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Endoscopy experts review training, assessment evidence
Endoscopic training is increasingly complex as benchmarks for quality evolve and tools and procedures advance with innovation.
A team of experts, led by Matthew J. Whitson, MD, with Hofstra University/Northwell Health in Hempstead, N.Y., aimed to simplify challenges for educators and clinical endoscopists with a review of tools and techniques for education, as well as assessment methods.
Their review was published in the Techniques and Innovations in Gastrointestinal Endoscopy.
Giving feedback
Key steps to effective feedback include first talking about the goals for the endoscopy session, then careful observation, but minimal feedback during the endoscopy. Most of the feedback should come after the endoscopy, the authors wrote.
A paper by Walsh et al. demonstrated that with beginning endoscopists, giving feedback afterward led to long-term skill development as compared with short-term benefits of frequent feedback in the middle of procedures.
Feedback should be constructive and specific with emphasis on goals for the next procedure. It should be delivered in a respectful, nonthreatening way for greatest effectiveness.
Mastery learning
In this model, each trainee must achieve competence in specific skills to progress to the next level.
“For example, the trainee must master retroflexion in the stomach prior to attempting clip hemostasis in the stomach,” the authors wrote.
Repetitively practicing the skill is coupled with direct feedback.
Mastery learning is often paired with simulation so trainees can practice in a safe space before working with patients.
Cognitive load theory
Knowing the challenges of learners can help educators with instruction techniques. An important concept is cognitive load theory (CLT). CLT is focused on the working memory of a learner and the harm that an overload of information can have on learning. A learner’s working memory can process only a few pieces of information at any given time, the theory states.
One mitigation strategy by educators may be to assign a trainee a smaller piece of a specific task appropriate to the trainee’s skill level.
“For example, an early trainee endoscopist may be able to inject epinephrine for a bleeding vessel, but not be ready to perform effective BiCap cautery,” the authors suggested.
Different learning styles
Learning styles include visual, aural, reading/writing, and kinesthetic styles (when learners need to touch or manipulate to learn a skill).
“A study of surgical trainees demonstrated that kinesthetic learning was the most preferred unimodal learning style of those entering the field,” the authors wrote.
Dr. Whitson and coauthors gave examples of working with trainees with different learning styles.
A trainee who learns visually, they say, might need to learn about “loop reduction” by looking at images of alpha or beta loops or using ScopeGuide during endoscopy. A kinesthetic learner may need to feel a successful loop reduction with hands on the endoscope during simulation to understand the skill better.
“There is some suggestion that the millennial generation – the demographic of the current gastroenterology fellows – may have higher preferences for kinesthetic learning,” the authors wrote.
Role of simulation
The Accreditation Council for Graduate Medical Education, which oversees Gastroenterology Fellowship training, mandates simulation in gastroenterology education but does not specify endoscopic simulation. The American Board of Surgeons, however, does require their trainees to complete the flexible endoscopic curriculum, which is simulation-based.
Simulator use appears particularly helpful early in training. One study demonstrated that colonoscopy simulation has benefit in the first 30 colonoscopies in depth of insertion, independent completion, and ability to identify landmarks.
However, another study showed simulation after 50 colonoscopies has shown no benefit, the authors wrote. Finding uses for simulators beyond diagnostics will be important for justifying buying more of them for medical centers given the high cost.
Procedural volume
Dr. Whitson and colleagues wrote that using sheer volume of procedures as a measure of competency is falling out of favor and there is recognition in the field that competency will come at different times and at different volumes for individual trainees.
A study assessing competency in esophagogastroduodenoscopy (EGD), for example, demonstrated that, while most trainees will achieve independent intubation rates of the second part of the duodenum by 150 procedures, it will take between 200 and 250 for the average fellow to reach competency of all motor skills for a standard EGD, and 300 to become efficient (Gastrointest Endosc. 2019;90(4):613-20).
Assessment of skills has evolved from numbers of procedures to competency-based assessments to the development of direct observation tools.
Coaching for the practicing endoscopist
Most studies on coaching have focused on trainees, but coaching can be used with experienced endoscopists as well.
One study investigated use of direct verbal coaching to train experienced practitioners in water immersion colonoscopy “which resulted in shorter cecal intubation times, improved [adenoma detection rate], and less use of sedation during procedures,” the authors noted. Another study currently underway in the United Kingdom uses electronic feedback coupled with education and training to change behaviors to improve polyp detection performance in colonoscopy.
The authors noted that using one of these tools or strategies does not preclude using another.
“[I]n fact educators likely will recognize the utility of incorporating multiple of these techniques in the same endoscopy session with a trainee,” the authors wrote.
One author holds stock in Boston Scientific. The remaining authors disclose no conflicts.
Whitson, Williams, and Shah eloquently and thoroughly explore the principles central to successful training and review the latest understanding of best practices to apply them. Beyond fellows, this will have ongoing relevance to practicing endoscopists as they must learn new skills and in turn apply them in teaching others.
The authors rightly emphasize the concern for cognitive overload. In practice, a maximum of one or two take-home lessons per mentored training session is a good rule of thumb; the converse should be equally emphasized, that every single proctored training examination ought to be mined for at least one relevant lesson, be it technical, cognitive, or another nontechnical pearl related to teamwork, professionalism, and so on.
Much simulator investigation to date, including my own, has focused on technical skills and performance outcomes – more work is needed especially in web, simulator, and even AI-based tools to teach cognitive skills for recognizing abnormalities, identifying them, and making real-time evidence-based decisions. The value of simulator-based teaching of endoscopic nontechnical skills, practice in troubleshooting common mishaps, and teaching by counter example of what not to do are other areas of great promise. There is not yet a prescribed, evidence-based guideline regarding which simulation devices should be used, at what stages of fellowship, and how often; however, the principles described in this paper provide the road map for how simulation ought to be integrated into endoscopic teaching.
Jonathan Cohen, MD is a clinical professor of medicine at New York University. He is the Editor of “Successful Training in Gastrointestinal Endoscopy,” 2nd ed. (Hoboken, N.J.: Wiley-Blackwell, 2022) and an investigator in ex vivo and computer endoscopy simulators. He is a consultant for Olympus America and Micro-Tech Endoscopy, receives royalties from Wouters-Kluwer and Wiley, and holds stock in GI Windows, Virtual Health Partners, ROMtech, and MD Medical Navigators.
Whitson, Williams, and Shah eloquently and thoroughly explore the principles central to successful training and review the latest understanding of best practices to apply them. Beyond fellows, this will have ongoing relevance to practicing endoscopists as they must learn new skills and in turn apply them in teaching others.
The authors rightly emphasize the concern for cognitive overload. In practice, a maximum of one or two take-home lessons per mentored training session is a good rule of thumb; the converse should be equally emphasized, that every single proctored training examination ought to be mined for at least one relevant lesson, be it technical, cognitive, or another nontechnical pearl related to teamwork, professionalism, and so on.
Much simulator investigation to date, including my own, has focused on technical skills and performance outcomes – more work is needed especially in web, simulator, and even AI-based tools to teach cognitive skills for recognizing abnormalities, identifying them, and making real-time evidence-based decisions. The value of simulator-based teaching of endoscopic nontechnical skills, practice in troubleshooting common mishaps, and teaching by counter example of what not to do are other areas of great promise. There is not yet a prescribed, evidence-based guideline regarding which simulation devices should be used, at what stages of fellowship, and how often; however, the principles described in this paper provide the road map for how simulation ought to be integrated into endoscopic teaching.
Jonathan Cohen, MD is a clinical professor of medicine at New York University. He is the Editor of “Successful Training in Gastrointestinal Endoscopy,” 2nd ed. (Hoboken, N.J.: Wiley-Blackwell, 2022) and an investigator in ex vivo and computer endoscopy simulators. He is a consultant for Olympus America and Micro-Tech Endoscopy, receives royalties from Wouters-Kluwer and Wiley, and holds stock in GI Windows, Virtual Health Partners, ROMtech, and MD Medical Navigators.
Whitson, Williams, and Shah eloquently and thoroughly explore the principles central to successful training and review the latest understanding of best practices to apply them. Beyond fellows, this will have ongoing relevance to practicing endoscopists as they must learn new skills and in turn apply them in teaching others.
The authors rightly emphasize the concern for cognitive overload. In practice, a maximum of one or two take-home lessons per mentored training session is a good rule of thumb; the converse should be equally emphasized, that every single proctored training examination ought to be mined for at least one relevant lesson, be it technical, cognitive, or another nontechnical pearl related to teamwork, professionalism, and so on.
Much simulator investigation to date, including my own, has focused on technical skills and performance outcomes – more work is needed especially in web, simulator, and even AI-based tools to teach cognitive skills for recognizing abnormalities, identifying them, and making real-time evidence-based decisions. The value of simulator-based teaching of endoscopic nontechnical skills, practice in troubleshooting common mishaps, and teaching by counter example of what not to do are other areas of great promise. There is not yet a prescribed, evidence-based guideline regarding which simulation devices should be used, at what stages of fellowship, and how often; however, the principles described in this paper provide the road map for how simulation ought to be integrated into endoscopic teaching.
Jonathan Cohen, MD is a clinical professor of medicine at New York University. He is the Editor of “Successful Training in Gastrointestinal Endoscopy,” 2nd ed. (Hoboken, N.J.: Wiley-Blackwell, 2022) and an investigator in ex vivo and computer endoscopy simulators. He is a consultant for Olympus America and Micro-Tech Endoscopy, receives royalties from Wouters-Kluwer and Wiley, and holds stock in GI Windows, Virtual Health Partners, ROMtech, and MD Medical Navigators.
Endoscopic training is increasingly complex as benchmarks for quality evolve and tools and procedures advance with innovation.
A team of experts, led by Matthew J. Whitson, MD, with Hofstra University/Northwell Health in Hempstead, N.Y., aimed to simplify challenges for educators and clinical endoscopists with a review of tools and techniques for education, as well as assessment methods.
Their review was published in the Techniques and Innovations in Gastrointestinal Endoscopy.
Giving feedback
Key steps to effective feedback include first talking about the goals for the endoscopy session, then careful observation, but minimal feedback during the endoscopy. Most of the feedback should come after the endoscopy, the authors wrote.
A paper by Walsh et al. demonstrated that with beginning endoscopists, giving feedback afterward led to long-term skill development as compared with short-term benefits of frequent feedback in the middle of procedures.
Feedback should be constructive and specific with emphasis on goals for the next procedure. It should be delivered in a respectful, nonthreatening way for greatest effectiveness.
Mastery learning
In this model, each trainee must achieve competence in specific skills to progress to the next level.
“For example, the trainee must master retroflexion in the stomach prior to attempting clip hemostasis in the stomach,” the authors wrote.
Repetitively practicing the skill is coupled with direct feedback.
Mastery learning is often paired with simulation so trainees can practice in a safe space before working with patients.
Cognitive load theory
Knowing the challenges of learners can help educators with instruction techniques. An important concept is cognitive load theory (CLT). CLT is focused on the working memory of a learner and the harm that an overload of information can have on learning. A learner’s working memory can process only a few pieces of information at any given time, the theory states.
One mitigation strategy by educators may be to assign a trainee a smaller piece of a specific task appropriate to the trainee’s skill level.
“For example, an early trainee endoscopist may be able to inject epinephrine for a bleeding vessel, but not be ready to perform effective BiCap cautery,” the authors suggested.
Different learning styles
Learning styles include visual, aural, reading/writing, and kinesthetic styles (when learners need to touch or manipulate to learn a skill).
“A study of surgical trainees demonstrated that kinesthetic learning was the most preferred unimodal learning style of those entering the field,” the authors wrote.
Dr. Whitson and coauthors gave examples of working with trainees with different learning styles.
A trainee who learns visually, they say, might need to learn about “loop reduction” by looking at images of alpha or beta loops or using ScopeGuide during endoscopy. A kinesthetic learner may need to feel a successful loop reduction with hands on the endoscope during simulation to understand the skill better.
“There is some suggestion that the millennial generation – the demographic of the current gastroenterology fellows – may have higher preferences for kinesthetic learning,” the authors wrote.
Role of simulation
The Accreditation Council for Graduate Medical Education, which oversees Gastroenterology Fellowship training, mandates simulation in gastroenterology education but does not specify endoscopic simulation. The American Board of Surgeons, however, does require their trainees to complete the flexible endoscopic curriculum, which is simulation-based.
Simulator use appears particularly helpful early in training. One study demonstrated that colonoscopy simulation has benefit in the first 30 colonoscopies in depth of insertion, independent completion, and ability to identify landmarks.
However, another study showed simulation after 50 colonoscopies has shown no benefit, the authors wrote. Finding uses for simulators beyond diagnostics will be important for justifying buying more of them for medical centers given the high cost.
Procedural volume
Dr. Whitson and colleagues wrote that using sheer volume of procedures as a measure of competency is falling out of favor and there is recognition in the field that competency will come at different times and at different volumes for individual trainees.
A study assessing competency in esophagogastroduodenoscopy (EGD), for example, demonstrated that, while most trainees will achieve independent intubation rates of the second part of the duodenum by 150 procedures, it will take between 200 and 250 for the average fellow to reach competency of all motor skills for a standard EGD, and 300 to become efficient (Gastrointest Endosc. 2019;90(4):613-20).
Assessment of skills has evolved from numbers of procedures to competency-based assessments to the development of direct observation tools.
Coaching for the practicing endoscopist
Most studies on coaching have focused on trainees, but coaching can be used with experienced endoscopists as well.
One study investigated use of direct verbal coaching to train experienced practitioners in water immersion colonoscopy “which resulted in shorter cecal intubation times, improved [adenoma detection rate], and less use of sedation during procedures,” the authors noted. Another study currently underway in the United Kingdom uses electronic feedback coupled with education and training to change behaviors to improve polyp detection performance in colonoscopy.
The authors noted that using one of these tools or strategies does not preclude using another.
“[I]n fact educators likely will recognize the utility of incorporating multiple of these techniques in the same endoscopy session with a trainee,” the authors wrote.
One author holds stock in Boston Scientific. The remaining authors disclose no conflicts.
Endoscopic training is increasingly complex as benchmarks for quality evolve and tools and procedures advance with innovation.
A team of experts, led by Matthew J. Whitson, MD, with Hofstra University/Northwell Health in Hempstead, N.Y., aimed to simplify challenges for educators and clinical endoscopists with a review of tools and techniques for education, as well as assessment methods.
Their review was published in the Techniques and Innovations in Gastrointestinal Endoscopy.
Giving feedback
Key steps to effective feedback include first talking about the goals for the endoscopy session, then careful observation, but minimal feedback during the endoscopy. Most of the feedback should come after the endoscopy, the authors wrote.
A paper by Walsh et al. demonstrated that with beginning endoscopists, giving feedback afterward led to long-term skill development as compared with short-term benefits of frequent feedback in the middle of procedures.
Feedback should be constructive and specific with emphasis on goals for the next procedure. It should be delivered in a respectful, nonthreatening way for greatest effectiveness.
Mastery learning
In this model, each trainee must achieve competence in specific skills to progress to the next level.
“For example, the trainee must master retroflexion in the stomach prior to attempting clip hemostasis in the stomach,” the authors wrote.
Repetitively practicing the skill is coupled with direct feedback.
Mastery learning is often paired with simulation so trainees can practice in a safe space before working with patients.
Cognitive load theory
Knowing the challenges of learners can help educators with instruction techniques. An important concept is cognitive load theory (CLT). CLT is focused on the working memory of a learner and the harm that an overload of information can have on learning. A learner’s working memory can process only a few pieces of information at any given time, the theory states.
One mitigation strategy by educators may be to assign a trainee a smaller piece of a specific task appropriate to the trainee’s skill level.
“For example, an early trainee endoscopist may be able to inject epinephrine for a bleeding vessel, but not be ready to perform effective BiCap cautery,” the authors suggested.
Different learning styles
Learning styles include visual, aural, reading/writing, and kinesthetic styles (when learners need to touch or manipulate to learn a skill).
“A study of surgical trainees demonstrated that kinesthetic learning was the most preferred unimodal learning style of those entering the field,” the authors wrote.
Dr. Whitson and coauthors gave examples of working with trainees with different learning styles.
A trainee who learns visually, they say, might need to learn about “loop reduction” by looking at images of alpha or beta loops or using ScopeGuide during endoscopy. A kinesthetic learner may need to feel a successful loop reduction with hands on the endoscope during simulation to understand the skill better.
“There is some suggestion that the millennial generation – the demographic of the current gastroenterology fellows – may have higher preferences for kinesthetic learning,” the authors wrote.
Role of simulation
The Accreditation Council for Graduate Medical Education, which oversees Gastroenterology Fellowship training, mandates simulation in gastroenterology education but does not specify endoscopic simulation. The American Board of Surgeons, however, does require their trainees to complete the flexible endoscopic curriculum, which is simulation-based.
Simulator use appears particularly helpful early in training. One study demonstrated that colonoscopy simulation has benefit in the first 30 colonoscopies in depth of insertion, independent completion, and ability to identify landmarks.
However, another study showed simulation after 50 colonoscopies has shown no benefit, the authors wrote. Finding uses for simulators beyond diagnostics will be important for justifying buying more of them for medical centers given the high cost.
Procedural volume
Dr. Whitson and colleagues wrote that using sheer volume of procedures as a measure of competency is falling out of favor and there is recognition in the field that competency will come at different times and at different volumes for individual trainees.
A study assessing competency in esophagogastroduodenoscopy (EGD), for example, demonstrated that, while most trainees will achieve independent intubation rates of the second part of the duodenum by 150 procedures, it will take between 200 and 250 for the average fellow to reach competency of all motor skills for a standard EGD, and 300 to become efficient (Gastrointest Endosc. 2019;90(4):613-20).
Assessment of skills has evolved from numbers of procedures to competency-based assessments to the development of direct observation tools.
Coaching for the practicing endoscopist
Most studies on coaching have focused on trainees, but coaching can be used with experienced endoscopists as well.
One study investigated use of direct verbal coaching to train experienced practitioners in water immersion colonoscopy “which resulted in shorter cecal intubation times, improved [adenoma detection rate], and less use of sedation during procedures,” the authors noted. Another study currently underway in the United Kingdom uses electronic feedback coupled with education and training to change behaviors to improve polyp detection performance in colonoscopy.
The authors noted that using one of these tools or strategies does not preclude using another.
“[I]n fact educators likely will recognize the utility of incorporating multiple of these techniques in the same endoscopy session with a trainee,” the authors wrote.
One author holds stock in Boston Scientific. The remaining authors disclose no conflicts.
FROM TECHNIQUES AND INNOVATIONS IN GASTROINTESTINAL ENDOSCOPY
Commentary: Clinical Use of SGLT2 Inhibitors, GLP-1RA, and Insulin, September 2022
Many sodium-glucose cotransporter-2 (SGLT2) inhibitors are approved for use at two doses, but there are few clinical data regarding the metabolic impact of uptitrating an SGLT2 inhibitor from the lower to the higher dose in clinical practice. Matsumura and colleagues published the results of a retrospective, longitudinal study at a single institution in Japan. A total of 52 participants who were treated with 10 mg empagliflozin once daily were analyzed at 26 weeks after the dose had been increased to 25 mg once daily. The researchers reported a 0.6 kg weight reduction, a 0.15% reduction in A1c, and a 22.1 mg/dL reduction in triglycerides in the participants on the higher dose of empagliflozin. Although the benefits of the higher dose were rather small, this study does aid the clinician regarding the clinical impact of increasing the dose of empagliflozin.
Outcome studies with SGLT2 inhibitors have shown reductions in major adverse cardiovascular events (MACE), heart failure hospitalization, and mortality. However, clinicians may be reluctant to initiate SGLT2 inhibitors in frail individuals as they are often excluded from randomized trials and may be more likely to have side effects from this class of medications. Wood and colleagues conducted a cohort study in Australia, comparing the effectiveness of SGLT2 inhibitors to that of dipeptidyl peptidase-4 (DPP-4) inhibitors. The study was done with individuals with type 2 diabetes who were initiated on these agents within 60 days of a hospital discharge. It was noted that SGLT2 inhibitors significantly reduced MACE, heart failure hospitalization, and mortality compared with DPP-4 inhibitors, and this benefit was present in both frail and nonfrail individuals. The study did not report on tolerability issues and is limited by the cohort design, but it does suggest a cardiovascular benefit among frail patients with type 2 diabetes who are treated with SGLT2 inhibitors, and it may be reassuring when considering an SGLT2 inhibitor in a frail person.
In my July 2022 commentary, I discussed the results of AWARD-PEDS, which demonstrated a significant A1c reduction but no weight loss with the glucagon-like peptide-1 receptor agonist (GLP-1RA) dulaglutide in youth with type 2 diabetes. Tamborlane and colleagues have now reported the results of a randomized trial that studied the efficacy and safety of 2 mg exenatide once weekly in youth with type 2 diabetes. Similarly to the AWARD-PEDS study, A1c was significantly reduced compared with placebo, with a difference of -0.85% at 24 weeks. Also similarly to AWARD-PEDS, there was no significant difference in body weight between the GLP-1RA and placebo groups. There are now three studies showing glycemic benefits but little weight loss with GLP-1RA treatment in youth with type 2 diabetes, and while the glycemic benefits are encouraging, it remains perplexing why these studies have not demonstrated the weight loss that has consistently been demonstrated in adult studies of GLP-1RA.
Clinicians often choose a second-generation basal insulin analog (glargine U300, degludec) over a first-generation basal analog (glargine U100, detemir) because of lower rates of hypoglycemia. Randomized clinical trials and real-world evidence (RWE) studies comparing glargine U100 vs degludec have shown somewhat inconsistent results. In the newest RWE study comparing these two second-generation analogs, RESTORE-2 NAIVE, Fadini and colleagues reported that 6 months after initiating either glargine U300 or degludec in insulin-naive type 2 diabetes, there was a similar improvement in glycemia, no weight gain, and low hypoglycemia rates in each group. RESTORE-2 is another study demonstrating similar results between the two second-generation insulin analogs and helps build our understanding that these two insulins are more similar than different.
Many sodium-glucose cotransporter-2 (SGLT2) inhibitors are approved for use at two doses, but there are few clinical data regarding the metabolic impact of uptitrating an SGLT2 inhibitor from the lower to the higher dose in clinical practice. Matsumura and colleagues published the results of a retrospective, longitudinal study at a single institution in Japan. A total of 52 participants who were treated with 10 mg empagliflozin once daily were analyzed at 26 weeks after the dose had been increased to 25 mg once daily. The researchers reported a 0.6 kg weight reduction, a 0.15% reduction in A1c, and a 22.1 mg/dL reduction in triglycerides in the participants on the higher dose of empagliflozin. Although the benefits of the higher dose were rather small, this study does aid the clinician regarding the clinical impact of increasing the dose of empagliflozin.
Outcome studies with SGLT2 inhibitors have shown reductions in major adverse cardiovascular events (MACE), heart failure hospitalization, and mortality. However, clinicians may be reluctant to initiate SGLT2 inhibitors in frail individuals as they are often excluded from randomized trials and may be more likely to have side effects from this class of medications. Wood and colleagues conducted a cohort study in Australia, comparing the effectiveness of SGLT2 inhibitors to that of dipeptidyl peptidase-4 (DPP-4) inhibitors. The study was done with individuals with type 2 diabetes who were initiated on these agents within 60 days of a hospital discharge. It was noted that SGLT2 inhibitors significantly reduced MACE, heart failure hospitalization, and mortality compared with DPP-4 inhibitors, and this benefit was present in both frail and nonfrail individuals. The study did not report on tolerability issues and is limited by the cohort design, but it does suggest a cardiovascular benefit among frail patients with type 2 diabetes who are treated with SGLT2 inhibitors, and it may be reassuring when considering an SGLT2 inhibitor in a frail person.
In my July 2022 commentary, I discussed the results of AWARD-PEDS, which demonstrated a significant A1c reduction but no weight loss with the glucagon-like peptide-1 receptor agonist (GLP-1RA) dulaglutide in youth with type 2 diabetes. Tamborlane and colleagues have now reported the results of a randomized trial that studied the efficacy and safety of 2 mg exenatide once weekly in youth with type 2 diabetes. Similarly to the AWARD-PEDS study, A1c was significantly reduced compared with placebo, with a difference of -0.85% at 24 weeks. Also similarly to AWARD-PEDS, there was no significant difference in body weight between the GLP-1RA and placebo groups. There are now three studies showing glycemic benefits but little weight loss with GLP-1RA treatment in youth with type 2 diabetes, and while the glycemic benefits are encouraging, it remains perplexing why these studies have not demonstrated the weight loss that has consistently been demonstrated in adult studies of GLP-1RA.
Clinicians often choose a second-generation basal insulin analog (glargine U300, degludec) over a first-generation basal analog (glargine U100, detemir) because of lower rates of hypoglycemia. Randomized clinical trials and real-world evidence (RWE) studies comparing glargine U100 vs degludec have shown somewhat inconsistent results. In the newest RWE study comparing these two second-generation analogs, RESTORE-2 NAIVE, Fadini and colleagues reported that 6 months after initiating either glargine U300 or degludec in insulin-naive type 2 diabetes, there was a similar improvement in glycemia, no weight gain, and low hypoglycemia rates in each group. RESTORE-2 is another study demonstrating similar results between the two second-generation insulin analogs and helps build our understanding that these two insulins are more similar than different.
Many sodium-glucose cotransporter-2 (SGLT2) inhibitors are approved for use at two doses, but there are few clinical data regarding the metabolic impact of uptitrating an SGLT2 inhibitor from the lower to the higher dose in clinical practice. Matsumura and colleagues published the results of a retrospective, longitudinal study at a single institution in Japan. A total of 52 participants who were treated with 10 mg empagliflozin once daily were analyzed at 26 weeks after the dose had been increased to 25 mg once daily. The researchers reported a 0.6 kg weight reduction, a 0.15% reduction in A1c, and a 22.1 mg/dL reduction in triglycerides in the participants on the higher dose of empagliflozin. Although the benefits of the higher dose were rather small, this study does aid the clinician regarding the clinical impact of increasing the dose of empagliflozin.
Outcome studies with SGLT2 inhibitors have shown reductions in major adverse cardiovascular events (MACE), heart failure hospitalization, and mortality. However, clinicians may be reluctant to initiate SGLT2 inhibitors in frail individuals as they are often excluded from randomized trials and may be more likely to have side effects from this class of medications. Wood and colleagues conducted a cohort study in Australia, comparing the effectiveness of SGLT2 inhibitors to that of dipeptidyl peptidase-4 (DPP-4) inhibitors. The study was done with individuals with type 2 diabetes who were initiated on these agents within 60 days of a hospital discharge. It was noted that SGLT2 inhibitors significantly reduced MACE, heart failure hospitalization, and mortality compared with DPP-4 inhibitors, and this benefit was present in both frail and nonfrail individuals. The study did not report on tolerability issues and is limited by the cohort design, but it does suggest a cardiovascular benefit among frail patients with type 2 diabetes who are treated with SGLT2 inhibitors, and it may be reassuring when considering an SGLT2 inhibitor in a frail person.
In my July 2022 commentary, I discussed the results of AWARD-PEDS, which demonstrated a significant A1c reduction but no weight loss with the glucagon-like peptide-1 receptor agonist (GLP-1RA) dulaglutide in youth with type 2 diabetes. Tamborlane and colleagues have now reported the results of a randomized trial that studied the efficacy and safety of 2 mg exenatide once weekly in youth with type 2 diabetes. Similarly to the AWARD-PEDS study, A1c was significantly reduced compared with placebo, with a difference of -0.85% at 24 weeks. Also similarly to AWARD-PEDS, there was no significant difference in body weight between the GLP-1RA and placebo groups. There are now three studies showing glycemic benefits but little weight loss with GLP-1RA treatment in youth with type 2 diabetes, and while the glycemic benefits are encouraging, it remains perplexing why these studies have not demonstrated the weight loss that has consistently been demonstrated in adult studies of GLP-1RA.
Clinicians often choose a second-generation basal insulin analog (glargine U300, degludec) over a first-generation basal analog (glargine U100, detemir) because of lower rates of hypoglycemia. Randomized clinical trials and real-world evidence (RWE) studies comparing glargine U100 vs degludec have shown somewhat inconsistent results. In the newest RWE study comparing these two second-generation analogs, RESTORE-2 NAIVE, Fadini and colleagues reported that 6 months after initiating either glargine U300 or degludec in insulin-naive type 2 diabetes, there was a similar improvement in glycemia, no weight gain, and low hypoglycemia rates in each group. RESTORE-2 is another study demonstrating similar results between the two second-generation insulin analogs and helps build our understanding that these two insulins are more similar than different.
Reduced-lactose infant formula related to higher risk of obesity later
Doctors may want to advise parents against giving their infants lactose-reduced infant formula unless absolutely necessary, because doing so may be setting babies up for an increased risk of obesity in toddlerhood, new research shows.
Infants who drink infant formula instead of breast milk already carry an increased risk of obesity. But the new study, published in The American Journal of Clinical Nutrition, found a difference in types of formula and obesity outcomes for children.
Babies under 1 year who received lactose-reduced formula made partially of corn syrup solids were at a 10% greater risk (risk ratio, 1.10; 95% confidence interval, 1.02, 1.20; P = .02) of being obese by age 2 than infants who received regular cow’s milk formula.
“This is even another reason to not use a low-lactose formula,” said Mark R. Corkins, MD, division chief of pediatric gastroenterology, hepatology, and nutrition at the University of Tennessee Health Science Center, Memphis, who was not involved in the study. “Parents think if babies are fussy, or they spit up, they have lactose intolerance, but if you look at the actual numbers, lactose intolerance in infants is rare.”
Actual lactose intolerance in infancy is the result of a newborn receiving the same mutated gene from both parents, called congenital lactase deficiency, said Dr. Corkins.
“The reason the low-lactose formulas are even on the market is because parents want them, and they think their kid is lactose intolerant, but they are not,” Dr. Corkins said.
Researchers from the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) in southern California and the University of Southern California, Los Angeles, analyzed data from over 15,000 infants in southern California enrolled in WIC.
Records from infants born between Sept. 2012 and March 2016 were separated into two groups: infants that had stopped breastfeeding by month 3 and had started reduced-lactose formula and infants who received all other forms of formula. Over 80% of infants in both groups were Hispanic.
Infants who received the reduced-lactose formula with corn syrup solids were at an 8% increased risk of obesity by age 3 (RR = 1.08; 95% CI, 1.02, 1.15; P = .01), compared with children who received regular cow’s milk formula, and a 7% increased risk by age 4 (RR = 1.07; 95% CI; 1.01, 1.14; P = .01).
Tara Williams, MD, pediatrician and breastfeeding specialist associated with the Florida Chapter of American Academy of Pediatrics, said the findings should make pediatricians, parents, and others pause and consider what infant formulas contain.
She explained that babies who receive formula have higher obesity risk than babies who are breastfed overall. But research into the effects of different types of formula is relatively new. She said there may be a few reasons for the association between reduced-lactose, corn syrup solid formula and a higher risk of obesity.
“The addition of the corn syrup really starts to potentially teach that child to like sweet things,” Dr. Williams said, which in turn can lead to less healthy eating habits in childhood and adulthood.
Or, it may be that parents who tend to give their children lactose-reduced formula are less likely to be tolerant of fussy babies and end up feeding their babies more, Dr. Williams hypothesized.
In addition, emerging research shows corn syrup may act differently from other sugars in the gut microbiome and as it is metabolized in the liver, leading to weight gain.
Although parents make individual choices for what kind of formula to feed their infants, states play a large role in these choices. In 2018, 45% of babies in the United States were eligible for WIC, which is funded through the federal government but administered by states. State WIC programs request bids from formula manufacturers, and products chosen are then redeemed at retailers by parents.
“Now that we’re starting to see a signal that perhaps some formulas will have a potentially added risk of obesity for participants, states may say that when we’re helping mothers select among the formulas, we need to be very explicit about this additional risk,” said Christopher Anderson, PhD, MSPH, associate research scientist at the southern California Public Health Foundation Enterprises WIC and lead author of the study.
Dr. Williams said more research to do similar analyses in other populations is needed to draw cause and effect conclusions, while Dr. Corkins said he’d like to see more research into the amount of formula eaten and health connections to types of formula.
“We know as soon as you sign up for a baby registry at Target, you’re getting formula samples in the mail. You’re very aggressively marketed to; it’s a $55 billion industry,” Dr. Williams said. “And their goal is to sell their product – not to promote the health of infants. “This research certainly will cause us to pause and consider what we are feeding our infants in the United States and how we allow companies to market their products.”
Dr. Goran receives book royalties from Penguin Random House and is a scientific consultant for Yumi Foods and Else Nutrition. All other authors disclosed no conflicts of interest. Dr. Corkins reports working at a clinic that’s the site of a Takeda pharmaceutical research study. Dr. Williams reports no relevant financial relationships.
Doctors may want to advise parents against giving their infants lactose-reduced infant formula unless absolutely necessary, because doing so may be setting babies up for an increased risk of obesity in toddlerhood, new research shows.
Infants who drink infant formula instead of breast milk already carry an increased risk of obesity. But the new study, published in The American Journal of Clinical Nutrition, found a difference in types of formula and obesity outcomes for children.
Babies under 1 year who received lactose-reduced formula made partially of corn syrup solids were at a 10% greater risk (risk ratio, 1.10; 95% confidence interval, 1.02, 1.20; P = .02) of being obese by age 2 than infants who received regular cow’s milk formula.
“This is even another reason to not use a low-lactose formula,” said Mark R. Corkins, MD, division chief of pediatric gastroenterology, hepatology, and nutrition at the University of Tennessee Health Science Center, Memphis, who was not involved in the study. “Parents think if babies are fussy, or they spit up, they have lactose intolerance, but if you look at the actual numbers, lactose intolerance in infants is rare.”
Actual lactose intolerance in infancy is the result of a newborn receiving the same mutated gene from both parents, called congenital lactase deficiency, said Dr. Corkins.
“The reason the low-lactose formulas are even on the market is because parents want them, and they think their kid is lactose intolerant, but they are not,” Dr. Corkins said.
Researchers from the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) in southern California and the University of Southern California, Los Angeles, analyzed data from over 15,000 infants in southern California enrolled in WIC.
Records from infants born between Sept. 2012 and March 2016 were separated into two groups: infants that had stopped breastfeeding by month 3 and had started reduced-lactose formula and infants who received all other forms of formula. Over 80% of infants in both groups were Hispanic.
Infants who received the reduced-lactose formula with corn syrup solids were at an 8% increased risk of obesity by age 3 (RR = 1.08; 95% CI, 1.02, 1.15; P = .01), compared with children who received regular cow’s milk formula, and a 7% increased risk by age 4 (RR = 1.07; 95% CI; 1.01, 1.14; P = .01).
Tara Williams, MD, pediatrician and breastfeeding specialist associated with the Florida Chapter of American Academy of Pediatrics, said the findings should make pediatricians, parents, and others pause and consider what infant formulas contain.
She explained that babies who receive formula have higher obesity risk than babies who are breastfed overall. But research into the effects of different types of formula is relatively new. She said there may be a few reasons for the association between reduced-lactose, corn syrup solid formula and a higher risk of obesity.
“The addition of the corn syrup really starts to potentially teach that child to like sweet things,” Dr. Williams said, which in turn can lead to less healthy eating habits in childhood and adulthood.
Or, it may be that parents who tend to give their children lactose-reduced formula are less likely to be tolerant of fussy babies and end up feeding their babies more, Dr. Williams hypothesized.
In addition, emerging research shows corn syrup may act differently from other sugars in the gut microbiome and as it is metabolized in the liver, leading to weight gain.
Although parents make individual choices for what kind of formula to feed their infants, states play a large role in these choices. In 2018, 45% of babies in the United States were eligible for WIC, which is funded through the federal government but administered by states. State WIC programs request bids from formula manufacturers, and products chosen are then redeemed at retailers by parents.
“Now that we’re starting to see a signal that perhaps some formulas will have a potentially added risk of obesity for participants, states may say that when we’re helping mothers select among the formulas, we need to be very explicit about this additional risk,” said Christopher Anderson, PhD, MSPH, associate research scientist at the southern California Public Health Foundation Enterprises WIC and lead author of the study.
Dr. Williams said more research to do similar analyses in other populations is needed to draw cause and effect conclusions, while Dr. Corkins said he’d like to see more research into the amount of formula eaten and health connections to types of formula.
“We know as soon as you sign up for a baby registry at Target, you’re getting formula samples in the mail. You’re very aggressively marketed to; it’s a $55 billion industry,” Dr. Williams said. “And their goal is to sell their product – not to promote the health of infants. “This research certainly will cause us to pause and consider what we are feeding our infants in the United States and how we allow companies to market their products.”
Dr. Goran receives book royalties from Penguin Random House and is a scientific consultant for Yumi Foods and Else Nutrition. All other authors disclosed no conflicts of interest. Dr. Corkins reports working at a clinic that’s the site of a Takeda pharmaceutical research study. Dr. Williams reports no relevant financial relationships.
Doctors may want to advise parents against giving their infants lactose-reduced infant formula unless absolutely necessary, because doing so may be setting babies up for an increased risk of obesity in toddlerhood, new research shows.
Infants who drink infant formula instead of breast milk already carry an increased risk of obesity. But the new study, published in The American Journal of Clinical Nutrition, found a difference in types of formula and obesity outcomes for children.
Babies under 1 year who received lactose-reduced formula made partially of corn syrup solids were at a 10% greater risk (risk ratio, 1.10; 95% confidence interval, 1.02, 1.20; P = .02) of being obese by age 2 than infants who received regular cow’s milk formula.
“This is even another reason to not use a low-lactose formula,” said Mark R. Corkins, MD, division chief of pediatric gastroenterology, hepatology, and nutrition at the University of Tennessee Health Science Center, Memphis, who was not involved in the study. “Parents think if babies are fussy, or they spit up, they have lactose intolerance, but if you look at the actual numbers, lactose intolerance in infants is rare.”
Actual lactose intolerance in infancy is the result of a newborn receiving the same mutated gene from both parents, called congenital lactase deficiency, said Dr. Corkins.
“The reason the low-lactose formulas are even on the market is because parents want them, and they think their kid is lactose intolerant, but they are not,” Dr. Corkins said.
Researchers from the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) in southern California and the University of Southern California, Los Angeles, analyzed data from over 15,000 infants in southern California enrolled in WIC.
Records from infants born between Sept. 2012 and March 2016 were separated into two groups: infants that had stopped breastfeeding by month 3 and had started reduced-lactose formula and infants who received all other forms of formula. Over 80% of infants in both groups were Hispanic.
Infants who received the reduced-lactose formula with corn syrup solids were at an 8% increased risk of obesity by age 3 (RR = 1.08; 95% CI, 1.02, 1.15; P = .01), compared with children who received regular cow’s milk formula, and a 7% increased risk by age 4 (RR = 1.07; 95% CI; 1.01, 1.14; P = .01).
Tara Williams, MD, pediatrician and breastfeeding specialist associated with the Florida Chapter of American Academy of Pediatrics, said the findings should make pediatricians, parents, and others pause and consider what infant formulas contain.
She explained that babies who receive formula have higher obesity risk than babies who are breastfed overall. But research into the effects of different types of formula is relatively new. She said there may be a few reasons for the association between reduced-lactose, corn syrup solid formula and a higher risk of obesity.
“The addition of the corn syrup really starts to potentially teach that child to like sweet things,” Dr. Williams said, which in turn can lead to less healthy eating habits in childhood and adulthood.
Or, it may be that parents who tend to give their children lactose-reduced formula are less likely to be tolerant of fussy babies and end up feeding their babies more, Dr. Williams hypothesized.
In addition, emerging research shows corn syrup may act differently from other sugars in the gut microbiome and as it is metabolized in the liver, leading to weight gain.
Although parents make individual choices for what kind of formula to feed their infants, states play a large role in these choices. In 2018, 45% of babies in the United States were eligible for WIC, which is funded through the federal government but administered by states. State WIC programs request bids from formula manufacturers, and products chosen are then redeemed at retailers by parents.
“Now that we’re starting to see a signal that perhaps some formulas will have a potentially added risk of obesity for participants, states may say that when we’re helping mothers select among the formulas, we need to be very explicit about this additional risk,” said Christopher Anderson, PhD, MSPH, associate research scientist at the southern California Public Health Foundation Enterprises WIC and lead author of the study.
Dr. Williams said more research to do similar analyses in other populations is needed to draw cause and effect conclusions, while Dr. Corkins said he’d like to see more research into the amount of formula eaten and health connections to types of formula.
“We know as soon as you sign up for a baby registry at Target, you’re getting formula samples in the mail. You’re very aggressively marketed to; it’s a $55 billion industry,” Dr. Williams said. “And their goal is to sell their product – not to promote the health of infants. “This research certainly will cause us to pause and consider what we are feeding our infants in the United States and how we allow companies to market their products.”
Dr. Goran receives book royalties from Penguin Random House and is a scientific consultant for Yumi Foods and Else Nutrition. All other authors disclosed no conflicts of interest. Dr. Corkins reports working at a clinic that’s the site of a Takeda pharmaceutical research study. Dr. Williams reports no relevant financial relationships.
FROM AMERICAN JOURNAL OF CLINICAL NUTRITION
DOJ: Indiana nurses allowed controlled substances during opioid recovery
, according to a statement released Sept. 1.
In March, the U.S. Department of Justice (DOJ) announced the findings of its investigation, stating that the board “violated the ADA by prohibiting nurses who take medication to treat OUD from participating in the Indiana State Nursing Assistance Program [ISNAP].”
ISNAP rehabilitates and monitors nurses with substance use disorders, and the nursing board contracts with vendors to administer the program. Nurses seeking recovery must typically enroll in ISNAP and complete the 1-year program to maintain an active nursing license or have a license reinstated.
Following the investigation, the nursing board was instructed to implement corrective measures, such as revising policies and handbooks and training nursing board staff and vendors on ADA guidelines and nondiscriminatory practices.
The state’s professional organization for nurses said the remediation efforts will help nurses who are struggling with opioid addiction.
Katherine Feley, DNP, RN, chief executive officer of the Indiana State Nurses Association, told this news organization, “Allowing nurses who take medication to treat OUD to remain on their medication when participating in [ISNAP] will avoid making nurses choose between their health and their profession. This improvement will increase access to treatment resources, enabling more nurses to complete treatment and progress toward a safe return to work.”
The DOJ opened an investigation after receiving a complaint from a nurse in which she alleged that she was denied participation in ISNAP because of her use of prescription medication for OUD. In 2013, while participating in a methadone maintenance program, the nurse was told she had to taper off the medication because ISNAP utilizes an “abstinence-based” model. Because of these restrictions, she could not complete the program, and her nursing license was suspended in late 2014.
In 2016, her physician prescribed a new medication, buprenorphine, and the nurse attempted to enroll in ISNAP again. The program vendor instructed her to taper off the drug within 3 months of enrollment, something her physician believed “would come with a significant risk of relapse [and possibly] death.” The nurse was unable to qualify for reinstatement of her license.
As part of the settlement, the nursing board has agreed to pay a total of $70,000 in damages to the complainant and report compliance with new guidelines to the DOJ every 6 months.
The DOJ says ISNAP’s OUD abstinence policy does not conform with the state’s statute, which mandates that substance abuse rehabilitation services be provided for nurses.
“Indiana may not deny individuals lifesaving medications, including medications that treat [OUD], based on stereotypes and misinformation,” Assistant Attorney General Kristen Clarke of the Justice Department’s Civil Rights Division said of the settlement. “Requiring nurses to stop taking prescribed medication as a condition of maintaining a nursing license violates the ADA and not only creates barriers to recovery but inappropriately limits employment opportunities based on disability.”
In April, the DOJ issued guidance for protecting the civil rights of people with OUD under the ADA to ensure that individuals seeking treatment or recovery can continue participating in society and the workplace.
“The opioid epidemic has greatly impacted professionals and families of all walks of life, and Indiana nurses have the right to seek medically approved treatment for [OUD] under federal law,” U.S. Attorney Zachary A. Myers, of the Southern District of Indiana, said of the settlement. “Following the Justice Department’s findings and the parties’ settlement agreement, Indiana must now enact policies to ensure that Hoosier nurses will not be forced to choose between their recovery and their livelihoods.”
Under the terms of the agreement, the nursing board must allow nurses who are taking OUD medication to participate in ISNAP when the medication is prescribed by a licensed practitioner as part of a medically necessary treatment plan and is incorporated into a recovery monitoring agreement.
A version of this article first appeared on Medscape.com.
, according to a statement released Sept. 1.
In March, the U.S. Department of Justice (DOJ) announced the findings of its investigation, stating that the board “violated the ADA by prohibiting nurses who take medication to treat OUD from participating in the Indiana State Nursing Assistance Program [ISNAP].”
ISNAP rehabilitates and monitors nurses with substance use disorders, and the nursing board contracts with vendors to administer the program. Nurses seeking recovery must typically enroll in ISNAP and complete the 1-year program to maintain an active nursing license or have a license reinstated.
Following the investigation, the nursing board was instructed to implement corrective measures, such as revising policies and handbooks and training nursing board staff and vendors on ADA guidelines and nondiscriminatory practices.
The state’s professional organization for nurses said the remediation efforts will help nurses who are struggling with opioid addiction.
Katherine Feley, DNP, RN, chief executive officer of the Indiana State Nurses Association, told this news organization, “Allowing nurses who take medication to treat OUD to remain on their medication when participating in [ISNAP] will avoid making nurses choose between their health and their profession. This improvement will increase access to treatment resources, enabling more nurses to complete treatment and progress toward a safe return to work.”
The DOJ opened an investigation after receiving a complaint from a nurse in which she alleged that she was denied participation in ISNAP because of her use of prescription medication for OUD. In 2013, while participating in a methadone maintenance program, the nurse was told she had to taper off the medication because ISNAP utilizes an “abstinence-based” model. Because of these restrictions, she could not complete the program, and her nursing license was suspended in late 2014.
In 2016, her physician prescribed a new medication, buprenorphine, and the nurse attempted to enroll in ISNAP again. The program vendor instructed her to taper off the drug within 3 months of enrollment, something her physician believed “would come with a significant risk of relapse [and possibly] death.” The nurse was unable to qualify for reinstatement of her license.
As part of the settlement, the nursing board has agreed to pay a total of $70,000 in damages to the complainant and report compliance with new guidelines to the DOJ every 6 months.
The DOJ says ISNAP’s OUD abstinence policy does not conform with the state’s statute, which mandates that substance abuse rehabilitation services be provided for nurses.
“Indiana may not deny individuals lifesaving medications, including medications that treat [OUD], based on stereotypes and misinformation,” Assistant Attorney General Kristen Clarke of the Justice Department’s Civil Rights Division said of the settlement. “Requiring nurses to stop taking prescribed medication as a condition of maintaining a nursing license violates the ADA and not only creates barriers to recovery but inappropriately limits employment opportunities based on disability.”
In April, the DOJ issued guidance for protecting the civil rights of people with OUD under the ADA to ensure that individuals seeking treatment or recovery can continue participating in society and the workplace.
“The opioid epidemic has greatly impacted professionals and families of all walks of life, and Indiana nurses have the right to seek medically approved treatment for [OUD] under federal law,” U.S. Attorney Zachary A. Myers, of the Southern District of Indiana, said of the settlement. “Following the Justice Department’s findings and the parties’ settlement agreement, Indiana must now enact policies to ensure that Hoosier nurses will not be forced to choose between their recovery and their livelihoods.”
Under the terms of the agreement, the nursing board must allow nurses who are taking OUD medication to participate in ISNAP when the medication is prescribed by a licensed practitioner as part of a medically necessary treatment plan and is incorporated into a recovery monitoring agreement.
A version of this article first appeared on Medscape.com.
, according to a statement released Sept. 1.
In March, the U.S. Department of Justice (DOJ) announced the findings of its investigation, stating that the board “violated the ADA by prohibiting nurses who take medication to treat OUD from participating in the Indiana State Nursing Assistance Program [ISNAP].”
ISNAP rehabilitates and monitors nurses with substance use disorders, and the nursing board contracts with vendors to administer the program. Nurses seeking recovery must typically enroll in ISNAP and complete the 1-year program to maintain an active nursing license or have a license reinstated.
Following the investigation, the nursing board was instructed to implement corrective measures, such as revising policies and handbooks and training nursing board staff and vendors on ADA guidelines and nondiscriminatory practices.
The state’s professional organization for nurses said the remediation efforts will help nurses who are struggling with opioid addiction.
Katherine Feley, DNP, RN, chief executive officer of the Indiana State Nurses Association, told this news organization, “Allowing nurses who take medication to treat OUD to remain on their medication when participating in [ISNAP] will avoid making nurses choose between their health and their profession. This improvement will increase access to treatment resources, enabling more nurses to complete treatment and progress toward a safe return to work.”
The DOJ opened an investigation after receiving a complaint from a nurse in which she alleged that she was denied participation in ISNAP because of her use of prescription medication for OUD. In 2013, while participating in a methadone maintenance program, the nurse was told she had to taper off the medication because ISNAP utilizes an “abstinence-based” model. Because of these restrictions, she could not complete the program, and her nursing license was suspended in late 2014.
In 2016, her physician prescribed a new medication, buprenorphine, and the nurse attempted to enroll in ISNAP again. The program vendor instructed her to taper off the drug within 3 months of enrollment, something her physician believed “would come with a significant risk of relapse [and possibly] death.” The nurse was unable to qualify for reinstatement of her license.
As part of the settlement, the nursing board has agreed to pay a total of $70,000 in damages to the complainant and report compliance with new guidelines to the DOJ every 6 months.
The DOJ says ISNAP’s OUD abstinence policy does not conform with the state’s statute, which mandates that substance abuse rehabilitation services be provided for nurses.
“Indiana may not deny individuals lifesaving medications, including medications that treat [OUD], based on stereotypes and misinformation,” Assistant Attorney General Kristen Clarke of the Justice Department’s Civil Rights Division said of the settlement. “Requiring nurses to stop taking prescribed medication as a condition of maintaining a nursing license violates the ADA and not only creates barriers to recovery but inappropriately limits employment opportunities based on disability.”
In April, the DOJ issued guidance for protecting the civil rights of people with OUD under the ADA to ensure that individuals seeking treatment or recovery can continue participating in society and the workplace.
“The opioid epidemic has greatly impacted professionals and families of all walks of life, and Indiana nurses have the right to seek medically approved treatment for [OUD] under federal law,” U.S. Attorney Zachary A. Myers, of the Southern District of Indiana, said of the settlement. “Following the Justice Department’s findings and the parties’ settlement agreement, Indiana must now enact policies to ensure that Hoosier nurses will not be forced to choose between their recovery and their livelihoods.”
Under the terms of the agreement, the nursing board must allow nurses who are taking OUD medication to participate in ISNAP when the medication is prescribed by a licensed practitioner as part of a medically necessary treatment plan and is incorporated into a recovery monitoring agreement.
A version of this article first appeared on Medscape.com.
Muscling through the data
Statins have, overall, been a remarkably beneficial class of drugs. Yes, you occasionally get patients who see them as part of some huge pharma-government conspiracy (along with vaccines and 5G, presumably) but the data are there to support them.
One of the issues with them is myalgias. We all see this to varying degrees. We all warn patients about it, as do their pharmacists, the information sheets from the pharmacy, some TV show, a Facebook friend, that guy in their Tuesday bowling league ... etc.
It is a legitimate concern. Some people definitely do get muscle cramps from them and need to come off. Scanning the medication list of someone who comes in with muscle cramps is a key part of the case.
Recently, the Lancet published a meta-analysis on the subject and found that, While previous data suggested rates of myalgias as high as 29%, this paper found it was closer to 7% compared with placebo. Only one in 15 of the muscle-related reports by patients while taking statins were clearly caused by the drug.
The power of suggestion is remarkable indeed.
The study is interesting. It might be correct.
But try telling that to the patients.
We all have patients who will get pretty much any side effect we mention, or that they read about online. That’s just human nature for some. But even reasonable adults can confuse things. The guy who starts Lipitor one week then helps his daughter move into her apartment the next. The lady who starts Crestor while training for a half-marathon. And so on.
The fact is that a lot of people take statins. And a lot of people (like, pretty much all of us) do things that can cause muscle injuries. Sooner or later these lines are going to intersect, but that doesn’t mean they have anything to do with each other.
It’s a lot harder to explain that, and have people believe it, once they’ve convinced themselves otherwise. Pravachol definitely did this, Dr. Google said so. It doesn’t help that trust in doctors, and health care science in general, has been eroded by political pundits and nonmedical experts during the COVID-19 pandemic. To some people our years of experience and training are nothing compared to what an anonymous guy on Parler told them.
Certainly this paper will help. A lot of people can benefit from statins. With this data maybe we can convince some to give them a fair shot.
But, as we’ve all experienced in practice, sometimes no amount of solid data will change the mind of someone who’s already made theirs up.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Statins have, overall, been a remarkably beneficial class of drugs. Yes, you occasionally get patients who see them as part of some huge pharma-government conspiracy (along with vaccines and 5G, presumably) but the data are there to support them.
One of the issues with them is myalgias. We all see this to varying degrees. We all warn patients about it, as do their pharmacists, the information sheets from the pharmacy, some TV show, a Facebook friend, that guy in their Tuesday bowling league ... etc.
It is a legitimate concern. Some people definitely do get muscle cramps from them and need to come off. Scanning the medication list of someone who comes in with muscle cramps is a key part of the case.
Recently, the Lancet published a meta-analysis on the subject and found that, While previous data suggested rates of myalgias as high as 29%, this paper found it was closer to 7% compared with placebo. Only one in 15 of the muscle-related reports by patients while taking statins were clearly caused by the drug.
The power of suggestion is remarkable indeed.
The study is interesting. It might be correct.
But try telling that to the patients.
We all have patients who will get pretty much any side effect we mention, or that they read about online. That’s just human nature for some. But even reasonable adults can confuse things. The guy who starts Lipitor one week then helps his daughter move into her apartment the next. The lady who starts Crestor while training for a half-marathon. And so on.
The fact is that a lot of people take statins. And a lot of people (like, pretty much all of us) do things that can cause muscle injuries. Sooner or later these lines are going to intersect, but that doesn’t mean they have anything to do with each other.
It’s a lot harder to explain that, and have people believe it, once they’ve convinced themselves otherwise. Pravachol definitely did this, Dr. Google said so. It doesn’t help that trust in doctors, and health care science in general, has been eroded by political pundits and nonmedical experts during the COVID-19 pandemic. To some people our years of experience and training are nothing compared to what an anonymous guy on Parler told them.
Certainly this paper will help. A lot of people can benefit from statins. With this data maybe we can convince some to give them a fair shot.
But, as we’ve all experienced in practice, sometimes no amount of solid data will change the mind of someone who’s already made theirs up.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Statins have, overall, been a remarkably beneficial class of drugs. Yes, you occasionally get patients who see them as part of some huge pharma-government conspiracy (along with vaccines and 5G, presumably) but the data are there to support them.
One of the issues with them is myalgias. We all see this to varying degrees. We all warn patients about it, as do their pharmacists, the information sheets from the pharmacy, some TV show, a Facebook friend, that guy in their Tuesday bowling league ... etc.
It is a legitimate concern. Some people definitely do get muscle cramps from them and need to come off. Scanning the medication list of someone who comes in with muscle cramps is a key part of the case.
Recently, the Lancet published a meta-analysis on the subject and found that, While previous data suggested rates of myalgias as high as 29%, this paper found it was closer to 7% compared with placebo. Only one in 15 of the muscle-related reports by patients while taking statins were clearly caused by the drug.
The power of suggestion is remarkable indeed.
The study is interesting. It might be correct.
But try telling that to the patients.
We all have patients who will get pretty much any side effect we mention, or that they read about online. That’s just human nature for some. But even reasonable adults can confuse things. The guy who starts Lipitor one week then helps his daughter move into her apartment the next. The lady who starts Crestor while training for a half-marathon. And so on.
The fact is that a lot of people take statins. And a lot of people (like, pretty much all of us) do things that can cause muscle injuries. Sooner or later these lines are going to intersect, but that doesn’t mean they have anything to do with each other.
It’s a lot harder to explain that, and have people believe it, once they’ve convinced themselves otherwise. Pravachol definitely did this, Dr. Google said so. It doesn’t help that trust in doctors, and health care science in general, has been eroded by political pundits and nonmedical experts during the COVID-19 pandemic. To some people our years of experience and training are nothing compared to what an anonymous guy on Parler told them.
Certainly this paper will help. A lot of people can benefit from statins. With this data maybe we can convince some to give them a fair shot.
But, as we’ve all experienced in practice, sometimes no amount of solid data will change the mind of someone who’s already made theirs up.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
WIC review finds broad benefits, knowledge gaps
How exactly the national program achieves these outcomes, however, remains unclear, and study quality shows room for improvement, reported co–lead authors Maya Venkataramani, MD, MPH and S. Michelle Ogunwole, MD, PhD of Johns Hopkins University, Baltimore, and colleagues.
The WIC program, which has been serving low-income women and young children since 1974, “provides supplemental foods, nutrition education and breastfeeding support, screening and referrals to medical and social services, and support for high-risk pregnancies,” the investigators wrote in Annals of Internal Medicine. The U.S. Food and Nutrition Service administers the program.
The authors conducted a systematic review of 20 observational studies aimed at determining the impacts of WIC participation on maternal, neonatal-birth, and infant-child health outcomes.
All studies included in the review began in or after 2009, when the WIC food package was revised to better address diet-related chronic diseases. For inclusion in the review, studies were required to have a WIC-eligible comparison group. Included research also evaluated the relationship between WIC participation and the prespecified health outcomes.
“We found only 20 studies that fulfilled our rigorous study inclusion criteria for these specific outcomes,” the investigators wrote. “In some areas, the evidence was absent, and in others, the strength of evidence (SOE) was moderate or low.”
Six outcome categories were assessed: maternal morbidity, maternal pregnancy outcomes, maternal health behaviors, maternal health care utilization, child morbidity, and childhood health care utilization. Of these, maternal health care utilization had the most robust body of evidence, while data from studies evaluating maternal morbidity and child morbidity were deemed insufficient.
Based on eligible studies, WIC participation was associated with reduced risks of insufficient weight gain in pregnancy, preterm birth, low infant birthweight, and infant mortality. Participation was also associated with an increased likelihood of infant and child health care utilization, such as routine immunizations.
Growing evidence should drive enrollment
“Growing evidence points to WIC as a way to reduce risk of preterm birth and other adverse outcomes,” said Laura Jelliffe-Pawlowski, PhD, MS, professor at the University of California, San Francisco and a director for the UCSF California Preterm Birth Initiative.
Dr. Jelliffe-Pawlowski, who conducted a California-based study included in the paper, said the review is noteworthy because it shows that WIC-associated benefits are observed across locations.
“It’s not just in California; it’s across the country,” she said. “It’s a national call to action – where there’s partnership between national-, state- and community-level WIC programs – to make WIC as accessible as possible, and reflect community wants and needs, so that more people enroll, and more people stay enrolled.”
Dr. Jelliffe-Pawlowski’s coauthor on the California study, Rita Hamad, MD, PhD, associate professor of family & community medicine at UCSF and associate director of the UCSF Center for Health Equity, encouraged health care providers to drive WIC enrollment, noting that, presently, only one in four eligible 4-year-olds participates.
“Physicians and other health care stakeholders can help patients benefit from this program by encouraging them to sign up, and even by providing sign-up support in the form of a social worker or other staff member,” Dr. Hamad said. “There is also literature on the types of interventions that improve take-up of safety net programs that providers can look to.”
Goals of future research
Optimizing WIC operations, however, is only half the battle, considering the evidence gaps revealed by the review.
“We still need stronger studies that use more rigorous study designs ... to provide more convincing evidence to policymakers, as well as more evidence on long-term impacts,” Dr. Hamad said. “We also need to better understand why take-up is low in these programs despite these potential health benefits. Then we can make sure that economically disadvantaged families receive the benefits for which they are eligible through interventions to improve participation rates.”
Ideally, WIC programs would receive additional funding for independent parties to evaluate health outcomes, according to Ashwini Lakshmanan, MD, MS, MPH, associate professor in the department of health systems science at Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, Calif.
Dr. Lakshmanan, who previously evaluated the benefits of WIC participation for high-risk infants, noted that randomized clinical trials would be unethical in this setting, yet data collection can still be “very conscientious and intentional,” with a focus on policy-shaping outcome metrics like immunizations and pediatric health care visits.
“The main point is thinking about it at the forefront, and not retrospectively,” Dr. Lakshmanan said.
Dr. Ogunwole, who led the present review, suggested in a written comment that future studies “could employ robust statistical methods (propensity matching, fixed effects models, etc.) to help reduce bias.”
She also recommended evaluating innovations in WIC programs; for example, adding a health coach, or conducting a cooking skills intervention.
Studies are also needed to better understand the various obstacles to WIC success, such as misconceptions about the program, discrimination, and barriers to enrollment, Dr. Ogunwole added.
“WIC enrollment has been decreasing for a number of years, and this was occurring prepandemic as well,” she said. “More work needs to be done to understand this issue.”
The study was supported by the Agency for Healthcare Research and Quality, U.S. Department of Health & Human Services. The investigators and interviewees disclosed no conflicts of interest.
How exactly the national program achieves these outcomes, however, remains unclear, and study quality shows room for improvement, reported co–lead authors Maya Venkataramani, MD, MPH and S. Michelle Ogunwole, MD, PhD of Johns Hopkins University, Baltimore, and colleagues.
The WIC program, which has been serving low-income women and young children since 1974, “provides supplemental foods, nutrition education and breastfeeding support, screening and referrals to medical and social services, and support for high-risk pregnancies,” the investigators wrote in Annals of Internal Medicine. The U.S. Food and Nutrition Service administers the program.
The authors conducted a systematic review of 20 observational studies aimed at determining the impacts of WIC participation on maternal, neonatal-birth, and infant-child health outcomes.
All studies included in the review began in or after 2009, when the WIC food package was revised to better address diet-related chronic diseases. For inclusion in the review, studies were required to have a WIC-eligible comparison group. Included research also evaluated the relationship between WIC participation and the prespecified health outcomes.
“We found only 20 studies that fulfilled our rigorous study inclusion criteria for these specific outcomes,” the investigators wrote. “In some areas, the evidence was absent, and in others, the strength of evidence (SOE) was moderate or low.”
Six outcome categories were assessed: maternal morbidity, maternal pregnancy outcomes, maternal health behaviors, maternal health care utilization, child morbidity, and childhood health care utilization. Of these, maternal health care utilization had the most robust body of evidence, while data from studies evaluating maternal morbidity and child morbidity were deemed insufficient.
Based on eligible studies, WIC participation was associated with reduced risks of insufficient weight gain in pregnancy, preterm birth, low infant birthweight, and infant mortality. Participation was also associated with an increased likelihood of infant and child health care utilization, such as routine immunizations.
Growing evidence should drive enrollment
“Growing evidence points to WIC as a way to reduce risk of preterm birth and other adverse outcomes,” said Laura Jelliffe-Pawlowski, PhD, MS, professor at the University of California, San Francisco and a director for the UCSF California Preterm Birth Initiative.
Dr. Jelliffe-Pawlowski, who conducted a California-based study included in the paper, said the review is noteworthy because it shows that WIC-associated benefits are observed across locations.
“It’s not just in California; it’s across the country,” she said. “It’s a national call to action – where there’s partnership between national-, state- and community-level WIC programs – to make WIC as accessible as possible, and reflect community wants and needs, so that more people enroll, and more people stay enrolled.”
Dr. Jelliffe-Pawlowski’s coauthor on the California study, Rita Hamad, MD, PhD, associate professor of family & community medicine at UCSF and associate director of the UCSF Center for Health Equity, encouraged health care providers to drive WIC enrollment, noting that, presently, only one in four eligible 4-year-olds participates.
“Physicians and other health care stakeholders can help patients benefit from this program by encouraging them to sign up, and even by providing sign-up support in the form of a social worker or other staff member,” Dr. Hamad said. “There is also literature on the types of interventions that improve take-up of safety net programs that providers can look to.”
Goals of future research
Optimizing WIC operations, however, is only half the battle, considering the evidence gaps revealed by the review.
“We still need stronger studies that use more rigorous study designs ... to provide more convincing evidence to policymakers, as well as more evidence on long-term impacts,” Dr. Hamad said. “We also need to better understand why take-up is low in these programs despite these potential health benefits. Then we can make sure that economically disadvantaged families receive the benefits for which they are eligible through interventions to improve participation rates.”
Ideally, WIC programs would receive additional funding for independent parties to evaluate health outcomes, according to Ashwini Lakshmanan, MD, MS, MPH, associate professor in the department of health systems science at Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, Calif.
Dr. Lakshmanan, who previously evaluated the benefits of WIC participation for high-risk infants, noted that randomized clinical trials would be unethical in this setting, yet data collection can still be “very conscientious and intentional,” with a focus on policy-shaping outcome metrics like immunizations and pediatric health care visits.
“The main point is thinking about it at the forefront, and not retrospectively,” Dr. Lakshmanan said.
Dr. Ogunwole, who led the present review, suggested in a written comment that future studies “could employ robust statistical methods (propensity matching, fixed effects models, etc.) to help reduce bias.”
She also recommended evaluating innovations in WIC programs; for example, adding a health coach, or conducting a cooking skills intervention.
Studies are also needed to better understand the various obstacles to WIC success, such as misconceptions about the program, discrimination, and barriers to enrollment, Dr. Ogunwole added.
“WIC enrollment has been decreasing for a number of years, and this was occurring prepandemic as well,” she said. “More work needs to be done to understand this issue.”
The study was supported by the Agency for Healthcare Research and Quality, U.S. Department of Health & Human Services. The investigators and interviewees disclosed no conflicts of interest.
How exactly the national program achieves these outcomes, however, remains unclear, and study quality shows room for improvement, reported co–lead authors Maya Venkataramani, MD, MPH and S. Michelle Ogunwole, MD, PhD of Johns Hopkins University, Baltimore, and colleagues.
The WIC program, which has been serving low-income women and young children since 1974, “provides supplemental foods, nutrition education and breastfeeding support, screening and referrals to medical and social services, and support for high-risk pregnancies,” the investigators wrote in Annals of Internal Medicine. The U.S. Food and Nutrition Service administers the program.
The authors conducted a systematic review of 20 observational studies aimed at determining the impacts of WIC participation on maternal, neonatal-birth, and infant-child health outcomes.
All studies included in the review began in or after 2009, when the WIC food package was revised to better address diet-related chronic diseases. For inclusion in the review, studies were required to have a WIC-eligible comparison group. Included research also evaluated the relationship between WIC participation and the prespecified health outcomes.
“We found only 20 studies that fulfilled our rigorous study inclusion criteria for these specific outcomes,” the investigators wrote. “In some areas, the evidence was absent, and in others, the strength of evidence (SOE) was moderate or low.”
Six outcome categories were assessed: maternal morbidity, maternal pregnancy outcomes, maternal health behaviors, maternal health care utilization, child morbidity, and childhood health care utilization. Of these, maternal health care utilization had the most robust body of evidence, while data from studies evaluating maternal morbidity and child morbidity were deemed insufficient.
Based on eligible studies, WIC participation was associated with reduced risks of insufficient weight gain in pregnancy, preterm birth, low infant birthweight, and infant mortality. Participation was also associated with an increased likelihood of infant and child health care utilization, such as routine immunizations.
Growing evidence should drive enrollment
“Growing evidence points to WIC as a way to reduce risk of preterm birth and other adverse outcomes,” said Laura Jelliffe-Pawlowski, PhD, MS, professor at the University of California, San Francisco and a director for the UCSF California Preterm Birth Initiative.
Dr. Jelliffe-Pawlowski, who conducted a California-based study included in the paper, said the review is noteworthy because it shows that WIC-associated benefits are observed across locations.
“It’s not just in California; it’s across the country,” she said. “It’s a national call to action – where there’s partnership between national-, state- and community-level WIC programs – to make WIC as accessible as possible, and reflect community wants and needs, so that more people enroll, and more people stay enrolled.”
Dr. Jelliffe-Pawlowski’s coauthor on the California study, Rita Hamad, MD, PhD, associate professor of family & community medicine at UCSF and associate director of the UCSF Center for Health Equity, encouraged health care providers to drive WIC enrollment, noting that, presently, only one in four eligible 4-year-olds participates.
“Physicians and other health care stakeholders can help patients benefit from this program by encouraging them to sign up, and even by providing sign-up support in the form of a social worker or other staff member,” Dr. Hamad said. “There is also literature on the types of interventions that improve take-up of safety net programs that providers can look to.”
Goals of future research
Optimizing WIC operations, however, is only half the battle, considering the evidence gaps revealed by the review.
“We still need stronger studies that use more rigorous study designs ... to provide more convincing evidence to policymakers, as well as more evidence on long-term impacts,” Dr. Hamad said. “We also need to better understand why take-up is low in these programs despite these potential health benefits. Then we can make sure that economically disadvantaged families receive the benefits for which they are eligible through interventions to improve participation rates.”
Ideally, WIC programs would receive additional funding for independent parties to evaluate health outcomes, according to Ashwini Lakshmanan, MD, MS, MPH, associate professor in the department of health systems science at Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, Calif.
Dr. Lakshmanan, who previously evaluated the benefits of WIC participation for high-risk infants, noted that randomized clinical trials would be unethical in this setting, yet data collection can still be “very conscientious and intentional,” with a focus on policy-shaping outcome metrics like immunizations and pediatric health care visits.
“The main point is thinking about it at the forefront, and not retrospectively,” Dr. Lakshmanan said.
Dr. Ogunwole, who led the present review, suggested in a written comment that future studies “could employ robust statistical methods (propensity matching, fixed effects models, etc.) to help reduce bias.”
She also recommended evaluating innovations in WIC programs; for example, adding a health coach, or conducting a cooking skills intervention.
Studies are also needed to better understand the various obstacles to WIC success, such as misconceptions about the program, discrimination, and barriers to enrollment, Dr. Ogunwole added.
“WIC enrollment has been decreasing for a number of years, and this was occurring prepandemic as well,” she said. “More work needs to be done to understand this issue.”
The study was supported by the Agency for Healthcare Research and Quality, U.S. Department of Health & Human Services. The investigators and interviewees disclosed no conflicts of interest.
FROM ANNALS OF INTERNAL MEDICINE
In the rush to curtail abortion, states adopt a jumbled stew of definitions for human life
As life-preserving medical technology advanced in the second half of the 20th century, doctors and families were faced with a thorny decision, one with weighty legal and moral implications: How should we define when life ends? Cardiopulmonary bypass machines could keep the blood pumping and ventilators could maintain breathing long after a patient’s natural ability to perform those vital functions had ceased.
After decades of deliberations involving physicians, bioethicists, attorneys, and theologians, a U.S. presidential commission in 1981 settled on a scientifically derived dividing line between life and death that has endured, more or less, ever since: A person was considered dead when the entire brain – including the brain stem, its most primitive portion – was no longer functioning, even if other vital functions could be maintained indefinitely through artificial life support.
In the decades since, the committee’s criteria have served as a foundation for laws in most states adopting brain death as a standard for legal death.
Now, with the overturning of Roe v. Wade and dozens of states rushing to impose abortion restrictions, At conception, the hint of a heartbeat, a first breath, the ability to survive outside the womb with the help of the latest technology?
That we’ve been able to devise and apply uniform clinical standards for when life ends, but not when it begins, is due largely to the legal and political maelstrom around abortion. And in the 2 months since the U.S. Supreme Court issued its opinion in Dobbs v. Jackson Women’s Health Organization, eliminating a longstanding federal right to abortion, state legislators are eagerly bounding into that void, looking to codify into law assorted definitions of life that carry profound repercussions for abortion rights, birth control, and assisted reproduction, as well as civil and criminal law.
“The court said that when life begins is up to whoever is running your state – whether they are wrong or not, or you agree with them or not,” said Mary Ziegler, a law professor at the University of California, Davis, who has written several books on the history of abortion.
Unlike the debate over death, which delved into exquisite medical and scientific detail, the legislative scramble to determine when life’s building blocks reach a threshold that warrants government protection as human life has generally ignored the input of mainstream medical professionals.
Instead, red states across much of the South and portions of the Midwest are adopting language drafted by elected officials that is informed by conservative Christian doctrine, often with little scientific underpinning.
A handful of Republican-led states, including Arkansas, Kentucky, Missouri, and Oklahoma, have passed laws declaring that life begins at fertilization, a contention that opens the door to a host of pregnancy-related litigation. This includes wrongful death lawsuits brought on behalf of the estate of an embryo by disgruntled ex-partners against physicians and women who end a pregnancy or even miscarry. (One such lawsuit is underway in Arizona. Another reached the Alabama Supreme Court.)
In Kentucky, the law outlawing abortion uses morally explosive terms to define pregnancy as “the human female reproductive condition of having a living unborn human being within her body throughout the entire embryonic and fetal stages of the unborn child from fertilization to full gestation and childbirth.”
Several other states, including Georgia, have adopted measures equating life with the point at which an embryo’s nascent cardiac activity can be detected by an ultrasound, at around 6 weeks of gestation. Many such laws mischaracterize the flickering electrical impulses detectable at that stage as a heartbeat, including in Georgia, whose Department of Revenue recently announced that “any unborn child with a detectable human heartbeat” can be claimed as a dependent.
The Supreme Court’s 1973 decision in Roe v. Wade that established a constitutional right to abortion did not define a moment when life begins. The opinion, written by Justice Harry Blackmun, observed that the Constitution does not provide a definition of “person,” though it extends protections to those born or naturalized in the United States. The court majority made note of the many disparate views among religions and scientists on when life begins, and concluded it was not up to the states to adopt one theory of life.
Instead, Roe created a framework intended to balance a pregnant woman’s right to make decisions about her body with a public interest in protecting potential human life. That decision and a key ruling that followed generally recognized a woman’s right to abortion up to the point medical professionals judge a fetus viable to survive outside the uterus, at about 24 weeks of gestation.
In decisively overturning Roe in June, the Supreme Court’s conservative majority drew on legal arguments that have shaped another contentious end-of-life issue. The legal standard employed in Dobbs – that there is no right to abortion in the federal Constitution and that states can decide on their own – is the same rationale used in 1997 when the Supreme Court said terminally ill people did not have a constitutional right to medically assisted death. That decision, Washington v. Glucksberg, is mentioned 15 times in the majority opinion for Dobbs and a concurrence by Justice Clarence Thomas.
Often, the same groups that have led the fight to outlaw abortion have also challenged medical aid-in-dying laws. Even after Dobbs, so-called right-to-die laws remain far less common than those codifying state abortion rights. Ten states allow physicians to prescribe lethal doses of medicine for terminally ill patients. Doctors are still prohibited from administering the drugs.
James Bopp, general counsel for the National Right to Life Committee who has been central to the efforts to outlaw abortion, said that both abortion and medically assisted death, which he refers to as physician-assisted suicide, endanger society.
“Every individual human life has inherent value and is sacred,” said Mr. Bopp. “The government has the duty to protect that life.”
Both issues raise profound societal questions: Can the government keep a patient on life support against his wishes, or force a woman to give birth? Can states bar their own residents from going to other states to end a pregnancy, or prohibit out-of-state patients from coming in to seek medically assisted death? And who gets to decide, particularly if the answer imposes a singular religious viewpoint?
Just as there are legal implications that flow from determining a person’s death, from organ donation to inheritance, the implied rights held by a legally recognized zygote are potentially vast. Will death certificates be issued for every lost pregnancy? Will miscarriages be investigated? When will Social Security numbers be issued? How will census counts be tallied and congressional districts drawn?
Medical professionals and bioethicists caution that both the beginning and end of life are complicated biological processes that are not defined by a single identifiable moment – and are ill suited to the political arena.
“Unfortunately, biological occurrences are not events, they are processes,” said David Magnus, PhD, director of the Stanford (Calif.) Center for Biomedical Ethics.
Moreover, asking doctors “What is life?” or “What is death?” may miss the point, said Dr. Magnus: “Medicine can answer the question ‘When does a biological organism cease to exist?’ But they can’t answer the question ‘When does a person begin or end?’ because those are metaphysical issues.”
Ben Sarbey, a doctoral candidate in the department of philosophy at Duke University, Durham, N.C., who studies medical ethics, echoed that perspective, recounting the Paradox of the Heap, a thought experiment that involves placing grains of sand one on top of the next. The philosophical quandary is this: At what point do those grains of sand become something more – a heap?
“We’re going to have a rough time placing a dividing line that this counts as a person and this does not count as a person,” he said. “Many things count as life – a sperm counts as life, a person in a persistent vegetative state counts as life – but does that constitute a person that we should be protecting?”
Even as debate over the court’s abortion decision percolates, the 1981 federal statute that grew out of the presidential committee’s findings, the Uniform Determination of Death Act, is also under review. In 2022, the Uniform Law Commission, a nonpartisan group of legal experts that drafts laws intended for adoption in multiple states, has taken up the work to revisit the definition of death.
The group will consider sharpening the medical standards for brain death in light of advances in the understanding of brain function. And they will look to address lingering questions raised in recent years as families and religious groups have waged heated legal battles over terminating artificial life support for patients with no brain wave activity.
Mr. Bopp, with the National Right to Life Committee, is among those serving on advisory panels for the effort, along with an array of doctors, philosophers, and medical ethicists. The concept of “personhood” that infuses the antiabortion movement’s broader push for fetal rights is expected to be an underlying topic, albeit in mirror image: When does a life form cease being a person?
Dr. Magnus, who is also serving on an advisory panel, has no doubt the commission will reach a consensus, a sober resolution rooted in science. What’s less clear, he said, is whether in today’s political environment that updated definition will hold the same sway, an enduring legal standard embraced across states.
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
As life-preserving medical technology advanced in the second half of the 20th century, doctors and families were faced with a thorny decision, one with weighty legal and moral implications: How should we define when life ends? Cardiopulmonary bypass machines could keep the blood pumping and ventilators could maintain breathing long after a patient’s natural ability to perform those vital functions had ceased.
After decades of deliberations involving physicians, bioethicists, attorneys, and theologians, a U.S. presidential commission in 1981 settled on a scientifically derived dividing line between life and death that has endured, more or less, ever since: A person was considered dead when the entire brain – including the brain stem, its most primitive portion – was no longer functioning, even if other vital functions could be maintained indefinitely through artificial life support.
In the decades since, the committee’s criteria have served as a foundation for laws in most states adopting brain death as a standard for legal death.
Now, with the overturning of Roe v. Wade and dozens of states rushing to impose abortion restrictions, At conception, the hint of a heartbeat, a first breath, the ability to survive outside the womb with the help of the latest technology?
That we’ve been able to devise and apply uniform clinical standards for when life ends, but not when it begins, is due largely to the legal and political maelstrom around abortion. And in the 2 months since the U.S. Supreme Court issued its opinion in Dobbs v. Jackson Women’s Health Organization, eliminating a longstanding federal right to abortion, state legislators are eagerly bounding into that void, looking to codify into law assorted definitions of life that carry profound repercussions for abortion rights, birth control, and assisted reproduction, as well as civil and criminal law.
“The court said that when life begins is up to whoever is running your state – whether they are wrong or not, or you agree with them or not,” said Mary Ziegler, a law professor at the University of California, Davis, who has written several books on the history of abortion.
Unlike the debate over death, which delved into exquisite medical and scientific detail, the legislative scramble to determine when life’s building blocks reach a threshold that warrants government protection as human life has generally ignored the input of mainstream medical professionals.
Instead, red states across much of the South and portions of the Midwest are adopting language drafted by elected officials that is informed by conservative Christian doctrine, often with little scientific underpinning.
A handful of Republican-led states, including Arkansas, Kentucky, Missouri, and Oklahoma, have passed laws declaring that life begins at fertilization, a contention that opens the door to a host of pregnancy-related litigation. This includes wrongful death lawsuits brought on behalf of the estate of an embryo by disgruntled ex-partners against physicians and women who end a pregnancy or even miscarry. (One such lawsuit is underway in Arizona. Another reached the Alabama Supreme Court.)
In Kentucky, the law outlawing abortion uses morally explosive terms to define pregnancy as “the human female reproductive condition of having a living unborn human being within her body throughout the entire embryonic and fetal stages of the unborn child from fertilization to full gestation and childbirth.”
Several other states, including Georgia, have adopted measures equating life with the point at which an embryo’s nascent cardiac activity can be detected by an ultrasound, at around 6 weeks of gestation. Many such laws mischaracterize the flickering electrical impulses detectable at that stage as a heartbeat, including in Georgia, whose Department of Revenue recently announced that “any unborn child with a detectable human heartbeat” can be claimed as a dependent.
The Supreme Court’s 1973 decision in Roe v. Wade that established a constitutional right to abortion did not define a moment when life begins. The opinion, written by Justice Harry Blackmun, observed that the Constitution does not provide a definition of “person,” though it extends protections to those born or naturalized in the United States. The court majority made note of the many disparate views among religions and scientists on when life begins, and concluded it was not up to the states to adopt one theory of life.
Instead, Roe created a framework intended to balance a pregnant woman’s right to make decisions about her body with a public interest in protecting potential human life. That decision and a key ruling that followed generally recognized a woman’s right to abortion up to the point medical professionals judge a fetus viable to survive outside the uterus, at about 24 weeks of gestation.
In decisively overturning Roe in June, the Supreme Court’s conservative majority drew on legal arguments that have shaped another contentious end-of-life issue. The legal standard employed in Dobbs – that there is no right to abortion in the federal Constitution and that states can decide on their own – is the same rationale used in 1997 when the Supreme Court said terminally ill people did not have a constitutional right to medically assisted death. That decision, Washington v. Glucksberg, is mentioned 15 times in the majority opinion for Dobbs and a concurrence by Justice Clarence Thomas.
Often, the same groups that have led the fight to outlaw abortion have also challenged medical aid-in-dying laws. Even after Dobbs, so-called right-to-die laws remain far less common than those codifying state abortion rights. Ten states allow physicians to prescribe lethal doses of medicine for terminally ill patients. Doctors are still prohibited from administering the drugs.
James Bopp, general counsel for the National Right to Life Committee who has been central to the efforts to outlaw abortion, said that both abortion and medically assisted death, which he refers to as physician-assisted suicide, endanger society.
“Every individual human life has inherent value and is sacred,” said Mr. Bopp. “The government has the duty to protect that life.”
Both issues raise profound societal questions: Can the government keep a patient on life support against his wishes, or force a woman to give birth? Can states bar their own residents from going to other states to end a pregnancy, or prohibit out-of-state patients from coming in to seek medically assisted death? And who gets to decide, particularly if the answer imposes a singular religious viewpoint?
Just as there are legal implications that flow from determining a person’s death, from organ donation to inheritance, the implied rights held by a legally recognized zygote are potentially vast. Will death certificates be issued for every lost pregnancy? Will miscarriages be investigated? When will Social Security numbers be issued? How will census counts be tallied and congressional districts drawn?
Medical professionals and bioethicists caution that both the beginning and end of life are complicated biological processes that are not defined by a single identifiable moment – and are ill suited to the political arena.
“Unfortunately, biological occurrences are not events, they are processes,” said David Magnus, PhD, director of the Stanford (Calif.) Center for Biomedical Ethics.
Moreover, asking doctors “What is life?” or “What is death?” may miss the point, said Dr. Magnus: “Medicine can answer the question ‘When does a biological organism cease to exist?’ But they can’t answer the question ‘When does a person begin or end?’ because those are metaphysical issues.”
Ben Sarbey, a doctoral candidate in the department of philosophy at Duke University, Durham, N.C., who studies medical ethics, echoed that perspective, recounting the Paradox of the Heap, a thought experiment that involves placing grains of sand one on top of the next. The philosophical quandary is this: At what point do those grains of sand become something more – a heap?
“We’re going to have a rough time placing a dividing line that this counts as a person and this does not count as a person,” he said. “Many things count as life – a sperm counts as life, a person in a persistent vegetative state counts as life – but does that constitute a person that we should be protecting?”
Even as debate over the court’s abortion decision percolates, the 1981 federal statute that grew out of the presidential committee’s findings, the Uniform Determination of Death Act, is also under review. In 2022, the Uniform Law Commission, a nonpartisan group of legal experts that drafts laws intended for adoption in multiple states, has taken up the work to revisit the definition of death.
The group will consider sharpening the medical standards for brain death in light of advances in the understanding of brain function. And they will look to address lingering questions raised in recent years as families and religious groups have waged heated legal battles over terminating artificial life support for patients with no brain wave activity.
Mr. Bopp, with the National Right to Life Committee, is among those serving on advisory panels for the effort, along with an array of doctors, philosophers, and medical ethicists. The concept of “personhood” that infuses the antiabortion movement’s broader push for fetal rights is expected to be an underlying topic, albeit in mirror image: When does a life form cease being a person?
Dr. Magnus, who is also serving on an advisory panel, has no doubt the commission will reach a consensus, a sober resolution rooted in science. What’s less clear, he said, is whether in today’s political environment that updated definition will hold the same sway, an enduring legal standard embraced across states.
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
As life-preserving medical technology advanced in the second half of the 20th century, doctors and families were faced with a thorny decision, one with weighty legal and moral implications: How should we define when life ends? Cardiopulmonary bypass machines could keep the blood pumping and ventilators could maintain breathing long after a patient’s natural ability to perform those vital functions had ceased.
After decades of deliberations involving physicians, bioethicists, attorneys, and theologians, a U.S. presidential commission in 1981 settled on a scientifically derived dividing line between life and death that has endured, more or less, ever since: A person was considered dead when the entire brain – including the brain stem, its most primitive portion – was no longer functioning, even if other vital functions could be maintained indefinitely through artificial life support.
In the decades since, the committee’s criteria have served as a foundation for laws in most states adopting brain death as a standard for legal death.
Now, with the overturning of Roe v. Wade and dozens of states rushing to impose abortion restrictions, At conception, the hint of a heartbeat, a first breath, the ability to survive outside the womb with the help of the latest technology?
That we’ve been able to devise and apply uniform clinical standards for when life ends, but not when it begins, is due largely to the legal and political maelstrom around abortion. And in the 2 months since the U.S. Supreme Court issued its opinion in Dobbs v. Jackson Women’s Health Organization, eliminating a longstanding federal right to abortion, state legislators are eagerly bounding into that void, looking to codify into law assorted definitions of life that carry profound repercussions for abortion rights, birth control, and assisted reproduction, as well as civil and criminal law.
“The court said that when life begins is up to whoever is running your state – whether they are wrong or not, or you agree with them or not,” said Mary Ziegler, a law professor at the University of California, Davis, who has written several books on the history of abortion.
Unlike the debate over death, which delved into exquisite medical and scientific detail, the legislative scramble to determine when life’s building blocks reach a threshold that warrants government protection as human life has generally ignored the input of mainstream medical professionals.
Instead, red states across much of the South and portions of the Midwest are adopting language drafted by elected officials that is informed by conservative Christian doctrine, often with little scientific underpinning.
A handful of Republican-led states, including Arkansas, Kentucky, Missouri, and Oklahoma, have passed laws declaring that life begins at fertilization, a contention that opens the door to a host of pregnancy-related litigation. This includes wrongful death lawsuits brought on behalf of the estate of an embryo by disgruntled ex-partners against physicians and women who end a pregnancy or even miscarry. (One such lawsuit is underway in Arizona. Another reached the Alabama Supreme Court.)
In Kentucky, the law outlawing abortion uses morally explosive terms to define pregnancy as “the human female reproductive condition of having a living unborn human being within her body throughout the entire embryonic and fetal stages of the unborn child from fertilization to full gestation and childbirth.”
Several other states, including Georgia, have adopted measures equating life with the point at which an embryo’s nascent cardiac activity can be detected by an ultrasound, at around 6 weeks of gestation. Many such laws mischaracterize the flickering electrical impulses detectable at that stage as a heartbeat, including in Georgia, whose Department of Revenue recently announced that “any unborn child with a detectable human heartbeat” can be claimed as a dependent.
The Supreme Court’s 1973 decision in Roe v. Wade that established a constitutional right to abortion did not define a moment when life begins. The opinion, written by Justice Harry Blackmun, observed that the Constitution does not provide a definition of “person,” though it extends protections to those born or naturalized in the United States. The court majority made note of the many disparate views among religions and scientists on when life begins, and concluded it was not up to the states to adopt one theory of life.
Instead, Roe created a framework intended to balance a pregnant woman’s right to make decisions about her body with a public interest in protecting potential human life. That decision and a key ruling that followed generally recognized a woman’s right to abortion up to the point medical professionals judge a fetus viable to survive outside the uterus, at about 24 weeks of gestation.
In decisively overturning Roe in June, the Supreme Court’s conservative majority drew on legal arguments that have shaped another contentious end-of-life issue. The legal standard employed in Dobbs – that there is no right to abortion in the federal Constitution and that states can decide on their own – is the same rationale used in 1997 when the Supreme Court said terminally ill people did not have a constitutional right to medically assisted death. That decision, Washington v. Glucksberg, is mentioned 15 times in the majority opinion for Dobbs and a concurrence by Justice Clarence Thomas.
Often, the same groups that have led the fight to outlaw abortion have also challenged medical aid-in-dying laws. Even after Dobbs, so-called right-to-die laws remain far less common than those codifying state abortion rights. Ten states allow physicians to prescribe lethal doses of medicine for terminally ill patients. Doctors are still prohibited from administering the drugs.
James Bopp, general counsel for the National Right to Life Committee who has been central to the efforts to outlaw abortion, said that both abortion and medically assisted death, which he refers to as physician-assisted suicide, endanger society.
“Every individual human life has inherent value and is sacred,” said Mr. Bopp. “The government has the duty to protect that life.”
Both issues raise profound societal questions: Can the government keep a patient on life support against his wishes, or force a woman to give birth? Can states bar their own residents from going to other states to end a pregnancy, or prohibit out-of-state patients from coming in to seek medically assisted death? And who gets to decide, particularly if the answer imposes a singular religious viewpoint?
Just as there are legal implications that flow from determining a person’s death, from organ donation to inheritance, the implied rights held by a legally recognized zygote are potentially vast. Will death certificates be issued for every lost pregnancy? Will miscarriages be investigated? When will Social Security numbers be issued? How will census counts be tallied and congressional districts drawn?
Medical professionals and bioethicists caution that both the beginning and end of life are complicated biological processes that are not defined by a single identifiable moment – and are ill suited to the political arena.
“Unfortunately, biological occurrences are not events, they are processes,” said David Magnus, PhD, director of the Stanford (Calif.) Center for Biomedical Ethics.
Moreover, asking doctors “What is life?” or “What is death?” may miss the point, said Dr. Magnus: “Medicine can answer the question ‘When does a biological organism cease to exist?’ But they can’t answer the question ‘When does a person begin or end?’ because those are metaphysical issues.”
Ben Sarbey, a doctoral candidate in the department of philosophy at Duke University, Durham, N.C., who studies medical ethics, echoed that perspective, recounting the Paradox of the Heap, a thought experiment that involves placing grains of sand one on top of the next. The philosophical quandary is this: At what point do those grains of sand become something more – a heap?
“We’re going to have a rough time placing a dividing line that this counts as a person and this does not count as a person,” he said. “Many things count as life – a sperm counts as life, a person in a persistent vegetative state counts as life – but does that constitute a person that we should be protecting?”
Even as debate over the court’s abortion decision percolates, the 1981 federal statute that grew out of the presidential committee’s findings, the Uniform Determination of Death Act, is also under review. In 2022, the Uniform Law Commission, a nonpartisan group of legal experts that drafts laws intended for adoption in multiple states, has taken up the work to revisit the definition of death.
The group will consider sharpening the medical standards for brain death in light of advances in the understanding of brain function. And they will look to address lingering questions raised in recent years as families and religious groups have waged heated legal battles over terminating artificial life support for patients with no brain wave activity.
Mr. Bopp, with the National Right to Life Committee, is among those serving on advisory panels for the effort, along with an array of doctors, philosophers, and medical ethicists. The concept of “personhood” that infuses the antiabortion movement’s broader push for fetal rights is expected to be an underlying topic, albeit in mirror image: When does a life form cease being a person?
Dr. Magnus, who is also serving on an advisory panel, has no doubt the commission will reach a consensus, a sober resolution rooted in science. What’s less clear, he said, is whether in today’s political environment that updated definition will hold the same sway, an enduring legal standard embraced across states.
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
Botanical Briefs: Tulipalin A
Cutaneous Manifestations
Contact dermatitis is a common problem for individuals who work in the floral industry. Hand dermatitis has been reported in as many as 26% of floral employees.1Tulipa species have been identified as one of the most common causes of hand dermatitis. Tulipalin A (α-methylene-γ-butyrolactone) is the main sensitizer in tulips (Figure 1) and its precursor tuliposide A also occurs both in tulips and the Peruvian lily (Alstroemeria).
In a 1996 study, 18% (9/51) of tulip workers were found to be allergic to tulipalin A.2 In a more recent study of 164 tulip workers, 48 (29.3%) had clinical evidence of contact dermatitis and subsequently underwent patch testing; 17 (35.4%) showed a positive reaction to either tulipalin A or to tulip-bulb extract.3 Itching was the most common symptom (39 workers [81.3%]) and hand eczema at the tip of the thumb and index finger was the most common finding. In 9 (18.8%) workers, eczema had spread to other body parts including the forearm, face, legs, and abdomen.3
Peruvian lily is widely used in floral arrangements and has become a leading cause of hand dermatitis in florists (Figure 2). Large amounts of free tulipalin A are present in bulb scales of tulips, along with a small amount of tuliposide A. In young developing shoots, the situation is reversed: Both compounds are found in all parts of the plant to some degree, though tulipalin A is the major allergen, and more mature parts of the plant and bulb are most allergenic.
Cultural Considerations
In traditional Kurdish cuisine, raw herbs are part of snacking or are served as a side dish (sawza). Snacks often are consumed raw on the spot. Tulipa montana, Tulipa armena, and possibly other Tulipa species are consumed as a snack.4 Traditionally, Tulipa systola is consumed by the Kurds as an anti-inflammatory medicine and for pain relief. It also has been proposed that T systola has antioxidant properties.5 Cooked tulip also has been consumed in time of famine in Europe, though none of these dietary practices are recommended.4
Clinical Presentation
“Tulip fingers” describes the most common presentation of contact dermatitis caused by tulip bulbs. Erythematous scaling plaques are seen in the periungual skin and first and second fingertips of the dominant hand. Other manifestations include diffuse dry dermatitis of the hand; paronychia; pulpitis; and secondary spread to the face, neck, arms, and genitalia, with eczematous papules and plaques.6 Clinical signs include erythema, vesicles, hyperkeratosis, and exfoliation of the fingertips. The allergen also can cause airborne contact dermatitis and manifest as conjunctivitis, rhinitis, and asthma.2 A considerable number of tulip workers develop paresthesia and tenderness in the fingertips within several hours after working with tulip bulbs, known as “tulip fire.”7
Plant Facts
There are approximately 250 genera of bulbous plants. Tulips are members of the genus Tulipa and family Liliaceae. Tulips often are thought of as native to southwest central Asia and Turkey8; however, Tulipa sylvestris is native to Portugal, Spain, and North Africa.
Etymology and Symbolism—The word tulip is derived from the Turkish word türbent meaning a turban, possibly because the flower is compared to turbans worn by men of the Ottoman Empire in the 16th century. In Turkish culture, the tulip is a symbol of paradise on earth and can have divine status. In the Netherlands, on the other hand, the tulip represents the briefness of life.
History—By 1562, tulip bulbs had already been introduced to Holland by merchants. However, the first shipment of tulip bulbs was mistaken by the Dutch for onions and were either roasted over a fire or perished when planted in gardens with vegetables. Carolus Clusius—botanist, director of the imperial medical garden in Vienna and recipient of many plants through diplomatic channels—was particularly fond of flower bulbs and contributed to the popularity of the tulip in Europe by sending bulbs and seeds to other European countries.
In the early 17th century, the tulip craze began in France, fueled by a viral disease of tulips that produced variegated color patterns on the petals; entire properties were sold in exchange for a single tulip bulb. The tulip craze drifted from France to Holland in 1634 for 3 years before the tulip market collapsed.
More recently, in 2003 investors started a multimillion-euro tulip fund in the Netherlands to develop new varieties of tulip. Tulip bulbs were used to create money with high percentages over the selling price. With exorbitant pricing and ever-changing ownership of bulbs—bulbs were bought and sold as many as 10 times—the tulip fund collapsed 1 year later and investors lost their money. Bulb speculators then took their profit abroad. In 2006, bulb owners were charged with fraud; the tulip craze often is cited as one of the early major stock market collapses.
Tulips continue to grow in popularity. Today, nearly 6000 cultivars are registered, with 40 new cultivars registered every 5 years.9
Identifying Features
At the base of the erect tulip plant is a cluster of 2 or 3 thick bluish-green leaves. Three petals and 3 sepals make up the solitary bell-shaped flower. Many tulips can propagate only by means of their scaly bulbs. The flowers arise from the tips of stems in different solid colors, except true blue—from pure white to all shades of yellow, red, and a deep purple that is almost black. Solid-color tulips are called “self-colored.” So-called broken tulips are individual flowers with multiple colors, a condition caused by a viral disease transmitted by aphids.10
Tulip Allergen
Tuliposide A is found in many species of the genera Tulipa, Alstroemeria, and Erythronium.6 So far, 7 analogs have been identified: 1-tuliposide A and B; 6-tuliposide A and B; and tuliposides D, E, and F. 6-Tuliposide A and B are the principal tuliposides found in tulip cultivars.11 With trauma and maturation, tuliposides A and B are hydrolyzed to tulipalin A and tulipalin B, respectively.
Tulipalin A and tulipalin B have antimicrobial properties against bacteria and fungi; tulipalin A is mostly an antifungal agent, and tulipalin B has mostly bacteriostatic characteristics.12 The highest concentration of tulipalin A is found in the outer layer of the bulb, followed by (in descending order) the stem, leaves, and petals.13
The prevalence of tulipalin A allergy led the German Federal Institute for Risk Assessment to assign tuliposide A and tulipalin A to category B, which is a “solid-based indication for contact allergenic effects”; both chemicals also are considered skin sensitizers, defined by the Globally Harmonized System of Classification and Labelling of Chemicals of the United Nations as a substance that will induce an allergic response following skin contact.14 Patients who are allergic to tulips have cross-sensitivity to Alstroemeria because tuliposide A and its metabolites are found in both plants.15
Symptoms of an allergic response to tulipalin A can be immediate or delayed.14 The most common allergic contact dermatitis caused by tulip bulbs is type IV hypersensitivity, though type I reactions can occur. Symptoms of a type I reaction including contact urticaria, rhinitis, hoarseness, and dyspnea have been reported.14
The variety of tulip handled also contributes to the severity of dermatitis. Handling bulbs of Rose Copeland variety tulips and cutting the flowers of Preludium tulips have been associated with more severe allergic dermatitis presentations, whereas the Red Emperor tulip was found to have less tuliposide A and thus provoke a weaker patch-test reaction.7
A Word About Garlic—Garlic is in the subfamily Allioideae (formerly Alliaceae) taxonomically related to the tulip family (Liliaceae). Garlic also can cause hand dermatitis in cooks, with a similar clinical appearance as tulip fingers. Gas chromatography has shown that garlic contains predominantly tuliposide B, which has been found to be much less allergenic than tuliposide A.7,16
Prevention of Tulipa Dermatitis
Tuliposide A and its metabolites can be found in storehouses and trucks used to transport tulips, in clothing, and in any other place where dust containing the allergen has settled. The best prevention against contact dermatitis is to avoid the inciting plants. Gloves may prevent contact dermatitis due to tuliposide A, which penetrates vinyl but not nitrile gloves. Barrier creams have been proposed, but data are scant.1
- Thiboutot DM, Hamory BH, Marks JG Jr. Dermatoses among floral shop workers. J Am Acad Dermatol. 1990;22:54-58. doi: 10.1016/0190-9622(90)70007-5
- Bruze M, Bjorkner B, Hellstrom AC. Occupational dermatoses in nursery workers. Am J Contact Dermat. 1996;7:100-103.
- Hassan I, Rasool F, Akhtar S, et al. Contact dermatitis caused by tulips: identification of contact sensitizers in tulip works of Kashmir Valley in North India. Contact Dermatitis. 2018;78:64-69. doi:10.1111/cod.12870
- Pieroni A, Zahir H, Amin HI, et al. Where tulips and crocuses are popular food snacks: Kurdish traditional foraging reveals traces of mobile pastoralism in Southern Iraqi Kurdistan. J Ethnobiol Ethnomed. 2019;15:59. doi:10.1186/s13002-019-0341-0
- Amin HIM, Ibrahim MF, Hussain FHS, et al. Phytochemistry and ethnopharmacology of some medicine plants used in the Kurdistan region of Iraq. Nat Prod Commun. 2016;11:291-296.
- Crawford GH. Botanical dermatology [Plant identification – other families: Liliaceae]. Medscape. Updated June 10, 2021. Accessed August 18, 2022. https://emedicine.medscape.com/article/1090097-overview#a3
- Gette MT, Marks JE Jr. Tulip fingers. Arch Dermatol. 1990;126:203-205.
- Bruynzeel DP. Bulb dermatitis: dermatological problems in the flower bulb industries. Contact Dermatitis. 1997;37:70-77. doi:10.1111/j.1600-0536.1997.tb00042.x
- Christenhusz MJ, Govaerts RHA, David J, et al. Tiptoe through the tulips—cultural history, molecular phylogenetics and classification of Tulipa (Liliaceae). Bot J Linn Soc. 2013;172:280-328. doi:10.1111/boj.12061
- The Editors of Encyclopaedia Britannica. Tulip. Encyclopedia Britannica. Updated July 4, 2022. Accessed August 18, 2022. https://www.britannica.com/plant/tulip
- Hausen BM. Airborne contact dermatitis caused by tulip bulbs. J Am Acad Dermatol. 1982;7:500-503. doi:10.1016/s0190-9622(82)70132-x
- Nomura T, Ogita S, Kato Y. A novel lactone-forming carboxylesterase: molecular identification of a tuliposide A-converting enzyme in tulip. Plant Physiol. 2012;159:565-578. doi:10.1104/pp.112.195388
- Khalid MM, Greenberg MI. Tulip finger. Clin Toxicol (Phila). 2018; 56:860. doi:10.1080/15563650.2018.1440588
- McCluskey J, Bourgeois M, Harbison R. Tulipalin A induced phytotoxicity. Int J Crit Illn Inj Sci. 2014;4:181-183. doi:10.4103/2229-5151.134187
- Marks JG Jr. Allergic contact dermatitis to Alstroemeria. Arch Dermatol. 1988;124:914-916.
- Sasseville D. Clinical patterns of phytodermatitis. Dermatol Clin. 2009;27:299-308. doi:10.1016/j.det.2009.05.010
Cutaneous Manifestations
Contact dermatitis is a common problem for individuals who work in the floral industry. Hand dermatitis has been reported in as many as 26% of floral employees.1Tulipa species have been identified as one of the most common causes of hand dermatitis. Tulipalin A (α-methylene-γ-butyrolactone) is the main sensitizer in tulips (Figure 1) and its precursor tuliposide A also occurs both in tulips and the Peruvian lily (Alstroemeria).
In a 1996 study, 18% (9/51) of tulip workers were found to be allergic to tulipalin A.2 In a more recent study of 164 tulip workers, 48 (29.3%) had clinical evidence of contact dermatitis and subsequently underwent patch testing; 17 (35.4%) showed a positive reaction to either tulipalin A or to tulip-bulb extract.3 Itching was the most common symptom (39 workers [81.3%]) and hand eczema at the tip of the thumb and index finger was the most common finding. In 9 (18.8%) workers, eczema had spread to other body parts including the forearm, face, legs, and abdomen.3
Peruvian lily is widely used in floral arrangements and has become a leading cause of hand dermatitis in florists (Figure 2). Large amounts of free tulipalin A are present in bulb scales of tulips, along with a small amount of tuliposide A. In young developing shoots, the situation is reversed: Both compounds are found in all parts of the plant to some degree, though tulipalin A is the major allergen, and more mature parts of the plant and bulb are most allergenic.
Cultural Considerations
In traditional Kurdish cuisine, raw herbs are part of snacking or are served as a side dish (sawza). Snacks often are consumed raw on the spot. Tulipa montana, Tulipa armena, and possibly other Tulipa species are consumed as a snack.4 Traditionally, Tulipa systola is consumed by the Kurds as an anti-inflammatory medicine and for pain relief. It also has been proposed that T systola has antioxidant properties.5 Cooked tulip also has been consumed in time of famine in Europe, though none of these dietary practices are recommended.4
Clinical Presentation
“Tulip fingers” describes the most common presentation of contact dermatitis caused by tulip bulbs. Erythematous scaling plaques are seen in the periungual skin and first and second fingertips of the dominant hand. Other manifestations include diffuse dry dermatitis of the hand; paronychia; pulpitis; and secondary spread to the face, neck, arms, and genitalia, with eczematous papules and plaques.6 Clinical signs include erythema, vesicles, hyperkeratosis, and exfoliation of the fingertips. The allergen also can cause airborne contact dermatitis and manifest as conjunctivitis, rhinitis, and asthma.2 A considerable number of tulip workers develop paresthesia and tenderness in the fingertips within several hours after working with tulip bulbs, known as “tulip fire.”7
Plant Facts
There are approximately 250 genera of bulbous plants. Tulips are members of the genus Tulipa and family Liliaceae. Tulips often are thought of as native to southwest central Asia and Turkey8; however, Tulipa sylvestris is native to Portugal, Spain, and North Africa.
Etymology and Symbolism—The word tulip is derived from the Turkish word türbent meaning a turban, possibly because the flower is compared to turbans worn by men of the Ottoman Empire in the 16th century. In Turkish culture, the tulip is a symbol of paradise on earth and can have divine status. In the Netherlands, on the other hand, the tulip represents the briefness of life.
History—By 1562, tulip bulbs had already been introduced to Holland by merchants. However, the first shipment of tulip bulbs was mistaken by the Dutch for onions and were either roasted over a fire or perished when planted in gardens with vegetables. Carolus Clusius—botanist, director of the imperial medical garden in Vienna and recipient of many plants through diplomatic channels—was particularly fond of flower bulbs and contributed to the popularity of the tulip in Europe by sending bulbs and seeds to other European countries.
In the early 17th century, the tulip craze began in France, fueled by a viral disease of tulips that produced variegated color patterns on the petals; entire properties were sold in exchange for a single tulip bulb. The tulip craze drifted from France to Holland in 1634 for 3 years before the tulip market collapsed.
More recently, in 2003 investors started a multimillion-euro tulip fund in the Netherlands to develop new varieties of tulip. Tulip bulbs were used to create money with high percentages over the selling price. With exorbitant pricing and ever-changing ownership of bulbs—bulbs were bought and sold as many as 10 times—the tulip fund collapsed 1 year later and investors lost their money. Bulb speculators then took their profit abroad. In 2006, bulb owners were charged with fraud; the tulip craze often is cited as one of the early major stock market collapses.
Tulips continue to grow in popularity. Today, nearly 6000 cultivars are registered, with 40 new cultivars registered every 5 years.9
Identifying Features
At the base of the erect tulip plant is a cluster of 2 or 3 thick bluish-green leaves. Three petals and 3 sepals make up the solitary bell-shaped flower. Many tulips can propagate only by means of their scaly bulbs. The flowers arise from the tips of stems in different solid colors, except true blue—from pure white to all shades of yellow, red, and a deep purple that is almost black. Solid-color tulips are called “self-colored.” So-called broken tulips are individual flowers with multiple colors, a condition caused by a viral disease transmitted by aphids.10
Tulip Allergen
Tuliposide A is found in many species of the genera Tulipa, Alstroemeria, and Erythronium.6 So far, 7 analogs have been identified: 1-tuliposide A and B; 6-tuliposide A and B; and tuliposides D, E, and F. 6-Tuliposide A and B are the principal tuliposides found in tulip cultivars.11 With trauma and maturation, tuliposides A and B are hydrolyzed to tulipalin A and tulipalin B, respectively.
Tulipalin A and tulipalin B have antimicrobial properties against bacteria and fungi; tulipalin A is mostly an antifungal agent, and tulipalin B has mostly bacteriostatic characteristics.12 The highest concentration of tulipalin A is found in the outer layer of the bulb, followed by (in descending order) the stem, leaves, and petals.13
The prevalence of tulipalin A allergy led the German Federal Institute for Risk Assessment to assign tuliposide A and tulipalin A to category B, which is a “solid-based indication for contact allergenic effects”; both chemicals also are considered skin sensitizers, defined by the Globally Harmonized System of Classification and Labelling of Chemicals of the United Nations as a substance that will induce an allergic response following skin contact.14 Patients who are allergic to tulips have cross-sensitivity to Alstroemeria because tuliposide A and its metabolites are found in both plants.15
Symptoms of an allergic response to tulipalin A can be immediate or delayed.14 The most common allergic contact dermatitis caused by tulip bulbs is type IV hypersensitivity, though type I reactions can occur. Symptoms of a type I reaction including contact urticaria, rhinitis, hoarseness, and dyspnea have been reported.14
The variety of tulip handled also contributes to the severity of dermatitis. Handling bulbs of Rose Copeland variety tulips and cutting the flowers of Preludium tulips have been associated with more severe allergic dermatitis presentations, whereas the Red Emperor tulip was found to have less tuliposide A and thus provoke a weaker patch-test reaction.7
A Word About Garlic—Garlic is in the subfamily Allioideae (formerly Alliaceae) taxonomically related to the tulip family (Liliaceae). Garlic also can cause hand dermatitis in cooks, with a similar clinical appearance as tulip fingers. Gas chromatography has shown that garlic contains predominantly tuliposide B, which has been found to be much less allergenic than tuliposide A.7,16
Prevention of Tulipa Dermatitis
Tuliposide A and its metabolites can be found in storehouses and trucks used to transport tulips, in clothing, and in any other place where dust containing the allergen has settled. The best prevention against contact dermatitis is to avoid the inciting plants. Gloves may prevent contact dermatitis due to tuliposide A, which penetrates vinyl but not nitrile gloves. Barrier creams have been proposed, but data are scant.1
Cutaneous Manifestations
Contact dermatitis is a common problem for individuals who work in the floral industry. Hand dermatitis has been reported in as many as 26% of floral employees.1Tulipa species have been identified as one of the most common causes of hand dermatitis. Tulipalin A (α-methylene-γ-butyrolactone) is the main sensitizer in tulips (Figure 1) and its precursor tuliposide A also occurs both in tulips and the Peruvian lily (Alstroemeria).
In a 1996 study, 18% (9/51) of tulip workers were found to be allergic to tulipalin A.2 In a more recent study of 164 tulip workers, 48 (29.3%) had clinical evidence of contact dermatitis and subsequently underwent patch testing; 17 (35.4%) showed a positive reaction to either tulipalin A or to tulip-bulb extract.3 Itching was the most common symptom (39 workers [81.3%]) and hand eczema at the tip of the thumb and index finger was the most common finding. In 9 (18.8%) workers, eczema had spread to other body parts including the forearm, face, legs, and abdomen.3
Peruvian lily is widely used in floral arrangements and has become a leading cause of hand dermatitis in florists (Figure 2). Large amounts of free tulipalin A are present in bulb scales of tulips, along with a small amount of tuliposide A. In young developing shoots, the situation is reversed: Both compounds are found in all parts of the plant to some degree, though tulipalin A is the major allergen, and more mature parts of the plant and bulb are most allergenic.
Cultural Considerations
In traditional Kurdish cuisine, raw herbs are part of snacking or are served as a side dish (sawza). Snacks often are consumed raw on the spot. Tulipa montana, Tulipa armena, and possibly other Tulipa species are consumed as a snack.4 Traditionally, Tulipa systola is consumed by the Kurds as an anti-inflammatory medicine and for pain relief. It also has been proposed that T systola has antioxidant properties.5 Cooked tulip also has been consumed in time of famine in Europe, though none of these dietary practices are recommended.4
Clinical Presentation
“Tulip fingers” describes the most common presentation of contact dermatitis caused by tulip bulbs. Erythematous scaling plaques are seen in the periungual skin and first and second fingertips of the dominant hand. Other manifestations include diffuse dry dermatitis of the hand; paronychia; pulpitis; and secondary spread to the face, neck, arms, and genitalia, with eczematous papules and plaques.6 Clinical signs include erythema, vesicles, hyperkeratosis, and exfoliation of the fingertips. The allergen also can cause airborne contact dermatitis and manifest as conjunctivitis, rhinitis, and asthma.2 A considerable number of tulip workers develop paresthesia and tenderness in the fingertips within several hours after working with tulip bulbs, known as “tulip fire.”7
Plant Facts
There are approximately 250 genera of bulbous plants. Tulips are members of the genus Tulipa and family Liliaceae. Tulips often are thought of as native to southwest central Asia and Turkey8; however, Tulipa sylvestris is native to Portugal, Spain, and North Africa.
Etymology and Symbolism—The word tulip is derived from the Turkish word türbent meaning a turban, possibly because the flower is compared to turbans worn by men of the Ottoman Empire in the 16th century. In Turkish culture, the tulip is a symbol of paradise on earth and can have divine status. In the Netherlands, on the other hand, the tulip represents the briefness of life.
History—By 1562, tulip bulbs had already been introduced to Holland by merchants. However, the first shipment of tulip bulbs was mistaken by the Dutch for onions and were either roasted over a fire or perished when planted in gardens with vegetables. Carolus Clusius—botanist, director of the imperial medical garden in Vienna and recipient of many plants through diplomatic channels—was particularly fond of flower bulbs and contributed to the popularity of the tulip in Europe by sending bulbs and seeds to other European countries.
In the early 17th century, the tulip craze began in France, fueled by a viral disease of tulips that produced variegated color patterns on the petals; entire properties were sold in exchange for a single tulip bulb. The tulip craze drifted from France to Holland in 1634 for 3 years before the tulip market collapsed.
More recently, in 2003 investors started a multimillion-euro tulip fund in the Netherlands to develop new varieties of tulip. Tulip bulbs were used to create money with high percentages over the selling price. With exorbitant pricing and ever-changing ownership of bulbs—bulbs were bought and sold as many as 10 times—the tulip fund collapsed 1 year later and investors lost their money. Bulb speculators then took their profit abroad. In 2006, bulb owners were charged with fraud; the tulip craze often is cited as one of the early major stock market collapses.
Tulips continue to grow in popularity. Today, nearly 6000 cultivars are registered, with 40 new cultivars registered every 5 years.9
Identifying Features
At the base of the erect tulip plant is a cluster of 2 or 3 thick bluish-green leaves. Three petals and 3 sepals make up the solitary bell-shaped flower. Many tulips can propagate only by means of their scaly bulbs. The flowers arise from the tips of stems in different solid colors, except true blue—from pure white to all shades of yellow, red, and a deep purple that is almost black. Solid-color tulips are called “self-colored.” So-called broken tulips are individual flowers with multiple colors, a condition caused by a viral disease transmitted by aphids.10
Tulip Allergen
Tuliposide A is found in many species of the genera Tulipa, Alstroemeria, and Erythronium.6 So far, 7 analogs have been identified: 1-tuliposide A and B; 6-tuliposide A and B; and tuliposides D, E, and F. 6-Tuliposide A and B are the principal tuliposides found in tulip cultivars.11 With trauma and maturation, tuliposides A and B are hydrolyzed to tulipalin A and tulipalin B, respectively.
Tulipalin A and tulipalin B have antimicrobial properties against bacteria and fungi; tulipalin A is mostly an antifungal agent, and tulipalin B has mostly bacteriostatic characteristics.12 The highest concentration of tulipalin A is found in the outer layer of the bulb, followed by (in descending order) the stem, leaves, and petals.13
The prevalence of tulipalin A allergy led the German Federal Institute for Risk Assessment to assign tuliposide A and tulipalin A to category B, which is a “solid-based indication for contact allergenic effects”; both chemicals also are considered skin sensitizers, defined by the Globally Harmonized System of Classification and Labelling of Chemicals of the United Nations as a substance that will induce an allergic response following skin contact.14 Patients who are allergic to tulips have cross-sensitivity to Alstroemeria because tuliposide A and its metabolites are found in both plants.15
Symptoms of an allergic response to tulipalin A can be immediate or delayed.14 The most common allergic contact dermatitis caused by tulip bulbs is type IV hypersensitivity, though type I reactions can occur. Symptoms of a type I reaction including contact urticaria, rhinitis, hoarseness, and dyspnea have been reported.14
The variety of tulip handled also contributes to the severity of dermatitis. Handling bulbs of Rose Copeland variety tulips and cutting the flowers of Preludium tulips have been associated with more severe allergic dermatitis presentations, whereas the Red Emperor tulip was found to have less tuliposide A and thus provoke a weaker patch-test reaction.7
A Word About Garlic—Garlic is in the subfamily Allioideae (formerly Alliaceae) taxonomically related to the tulip family (Liliaceae). Garlic also can cause hand dermatitis in cooks, with a similar clinical appearance as tulip fingers. Gas chromatography has shown that garlic contains predominantly tuliposide B, which has been found to be much less allergenic than tuliposide A.7,16
Prevention of Tulipa Dermatitis
Tuliposide A and its metabolites can be found in storehouses and trucks used to transport tulips, in clothing, and in any other place where dust containing the allergen has settled. The best prevention against contact dermatitis is to avoid the inciting plants. Gloves may prevent contact dermatitis due to tuliposide A, which penetrates vinyl but not nitrile gloves. Barrier creams have been proposed, but data are scant.1
- Thiboutot DM, Hamory BH, Marks JG Jr. Dermatoses among floral shop workers. J Am Acad Dermatol. 1990;22:54-58. doi: 10.1016/0190-9622(90)70007-5
- Bruze M, Bjorkner B, Hellstrom AC. Occupational dermatoses in nursery workers. Am J Contact Dermat. 1996;7:100-103.
- Hassan I, Rasool F, Akhtar S, et al. Contact dermatitis caused by tulips: identification of contact sensitizers in tulip works of Kashmir Valley in North India. Contact Dermatitis. 2018;78:64-69. doi:10.1111/cod.12870
- Pieroni A, Zahir H, Amin HI, et al. Where tulips and crocuses are popular food snacks: Kurdish traditional foraging reveals traces of mobile pastoralism in Southern Iraqi Kurdistan. J Ethnobiol Ethnomed. 2019;15:59. doi:10.1186/s13002-019-0341-0
- Amin HIM, Ibrahim MF, Hussain FHS, et al. Phytochemistry and ethnopharmacology of some medicine plants used in the Kurdistan region of Iraq. Nat Prod Commun. 2016;11:291-296.
- Crawford GH. Botanical dermatology [Plant identification – other families: Liliaceae]. Medscape. Updated June 10, 2021. Accessed August 18, 2022. https://emedicine.medscape.com/article/1090097-overview#a3
- Gette MT, Marks JE Jr. Tulip fingers. Arch Dermatol. 1990;126:203-205.
- Bruynzeel DP. Bulb dermatitis: dermatological problems in the flower bulb industries. Contact Dermatitis. 1997;37:70-77. doi:10.1111/j.1600-0536.1997.tb00042.x
- Christenhusz MJ, Govaerts RHA, David J, et al. Tiptoe through the tulips—cultural history, molecular phylogenetics and classification of Tulipa (Liliaceae). Bot J Linn Soc. 2013;172:280-328. doi:10.1111/boj.12061
- The Editors of Encyclopaedia Britannica. Tulip. Encyclopedia Britannica. Updated July 4, 2022. Accessed August 18, 2022. https://www.britannica.com/plant/tulip
- Hausen BM. Airborne contact dermatitis caused by tulip bulbs. J Am Acad Dermatol. 1982;7:500-503. doi:10.1016/s0190-9622(82)70132-x
- Nomura T, Ogita S, Kato Y. A novel lactone-forming carboxylesterase: molecular identification of a tuliposide A-converting enzyme in tulip. Plant Physiol. 2012;159:565-578. doi:10.1104/pp.112.195388
- Khalid MM, Greenberg MI. Tulip finger. Clin Toxicol (Phila). 2018; 56:860. doi:10.1080/15563650.2018.1440588
- McCluskey J, Bourgeois M, Harbison R. Tulipalin A induced phytotoxicity. Int J Crit Illn Inj Sci. 2014;4:181-183. doi:10.4103/2229-5151.134187
- Marks JG Jr. Allergic contact dermatitis to Alstroemeria. Arch Dermatol. 1988;124:914-916.
- Sasseville D. Clinical patterns of phytodermatitis. Dermatol Clin. 2009;27:299-308. doi:10.1016/j.det.2009.05.010
- Thiboutot DM, Hamory BH, Marks JG Jr. Dermatoses among floral shop workers. J Am Acad Dermatol. 1990;22:54-58. doi: 10.1016/0190-9622(90)70007-5
- Bruze M, Bjorkner B, Hellstrom AC. Occupational dermatoses in nursery workers. Am J Contact Dermat. 1996;7:100-103.
- Hassan I, Rasool F, Akhtar S, et al. Contact dermatitis caused by tulips: identification of contact sensitizers in tulip works of Kashmir Valley in North India. Contact Dermatitis. 2018;78:64-69. doi:10.1111/cod.12870
- Pieroni A, Zahir H, Amin HI, et al. Where tulips and crocuses are popular food snacks: Kurdish traditional foraging reveals traces of mobile pastoralism in Southern Iraqi Kurdistan. J Ethnobiol Ethnomed. 2019;15:59. doi:10.1186/s13002-019-0341-0
- Amin HIM, Ibrahim MF, Hussain FHS, et al. Phytochemistry and ethnopharmacology of some medicine plants used in the Kurdistan region of Iraq. Nat Prod Commun. 2016;11:291-296.
- Crawford GH. Botanical dermatology [Plant identification – other families: Liliaceae]. Medscape. Updated June 10, 2021. Accessed August 18, 2022. https://emedicine.medscape.com/article/1090097-overview#a3
- Gette MT, Marks JE Jr. Tulip fingers. Arch Dermatol. 1990;126:203-205.
- Bruynzeel DP. Bulb dermatitis: dermatological problems in the flower bulb industries. Contact Dermatitis. 1997;37:70-77. doi:10.1111/j.1600-0536.1997.tb00042.x
- Christenhusz MJ, Govaerts RHA, David J, et al. Tiptoe through the tulips—cultural history, molecular phylogenetics and classification of Tulipa (Liliaceae). Bot J Linn Soc. 2013;172:280-328. doi:10.1111/boj.12061
- The Editors of Encyclopaedia Britannica. Tulip. Encyclopedia Britannica. Updated July 4, 2022. Accessed August 18, 2022. https://www.britannica.com/plant/tulip
- Hausen BM. Airborne contact dermatitis caused by tulip bulbs. J Am Acad Dermatol. 1982;7:500-503. doi:10.1016/s0190-9622(82)70132-x
- Nomura T, Ogita S, Kato Y. A novel lactone-forming carboxylesterase: molecular identification of a tuliposide A-converting enzyme in tulip. Plant Physiol. 2012;159:565-578. doi:10.1104/pp.112.195388
- Khalid MM, Greenberg MI. Tulip finger. Clin Toxicol (Phila). 2018; 56:860. doi:10.1080/15563650.2018.1440588
- McCluskey J, Bourgeois M, Harbison R. Tulipalin A induced phytotoxicity. Int J Crit Illn Inj Sci. 2014;4:181-183. doi:10.4103/2229-5151.134187
- Marks JG Jr. Allergic contact dermatitis to Alstroemeria. Arch Dermatol. 1988;124:914-916.
- Sasseville D. Clinical patterns of phytodermatitis. Dermatol Clin. 2009;27:299-308. doi:10.1016/j.det.2009.05.010
Practice Points
- Tulips are a common cause of contact dermatitis among floral workers.
- Tulipalin A is the primary sensitizer in tulips causing allergic contact dermatitis.
- The best preventative for tulip contact dermatitis is avoiding the inciting plants.
Disparities of Cutaneous Malignancies in the US Military
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
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.
- Powers JG, Patel NA, Powers EM, et al. Skin cancer risk factors and preventative behaviors among United States military veterans deployed to Iraq and Afghanistan. J Invest Dermatol. 2015;135:2871-2873.
- Riemenschneider K, Liu J, Powers JG. Skin cancer in the military: a systematic review of melanoma and nonmelanoma skin cancer incidence, prevention, and screening among active duty and veteran personnel. J Am Acad Dermatol. 2018;78:1185-1192.
- Brown J, Kopf AW, Rigel DS, et al. Malignant melanoma in World War II veterans. Int J Dermatol. 1984;23:661-663.
- Zhou J, Enewold L, Zahm SH, et al. Melanoma incidence rates among whites in the U.S. Military. Cancer Epidemiol Biomarkers Prev. 2011;20:318-323.
- Lea CS, Efird JT, Toland AE, et al. Melanoma incidence rates in active duty military personnel compared with a population-based registry in the United States, 2000-2007. Mil Med. 2014;179:247-253.
- Sanlorenzo M, Vujic I, Posch C, et al. The risk of melanoma in pilots and cabin crew: UV measurements in flying airplanes. JAMA Dermatol. 2015;151:450-452.
- Lee T, Taubman SB, Williams VF. Incident diagnoses of non-melanoma skin cancer, active component, U.S. Armed Forces, 2005-2014. MSMR. 2016;23:2-6.
- Ramani ML, Bennett RG. High prevalence of skin cancer in World War II servicemen stationed in the Pacific theater. J Am Acad Dermatol. 1993;28:733-737.
- Henning JS, Firoz, BF. Combat dermatology: the prevalence of skin disease in a deployed dermatology clinic in Iraq. J Drugs Dermatol. 2010;9:210-214.
- Gerall CD, Sippel MR, Yracheta JL, et al. Microcystic adnexal carcinoma: a rare, commonly misdiagnosed malignancy. Mil Med. 2019;184:948-950.
- Wilkison B, Wong E. Skin cancer in military pilots: a special population with special risk factors. Cutis. 2017;100:218-220.
- Proctor SP, Heaton KJ, Smith KW, et al. The Occupational JP8 Neuroepidemiology Study (OJENES): repeated workday exposure and central nervous system functioning among US Air Force personnel. Neurotoxicology. 2011;32:799-808.
- Soldiers protect themselves from skin cancer. US Army website. Published February 28, 2019. Accessed August 21, 2022. https://www.army.mil/article/17601/soldiers_protect_themselves_from_skin_cancer
- Fisher V, Lee D, McGrath J, et al. Veterans speak up: current warnings on skin cancer miss the target, suggestions for improvement. Mil Med. 2015;180:892-897.
- Rogers HW, Weinstick MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol. 2010;146:283-287.
- Sun safety. Army Public Health Center website. Updated June 6, 2019. Accessed August 21, 2022. https://phc.amedd.army.mil/topics/discond/hipss/Pages/Sun-Safety.aspx
- Outdoor ultraviolet radiation hazards and protection. Army Public Health Center website. Accessed August 21, 2022. https://phc.amedd.army.mil/PHC%20Resource%20Library/OutdoorUltravioletRadiationHazardsandProtection_FS_24-017-1115.pdf
- Saraiya M, Frank E, Elon L, et al. Personal and clinical skin cancer prevention practices of US women physicians. Arch Dermatol. 2000;136:633-642.
- What to look for: ABCDEs of melanoma. American Academy of Dermatology website. Accessed August 21, 2022. https://www.aad.org/public/diseases/skin-cancer/find/at-risk/abcdes
- Detect skin cancer: how to perform a skin self-exam. American Academy of Dermatology website. Accessed August 21, 2022. https://www.aad.org/public/diseases/skin-cancer/find/check-skin
- Hwang JS, Lappan CM, Sperling LC, et al. Utilization of telemedicine in the US military in a deployed setting. Mil Med. 2014;179:1347-1353.
- Bartling SJ, Rivard SC, Meyerle JH. Melanoma in an active duty marine. Mil Med. 2017;182:2034-2039.
- Day WG, Shirvastava V, Roman JW. Synchronous teledermoscopy in military treatment facilities. Mil Med. 2020;185:1334-1337.
- Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373:1618-1626.
- Bavinck JN, Tieben LM, Van der Woude FJ, et al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol. 1995;13:1933-1938.
- Wulf HC, Pavel S, Stender I, et al. Topical photodynamic therapy for prevention of new skin lesions in renal transplant recipients. Acta Derm Venereol. 2006;86:25-28.
- Weinstock MA, Thwin SS, Siegel JA, et al; Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial (VAKCC) Group. Chemoprevention of basal and squamous cell carcinoma with a single course of fluorouracil, 5%, cream: a randomized clinical trial. JAMA Dermatol. 2018;154:167-174.
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
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
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.
- Powers JG, Patel NA, Powers EM, et al. Skin cancer risk factors and preventative behaviors among United States military veterans deployed to Iraq and Afghanistan. J Invest Dermatol. 2015;135:2871-2873.
- Riemenschneider K, Liu J, Powers JG. Skin cancer in the military: a systematic review of melanoma and nonmelanoma skin cancer incidence, prevention, and screening among active duty and veteran personnel. J Am Acad Dermatol. 2018;78:1185-1192.
- Brown J, Kopf AW, Rigel DS, et al. Malignant melanoma in World War II veterans. Int J Dermatol. 1984;23:661-663.
- Zhou J, Enewold L, Zahm SH, et al. Melanoma incidence rates among whites in the U.S. Military. Cancer Epidemiol Biomarkers Prev. 2011;20:318-323.
- Lea CS, Efird JT, Toland AE, et al. Melanoma incidence rates in active duty military personnel compared with a population-based registry in the United States, 2000-2007. Mil Med. 2014;179:247-253.
- Sanlorenzo M, Vujic I, Posch C, et al. The risk of melanoma in pilots and cabin crew: UV measurements in flying airplanes. JAMA Dermatol. 2015;151:450-452.
- Lee T, Taubman SB, Williams VF. Incident diagnoses of non-melanoma skin cancer, active component, U.S. Armed Forces, 2005-2014. MSMR. 2016;23:2-6.
- Ramani ML, Bennett RG. High prevalence of skin cancer in World War II servicemen stationed in the Pacific theater. J Am Acad Dermatol. 1993;28:733-737.
- Henning JS, Firoz, BF. Combat dermatology: the prevalence of skin disease in a deployed dermatology clinic in Iraq. J Drugs Dermatol. 2010;9:210-214.
- Gerall CD, Sippel MR, Yracheta JL, et al. Microcystic adnexal carcinoma: a rare, commonly misdiagnosed malignancy. Mil Med. 2019;184:948-950.
- Wilkison B, Wong E. Skin cancer in military pilots: a special population with special risk factors. Cutis. 2017;100:218-220.
- Proctor SP, Heaton KJ, Smith KW, et al. The Occupational JP8 Neuroepidemiology Study (OJENES): repeated workday exposure and central nervous system functioning among US Air Force personnel. Neurotoxicology. 2011;32:799-808.
- Soldiers protect themselves from skin cancer. US Army website. Published February 28, 2019. Accessed August 21, 2022. https://www.army.mil/article/17601/soldiers_protect_themselves_from_skin_cancer
- Fisher V, Lee D, McGrath J, et al. Veterans speak up: current warnings on skin cancer miss the target, suggestions for improvement. Mil Med. 2015;180:892-897.
- Rogers HW, Weinstick MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol. 2010;146:283-287.
- Sun safety. Army Public Health Center website. Updated June 6, 2019. Accessed August 21, 2022. https://phc.amedd.army.mil/topics/discond/hipss/Pages/Sun-Safety.aspx
- Outdoor ultraviolet radiation hazards and protection. Army Public Health Center website. Accessed August 21, 2022. https://phc.amedd.army.mil/PHC%20Resource%20Library/OutdoorUltravioletRadiationHazardsandProtection_FS_24-017-1115.pdf
- Saraiya M, Frank E, Elon L, et al. Personal and clinical skin cancer prevention practices of US women physicians. Arch Dermatol. 2000;136:633-642.
- What to look for: ABCDEs of melanoma. American Academy of Dermatology website. Accessed August 21, 2022. https://www.aad.org/public/diseases/skin-cancer/find/at-risk/abcdes
- Detect skin cancer: how to perform a skin self-exam. American Academy of Dermatology website. Accessed August 21, 2022. https://www.aad.org/public/diseases/skin-cancer/find/check-skin
- Hwang JS, Lappan CM, Sperling LC, et al. Utilization of telemedicine in the US military in a deployed setting. Mil Med. 2014;179:1347-1353.
- Bartling SJ, Rivard SC, Meyerle JH. Melanoma in an active duty marine. Mil Med. 2017;182:2034-2039.
- Day WG, Shirvastava V, Roman JW. Synchronous teledermoscopy in military treatment facilities. Mil Med. 2020;185:1334-1337.
- Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373:1618-1626.
- Bavinck JN, Tieben LM, Van der Woude FJ, et al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol. 1995;13:1933-1938.
- Wulf HC, Pavel S, Stender I, et al. Topical photodynamic therapy for prevention of new skin lesions in renal transplant recipients. Acta Derm Venereol. 2006;86:25-28.
- Weinstock MA, Thwin SS, Siegel JA, et al; Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial (VAKCC) Group. Chemoprevention of basal and squamous cell carcinoma with a single course of fluorouracil, 5%, cream: a randomized clinical trial. JAMA Dermatol. 2018;154:167-174.
- Powers JG, Patel NA, Powers EM, et al. Skin cancer risk factors and preventative behaviors among United States military veterans deployed to Iraq and Afghanistan. J Invest Dermatol. 2015;135:2871-2873.
- Riemenschneider K, Liu J, Powers JG. Skin cancer in the military: a systematic review of melanoma and nonmelanoma skin cancer incidence, prevention, and screening among active duty and veteran personnel. J Am Acad Dermatol. 2018;78:1185-1192.
- Brown J, Kopf AW, Rigel DS, et al. Malignant melanoma in World War II veterans. Int J Dermatol. 1984;23:661-663.
- Zhou J, Enewold L, Zahm SH, et al. Melanoma incidence rates among whites in the U.S. Military. Cancer Epidemiol Biomarkers Prev. 2011;20:318-323.
- Lea CS, Efird JT, Toland AE, et al. Melanoma incidence rates in active duty military personnel compared with a population-based registry in the United States, 2000-2007. Mil Med. 2014;179:247-253.
- Sanlorenzo M, Vujic I, Posch C, et al. The risk of melanoma in pilots and cabin crew: UV measurements in flying airplanes. JAMA Dermatol. 2015;151:450-452.
- Lee T, Taubman SB, Williams VF. Incident diagnoses of non-melanoma skin cancer, active component, U.S. Armed Forces, 2005-2014. MSMR. 2016;23:2-6.
- Ramani ML, Bennett RG. High prevalence of skin cancer in World War II servicemen stationed in the Pacific theater. J Am Acad Dermatol. 1993;28:733-737.
- Henning JS, Firoz, BF. Combat dermatology: the prevalence of skin disease in a deployed dermatology clinic in Iraq. J Drugs Dermatol. 2010;9:210-214.
- Gerall CD, Sippel MR, Yracheta JL, et al. Microcystic adnexal carcinoma: a rare, commonly misdiagnosed malignancy. Mil Med. 2019;184:948-950.
- Wilkison B, Wong E. Skin cancer in military pilots: a special population with special risk factors. Cutis. 2017;100:218-220.
- Proctor SP, Heaton KJ, Smith KW, et al. The Occupational JP8 Neuroepidemiology Study (OJENES): repeated workday exposure and central nervous system functioning among US Air Force personnel. Neurotoxicology. 2011;32:799-808.
- Soldiers protect themselves from skin cancer. US Army website. Published February 28, 2019. Accessed August 21, 2022. https://www.army.mil/article/17601/soldiers_protect_themselves_from_skin_cancer
- Fisher V, Lee D, McGrath J, et al. Veterans speak up: current warnings on skin cancer miss the target, suggestions for improvement. Mil Med. 2015;180:892-897.
- Rogers HW, Weinstick MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol. 2010;146:283-287.
- Sun safety. Army Public Health Center website. Updated June 6, 2019. Accessed August 21, 2022. https://phc.amedd.army.mil/topics/discond/hipss/Pages/Sun-Safety.aspx
- Outdoor ultraviolet radiation hazards and protection. Army Public Health Center website. Accessed August 21, 2022. https://phc.amedd.army.mil/PHC%20Resource%20Library/OutdoorUltravioletRadiationHazardsandProtection_FS_24-017-1115.pdf
- Saraiya M, Frank E, Elon L, et al. Personal and clinical skin cancer prevention practices of US women physicians. Arch Dermatol. 2000;136:633-642.
- What to look for: ABCDEs of melanoma. American Academy of Dermatology website. Accessed August 21, 2022. https://www.aad.org/public/diseases/skin-cancer/find/at-risk/abcdes
- Detect skin cancer: how to perform a skin self-exam. American Academy of Dermatology website. Accessed August 21, 2022. https://www.aad.org/public/diseases/skin-cancer/find/check-skin
- Hwang JS, Lappan CM, Sperling LC, et al. Utilization of telemedicine in the US military in a deployed setting. Mil Med. 2014;179:1347-1353.
- Bartling SJ, Rivard SC, Meyerle JH. Melanoma in an active duty marine. Mil Med. 2017;182:2034-2039.
- Day WG, Shirvastava V, Roman JW. Synchronous teledermoscopy in military treatment facilities. Mil Med. 2020;185:1334-1337.
- Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373:1618-1626.
- Bavinck JN, Tieben LM, Van der Woude FJ, et al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol. 1995;13:1933-1938.
- Wulf HC, Pavel S, Stender I, et al. Topical photodynamic therapy for prevention of new skin lesions in renal transplant recipients. Acta Derm Venereol. 2006;86:25-28.
- Weinstock MA, Thwin SS, Siegel JA, et al; Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial (VAKCC) Group. Chemoprevention of basal and squamous cell carcinoma with a single course of fluorouracil, 5%, cream: a randomized clinical trial. JAMA Dermatol. 2018;154:167-174.
Practice Points
- Skin cancer is more prevalent among military personnel and veterans, especially those in the US Air Force. Frequent and/or prolonged sun exposure and lack of sun protection may be key factors.
- Future research should compare the prevalence of skin cancer in nonpilot military populations to the general US population; explore racial and ethnic differences by military branch and their influence on skin cancers; analyze each branch’s sun-protective measures, 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; and explore the effects of appropriate military skin cancer intervention and screening programs.
Association of BRAF V600E Status of Incident Melanoma and Risk for a Second Primary Malignancy: A Population-Based Study
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 groups4-7; 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.8,9
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.
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.
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
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.
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 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
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.
Acknowledgment—We thank Ms. Jayne H. Feind (Rochester, Minnesota) for assistance with study coordination.
- American Cancer Society. Key statistics for melanoma skin cancer. Updated January 12, 2022. Accessed August 15, 2022.https://www.cancer.org/cancer/melanoma-skin-cancer/about/key-statistics.html
- American Cancer Society. Second Cancers After Melanoma Skin Cancer. Accessed August 19, 2022. https://www.cancer.org/cancer/melanoma-skin-cancer/after-treatment/second-cancers.html
- Spanogle JP, Clarke CA, Aroner S, et al. Risk of second primary malignancies following cutaneous melanoma diagnosis: a population-based study. J Am Acad Dermatol. 2010;62:757-767.
- Olazagasti Lourido JM, Ma JE, Lohse CM, et al. Increasing incidence of melanoma in the elderly: an epidemiological study in Olmsted County, Minnesota. Mayo Clin Proc. 2016;91:1555-1562.
- Reed KB, Brewer JD, Lohse CM, et al. Increasing incidence of melanoma among young adults: an epidemiological study in Olmsted County, Minnesota. Mayo Clin Proc. 2012;87:328-334.
- Lowe GC, Brewer JD, Peters MS, et al. Incidence of melanoma in the pediatric population: a population-based study in Olmsted County, Minnesota. Pediatr Derm. 2015;32:618-620.
- Lowe GC, Saavedra A, Reed KB, et al. Increasing incidence of melanoma among middle-aged adults: an epidemiologic study in Olmsted County, Minnesota. Mayo Clin Proc. 2014;89:52-59.
- Ascierto PA, Kirkwood JM, Grob JJ, et al. The role of BRAF V600 mutation in melanoma [editorial]. J Transl Med. 2012;10:85.
- Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949-954.
- Miller AJ, Mihm MC Jr. Melanoma. N Engl J Med. 2006;355:51-65.
- Tiacci E, Trifonov V, Schiavoni G, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011;364:2305-2315.
- Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer. 2005;12:245-262.
- Moreau S, Saiag P, Aegerter P, et al. Prognostic value of BRAF(V600) mutations in melanoma patients after resection of metastatic lymph nodes. Ann Surg Oncol. 2012;19:4314-4321.
- Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107-114.
- von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61:344-349.
- Rocca WA, Yawn BP, St Sauver JL, et al. History of the Rochester Epidemiology Project: half a century of medical records linkage in a US population. Mayo Clin Proc. 2012;87:1202-1213.
- St. Sauver JL, Grossardt BR, Yawn BP, et al. Data resource profile: the Rochester Epidemiology Project (REP) medical records-linkage system. Int J Epidemiol. 2012;41:1614-1624.
- National Cancer Institute. Staging: melanoma of the skin, vulva, penis and scrotum staging. Accessed August 15, 2022. https://training.seer.cancer.gov/melanoma/abstract-code-stage/staging.html
- Pakhomov SV, Buntrock JD, Chute CG. Automating the assignment of diagnosis codes to patient encounters using example-based and machine learning techniques. J Am Med Inform Assoc. 2006;13:516-525.
- Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135-2147.
- Thomas NE, Edmiston SN, Alexander A, et al. Number of nevi and early-life ambient UV exposure are associated with BRAF-mutant melanoma. Cancer Epidemiol Biomarkers Prev. 2007;16:991-997.
- German Cancer Research Center. Why identical mutations cause different types of cancer. July 19, 2021. Accessed August 15, 2022. https://www.dkfz.de/en/presse/pressemitteilungen/2021/dkfz-pm-21-41-Why-identical-mutations-cause-different-types-of-cancer.php
- Falcomatà C, Bärthel S, Ulrich A, et al. Genetic screens identify a context-specific PI3K/p27Kip1 node driving extrahepatic biliary cancer. Cancer Discov. 2021;11:3158-3177.
- Guan H, Ji M, Bao R, et al. Association of high iodine intake with the T1799A BRAF mutation in papillary thyroid cancer. J Clin Endocrinol Metab. 2009;94:1612-1617.
- Wish TA, Hyde AJ, Parfrey PS, et al. Increased cancer predisposition in family members of colorectal cancer patients harboring the p.V600E BRAF mutation: a population-based study. Cancer Epidemiol Biomarkers Prev. 2010;19:1831-1839.
- Zebary A, Omholt K, Vassilaki I, et al. KIT, NRAS, BRAF and PTEN mutations in a sample of Swedish patients with acral lentiginous melanoma. J Dermatol Sci. 2013;72:284-289.
- Si L, Kong Y, Xu X, et al. Prevalence of BRAF V600E mutation in Chinese melanoma patients: large scale analysis of BRAF and NRAS mutations in a 432-case cohort. Eur J Cancer. 2012;48:94-100.
- Safaee Ardekani G, Jafarnejad SM, Khosravi S, et al. Disease progression and patient survival are significantly influenced by BRAF protein expression in primary melanoma. Br J Dermatol. 2013;169:320-328.
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 groups4-7; 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.8,9
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.
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.
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
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.
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 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
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.
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 groups4-7; 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.8,9
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.
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.
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
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.
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 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
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.
Acknowledgment—We thank Ms. Jayne H. Feind (Rochester, Minnesota) for assistance with study coordination.
- American Cancer Society. Key statistics for melanoma skin cancer. Updated January 12, 2022. Accessed August 15, 2022.https://www.cancer.org/cancer/melanoma-skin-cancer/about/key-statistics.html
- American Cancer Society. Second Cancers After Melanoma Skin Cancer. Accessed August 19, 2022. https://www.cancer.org/cancer/melanoma-skin-cancer/after-treatment/second-cancers.html
- Spanogle JP, Clarke CA, Aroner S, et al. Risk of second primary malignancies following cutaneous melanoma diagnosis: a population-based study. J Am Acad Dermatol. 2010;62:757-767.
- Olazagasti Lourido JM, Ma JE, Lohse CM, et al. Increasing incidence of melanoma in the elderly: an epidemiological study in Olmsted County, Minnesota. Mayo Clin Proc. 2016;91:1555-1562.
- Reed KB, Brewer JD, Lohse CM, et al. Increasing incidence of melanoma among young adults: an epidemiological study in Olmsted County, Minnesota. Mayo Clin Proc. 2012;87:328-334.
- Lowe GC, Brewer JD, Peters MS, et al. Incidence of melanoma in the pediatric population: a population-based study in Olmsted County, Minnesota. Pediatr Derm. 2015;32:618-620.
- Lowe GC, Saavedra A, Reed KB, et al. Increasing incidence of melanoma among middle-aged adults: an epidemiologic study in Olmsted County, Minnesota. Mayo Clin Proc. 2014;89:52-59.
- Ascierto PA, Kirkwood JM, Grob JJ, et al. The role of BRAF V600 mutation in melanoma [editorial]. J Transl Med. 2012;10:85.
- Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949-954.
- Miller AJ, Mihm MC Jr. Melanoma. N Engl J Med. 2006;355:51-65.
- Tiacci E, Trifonov V, Schiavoni G, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011;364:2305-2315.
- Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer. 2005;12:245-262.
- Moreau S, Saiag P, Aegerter P, et al. Prognostic value of BRAF(V600) mutations in melanoma patients after resection of metastatic lymph nodes. Ann Surg Oncol. 2012;19:4314-4321.
- Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107-114.
- von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61:344-349.
- Rocca WA, Yawn BP, St Sauver JL, et al. History of the Rochester Epidemiology Project: half a century of medical records linkage in a US population. Mayo Clin Proc. 2012;87:1202-1213.
- St. Sauver JL, Grossardt BR, Yawn BP, et al. Data resource profile: the Rochester Epidemiology Project (REP) medical records-linkage system. Int J Epidemiol. 2012;41:1614-1624.
- National Cancer Institute. Staging: melanoma of the skin, vulva, penis and scrotum staging. Accessed August 15, 2022. https://training.seer.cancer.gov/melanoma/abstract-code-stage/staging.html
- Pakhomov SV, Buntrock JD, Chute CG. Automating the assignment of diagnosis codes to patient encounters using example-based and machine learning techniques. J Am Med Inform Assoc. 2006;13:516-525.
- Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135-2147.
- Thomas NE, Edmiston SN, Alexander A, et al. Number of nevi and early-life ambient UV exposure are associated with BRAF-mutant melanoma. Cancer Epidemiol Biomarkers Prev. 2007;16:991-997.
- German Cancer Research Center. Why identical mutations cause different types of cancer. July 19, 2021. Accessed August 15, 2022. https://www.dkfz.de/en/presse/pressemitteilungen/2021/dkfz-pm-21-41-Why-identical-mutations-cause-different-types-of-cancer.php
- Falcomatà C, Bärthel S, Ulrich A, et al. Genetic screens identify a context-specific PI3K/p27Kip1 node driving extrahepatic biliary cancer. Cancer Discov. 2021;11:3158-3177.
- Guan H, Ji M, Bao R, et al. Association of high iodine intake with the T1799A BRAF mutation in papillary thyroid cancer. J Clin Endocrinol Metab. 2009;94:1612-1617.
- Wish TA, Hyde AJ, Parfrey PS, et al. Increased cancer predisposition in family members of colorectal cancer patients harboring the p.V600E BRAF mutation: a population-based study. Cancer Epidemiol Biomarkers Prev. 2010;19:1831-1839.
- Zebary A, Omholt K, Vassilaki I, et al. KIT, NRAS, BRAF and PTEN mutations in a sample of Swedish patients with acral lentiginous melanoma. J Dermatol Sci. 2013;72:284-289.
- Si L, Kong Y, Xu X, et al. Prevalence of BRAF V600E mutation in Chinese melanoma patients: large scale analysis of BRAF and NRAS mutations in a 432-case cohort. Eur J Cancer. 2012;48:94-100.
- Safaee Ardekani G, Jafarnejad SM, Khosravi S, et al. Disease progression and patient survival are significantly influenced by BRAF protein expression in primary melanoma. Br J Dermatol. 2013;169:320-328.
- American Cancer Society. Key statistics for melanoma skin cancer. Updated January 12, 2022. Accessed August 15, 2022.https://www.cancer.org/cancer/melanoma-skin-cancer/about/key-statistics.html
- American Cancer Society. Second Cancers After Melanoma Skin Cancer. Accessed August 19, 2022. https://www.cancer.org/cancer/melanoma-skin-cancer/after-treatment/second-cancers.html
- Spanogle JP, Clarke CA, Aroner S, et al. Risk of second primary malignancies following cutaneous melanoma diagnosis: a population-based study. J Am Acad Dermatol. 2010;62:757-767.
- Olazagasti Lourido JM, Ma JE, Lohse CM, et al. Increasing incidence of melanoma in the elderly: an epidemiological study in Olmsted County, Minnesota. Mayo Clin Proc. 2016;91:1555-1562.
- Reed KB, Brewer JD, Lohse CM, et al. Increasing incidence of melanoma among young adults: an epidemiological study in Olmsted County, Minnesota. Mayo Clin Proc. 2012;87:328-334.
- Lowe GC, Brewer JD, Peters MS, et al. Incidence of melanoma in the pediatric population: a population-based study in Olmsted County, Minnesota. Pediatr Derm. 2015;32:618-620.
- Lowe GC, Saavedra A, Reed KB, et al. Increasing incidence of melanoma among middle-aged adults: an epidemiologic study in Olmsted County, Minnesota. Mayo Clin Proc. 2014;89:52-59.
- Ascierto PA, Kirkwood JM, Grob JJ, et al. The role of BRAF V600 mutation in melanoma [editorial]. J Transl Med. 2012;10:85.
- Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949-954.
- Miller AJ, Mihm MC Jr. Melanoma. N Engl J Med. 2006;355:51-65.
- Tiacci E, Trifonov V, Schiavoni G, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011;364:2305-2315.
- Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer. 2005;12:245-262.
- Moreau S, Saiag P, Aegerter P, et al. Prognostic value of BRAF(V600) mutations in melanoma patients after resection of metastatic lymph nodes. Ann Surg Oncol. 2012;19:4314-4321.
- Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107-114.
- von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61:344-349.
- Rocca WA, Yawn BP, St Sauver JL, et al. History of the Rochester Epidemiology Project: half a century of medical records linkage in a US population. Mayo Clin Proc. 2012;87:1202-1213.
- St. Sauver JL, Grossardt BR, Yawn BP, et al. Data resource profile: the Rochester Epidemiology Project (REP) medical records-linkage system. Int J Epidemiol. 2012;41:1614-1624.
- National Cancer Institute. Staging: melanoma of the skin, vulva, penis and scrotum staging. Accessed August 15, 2022. https://training.seer.cancer.gov/melanoma/abstract-code-stage/staging.html
- Pakhomov SV, Buntrock JD, Chute CG. Automating the assignment of diagnosis codes to patient encounters using example-based and machine learning techniques. J Am Med Inform Assoc. 2006;13:516-525.
- Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135-2147.
- Thomas NE, Edmiston SN, Alexander A, et al. Number of nevi and early-life ambient UV exposure are associated with BRAF-mutant melanoma. Cancer Epidemiol Biomarkers Prev. 2007;16:991-997.
- German Cancer Research Center. Why identical mutations cause different types of cancer. July 19, 2021. Accessed August 15, 2022. https://www.dkfz.de/en/presse/pressemitteilungen/2021/dkfz-pm-21-41-Why-identical-mutations-cause-different-types-of-cancer.php
- Falcomatà C, Bärthel S, Ulrich A, et al. Genetic screens identify a context-specific PI3K/p27Kip1 node driving extrahepatic biliary cancer. Cancer Discov. 2021;11:3158-3177.
- Guan H, Ji M, Bao R, et al. Association of high iodine intake with the T1799A BRAF mutation in papillary thyroid cancer. J Clin Endocrinol Metab. 2009;94:1612-1617.
- Wish TA, Hyde AJ, Parfrey PS, et al. Increased cancer predisposition in family members of colorectal cancer patients harboring the p.V600E BRAF mutation: a population-based study. Cancer Epidemiol Biomarkers Prev. 2010;19:1831-1839.
- Zebary A, Omholt K, Vassilaki I, et al. KIT, NRAS, BRAF and PTEN mutations in a sample of Swedish patients with acral lentiginous melanoma. J Dermatol Sci. 2013;72:284-289.
- Si L, Kong Y, Xu X, et al. Prevalence of BRAF V600E mutation in Chinese melanoma patients: large scale analysis of BRAF and NRAS mutations in a 432-case cohort. Eur J Cancer. 2012;48:94-100.
- Safaee Ardekani G, Jafarnejad SM, Khosravi S, et al. Disease progression and patient survival are significantly influenced by BRAF protein expression in primary melanoma. Br J Dermatol. 2013;169:320-328.
Practice Points
- Dermatologists should be aware of the long-term risk of second primary malignancies after an incident melanoma.
- BRAF mutations occur in melanomas and several other cancers. Our study found that melanoma BRAF V600E expression is associated with an increased risk for basal cell carcinomas.