with a Sun Protection Factor (SPF) of at least 30 to all exposed skin. "Broad-spectrum" provides protection from both ultraviolet A (UVA) and ultraviolet B (UVB) rays. Reapply approximately every two hours, even on cloudy days, and after swimming or sweating.
Wear protective clothing, such as a long-sleeved shirt, pants, a wide-brimmed hat, and sunglasses, where possible.
Seek shade when appropriate. Remember that the sun's rays are strongest between 10 a.m. and 4 p.m. If your shadow is shorter than you are, seek shade.
Protect children from sun exposure by playing in the shade, wearing protective clothing, and applying sunscreen.
Use extra caution near water, snow, and sand because they reflect the damaging rays of the sun, which can increase your chance of sunburn.
Get vitamin D safely through a healthy diet that may include vitamin supplements. Don't seek the sun.6
Avoid tanning beds. Ultraviolet light from the sun and tanning beds can cause skin cancer and wrinkling. If you want to look like you've been in the sun, consider using a sunless self-tanning product, but continue to use sunscreen with it.
Check your birthday suit on your birthday. If you notice anything changing, growing, or bleeding on your skin, see us, at Water’s Edge. Skin cancer is very treatable when caught early

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Jacobs 2007 et.al (Journal)

Created By: Sarah Nguyen

http://jnci.oxfordjournals.org/content/99/8/608.full?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&andorexacttitle=and&andorexacttitleabs=and&fulltext=aspirin+and+melanoma+cancer&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT#content-block

Abstract

Background  [1] Epidemiologic evidence indicates that aspirin use is associated with reduced risks of colon cancer and possibly several other cancers, including prostate and breast cancers. Recent results from the Women's Health Study randomized trial indicate that long-term use of low-dose aspirin (100 mg every other day) does not substantially reduce cancer risk. However, the potential effect of long-term daily use of higher doses of aspirin on cancer incidence remains uncertain.

Methods   [2] We examined associations between long-term daily use of adult-strength aspirin (≥325 mg/day) and both overall cancer incidence and incidence of 10 types of cancer among 69810 men and 76303 women participating in the Cancer Prevention Study II Nutrition Cohort, a relatively elderly population. Aspirin use was reported at enrollment in 1992–1993 and updated in 1997, 1999, and 2001. Multivariable Cox proportional hazards regression was used to calculate rate ratios (RRs).

Results During follow-up through June 2003, 10931 men and 7196 women were diagnosed with cancer. Long-term (≥5 years) daily use of adult-strength aspirin, compared with no use, was associated with lower overall cancer incidence in men (multivariable-adjusted RR = 0.84, 95% confidence interval [CI] = 0.76 to 0.93) and non–statistically significantly lower overall cancer incidence in women (multivariable-adjusted RR = 0.86, 95% CI = 0.73 to 1.03). Overall cancer incidence per 100000 person-years (standardized to the age distributions of men and women in the study) with long-term daily aspirin use and no aspirin use was 1858 and 2163, respectively, among men and 1083 and 1169, respectively, among women. Long-term daily aspirin use was associated with lower incidence of colorectal cancer (RR = 0.68, 95% CI = 0.52 to 0.90 among men and women combined) and prostate cancer (RR = 0.81, 95% CI = 0.70 to 0.94) and a non–statistically significant lower risk of female breast cancer (RR = 0.83, 95% CI = 0.63 to 1.10).

Conclusions [3] Long-term daily use of adult-strength aspirin may be associated with modestly reduced overall cancer incidence in populations among whom colorectal, prostate, and breast cancers are common.

CONTEXT AND CAVEATS

Prior knowledge

Aspirin use is associated with reduced risk of colon cancer.

Study design

Risks of 10 types of cancer were estimated among mainly elderly men and women from the Cancer Prevention Study II Nutrition Cohort from surveys of aspirin use and cancer diagnosis.

Contribution

Daily use of adult-strength aspirin for 5 or more years was associated with reduced risks of overall cancer and prostate cancer among men and of colorectal cancer among men and women combined.

Implications

Daily use of adult-strength aspirin for 5 or more years may be associated with reductions in cancer incidence among populations in which incidence of colorectal, prostate, and breast cancers is high.

Limitations

[4] Being an observational study, it is subjected to confounding by factors that are associated with aspirin use and cancer risk that were not measured and/or may not be measurable. No data on potentially harmful side effects from daily long-term use of adult-strength aspirin were gathered.

Recently, the Women's Health Study, a large 10-year randomized trial of alternate-day low-dose aspirin (100 mg every other day) showed no reduced risk of any cancer in aspirin users (1). However, the potential effect of daily adult-strength aspirin (i.e., ≥325 mg/day) on overall cancer incidence or on incidence of specific individual cancers remains uncertain. Considerable evidence suggests that aspirin use could reduce risk of several cancers. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the development of many different types of cancers in rodent models, including cancers of the colorectum, breast, prostate, lung, skin, and bladder (2). It has been hypothesized that aspirin may inhibit carcinogenesis by reducing the synthesis of prostaglandins by cyclooxgenase (COX)-1 and COX-2 enzymes (3). Aspirin reduced risk of colorectal polyp recurrence in two randomized trials (4,5) and has been consistently associated with lower risk of colorectal cancer in observational studies (2), although the optimal dose associated with reduced colorectal cancer risk remains unclear. Meta-analyses of observational studies have reported considerably reduced risk of gastric and esophageal cancer with aspirin use (6), although these cancers are not common in the United States. Meta-analyses of observational studies have also reported smaller, but statistically significant, reductions in risk of breast (6), prostate (7), and lung cancers (8) with aspirin use, and some studies have also suggested reduced risk of other cancers (9).

Although many epidemiologic studies have examined the association between aspirin use and individual cancers, it is difficult to use results of these studies to assess the overall potential cancer prevention benefit of any particular aspirin regimen. Studies of individual cancers have examined widely varying levels of aspirin use. In addition, publication bias is a concern in that researchers may prioritize the publication of results for individual cancers that show associations with aspirin use in their study population. Studies of overall cancer incidence may be more useful with respect to assessing aspirin's overall potential cancer prevention benefits, but few studies have examined overall cancer incidence. In a randomized trial of aspirin for cardiovascular disease prevention among male British doctors (10), cancer incidence rates (examined as a secondary outcome) were not statistically significantly reduced among men randomly assigned to 500 mg aspirin daily. However, this trial included only 5139 men followed for a maximum of 6 years and, therefore, may have been too small and short in duration to provide important information about the potential effects of long-term aspirin use on cancer. Use of prescription low-dose aspirin (≤150 mg/day) was associated with slightly increased overall cancer incidence in a Danish pharmacy database analysis (11), although there was no evidence of increasing risk with duration of use, and results could not be adjusted for smoking. In the National Health and Nutrition Examination Survey (NHANES)-I cohort (12), use of any aspirin during the month before enrollment was associated with a modest but statistically significant reduction in overall cancer incidence, but duration of use was not examined. To our knowledge, no previous studies have examined the association between long-term daily aspirin use and overall cancer incidence.

[5] Any meaningful effect of aspirin use on overall cancer incidence could be of considerable importance. Unlike other traditional NSAIDs or COX-2 inhibitors, aspirin has been proven in numerous randomized trials to reduce risk of cardiovascular events, although this cardiovascular benefit is accompanied by increased risk of serious gastrointestinal bleeding, both at low doses (e.g., approximately 80 mg, a common dose in tablets intended for children or specifically for cardiovascular disease prevention) and at “adult-strength” doses (defined here as at least 325 mg, the lowest standard dose in tablets intended for adults in the United States) (1315). The US Preventive Services Task Force recommends consideration of aspirin therapy in individuals for whom the coronary heart disease benefits are likely to exceed the risks of serious bleeding events but does not specify an optimum dose (16). If daily use of adult-strength aspirin were to reduce overall cancer risk, there could be important implications with respect to who should be taking aspirin and at what dose. We therefore examined the association between long-term daily use of adult-strength aspirin and overall cancer incidence in a large cohort of predominantly elderly US men and women, using detailed information on aspirin use reported at several different time points.

Subjects and Methods

Study Cohort

Men and women in this analysis were drawn from the 86404 men and 97786 women in the Cancer Prevention Study II Nutrition Cohort (hereafter called the Nutrition Cohort), a prospective study of cancer incidence and mortality among US men and women that was established in 1992–1993 and has been described in detail elsewhere (17). The Nutrition Cohort is a subgroup of the approximately 1.2 million participants in the Cancer Prevention Study II (CPS-II), a prospective study of cancer mortality that was established by the American Cancer Society in 1982. The Emory University Institutional Review Board approves all aspects of the Nutrition Cohort. At enrollment in 1992–1993, Nutrition Cohort participants completed a mailed self-administered questionnaire that included information on demographic, medical, and lifestyle factors. Follow-up questionnaires to update exposure information and to ascertain newly diagnosed cancers were mailed in 1997, 1999, 2001, and 2003. The response rate among living participants for each of these follow-up questionnaires was at least 89%. Written informed consent to participate in the study was implied by return of the completed questionnaires.

For this analysis, we excluded 3232 men and 3212 women who were lost to follow-up (those who were alive at the time of the first follow-up questionnaire in 1997 but did not return the 1997 follow-up questionnaire or any later questionnaire). We also excluded participants with a history of cancer other than nonmelanoma skin cancer at enrollment (9761 men and 13084 women). In addition, we excluded participants with incomplete information on smoking status or use of aspirin or other NSAIDs at enrollment (3566 men and 5171 women) or with missing information on year of cancer diagnosis (35 men and 16 women). After these exclusions, a total of 69810 men and 76303 women remained for analysis.

Case Ascertainment

We documented 18127 participants (10931 men and 7196 women) who were diagnosed with cancer between enrollment in 1992–1993 and June 30, 2003. Of these, 14703 diagnoses were initially identified by self-report on the 1997, 1999, 2001, or 2003 follow-up questionnaires and subsequently verified by obtaining medical records or, when complete medical records could not be obtained, through linkage with state registries (17). A previous comparison (18) of self-reports with information from state cancer registries has demonstrated that participants in the Nutrition Cohort can accurately self-report a cancer diagnosis (sensitivity = 0.93). An additional 3424 participants were identified as having died from cancer through linkage of the cohort with the National Death Index (19). For these 3424 case subjects, the death certificate listed cancer as the primary cause of death between the date of enrollment and December 31, 2002. A total of 2894 self-reports of cancer diagnoses could not be verified and therefore were not counted as cases.

Ascertainment of aspirin use.

Aspirin use was reported on questionnaires in 1982 (at enrollment into the larger CPS-II mortality cohort), 1992–1993 (at enrollment into the Nutrition Cohort), 1997, 1999, and 2001. The 1982 questionnaire asked for “times per month” that aspirin was used in the last month. The questionnaire completed in 1992–1993 (hereafter referred to as the 1992 questionnaire) asked for average days per month of aspirin use during the past year, the average number of pills taken on days used, and the number of years of use. Follow-up questionnaires in 1997, 1999, and 2001 asked similar questions about days per month and pills per day but asked separately about use of low-dose (or “baby”) aspirin and adult-strength aspirin.

Statistical analysis.

We used Cox proportional hazards modeling (20) to calculate rate ratios (RRs) for cancer incidence associated with aspirin use adjusted for age and potential cancer risk factors. The time axis used was follow-up time since enrollment in 1992–1993. For analyses of overall cancer incidence, diagnosis date was defined as the date of first cancer diagnosis. In addition to examining overall cancer incidence, we also examined the association between aspirin use and the incidence of the 10 individual cancers for which statistical power was greatest (based on the number of expected cases among long-term daily aspirin users). For analyses of individual cancer sites, date of diagnosis was defined as the diagnosis date of the individual cancer of interest, regardless of whether a different cancer had been diagnosed earlier in the follow-up period.

Our analyses were designed specifically to examine long-term daily use of adult-strength aspirin. We had insufficient statistical power to examine long-term use of low-dose aspirin. Although aspirin dose was not reported on the 1982 or 1992 questionnaires, we considered all aspirin use reported in 1982 or 1992 to be adult-strength aspirin. It is unlikely that substantial numbers of our participants were taking daily low-dose aspirin in or before 1992 because the efficacy of low-dose aspirin for cardiovascular disease prevention was not well established in 1992 (21). Daily use of adult-strength aspirin was defined as use at least 30 “times” per month in 1982 and as 30 or 31 days per month in 1992, 1997, 1999, or 2001. Although years of aspirin use was reported at enrollment, frequency of past use was not assessed. We therefore defined duration of daily use based on having reported current daily aspirin use on two or more consecutive questionnaires, as detailed below.

We created a time-dependent variable for aspirin use with four categories: 1) never reported use; 2) low dose, less than daily, or past use only; 3) current daily use of adult-strength aspirin for less than 5 years; and 4) current daily use of adult-strength aspirin for 5 or more years. This comparison is similar to that used in previous analyses of aspirin and other NSAIDs in this cohort (22,23). Participants were categorized as daily users of adult-strength aspirin for 5 or more years if they met the following criteria: 1) for the 1992–1997 follow-up interval, if they had reported at least 5 years of aspirin use on the 1992 questionnaire and daily aspirin use on the 1982 and 1992 questionnaires; 2) for the 1997–1999 follow-up interval, if they had reported daily aspirin use on the 1992 and 1997 questionnaires (not including low-dose aspirin); 3) for the 1999–2001 follow-up interval, if they had reported daily aspirin use on the 1992, 1997, and 1999 questionnaires (not including low-dose aspirin); 4) for the 2001–2003 follow-up interval, if they had reported daily aspirin use on the 1997, 1999, and 2001 questionnaires (not including low-dose aspirin).

During each follow-up interval, participants who had not reported any aspirin use on either the questionnaire at the start of that follow-up interval or on any previous questionnaire were categorized as never users; those who were neither never users nor current daily users of adult-strength aspirin were grouped into a mixed-use category that included less than daily, low-dose, and past users. At the start of each follow-up interval, we censored participants whose aspirin use status could not be updated due either to missing or invalid aspirin data on the follow-up questionnaire or failure to return the follow-up questionnaire.

Age was adjusted for using the stratified Cox procedure with 1-year age strata (24). Additional potential confounders that were included in all multivariable models were race (white, black, other or missing); education (less than high school, high school graduate, some college, college graduate, graduate school, or unclassifiable); smoking status (never, former: <20 years, ≥20 years, or years unknown, current: <40 or ≥40 years); physical activity level (<3.5, 3.5 to <4.5, 4.5 to <14.0, 14.0 to <24.5, ≥24.5 metabolic equivalents/wk, or unclassifiable); body mass index (BMI, <22.5, 22.5 to <25, 25.0 to <27.5, 27.5 to <30, ≥30 kg/m2, or unclassifiable); history of heart attack, diabetes, or hypertension (yes or no); colorectal endoscopy (yes or no); and use of NSAIDs other than aspirin (none, 1–29, or ≥ 30 pills per month). Use of nonaspirin NSAIDs (in pills per month) was modeled as frequency of use during the 1992–1997 follow-up interval (when duration of NSAID use could not be calculated) and duration of regular NSAID use during the remainder of follow-up, as described for a previous analysis in this cohort (23). Models that included men were also adjusted for history of prostate-specific antigen (PSA) testing, and models that included women were also adjusted for use of hormone replacement therapy and for history of mammography. Models that included both men and women were also adjusted for sex. Mammography was modeled using a time-dependent variable for having had a mammography in the previous 2 years. Follow-up after 1997 (the first time information on PSA testing and colorectal endoscopy was collected) was adjusted for PSA testing using time-dependent variables for having had PSA test during the previous follow-up interval and for ever having had a colorectal endoscopy. Except for the time-dependent variables described above, potential confounders were modeled based on status at enrollment. Categories were chosen to be similar to those used in previous analyses in this cohort. Further adjustment for nutritional factors, including use of alcohol, multivitamins, and calcium supplements, and intake of saturated fat and vegetables had negligible effects on results.

We examined whether the association between long-term daily aspirin use (defined as daily use of adult-strength aspirin for ≥5 years) and overall cancer incidence varied by cigarette smoking status, BMI, attained age, and follow-up time by modeling multiplicative interaction terms between long-term daily aspirin use and variables for BMI, attained age, follow-up time (all modeled as continuous variables), and cigarette smoking status (never, former, current). Two-sided P values for interaction were calculated using the likelihood ratio statistic (25); P value of less than .05 was considered to be statistically significant.

Results

At enrollment in 1992–1993, only 2.3% of male participants and 1.3% of female participants met our definition for being long-term daily aspirin users. However, the prevalence of long-term daily aspirin use increased during the follow-up period. Long-term daily aspirin users contributed 4.6% of the person-time included in this analysis among men and 2.1% of that among women. Most long-term daily aspirin users reported using either one aspirin pill per day (79% of person-time among men, 56% of person-time among women) or two aspirin pills per day (11% of person-time among men, 20% of person-time among women).

At enrollment in 1992–1993, participants who were long-term daily aspirin users were, on average, older and slightly more likely to be white than participants who reported no aspirin use (Table 1), although nearly all participants in this cohort were white and older than age 50 years, regardless of aspirin use. Long-term daily aspirin users were slightly more likely than nonusers to be highly educated, to be former smokers rather than never smokers, to have a high BMI, and to use nonaspirin NSAIDs. In addition, long-term daily aspirin users were considerably more likely than nonusers to have had a history of heart attack, diabetes, or hypertension, presumably reflecting the use of aspirin to prevent cardiovascular disease. Among women, long-term daily aspirin users were more likely than nonusers to use hormone replacement therapy (41% versus 30%) but were not more likely to have reported a mammogram in the last year (64% in both groups). Information on PSA testing and colorectal endoscopy was first collected in 1997. At that time, long-term daily aspirin users were slightly more likely than nonusers to have ever had a PSA test (77% versus 71% among men) or a colorectal endoscopy (61% versus 55% among men, 52% versus 50% among women).

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Table 1

Selected cancer risk factors by aspirin use at enrollment of the Cancer Prevention Study II Nutrition Cohort in 1992–1993*

Long-term daily aspirin use was associated with lower overall cancer incidence than no use in men (multivariable-adjusted RR = 0.84, 95% confidence interval [CI] = 0.76 to 0.93) and women (multivariable-adjusted RR = 0.86, 95% CI = 0.73 to 1.03), although the association was not statistically significant in women (P = .10) (Table 2). These multivariable-adjusted rate ratios were slightly lower than those adjusted only for age (in men, age-adjusted RR = 0.85, 95% CI = 0.77 to 0.94; in women, age-adjusted RR = 0.91, 95% CI = 0.77 to 1.08). Current use of adult-strength aspirin for less than 5 years was not associated with overall cancer incidence in either men or women. The absolute cancer incidence rate per 100000 person-years (standardized to the age distributions of men and women in the study using 5-year age categories) was 1858 among men with long-term daily aspirin use, 2163 among men who never reported using aspirin, 1083 among women with long-term daily aspirin use, and 1169 among women who never reported using aspirin.

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Table 2

Overall cancer incidence by duration of daily adult-strength aspirin use, Cancer Prevention Study II Nutrition Cohort, 1992–2003*

The association between long-term daily aspirin use and overall cancer incidence did not change substantially when we excluded participants who had ever reported use of NSAIDs other than aspirin (RR = 0.88, 95% CI = 0.79 to 0.98 among men; RR = 0.85, 95% CI = 0.69 to 1.04 among women). We found no statistically significant differences in the association between long-term daily aspirin use and overall cancer incidence in either men or women, by attained age, BMI, smoking status, or follow-up year. In analyses restricted to participants who were current smokers at enrollment, long-term daily aspirin use was not associated with reduced risk of cancer among either men (RR = 1.08, 95% CI = 0.80 to 1.45) or women (RR = 1.13, 95% CI = 0.72 to 1.76), although statistical power was limited by the low prevalence of smoking, and these results should therefore be interpreted cautiously. In analyses by follow-up interval, the rate ratio for cancer associated with long-term daily aspirin use among men was 0.89 (95% CI = 0.75 to 1.06) during the 1992–1997 interval and 0.81 (95% CI = 0.71 to 0.92) during the 1997–2003 interval. The rate ratio for cancer associated with long-term daily aspirin use among women was 0.94 (95% CI = 0.70 to 1.26) during the 1992–1997 interval and 0.79 (95% CI = 0.64 to 0.99) during the 1997–2003 interval.

In analyses of individual cancers (Table 3), long-term daily aspirin use was associated with a statistically significant reduction in risk of colorectal cancer among both sexes combined (RR = 0.68, 95% CI = 0.52 to 0.90). This association was not statistically significantly different by sex (RR = 0.76, 95% CI = 0.55 to 1.04 in men, RR = 0.45, 95% CI = 0.24 to 0.86 in women). Long-term daily aspirin use was also associated with a statistically significant reduction in risk of prostate cancer (RR = 0.81, 95% CI = 0.70 to 0.94). The risk of female breast cancer was also reduced but not statistically significantly so (RR = 0.83, 95% CI = 0.63 to 1.10). These results for prostate and breast cancers are similar to those reported in previous analyses of this cohort (22,23), although this analysis includes 2 additional years of follow-up. Shorter term daily aspirin use (use for <5 years) was not associated with incidence of any cancer examined. Results for each individual cancer were not substantially changed when we excluded follow-up time occurring after a diagnosis of a different type of cancer (data not shown).

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Table 3

Incidence of individual common cancers by duration of daily adult-strength aspirin use, Cancer Prevention Study II Nutrition Cohort, 1992–2003*

Discussion

In this study, daily use of adult-strength aspirin for 5 or more years was associated with approximately 15% less overall cancer incidence, as compared with no use, in both men and women, although among women, this association was not statistically significant. The lower overall cancer incidence associated with long-term daily aspirin use was primarily the result of approximately 30% less colorectal cancer incidence, approximately 20% lower prostate cancer incidence, and approximately 15% lower incidence of female breast cancer, although the reduction in female breast cancer was not statistically significant.

Comparing our results with those of previous studies is difficult because we specifically examined aspirin use that was both daily and long term, whereas in nearly all previous studies, aspirin use was defined as including less frequent and/or short-term usage. In the NHANES-I cohort, any aspirin use during the 30 days before enrollment was associated with a statistically significant 17% reduction in overall cancer incidence, but duration of aspirin use was not examined (12). In a meta-analysis of observational studies of colon cancer, daily aspirin use was associated with an approximately 50% reduction in risk (9). Meta-analyses that included a large number of observational studies have reported aspirin use to be associated with a 10% reduction in risk of prostate cancer (7) and a 23% reduction in risk of breast cancer (6). Results from the meta-analyses of breast and prostate cancers did not consider duration of use and were based on combining risk estimates from individual studies that used different measures of aspirin use (generally ranging from at least once a week to daily use). Given that we specifically examined daily aspirin use for at least 5 years, we might have expected to observe larger reductions in cancer risk than those reported by the meta-analyses. Instead, our results suggest that even long-term daily aspirin use is likely to be associated with relatively small, although still potentially clinically relevant, reductions in cancer risk.

We found no association between long-term daily aspirin use and risk of lung cancer or other individual cancers examined (bladder cancer, melanoma, leukemia, non-Hodgkin lymphoma, pancreatic cancer, and kidney cancer). Our null results with respect to lung cancer differ from those of a recent meta-analysis that reported “regular” aspirin use to be associated with a 27% reduction in risk (8). However, results of this meta-analysis were influenced by substantial reductions in risk observed in two hospital-based case–control studies (26,27), whereas results from prospective studies have been inconsistent (8,28). Most previous studies of the other individual cancers we examined produced null results, although statistically significant associations with aspirin use have been observed in at least one study of each of these cancers (9). There were limited numbers of these less common cancers in our study; therefore, moderate-sized associations with long-term aspirin use remain plausible.

A limitation of our study, and of all observational studies of aspirin use, is that we cannot rule out confounding by unmeasured factors associated with both aspirin use and cancer risk. However, adjustment for measured risk factors strengthened, rather than attenuated, our results. We did not have information on the reason for daily aspirin use. However, it is likely that many daily users were taking aspirin for cardiovascular disease prevention, given that the prevalence of cardiovascular risk factors was high among daily aspirin users and that most daily aspirin users were taking only one aspirin per day. An additional limitation is that we did not have sufficient statistical power to examine long-term daily use of low-dose aspirin.

Strengths of this study include its prospective design, large size, and the availability of detailed information on aspirin use updated at several different time points. Because of these strengths, we could comprehensively examine the association between cancer risk and a relatively well-defined, and potentially clinically usable, regimen of aspirin use (long-term daily use of adult-strength aspirin) that has not previously been studied with respect to cancer.

The results in our study with respect to overall cancer incidence were strongly influenced by the three most common cancers in this cohort, prostate cancer, breast cancer, and colorectal cancer. Therefore, our results with respect to overall cancer incidence cannot be generalized to populations in which these cancers do not account for a substantial proportion of overall cancer incidence.

Our results do not have immediate clinical implications. Confirmation from randomized trials is necessary before a reduction in cancer risk could be considered a benefit of using adult-strength aspirin. Our results indicate that a randomized trial examining the effect of aspirin on cancer incidence would need to be both large and long term, probably lasting a minimum of 10 years. More evidence is needed before any such trial can be justified. This evidence could come from additional large observational studies with detailed and prospectively collected information on dose, frequency, and duration of aspirin use. In addition, if appropriate biomarkers of breast and prostate carcinogenesis could be identified, the effect of aspirin on these biomarkers could be tested in relatively short-term randomized trials, potentially providing further evidence to justify a long-term randomized trial examining cancer incidence. Further research to clarify the potential influence of aspirin on cancer risk will be challenging. However, if daily adult-strength aspirin use is ultimately found to meaningfully reduce overall cancer risk, there could be important clinical implications with respect to who should be taking aspirin and at what dose.

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Asgari 2008 et.al (Journal)

Created By: Sarah Nguyen

http://jnci.oxfordjournals.org/content/100/13/967.full?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&andorexacttitle=and&andorexacttitleabs=and&fulltext=aspirin+and+melanoma+cancer&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

Abstract

[1] 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.

CONTEXT AND CAVEATS

Prior knowledge

Results of laboratory studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) may have chemopreventive activity and therapeutic efficacy against melanoma.

Study design

Prospective cohort study to investigate whether commonly used over-the-counter and prescription NSAIDs are associated with melanoma risk.

Contribution

After adjusting for melanoma risk factors and indications for NSAID use, no association between NSAID use and melanoma risk was found.

Implications

NSAIDs do not appear to be good candidates for the chemoprevention of melanoma.

Limitations

Detailed information on some known melanoma risk factors such as sunlight exposure and number of nevi was not available. The actual NSAIDs dose per day was not ascertained. The average follow-up was only 5 years, which may be insufficient to detect an effect because the lag time between the initiation and diagnosis of melanoma may be on the order of decades.

Epidemiological studies have demonstrated chemopreventative benefits of nonsteroidal anti-inflammatory drugs (NSAIDs) for total cancer incidence and mortality (1,2) and for site-specific cancers such as those of the colon (3,4), breast (5), or prostate (6). Few epidemiological studies have examined the association of NSAIDs with melanoma risk and have found conflicting results (1,79). NSAIDs block cyclooxygenase enzymes, which inhibit the synthesis of proinflammatory molecules that play a role in tumor growth and development (10,11). Cyclooxygenase expression has been associated with melanoma invasion (12) and metastasis (13). Thus, NSAIDs could play a role in the chemoprevention of melanoma.

[2] We conducted a prospective study of the Vitamins and Lifestyle (VITAL) cohort to investigate whether commonly used over-the-counter and prescription NSAIDs are associated with melanoma risk. The VITAL study recruited 77 719 men and women aged 50–76 years in western Washington state from October 1, 2000, through December 31, 2002, and ascertained detailed information about lifestyle, dietary, and cancer risk factors by use of a baseline questionnaire. Further study details have been published previously (14). This study was approved by the Fred Hutchinson Cancer Research Center Institutional Review Board.

[3] Participants were excluded if they reported a melanoma diagnosis at baseline (n = 1557), had missing data on NSAID use (n = 6652), or were nonwhite or did not report their race (n = 5701), leaving a total of 63 809 participants for this analysis. Participants self-reported NSAID exposure in the previous 10 years, noting years and frequency of their use of low-dose (81 mg) and regular- (325 mg) or extra-strength aspirin, ibuprofen, naproxen, and celecoxib or rofecoxib. Women also reported their intake of piroxicam and indomethacin. Ever use was defined as taking the medication at least once a week for a year in the 10-year period before baseline. Dose was computed as the average number of days per week of use for the 10 years before enrollment (ie, [days per week x years of use]/10).

Through linkage of the VITAL database to the NCI Surveillance, Epidemiology, and End Results cancer registry, 349 patients with incident cases of malignant melanoma were identified between baseline and December 31, 2005. Cox proportional hazards models were used to estimate age- and multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for melanoma risk. Age was used as the time scale. We observed no violation of the proportional hazards by age with the Wald test. Nonusers of any NSAID were the common reference for all four drug exposures (ie, any NSAID; any NSAID excluding low-dose aspirin; regular- or extra-strength aspirin; and nonaspirin NSAIDs). The censor date was defined as the earliest date of withdrawal from the study (0.03%, n = 21), death (3.6%, n = 2720), out-of-area move (4.6%, n = 3486), or the end of follow-up on December 31, 2005. To control for confounding by indication, we adjusted for self-reported medical conditions that indicated (cardiovascular disease, chronic pain, arthritis) or contraindicated (kidney disease, gastric ulcer) NSAID use (as described in Table 1). Established or possible risk factors for melanoma were also included in the model; other lifestyle factors such as body mass index, total physical activity, and smoking history were not found to be confounding factors. To examine the association between participant characteristics and NSAID use (Table 1), odds ratios were calculated by logistic regression. All statistical tests were two-sided.

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Table 1

Association between participant characteristics and nonsteroidal anti-inflammatory drug use among 63 809 participants in the Vitamins and Lifestyle cohort (2000–2005)*

Among the 63 809 cohort participants, 40 200 (63%) regularly used any type of NSAIDs at least once a week for 1 year in the 10-year period before enrollment. Factors associated with regular NSAID use are given inTable 1. Multivariable associations between NSAID use and the risk of melanoma are summarized in Table 2. None of our four NSAID exposures examined (whether expressed as overall use, duration, or dose) was associated with melanoma risk. Compared with nonuse, no melanoma risk reduction was detected with use (≥4 d/wk on average over the past 10 years) for any NSAID dose (HR = 1.12, 95% CI = 0.84 to 1.48), any NSAID excluding low-dose aspirin (HR = 1.03, 95% CI = 0.74 to 1.43), regular- or extra-strength aspirin (HR = 1.10, 95% CI = 0.76 to 1.58), or nonaspirin NSAIDs (HR = 1.22, 95% CI = 0.75 to 1.99). We also observed no difference in melanoma risk among males (HR = 1.21, 95% CI = 0.85 to 1.71) or among females (HR = 1.01, 95% CI = 0.63 to 1.60; Pinteraction = .63) for dose of any NSAID.

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Table 2

Association between nonsteroidal anti-inflammatory drug use and incident melanoma in the Vitamins and Lifestyle cohort (2000–2005)

There were 157 patients with in situ melanoma and 191 with invasive (including local, regional, and distant) melanoma. The association between dose of any NSAID use and the risk of in situ melanoma (HR = 1.17, 95% CI = 0.77 to 1.78, >4 days a week vs none) was not appreciably different than the risk of invasive melanoma (HR = 1.09, 95% CI = 0.75 to 1.57; Pinteraction = .38). Furthermore, we did not observe an association between dose of any NSAID use and the risk of metastatic melanoma, defined as regional or distant disease (HR = 1.09, 95% CI = 0.33 to 3.62; n = 23). Lastly, we did not detect an association between dose of any NSAID use and tumor thickness (n = 172 and Ptrend = .98).

[4] In conclusion, we found no evidence to support an association between NSAID use and decreased melanoma risk. The lack of effect was persistent even though our NSAIDs variables accounted for frequency and duration of NSAID use and we considered the major classes of NSAIDs separately and combined. Our findings are consistent with a recently published large prospective study (6) that also found no association between duration of daily regular-strength aspirin use and the risk of incident melanoma. Although clinical reports of patients with surgically incurable or metastatic melanoma who demonstrated regression or complete remission with NSAID treatment have been published (15,16) and the rate of melanoma metastasis has been shown to be lower for patients using NSAIDs than nonusers (8), we did not observe an association between dose of any NSAID and tumor invasion, tumor thickness, or metastatic potential.

This study had several limitations, including the absence of detailed information on some known melanoma risk factors such as sunlight exposure and number of nevi. However, adjusting for risk factors of melanoma did not alter the risks in the multivariable model, and so it is unlikely that including residual risk factors would appreciably change the results. Also, the actual NSAID pills per day was not ascertained. Finally, the follow-up time between the 10-year period for which we had NSAID use data and cancer incidence was only 5 years on average, which may not be sufficient if the lag time between the initiation and diagnosis of melanoma is on the order of decades.

Strengths of this investigation include its prospective design, large cohort size, and the availability of baseline information on major potential confounding factors (including constitutional, personal, and family skin cancer history and patient numbers). In addition, we obtained data on long-term use of NSAIDs including commonly used over-the-counter NSAIDs.

We found no association between self-reported NSAID use and melanoma risk. Given the potential side effects of NSAIDs, including gastric ulcers, the search must continue for a good chemopreventive agent for melanoma.

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