Occupational sun exposure is a well-known risk factor for the development of melanoma and nonmelanoma skin cancer (NMSC). In addition to sun exposure, US military personnel may face other risk factors such as lack of access to adequate sun protection, work in equatorial latitudes, and increased exposure to carcinogens. In one study, fewer than 30% of surveyed soldiers reported regular sunscreen use during deployment and reported the face, neck, and upper extremities were unprotected at least 70% of the time.¹ Skin cancer risk factors that are more common in military service members include inadequate sunscreen access, insufficient sun protection, harsh weather conditions, more immediate safety concerns than sun protection, and male gender. A higher incidence of melanoma and NMSC has been correlated with the more common demographics of US veterans such as male sex, older age, and White race.²

Although not uncommon in both civilian and military populations, we present the case of a military service member who developed skin cancer at an early age potentially due to occupational sun exposure. We also provide a review of the literature to examine the risk factors and incidence of melanoma and NMSC in US military personnel and veterans and provide recommendations for skin cancer prevention, screening, and intervention in the military population.

Case Report

A 37-year-old White active-duty male service member in the US Navy (USN) presented with a nonhealing lesion on the nose of 2 years’ duration that had been gradually growing and bleeding for several weeks. He participated in several sea deployments while onboard a naval destroyer over his 10-year military career. He did not routinely use sunscreen during his deployments. His personal and family medical history lacked risk factors for skin cancer other than his skin tone and frequent sun exposure.

Physical examination revealed a 1-cm ulcerated plaque with rolled borders and prominent telangiectases on the mid nasal dorsum. A shave biopsy was performed to confirm the diagnosis of nodular basal cell carcinoma (BCC). The patient underwent Mohs micrographic surgery, which required repair with an advancement flap. He currently continues his active-duty service and is preparing for his next overseas deployment.

Literature Review

We conducted a review of PubMed articles indexed for MEDLINE using the search terms skin cancer, melanoma, nonmelanoma skin cancer, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, Merkel cell carcinoma, dermatofibrosarcoma protuberans, or sebaceous carcinoma along with military, Army, Navy, Air Force, or veterans. Studies from January 1984 to April 2020 were included in our qualitative review. All articles were reviewed, and those that did not examine skin cancer and the military population in the United States were excluded. Relevant data, such as results of skin cancer incidence or risk factors or insights about developing skin cancer in this affected population, were extracted from the selected publications.

Several studies showed overall increased age-adjusted incidence rates of melanoma and NMSC among military service personnel compared to age-matched controls in the general population.² A survey of draft-age men during World War II found a slightly higher percentage of respondents with history of melanoma compared to the control group (83% [74/89] vs 76% [49/65]). Of those who had a history of melanoma, 34% (30/89) served in the tropics compared to 6% (4/65) in the control group.³ A tumor registry review found the age-adjusted melanoma incidence rates per 100,000 person-years for White individuals in the military vs the general population was 33.6 vs 27.5 among those aged 45 to 49 years, 49.8 vs 32.2 among those aged 50 to 54 years, and 178.5 vs 39.2 among those aged 55 to 59 years.⁴ Among published literature reviews, members of the US Air Force (USAF) had the highest rates of melanoma compared to other military branches, with an incidence rate of 7.6 vs 6.3 among USAF males vs Army males and 9.0 vs 5.5 among USAF females vs Army females.⁴ These findings were further supported by another study showing a higher incidence rate of melanoma in USAF members compared to Army personnel (17.8 vs 9.5) and a 62% greater melanoma incidence in active-duty military personnel compared to the general population when adjusted for age, race, sex, and year of diagnosis.⁵ Additionally, a meta-analysis reported a standardized incidence ratio of 1.4 (95% CI, 1.1-1.9) for malignant melanoma and 1.8 (95% CI, 1.3-2.8) for NMSC among military pilots compared to the general population.⁶ It is important to note that these data are limited to published peer-reviewed studies within PubMed and may not reflect the true skin cancer incidence.

More comprehensive studies are needed to compare NMSC incidence rates in nonpilot military populations compared to the general population. From 2005 to 2014, the average annual NMSC incidence rate in the USAF was 64.4 per 100,000 person-years, with the highest rate at 97.4 per 100,000 person-years in 2007.⁷ However, this study did not directly compare military service members to the general population. Service in tropical environments among World War II veterans was associated with an increased risk for NMSC. Sixty-six percent of patients with BCC (n=197) and 68% with squamous cell carcinoma (SCC)(n=41) were stationed in the Pacific, despite the number and demographics of soldiers deployed to the Pacific and Europe being approximately equal.⁸ During a 6-month period in 2008, a Combat Dermatology Clinic in Iraq showed 5% (n=129) of visits were for treatment of actinic keratoses (AKs), while 8% of visits (n=205) were related to skin cancer, including BCC, SCC, mycosis fungoides, and melanoma.⁹ Overall, these studies confirm a higher rate of melanoma in military service members vs the general population and indicate USAF members may be at the greatest risk for developing melanoma and NMSC among the service branches. Further studies are needed to elucidate why this might be the case and should concentrate on demographics, service locations, uniform wear and personal protective equipment standards, and use of sun-protective measures across each service branch.

Our search yielded no aggregate studies to determine if there is an increased rate of other types of skin cancer in military service members such as Merkel cell carcinoma, dermatofibrosarcoma protuberans, and microcystic adnexal carcinoma (MAC). Gerall et al¹⁰ described a case of MAC in a 43-year-old USAF U-2 pilot with a 15-year history of a slow-growing soft-tissue nodule on the cheek. The patient’s young age differed from the typical age of MAC occurrence (ie, 60–70 years), which led to the possibility that his profession contributed to the development of MAC and the relatively young age of onset.¹⁰

Etiology of Disease

The results of our literature review indicated that skin cancers are more prevalent among active-duty military personnel and veterans than in the general population; they also suggest that frequent sun exposure and lack of sun protection may be key etiologic factors. In 2015, only 23% of veterans (n=49) reported receiving skin cancer awareness education from the US Military.¹ Among soldiers returning from Iraq and Afghanistan (n=212), only 13% reported routine sunscreen use, and less than 30% reported having routine access to sunscreen while working more than 4 hours per day in direct sunlight or 75% of the day working in direct sunlight. Of these, the majority reported sustaining at least 1 sunburn, while 43% had at least 2 sunburns and 20% reported a history of a blistering sunburn during deployment.¹ The intermittent exposure hypothesis—defined as the theory that intense periods of exposure to UV radiation increase the risk for melanoma more than chronic cumulative UV radiation exposure—may explain how occupational exposure in the military may lead to increased skin cancer incidence. Individuals exposed to brief periods of intense, inconsistent, or unpredictable UV radiation may lack protective adaptive mechanisms compared to those who are chronically exposed.²

Exposure to UV radiation at higher altitudes (with corresponding higher UV energy) and altered sleep-wake cycles (with resulting altered immune defenses) may contribute to higher rates of melanoma and NMSC among USAF pilots.¹¹ During a 57-minute flight at 30,000-ft altitude, a pilot is exposed to a UVA dose equivalent to 20 minutes inside a tanning booth.¹² Although UVB transmission through plastic and glass windshields was reported to be less than 1%, UVA transmission ranged from 0.4% to 53.5%. The UVA dose for a pilot flying a light aircraft in Las Vegas, Nevada, was reported to be 127 μW/cm² at ground level vs 242 μW/cm² at a 30,000-ft altitude.¹² Therefore, cosmic radiation exposure for military pilots is higher than for commercial pilots, as they fly at higher altitudes. U-2 pilots are exposed to 20 times the cosmic radiation dose at sea level and 10 times the exposure of commercial pilots.¹⁰

It currently is unknown why service in the USAF would increase skin cancer risk compared to service in other branches; however, there are some differences between military branches that require further research, including ethnic demographics, uniform wear and personal protective equipment standards, duty assignment locations, and the hours the military members are asked to work outside with direct sunlight exposure for each branch of service. Environmental exposures may differ based on the military branch gear requirements; for example, when on the flight line or flight deck, USN aircrews are required to wear cranials (helmets), eyewear (visor or goggles), and long-sleeved shirts. When at sea, USN flight crews wear gloves, headgear, goggles, pants, and long-sleeved shirts to identify their duty onboard. All of these measures offer good sun protection and are carried over to the land-based flight lines in the USN and Marine Corps. Neither the Army nor the USAF commonly utilize these practices. Conversely, the USAF does not allow flight line workers including fuelers, maintainers, and aircrew to wear coveralls due to the risk of being blown off, becoming foreign object debris, and being sucked into jet engines. However, in-flight protective gear such as goggles, gloves, and coveralls are worn.¹² Perhaps the USAF may attract, recruit, or commission people with inherently more risk for skin cancer (eg, White individuals). How racial and ethnic factors may affect skin cancer incidence in military branches is an area for future research efforts.

Recommendations

Given the considerable increase in risk factors, efforts are needed to reduce the disparity in skin cancer rates between US military personnel and their civilian counterparts through appropriate prevention, screening, and intervention programs.

Prevention—In wartime settings as well as in training and other peacetime activities, active-duty military members cannot avoid harmful midday sun exposure. Additionally, application and reapplication of sunscreen can be challenging. Sunscreen, broad-spectrum lip balm, and wide-brimmed “boonie” hats can be ordered by supply personnel.¹³ We recommend that a standard sunscreen supply be available to all active-duty military service members. The long-sleeved, tightly woven fabric of military uniforms also can provide protection from the sun but can be difficult to tolerate for extended periods of time in warm climates. Breathable, lightweight, sun-protective clothing is commercially available and could be incorporated into military uniforms.

All service members should be educated about skin cancer risks while addressing common myths and inaccuracies. Fifty percent (n=50) of surveyed veterans thought discussions of skin cancer prevention and safety during basic training could help prevent skin cancer in service members.¹⁴ Suggestions from respondents included education about sun exposure consequences, use of graphic images of skin cancer in teaching, providing protective clothing and sunscreen to active-duty military service members, and discussion about sun protection with physicians during annual physicals. When veterans with a history of skin cancer were surveyed about their personal risk for skin cancer, most believed they were at little risk (average perceived risk response score, 2.2 out of 5 [1=no risk; 5=high risk]).¹⁴ The majority explained that they did not seek sun protection after warnings of skin cancer risk because they did not think skin cancer would happen to them,¹⁴ though the incidence of NMSC in the United States at the time of these surveys was estimated to be 3.5 million per year.^14,15 Another study found that only 13% of veterans knew the back is the most common site of melanoma in men.¹ The Army Public Health Center has informational fact sheets available online or in dermatologists’ offices that detail correct sunscreen application techniques and how to reduce sun exposure.^16,17 However, military service members reported that they prefer physicians to communicate with them directly about skin cancer risks vs reading brochures in physician offices or gaining information from television, radio, military training, or the Internet (4.4 out 5 rating for communication methods of risks associated with skin cancer [1=ineffective; 5=very effective]).¹⁴ However, only 27% of nondermatologist physicians counseled or screened their patients on skin cancer or sunscreen yearly, 49% even less frequently, with 24% never counseling or screening at all. Because not all service members may be able to regularly see a dermatologist, efforts should be focused on increasing primary care physician awareness on counseling and screening.¹⁸

Early Detection—Military service members should be educated on how to perform skin self-examinations to alert their providers earlier to concerning lesions. The American Academy of Dermatology publishes infographics regarding the ABCDEs of melanoma and how to perform skin self-examinations.^19,20 Although the US Preventive Services Task Force concluded there was insufficient evidence to recommend skin self-examination for all adults, the increased risk that military service members and veterans have requires further studies to examine the utility of self-screening in this population.²⁰ Given the evidence of a higher incidence of melanoma in military service members vs the general population after 45 years of age,⁴ we recommend starting yearly in-person screenings performed by primary care physicians or dermatologists at this age. Ensuring every service member has routine in-office skin examinations can be difficult given the limited number of active-duty military dermatologists. Civilian dermatologists also could be helpful in this respect.

Teleconsultation, teledermoscopy, or store-and-forward imaging services for concerning lesions could be utilized when in-person consultations with a dermatologist are not feasible or cannot be performed in a timely manner. From 2004 to 2012, 40% of 10,817 teleconsultations were dermatology consultations from deployed or remote environments.²¹ Teleconsultation can be performed via email through the global military teleconsultation portal.²² These methods can lead to earlier detection of skin cancer rather than delaying evaluation for an in-person consultation.²³

Intervention—High-risk patients who have been diagnosed with NMSC or many AKs should consider oral, procedural, or topical chemoprevention to reduce the risk for additional skin cancers as both primary and secondary prevention. In a double-blind, randomized, controlled trial of 386 individuals with a history of 2 or more NMSCs, participants were randomly assigned to receive either 500 mg of nicotinamide twice daily or placebo for 12 months. Compared to the placebo group, the nicotinamide group had a 23% lower rate of new NMSCs and an 11% lower rate of new AKs at 12 months.²⁴ The use of acitretin also has been studied in transplant recipients for the chemoprevention of NMSC. In a double-blind, randomized, controlled trial of renal transplant recipients with more than 10 AKs randomized to receive either 30 mg/d of acitretin or placebo for 6 months, 11% of the acitretin group reported a new NMSC compared to 47% in the placebo group.²⁵ An open-label study of 27 renal transplant recipients treated with methyl-esterified aminolevulinic acid–photodynamic therapy and red light demonstrated an increased mean time to occurrence of an AK, SCC, BCC, keratoacanthoma, or wart from 6.8 months in untreated areas compared to 9.6 months in treated areas.²⁵ In active-duty locations where access to red and blue light sources is unavailable, the use of daylight photodynamic therapy can be considered, as it does not require any special equipment. Topical treatments such as 5-fluorouracil and imiquimod can be used for treatment and chemoprevention of NMSC. In a follow-up study from the Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial, patients who applied 5-fluorouracil cream 5% twice daily to the face and ears for 4 weeks had a 75% risk reduction in developing SCC requiring surgery compared to the control group for the first year after treatment.^26,27

Final Thoughts

Focusing on the efforts we propose can help the US Military expand their prevention, screening, and intervention programs for skin cancer in service members. Further research can then be performed to determine which programs have the greatest impact on rates of skin cancer among military and veteran personnel. Given these higher incidences and risk of exposure for skin cancer among service members, the various services may consider mandating sunscreen use as part of the uniform to prevent skin cancer. To maximize effectiveness, these efforts to prevent the development of skin cancer among military and veteran personnel should be adopted nationally.

Occupational sun exposure is a well-known risk factor for the development of melanoma and nonmelanoma skin cancer (NMSC). In addition to sun exposure, US military personnel may face other risk factors such as lack of access to adequate sun protection, work in equatorial latitudes, and increased exposure to carcinogens. In one study, fewer than 30% of surveyed soldiers reported regular sunscreen use during deployment and reported the face, neck, and upper extremities were unprotected at least 70% of the time.¹ Skin cancer risk factors that are more common in military service members include inadequate sunscreen access, insufficient sun protection, harsh weather conditions, more immediate safety concerns than sun protection, and male gender. A higher incidence of melanoma and NMSC has been correlated with the more common demographics of US veterans such as male sex, older age, and White race.²

Although not uncommon in both civilian and military populations, we present the case of a military service member who developed skin cancer at an early age potentially due to occupational sun exposure. We also provide a review of the literature to examine the risk factors and incidence of melanoma and NMSC in US military personnel and veterans and provide recommendations for skin cancer prevention, screening, and intervention in the military population.

Case Report

A 37-year-old White active-duty male service member in the US Navy (USN) presented with a nonhealing lesion on the nose of 2 years’ duration that had been gradually growing and bleeding for several weeks. He participated in several sea deployments while onboard a naval destroyer over his 10-year military career. He did not routinely use sunscreen during his deployments. His personal and family medical history lacked risk factors for skin cancer other than his skin tone and frequent sun exposure.

Physical examination revealed a 1-cm ulcerated plaque with rolled borders and prominent telangiectases on the mid nasal dorsum. A shave biopsy was performed to confirm the diagnosis of nodular basal cell carcinoma (BCC). The patient underwent Mohs micrographic surgery, which required repair with an advancement flap. He currently continues his active-duty service and is preparing for his next overseas deployment.

Literature Review

We conducted a review of PubMed articles indexed for MEDLINE using the search terms skin cancer, melanoma, nonmelanoma skin cancer, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, Merkel cell carcinoma, dermatofibrosarcoma protuberans, or sebaceous carcinoma along with military, Army, Navy, Air Force, or veterans. Studies from January 1984 to April 2020 were included in our qualitative review. All articles were reviewed, and those that did not examine skin cancer and the military population in the United States were excluded. Relevant data, such as results of skin cancer incidence or risk factors or insights about developing skin cancer in this affected population, were extracted from the selected publications.

Several studies showed overall increased age-adjusted incidence rates of melanoma and NMSC among military service personnel compared to age-matched controls in the general population.² A survey of draft-age men during World War II found a slightly higher percentage of respondents with history of melanoma compared to the control group (83% [74/89] vs 76% [49/65]). Of those who had a history of melanoma, 34% (30/89) served in the tropics compared to 6% (4/65) in the control group.³ A tumor registry review found the age-adjusted melanoma incidence rates per 100,000 person-years for White individuals in the military vs the general population was 33.6 vs 27.5 among those aged 45 to 49 years, 49.8 vs 32.2 among those aged 50 to 54 years, and 178.5 vs 39.2 among those aged 55 to 59 years.⁴ Among published literature reviews, members of the US Air Force (USAF) had the highest rates of melanoma compared to other military branches, with an incidence rate of 7.6 vs 6.3 among USAF males vs Army males and 9.0 vs 5.5 among USAF females vs Army females.⁴ These findings were further supported by another study showing a higher incidence rate of melanoma in USAF members compared to Army personnel (17.8 vs 9.5) and a 62% greater melanoma incidence in active-duty military personnel compared to the general population when adjusted for age, race, sex, and year of diagnosis.⁵ Additionally, a meta-analysis reported a standardized incidence ratio of 1.4 (95% CI, 1.1-1.9) for malignant melanoma and 1.8 (95% CI, 1.3-2.8) for NMSC among military pilots compared to the general population.⁶ It is important to note that these data are limited to published peer-reviewed studies within PubMed and may not reflect the true skin cancer incidence.

More comprehensive studies are needed to compare NMSC incidence rates in nonpilot military populations compared to the general population. From 2005 to 2014, the average annual NMSC incidence rate in the USAF was 64.4 per 100,000 person-years, with the highest rate at 97.4 per 100,000 person-years in 2007.⁷ However, this study did not directly compare military service members to the general population. Service in tropical environments among World War II veterans was associated with an increased risk for NMSC. Sixty-six percent of patients with BCC (n=197) and 68% with squamous cell carcinoma (SCC)(n=41) were stationed in the Pacific, despite the number and demographics of soldiers deployed to the Pacific and Europe being approximately equal.⁸ During a 6-month period in 2008, a Combat Dermatology Clinic in Iraq showed 5% (n=129) of visits were for treatment of actinic keratoses (AKs), while 8% of visits (n=205) were related to skin cancer, including BCC, SCC, mycosis fungoides, and melanoma.⁹ Overall, these studies confirm a higher rate of melanoma in military service members vs the general population and indicate USAF members may be at the greatest risk for developing melanoma and NMSC among the service branches. Further studies are needed to elucidate why this might be the case and should concentrate on demographics, service locations, uniform wear and personal protective equipment standards, and use of sun-protective measures across each service branch.

Our search yielded no aggregate studies to determine if there is an increased rate of other types of skin cancer in military service members such as Merkel cell carcinoma, dermatofibrosarcoma protuberans, and microcystic adnexal carcinoma (MAC). Gerall et al¹⁰ described a case of MAC in a 43-year-old USAF U-2 pilot with a 15-year history of a slow-growing soft-tissue nodule on the cheek. The patient’s young age differed from the typical age of MAC occurrence (ie, 60–70 years), which led to the possibility that his profession contributed to the development of MAC and the relatively young age of onset.¹⁰

Etiology of Disease

The results of our literature review indicated that skin cancers are more prevalent among active-duty military personnel and veterans than in the general population; they also suggest that frequent sun exposure and lack of sun protection may be key etiologic factors. In 2015, only 23% of veterans (n=49) reported receiving skin cancer awareness education from the US Military.¹ Among soldiers returning from Iraq and Afghanistan (n=212), only 13% reported routine sunscreen use, and less than 30% reported having routine access to sunscreen while working more than 4 hours per day in direct sunlight or 75% of the day working in direct sunlight. Of these, the majority reported sustaining at least 1 sunburn, while 43% had at least 2 sunburns and 20% reported a history of a blistering sunburn during deployment.¹ The intermittent exposure hypothesis—defined as the theory that intense periods of exposure to UV radiation increase the risk for melanoma more than chronic cumulative UV radiation exposure—may explain how occupational exposure in the military may lead to increased skin cancer incidence. Individuals exposed to brief periods of intense, inconsistent, or unpredictable UV radiation may lack protective adaptive mechanisms compared to those who are chronically exposed.²

Exposure to UV radiation at higher altitudes (with corresponding higher UV energy) and altered sleep-wake cycles (with resulting altered immune defenses) may contribute to higher rates of melanoma and NMSC among USAF pilots.¹¹ During a 57-minute flight at 30,000-ft altitude, a pilot is exposed to a UVA dose equivalent to 20 minutes inside a tanning booth.¹² Although UVB transmission through plastic and glass windshields was reported to be less than 1%, UVA transmission ranged from 0.4% to 53.5%. The UVA dose for a pilot flying a light aircraft in Las Vegas, Nevada, was reported to be 127 μW/cm² at ground level vs 242 μW/cm² at a 30,000-ft altitude.¹² Therefore, cosmic radiation exposure for military pilots is higher than for commercial pilots, as they fly at higher altitudes. U-2 pilots are exposed to 20 times the cosmic radiation dose at sea level and 10 times the exposure of commercial pilots.¹⁰

It currently is unknown why service in the USAF would increase skin cancer risk compared to service in other branches; however, there are some differences between military branches that require further research, including ethnic demographics, uniform wear and personal protective equipment standards, duty assignment locations, and the hours the military members are asked to work outside with direct sunlight exposure for each branch of service. Environmental exposures may differ based on the military branch gear requirements; for example, when on the flight line or flight deck, USN aircrews are required to wear cranials (helmets), eyewear (visor or goggles), and long-sleeved shirts. When at sea, USN flight crews wear gloves, headgear, goggles, pants, and long-sleeved shirts to identify their duty onboard. All of these measures offer good sun protection and are carried over to the land-based flight lines in the USN and Marine Corps. Neither the Army nor the USAF commonly utilize these practices. Conversely, the USAF does not allow flight line workers including fuelers, maintainers, and aircrew to wear coveralls due to the risk of being blown off, becoming foreign object debris, and being sucked into jet engines. However, in-flight protective gear such as goggles, gloves, and coveralls are worn.¹² Perhaps the USAF may attract, recruit, or commission people with inherently more risk for skin cancer (eg, White individuals). How racial and ethnic factors may affect skin cancer incidence in military branches is an area for future research efforts.

Recommendations

Given the considerable increase in risk factors, efforts are needed to reduce the disparity in skin cancer rates between US military personnel and their civilian counterparts through appropriate prevention, screening, and intervention programs.

Prevention—In wartime settings as well as in training and other peacetime activities, active-duty military members cannot avoid harmful midday sun exposure. Additionally, application and reapplication of sunscreen can be challenging. Sunscreen, broad-spectrum lip balm, and wide-brimmed “boonie” hats can be ordered by supply personnel.¹³ We recommend that a standard sunscreen supply be available to all active-duty military service members. The long-sleeved, tightly woven fabric of military uniforms also can provide protection from the sun but can be difficult to tolerate for extended periods of time in warm climates. Breathable, lightweight, sun-protective clothing is commercially available and could be incorporated into military uniforms.

All service members should be educated about skin cancer risks while addressing common myths and inaccuracies. Fifty percent (n=50) of surveyed veterans thought discussions of skin cancer prevention and safety during basic training could help prevent skin cancer in service members.¹⁴ Suggestions from respondents included education about sun exposure consequences, use of graphic images of skin cancer in teaching, providing protective clothing and sunscreen to active-duty military service members, and discussion about sun protection with physicians during annual physicals. When veterans with a history of skin cancer were surveyed about their personal risk for skin cancer, most believed they were at little risk (average perceived risk response score, 2.2 out of 5 [1=no risk; 5=high risk]).¹⁴ The majority explained that they did not seek sun protection after warnings of skin cancer risk because they did not think skin cancer would happen to them,¹⁴ though the incidence of NMSC in the United States at the time of these surveys was estimated to be 3.5 million per year.^14,15 Another study found that only 13% of veterans knew the back is the most common site of melanoma in men.¹ The Army Public Health Center has informational fact sheets available online or in dermatologists’ offices that detail correct sunscreen application techniques and how to reduce sun exposure.^16,17 However, military service members reported that they prefer physicians to communicate with them directly about skin cancer risks vs reading brochures in physician offices or gaining information from television, radio, military training, or the Internet (4.4 out 5 rating for communication methods of risks associated with skin cancer [1=ineffective; 5=very effective]).¹⁴ However, only 27% of nondermatologist physicians counseled or screened their patients on skin cancer or sunscreen yearly, 49% even less frequently, with 24% never counseling or screening at all. Because not all service members may be able to regularly see a dermatologist, efforts should be focused on increasing primary care physician awareness on counseling and screening.¹⁸

Early Detection—Military service members should be educated on how to perform skin self-examinations to alert their providers earlier to concerning lesions. The American Academy of Dermatology publishes infographics regarding the ABCDEs of melanoma and how to perform skin self-examinations.^19,20 Although the US Preventive Services Task Force concluded there was insufficient evidence to recommend skin self-examination for all adults, the increased risk that military service members and veterans have requires further studies to examine the utility of self-screening in this population.²⁰ Given the evidence of a higher incidence of melanoma in military service members vs the general population after 45 years of age,⁴ we recommend starting yearly in-person screenings performed by primary care physicians or dermatologists at this age. Ensuring every service member has routine in-office skin examinations can be difficult given the limited number of active-duty military dermatologists. Civilian dermatologists also could be helpful in this respect.

Teleconsultation, teledermoscopy, or store-and-forward imaging services for concerning lesions could be utilized when in-person consultations with a dermatologist are not feasible or cannot be performed in a timely manner. From 2004 to 2012, 40% of 10,817 teleconsultations were dermatology consultations from deployed or remote environments.²¹ Teleconsultation can be performed via email through the global military teleconsultation portal.²² These methods can lead to earlier detection of skin cancer rather than delaying evaluation for an in-person consultation.²³

Intervention—High-risk patients who have been diagnosed with NMSC or many AKs should consider oral, procedural, or topical chemoprevention to reduce the risk for additional skin cancers as both primary and secondary prevention. In a double-blind, randomized, controlled trial of 386 individuals with a history of 2 or more NMSCs, participants were randomly assigned to receive either 500 mg of nicotinamide twice daily or placebo for 12 months. Compared to the placebo group, the nicotinamide group had a 23% lower rate of new NMSCs and an 11% lower rate of new AKs at 12 months.²⁴ The use of acitretin also has been studied in transplant recipients for the chemoprevention of NMSC. In a double-blind, randomized, controlled trial of renal transplant recipients with more than 10 AKs randomized to receive either 30 mg/d of acitretin or placebo for 6 months, 11% of the acitretin group reported a new NMSC compared to 47% in the placebo group.²⁵ An open-label study of 27 renal transplant recipients treated with methyl-esterified aminolevulinic acid–photodynamic therapy and red light demonstrated an increased mean time to occurrence of an AK, SCC, BCC, keratoacanthoma, or wart from 6.8 months in untreated areas compared to 9.6 months in treated areas.²⁵ In active-duty locations where access to red and blue light sources is unavailable, the use of daylight photodynamic therapy can be considered, as it does not require any special equipment. Topical treatments such as 5-fluorouracil and imiquimod can be used for treatment and chemoprevention of NMSC. In a follow-up study from the Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial, patients who applied 5-fluorouracil cream 5% twice daily to the face and ears for 4 weeks had a 75% risk reduction in developing SCC requiring surgery compared to the control group for the first year after treatment.^26,27

Final Thoughts

Focusing on the efforts we propose can help the US Military expand their prevention, screening, and intervention programs for skin cancer in service members. Further research can then be performed to determine which programs have the greatest impact on rates of skin cancer among military and veteran personnel. Given these higher incidences and risk of exposure for skin cancer among service members, the various services may consider mandating sunscreen use as part of the uniform to prevent skin cancer. To maximize effectiveness, these efforts to prevent the development of skin cancer among military and veteran personnel should be adopted nationally.

Occupational sun exposure is a well-known risk factor for the development of melanoma and nonmelanoma skin cancer (NMSC). In addition to sun exposure, US military personnel may face other risk factors such as lack of access to adequate sun protection, work in equatorial latitudes, and increased exposure to carcinogens. In one study, fewer than 30% of surveyed soldiers reported regular sunscreen use during deployment and reported the face, neck, and upper extremities were unprotected at least 70% of the time.¹ Skin cancer risk factors that are more common in military service members include inadequate sunscreen access, insufficient sun protection, harsh weather conditions, more immediate safety concerns than sun protection, and male gender. A higher incidence of melanoma and NMSC has been correlated with the more common demographics of US veterans such as male sex, older age, and White race.²

Although not uncommon in both civilian and military populations, we present the case of a military service member who developed skin cancer at an early age potentially due to occupational sun exposure. We also provide a review of the literature to examine the risk factors and incidence of melanoma and NMSC in US military personnel and veterans and provide recommendations for skin cancer prevention, screening, and intervention in the military population.

Case Report

A 37-year-old White active-duty male service member in the US Navy (USN) presented with a nonhealing lesion on the nose of 2 years’ duration that had been gradually growing and bleeding for several weeks. He participated in several sea deployments while onboard a naval destroyer over his 10-year military career. He did not routinely use sunscreen during his deployments. His personal and family medical history lacked risk factors for skin cancer other than his skin tone and frequent sun exposure.

Physical examination revealed a 1-cm ulcerated plaque with rolled borders and prominent telangiectases on the mid nasal dorsum. A shave biopsy was performed to confirm the diagnosis of nodular basal cell carcinoma (BCC). The patient underwent Mohs micrographic surgery, which required repair with an advancement flap. He currently continues his active-duty service and is preparing for his next overseas deployment.

Literature Review

We conducted a review of PubMed articles indexed for MEDLINE using the search terms skin cancer, melanoma, nonmelanoma skin cancer, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, Merkel cell carcinoma, dermatofibrosarcoma protuberans, or sebaceous carcinoma along with military, Army, Navy, Air Force, or veterans. Studies from January 1984 to April 2020 were included in our qualitative review. All articles were reviewed, and those that did not examine skin cancer and the military population in the United States were excluded. Relevant data, such as results of skin cancer incidence or risk factors or insights about developing skin cancer in this affected population, were extracted from the selected publications.

Several studies showed overall increased age-adjusted incidence rates of melanoma and NMSC among military service personnel compared to age-matched controls in the general population.² A survey of draft-age men during World War II found a slightly higher percentage of respondents with history of melanoma compared to the control group (83% [74/89] vs 76% [49/65]). Of those who had a history of melanoma, 34% (30/89) served in the tropics compared to 6% (4/65) in the control group.³ A tumor registry review found the age-adjusted melanoma incidence rates per 100,000 person-years for White individuals in the military vs the general population was 33.6 vs 27.5 among those aged 45 to 49 years, 49.8 vs 32.2 among those aged 50 to 54 years, and 178.5 vs 39.2 among those aged 55 to 59 years.⁴ Among published literature reviews, members of the US Air Force (USAF) had the highest rates of melanoma compared to other military branches, with an incidence rate of 7.6 vs 6.3 among USAF males vs Army males and 9.0 vs 5.5 among USAF females vs Army females.⁴ These findings were further supported by another study showing a higher incidence rate of melanoma in USAF members compared to Army personnel (17.8 vs 9.5) and a 62% greater melanoma incidence in active-duty military personnel compared to the general population when adjusted for age, race, sex, and year of diagnosis.⁵ Additionally, a meta-analysis reported a standardized incidence ratio of 1.4 (95% CI, 1.1-1.9) for malignant melanoma and 1.8 (95% CI, 1.3-2.8) for NMSC among military pilots compared to the general population.⁶ It is important to note that these data are limited to published peer-reviewed studies within PubMed and may not reflect the true skin cancer incidence.

More comprehensive studies are needed to compare NMSC incidence rates in nonpilot military populations compared to the general population. From 2005 to 2014, the average annual NMSC incidence rate in the USAF was 64.4 per 100,000 person-years, with the highest rate at 97.4 per 100,000 person-years in 2007.⁷ However, this study did not directly compare military service members to the general population. Service in tropical environments among World War II veterans was associated with an increased risk for NMSC. Sixty-six percent of patients with BCC (n=197) and 68% with squamous cell carcinoma (SCC)(n=41) were stationed in the Pacific, despite the number and demographics of soldiers deployed to the Pacific and Europe being approximately equal.⁸ During a 6-month period in 2008, a Combat Dermatology Clinic in Iraq showed 5% (n=129) of visits were for treatment of actinic keratoses (AKs), while 8% of visits (n=205) were related to skin cancer, including BCC, SCC, mycosis fungoides, and melanoma.⁹ Overall, these studies confirm a higher rate of melanoma in military service members vs the general population and indicate USAF members may be at the greatest risk for developing melanoma and NMSC among the service branches. Further studies are needed to elucidate why this might be the case and should concentrate on demographics, service locations, uniform wear and personal protective equipment standards, and use of sun-protective measures across each service branch.

Our search yielded no aggregate studies to determine if there is an increased rate of other types of skin cancer in military service members such as Merkel cell carcinoma, dermatofibrosarcoma protuberans, and microcystic adnexal carcinoma (MAC). Gerall et al¹⁰ described a case of MAC in a 43-year-old USAF U-2 pilot with a 15-year history of a slow-growing soft-tissue nodule on the cheek. The patient’s young age differed from the typical age of MAC occurrence (ie, 60–70 years), which led to the possibility that his profession contributed to the development of MAC and the relatively young age of onset.¹⁰

Etiology of Disease

The results of our literature review indicated that skin cancers are more prevalent among active-duty military personnel and veterans than in the general population; they also suggest that frequent sun exposure and lack of sun protection may be key etiologic factors. In 2015, only 23% of veterans (n=49) reported receiving skin cancer awareness education from the US Military.¹ Among soldiers returning from Iraq and Afghanistan (n=212), only 13% reported routine sunscreen use, and less than 30% reported having routine access to sunscreen while working more than 4 hours per day in direct sunlight or 75% of the day working in direct sunlight. Of these, the majority reported sustaining at least 1 sunburn, while 43% had at least 2 sunburns and 20% reported a history of a blistering sunburn during deployment.¹ The intermittent exposure hypothesis—defined as the theory that intense periods of exposure to UV radiation increase the risk for melanoma more than chronic cumulative UV radiation exposure—may explain how occupational exposure in the military may lead to increased skin cancer incidence. Individuals exposed to brief periods of intense, inconsistent, or unpredictable UV radiation may lack protective adaptive mechanisms compared to those who are chronically exposed.²

Exposure to UV radiation at higher altitudes (with corresponding higher UV energy) and altered sleep-wake cycles (with resulting altered immune defenses) may contribute to higher rates of melanoma and NMSC among USAF pilots.¹¹ During a 57-minute flight at 30,000-ft altitude, a pilot is exposed to a UVA dose equivalent to 20 minutes inside a tanning booth.¹² Although UVB transmission through plastic and glass windshields was reported to be less than 1%, UVA transmission ranged from 0.4% to 53.5%. The UVA dose for a pilot flying a light aircraft in Las Vegas, Nevada, was reported to be 127 μW/cm² at ground level vs 242 μW/cm² at a 30,000-ft altitude.¹² Therefore, cosmic radiation exposure for military pilots is higher than for commercial pilots, as they fly at higher altitudes. U-2 pilots are exposed to 20 times the cosmic radiation dose at sea level and 10 times the exposure of commercial pilots.¹⁰

It currently is unknown why service in the USAF would increase skin cancer risk compared to service in other branches; however, there are some differences between military branches that require further research, including ethnic demographics, uniform wear and personal protective equipment standards, duty assignment locations, and the hours the military members are asked to work outside with direct sunlight exposure for each branch of service. Environmental exposures may differ based on the military branch gear requirements; for example, when on the flight line or flight deck, USN aircrews are required to wear cranials (helmets), eyewear (visor or goggles), and long-sleeved shirts. When at sea, USN flight crews wear gloves, headgear, goggles, pants, and long-sleeved shirts to identify their duty onboard. All of these measures offer good sun protection and are carried over to the land-based flight lines in the USN and Marine Corps. Neither the Army nor the USAF commonly utilize these practices. Conversely, the USAF does not allow flight line workers including fuelers, maintainers, and aircrew to wear coveralls due to the risk of being blown off, becoming foreign object debris, and being sucked into jet engines. However, in-flight protective gear such as goggles, gloves, and coveralls are worn.¹² Perhaps the USAF may attract, recruit, or commission people with inherently more risk for skin cancer (eg, White individuals). How racial and ethnic factors may affect skin cancer incidence in military branches is an area for future research efforts.

Recommendations

Given the considerable increase in risk factors, efforts are needed to reduce the disparity in skin cancer rates between US military personnel and their civilian counterparts through appropriate prevention, screening, and intervention programs.

Prevention—In wartime settings as well as in training and other peacetime activities, active-duty military members cannot avoid harmful midday sun exposure. Additionally, application and reapplication of sunscreen can be challenging. Sunscreen, broad-spectrum lip balm, and wide-brimmed “boonie” hats can be ordered by supply personnel.¹³ We recommend that a standard sunscreen supply be available to all active-duty military service members. The long-sleeved, tightly woven fabric of military uniforms also can provide protection from the sun but can be difficult to tolerate for extended periods of time in warm climates. Breathable, lightweight, sun-protective clothing is commercially available and could be incorporated into military uniforms.

All service members should be educated about skin cancer risks while addressing common myths and inaccuracies. Fifty percent (n=50) of surveyed veterans thought discussions of skin cancer prevention and safety during basic training could help prevent skin cancer in service members.¹⁴ Suggestions from respondents included education about sun exposure consequences, use of graphic images of skin cancer in teaching, providing protective clothing and sunscreen to active-duty military service members, and discussion about sun protection with physicians during annual physicals. When veterans with a history of skin cancer were surveyed about their personal risk for skin cancer, most believed they were at little risk (average perceived risk response score, 2.2 out of 5 [1=no risk; 5=high risk]).¹⁴ The majority explained that they did not seek sun protection after warnings of skin cancer risk because they did not think skin cancer would happen to them,¹⁴ though the incidence of NMSC in the United States at the time of these surveys was estimated to be 3.5 million per year.^14,15 Another study found that only 13% of veterans knew the back is the most common site of melanoma in men.¹ The Army Public Health Center has informational fact sheets available online or in dermatologists’ offices that detail correct sunscreen application techniques and how to reduce sun exposure.^16,17 However, military service members reported that they prefer physicians to communicate with them directly about skin cancer risks vs reading brochures in physician offices or gaining information from television, radio, military training, or the Internet (4.4 out 5 rating for communication methods of risks associated with skin cancer [1=ineffective; 5=very effective]).¹⁴ However, only 27% of nondermatologist physicians counseled or screened their patients on skin cancer or sunscreen yearly, 49% even less frequently, with 24% never counseling or screening at all. Because not all service members may be able to regularly see a dermatologist, efforts should be focused on increasing primary care physician awareness on counseling and screening.¹⁸

Early Detection—Military service members should be educated on how to perform skin self-examinations to alert their providers earlier to concerning lesions. The American Academy of Dermatology publishes infographics regarding the ABCDEs of melanoma and how to perform skin self-examinations.^19,20 Although the US Preventive Services Task Force concluded there was insufficient evidence to recommend skin self-examination for all adults, the increased risk that military service members and veterans have requires further studies to examine the utility of self-screening in this population.²⁰ Given the evidence of a higher incidence of melanoma in military service members vs the general population after 45 years of age,⁴ we recommend starting yearly in-person screenings performed by primary care physicians or dermatologists at this age. Ensuring every service member has routine in-office skin examinations can be difficult given the limited number of active-duty military dermatologists. Civilian dermatologists also could be helpful in this respect.

Teleconsultation, teledermoscopy, or store-and-forward imaging services for concerning lesions could be utilized when in-person consultations with a dermatologist are not feasible or cannot be performed in a timely manner. From 2004 to 2012, 40% of 10,817 teleconsultations were dermatology consultations from deployed or remote environments.²¹ Teleconsultation can be performed via email through the global military teleconsultation portal.²² These methods can lead to earlier detection of skin cancer rather than delaying evaluation for an in-person consultation.²³

Intervention—High-risk patients who have been diagnosed with NMSC or many AKs should consider oral, procedural, or topical chemoprevention to reduce the risk for additional skin cancers as both primary and secondary prevention. In a double-blind, randomized, controlled trial of 386 individuals with a history of 2 or more NMSCs, participants were randomly assigned to receive either 500 mg of nicotinamide twice daily or placebo for 12 months. Compared to the placebo group, the nicotinamide group had a 23% lower rate of new NMSCs and an 11% lower rate of new AKs at 12 months.²⁴ The use of acitretin also has been studied in transplant recipients for the chemoprevention of NMSC. In a double-blind, randomized, controlled trial of renal transplant recipients with more than 10 AKs randomized to receive either 30 mg/d of acitretin or placebo for 6 months, 11% of the acitretin group reported a new NMSC compared to 47% in the placebo group.²⁵ An open-label study of 27 renal transplant recipients treated with methyl-esterified aminolevulinic acid–photodynamic therapy and red light demonstrated an increased mean time to occurrence of an AK, SCC, BCC, keratoacanthoma, or wart from 6.8 months in untreated areas compared to 9.6 months in treated areas.²⁵ In active-duty locations where access to red and blue light sources is unavailable, the use of daylight photodynamic therapy can be considered, as it does not require any special equipment. Topical treatments such as 5-fluorouracil and imiquimod can be used for treatment and chemoprevention of NMSC. In a follow-up study from the Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial, patients who applied 5-fluorouracil cream 5% twice daily to the face and ears for 4 weeks had a 75% risk reduction in developing SCC requiring surgery compared to the control group for the first year after treatment.^26,27

Final Thoughts

Focusing on the efforts we propose can help the US Military expand their prevention, screening, and intervention programs for skin cancer in service members. Further research can then be performed to determine which programs have the greatest impact on rates of skin cancer among military and veteran personnel. Given these higher incidences and risk of exposure for skin cancer among service members, the various services may consider mandating sunscreen use as part of the uniform to prevent skin cancer. To maximize effectiveness, these efforts to prevent the development of skin cancer among military and veteran personnel should be adopted nationally.

The incidence of cutaneous melanoma in the United States has increased in the last 30 years, with the American Cancer Society estimating that 99,780 new melanomas will be diagnosed and 7650 melanoma-related deaths will occur in 2022.¹ Patients with melanoma have an increased risk for developing a second primary melanoma or other malignancy, such as salivary gland, small intestine, breast, prostate, renal, or thyroid cancer, but most commonly nonmelanoma skin cancer.^2,3 The incidence rate of melanoma among residents of Olmsted County, Minnesota, from 1970 through 2009 has already been described for various age groups^4-7; however, the incidence of a second primary malignancy, including melanoma, within these incident cohorts remains unknown.

Mutations in the BRAF oncogene occur in approximately 50% of melanomas.^8,9They cause downstream activation of the mitogen-activated protein kinase signaling pathway, stimulating growth in melanoma cell lines.¹⁰BRAF mutations also occur in hairy cell leukemia, papillary thyroid cancers, colorectal cancers, liver cancers, gliomas, lung cancers, sarcomas, ovarian cancers, and breast cancers, with incidence rates varying from 2% to 100%.^9,11,12 V600E is the most common somatic BRAF mutation (>90%) and is linked to survival in melanoma.¹³ Targeted therapies with small-molecule BRAF and MEK inhibitors have notably improved survival of patients with advanced or metastatic disease,¹⁴ and molecular testing for BRAF mutations is routinely recommended for patients with advanced melanoma.

Although the BRAF mutation event in melanoma is sporadic and should not necessarily affect the development of an unrelated malignancy, we hypothesized that the exposures that may have predisposed a particular individual to a BRAF-mutated melanoma also may have a higher chance of predisposing that individual to the development of another primary malignancy. In this population-based study, we aimed to determine whether the specific melanoma feature of mutant BRAF V600E expression was associated with the development of a second primary malignancy.

Methods

This study was approved by the institutional review boards of the Mayo Clinic and Olmsted Medical Center (both in Rochester, Minnesota). The reporting of this study is compliant with the Strengthening the Reporting of Observational Studies in Epidemiology statement.¹⁵

Patient Selection and BRAF Assessment—The Rochester Epidemiology Project (REP) links comprehensive health care records for virtually all residents of Olmsted County, Minnesota, across different medical providers. The REP provides an index of diagnostic and therapeutic procedures, tracks timelines and outcomes of individuals and their medical conditions, and is ideal for population-based studies. Since its inception in 1966, the REP has provided the resource for more than 2000 peer-reviewed publications.^16,17

We obtained a list of all residents of Olmsted County aged 18 to 60 years who had a melanoma diagnosed according to the International Classification of Diseases, Ninth Revision, from January 1, 1970, through December 30, 2009; these cohorts have been analyzed previously.^4-7 Of the 638 individuals identified, 380 had a melanoma tissue block on file at Mayo Clinic with enough tumor present in available tissue blocks for BRAF assessment. All specimens were reviewed by a board-certified dermatopathologist (J.S.L.) to confirm the diagnosis of melanoma. Tissue blocks were recut, and formalin-fixed, paraffin-embedded tissue sections were stained for BRAF V600E (Spring Bioscience Corporation). BRAF-stained specimens and the associated hematoxylin and eosin−stained slides were reviewed. Melanocyte cytoplasmic staining for BRAF was graded as negative if no staining was evident. BRAF was graded as positive if focal or partial staining was observed (<50% of tumor or low BRAF expression) or if diffuse staining was evident (>50% of tumor or high BRAF expression).

Using resources of the REP, we confirmed patients’ residency status in Olmsted County at the time of diagnosis of the incident melanoma. Patients who denied access to their medical records for research purposes were excluded. We used the complete record of each patient to confirm the date of diagnosis of the incident melanoma. Baseline characteristics of patients and their incident melanomas (eg, anatomic site and pathologic stage according to the American Joint Committee on Cancer classification) were obtained. When only the Clark level was included in the dermatopathology report, the corresponding Breslow thickness was extrapolated from the Clark level,¹⁸ and the pathologic stage according to the American Joint Committee on Cancer classification (7th edition) was determined.

For our study, specific diagnostic codes—International Classification of Diseases, Ninth and Tenth Revisions; Hospital International Classification of Diseases Adaptation¹⁹; and Berkson¹⁶—were applied across individual records to identify all second primary malignancies using the resources of the REP. The diagnosis date, morphology, and anatomic location of second primary malignancies were confirmed from examination of the clinical records. For squamous cell carcinomas and basal cell carcinomas (BCCs), of which multiple tumors could potentially occur in a single patient, the dates of the earliest squamous cell carcinomas and BCCs that occurred before and after the incident melanoma were used. For second primary malignancies, the biopsy date was used as the diagnosis date, except for a few patients who presented with such advanced-stage cancer that the diagnosis was ascertained by clinical examination and radiologic imaging alone.

Statistical Analysis—Baseline characteristics were compared by BRAF V600E expression using Wilcoxon rank sum and χ² tests. The rate of developing a second primary malignancy at 5, 10, 15, and 20 years after the incident malignant melanoma was estimated with the Kaplan-Meier method. The duration of follow-up was calculated from the incident melanoma date to the second primary malignancy date or the last follow-up date. Patients with a history of the malignancy of interest, except skin cancers, before the incident melanoma date were excluded because it was not possible to distinguish between recurrence of a prior malignancy and a second primary malignancy. Associations of BRAF V600E expression with the development of a second primary malignancy were evaluated with Cox proportional hazards regression models and summarized with hazard ratios (HRs) and 95% CIs; all associations were adjusted for potential confounders such as age at the incident melanoma, year of the incident melanoma, and sex.

Results

Demographics—Table 1 shows the demographic and melanoma-specific characteristics of the 380 patients evaluated for mutant BRAF V600E expression. At last follow-up, 48 patients had died at a median (interquartile range [IQR]) of 6.7 (1.7–14.0) years after the incident melanoma. The median (IQR) duration of follow-up for the 332 living patients was 11.8 (9.1–18.3) years. Three hundred seventy-eight (99%) patients were White. One hundred thirty-three (35%) and 247 (65%) patients were confirmed to have BRAF V600E–positive and BRAF V600E–negative melanomas, respectively.

Cumulative Incidence of Second Primary Melanoma—Of 133 patients with positive BRAF V600E expression, we identified 14 (10.5%), 1 (0.8%), and 1 (0.8%) who had 1, 2, and 4 subsequent melanomas, respectively. Of the 247 patients with negative BRAF V600E expression, we identified 15 (6%), 4 (1.6%), 2 (0.8%), and 1 (0.4%) patients who had 1, 2, 3, and 4 subsequent melanomas, respectively; BRAF V600E expression was not associated with the number of subsequent melanomas (P=.37; Wilcoxon rank sum test). The cumulative incidences of developing a second primary melanoma (n=38 among the 380 patients studied) at 5, 10, 15, and 20 years after the incident melanoma were 5.3%, 7.6%, 8.1%, and 14.6%, respectively.

Cumulative Incidence of All Second Primary Malignancies—Of the 380 patients studied, 60 (16%) had at least 1 malignancy diagnosed before the incident melanoma. Of the remaining 320 patients, 104 later had at least 1 malignancy develop, including a second primary melanoma, at a median (IQR) of 8.0 (2.7–16.2) years after the incident melanoma; the 104 patients with at least 1 subsequent malignancy included 40 with BRAF-positive and 64 with BRAF-negative melanomas. The cumulative incidences of developing at least 1 malignancy of any kind at 5, 10, 15, and 20 years after the incident melanoma were 15.0%, 20.5%, 31.2%, and 47.0%, respectively. Table 2 shows the number of patients with at least 1 second primary malignancy after the incident melanoma stratified by BRAF status.

BRAF V600E Expression and Association With Second Primary Malignancy—The eTable shows the associations of mutant BRAF V600E expression status with the development of a new primary malignancy. Malignancies affecting fewer than 10 patients were excluded from the analysis because there were too few events to support the Cox model. Positive BRAF V600E expression was associated with subsequent development of BCCs (HR, 2.32; 95% CI, 1.35-3.99; P=.002) and the development of all combined second primary malignancies excluding melanoma (HR, 1.65; 95% CI, 1.06-2.56; P=.03). However, BRAF V600E status was no longer a significant factor when all second primary malignancies, including second melanomas, were considered (P=.06). Table 3 shows the 5-, 10-, 15-, and 20-year cumulative incidences of all second primary malignancies according to mutant BRAF status.

Comment

Association of BRAF V600E Expression With Second Primary Malignancies—BRAF V600E expression of an incident melanoma was associated with the development of all combined second primary malignancies excluding melanoma; however, this association was not statistically significant when second primary melanomas were included. A possible explanation is that individuals with more than 1 primary melanoma possess additional genetic risk—CDKN2A or CDKN4 gene mutations or MC1R variation—that outweighed the effect of BRAF expression in the statistical analysis.

The 5- and 10-year cumulative incidences of all second primary malignancies excluding second primary melanoma were similar between BRAF-positive and BRAF-negative melanoma, but the 15- and 20-year cumulative incidences were greater for the BRAF-positive cohort. This could reflect the association of BRAF expression with BCCs and the increased likelihood of their occurrence with cumulative sun exposure and advancing age. BRAF expression was associated with the development of BCCs, but the reason for this association was unclear. BRAF-mutated melanoma occurs more frequently on sun-protected sites,²⁰ whereas sporadic BCC generally occurs on sun-exposed sites. However, BRAF-mutated melanoma is associated with high levels of ambient UV exposure early in life, particularly birth through 20 years of age,²¹ and we speculate that such early UV exposure influences the later development of BCCs. The lack of an association between BRAF positivity and the development of other specific cancers is possibly because the mutation is somatic and not inherited or germline, as with the CDKN2A mutation, and/or because of the small size of our cohorts.

Development of BRAF-Mutated Cancers—It currently is not understood why the same somatic mutation can cause different types of cancer. A recent translational research study showed that in mice models, precursor cells of the pancreas and bile duct responded differently when exposed to PIK3CA and KRAS oncogenes, and tumorigenesis is influenced by specific cooperating genetic events in the tissue microenvironment. Future research investigating these molecular interactions may lead to better understanding of cancer pathogenesis and direct the design of new targeted therapies.^22,23

Regarding environmental influences on the development of BRAF-mutated cancers, we found 1 population-based study that identified an association between high iodine content of drinking water and the prevalence of T1799A BRAF papillary thyroid carcinoma in 5 regions in China.²⁴ Another study identified an increased risk for colorectal cancer and nonmelanoma skin cancer in the first-degree relatives of index patients with BRAF V600E colorectal cancer.²⁵ Two studies by institutions in China and Sweden reported the frequency of BRAF mutations in cohorts of patients with melanoma.^26,27

Additional studies investigating a possible association between BRAF-mutated melanoma and other cancers with larger numbers of participants than in our study may become more feasible in the future with increased routine genetic testing of biopsied cancers.

Study Limitations—Limitations of this retrospective epidemiologic study include the possibility of ascertainment bias during data collection. We did not account for known risk factors for cancer (eg, excessive sun exposure, smoking). The Olmsted County population is mostly White, and residents have relatively easy access to health care; these factors should be considered when generalizing the results to other populations. Basal cell carcinomas are common skin cancers, and there may be other risk factors influencing the development of BCCs in our cohort. BRAF mutation analysis was available in only a small number of patients (n=380; aged 18–60 years), which would have reduced our capacity to identify statistically significant associations. A positive BRAF result did not differentiate between high and low expression levels, but expression levels may affect patient outcomes. One study showed that high BRAF expression correlated with significantly poorer overall (P=.009) and disease-specific 5-year survival (P=.007) for 232 patients with primary melanoma.²⁸

The main clinical implications from this study are that we do not have enough evidence to recommend BRAF testing for all incident melanomas, and BRAF-mutated melanomas cannot be associated with increased risk for developing other forms of cancer, with the possible exception of BCCs. Future research should assess BRAF mutation status of any second primary malignancies that arise after an incident BRAF-positive melanoma.

Conclusion

Physicians should be aware of the risk for a second primary malignancy after an incident melanoma, and we emphasize the importance of long-term cancer surveillance. The association between BRAF expression in incident melanomas and a higher rate of BCC development may provide indirect evidence that high levels of UV light exposure in early life can increase the risk for BCCs later. Although BRAF mutations occur in several nonmelanoma cancers, further studies are needed to determine whether BRAF tissue expression in melanoma affects the development of other cancers.

Acknowledgment—We thank Ms. Jayne H. Feind (Rochester, Minnesota) for assistance with study coordination.

The incidence of cutaneous melanoma in the United States has increased in the last 30 years, with the American Cancer Society estimating that 99,780 new melanomas will be diagnosed and 7650 melanoma-related deaths will occur in 2022.¹ Patients with melanoma have an increased risk for developing a second primary melanoma or other malignancy, such as salivary gland, small intestine, breast, prostate, renal, or thyroid cancer, but most commonly nonmelanoma skin cancer.^2,3 The incidence rate of melanoma among residents of Olmsted County, Minnesota, from 1970 through 2009 has already been described for various age groups^4-7; however, the incidence of a second primary malignancy, including melanoma, within these incident cohorts remains unknown.

Mutations in the BRAF oncogene occur in approximately 50% of melanomas.^8,9They cause downstream activation of the mitogen-activated protein kinase signaling pathway, stimulating growth in melanoma cell lines.¹⁰BRAF mutations also occur in hairy cell leukemia, papillary thyroid cancers, colorectal cancers, liver cancers, gliomas, lung cancers, sarcomas, ovarian cancers, and breast cancers, with incidence rates varying from 2% to 100%.^9,11,12 V600E is the most common somatic BRAF mutation (>90%) and is linked to survival in melanoma.¹³ Targeted therapies with small-molecule BRAF and MEK inhibitors have notably improved survival of patients with advanced or metastatic disease,¹⁴ and molecular testing for BRAF mutations is routinely recommended for patients with advanced melanoma.

Although the BRAF mutation event in melanoma is sporadic and should not necessarily affect the development of an unrelated malignancy, we hypothesized that the exposures that may have predisposed a particular individual to a BRAF-mutated melanoma also may have a higher chance of predisposing that individual to the development of another primary malignancy. In this population-based study, we aimed to determine whether the specific melanoma feature of mutant BRAF V600E expression was associated with the development of a second primary malignancy.

Methods

This study was approved by the institutional review boards of the Mayo Clinic and Olmsted Medical Center (both in Rochester, Minnesota). The reporting of this study is compliant with the Strengthening the Reporting of Observational Studies in Epidemiology statement.¹⁵

Patient Selection and BRAF Assessment—The Rochester Epidemiology Project (REP) links comprehensive health care records for virtually all residents of Olmsted County, Minnesota, across different medical providers. The REP provides an index of diagnostic and therapeutic procedures, tracks timelines and outcomes of individuals and their medical conditions, and is ideal for population-based studies. Since its inception in 1966, the REP has provided the resource for more than 2000 peer-reviewed publications.^16,17

We obtained a list of all residents of Olmsted County aged 18 to 60 years who had a melanoma diagnosed according to the International Classification of Diseases, Ninth Revision, from January 1, 1970, through December 30, 2009; these cohorts have been analyzed previously.^4-7 Of the 638 individuals identified, 380 had a melanoma tissue block on file at Mayo Clinic with enough tumor present in available tissue blocks for BRAF assessment. All specimens were reviewed by a board-certified dermatopathologist (J.S.L.) to confirm the diagnosis of melanoma. Tissue blocks were recut, and formalin-fixed, paraffin-embedded tissue sections were stained for BRAF V600E (Spring Bioscience Corporation). BRAF-stained specimens and the associated hematoxylin and eosin−stained slides were reviewed. Melanocyte cytoplasmic staining for BRAF was graded as negative if no staining was evident. BRAF was graded as positive if focal or partial staining was observed (<50% of tumor or low BRAF expression) or if diffuse staining was evident (>50% of tumor or high BRAF expression).

Using resources of the REP, we confirmed patients’ residency status in Olmsted County at the time of diagnosis of the incident melanoma. Patients who denied access to their medical records for research purposes were excluded. We used the complete record of each patient to confirm the date of diagnosis of the incident melanoma. Baseline characteristics of patients and their incident melanomas (eg, anatomic site and pathologic stage according to the American Joint Committee on Cancer classification) were obtained. When only the Clark level was included in the dermatopathology report, the corresponding Breslow thickness was extrapolated from the Clark level,¹⁸ and the pathologic stage according to the American Joint Committee on Cancer classification (7th edition) was determined.

For our study, specific diagnostic codes—International Classification of Diseases, Ninth and Tenth Revisions; Hospital International Classification of Diseases Adaptation¹⁹; and Berkson¹⁶—were applied across individual records to identify all second primary malignancies using the resources of the REP. The diagnosis date, morphology, and anatomic location of second primary malignancies were confirmed from examination of the clinical records. For squamous cell carcinomas and basal cell carcinomas (BCCs), of which multiple tumors could potentially occur in a single patient, the dates of the earliest squamous cell carcinomas and BCCs that occurred before and after the incident melanoma were used. For second primary malignancies, the biopsy date was used as the diagnosis date, except for a few patients who presented with such advanced-stage cancer that the diagnosis was ascertained by clinical examination and radiologic imaging alone.

Statistical Analysis—Baseline characteristics were compared by BRAF V600E expression using Wilcoxon rank sum and χ² tests. The rate of developing a second primary malignancy at 5, 10, 15, and 20 years after the incident malignant melanoma was estimated with the Kaplan-Meier method. The duration of follow-up was calculated from the incident melanoma date to the second primary malignancy date or the last follow-up date. Patients with a history of the malignancy of interest, except skin cancers, before the incident melanoma date were excluded because it was not possible to distinguish between recurrence of a prior malignancy and a second primary malignancy. Associations of BRAF V600E expression with the development of a second primary malignancy were evaluated with Cox proportional hazards regression models and summarized with hazard ratios (HRs) and 95% CIs; all associations were adjusted for potential confounders such as age at the incident melanoma, year of the incident melanoma, and sex.

Results

Demographics—Table 1 shows the demographic and melanoma-specific characteristics of the 380 patients evaluated for mutant BRAF V600E expression. At last follow-up, 48 patients had died at a median (interquartile range [IQR]) of 6.7 (1.7–14.0) years after the incident melanoma. The median (IQR) duration of follow-up for the 332 living patients was 11.8 (9.1–18.3) years. Three hundred seventy-eight (99%) patients were White. One hundred thirty-three (35%) and 247 (65%) patients were confirmed to have BRAF V600E–positive and BRAF V600E–negative melanomas, respectively.

Cumulative Incidence of Second Primary Melanoma—Of 133 patients with positive BRAF V600E expression, we identified 14 (10.5%), 1 (0.8%), and 1 (0.8%) who had 1, 2, and 4 subsequent melanomas, respectively. Of the 247 patients with negative BRAF V600E expression, we identified 15 (6%), 4 (1.6%), 2 (0.8%), and 1 (0.4%) patients who had 1, 2, 3, and 4 subsequent melanomas, respectively; BRAF V600E expression was not associated with the number of subsequent melanomas (P=.37; Wilcoxon rank sum test). The cumulative incidences of developing a second primary melanoma (n=38 among the 380 patients studied) at 5, 10, 15, and 20 years after the incident melanoma were 5.3%, 7.6%, 8.1%, and 14.6%, respectively.

Cumulative Incidence of All Second Primary Malignancies—Of the 380 patients studied, 60 (16%) had at least 1 malignancy diagnosed before the incident melanoma. Of the remaining 320 patients, 104 later had at least 1 malignancy develop, including a second primary melanoma, at a median (IQR) of 8.0 (2.7–16.2) years after the incident melanoma; the 104 patients with at least 1 subsequent malignancy included 40 with BRAF-positive and 64 with BRAF-negative melanomas. The cumulative incidences of developing at least 1 malignancy of any kind at 5, 10, 15, and 20 years after the incident melanoma were 15.0%, 20.5%, 31.2%, and 47.0%, respectively. Table 2 shows the number of patients with at least 1 second primary malignancy after the incident melanoma stratified by BRAF status.

BRAF V600E Expression and Association With Second Primary Malignancy—The eTable shows the associations of mutant BRAF V600E expression status with the development of a new primary malignancy. Malignancies affecting fewer than 10 patients were excluded from the analysis because there were too few events to support the Cox model. Positive BRAF V600E expression was associated with subsequent development of BCCs (HR, 2.32; 95% CI, 1.35-3.99; P=.002) and the development of all combined second primary malignancies excluding melanoma (HR, 1.65; 95% CI, 1.06-2.56; P=.03). However, BRAF V600E status was no longer a significant factor when all second primary malignancies, including second melanomas, were considered (P=.06). Table 3 shows the 5-, 10-, 15-, and 20-year cumulative incidences of all second primary malignancies according to mutant BRAF status.

Comment

Association of BRAF V600E Expression With Second Primary Malignancies—BRAF V600E expression of an incident melanoma was associated with the development of all combined second primary malignancies excluding melanoma; however, this association was not statistically significant when second primary melanomas were included. A possible explanation is that individuals with more than 1 primary melanoma possess additional genetic risk—CDKN2A or CDKN4 gene mutations or MC1R variation—that outweighed the effect of BRAF expression in the statistical analysis.

The 5- and 10-year cumulative incidences of all second primary malignancies excluding second primary melanoma were similar between BRAF-positive and BRAF-negative melanoma, but the 15- and 20-year cumulative incidences were greater for the BRAF-positive cohort. This could reflect the association of BRAF expression with BCCs and the increased likelihood of their occurrence with cumulative sun exposure and advancing age. BRAF expression was associated with the development of BCCs, but the reason for this association was unclear. BRAF-mutated melanoma occurs more frequently on sun-protected sites,²⁰ whereas sporadic BCC generally occurs on sun-exposed sites. However, BRAF-mutated melanoma is associated with high levels of ambient UV exposure early in life, particularly birth through 20 years of age,²¹ and we speculate that such early UV exposure influences the later development of BCCs. The lack of an association between BRAF positivity and the development of other specific cancers is possibly because the mutation is somatic and not inherited or germline, as with the CDKN2A mutation, and/or because of the small size of our cohorts.

Development of BRAF-Mutated Cancers—It currently is not understood why the same somatic mutation can cause different types of cancer. A recent translational research study showed that in mice models, precursor cells of the pancreas and bile duct responded differently when exposed to PIK3CA and KRAS oncogenes, and tumorigenesis is influenced by specific cooperating genetic events in the tissue microenvironment. Future research investigating these molecular interactions may lead to better understanding of cancer pathogenesis and direct the design of new targeted therapies.^22,23

Regarding environmental influences on the development of BRAF-mutated cancers, we found 1 population-based study that identified an association between high iodine content of drinking water and the prevalence of T1799A BRAF papillary thyroid carcinoma in 5 regions in China.²⁴ Another study identified an increased risk for colorectal cancer and nonmelanoma skin cancer in the first-degree relatives of index patients with BRAF V600E colorectal cancer.²⁵ Two studies by institutions in China and Sweden reported the frequency of BRAF mutations in cohorts of patients with melanoma.^26,27

Additional studies investigating a possible association between BRAF-mutated melanoma and other cancers with larger numbers of participants than in our study may become more feasible in the future with increased routine genetic testing of biopsied cancers.

Study Limitations—Limitations of this retrospective epidemiologic study include the possibility of ascertainment bias during data collection. We did not account for known risk factors for cancer (eg, excessive sun exposure, smoking). The Olmsted County population is mostly White, and residents have relatively easy access to health care; these factors should be considered when generalizing the results to other populations. Basal cell carcinomas are common skin cancers, and there may be other risk factors influencing the development of BCCs in our cohort. BRAF mutation analysis was available in only a small number of patients (n=380; aged 18–60 years), which would have reduced our capacity to identify statistically significant associations. A positive BRAF result did not differentiate between high and low expression levels, but expression levels may affect patient outcomes. One study showed that high BRAF expression correlated with significantly poorer overall (P=.009) and disease-specific 5-year survival (P=.007) for 232 patients with primary melanoma.²⁸

The main clinical implications from this study are that we do not have enough evidence to recommend BRAF testing for all incident melanomas, and BRAF-mutated melanomas cannot be associated with increased risk for developing other forms of cancer, with the possible exception of BCCs. Future research should assess BRAF mutation status of any second primary malignancies that arise after an incident BRAF-positive melanoma.

Conclusion

Physicians should be aware of the risk for a second primary malignancy after an incident melanoma, and we emphasize the importance of long-term cancer surveillance. The association between BRAF expression in incident melanomas and a higher rate of BCC development may provide indirect evidence that high levels of UV light exposure in early life can increase the risk for BCCs later. Although BRAF mutations occur in several nonmelanoma cancers, further studies are needed to determine whether BRAF tissue expression in melanoma affects the development of other cancers.

Acknowledgment—We thank Ms. Jayne H. Feind (Rochester, Minnesota) for assistance with study coordination.

The incidence of cutaneous melanoma in the United States has increased in the last 30 years, with the American Cancer Society estimating that 99,780 new melanomas will be diagnosed and 7650 melanoma-related deaths will occur in 2022.¹ Patients with melanoma have an increased risk for developing a second primary melanoma or other malignancy, such as salivary gland, small intestine, breast, prostate, renal, or thyroid cancer, but most commonly nonmelanoma skin cancer.^2,3 The incidence rate of melanoma among residents of Olmsted County, Minnesota, from 1970 through 2009 has already been described for various age groups^4-7; however, the incidence of a second primary malignancy, including melanoma, within these incident cohorts remains unknown.

Mutations in the BRAF oncogene occur in approximately 50% of melanomas.^8,9They cause downstream activation of the mitogen-activated protein kinase signaling pathway, stimulating growth in melanoma cell lines.¹⁰BRAF mutations also occur in hairy cell leukemia, papillary thyroid cancers, colorectal cancers, liver cancers, gliomas, lung cancers, sarcomas, ovarian cancers, and breast cancers, with incidence rates varying from 2% to 100%.^9,11,12 V600E is the most common somatic BRAF mutation (>90%) and is linked to survival in melanoma.¹³ Targeted therapies with small-molecule BRAF and MEK inhibitors have notably improved survival of patients with advanced or metastatic disease,¹⁴ and molecular testing for BRAF mutations is routinely recommended for patients with advanced melanoma.

Although the BRAF mutation event in melanoma is sporadic and should not necessarily affect the development of an unrelated malignancy, we hypothesized that the exposures that may have predisposed a particular individual to a BRAF-mutated melanoma also may have a higher chance of predisposing that individual to the development of another primary malignancy. In this population-based study, we aimed to determine whether the specific melanoma feature of mutant BRAF V600E expression was associated with the development of a second primary malignancy.

Methods

This study was approved by the institutional review boards of the Mayo Clinic and Olmsted Medical Center (both in Rochester, Minnesota). The reporting of this study is compliant with the Strengthening the Reporting of Observational Studies in Epidemiology statement.¹⁵

Patient Selection and BRAF Assessment—The Rochester Epidemiology Project (REP) links comprehensive health care records for virtually all residents of Olmsted County, Minnesota, across different medical providers. The REP provides an index of diagnostic and therapeutic procedures, tracks timelines and outcomes of individuals and their medical conditions, and is ideal for population-based studies. Since its inception in 1966, the REP has provided the resource for more than 2000 peer-reviewed publications.^16,17

We obtained a list of all residents of Olmsted County aged 18 to 60 years who had a melanoma diagnosed according to the International Classification of Diseases, Ninth Revision, from January 1, 1970, through December 30, 2009; these cohorts have been analyzed previously.^4-7 Of the 638 individuals identified, 380 had a melanoma tissue block on file at Mayo Clinic with enough tumor present in available tissue blocks for BRAF assessment. All specimens were reviewed by a board-certified dermatopathologist (J.S.L.) to confirm the diagnosis of melanoma. Tissue blocks were recut, and formalin-fixed, paraffin-embedded tissue sections were stained for BRAF V600E (Spring Bioscience Corporation). BRAF-stained specimens and the associated hematoxylin and eosin−stained slides were reviewed. Melanocyte cytoplasmic staining for BRAF was graded as negative if no staining was evident. BRAF was graded as positive if focal or partial staining was observed (<50% of tumor or low BRAF expression) or if diffuse staining was evident (>50% of tumor or high BRAF expression).

Using resources of the REP, we confirmed patients’ residency status in Olmsted County at the time of diagnosis of the incident melanoma. Patients who denied access to their medical records for research purposes were excluded. We used the complete record of each patient to confirm the date of diagnosis of the incident melanoma. Baseline characteristics of patients and their incident melanomas (eg, anatomic site and pathologic stage according to the American Joint Committee on Cancer classification) were obtained. When only the Clark level was included in the dermatopathology report, the corresponding Breslow thickness was extrapolated from the Clark level,¹⁸ and the pathologic stage according to the American Joint Committee on Cancer classification (7th edition) was determined.

For our study, specific diagnostic codes—International Classification of Diseases, Ninth and Tenth Revisions; Hospital International Classification of Diseases Adaptation¹⁹; and Berkson¹⁶—were applied across individual records to identify all second primary malignancies using the resources of the REP. The diagnosis date, morphology, and anatomic location of second primary malignancies were confirmed from examination of the clinical records. For squamous cell carcinomas and basal cell carcinomas (BCCs), of which multiple tumors could potentially occur in a single patient, the dates of the earliest squamous cell carcinomas and BCCs that occurred before and after the incident melanoma were used. For second primary malignancies, the biopsy date was used as the diagnosis date, except for a few patients who presented with such advanced-stage cancer that the diagnosis was ascertained by clinical examination and radiologic imaging alone.

Statistical Analysis—Baseline characteristics were compared by BRAF V600E expression using Wilcoxon rank sum and χ² tests. The rate of developing a second primary malignancy at 5, 10, 15, and 20 years after the incident malignant melanoma was estimated with the Kaplan-Meier method. The duration of follow-up was calculated from the incident melanoma date to the second primary malignancy date or the last follow-up date. Patients with a history of the malignancy of interest, except skin cancers, before the incident melanoma date were excluded because it was not possible to distinguish between recurrence of a prior malignancy and a second primary malignancy. Associations of BRAF V600E expression with the development of a second primary malignancy were evaluated with Cox proportional hazards regression models and summarized with hazard ratios (HRs) and 95% CIs; all associations were adjusted for potential confounders such as age at the incident melanoma, year of the incident melanoma, and sex.

Results

Demographics—Table 1 shows the demographic and melanoma-specific characteristics of the 380 patients evaluated for mutant BRAF V600E expression. At last follow-up, 48 patients had died at a median (interquartile range [IQR]) of 6.7 (1.7–14.0) years after the incident melanoma. The median (IQR) duration of follow-up for the 332 living patients was 11.8 (9.1–18.3) years. Three hundred seventy-eight (99%) patients were White. One hundred thirty-three (35%) and 247 (65%) patients were confirmed to have BRAF V600E–positive and BRAF V600E–negative melanomas, respectively.

Cumulative Incidence of Second Primary Melanoma—Of 133 patients with positive BRAF V600E expression, we identified 14 (10.5%), 1 (0.8%), and 1 (0.8%) who had 1, 2, and 4 subsequent melanomas, respectively. Of the 247 patients with negative BRAF V600E expression, we identified 15 (6%), 4 (1.6%), 2 (0.8%), and 1 (0.4%) patients who had 1, 2, 3, and 4 subsequent melanomas, respectively; BRAF V600E expression was not associated with the number of subsequent melanomas (P=.37; Wilcoxon rank sum test). The cumulative incidences of developing a second primary melanoma (n=38 among the 380 patients studied) at 5, 10, 15, and 20 years after the incident melanoma were 5.3%, 7.6%, 8.1%, and 14.6%, respectively.

Cumulative Incidence of All Second Primary Malignancies—Of the 380 patients studied, 60 (16%) had at least 1 malignancy diagnosed before the incident melanoma. Of the remaining 320 patients, 104 later had at least 1 malignancy develop, including a second primary melanoma, at a median (IQR) of 8.0 (2.7–16.2) years after the incident melanoma; the 104 patients with at least 1 subsequent malignancy included 40 with BRAF-positive and 64 with BRAF-negative melanomas. The cumulative incidences of developing at least 1 malignancy of any kind at 5, 10, 15, and 20 years after the incident melanoma were 15.0%, 20.5%, 31.2%, and 47.0%, respectively. Table 2 shows the number of patients with at least 1 second primary malignancy after the incident melanoma stratified by BRAF status.

BRAF V600E Expression and Association With Second Primary Malignancy—The eTable shows the associations of mutant BRAF V600E expression status with the development of a new primary malignancy. Malignancies affecting fewer than 10 patients were excluded from the analysis because there were too few events to support the Cox model. Positive BRAF V600E expression was associated with subsequent development of BCCs (HR, 2.32; 95% CI, 1.35-3.99; P=.002) and the development of all combined second primary malignancies excluding melanoma (HR, 1.65; 95% CI, 1.06-2.56; P=.03). However, BRAF V600E status was no longer a significant factor when all second primary malignancies, including second melanomas, were considered (P=.06). Table 3 shows the 5-, 10-, 15-, and 20-year cumulative incidences of all second primary malignancies according to mutant BRAF status.

Comment

Association of BRAF V600E Expression With Second Primary Malignancies—BRAF V600E expression of an incident melanoma was associated with the development of all combined second primary malignancies excluding melanoma; however, this association was not statistically significant when second primary melanomas were included. A possible explanation is that individuals with more than 1 primary melanoma possess additional genetic risk—CDKN2A or CDKN4 gene mutations or MC1R variation—that outweighed the effect of BRAF expression in the statistical analysis.

The 5- and 10-year cumulative incidences of all second primary malignancies excluding second primary melanoma were similar between BRAF-positive and BRAF-negative melanoma, but the 15- and 20-year cumulative incidences were greater for the BRAF-positive cohort. This could reflect the association of BRAF expression with BCCs and the increased likelihood of their occurrence with cumulative sun exposure and advancing age. BRAF expression was associated with the development of BCCs, but the reason for this association was unclear. BRAF-mutated melanoma occurs more frequently on sun-protected sites,²⁰ whereas sporadic BCC generally occurs on sun-exposed sites. However, BRAF-mutated melanoma is associated with high levels of ambient UV exposure early in life, particularly birth through 20 years of age,²¹ and we speculate that such early UV exposure influences the later development of BCCs. The lack of an association between BRAF positivity and the development of other specific cancers is possibly because the mutation is somatic and not inherited or germline, as with the CDKN2A mutation, and/or because of the small size of our cohorts.

Development of BRAF-Mutated Cancers—It currently is not understood why the same somatic mutation can cause different types of cancer. A recent translational research study showed that in mice models, precursor cells of the pancreas and bile duct responded differently when exposed to PIK3CA and KRAS oncogenes, and tumorigenesis is influenced by specific cooperating genetic events in the tissue microenvironment. Future research investigating these molecular interactions may lead to better understanding of cancer pathogenesis and direct the design of new targeted therapies.^22,23

Regarding environmental influences on the development of BRAF-mutated cancers, we found 1 population-based study that identified an association between high iodine content of drinking water and the prevalence of T1799A BRAF papillary thyroid carcinoma in 5 regions in China.²⁴ Another study identified an increased risk for colorectal cancer and nonmelanoma skin cancer in the first-degree relatives of index patients with BRAF V600E colorectal cancer.²⁵ Two studies by institutions in China and Sweden reported the frequency of BRAF mutations in cohorts of patients with melanoma.^26,27

Additional studies investigating a possible association between BRAF-mutated melanoma and other cancers with larger numbers of participants than in our study may become more feasible in the future with increased routine genetic testing of biopsied cancers.

Study Limitations—Limitations of this retrospective epidemiologic study include the possibility of ascertainment bias during data collection. We did not account for known risk factors for cancer (eg, excessive sun exposure, smoking). The Olmsted County population is mostly White, and residents have relatively easy access to health care; these factors should be considered when generalizing the results to other populations. Basal cell carcinomas are common skin cancers, and there may be other risk factors influencing the development of BCCs in our cohort. BRAF mutation analysis was available in only a small number of patients (n=380; aged 18–60 years), which would have reduced our capacity to identify statistically significant associations. A positive BRAF result did not differentiate between high and low expression levels, but expression levels may affect patient outcomes. One study showed that high BRAF expression correlated with significantly poorer overall (P=.009) and disease-specific 5-year survival (P=.007) for 232 patients with primary melanoma.²⁸

The main clinical implications from this study are that we do not have enough evidence to recommend BRAF testing for all incident melanomas, and BRAF-mutated melanomas cannot be associated with increased risk for developing other forms of cancer, with the possible exception of BCCs. Future research should assess BRAF mutation status of any second primary malignancies that arise after an incident BRAF-positive melanoma.

Conclusion

Physicians should be aware of the risk for a second primary malignancy after an incident melanoma, and we emphasize the importance of long-term cancer surveillance. The association between BRAF expression in incident melanomas and a higher rate of BCC development may provide indirect evidence that high levels of UV light exposure in early life can increase the risk for BCCs later. Although BRAF mutations occur in several nonmelanoma cancers, further studies are needed to determine whether BRAF tissue expression in melanoma affects the development of other cancers.

Acknowledgment—We thank Ms. Jayne H. Feind (Rochester, Minnesota) for assistance with study coordination.

The US Department of Veterans Affairs (VA) has submitted an interim final rule amending its medical regulations to remove the exclusion on abortion counseling and establish exceptions to the exclusion on abortions.

With this rule, the VA will now offer veterans abortion counseling and abortions—specifically, when the life or health of the pregnant veteran would be endangered if the pregnancy were carried to term, or in cases of rape or incest. Beneficiaries enrolled in CHAMPVA will have the same access to care.

“As abortion bans come into force across the country,” the interim final rule indicates, “veterans in many states are no longer assured access to abortion services in their communities, even when those services are needed… Unless VA removes its existing prohibitions on abortion-related care and makes clear that needed abortion-related care is authorized, these veterans will face serious threats to their life and health.”

“This is a patient safety decision,” said Denis McDonough, Secretary of Veterans Affairs. “Pregnant veterans and VA beneficiaries deserve to have access to world-class reproductive care when they need it most. That’s what our nation owes them, and that’s what we at VA will deliver.”

The rule is the VA’s latest response to the June 24, 2022, Dobbs v Jackson Women’s Health Organization Supreme Court decision, which overruled Roe v Wade and Planned Parenthood of Southeastern Pennsylvania v Casey. “After Dobbs,” according to the rule summary, “certain States have begun to enforce existing abortion bans and restrictions on care, and are proposing and enacting new ones, creating urgent risks to the lives and health of pregnant veterans and CHAMPVA beneficiaries in these states.” The VA is “acting to help to ensure that, irrespective of what laws or policies States may impose” veterans will be able to receive needed care.

Restricting access to abortion care has well-documented adverse health consequences, including a higher risk of loss of future fertility, significant morbidity, or death. Veterans are also at greater risk of experiencing pregnancy-related complications due to increased rates of chronic health conditions. “We came to this decision after listening to VA health care providers and veterans across the country, who sounded the alarm that abortion restrictions are creating a medical emergency for those we serve,” said Under Secretary for Health Shereef Elnahal, MD, MBA. “Offering this care will save veterans’ health and lives, and there is nothing more important than that.”

Services will be authorized immediately after the interim final rule is published. VA is taking steps to guarantee abortion-related care anywhere in the country. VA employees, when working within the scope of their federal employment, may provide authorized services regardless of state restrictions.

The determination of whether the “life and health of the pregnant veteran would be endangered if the pregnancy were carried to term” will be made on a case-by-case basis after “careful consultation” between VA health care professionals and their patients, the VA says. In cases of rape or incest, self-reporting from a veteran or VA beneficiary will constitute sufficient evidence that an act of rape or incest occurred.

The interim final rule will be available for public comment for 30 days after it is published.

The US Department of Veterans Affairs (VA) has submitted an interim final rule amending its medical regulations to remove the exclusion on abortion counseling and establish exceptions to the exclusion on abortions.

With this rule, the VA will now offer veterans abortion counseling and abortions—specifically, when the life or health of the pregnant veteran would be endangered if the pregnancy were carried to term, or in cases of rape or incest. Beneficiaries enrolled in CHAMPVA will have the same access to care.

“As abortion bans come into force across the country,” the interim final rule indicates, “veterans in many states are no longer assured access to abortion services in their communities, even when those services are needed… Unless VA removes its existing prohibitions on abortion-related care and makes clear that needed abortion-related care is authorized, these veterans will face serious threats to their life and health.”

“This is a patient safety decision,” said Denis McDonough, Secretary of Veterans Affairs. “Pregnant veterans and VA beneficiaries deserve to have access to world-class reproductive care when they need it most. That’s what our nation owes them, and that’s what we at VA will deliver.”

The rule is the VA’s latest response to the June 24, 2022, Dobbs v Jackson Women’s Health Organization Supreme Court decision, which overruled Roe v Wade and Planned Parenthood of Southeastern Pennsylvania v Casey. “After Dobbs,” according to the rule summary, “certain States have begun to enforce existing abortion bans and restrictions on care, and are proposing and enacting new ones, creating urgent risks to the lives and health of pregnant veterans and CHAMPVA beneficiaries in these states.” The VA is “acting to help to ensure that, irrespective of what laws or policies States may impose” veterans will be able to receive needed care.

Restricting access to abortion care has well-documented adverse health consequences, including a higher risk of loss of future fertility, significant morbidity, or death. Veterans are also at greater risk of experiencing pregnancy-related complications due to increased rates of chronic health conditions. “We came to this decision after listening to VA health care providers and veterans across the country, who sounded the alarm that abortion restrictions are creating a medical emergency for those we serve,” said Under Secretary for Health Shereef Elnahal, MD, MBA. “Offering this care will save veterans’ health and lives, and there is nothing more important than that.”

Services will be authorized immediately after the interim final rule is published. VA is taking steps to guarantee abortion-related care anywhere in the country. VA employees, when working within the scope of their federal employment, may provide authorized services regardless of state restrictions.

The determination of whether the “life and health of the pregnant veteran would be endangered if the pregnancy were carried to term” will be made on a case-by-case basis after “careful consultation” between VA health care professionals and their patients, the VA says. In cases of rape or incest, self-reporting from a veteran or VA beneficiary will constitute sufficient evidence that an act of rape or incest occurred.

The interim final rule will be available for public comment for 30 days after it is published.

The US Department of Veterans Affairs (VA) has submitted an interim final rule amending its medical regulations to remove the exclusion on abortion counseling and establish exceptions to the exclusion on abortions.

With this rule, the VA will now offer veterans abortion counseling and abortions—specifically, when the life or health of the pregnant veteran would be endangered if the pregnancy were carried to term, or in cases of rape or incest. Beneficiaries enrolled in CHAMPVA will have the same access to care.

“As abortion bans come into force across the country,” the interim final rule indicates, “veterans in many states are no longer assured access to abortion services in their communities, even when those services are needed… Unless VA removes its existing prohibitions on abortion-related care and makes clear that needed abortion-related care is authorized, these veterans will face serious threats to their life and health.”

“This is a patient safety decision,” said Denis McDonough, Secretary of Veterans Affairs. “Pregnant veterans and VA beneficiaries deserve to have access to world-class reproductive care when they need it most. That’s what our nation owes them, and that’s what we at VA will deliver.”

The rule is the VA’s latest response to the June 24, 2022, Dobbs v Jackson Women’s Health Organization Supreme Court decision, which overruled Roe v Wade and Planned Parenthood of Southeastern Pennsylvania v Casey. “After Dobbs,” according to the rule summary, “certain States have begun to enforce existing abortion bans and restrictions on care, and are proposing and enacting new ones, creating urgent risks to the lives and health of pregnant veterans and CHAMPVA beneficiaries in these states.” The VA is “acting to help to ensure that, irrespective of what laws or policies States may impose” veterans will be able to receive needed care.

Restricting access to abortion care has well-documented adverse health consequences, including a higher risk of loss of future fertility, significant morbidity, or death. Veterans are also at greater risk of experiencing pregnancy-related complications due to increased rates of chronic health conditions. “We came to this decision after listening to VA health care providers and veterans across the country, who sounded the alarm that abortion restrictions are creating a medical emergency for those we serve,” said Under Secretary for Health Shereef Elnahal, MD, MBA. “Offering this care will save veterans’ health and lives, and there is nothing more important than that.”

Services will be authorized immediately after the interim final rule is published. VA is taking steps to guarantee abortion-related care anywhere in the country. VA employees, when working within the scope of their federal employment, may provide authorized services regardless of state restrictions.

The determination of whether the “life and health of the pregnant veteran would be endangered if the pregnancy were carried to term” will be made on a case-by-case basis after “careful consultation” between VA health care professionals and their patients, the VA says. In cases of rape or incest, self-reporting from a veteran or VA beneficiary will constitute sufficient evidence that an act of rape or incest occurred.

The interim final rule will be available for public comment for 30 days after it is published.

Cellulitis is an infection of the skin and skin-associated structures characterized by redness, warmth, swelling, and pain of the affected area. Cellulitis most commonly occurs in middle-aged and older adults and frequently affects the lower extremities.¹ Serious complications of cellulitis such as bacteremia, metastatic infection, and sepsis are rare, and most cases of cellulitis in patients with normal vital signs and mental status can be managed with outpatient treatment.²

Diagnosis of cellulitis can be confounded by a number of similarly presenting conditions collectively known as pseudocellulitis, such as venous stasis dermatitis and deep vein thrombosis.¹ Misdiagnosis of cellulitis is common, with rates exceeding 30% among hospitalized patients initially diagnosed with cellulitis.^3,4 Dermatology or infectious disease assessment is considered the diagnostic gold standard for cellulitis^4,5 but is not always readily available, especially in resource-constrained settings.

Most cases of uncomplicated cellulitis can be managed with outpatient treatment, especially because serious complications are rare. Frequent misdiagnosis leads to repeat or unnecessary hospitalization and antibiosis. Exceptions necessitating hospitalization usually are predicated on signs of systemic infection, severe immunocompromised states, or failure of prior outpatient therapy.⁶ Such presentations can be distinguished by corresponding notable historical or examination factors, such as vital sign abnormalities suggesting systemic infection or history of malignancy leading to an immunocompromised state.

We sought to evaluate factors leading to the diagnosis of cellulitis in a cohort of patients with uncomplicated presentations receiving dermatology consultation to emphasize findings indicative of cellulitis in the absence of clinical or historical factors suggestive of other conditions necessitating hospitalization, such as systemic infection.

Methods

Study Participants—A prospective cohort study of patients presenting to an emergency department (ED) between October 2012 and January 2017 at an urban academic medical center in Boston, Massachusetts, was conducted with approval of study design and procedures by the relevant institutional review board. Patients older than 18 years were eligible for inclusion if given an initial diagnosis of cellulitis by an ED physician. Patients were excluded if incarcerated, pregnant, or unable to provide informed consent. Other exclusion criteria includedinfections overlying temporary or permanent indwelling hardware, animal or human bites, or sites of recent surgery (within the prior 4 weeks); preceding antibiotic treatment for more than 24 hours; or clinical or radiographic evidence of complications requiring alternative management such as osteomyelitis or abscess. Patients presenting with an elevated heart rate (>100 beats per minute) or body temperature (>100.5 °F [38.1 °C]) also were excluded. Eligible patients were enrolled upon providing written informed consent, and no remuneration was offered for participation.

Dermatology Consultation Intervention—A random subset of enrolled patients received dermatology consultation within 24 hours of presentation. Consultation consisted of a patient interview and physical examination with care recommendations to relevant ED and inpatient teams. Consultations confirmed the presence or absence of cellulitis as the primary outcome and also noted the presence of any pseudocellulitis diagnoses either occurring concomitantly with or mimicking cellulitis as a secondary outcome.

Statistical Analysis—Patient characteristics were analyzed to identify factors independently associated with the diagnosis of cellulitis in cases affecting the lower extremities. Factors were recorded with categorical variables reported as counts and percentages and continuous variables as means and standard deviations. Univariate analyses between categorical variables or discretized continuous variables and cellulitis diagnosis were conducted via Fisher exact test to identify a preliminary set of potential risk factors. Continuous variables were discretized at multiple incremental values with the discretization most significantly associated with cellulitis diagnosis selected as a preliminary risk factor. Multivariate analyses involved using any objective preliminary factor meeting a significance threshold of P<.1 in univariate comparisons in a multivariate logistic regression model for prediction of cellulitis diagnosis with corresponding calculation of odds ratios with confidence intervals and receiver operating characteristic. Factors with confidence intervals that excluded 1 were considered significant independent predictors of cellulitis. Analyses were performed using Python version 3.8 (Python Software Foundation).

Of 1359 patients screened for eligibility, 104 patients with presumed lower extremity cellulitis undergoing dermatology consultation were included in this study (Figure). The mean patient age (SD) was 60.4 (19.2) years, and 63.5% of patients were male. In the study population, 63 (60.6%) patients received a final diagnosis of cellulitis. The most common pseudocellulitis diagnosis identified was venous stasis dermatitis, which occurred in 12 (11.5%) patients with concomitant cellulitis and in 12 (11.5%) patients mimicking cellulitis (Table).

Univariate comparisons revealed a diverse set of historical, examination, and laboratory factors associated with cellulitis diagnosis. Diagnosis of cellulitis was associated with unilateral presentation, recent trauma to the affected site, and history of cellulitis or onychomycosis. Diagnosis of cellulitis also was associated with elevated white blood cell count, absolute neutrophil count, C-reactive protein, body mass index, hematocrit, and platelet count; age less than 75 years; and lower serum sodium and serum chloride levels. These were the independent factors included in the multivariate analysis, which consisted of a logistic regression model for prediction of cellulitis (eTable).

Multivariate logistic regression on all preliminary factors significantly associated with cellulitis diagnosis in univariate comparisons demonstrated leukocytosis, which was defined as having a white blood cell count exceeding 11,000/μL, unilateral presentation, history of onychomycosis, and trauma to the affected site as significant independent predictors of cellulitis diagnosis; history of cellulitis approached significance (eTable). Unilateral presentation and leukocytosis were the strongest predictors; having either of these factors had a sensitivity of 93.7% and a negative predictive value of 76.5%.

Comment

Importance of Identifying Pseudocellulitis—Successful diagnosis of cellulitis can be confounded by pseudocellulitis that can present concomitantly with or in lieu of cellulitis itself. Although cellulitis mostly affects the lower extremities in adults, pseudocellulitis also was common in this study population of patients with suspected lower extremity cellulitis, occurring both as a mimicker and concomitantly with cellulitis with substantial frequency. Notably, among patients with both venous stasis dermatitis and cellulitis diagnosed, most patients (n=10/12; 83.3%) had unilateral presentations of cellulitis as evidenced by signs and symptoms more notably affecting one lower extremity than the other. These findings suggest that certain pseudocellulitis diagnoses may predispose patients to cellulitis by disrupting the skin barrier, leading to bacterial infiltration; however, these pseudocellulitis diagnoses typically affect both lower extremities equally,¹ and asymmetric involvement suggests the presence of overlying cellulitis. Furthermore, the most common pseudocellulitis entities found, such as venous stasis dermatitis, hematoma, and eczema, do not benefit from antibiotic treatment and require alternative therapy.¹ Successful discrimination of these pseudocellulitis entities is critical to bolster proper antibiotic stewardship and discourage unnecessary hospitalization.

Independent Predictors of Cellulitis—Unilateral presentation and leukocytosis each emerged as strong independent predictors of cellulitis diagnosis in this study. Having either of these factors furthermore demonstrated high sensitivity and negative predictive value for cellulitis diagnosis. Other notable risk factors were history of onychomycosis, cellulitis, and trauma to the affected site. Prior studies have identified similar historical factors as predisposing patients to cellulitis.^7-9 Interestingly, warmth of the affected area on physical examination emerged as strongly associated with cellulitis but was not included in the final predictive model because of its subjective determination. These factors may be especially important in diagnosing cellulitis in patients without concerning vital signs and with concomitant or prior pseudocellulitis.

Study Limitations—This study was limited to patients with uncomplicated presentations to emphasize discrimination of factors associated with cellulitis in the absence of suggestive signs of infection, such as vital sign abnormalities. Signs such as fever and tachypnea have been previously correlated to outpatient treatment failure and necessity for hospitalization.^10-12 This study instead focused on patients without concerning vital signs to reduce confounding by such factors in more severe presentations that heighten suspicion for infection and increase likelihood of additional treatment measures. For such patients, suggestive historical factors, such as those discovered in this study, should be considered instead. Interestingly, increased age did not emerge as a significant predictor in this population in contrast to other predictive models that included patients with vital sign abnormalities. Notably, older patients tend to have more variable vital signs, especially in response to physiologic stressors such as infection.¹³ As such, age may serve as a proxy for vital sign abnormalities to some degree in such predictive models, leading to heightened suspicion for infection in older patients. This study demonstrated that in the absence of concerning vital signs, historical rather than demographic factors are more predictive of cellulitis.

Conclusion

Unilateral presentation and leukocytosis emerged as strong independent predictors of lower extremity cellulitis in patients with uncomplicated presentations. Having either of these factors had a sensitivity of 93.7% and a negative predictive value of 76.5%. Other factors such as history of cellulitis, onychomycosis, and recent trauma to the affected site emerged as additional predictors. These historical, examination, and laboratory characteristics may be especially useful for successful diagnosis of cellulitis in varied practice settings, including outpatient clinics and EDs.

Cellulitis is an infection of the skin and skin-associated structures characterized by redness, warmth, swelling, and pain of the affected area. Cellulitis most commonly occurs in middle-aged and older adults and frequently affects the lower extremities.¹ Serious complications of cellulitis such as bacteremia, metastatic infection, and sepsis are rare, and most cases of cellulitis in patients with normal vital signs and mental status can be managed with outpatient treatment.²

Diagnosis of cellulitis can be confounded by a number of similarly presenting conditions collectively known as pseudocellulitis, such as venous stasis dermatitis and deep vein thrombosis.¹ Misdiagnosis of cellulitis is common, with rates exceeding 30% among hospitalized patients initially diagnosed with cellulitis.^3,4 Dermatology or infectious disease assessment is considered the diagnostic gold standard for cellulitis^4,5 but is not always readily available, especially in resource-constrained settings.

Most cases of uncomplicated cellulitis can be managed with outpatient treatment, especially because serious complications are rare. Frequent misdiagnosis leads to repeat or unnecessary hospitalization and antibiosis. Exceptions necessitating hospitalization usually are predicated on signs of systemic infection, severe immunocompromised states, or failure of prior outpatient therapy.⁶ Such presentations can be distinguished by corresponding notable historical or examination factors, such as vital sign abnormalities suggesting systemic infection or history of malignancy leading to an immunocompromised state.

We sought to evaluate factors leading to the diagnosis of cellulitis in a cohort of patients with uncomplicated presentations receiving dermatology consultation to emphasize findings indicative of cellulitis in the absence of clinical or historical factors suggestive of other conditions necessitating hospitalization, such as systemic infection.

Methods

Study Participants—A prospective cohort study of patients presenting to an emergency department (ED) between October 2012 and January 2017 at an urban academic medical center in Boston, Massachusetts, was conducted with approval of study design and procedures by the relevant institutional review board. Patients older than 18 years were eligible for inclusion if given an initial diagnosis of cellulitis by an ED physician. Patients were excluded if incarcerated, pregnant, or unable to provide informed consent. Other exclusion criteria includedinfections overlying temporary or permanent indwelling hardware, animal or human bites, or sites of recent surgery (within the prior 4 weeks); preceding antibiotic treatment for more than 24 hours; or clinical or radiographic evidence of complications requiring alternative management such as osteomyelitis or abscess. Patients presenting with an elevated heart rate (>100 beats per minute) or body temperature (>100.5 °F [38.1 °C]) also were excluded. Eligible patients were enrolled upon providing written informed consent, and no remuneration was offered for participation.

Dermatology Consultation Intervention—A random subset of enrolled patients received dermatology consultation within 24 hours of presentation. Consultation consisted of a patient interview and physical examination with care recommendations to relevant ED and inpatient teams. Consultations confirmed the presence or absence of cellulitis as the primary outcome and also noted the presence of any pseudocellulitis diagnoses either occurring concomitantly with or mimicking cellulitis as a secondary outcome.

Statistical Analysis—Patient characteristics were analyzed to identify factors independently associated with the diagnosis of cellulitis in cases affecting the lower extremities. Factors were recorded with categorical variables reported as counts and percentages and continuous variables as means and standard deviations. Univariate analyses between categorical variables or discretized continuous variables and cellulitis diagnosis were conducted via Fisher exact test to identify a preliminary set of potential risk factors. Continuous variables were discretized at multiple incremental values with the discretization most significantly associated with cellulitis diagnosis selected as a preliminary risk factor. Multivariate analyses involved using any objective preliminary factor meeting a significance threshold of P<.1 in univariate comparisons in a multivariate logistic regression model for prediction of cellulitis diagnosis with corresponding calculation of odds ratios with confidence intervals and receiver operating characteristic. Factors with confidence intervals that excluded 1 were considered significant independent predictors of cellulitis. Analyses were performed using Python version 3.8 (Python Software Foundation).

Of 1359 patients screened for eligibility, 104 patients with presumed lower extremity cellulitis undergoing dermatology consultation were included in this study (Figure). The mean patient age (SD) was 60.4 (19.2) years, and 63.5% of patients were male. In the study population, 63 (60.6%) patients received a final diagnosis of cellulitis. The most common pseudocellulitis diagnosis identified was venous stasis dermatitis, which occurred in 12 (11.5%) patients with concomitant cellulitis and in 12 (11.5%) patients mimicking cellulitis (Table).

Univariate comparisons revealed a diverse set of historical, examination, and laboratory factors associated with cellulitis diagnosis. Diagnosis of cellulitis was associated with unilateral presentation, recent trauma to the affected site, and history of cellulitis or onychomycosis. Diagnosis of cellulitis also was associated with elevated white blood cell count, absolute neutrophil count, C-reactive protein, body mass index, hematocrit, and platelet count; age less than 75 years; and lower serum sodium and serum chloride levels. These were the independent factors included in the multivariate analysis, which consisted of a logistic regression model for prediction of cellulitis (eTable).

Multivariate logistic regression on all preliminary factors significantly associated with cellulitis diagnosis in univariate comparisons demonstrated leukocytosis, which was defined as having a white blood cell count exceeding 11,000/μL, unilateral presentation, history of onychomycosis, and trauma to the affected site as significant independent predictors of cellulitis diagnosis; history of cellulitis approached significance (eTable). Unilateral presentation and leukocytosis were the strongest predictors; having either of these factors had a sensitivity of 93.7% and a negative predictive value of 76.5%.

Comment

Importance of Identifying Pseudocellulitis—Successful diagnosis of cellulitis can be confounded by pseudocellulitis that can present concomitantly with or in lieu of cellulitis itself. Although cellulitis mostly affects the lower extremities in adults, pseudocellulitis also was common in this study population of patients with suspected lower extremity cellulitis, occurring both as a mimicker and concomitantly with cellulitis with substantial frequency. Notably, among patients with both venous stasis dermatitis and cellulitis diagnosed, most patients (n=10/12; 83.3%) had unilateral presentations of cellulitis as evidenced by signs and symptoms more notably affecting one lower extremity than the other. These findings suggest that certain pseudocellulitis diagnoses may predispose patients to cellulitis by disrupting the skin barrier, leading to bacterial infiltration; however, these pseudocellulitis diagnoses typically affect both lower extremities equally,¹ and asymmetric involvement suggests the presence of overlying cellulitis. Furthermore, the most common pseudocellulitis entities found, such as venous stasis dermatitis, hematoma, and eczema, do not benefit from antibiotic treatment and require alternative therapy.¹ Successful discrimination of these pseudocellulitis entities is critical to bolster proper antibiotic stewardship and discourage unnecessary hospitalization.

Independent Predictors of Cellulitis—Unilateral presentation and leukocytosis each emerged as strong independent predictors of cellulitis diagnosis in this study. Having either of these factors furthermore demonstrated high sensitivity and negative predictive value for cellulitis diagnosis. Other notable risk factors were history of onychomycosis, cellulitis, and trauma to the affected site. Prior studies have identified similar historical factors as predisposing patients to cellulitis.^7-9 Interestingly, warmth of the affected area on physical examination emerged as strongly associated with cellulitis but was not included in the final predictive model because of its subjective determination. These factors may be especially important in diagnosing cellulitis in patients without concerning vital signs and with concomitant or prior pseudocellulitis.

Study Limitations—This study was limited to patients with uncomplicated presentations to emphasize discrimination of factors associated with cellulitis in the absence of suggestive signs of infection, such as vital sign abnormalities. Signs such as fever and tachypnea have been previously correlated to outpatient treatment failure and necessity for hospitalization.^10-12 This study instead focused on patients without concerning vital signs to reduce confounding by such factors in more severe presentations that heighten suspicion for infection and increase likelihood of additional treatment measures. For such patients, suggestive historical factors, such as those discovered in this study, should be considered instead. Interestingly, increased age did not emerge as a significant predictor in this population in contrast to other predictive models that included patients with vital sign abnormalities. Notably, older patients tend to have more variable vital signs, especially in response to physiologic stressors such as infection.¹³ As such, age may serve as a proxy for vital sign abnormalities to some degree in such predictive models, leading to heightened suspicion for infection in older patients. This study demonstrated that in the absence of concerning vital signs, historical rather than demographic factors are more predictive of cellulitis.

Conclusion

Unilateral presentation and leukocytosis emerged as strong independent predictors of lower extremity cellulitis in patients with uncomplicated presentations. Having either of these factors had a sensitivity of 93.7% and a negative predictive value of 76.5%. Other factors such as history of cellulitis, onychomycosis, and recent trauma to the affected site emerged as additional predictors. These historical, examination, and laboratory characteristics may be especially useful for successful diagnosis of cellulitis in varied practice settings, including outpatient clinics and EDs.

Cellulitis is an infection of the skin and skin-associated structures characterized by redness, warmth, swelling, and pain of the affected area. Cellulitis most commonly occurs in middle-aged and older adults and frequently affects the lower extremities.¹ Serious complications of cellulitis such as bacteremia, metastatic infection, and sepsis are rare, and most cases of cellulitis in patients with normal vital signs and mental status can be managed with outpatient treatment.²

Diagnosis of cellulitis can be confounded by a number of similarly presenting conditions collectively known as pseudocellulitis, such as venous stasis dermatitis and deep vein thrombosis.¹ Misdiagnosis of cellulitis is common, with rates exceeding 30% among hospitalized patients initially diagnosed with cellulitis.^3,4 Dermatology or infectious disease assessment is considered the diagnostic gold standard for cellulitis^4,5 but is not always readily available, especially in resource-constrained settings.

Most cases of uncomplicated cellulitis can be managed with outpatient treatment, especially because serious complications are rare. Frequent misdiagnosis leads to repeat or unnecessary hospitalization and antibiosis. Exceptions necessitating hospitalization usually are predicated on signs of systemic infection, severe immunocompromised states, or failure of prior outpatient therapy.⁶ Such presentations can be distinguished by corresponding notable historical or examination factors, such as vital sign abnormalities suggesting systemic infection or history of malignancy leading to an immunocompromised state.

We sought to evaluate factors leading to the diagnosis of cellulitis in a cohort of patients with uncomplicated presentations receiving dermatology consultation to emphasize findings indicative of cellulitis in the absence of clinical or historical factors suggestive of other conditions necessitating hospitalization, such as systemic infection.

Methods

Study Participants—A prospective cohort study of patients presenting to an emergency department (ED) between October 2012 and January 2017 at an urban academic medical center in Boston, Massachusetts, was conducted with approval of study design and procedures by the relevant institutional review board. Patients older than 18 years were eligible for inclusion if given an initial diagnosis of cellulitis by an ED physician. Patients were excluded if incarcerated, pregnant, or unable to provide informed consent. Other exclusion criteria includedinfections overlying temporary or permanent indwelling hardware, animal or human bites, or sites of recent surgery (within the prior 4 weeks); preceding antibiotic treatment for more than 24 hours; or clinical or radiographic evidence of complications requiring alternative management such as osteomyelitis or abscess. Patients presenting with an elevated heart rate (>100 beats per minute) or body temperature (>100.5 °F [38.1 °C]) also were excluded. Eligible patients were enrolled upon providing written informed consent, and no remuneration was offered for participation.

Dermatology Consultation Intervention—A random subset of enrolled patients received dermatology consultation within 24 hours of presentation. Consultation consisted of a patient interview and physical examination with care recommendations to relevant ED and inpatient teams. Consultations confirmed the presence or absence of cellulitis as the primary outcome and also noted the presence of any pseudocellulitis diagnoses either occurring concomitantly with or mimicking cellulitis as a secondary outcome.

Statistical Analysis—Patient characteristics were analyzed to identify factors independently associated with the diagnosis of cellulitis in cases affecting the lower extremities. Factors were recorded with categorical variables reported as counts and percentages and continuous variables as means and standard deviations. Univariate analyses between categorical variables or discretized continuous variables and cellulitis diagnosis were conducted via Fisher exact test to identify a preliminary set of potential risk factors. Continuous variables were discretized at multiple incremental values with the discretization most significantly associated with cellulitis diagnosis selected as a preliminary risk factor. Multivariate analyses involved using any objective preliminary factor meeting a significance threshold of P<.1 in univariate comparisons in a multivariate logistic regression model for prediction of cellulitis diagnosis with corresponding calculation of odds ratios with confidence intervals and receiver operating characteristic. Factors with confidence intervals that excluded 1 were considered significant independent predictors of cellulitis. Analyses were performed using Python version 3.8 (Python Software Foundation).

Of 1359 patients screened for eligibility, 104 patients with presumed lower extremity cellulitis undergoing dermatology consultation were included in this study (Figure). The mean patient age (SD) was 60.4 (19.2) years, and 63.5% of patients were male. In the study population, 63 (60.6%) patients received a final diagnosis of cellulitis. The most common pseudocellulitis diagnosis identified was venous stasis dermatitis, which occurred in 12 (11.5%) patients with concomitant cellulitis and in 12 (11.5%) patients mimicking cellulitis (Table).

Univariate comparisons revealed a diverse set of historical, examination, and laboratory factors associated with cellulitis diagnosis. Diagnosis of cellulitis was associated with unilateral presentation, recent trauma to the affected site, and history of cellulitis or onychomycosis. Diagnosis of cellulitis also was associated with elevated white blood cell count, absolute neutrophil count, C-reactive protein, body mass index, hematocrit, and platelet count; age less than 75 years; and lower serum sodium and serum chloride levels. These were the independent factors included in the multivariate analysis, which consisted of a logistic regression model for prediction of cellulitis (eTable).

Multivariate logistic regression on all preliminary factors significantly associated with cellulitis diagnosis in univariate comparisons demonstrated leukocytosis, which was defined as having a white blood cell count exceeding 11,000/μL, unilateral presentation, history of onychomycosis, and trauma to the affected site as significant independent predictors of cellulitis diagnosis; history of cellulitis approached significance (eTable). Unilateral presentation and leukocytosis were the strongest predictors; having either of these factors had a sensitivity of 93.7% and a negative predictive value of 76.5%.

Comment

Importance of Identifying Pseudocellulitis—Successful diagnosis of cellulitis can be confounded by pseudocellulitis that can present concomitantly with or in lieu of cellulitis itself. Although cellulitis mostly affects the lower extremities in adults, pseudocellulitis also was common in this study population of patients with suspected lower extremity cellulitis, occurring both as a mimicker and concomitantly with cellulitis with substantial frequency. Notably, among patients with both venous stasis dermatitis and cellulitis diagnosed, most patients (n=10/12; 83.3%) had unilateral presentations of cellulitis as evidenced by signs and symptoms more notably affecting one lower extremity than the other. These findings suggest that certain pseudocellulitis diagnoses may predispose patients to cellulitis by disrupting the skin barrier, leading to bacterial infiltration; however, these pseudocellulitis diagnoses typically affect both lower extremities equally,¹ and asymmetric involvement suggests the presence of overlying cellulitis. Furthermore, the most common pseudocellulitis entities found, such as venous stasis dermatitis, hematoma, and eczema, do not benefit from antibiotic treatment and require alternative therapy.¹ Successful discrimination of these pseudocellulitis entities is critical to bolster proper antibiotic stewardship and discourage unnecessary hospitalization.

Independent Predictors of Cellulitis—Unilateral presentation and leukocytosis each emerged as strong independent predictors of cellulitis diagnosis in this study. Having either of these factors furthermore demonstrated high sensitivity and negative predictive value for cellulitis diagnosis. Other notable risk factors were history of onychomycosis, cellulitis, and trauma to the affected site. Prior studies have identified similar historical factors as predisposing patients to cellulitis.^7-9 Interestingly, warmth of the affected area on physical examination emerged as strongly associated with cellulitis but was not included in the final predictive model because of its subjective determination. These factors may be especially important in diagnosing cellulitis in patients without concerning vital signs and with concomitant or prior pseudocellulitis.

Study Limitations—This study was limited to patients with uncomplicated presentations to emphasize discrimination of factors associated with cellulitis in the absence of suggestive signs of infection, such as vital sign abnormalities. Signs such as fever and tachypnea have been previously correlated to outpatient treatment failure and necessity for hospitalization.^10-12 This study instead focused on patients without concerning vital signs to reduce confounding by such factors in more severe presentations that heighten suspicion for infection and increase likelihood of additional treatment measures. For such patients, suggestive historical factors, such as those discovered in this study, should be considered instead. Interestingly, increased age did not emerge as a significant predictor in this population in contrast to other predictive models that included patients with vital sign abnormalities. Notably, older patients tend to have more variable vital signs, especially in response to physiologic stressors such as infection.¹³ As such, age may serve as a proxy for vital sign abnormalities to some degree in such predictive models, leading to heightened suspicion for infection in older patients. This study demonstrated that in the absence of concerning vital signs, historical rather than demographic factors are more predictive of cellulitis.

Conclusion

Unilateral presentation and leukocytosis emerged as strong independent predictors of lower extremity cellulitis in patients with uncomplicated presentations. Having either of these factors had a sensitivity of 93.7% and a negative predictive value of 76.5%. Other factors such as history of cellulitis, onychomycosis, and recent trauma to the affected site emerged as additional predictors. These historical, examination, and laboratory characteristics may be especially useful for successful diagnosis of cellulitis in varied practice settings, including outpatient clinics and EDs.

Black Americans who go to church and pray regularly have better cardiovascular health than Black Americans who are not as religious or have no religious beliefs, according to a new study.

The study, published in the Journal of the American Heart Association, used survey responses and health screenings for 2,967 African Americans in and around Jackson, Mich.

Those who attended religious services frequently were 15% more likely to achieve an intermediate or ideal cardiovascular health score, based on criteria from the AHA.

Those who prayed privately regularly had a 12% increase in the chances of achieving an intermediate or ideal AHA metric for diet. Those who said they used “religious coping” were 14% more likely to have good cardiovascular health.

The study’s lead author, cardiologist LaPrincess C. Brewer, MD, of the Mayo Clinic in Rochester, Minn., said the results were somewhat surprising because diet, physical activity, and smoking are extremely difficult to change.

People in the study were grouped by their self-reported levels of spirituality, meaning belief in the existence of a supreme being, and how often they went to church services, prayed in private, and used religion to cope with stressful events and the challenges of life.

They were then grouped according to the health factors in the AHA’s Life’s Simple 7 (diet, physical activity, nicotine exposure, weight, cholesterol, blood pressure, and blood sugar levels). The association changed the Simple 7 to the Essential 8 last June, adding sleep.

Dr. Brewer said the study may help doctors better treat Black Americans, who, statistics show, tend to have poorer overall cardiovascular health than non-Hispanic White people. Death rates from heart disease are higher for Black Americans than white adults.

“Our findings highlight the substantial role that culturally tailored health promotion initiatives and recommendations for lifestyle change may play in advancing health equity,” Dr. Brewer said in a news release. “The cultural relevance of interventions may increase their likelihood of influencing cardiovascular health and also the sustainability and maintenance of healthy lifestyle changes.”

A version of this article first appeared on WebMD.com.

Black Americans who go to church and pray regularly have better cardiovascular health than Black Americans who are not as religious or have no religious beliefs, according to a new study.

The study, published in the Journal of the American Heart Association, used survey responses and health screenings for 2,967 African Americans in and around Jackson, Mich.

Those who attended religious services frequently were 15% more likely to achieve an intermediate or ideal cardiovascular health score, based on criteria from the AHA.

Those who prayed privately regularly had a 12% increase in the chances of achieving an intermediate or ideal AHA metric for diet. Those who said they used “religious coping” were 14% more likely to have good cardiovascular health.

The study’s lead author, cardiologist LaPrincess C. Brewer, MD, of the Mayo Clinic in Rochester, Minn., said the results were somewhat surprising because diet, physical activity, and smoking are extremely difficult to change.

People in the study were grouped by their self-reported levels of spirituality, meaning belief in the existence of a supreme being, and how often they went to church services, prayed in private, and used religion to cope with stressful events and the challenges of life.

They were then grouped according to the health factors in the AHA’s Life’s Simple 7 (diet, physical activity, nicotine exposure, weight, cholesterol, blood pressure, and blood sugar levels). The association changed the Simple 7 to the Essential 8 last June, adding sleep.

Dr. Brewer said the study may help doctors better treat Black Americans, who, statistics show, tend to have poorer overall cardiovascular health than non-Hispanic White people. Death rates from heart disease are higher for Black Americans than white adults.

“Our findings highlight the substantial role that culturally tailored health promotion initiatives and recommendations for lifestyle change may play in advancing health equity,” Dr. Brewer said in a news release. “The cultural relevance of interventions may increase their likelihood of influencing cardiovascular health and also the sustainability and maintenance of healthy lifestyle changes.”

A version of this article first appeared on WebMD.com.

Black Americans who go to church and pray regularly have better cardiovascular health than Black Americans who are not as religious or have no religious beliefs, according to a new study.

The study, published in the Journal of the American Heart Association, used survey responses and health screenings for 2,967 African Americans in and around Jackson, Mich.

Those who attended religious services frequently were 15% more likely to achieve an intermediate or ideal cardiovascular health score, based on criteria from the AHA.

Those who prayed privately regularly had a 12% increase in the chances of achieving an intermediate or ideal AHA metric for diet. Those who said they used “religious coping” were 14% more likely to have good cardiovascular health.

The study’s lead author, cardiologist LaPrincess C. Brewer, MD, of the Mayo Clinic in Rochester, Minn., said the results were somewhat surprising because diet, physical activity, and smoking are extremely difficult to change.

People in the study were grouped by their self-reported levels of spirituality, meaning belief in the existence of a supreme being, and how often they went to church services, prayed in private, and used religion to cope with stressful events and the challenges of life.

They were then grouped according to the health factors in the AHA’s Life’s Simple 7 (diet, physical activity, nicotine exposure, weight, cholesterol, blood pressure, and blood sugar levels). The association changed the Simple 7 to the Essential 8 last June, adding sleep.

Dr. Brewer said the study may help doctors better treat Black Americans, who, statistics show, tend to have poorer overall cardiovascular health than non-Hispanic White people. Death rates from heart disease are higher for Black Americans than white adults.

“Our findings highlight the substantial role that culturally tailored health promotion initiatives and recommendations for lifestyle change may play in advancing health equity,” Dr. Brewer said in a news release. “The cultural relevance of interventions may increase their likelihood of influencing cardiovascular health and also the sustainability and maintenance of healthy lifestyle changes.”

A version of this article first appeared on WebMD.com.

Health literacy is a multifaceted construct that encompasses the knowledge of health and health systems, utilization of information related to health, and ability to maintain health.¹ Low health literacy impairs health outcomes, disproportionately affecting socioeconomically disadvantaged populations, including racial minorities and the older population. Consistently, it is associated with fewer vaccinations and screenings, higher health care utilization, and poorer ability to take medications or interpret health information.²

With growing utilization of the Internet for health information,³ much patient education now occurs outside the clinic. Differential utilization of the Internet can exacerbate disparities in health outcomes: people with a lower family income more frequently engage in health information and dialogue online.³ Despite opportunities to improve literacy and narrow gaps in care, a lack of awareness, advocacy, and funding limit patient- and community-based initiatives. Herein, we discuss health literacy challenges in dermatology, offer potential solutions, and propose ways that stakeholders can prioritize health literacy advocacy to improve outcomes.

The Importance of Health Literacy in Dermatology

Dermatology patients often face challenges that demand greater health literacy. Active participation in health promotion, protection, and maintenance can remarkably improve outcomes. When patients understand disease pathogenesis and the rationale behind treatment choices, adherence to a treatment regimen might improve.

However, understanding dermatologic diseases and disorders can be challenging. First, many are chronic inflammatory conditions that require intricate treatment regimens. Second, the complexity of those diseases and disorders continues to grow in the era of new research and unprecedented expansion of treatment options.

For chronic conditions that require ongoing complex management, researchers have developed advanced patient tools. For instance, the eczema action plan helps atopic dermatitis patients manage conditions from home.⁴ However, patients with greater literacy and the ability to participate will better utilize such tools and have fewer uncontrolled flares. Patient tools meant to improve outcomes might, instead, widen gaps in care. Even with nonchronic conditions, such as nonmelanoma skin cancer, continued awareness and the need for preventive care, timely diagnosis, and appropriate intervention remain critical.

Limited Accessibility of Patient Education Materials

Patient education in dermatology occurs through several formats. Because online health resources are more readily available to those with less access to health care, the potential for such resources to narrow health disparities is immense. However, online resources have not adequately taken advantage of the opportunity to make health information openly accessible to its users. The readability of online patient education materials on a large expanse of dermatologic conditions is far too advanced.⁵ The readability level of some resources is as high as 17th grade (graduate school), which is much higher than the American Medical Association recommendation⁶ that patient education materials be presented at a 6th-grade level or less. Furthermore, the quality and comprehensiveness of content is highly variable. Rather than serving as an equalizer, the Internet may widen the gap as low health literacy continues to impair the accessibility of health information.

Solutions to Level the Playing Field

What can be done to increase the readability of patient education materials? Leveling the playing field begins with creating materials at an appropriate readability level, including online content, printed handouts, and after-visit summaries in the clinic. Writers of patient education materials should be cognizant of their choice of language and routinely use a free readability checker (https://readabilityformulas.com). Patient education materials should reflect the American Medical Association’s recommended 6th-grade level. Creators should maintain a high standard of quality and comprehensiveness; prior studies note no inverse correlation between readability and quality.⁵ In the age of multimedia presentation, non–print-based materials can be explored, such as audio or video for online content, podcasts, and webinars. Providers also should take the opportunity to be mindful of health literacy in clinic. Beyond assessing the readability of written resources for a patient, assessing that patient’s health literacy and tailoring one’s language will maximize engagement.

Systemic Change Is Needed

Ultimately, systemic change is needed to address the root causes of health literacy disparity, requiring advocacy for social welfare, public health, and public policy initiatives. In recognizing existing efforts, such as community outreach teams and hospital committees to evaluate health literacy materials, numerous barriers remain. Despite the notable impact of health literacy on health outcomes, there is a lack of advocacy and funds to conduct health literacy–related work.⁷ Because dermatologists provide holistic care and remain mindful of patients’ health literacy in the clinic, they should continue to advocate for increased awareness, improved funding, and support for local and federal initiatives.

Final Thoughts

With more opportunities to narrow gaps in care, it is more pertinent than ever to acknowledge the impact of health literacy on dermatology outcomes. Leveling the playing field begins with (1) an awareness of health literacy and (2) creating readable and comprehensible patient education content. Greater advocacy from community and professional organizations; increased funding from nonprofit organizations, industry, and federal institutions; and increased involvement by dermatologists in bringing greater attention to health literacy will improve outcomes in dermatology.

Health literacy is a multifaceted construct that encompasses the knowledge of health and health systems, utilization of information related to health, and ability to maintain health.¹ Low health literacy impairs health outcomes, disproportionately affecting socioeconomically disadvantaged populations, including racial minorities and the older population. Consistently, it is associated with fewer vaccinations and screenings, higher health care utilization, and poorer ability to take medications or interpret health information.²

With growing utilization of the Internet for health information,³ much patient education now occurs outside the clinic. Differential utilization of the Internet can exacerbate disparities in health outcomes: people with a lower family income more frequently engage in health information and dialogue online.³ Despite opportunities to improve literacy and narrow gaps in care, a lack of awareness, advocacy, and funding limit patient- and community-based initiatives. Herein, we discuss health literacy challenges in dermatology, offer potential solutions, and propose ways that stakeholders can prioritize health literacy advocacy to improve outcomes.

The Importance of Health Literacy in Dermatology

Dermatology patients often face challenges that demand greater health literacy. Active participation in health promotion, protection, and maintenance can remarkably improve outcomes. When patients understand disease pathogenesis and the rationale behind treatment choices, adherence to a treatment regimen might improve.

However, understanding dermatologic diseases and disorders can be challenging. First, many are chronic inflammatory conditions that require intricate treatment regimens. Second, the complexity of those diseases and disorders continues to grow in the era of new research and unprecedented expansion of treatment options.

For chronic conditions that require ongoing complex management, researchers have developed advanced patient tools. For instance, the eczema action plan helps atopic dermatitis patients manage conditions from home.⁴ However, patients with greater literacy and the ability to participate will better utilize such tools and have fewer uncontrolled flares. Patient tools meant to improve outcomes might, instead, widen gaps in care. Even with nonchronic conditions, such as nonmelanoma skin cancer, continued awareness and the need for preventive care, timely diagnosis, and appropriate intervention remain critical.

Limited Accessibility of Patient Education Materials

Patient education in dermatology occurs through several formats. Because online health resources are more readily available to those with less access to health care, the potential for such resources to narrow health disparities is immense. However, online resources have not adequately taken advantage of the opportunity to make health information openly accessible to its users. The readability of online patient education materials on a large expanse of dermatologic conditions is far too advanced.⁵ The readability level of some resources is as high as 17th grade (graduate school), which is much higher than the American Medical Association recommendation⁶ that patient education materials be presented at a 6th-grade level or less. Furthermore, the quality and comprehensiveness of content is highly variable. Rather than serving as an equalizer, the Internet may widen the gap as low health literacy continues to impair the accessibility of health information.

Solutions to Level the Playing Field

What can be done to increase the readability of patient education materials? Leveling the playing field begins with creating materials at an appropriate readability level, including online content, printed handouts, and after-visit summaries in the clinic. Writers of patient education materials should be cognizant of their choice of language and routinely use a free readability checker (https://readabilityformulas.com). Patient education materials should reflect the American Medical Association’s recommended 6th-grade level. Creators should maintain a high standard of quality and comprehensiveness; prior studies note no inverse correlation between readability and quality.⁵ In the age of multimedia presentation, non–print-based materials can be explored, such as audio or video for online content, podcasts, and webinars. Providers also should take the opportunity to be mindful of health literacy in clinic. Beyond assessing the readability of written resources for a patient, assessing that patient’s health literacy and tailoring one’s language will maximize engagement.

Systemic Change Is Needed

Ultimately, systemic change is needed to address the root causes of health literacy disparity, requiring advocacy for social welfare, public health, and public policy initiatives. In recognizing existing efforts, such as community outreach teams and hospital committees to evaluate health literacy materials, numerous barriers remain. Despite the notable impact of health literacy on health outcomes, there is a lack of advocacy and funds to conduct health literacy–related work.⁷ Because dermatologists provide holistic care and remain mindful of patients’ health literacy in the clinic, they should continue to advocate for increased awareness, improved funding, and support for local and federal initiatives.

Final Thoughts

With more opportunities to narrow gaps in care, it is more pertinent than ever to acknowledge the impact of health literacy on dermatology outcomes. Leveling the playing field begins with (1) an awareness of health literacy and (2) creating readable and comprehensible patient education content. Greater advocacy from community and professional organizations; increased funding from nonprofit organizations, industry, and federal institutions; and increased involvement by dermatologists in bringing greater attention to health literacy will improve outcomes in dermatology.

Health literacy is a multifaceted construct that encompasses the knowledge of health and health systems, utilization of information related to health, and ability to maintain health.¹ Low health literacy impairs health outcomes, disproportionately affecting socioeconomically disadvantaged populations, including racial minorities and the older population. Consistently, it is associated with fewer vaccinations and screenings, higher health care utilization, and poorer ability to take medications or interpret health information.²

With growing utilization of the Internet for health information,³ much patient education now occurs outside the clinic. Differential utilization of the Internet can exacerbate disparities in health outcomes: people with a lower family income more frequently engage in health information and dialogue online.³ Despite opportunities to improve literacy and narrow gaps in care, a lack of awareness, advocacy, and funding limit patient- and community-based initiatives. Herein, we discuss health literacy challenges in dermatology, offer potential solutions, and propose ways that stakeholders can prioritize health literacy advocacy to improve outcomes.

The Importance of Health Literacy in Dermatology

Dermatology patients often face challenges that demand greater health literacy. Active participation in health promotion, protection, and maintenance can remarkably improve outcomes. When patients understand disease pathogenesis and the rationale behind treatment choices, adherence to a treatment regimen might improve.

However, understanding dermatologic diseases and disorders can be challenging. First, many are chronic inflammatory conditions that require intricate treatment regimens. Second, the complexity of those diseases and disorders continues to grow in the era of new research and unprecedented expansion of treatment options.

For chronic conditions that require ongoing complex management, researchers have developed advanced patient tools. For instance, the eczema action plan helps atopic dermatitis patients manage conditions from home.⁴ However, patients with greater literacy and the ability to participate will better utilize such tools and have fewer uncontrolled flares. Patient tools meant to improve outcomes might, instead, widen gaps in care. Even with nonchronic conditions, such as nonmelanoma skin cancer, continued awareness and the need for preventive care, timely diagnosis, and appropriate intervention remain critical.

Limited Accessibility of Patient Education Materials

Patient education in dermatology occurs through several formats. Because online health resources are more readily available to those with less access to health care, the potential for such resources to narrow health disparities is immense. However, online resources have not adequately taken advantage of the opportunity to make health information openly accessible to its users. The readability of online patient education materials on a large expanse of dermatologic conditions is far too advanced.⁵ The readability level of some resources is as high as 17th grade (graduate school), which is much higher than the American Medical Association recommendation⁶ that patient education materials be presented at a 6th-grade level or less. Furthermore, the quality and comprehensiveness of content is highly variable. Rather than serving as an equalizer, the Internet may widen the gap as low health literacy continues to impair the accessibility of health information.

Solutions to Level the Playing Field

What can be done to increase the readability of patient education materials? Leveling the playing field begins with creating materials at an appropriate readability level, including online content, printed handouts, and after-visit summaries in the clinic. Writers of patient education materials should be cognizant of their choice of language and routinely use a free readability checker (https://readabilityformulas.com). Patient education materials should reflect the American Medical Association’s recommended 6th-grade level. Creators should maintain a high standard of quality and comprehensiveness; prior studies note no inverse correlation between readability and quality.⁵ In the age of multimedia presentation, non–print-based materials can be explored, such as audio or video for online content, podcasts, and webinars. Providers also should take the opportunity to be mindful of health literacy in clinic. Beyond assessing the readability of written resources for a patient, assessing that patient’s health literacy and tailoring one’s language will maximize engagement.

Systemic Change Is Needed

Ultimately, systemic change is needed to address the root causes of health literacy disparity, requiring advocacy for social welfare, public health, and public policy initiatives. In recognizing existing efforts, such as community outreach teams and hospital committees to evaluate health literacy materials, numerous barriers remain. Despite the notable impact of health literacy on health outcomes, there is a lack of advocacy and funds to conduct health literacy–related work.⁷ Because dermatologists provide holistic care and remain mindful of patients’ health literacy in the clinic, they should continue to advocate for increased awareness, improved funding, and support for local and federal initiatives.

Final Thoughts

With more opportunities to narrow gaps in care, it is more pertinent than ever to acknowledge the impact of health literacy on dermatology outcomes. Leveling the playing field begins with (1) an awareness of health literacy and (2) creating readable and comprehensible patient education content. Greater advocacy from community and professional organizations; increased funding from nonprofit organizations, industry, and federal institutions; and increased involvement by dermatologists in bringing greater attention to health literacy will improve outcomes in dermatology.

Black and minority groups are significantly underrepresented in major drug trials for leukemias and multiple myeloma (MM), compared with the proportions of these groups in the broader patient population, a new study concludes.  

“Our analysis shows that, over the past 10 years, participation in pivotal clinical trials investigating therapies for leukemias and MM is unrepresentative of the U.S. population,” say the authors, led by Jorge E. Cortes, MD, of the Georgia Cancer Center at Augusta University, Ga. “Trials should represent the population with the disease,” they comment.

The study was published in the Journal of Clinical Oncology.

“This study confirms that the U.S. cancer population for select hematologic malignancies was inadequately racially and ethnically represented in studies leading to drug approval,” comment the authors of an accompanying editorial.

“The results from this study should lead to questions about the generalizability of drug safety and efficacy in populations we serve as medical hematologists and oncologists,” say Mikkael A. Sekeres, MD, along with Namrata S. Chandhok, MD, both of the division of hematology, Sylvester Comprehensive Cancer Center, University of Miami.  

They pose the question, for instance, as physicians practicing in South Florida, where most of their patients are Hispanic, “can we apply the results of these pivotal studies – and drug labels – to them, without any sense of whether they metabolize the drug the same way as those included in the study or have the same biologic targets?”
 

Analysis of pivotal trials

For their study, Dr. Cortes and colleagues analyzed 61 pivotal trials for leukemia and MM leading to approval of the drugs from the U.S. Food and Drug Administration between 2011 and 2021.

They found that only two-thirds (67.2%) of these trials reported data pertaining to race, while about half (48.8%) reported on ethnicity.

The trials that did report data on race involved a total of 13,731 patients. The vast majority (81.6%) were White, and Black patients represented only 3.8%. Asian/Pacific Islanders made up 9.1%, and American Indians or Alaskan Natives made up just 0.12% of participants, with 1.5% categorized as other.

Among the trials reporting on ethnicity, 4.7% of patients were Hispanic, with 11.5% being Hispanic in acute lymphoblastic leukemia (ALL) trials and 7.6% Hispanic in chronic myeloid leukemia (CML) trials.

Slightly more than half (54.8%) of all trial participants were male, and patients’ average ages ranged from 41.7 to 67.3 years across all malignancies.

Of the minority groups, Asian/Pacific Islanders and Black people had the highest representation in trials involving CML, at 12.7% and 5.3%, respectively.

Their lowest representation was in chronic lymphocytic leukemia (CLL), at 3% and 1.1%, respectively.

Among the trials reporting ethnicity, Hispanic people were the highest representation, with percentages ranging from 3.8% of MM trials to 11.5% in ALL trials.
 

Inconsistent with patient populations

Next, the researchers compared the proportions of race/ethnic groups that were found among the participants of these pivotal trials with the proportions that would be expected in patient populations for each of these blood cancers (according to the U.S. Surveillance, Epidemiology, and End Results [SEER] database).

For example, White people made up 80.3% of participants in clinical trials of MM, whereas they represent 68.7% of patients with MM, a difference that was statistically significant (P < .0001).

The finding was similar for CML, with White people accounting for 90.5% of participants in clinical trials versus 82.5% of the patient population (P < .0001).

For AML, the difference was smaller, with respective percentages of 79.6 versus 77.3% (P = .0389).

For Black people, Asian/Pacific Islanders and Hispanic people, across all five cancer types that were analyzed, the proportion of participants in clinical trials was significantly lower than the proportion in the patient population.

The analysis also showed that females were overrepresented in clinical trials for two blood cancers. For MM, trial participation was 44.7%, while disease incidence was 41.7% (P < .0001), and for CML the proportions were 44.7% versus 39.5% (P = .0009). However, females were underrepresented in a third blood cancer: in AML, the proportions were 44.7% versus 60.5% (P < .0001).
 

Geographic location of trials often inaccessible

The study also highlighted an obstacle to minorities participating in clinical trials: geography.

For this analysis, the researchers looked at mortality rates for the various blood cancers.  

For AML, they found mortality rates were high across the whole of the United States, but centers conducting AML clinical trials were primarily in the Northeast, with no centers in the Midwest.

Key regions with high rates of AML mortality, low access to trials, and high minority representation were notably clustered in areas including east of the Carolinas, South Georgia, Alabama, and Mississippi, the authors noted.

“In many instances, trials were absent in areas with high mortality,” they report. “This makes access to clinical trials difficult, if not impossible, to patients who do not have the financial means for travel.”
 

Further action needed

Racial and ethnic disparities in clinical trials have been widely reported in numerous previous studies, the authors note.

Various initiatives have been launched in recent years to tackle the problem, including the National Institutes of Health Revitalization Act, FDA race and ethnicity guidance, and the International Conference for Harmonization guidance.

For oncology, the American Society of Clinical Oncology has also taken steps with the release of the new Equity, Diversity, and Inclusion Action Plan in 2021 to improve representation of minorities in research.

Dr. Cortes and colleagues suggest another step that is needed is standardized reporting of demographics of clinical trial participants.

“More importantly, efforts to increase representation of minorities and disadvantaged populations in clinical trials should be prioritized,” they say.

Dr. Cortes reports a consulting role and receiving research funding from many pharmaceutical companies. No other coauthors have financial disclosures. Dr. Chandhok reports honoraria from Healio, Clinical Care Options, and a consulting role with Servier. Dr. Sekeres reports a consulting role with Celgene, Millennium, Pfizer, Novartis, Syros Pharmaceuticals, Kurome Therapeutics, and institutional research funding from Takeda, Pfizer, Bristol Myers Squibb, Actuate Therapeutics, Sellas Life Sciences, and Bio-Path Holdings.

A version of this article first appeared on Medscape.com.

Black and minority groups are significantly underrepresented in major drug trials for leukemias and multiple myeloma (MM), compared with the proportions of these groups in the broader patient population, a new study concludes.  

“Our analysis shows that, over the past 10 years, participation in pivotal clinical trials investigating therapies for leukemias and MM is unrepresentative of the U.S. population,” say the authors, led by Jorge E. Cortes, MD, of the Georgia Cancer Center at Augusta University, Ga. “Trials should represent the population with the disease,” they comment.

The study was published in the Journal of Clinical Oncology.

“This study confirms that the U.S. cancer population for select hematologic malignancies was inadequately racially and ethnically represented in studies leading to drug approval,” comment the authors of an accompanying editorial.

“The results from this study should lead to questions about the generalizability of drug safety and efficacy in populations we serve as medical hematologists and oncologists,” say Mikkael A. Sekeres, MD, along with Namrata S. Chandhok, MD, both of the division of hematology, Sylvester Comprehensive Cancer Center, University of Miami.  

They pose the question, for instance, as physicians practicing in South Florida, where most of their patients are Hispanic, “can we apply the results of these pivotal studies – and drug labels – to them, without any sense of whether they metabolize the drug the same way as those included in the study or have the same biologic targets?”
 

Analysis of pivotal trials

For their study, Dr. Cortes and colleagues analyzed 61 pivotal trials for leukemia and MM leading to approval of the drugs from the U.S. Food and Drug Administration between 2011 and 2021.

They found that only two-thirds (67.2%) of these trials reported data pertaining to race, while about half (48.8%) reported on ethnicity.

The trials that did report data on race involved a total of 13,731 patients. The vast majority (81.6%) were White, and Black patients represented only 3.8%. Asian/Pacific Islanders made up 9.1%, and American Indians or Alaskan Natives made up just 0.12% of participants, with 1.5% categorized as other.

Among the trials reporting on ethnicity, 4.7% of patients were Hispanic, with 11.5% being Hispanic in acute lymphoblastic leukemia (ALL) trials and 7.6% Hispanic in chronic myeloid leukemia (CML) trials.

Slightly more than half (54.8%) of all trial participants were male, and patients’ average ages ranged from 41.7 to 67.3 years across all malignancies.

Of the minority groups, Asian/Pacific Islanders and Black people had the highest representation in trials involving CML, at 12.7% and 5.3%, respectively.

Their lowest representation was in chronic lymphocytic leukemia (CLL), at 3% and 1.1%, respectively.

Among the trials reporting ethnicity, Hispanic people were the highest representation, with percentages ranging from 3.8% of MM trials to 11.5% in ALL trials.
 

Inconsistent with patient populations

Next, the researchers compared the proportions of race/ethnic groups that were found among the participants of these pivotal trials with the proportions that would be expected in patient populations for each of these blood cancers (according to the U.S. Surveillance, Epidemiology, and End Results [SEER] database).

For example, White people made up 80.3% of participants in clinical trials of MM, whereas they represent 68.7% of patients with MM, a difference that was statistically significant (P < .0001).

The finding was similar for CML, with White people accounting for 90.5% of participants in clinical trials versus 82.5% of the patient population (P < .0001).

For AML, the difference was smaller, with respective percentages of 79.6 versus 77.3% (P = .0389).

For Black people, Asian/Pacific Islanders and Hispanic people, across all five cancer types that were analyzed, the proportion of participants in clinical trials was significantly lower than the proportion in the patient population.

The analysis also showed that females were overrepresented in clinical trials for two blood cancers. For MM, trial participation was 44.7%, while disease incidence was 41.7% (P < .0001), and for CML the proportions were 44.7% versus 39.5% (P = .0009). However, females were underrepresented in a third blood cancer: in AML, the proportions were 44.7% versus 60.5% (P < .0001).
 

Geographic location of trials often inaccessible

The study also highlighted an obstacle to minorities participating in clinical trials: geography.

For this analysis, the researchers looked at mortality rates for the various blood cancers.  

For AML, they found mortality rates were high across the whole of the United States, but centers conducting AML clinical trials were primarily in the Northeast, with no centers in the Midwest.

Key regions with high rates of AML mortality, low access to trials, and high minority representation were notably clustered in areas including east of the Carolinas, South Georgia, Alabama, and Mississippi, the authors noted.

“In many instances, trials were absent in areas with high mortality,” they report. “This makes access to clinical trials difficult, if not impossible, to patients who do not have the financial means for travel.”
 

Further action needed

Racial and ethnic disparities in clinical trials have been widely reported in numerous previous studies, the authors note.

Various initiatives have been launched in recent years to tackle the problem, including the National Institutes of Health Revitalization Act, FDA race and ethnicity guidance, and the International Conference for Harmonization guidance.

For oncology, the American Society of Clinical Oncology has also taken steps with the release of the new Equity, Diversity, and Inclusion Action Plan in 2021 to improve representation of minorities in research.

Dr. Cortes and colleagues suggest another step that is needed is standardized reporting of demographics of clinical trial participants.

“More importantly, efforts to increase representation of minorities and disadvantaged populations in clinical trials should be prioritized,” they say.

Dr. Cortes reports a consulting role and receiving research funding from many pharmaceutical companies. No other coauthors have financial disclosures. Dr. Chandhok reports honoraria from Healio, Clinical Care Options, and a consulting role with Servier. Dr. Sekeres reports a consulting role with Celgene, Millennium, Pfizer, Novartis, Syros Pharmaceuticals, Kurome Therapeutics, and institutional research funding from Takeda, Pfizer, Bristol Myers Squibb, Actuate Therapeutics, Sellas Life Sciences, and Bio-Path Holdings.

A version of this article first appeared on Medscape.com.

Black and minority groups are significantly underrepresented in major drug trials for leukemias and multiple myeloma (MM), compared with the proportions of these groups in the broader patient population, a new study concludes.  

“Our analysis shows that, over the past 10 years, participation in pivotal clinical trials investigating therapies for leukemias and MM is unrepresentative of the U.S. population,” say the authors, led by Jorge E. Cortes, MD, of the Georgia Cancer Center at Augusta University, Ga. “Trials should represent the population with the disease,” they comment.

The study was published in the Journal of Clinical Oncology.

“This study confirms that the U.S. cancer population for select hematologic malignancies was inadequately racially and ethnically represented in studies leading to drug approval,” comment the authors of an accompanying editorial.

“The results from this study should lead to questions about the generalizability of drug safety and efficacy in populations we serve as medical hematologists and oncologists,” say Mikkael A. Sekeres, MD, along with Namrata S. Chandhok, MD, both of the division of hematology, Sylvester Comprehensive Cancer Center, University of Miami.  

They pose the question, for instance, as physicians practicing in South Florida, where most of their patients are Hispanic, “can we apply the results of these pivotal studies – and drug labels – to them, without any sense of whether they metabolize the drug the same way as those included in the study or have the same biologic targets?”
 

Analysis of pivotal trials

For their study, Dr. Cortes and colleagues analyzed 61 pivotal trials for leukemia and MM leading to approval of the drugs from the U.S. Food and Drug Administration between 2011 and 2021.

They found that only two-thirds (67.2%) of these trials reported data pertaining to race, while about half (48.8%) reported on ethnicity.

The trials that did report data on race involved a total of 13,731 patients. The vast majority (81.6%) were White, and Black patients represented only 3.8%. Asian/Pacific Islanders made up 9.1%, and American Indians or Alaskan Natives made up just 0.12% of participants, with 1.5% categorized as other.

Among the trials reporting on ethnicity, 4.7% of patients were Hispanic, with 11.5% being Hispanic in acute lymphoblastic leukemia (ALL) trials and 7.6% Hispanic in chronic myeloid leukemia (CML) trials.

Slightly more than half (54.8%) of all trial participants were male, and patients’ average ages ranged from 41.7 to 67.3 years across all malignancies.

Of the minority groups, Asian/Pacific Islanders and Black people had the highest representation in trials involving CML, at 12.7% and 5.3%, respectively.

Their lowest representation was in chronic lymphocytic leukemia (CLL), at 3% and 1.1%, respectively.

Among the trials reporting ethnicity, Hispanic people were the highest representation, with percentages ranging from 3.8% of MM trials to 11.5% in ALL trials.
 

Inconsistent with patient populations

Next, the researchers compared the proportions of race/ethnic groups that were found among the participants of these pivotal trials with the proportions that would be expected in patient populations for each of these blood cancers (according to the U.S. Surveillance, Epidemiology, and End Results [SEER] database).

For example, White people made up 80.3% of participants in clinical trials of MM, whereas they represent 68.7% of patients with MM, a difference that was statistically significant (P < .0001).

The finding was similar for CML, with White people accounting for 90.5% of participants in clinical trials versus 82.5% of the patient population (P < .0001).

For AML, the difference was smaller, with respective percentages of 79.6 versus 77.3% (P = .0389).

For Black people, Asian/Pacific Islanders and Hispanic people, across all five cancer types that were analyzed, the proportion of participants in clinical trials was significantly lower than the proportion in the patient population.

The analysis also showed that females were overrepresented in clinical trials for two blood cancers. For MM, trial participation was 44.7%, while disease incidence was 41.7% (P < .0001), and for CML the proportions were 44.7% versus 39.5% (P = .0009). However, females were underrepresented in a third blood cancer: in AML, the proportions were 44.7% versus 60.5% (P < .0001).
 

Geographic location of trials often inaccessible

The study also highlighted an obstacle to minorities participating in clinical trials: geography.

For this analysis, the researchers looked at mortality rates for the various blood cancers.  

For AML, they found mortality rates were high across the whole of the United States, but centers conducting AML clinical trials were primarily in the Northeast, with no centers in the Midwest.

Key regions with high rates of AML mortality, low access to trials, and high minority representation were notably clustered in areas including east of the Carolinas, South Georgia, Alabama, and Mississippi, the authors noted.

“In many instances, trials were absent in areas with high mortality,” they report. “This makes access to clinical trials difficult, if not impossible, to patients who do not have the financial means for travel.”
 

Further action needed

Racial and ethnic disparities in clinical trials have been widely reported in numerous previous studies, the authors note.

Various initiatives have been launched in recent years to tackle the problem, including the National Institutes of Health Revitalization Act, FDA race and ethnicity guidance, and the International Conference for Harmonization guidance.

For oncology, the American Society of Clinical Oncology has also taken steps with the release of the new Equity, Diversity, and Inclusion Action Plan in 2021 to improve representation of minorities in research.

Dr. Cortes and colleagues suggest another step that is needed is standardized reporting of demographics of clinical trial participants.

“More importantly, efforts to increase representation of minorities and disadvantaged populations in clinical trials should be prioritized,” they say.

Dr. Cortes reports a consulting role and receiving research funding from many pharmaceutical companies. No other coauthors have financial disclosures. Dr. Chandhok reports honoraria from Healio, Clinical Care Options, and a consulting role with Servier. Dr. Sekeres reports a consulting role with Celgene, Millennium, Pfizer, Novartis, Syros Pharmaceuticals, Kurome Therapeutics, and institutional research funding from Takeda, Pfizer, Bristol Myers Squibb, Actuate Therapeutics, Sellas Life Sciences, and Bio-Path Holdings.

A version of this article first appeared on Medscape.com.

Whether coffee is good or bad for health is a frequent debate in the media, fueled by apparently conflicting studies suggesting the plethora of bioactive chemicals in the popular brew could either raise or lower cancer risk.

Now, an analysis by Cambridge scientists has suggested that while coffee is not associated with enhanced overall risk of non–digestive system cancers among people genetically predicted to drink more of it, consumption was associated with a higher risk of digestive system cancers.

Lynda Banzi/MDedge News

That risk was driven by a “strong association” with esophageal cancer, although this might be explained by a tendency for drinking it warm or hot, the study in the journal Clinical Nutrition suggested.

Regular coffee drinking has been linked to a slightly lower risk of all-cause mortality. However, it remains unclear whether coffee consumption is associated with a lower risk of dying from cancer.
 

Hotly debated

In 2016, a working group of international scientists convened by the International Agency for Research on Cancer (IARC) found no conclusive evidence for a carcinogenic effect of drinking coffee. However, the experts did find that drinking very hot beverages was a probable cause of esophageal cancer, making “the temperature, rather than the drinks themselves” the most likely cause, according to the organization’s director.

This latest study concurred. “We provide strong evidence for a causal relationship which is large in magnitude (threefold) and consistent across sensitivity analyses and in a replication study,” it stated.

The Cambridge researchers, assisted by colleagues at the Karolinska Institutet in Stockholm and Bristol Medical School, conducted a Mendelian randomization study to investigate causal associations between coffee consumption and 22 site-specific cancers using data of individuals of European descent in the UK Biobank.

They reported “no strong evidence supporting a causal relationship between genetically-predicted coffee consumption and the majority of cancers studied” (odds ratio [OR], in the main analysis 1.05, 95% confidence interval [CI], 0.98-1.14, P = .183), and remained without association after adjustments for predicted BMI, smoking, or alcohol consumption.

However, genetically predicted coffee consumption was linked to an increased risk of digestive system cancer (OR, 1.28, 95% CI, 1.09-1.51, P = .003), and the risk was largely attributed to “a strong association with esophageal cancer” (OR, 2.79, 95% CI, 1.73-4.50, P = 2.5x10^-5). This risk association remained persistent after adjustment for confounders, the researchers said.
 

Coffee or tea?

Further analysis of the data found that increased risk of esophageal cancer was consistently associated with genetically predicted coffee consumption by individuals with a preference for warm and hot drinks. Among this group, a similar esophageal cancer risk profile among those who reported drinking one to three cups of coffee a day and those who said they did not drink coffee was most likely due to a high prevalence of tea drinking, the study authors said.

“It is, therefore, plausible that a carcinogenic effect of coffee relates to thermal injury broadly, rather than being specific to coffee or its constituents,” said the scientists, who highlighted that this was also pointed out by the IARC in its statement 6 years ago.

Genetically predicted coffee consumption was also found to be associated with increased risk of multiple myeloma (OR, 2.25, 95% CI, 1.30-3.89, P = .004) and reduced ovarian cancer risk (OR, 0.63, 95% CI, 0.43-0.93, P = .020).

The authors concluded there was “evidence for coffee consumption being causally associated with risk of esophageal cancer, with some evidence this is related to a temperature effect.” Otherwise, “our results do not support a linear causal association with the majority of cancer types studied, other than limited evidence for harmful and protective associations with multiple myeloma and ovarian cancers respectively.”

Further studies were needed to investigate “the possible mechanisms of coffee consumption in esophageal carcinogenesis,” they said.

A version of this article first appeared on Medscape UK.

Whether coffee is good or bad for health is a frequent debate in the media, fueled by apparently conflicting studies suggesting the plethora of bioactive chemicals in the popular brew could either raise or lower cancer risk.

Now, an analysis by Cambridge scientists has suggested that while coffee is not associated with enhanced overall risk of non–digestive system cancers among people genetically predicted to drink more of it, consumption was associated with a higher risk of digestive system cancers.

Lynda Banzi/MDedge News

That risk was driven by a “strong association” with esophageal cancer, although this might be explained by a tendency for drinking it warm or hot, the study in the journal Clinical Nutrition suggested.

Regular coffee drinking has been linked to a slightly lower risk of all-cause mortality. However, it remains unclear whether coffee consumption is associated with a lower risk of dying from cancer.
 

Hotly debated

In 2016, a working group of international scientists convened by the International Agency for Research on Cancer (IARC) found no conclusive evidence for a carcinogenic effect of drinking coffee. However, the experts did find that drinking very hot beverages was a probable cause of esophageal cancer, making “the temperature, rather than the drinks themselves” the most likely cause, according to the organization’s director.

This latest study concurred. “We provide strong evidence for a causal relationship which is large in magnitude (threefold) and consistent across sensitivity analyses and in a replication study,” it stated.

The Cambridge researchers, assisted by colleagues at the Karolinska Institutet in Stockholm and Bristol Medical School, conducted a Mendelian randomization study to investigate causal associations between coffee consumption and 22 site-specific cancers using data of individuals of European descent in the UK Biobank.

They reported “no strong evidence supporting a causal relationship between genetically-predicted coffee consumption and the majority of cancers studied” (odds ratio [OR], in the main analysis 1.05, 95% confidence interval [CI], 0.98-1.14, P = .183), and remained without association after adjustments for predicted BMI, smoking, or alcohol consumption.

However, genetically predicted coffee consumption was linked to an increased risk of digestive system cancer (OR, 1.28, 95% CI, 1.09-1.51, P = .003), and the risk was largely attributed to “a strong association with esophageal cancer” (OR, 2.79, 95% CI, 1.73-4.50, P = 2.5x10^-5). This risk association remained persistent after adjustment for confounders, the researchers said.
 

Coffee or tea?

Further analysis of the data found that increased risk of esophageal cancer was consistently associated with genetically predicted coffee consumption by individuals with a preference for warm and hot drinks. Among this group, a similar esophageal cancer risk profile among those who reported drinking one to three cups of coffee a day and those who said they did not drink coffee was most likely due to a high prevalence of tea drinking, the study authors said.

“It is, therefore, plausible that a carcinogenic effect of coffee relates to thermal injury broadly, rather than being specific to coffee or its constituents,” said the scientists, who highlighted that this was also pointed out by the IARC in its statement 6 years ago.

Genetically predicted coffee consumption was also found to be associated with increased risk of multiple myeloma (OR, 2.25, 95% CI, 1.30-3.89, P = .004) and reduced ovarian cancer risk (OR, 0.63, 95% CI, 0.43-0.93, P = .020).

The authors concluded there was “evidence for coffee consumption being causally associated with risk of esophageal cancer, with some evidence this is related to a temperature effect.” Otherwise, “our results do not support a linear causal association with the majority of cancer types studied, other than limited evidence for harmful and protective associations with multiple myeloma and ovarian cancers respectively.”

Further studies were needed to investigate “the possible mechanisms of coffee consumption in esophageal carcinogenesis,” they said.

A version of this article first appeared on Medscape UK.

Whether coffee is good or bad for health is a frequent debate in the media, fueled by apparently conflicting studies suggesting the plethora of bioactive chemicals in the popular brew could either raise or lower cancer risk.

Now, an analysis by Cambridge scientists has suggested that while coffee is not associated with enhanced overall risk of non–digestive system cancers among people genetically predicted to drink more of it, consumption was associated with a higher risk of digestive system cancers.

Lynda Banzi/MDedge News

That risk was driven by a “strong association” with esophageal cancer, although this might be explained by a tendency for drinking it warm or hot, the study in the journal Clinical Nutrition suggested.

Regular coffee drinking has been linked to a slightly lower risk of all-cause mortality. However, it remains unclear whether coffee consumption is associated with a lower risk of dying from cancer.
 

Hotly debated

In 2016, a working group of international scientists convened by the International Agency for Research on Cancer (IARC) found no conclusive evidence for a carcinogenic effect of drinking coffee. However, the experts did find that drinking very hot beverages was a probable cause of esophageal cancer, making “the temperature, rather than the drinks themselves” the most likely cause, according to the organization’s director.

This latest study concurred. “We provide strong evidence for a causal relationship which is large in magnitude (threefold) and consistent across sensitivity analyses and in a replication study,” it stated.

The Cambridge researchers, assisted by colleagues at the Karolinska Institutet in Stockholm and Bristol Medical School, conducted a Mendelian randomization study to investigate causal associations between coffee consumption and 22 site-specific cancers using data of individuals of European descent in the UK Biobank.

They reported “no strong evidence supporting a causal relationship between genetically-predicted coffee consumption and the majority of cancers studied” (odds ratio [OR], in the main analysis 1.05, 95% confidence interval [CI], 0.98-1.14, P = .183), and remained without association after adjustments for predicted BMI, smoking, or alcohol consumption.

However, genetically predicted coffee consumption was linked to an increased risk of digestive system cancer (OR, 1.28, 95% CI, 1.09-1.51, P = .003), and the risk was largely attributed to “a strong association with esophageal cancer” (OR, 2.79, 95% CI, 1.73-4.50, P = 2.5x10^-5). This risk association remained persistent after adjustment for confounders, the researchers said.
 

Coffee or tea?

Further analysis of the data found that increased risk of esophageal cancer was consistently associated with genetically predicted coffee consumption by individuals with a preference for warm and hot drinks. Among this group, a similar esophageal cancer risk profile among those who reported drinking one to three cups of coffee a day and those who said they did not drink coffee was most likely due to a high prevalence of tea drinking, the study authors said.

“It is, therefore, plausible that a carcinogenic effect of coffee relates to thermal injury broadly, rather than being specific to coffee or its constituents,” said the scientists, who highlighted that this was also pointed out by the IARC in its statement 6 years ago.

Genetically predicted coffee consumption was also found to be associated with increased risk of multiple myeloma (OR, 2.25, 95% CI, 1.30-3.89, P = .004) and reduced ovarian cancer risk (OR, 0.63, 95% CI, 0.43-0.93, P = .020).

The authors concluded there was “evidence for coffee consumption being causally associated with risk of esophageal cancer, with some evidence this is related to a temperature effect.” Otherwise, “our results do not support a linear causal association with the majority of cancer types studied, other than limited evidence for harmful and protective associations with multiple myeloma and ovarian cancers respectively.”

Further studies were needed to investigate “the possible mechanisms of coffee consumption in esophageal carcinogenesis,” they said.

A version of this article first appeared on Medscape UK.

People who lift weights understand they’re playing a long game.

Once they get past the “newbie gains” – the quick and exciting increases in muscle strength and size – it takes time, effort, and patience to keep making progress.

Whether they know it or not, they’re also playing the longevity game.

A growing body of research shows that resistance training adds years to both lifespan and “healthspan” – the period of life when we’re in good health.

A 2022 study review from Japanese researchers linked “muscle-strengthening activities” to a 15% lower risk of all-cause mortality.

BeyondImages/Getty Images

Resistance exercise was also linked to a lower risk of cardiovascular disease (17%), cancer (12%), and diabetes (17%).

We’ve known for a long time that strength is an excellent predictor of future health. Lots of research has shown that, if all else is equal, stronger men and women have a much lower risk of dying during a given period than people with less strength.

This new research shows that strength training offers similar protection, regardless of the results of that training. So even if you don’t think you’re getting as strong or as lean as you’d like to be, you should keep it up – because chances are, you’re still helping your health in a big way.
 

How strength training helps as you age

For longevity, strength training seems to be especially effective for older adults, says Roger Fielding, PhD, of Tufts University Medford, Mass., who’s been studying the role of exercise in the aging process since the early 1990s.

“With aging, we see clear deficits in muscle function and bone health,” he says. “That all can be slowed, attenuated, or reversed with appropriate exercise.”

His concept of “appropriate” has changed a lot in the past 3 decades. “When I first started studying this stuff, we would try to give people a very formalized prescription” for strength training, he says.

That strength-training prescription typically included a lot of sets (three per exercise), moderate reps (8-12 per set), and relatively heavy weights. It also required professional supervision in a well-equipped gym, which was both unappealing and impractical for most of the target population.

“What I’ve learned is that even lower-intensity strength training, at home, without a lot of specialized equipment, has some benefits,” he says.

Which benefits? That’s harder to say.

The research linking resistance exercise to lower mortality comes from large, population-wide surveys, looking at tens or even hundreds of thousands of people. The broad category of “muscle-strengthening exercises” can include anything from calisthenics in the living room to a serious bodybuilding or power-lifting program.

They’re also based on self-reporting by the people studied. Because of that, “we should be careful how we interpret some of these studies,” Dr. Fielding says.
 

How much strength training should you do?

That warning seems especially appropriate for the study’s most surprising conclusion: The maximum longevity benefit comes from one or two resistance exercise sessions a week totaling 30-60 minutes.

The study adds that it’s unclear why more strength training would have diminishing or even negative returns.

Robert Linkul, owner of Training the Older Adult in Shingle Springs, Calif., thinks the answer is perfectly clear.

“Less might be more for the beginning lifter,” he says. That’s why his new clients typically begin with two 50-minute workouts a week. But after 3 months, they need to train three times a week to continue seeing gains.

He currently has 14 clients who have been with him at least 16 years. Most of them started in their 50s and are now in their 60s or 70s. If there were any downside to working out more than two times a week, he’s pretty sure he would’ve seen it by now.
 

Live longer and move longer, too

Mr. Linkul says that his training program includes a lot more than lifting. Clients start each workout with 10-15 minutes of mobility and warm-up exercises. That’s followed by 15 minutes of strength training and 15 minutes of high-intensity resistance training (HIRT).

HIRT uses functional exercises – lifting and carrying dumbbells or kettlebells; pushing or pulling a weighted sled – to improve strength and endurance at the same time.

“Most of the clients I get are training for real-life function,” Mr. Linkul says.

Falling is one of their biggest concerns, and for good reason: According to the World Health Organization, it’s the second-leading cause of unintentional injury–related deaths worldwide, behind only traffic accidents.

Their other major concern is losing their independence, which often follows a fall. “They want to feel they’re not near using a cane or a walker or being stuck in a wheelchair,” he says. “The more we train, the further we get from that.”

That’s where strength training offers its most unique advantages, according to a 2019 study from researchers at McMaster University, Hamilton, Ont. Resistance exercise is “particularly potent for maintaining mobility in older adults,” the study says.
 

Training for life

Traditional aerobic exercise also offers many of the same benefits, including longer life and a lower risk of cardiovascular disease, cancer, and diabetes.

But there’s no need to choose one or the other. As a recent study) noted, combining aerobic and strength exercises leads to a lower risk of early death than either of them separately.

Which makes perfect sense to Dr. Fielding.

“Usually, people who’re physically active aren’t just doing strength training alone,” he says. “Some exercise is better than no exercise,” and more is usually better than less. “People have to find things they like to do and want to do and are able to do consistently.”

A version of this article first appeared on WebMD.com.

People who lift weights understand they’re playing a long game.

Once they get past the “newbie gains” – the quick and exciting increases in muscle strength and size – it takes time, effort, and patience to keep making progress.

Whether they know it or not, they’re also playing the longevity game.

A growing body of research shows that resistance training adds years to both lifespan and “healthspan” – the period of life when we’re in good health.

A 2022 study review from Japanese researchers linked “muscle-strengthening activities” to a 15% lower risk of all-cause mortality.

BeyondImages/Getty Images

Resistance exercise was also linked to a lower risk of cardiovascular disease (17%), cancer (12%), and diabetes (17%).

We’ve known for a long time that strength is an excellent predictor of future health. Lots of research has shown that, if all else is equal, stronger men and women have a much lower risk of dying during a given period than people with less strength.

This new research shows that strength training offers similar protection, regardless of the results of that training. So even if you don’t think you’re getting as strong or as lean as you’d like to be, you should keep it up – because chances are, you’re still helping your health in a big way.
 

How strength training helps as you age

For longevity, strength training seems to be especially effective for older adults, says Roger Fielding, PhD, of Tufts University Medford, Mass., who’s been studying the role of exercise in the aging process since the early 1990s.

“With aging, we see clear deficits in muscle function and bone health,” he says. “That all can be slowed, attenuated, or reversed with appropriate exercise.”

His concept of “appropriate” has changed a lot in the past 3 decades. “When I first started studying this stuff, we would try to give people a very formalized prescription” for strength training, he says.

That strength-training prescription typically included a lot of sets (three per exercise), moderate reps (8-12 per set), and relatively heavy weights. It also required professional supervision in a well-equipped gym, which was both unappealing and impractical for most of the target population.

“What I’ve learned is that even lower-intensity strength training, at home, without a lot of specialized equipment, has some benefits,” he says.

Which benefits? That’s harder to say.

The research linking resistance exercise to lower mortality comes from large, population-wide surveys, looking at tens or even hundreds of thousands of people. The broad category of “muscle-strengthening exercises” can include anything from calisthenics in the living room to a serious bodybuilding or power-lifting program.

They’re also based on self-reporting by the people studied. Because of that, “we should be careful how we interpret some of these studies,” Dr. Fielding says.
 

How much strength training should you do?

That warning seems especially appropriate for the study’s most surprising conclusion: The maximum longevity benefit comes from one or two resistance exercise sessions a week totaling 30-60 minutes.

The study adds that it’s unclear why more strength training would have diminishing or even negative returns.

Robert Linkul, owner of Training the Older Adult in Shingle Springs, Calif., thinks the answer is perfectly clear.

“Less might be more for the beginning lifter,” he says. That’s why his new clients typically begin with two 50-minute workouts a week. But after 3 months, they need to train three times a week to continue seeing gains.

He currently has 14 clients who have been with him at least 16 years. Most of them started in their 50s and are now in their 60s or 70s. If there were any downside to working out more than two times a week, he’s pretty sure he would’ve seen it by now.
 

Live longer and move longer, too

Mr. Linkul says that his training program includes a lot more than lifting. Clients start each workout with 10-15 minutes of mobility and warm-up exercises. That’s followed by 15 minutes of strength training and 15 minutes of high-intensity resistance training (HIRT).

HIRT uses functional exercises – lifting and carrying dumbbells or kettlebells; pushing or pulling a weighted sled – to improve strength and endurance at the same time.

“Most of the clients I get are training for real-life function,” Mr. Linkul says.

Falling is one of their biggest concerns, and for good reason: According to the World Health Organization, it’s the second-leading cause of unintentional injury–related deaths worldwide, behind only traffic accidents.

Their other major concern is losing their independence, which often follows a fall. “They want to feel they’re not near using a cane or a walker or being stuck in a wheelchair,” he says. “The more we train, the further we get from that.”

That’s where strength training offers its most unique advantages, according to a 2019 study from researchers at McMaster University, Hamilton, Ont. Resistance exercise is “particularly potent for maintaining mobility in older adults,” the study says.
 

Training for life

Traditional aerobic exercise also offers many of the same benefits, including longer life and a lower risk of cardiovascular disease, cancer, and diabetes.

But there’s no need to choose one or the other. As a recent study) noted, combining aerobic and strength exercises leads to a lower risk of early death than either of them separately.

Which makes perfect sense to Dr. Fielding.

“Usually, people who’re physically active aren’t just doing strength training alone,” he says. “Some exercise is better than no exercise,” and more is usually better than less. “People have to find things they like to do and want to do and are able to do consistently.”

A version of this article first appeared on WebMD.com.

People who lift weights understand they’re playing a long game.

Once they get past the “newbie gains” – the quick and exciting increases in muscle strength and size – it takes time, effort, and patience to keep making progress.

Whether they know it or not, they’re also playing the longevity game.

A growing body of research shows that resistance training adds years to both lifespan and “healthspan” – the period of life when we’re in good health.

A 2022 study review from Japanese researchers linked “muscle-strengthening activities” to a 15% lower risk of all-cause mortality.

BeyondImages/Getty Images

Resistance exercise was also linked to a lower risk of cardiovascular disease (17%), cancer (12%), and diabetes (17%).

We’ve known for a long time that strength is an excellent predictor of future health. Lots of research has shown that, if all else is equal, stronger men and women have a much lower risk of dying during a given period than people with less strength.

This new research shows that strength training offers similar protection, regardless of the results of that training. So even if you don’t think you’re getting as strong or as lean as you’d like to be, you should keep it up – because chances are, you’re still helping your health in a big way.
 

How strength training helps as you age

For longevity, strength training seems to be especially effective for older adults, says Roger Fielding, PhD, of Tufts University Medford, Mass., who’s been studying the role of exercise in the aging process since the early 1990s.

“With aging, we see clear deficits in muscle function and bone health,” he says. “That all can be slowed, attenuated, or reversed with appropriate exercise.”

His concept of “appropriate” has changed a lot in the past 3 decades. “When I first started studying this stuff, we would try to give people a very formalized prescription” for strength training, he says.

That strength-training prescription typically included a lot of sets (three per exercise), moderate reps (8-12 per set), and relatively heavy weights. It also required professional supervision in a well-equipped gym, which was both unappealing and impractical for most of the target population.

“What I’ve learned is that even lower-intensity strength training, at home, without a lot of specialized equipment, has some benefits,” he says.

Which benefits? That’s harder to say.

The research linking resistance exercise to lower mortality comes from large, population-wide surveys, looking at tens or even hundreds of thousands of people. The broad category of “muscle-strengthening exercises” can include anything from calisthenics in the living room to a serious bodybuilding or power-lifting program.

They’re also based on self-reporting by the people studied. Because of that, “we should be careful how we interpret some of these studies,” Dr. Fielding says.
 

How much strength training should you do?

That warning seems especially appropriate for the study’s most surprising conclusion: The maximum longevity benefit comes from one or two resistance exercise sessions a week totaling 30-60 minutes.

The study adds that it’s unclear why more strength training would have diminishing or even negative returns.

Robert Linkul, owner of Training the Older Adult in Shingle Springs, Calif., thinks the answer is perfectly clear.

“Less might be more for the beginning lifter,” he says. That’s why his new clients typically begin with two 50-minute workouts a week. But after 3 months, they need to train three times a week to continue seeing gains.

He currently has 14 clients who have been with him at least 16 years. Most of them started in their 50s and are now in their 60s or 70s. If there were any downside to working out more than two times a week, he’s pretty sure he would’ve seen it by now.
 

Live longer and move longer, too

Mr. Linkul says that his training program includes a lot more than lifting. Clients start each workout with 10-15 minutes of mobility and warm-up exercises. That’s followed by 15 minutes of strength training and 15 minutes of high-intensity resistance training (HIRT).

HIRT uses functional exercises – lifting and carrying dumbbells or kettlebells; pushing or pulling a weighted sled – to improve strength and endurance at the same time.

“Most of the clients I get are training for real-life function,” Mr. Linkul says.

Falling is one of their biggest concerns, and for good reason: According to the World Health Organization, it’s the second-leading cause of unintentional injury–related deaths worldwide, behind only traffic accidents.

Their other major concern is losing their independence, which often follows a fall. “They want to feel they’re not near using a cane or a walker or being stuck in a wheelchair,” he says. “The more we train, the further we get from that.”

That’s where strength training offers its most unique advantages, according to a 2019 study from researchers at McMaster University, Hamilton, Ont. Resistance exercise is “particularly potent for maintaining mobility in older adults,” the study says.
 

Training for life

Traditional aerobic exercise also offers many of the same benefits, including longer life and a lower risk of cardiovascular disease, cancer, and diabetes.

But there’s no need to choose one or the other. As a recent study) noted, combining aerobic and strength exercises leads to a lower risk of early death than either of them separately.

Which makes perfect sense to Dr. Fielding.

“Usually, people who’re physically active aren’t just doing strength training alone,” he says. “Some exercise is better than no exercise,” and more is usually better than less. “People have to find things they like to do and want to do and are able to do consistently.”

A version of this article first appeared on WebMD.com.

Early rhythm control for patients with atrial fibrillation (AFib) improves cardiovascular outcomes regardless of an individual’s stroke risk, a large retrospective study finds.

These findings broaden support for early rhythm control, suggesting that physicians should be presenting the option to all patients diagnosed with AFib in routine clinical practice, lead author Daehoon Kim, MD, of Yonsei University, Seoul, South Korea, and colleagues reported.

In 2020, the EAST-AFNET 4 trial showed that early rhythm control was better than rate control for reducing adverse cardiovascular outcomes, but the trial only included patients at risk of stroke with a CHA2DS2-VASc score of at least 2, leaving it unclear whether healthier patients might benefit from the same approach.

“Although the primary indication for rhythm control is to alleviate AF[ib]-related symptoms and improve quality of life, the current guidelines suggest younger age and no or few comorbid conditions as factors favoring rhythm control,” the investigators wrote in Annals of Internal Medicine. “Thus, the effect of rhythm control on cardiovascular outcomes in this population requires elucidation.”
 

Methods and results

The present study aimed to address this knowledge gap by reviewing data from 54,216 patients with AFib who had rhythm control (ablation or medication) or rate control within one year of diagnosis. Among these patients, 69.3% would have qualified for the EAST-AFNET 4 trial based on higher stroke risk, while the remaining 30.7% of patients would not have been eligible because of lower stroke risk. Median age, consequently, was higher in the former group, at 70 years, versus 54 years in the latter group.

Evaluating the same primary composite outcome as the EAST-AFNET 4 trial (cardiovascular death, ischemic stroke, hospitalization for heart failure, or MI) showed that patients benefited from rhythm control over rate control regardless of risk group.

Those in the higher risk group had a 14% reduced risk of negative cardiovascular outcomes (weighted hazard ratio, 0.86; 95% confidence interval, 0.81-0.92), while those in the lower risk group had a 19% reduced risk of adverse cardiovascular outcomes (weighted HR, 0.81; 95% CI, 0.66-0.98). Safety profiles were similar across groups and management strategies.
 

Rhythm control well supported from statistical perspective

“We think that physicians should pursue early rhythm control in all patients diagnosed with AF[ib],” principal author Boyoung Joung, MD, PhD, of Yonsei University said in an interview. “Like catheter ablation, we support the idea that early rhythm control can be more effective and safely performed in younger and less frail populations.”

Xiaoxi Yao, PhD, MPH, associate professor of health services research at Mayo Clinic, Rochester, Minn., agreed that rhythm control is now well supported from a statistical perspective, but patients and physicians need to look beyond relative risk improvements, and remain pragmatic.

“There is a benefit, but the benefit is consistent in terms of hazard ratio, or relative risk,” Dr. Yao said in an interview. “You still find a smaller absolute risk difference.”

Patients in the United States – versus Korea where the investigators are based – also need to consider the out-of-pocket costs involved in rhythm control, Dr. Yao said, noting that unclear cost effectiveness may also prevent changes to American guidelines. Medication side effects and procedural risks should also be considered, she added, as well as time off from work needed for ablation.

Dr. Yao, who published a similar paper in June and previously evaluated the role of catheter ablation in routine practice, suggested that the youngest patients may have the most to gain from rhythm control. This is because even a small absolute benefit is magnified with time, she said.

“Since [younger patients] have another several decades to live ... then yes, there might be very significant long-term effects in terms of both symptom control and cardiovascular death and stroke,” Dr. Yao said.

For optimal patient selection, however, more advanced tools are needed, which is why Dr. Yao and her colleagues are exploring new technologies to improve risk-benefit analysis.

“We are not only interested in [a patient’s] baseline high or low risk, but also the extent of risk reduction [that rhythm control provides],” Dr. Yao said. “We are trying to see if there is an [artificial intelligence] or machine-learning approach that can help us provide each patient with a more accurate, individualized estimate to help them make their decision.”

Until then, Dr. Yao encouraged physicians to engage in shared decision-making with patients, making sure to discuss both statistical and practical considerations.

The study was funded by the Ministry of Health and Welfare and the Ministry of Food and Drug Safety of the Republic of Korea. The investigators and Dr. Yao reported no conflicts.

Early rhythm control for patients with atrial fibrillation (AFib) improves cardiovascular outcomes regardless of an individual’s stroke risk, a large retrospective study finds.

These findings broaden support for early rhythm control, suggesting that physicians should be presenting the option to all patients diagnosed with AFib in routine clinical practice, lead author Daehoon Kim, MD, of Yonsei University, Seoul, South Korea, and colleagues reported.

In 2020, the EAST-AFNET 4 trial showed that early rhythm control was better than rate control for reducing adverse cardiovascular outcomes, but the trial only included patients at risk of stroke with a CHA2DS2-VASc score of at least 2, leaving it unclear whether healthier patients might benefit from the same approach.

“Although the primary indication for rhythm control is to alleviate AF[ib]-related symptoms and improve quality of life, the current guidelines suggest younger age and no or few comorbid conditions as factors favoring rhythm control,” the investigators wrote in Annals of Internal Medicine. “Thus, the effect of rhythm control on cardiovascular outcomes in this population requires elucidation.”
 

Methods and results

The present study aimed to address this knowledge gap by reviewing data from 54,216 patients with AFib who had rhythm control (ablation or medication) or rate control within one year of diagnosis. Among these patients, 69.3% would have qualified for the EAST-AFNET 4 trial based on higher stroke risk, while the remaining 30.7% of patients would not have been eligible because of lower stroke risk. Median age, consequently, was higher in the former group, at 70 years, versus 54 years in the latter group.

Evaluating the same primary composite outcome as the EAST-AFNET 4 trial (cardiovascular death, ischemic stroke, hospitalization for heart failure, or MI) showed that patients benefited from rhythm control over rate control regardless of risk group.

Those in the higher risk group had a 14% reduced risk of negative cardiovascular outcomes (weighted hazard ratio, 0.86; 95% confidence interval, 0.81-0.92), while those in the lower risk group had a 19% reduced risk of adverse cardiovascular outcomes (weighted HR, 0.81; 95% CI, 0.66-0.98). Safety profiles were similar across groups and management strategies.
 

Rhythm control well supported from statistical perspective

“We think that physicians should pursue early rhythm control in all patients diagnosed with AF[ib],” principal author Boyoung Joung, MD, PhD, of Yonsei University said in an interview. “Like catheter ablation, we support the idea that early rhythm control can be more effective and safely performed in younger and less frail populations.”

Xiaoxi Yao, PhD, MPH, associate professor of health services research at Mayo Clinic, Rochester, Minn., agreed that rhythm control is now well supported from a statistical perspective, but patients and physicians need to look beyond relative risk improvements, and remain pragmatic.

“There is a benefit, but the benefit is consistent in terms of hazard ratio, or relative risk,” Dr. Yao said in an interview. “You still find a smaller absolute risk difference.”

Patients in the United States – versus Korea where the investigators are based – also need to consider the out-of-pocket costs involved in rhythm control, Dr. Yao said, noting that unclear cost effectiveness may also prevent changes to American guidelines. Medication side effects and procedural risks should also be considered, she added, as well as time off from work needed for ablation.

Dr. Yao, who published a similar paper in June and previously evaluated the role of catheter ablation in routine practice, suggested that the youngest patients may have the most to gain from rhythm control. This is because even a small absolute benefit is magnified with time, she said.

“Since [younger patients] have another several decades to live ... then yes, there might be very significant long-term effects in terms of both symptom control and cardiovascular death and stroke,” Dr. Yao said.

For optimal patient selection, however, more advanced tools are needed, which is why Dr. Yao and her colleagues are exploring new technologies to improve risk-benefit analysis.

“We are not only interested in [a patient’s] baseline high or low risk, but also the extent of risk reduction [that rhythm control provides],” Dr. Yao said. “We are trying to see if there is an [artificial intelligence] or machine-learning approach that can help us provide each patient with a more accurate, individualized estimate to help them make their decision.”

Until then, Dr. Yao encouraged physicians to engage in shared decision-making with patients, making sure to discuss both statistical and practical considerations.

The study was funded by the Ministry of Health and Welfare and the Ministry of Food and Drug Safety of the Republic of Korea. The investigators and Dr. Yao reported no conflicts.

Early rhythm control for patients with atrial fibrillation (AFib) improves cardiovascular outcomes regardless of an individual’s stroke risk, a large retrospective study finds.

These findings broaden support for early rhythm control, suggesting that physicians should be presenting the option to all patients diagnosed with AFib in routine clinical practice, lead author Daehoon Kim, MD, of Yonsei University, Seoul, South Korea, and colleagues reported.

In 2020, the EAST-AFNET 4 trial showed that early rhythm control was better than rate control for reducing adverse cardiovascular outcomes, but the trial only included patients at risk of stroke with a CHA2DS2-VASc score of at least 2, leaving it unclear whether healthier patients might benefit from the same approach.

“Although the primary indication for rhythm control is to alleviate AF[ib]-related symptoms and improve quality of life, the current guidelines suggest younger age and no or few comorbid conditions as factors favoring rhythm control,” the investigators wrote in Annals of Internal Medicine. “Thus, the effect of rhythm control on cardiovascular outcomes in this population requires elucidation.”
 

Methods and results

The present study aimed to address this knowledge gap by reviewing data from 54,216 patients with AFib who had rhythm control (ablation or medication) or rate control within one year of diagnosis. Among these patients, 69.3% would have qualified for the EAST-AFNET 4 trial based on higher stroke risk, while the remaining 30.7% of patients would not have been eligible because of lower stroke risk. Median age, consequently, was higher in the former group, at 70 years, versus 54 years in the latter group.

Evaluating the same primary composite outcome as the EAST-AFNET 4 trial (cardiovascular death, ischemic stroke, hospitalization for heart failure, or MI) showed that patients benefited from rhythm control over rate control regardless of risk group.

Those in the higher risk group had a 14% reduced risk of negative cardiovascular outcomes (weighted hazard ratio, 0.86; 95% confidence interval, 0.81-0.92), while those in the lower risk group had a 19% reduced risk of adverse cardiovascular outcomes (weighted HR, 0.81; 95% CI, 0.66-0.98). Safety profiles were similar across groups and management strategies.
 

Rhythm control well supported from statistical perspective

“We think that physicians should pursue early rhythm control in all patients diagnosed with AF[ib],” principal author Boyoung Joung, MD, PhD, of Yonsei University said in an interview. “Like catheter ablation, we support the idea that early rhythm control can be more effective and safely performed in younger and less frail populations.”

Xiaoxi Yao, PhD, MPH, associate professor of health services research at Mayo Clinic, Rochester, Minn., agreed that rhythm control is now well supported from a statistical perspective, but patients and physicians need to look beyond relative risk improvements, and remain pragmatic.

“There is a benefit, but the benefit is consistent in terms of hazard ratio, or relative risk,” Dr. Yao said in an interview. “You still find a smaller absolute risk difference.”

Patients in the United States – versus Korea where the investigators are based – also need to consider the out-of-pocket costs involved in rhythm control, Dr. Yao said, noting that unclear cost effectiveness may also prevent changes to American guidelines. Medication side effects and procedural risks should also be considered, she added, as well as time off from work needed for ablation.

Dr. Yao, who published a similar paper in June and previously evaluated the role of catheter ablation in routine practice, suggested that the youngest patients may have the most to gain from rhythm control. This is because even a small absolute benefit is magnified with time, she said.

“Since [younger patients] have another several decades to live ... then yes, there might be very significant long-term effects in terms of both symptom control and cardiovascular death and stroke,” Dr. Yao said.

For optimal patient selection, however, more advanced tools are needed, which is why Dr. Yao and her colleagues are exploring new technologies to improve risk-benefit analysis.

“We are not only interested in [a patient’s] baseline high or low risk, but also the extent of risk reduction [that rhythm control provides],” Dr. Yao said. “We are trying to see if there is an [artificial intelligence] or machine-learning approach that can help us provide each patient with a more accurate, individualized estimate to help them make their decision.”

Until then, Dr. Yao encouraged physicians to engage in shared decision-making with patients, making sure to discuss both statistical and practical considerations.

The study was funded by the Ministry of Health and Welfare and the Ministry of Food and Drug Safety of the Republic of Korea. The investigators and Dr. Yao reported no conflicts.