Version 11.0 of the 2021 revised European AIDS Clinical Society (EACS) Guidelines updates all aspects of HIV care and adds recommendations on COVID-19 and antiretroviral treatment (ART) in children and adolescents, the guidelines authors reported in HIV Medicine.

“Conducting a systematic and timely annual revision of all guidelines recommendations is an EACS cornerstone,” EACS Guidelines coordinator Lene Ryom, MD, PhD, DMSc, a researcher at the University of Copenhagen, said in an interview. “These revisions ensure that the EACS Guidelines remain clinically relevant, are updated with the latest scientific evidence, and that they cover all key aspects related to HIV management.”

Key revisions in this update include:
 

Antiretroviral therapy (ART)

• Six recommended treatment options for first-line regimens for ART-naive adults include triple-drug regimens consisting of tenofovir (either tenofovir disoproxil fumarate or tenofovir alafenamide) with either lamivudine or emtricitabine plus dolutegravir, raltegravir, bictegravir, or doravirine; abacavir/lamivudine plus dolutegravir; or dual therapy with emtricitabine plus dolutegravir. These drug combinations are recommended in single-tablet form if available.
• Alternatives consisting of triple-drug tenofovir-based regimens along with efavirenz, rilpivirine, or boosted darunavir, are advised when no recommended regimens are feasible.
• Bimonthly injections with long-acting cabotegravir plus rilpivirine are now advised as a switch option for people who are virologically suppressed.
• Pre-exposure prophylaxis on demand is advised for cisgender men, and PrEP may be continued during pregnancy and breastfeeding for people at risk of acquiring HIV.

Drug-drug interactions (DDIs) and other prescribing issues

• Four new DDI tables cover antituberculosis drugs, anxiolytics, hormone therapy, and COVID-19 therapies.

Comorbidities

• This update acknowledged the impact of the COVID-19 pandemic on routine health care, provides recommendations, and highlights the role of shared care and consultation for anxiety and other mental health disorders.
• Treatments involving diabetes, hypertension, cardiovascular disease, heart failure, chronic kidney disease, hypercholesterolemia, obesity, cancer, and sexual health have been updated, with new information about elderly and frail patients, women’s sexual health, and special considerations for transgender people.

Viral hepatitis coinfection

Immediate treatment of recently acquired hepatitis C is recommended for people living with HIV and ongoing risk behavior. Bulevirtide is added as a treatment option for hepatitis Delta virus.

Opportunistic infections and COVID-19

• The revision adds new guidance on management of HIV and COVID-19, covering epidemiology, risk factors for severe COVID-19, COVID-19 management, HIV care during a pandemic, HIV management during COVID-19 treatment, and management of long-term COVID-19 symptoms and prophylaxis.
• It includes guidance on management of tuberculosis meningitis, cryptococcosis, Pneumocystis jirovecii pneumonia, and drug-resistant tuberculosis.

Pediatric HIV infection treatments

• This new section, developed with the European pediatric research organization Penta, updates guidance for the use of preferred and alternative first-line drugs from birth to adolescence. Combinations include new child-friendly formulations of dolutegravir as early as 4 weeks of age and 3 kg (6.6 lb) of weight as well as an increased emphasis on dolutegravir as first-line preferred agent for all children except newborns. Abacavir is recommended for children younger than 3 months.
• ART regimens for children with infectious hepatitis or tuberculosis are also provided.

Laura Jane Waters, MD, a genitourinary consultant and HIV and hepatitis lead at Central and North West London National Health Service Mortimer Market Centre, and chair of the British HIV Association (BHIVA), shared her perspective on the revision. She was not involved with the EACS Guidelines revision.

“The addition of a section on COVID-19 in people with HIV, including management, drug interactions, and vaccination, is welcomed, as is the inclusion of key references and, for selected references, the key findings,” Dr. Waters said in an interview.

“Finally, for the first time, EACS covers pediatric HIV treatment by integrating with the Penta guidelines,” she added. “This is an important evolution, considering there are still cases of vertical HIV transmission in Europe, not to mention children living with HIV who have immigrated. Ensuring high and equitable standards of HIV treatment for young people is crucial.”

“This update to the always-pragmatic EACS guidelines further diverges from the United States Department of Health & Human Services guidelines,” Dr. Waters explained. “For 6 months, both guidelines preferred the same ... regimens for first-line therapy, but since DHSS removed raltegravir-based ART in June 2021 and EACS added doravirine-based regimens in October 2021, we’re back in the more familiar territory of EACS offering a broader range of preferred choices.”

Dr. Ryom noted that modern HIV care needs to consider managing coinfections, opportunistic diseases, comorbidities, aging, addictions, and mental health.

“Ensuring an integrated and personalized approach to HIV management is becoming increasingly important in an aging population living with HIV with the potential for complex needs,” she said.

The guidelines are available in several formats: as a free smartphone app, an interactive web version, and an online PDF.

Funding information was not provided. Dr. Ryom and several coauthors disclosed no relevant financial relationships. Most of the guideline coauthors declared financial relationships with pharmaceutical companies “outside the submitted work.” Dr. Waters provided no information on conflicts of interest.

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

Version 11.0 of the 2021 revised European AIDS Clinical Society (EACS) Guidelines updates all aspects of HIV care and adds recommendations on COVID-19 and antiretroviral treatment (ART) in children and adolescents, the guidelines authors reported in HIV Medicine.

“Conducting a systematic and timely annual revision of all guidelines recommendations is an EACS cornerstone,” EACS Guidelines coordinator Lene Ryom, MD, PhD, DMSc, a researcher at the University of Copenhagen, said in an interview. “These revisions ensure that the EACS Guidelines remain clinically relevant, are updated with the latest scientific evidence, and that they cover all key aspects related to HIV management.”

Key revisions in this update include:
 

Antiretroviral therapy (ART)

• Six recommended treatment options for first-line regimens for ART-naive adults include triple-drug regimens consisting of tenofovir (either tenofovir disoproxil fumarate or tenofovir alafenamide) with either lamivudine or emtricitabine plus dolutegravir, raltegravir, bictegravir, or doravirine; abacavir/lamivudine plus dolutegravir; or dual therapy with emtricitabine plus dolutegravir. These drug combinations are recommended in single-tablet form if available.
• Alternatives consisting of triple-drug tenofovir-based regimens along with efavirenz, rilpivirine, or boosted darunavir, are advised when no recommended regimens are feasible.
• Bimonthly injections with long-acting cabotegravir plus rilpivirine are now advised as a switch option for people who are virologically suppressed.
• Pre-exposure prophylaxis on demand is advised for cisgender men, and PrEP may be continued during pregnancy and breastfeeding for people at risk of acquiring HIV.

Drug-drug interactions (DDIs) and other prescribing issues

• Four new DDI tables cover antituberculosis drugs, anxiolytics, hormone therapy, and COVID-19 therapies.

Comorbidities

• This update acknowledged the impact of the COVID-19 pandemic on routine health care, provides recommendations, and highlights the role of shared care and consultation for anxiety and other mental health disorders.
• Treatments involving diabetes, hypertension, cardiovascular disease, heart failure, chronic kidney disease, hypercholesterolemia, obesity, cancer, and sexual health have been updated, with new information about elderly and frail patients, women’s sexual health, and special considerations for transgender people.

Viral hepatitis coinfection

Immediate treatment of recently acquired hepatitis C is recommended for people living with HIV and ongoing risk behavior. Bulevirtide is added as a treatment option for hepatitis Delta virus.

Opportunistic infections and COVID-19

• The revision adds new guidance on management of HIV and COVID-19, covering epidemiology, risk factors for severe COVID-19, COVID-19 management, HIV care during a pandemic, HIV management during COVID-19 treatment, and management of long-term COVID-19 symptoms and prophylaxis.
• It includes guidance on management of tuberculosis meningitis, cryptococcosis, Pneumocystis jirovecii pneumonia, and drug-resistant tuberculosis.

Pediatric HIV infection treatments

• This new section, developed with the European pediatric research organization Penta, updates guidance for the use of preferred and alternative first-line drugs from birth to adolescence. Combinations include new child-friendly formulations of dolutegravir as early as 4 weeks of age and 3 kg (6.6 lb) of weight as well as an increased emphasis on dolutegravir as first-line preferred agent for all children except newborns. Abacavir is recommended for children younger than 3 months.
• ART regimens for children with infectious hepatitis or tuberculosis are also provided.

Laura Jane Waters, MD, a genitourinary consultant and HIV and hepatitis lead at Central and North West London National Health Service Mortimer Market Centre, and chair of the British HIV Association (BHIVA), shared her perspective on the revision. She was not involved with the EACS Guidelines revision.

“The addition of a section on COVID-19 in people with HIV, including management, drug interactions, and vaccination, is welcomed, as is the inclusion of key references and, for selected references, the key findings,” Dr. Waters said in an interview.

“Finally, for the first time, EACS covers pediatric HIV treatment by integrating with the Penta guidelines,” she added. “This is an important evolution, considering there are still cases of vertical HIV transmission in Europe, not to mention children living with HIV who have immigrated. Ensuring high and equitable standards of HIV treatment for young people is crucial.”

“This update to the always-pragmatic EACS guidelines further diverges from the United States Department of Health & Human Services guidelines,” Dr. Waters explained. “For 6 months, both guidelines preferred the same ... regimens for first-line therapy, but since DHSS removed raltegravir-based ART in June 2021 and EACS added doravirine-based regimens in October 2021, we’re back in the more familiar territory of EACS offering a broader range of preferred choices.”

Dr. Ryom noted that modern HIV care needs to consider managing coinfections, opportunistic diseases, comorbidities, aging, addictions, and mental health.

“Ensuring an integrated and personalized approach to HIV management is becoming increasingly important in an aging population living with HIV with the potential for complex needs,” she said.

The guidelines are available in several formats: as a free smartphone app, an interactive web version, and an online PDF.

Funding information was not provided. Dr. Ryom and several coauthors disclosed no relevant financial relationships. Most of the guideline coauthors declared financial relationships with pharmaceutical companies “outside the submitted work.” Dr. Waters provided no information on conflicts of interest.

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

Version 11.0 of the 2021 revised European AIDS Clinical Society (EACS) Guidelines updates all aspects of HIV care and adds recommendations on COVID-19 and antiretroviral treatment (ART) in children and adolescents, the guidelines authors reported in HIV Medicine.

“Conducting a systematic and timely annual revision of all guidelines recommendations is an EACS cornerstone,” EACS Guidelines coordinator Lene Ryom, MD, PhD, DMSc, a researcher at the University of Copenhagen, said in an interview. “These revisions ensure that the EACS Guidelines remain clinically relevant, are updated with the latest scientific evidence, and that they cover all key aspects related to HIV management.”

Key revisions in this update include:
 

Antiretroviral therapy (ART)

• Six recommended treatment options for first-line regimens for ART-naive adults include triple-drug regimens consisting of tenofovir (either tenofovir disoproxil fumarate or tenofovir alafenamide) with either lamivudine or emtricitabine plus dolutegravir, raltegravir, bictegravir, or doravirine; abacavir/lamivudine plus dolutegravir; or dual therapy with emtricitabine plus dolutegravir. These drug combinations are recommended in single-tablet form if available.
• Alternatives consisting of triple-drug tenofovir-based regimens along with efavirenz, rilpivirine, or boosted darunavir, are advised when no recommended regimens are feasible.
• Bimonthly injections with long-acting cabotegravir plus rilpivirine are now advised as a switch option for people who are virologically suppressed.
• Pre-exposure prophylaxis on demand is advised for cisgender men, and PrEP may be continued during pregnancy and breastfeeding for people at risk of acquiring HIV.

Drug-drug interactions (DDIs) and other prescribing issues

• Four new DDI tables cover antituberculosis drugs, anxiolytics, hormone therapy, and COVID-19 therapies.

Comorbidities

• This update acknowledged the impact of the COVID-19 pandemic on routine health care, provides recommendations, and highlights the role of shared care and consultation for anxiety and other mental health disorders.
• Treatments involving diabetes, hypertension, cardiovascular disease, heart failure, chronic kidney disease, hypercholesterolemia, obesity, cancer, and sexual health have been updated, with new information about elderly and frail patients, women’s sexual health, and special considerations for transgender people.

Viral hepatitis coinfection

Immediate treatment of recently acquired hepatitis C is recommended for people living with HIV and ongoing risk behavior. Bulevirtide is added as a treatment option for hepatitis Delta virus.

Opportunistic infections and COVID-19

• The revision adds new guidance on management of HIV and COVID-19, covering epidemiology, risk factors for severe COVID-19, COVID-19 management, HIV care during a pandemic, HIV management during COVID-19 treatment, and management of long-term COVID-19 symptoms and prophylaxis.
• It includes guidance on management of tuberculosis meningitis, cryptococcosis, Pneumocystis jirovecii pneumonia, and drug-resistant tuberculosis.

Pediatric HIV infection treatments

• This new section, developed with the European pediatric research organization Penta, updates guidance for the use of preferred and alternative first-line drugs from birth to adolescence. Combinations include new child-friendly formulations of dolutegravir as early as 4 weeks of age and 3 kg (6.6 lb) of weight as well as an increased emphasis on dolutegravir as first-line preferred agent for all children except newborns. Abacavir is recommended for children younger than 3 months.
• ART regimens for children with infectious hepatitis or tuberculosis are also provided.

Laura Jane Waters, MD, a genitourinary consultant and HIV and hepatitis lead at Central and North West London National Health Service Mortimer Market Centre, and chair of the British HIV Association (BHIVA), shared her perspective on the revision. She was not involved with the EACS Guidelines revision.

“The addition of a section on COVID-19 in people with HIV, including management, drug interactions, and vaccination, is welcomed, as is the inclusion of key references and, for selected references, the key findings,” Dr. Waters said in an interview.

“Finally, for the first time, EACS covers pediatric HIV treatment by integrating with the Penta guidelines,” she added. “This is an important evolution, considering there are still cases of vertical HIV transmission in Europe, not to mention children living with HIV who have immigrated. Ensuring high and equitable standards of HIV treatment for young people is crucial.”

“This update to the always-pragmatic EACS guidelines further diverges from the United States Department of Health & Human Services guidelines,” Dr. Waters explained. “For 6 months, both guidelines preferred the same ... regimens for first-line therapy, but since DHSS removed raltegravir-based ART in June 2021 and EACS added doravirine-based regimens in October 2021, we’re back in the more familiar territory of EACS offering a broader range of preferred choices.”

Dr. Ryom noted that modern HIV care needs to consider managing coinfections, opportunistic diseases, comorbidities, aging, addictions, and mental health.

“Ensuring an integrated and personalized approach to HIV management is becoming increasingly important in an aging population living with HIV with the potential for complex needs,” she said.

The guidelines are available in several formats: as a free smartphone app, an interactive web version, and an online PDF.

Funding information was not provided. Dr. Ryom and several coauthors disclosed no relevant financial relationships. Most of the guideline coauthors declared financial relationships with pharmaceutical companies “outside the submitted work.” Dr. Waters provided no information on conflicts of interest.

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

Higher levels of specific carotenoid antioxidants in blood may help guard against age-related dementia, new research suggests.

Investigators found that individuals with the highest serum levels of lutein + zeaxanthin and beta-cryptoxanthin at baseline were less likely to have dementia decades later than were their peers with lower levels of these antioxidants.

Lutein and zeaxanthin are found in green leafy vegetables such as kale, spinach, broccoli, and peas. Beta-cryptoxanthin is found in fruits such as oranges, papaya, tangerines, and persimmons.

“Antioxidants may help protect the brain from oxidative stress, which can cause cell damage,” first author May A. Beydoun, PhD, with the National Institute on Aging (NIA), said in a news release. 

“This is the first nationally representative study to analyze blood levels of antioxidants in relation to dementia risk,” NIA scientific director Luigi Ferrucci, MD, said in an interview.

“Blood test results may be more representative of the actual antioxidant level than a person’s report of what kind of foods they regularly consume,” Dr. Ferrucci added.

The study was published online in Neurology.
 

Reduced dementia risk

The researchers tested associations and interactions of serum vitamins A, C and E, and total and individual serum carotenoids and interactions with incident Alzheimer’s disease (AD) and all-cause dementia.

They analyzed data from 7,283 participants in the Third National Health and Nutrition Examination Survey (NHANES III) who were at least 45 years old at baseline and followed for an average of 16-17 years.

They found serum levels of lutein + zeaxanthin were associated with reduced risk of all-cause dementia among people aged 65 and older in models adjusted for lifestyle.

For lutein + zeaxanthin, every standard deviation (SD) increase (roughly 15.4 µmol/liter) was associated with a 7% decrease in risk for dementia (hazard ratio [HR] 0.93; 95% confidence interval [CI], 0.87-0.99, P = .037). This association was attenuated somewhat after adjustment for socioeconomic status.

Serum levels of beta-cryptoxanthin showed a “strong” inverse relationship with all-cause dementia in age- and sex-adjusted models.

For beta-cryptoxanthin, every SD increase (roughly 8.6 µmol/liter) was associated with a 14% reduced risk for dementia in people aged 45 and older (HR, 0.86; 95% CI, 0.80-0.93, P < .001) and 65 and older (HR, 0.86; 95% CI, 0.80-0.93, P = .001).

This relationship remained strong in models adjusted for sociodemographic and socioeconomic factors but attenuated in subsequent models.

No associations were found for lycopene, alpha-carotene, beta-carotene, or vitamins A, C, or E in the fully adjusted models.

Antagonistic interactions were observed for vitamin A and alpha-carotene, vitamin A and beta-carotene, vitamin E and lycopene, and lycopene and beta-carotene, suggesting putative protective effects of one antioxidant at lower levels of the other, the researchers noted.

“This analysis of an observational study found that the most important carotenoids in potentially protecting the brain may be lutein + zeaxanthin and beta-cryptoxanthin. However, randomized controlled trials are needed to prove causality,” said Dr. Ferrucci.

“Experts do not yet know the daily level of antioxidant intake to promote healthy aging of the brain. More research is needed to establish the necessary level of antioxidant intake – through the diet and/or supplements – to promote brain health and healthy aging,” he added.
 

An important step forward

In an accompanying editorial, Babak Hooshmand, MD, PhD, and Miia Kivipelto, MD, PhD, with Karolinska Institute, Stockholm, noted that while nutrition and dietary components are “potential targets” for dementia risk reduction, observational studies to date have reported “inconsistent findings.”

This study is “an important step towards exploring the complex relationship between antioxidants and dementia because it accounts for factors that could possibly influence the associations and considers interactions between different components,” they wrote.

The findings are “challenging,” they added, because they may lead to the hypothesis that inhibition of oxidative damage by antioxidants might have beneficial effects on preventing dementia.

However, clinical trials of antioxidant supplementation have been mainly “disappointing” and a recent Cochrane review found a lack of evidence for supplement use to preserve cognitive function or prevent dementia, Dr. Hooshmand and Dr. Kivipelto noted.

They added that the study contributes to the belief that antioxidants don’t act independently of each other or other factors, including socioeconomic status and lifestyle, in the mediation of dementia risk.

“A careful examination of the evidence is required to learn how antioxidants influence the complex pathology of dementia, because it appears to be more to it than meets the eye,”they concluded.

The research was supported in part by the Intramural Research Program of the National Institutes of Health and the National Institute on Aging. Dr. Beydoun, Dr. Ferrucci, and Dr. Hooshmand report no relevant disclosures. Dr. Kivipelto has supported advisory boards for Combinostics, Roche, and Biogen.

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

Higher levels of specific carotenoid antioxidants in blood may help guard against age-related dementia, new research suggests.

Investigators found that individuals with the highest serum levels of lutein + zeaxanthin and beta-cryptoxanthin at baseline were less likely to have dementia decades later than were their peers with lower levels of these antioxidants.

Lutein and zeaxanthin are found in green leafy vegetables such as kale, spinach, broccoli, and peas. Beta-cryptoxanthin is found in fruits such as oranges, papaya, tangerines, and persimmons.

“Antioxidants may help protect the brain from oxidative stress, which can cause cell damage,” first author May A. Beydoun, PhD, with the National Institute on Aging (NIA), said in a news release. 

“This is the first nationally representative study to analyze blood levels of antioxidants in relation to dementia risk,” NIA scientific director Luigi Ferrucci, MD, said in an interview.

“Blood test results may be more representative of the actual antioxidant level than a person’s report of what kind of foods they regularly consume,” Dr. Ferrucci added.

The study was published online in Neurology.
 

Reduced dementia risk

The researchers tested associations and interactions of serum vitamins A, C and E, and total and individual serum carotenoids and interactions with incident Alzheimer’s disease (AD) and all-cause dementia.

They analyzed data from 7,283 participants in the Third National Health and Nutrition Examination Survey (NHANES III) who were at least 45 years old at baseline and followed for an average of 16-17 years.

They found serum levels of lutein + zeaxanthin were associated with reduced risk of all-cause dementia among people aged 65 and older in models adjusted for lifestyle.

For lutein + zeaxanthin, every standard deviation (SD) increase (roughly 15.4 µmol/liter) was associated with a 7% decrease in risk for dementia (hazard ratio [HR] 0.93; 95% confidence interval [CI], 0.87-0.99, P = .037). This association was attenuated somewhat after adjustment for socioeconomic status.

Serum levels of beta-cryptoxanthin showed a “strong” inverse relationship with all-cause dementia in age- and sex-adjusted models.

For beta-cryptoxanthin, every SD increase (roughly 8.6 µmol/liter) was associated with a 14% reduced risk for dementia in people aged 45 and older (HR, 0.86; 95% CI, 0.80-0.93, P < .001) and 65 and older (HR, 0.86; 95% CI, 0.80-0.93, P = .001).

This relationship remained strong in models adjusted for sociodemographic and socioeconomic factors but attenuated in subsequent models.

No associations were found for lycopene, alpha-carotene, beta-carotene, or vitamins A, C, or E in the fully adjusted models.

Antagonistic interactions were observed for vitamin A and alpha-carotene, vitamin A and beta-carotene, vitamin E and lycopene, and lycopene and beta-carotene, suggesting putative protective effects of one antioxidant at lower levels of the other, the researchers noted.

“This analysis of an observational study found that the most important carotenoids in potentially protecting the brain may be lutein + zeaxanthin and beta-cryptoxanthin. However, randomized controlled trials are needed to prove causality,” said Dr. Ferrucci.

“Experts do not yet know the daily level of antioxidant intake to promote healthy aging of the brain. More research is needed to establish the necessary level of antioxidant intake – through the diet and/or supplements – to promote brain health and healthy aging,” he added.
 

An important step forward

In an accompanying editorial, Babak Hooshmand, MD, PhD, and Miia Kivipelto, MD, PhD, with Karolinska Institute, Stockholm, noted that while nutrition and dietary components are “potential targets” for dementia risk reduction, observational studies to date have reported “inconsistent findings.”

This study is “an important step towards exploring the complex relationship between antioxidants and dementia because it accounts for factors that could possibly influence the associations and considers interactions between different components,” they wrote.

The findings are “challenging,” they added, because they may lead to the hypothesis that inhibition of oxidative damage by antioxidants might have beneficial effects on preventing dementia.

However, clinical trials of antioxidant supplementation have been mainly “disappointing” and a recent Cochrane review found a lack of evidence for supplement use to preserve cognitive function or prevent dementia, Dr. Hooshmand and Dr. Kivipelto noted.

They added that the study contributes to the belief that antioxidants don’t act independently of each other or other factors, including socioeconomic status and lifestyle, in the mediation of dementia risk.

“A careful examination of the evidence is required to learn how antioxidants influence the complex pathology of dementia, because it appears to be more to it than meets the eye,”they concluded.

The research was supported in part by the Intramural Research Program of the National Institutes of Health and the National Institute on Aging. Dr. Beydoun, Dr. Ferrucci, and Dr. Hooshmand report no relevant disclosures. Dr. Kivipelto has supported advisory boards for Combinostics, Roche, and Biogen.

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

Higher levels of specific carotenoid antioxidants in blood may help guard against age-related dementia, new research suggests.

Investigators found that individuals with the highest serum levels of lutein + zeaxanthin and beta-cryptoxanthin at baseline were less likely to have dementia decades later than were their peers with lower levels of these antioxidants.

Lutein and zeaxanthin are found in green leafy vegetables such as kale, spinach, broccoli, and peas. Beta-cryptoxanthin is found in fruits such as oranges, papaya, tangerines, and persimmons.

“Antioxidants may help protect the brain from oxidative stress, which can cause cell damage,” first author May A. Beydoun, PhD, with the National Institute on Aging (NIA), said in a news release. 

“This is the first nationally representative study to analyze blood levels of antioxidants in relation to dementia risk,” NIA scientific director Luigi Ferrucci, MD, said in an interview.

“Blood test results may be more representative of the actual antioxidant level than a person’s report of what kind of foods they regularly consume,” Dr. Ferrucci added.

The study was published online in Neurology.
 

Reduced dementia risk

The researchers tested associations and interactions of serum vitamins A, C and E, and total and individual serum carotenoids and interactions with incident Alzheimer’s disease (AD) and all-cause dementia.

They analyzed data from 7,283 participants in the Third National Health and Nutrition Examination Survey (NHANES III) who were at least 45 years old at baseline and followed for an average of 16-17 years.

They found serum levels of lutein + zeaxanthin were associated with reduced risk of all-cause dementia among people aged 65 and older in models adjusted for lifestyle.

For lutein + zeaxanthin, every standard deviation (SD) increase (roughly 15.4 µmol/liter) was associated with a 7% decrease in risk for dementia (hazard ratio [HR] 0.93; 95% confidence interval [CI], 0.87-0.99, P = .037). This association was attenuated somewhat after adjustment for socioeconomic status.

Serum levels of beta-cryptoxanthin showed a “strong” inverse relationship with all-cause dementia in age- and sex-adjusted models.

For beta-cryptoxanthin, every SD increase (roughly 8.6 µmol/liter) was associated with a 14% reduced risk for dementia in people aged 45 and older (HR, 0.86; 95% CI, 0.80-0.93, P < .001) and 65 and older (HR, 0.86; 95% CI, 0.80-0.93, P = .001).

This relationship remained strong in models adjusted for sociodemographic and socioeconomic factors but attenuated in subsequent models.

No associations were found for lycopene, alpha-carotene, beta-carotene, or vitamins A, C, or E in the fully adjusted models.

Antagonistic interactions were observed for vitamin A and alpha-carotene, vitamin A and beta-carotene, vitamin E and lycopene, and lycopene and beta-carotene, suggesting putative protective effects of one antioxidant at lower levels of the other, the researchers noted.

“This analysis of an observational study found that the most important carotenoids in potentially protecting the brain may be lutein + zeaxanthin and beta-cryptoxanthin. However, randomized controlled trials are needed to prove causality,” said Dr. Ferrucci.

“Experts do not yet know the daily level of antioxidant intake to promote healthy aging of the brain. More research is needed to establish the necessary level of antioxidant intake – through the diet and/or supplements – to promote brain health and healthy aging,” he added.
 

An important step forward

In an accompanying editorial, Babak Hooshmand, MD, PhD, and Miia Kivipelto, MD, PhD, with Karolinska Institute, Stockholm, noted that while nutrition and dietary components are “potential targets” for dementia risk reduction, observational studies to date have reported “inconsistent findings.”

This study is “an important step towards exploring the complex relationship between antioxidants and dementia because it accounts for factors that could possibly influence the associations and considers interactions between different components,” they wrote.

The findings are “challenging,” they added, because they may lead to the hypothesis that inhibition of oxidative damage by antioxidants might have beneficial effects on preventing dementia.

However, clinical trials of antioxidant supplementation have been mainly “disappointing” and a recent Cochrane review found a lack of evidence for supplement use to preserve cognitive function or prevent dementia, Dr. Hooshmand and Dr. Kivipelto noted.

They added that the study contributes to the belief that antioxidants don’t act independently of each other or other factors, including socioeconomic status and lifestyle, in the mediation of dementia risk.

“A careful examination of the evidence is required to learn how antioxidants influence the complex pathology of dementia, because it appears to be more to it than meets the eye,”they concluded.

The research was supported in part by the Intramural Research Program of the National Institutes of Health and the National Institute on Aging. Dr. Beydoun, Dr. Ferrucci, and Dr. Hooshmand report no relevant disclosures. Dr. Kivipelto has supported advisory boards for Combinostics, Roche, and Biogen.

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

BERLIN – Some breast cancer specialists still have misconceptions about the appropriate use of multigene signatures in making prognostic and treatment decisions in early-stage disease, a European survey suggests.

The authors found, for instance, that while most specialists agreed that molecular intrinsic subtypes had clinical utility for understanding prognosis in early-stage hormone receptor (HR)–positive disease and for identifying patients for whom chemotherapy could be safely avoided, about 1 in 4 experts either disagreed or felt neutral about the use of signatures in these settings.

Similarly, almost 75% of respondents felt that these signatures were not useful in the triple-negative or metastatic setting, but a small percentage believed they were, and about 10% were neutral.

“Considering that breast cancer multigene signatures were developed in the post menopausal HR+/HER2- early breast cancer setting, the fact that some experts consider [them] useful in triple-negative, HER2+ breast cancer or in the metastatic setting corroborates a misunderstanding on how to interpret the results,” study author Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milan, and colleagues wrote.

Dr. Curigliano, who is also head of the Division of Early Drug Development at the European Institute of Oncology, presented the survey findings on May 4 at the European Society for Medical Oncology (ESMO BCC) Breast Cancer Congress.

Although several breast cancer multigene signatures are available to profile early breast cancer, little information exists on how these signatures should be used in clinical practice.

To investigate, Dr. Curigliano and colleagues convened a scientific committee of eight breast cancer experts to develop a Delphi questionnaire to examine respondents’ opinions and uses of these signatures.

The questionnaire asked about the clinical utility of multigene signatures in breast cancer and recommendations for their use in clinical practice.

In all, 133 breast cancer specialists from 11 European countries completed the questionnaire. Respondents were about 49 years old on average, and most (86.5%) worked in a teaching hospital. More than 72% were medical oncologists; 12% were pathologists.

Consensus was considered to be reached when 70% or more of the respondents were in agreement on a topic.

Participants had “extensive experience in the management of breast cancer patients and have been using breast cancer multigene signatures in clinical practice,” Dr. Curigliano said.

Almost all respondents (93.6%) reported using breast cancer multigene signatures routinely or in selected patients, and 73.4% had more than 5 years of experience with them.

Overall, more than 70% of respondents agreed that identifying tumor intrinsic subtype via gene expression profiling was important in making prognostic and treatment decisions; however, a consensus was not reached on the use of immunohistochemistry.

In addition, most respondents (76%) agreed that identifying breast cancer molecular intrinsic subtypes had clinical utility for prognosis in early-stage HR-positive disease and for identifying patients for whom chemotherapy can be safely avoided (75%). However, in both cases, about one-quarter of respondents either disagreed or felt neutral.

No consensus was reached on the clinical utility of these subtypes for selecting the most appropriate chemotherapy treatment – two-thirds disagreed, while 13% agreed and 17% felt neutral.

When deciding on the use of chemotherapy in the adjuvant setting in early node-negative breast cancer, 88% of respondents felt that breast cancer multigene signatures were important. Moreover, 75% considered such signatures important when deciding whether to use chemotherapy in the adjuvant setting for patients with one to three positive lymph nodes. However, no consensus was reached on the utility of signatures for deciding whether to extend endocrine therapy in either setting.

When examining the usefulness of signatures in more special settings, the authors found that the vast majority (90%) of respondents believed that multigene signatures had clinical utility for postmenopausal early breast cancer patients, and 82% did not consider signatures clinically useful in the early-stage HER2-overexpressed setting.

In addition, 74% thought that breast cancer multigene signatures were not useful in triple-negative disease or in the metastatic setting.

Respondents did not reach a consensus on the clinical utility of multigene signatures in the neoadjuvant setting – only 27% considered them useful, and almost half did not.

The “low percentage” of respondents using the signatures in the neoadjuvant setting and the “misconception regarding the predictive value of these tests on chemotherapy benefits suggest there is still room for training on results interpretation [for breast cancer multigene signatures],” the authors write.

The study was sponsored by Veracyte. Dr. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, and Veracyte. No other relevant financial relationships were disclosed.

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

This article was updated 5/9/22.

BERLIN – Some breast cancer specialists still have misconceptions about the appropriate use of multigene signatures in making prognostic and treatment decisions in early-stage disease, a European survey suggests.

The authors found, for instance, that while most specialists agreed that molecular intrinsic subtypes had clinical utility for understanding prognosis in early-stage hormone receptor (HR)–positive disease and for identifying patients for whom chemotherapy could be safely avoided, about 1 in 4 experts either disagreed or felt neutral about the use of signatures in these settings.

Similarly, almost 75% of respondents felt that these signatures were not useful in the triple-negative or metastatic setting, but a small percentage believed they were, and about 10% were neutral.

“Considering that breast cancer multigene signatures were developed in the post menopausal HR+/HER2- early breast cancer setting, the fact that some experts consider [them] useful in triple-negative, HER2+ breast cancer or in the metastatic setting corroborates a misunderstanding on how to interpret the results,” study author Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milan, and colleagues wrote.

Dr. Curigliano, who is also head of the Division of Early Drug Development at the European Institute of Oncology, presented the survey findings on May 4 at the European Society for Medical Oncology (ESMO BCC) Breast Cancer Congress.

Although several breast cancer multigene signatures are available to profile early breast cancer, little information exists on how these signatures should be used in clinical practice.

To investigate, Dr. Curigliano and colleagues convened a scientific committee of eight breast cancer experts to develop a Delphi questionnaire to examine respondents’ opinions and uses of these signatures.

The questionnaire asked about the clinical utility of multigene signatures in breast cancer and recommendations for their use in clinical practice.

In all, 133 breast cancer specialists from 11 European countries completed the questionnaire. Respondents were about 49 years old on average, and most (86.5%) worked in a teaching hospital. More than 72% were medical oncologists; 12% were pathologists.

Consensus was considered to be reached when 70% or more of the respondents were in agreement on a topic.

Participants had “extensive experience in the management of breast cancer patients and have been using breast cancer multigene signatures in clinical practice,” Dr. Curigliano said.

Almost all respondents (93.6%) reported using breast cancer multigene signatures routinely or in selected patients, and 73.4% had more than 5 years of experience with them.

Overall, more than 70% of respondents agreed that identifying tumor intrinsic subtype via gene expression profiling was important in making prognostic and treatment decisions; however, a consensus was not reached on the use of immunohistochemistry.

In addition, most respondents (76%) agreed that identifying breast cancer molecular intrinsic subtypes had clinical utility for prognosis in early-stage HR-positive disease and for identifying patients for whom chemotherapy can be safely avoided (75%). However, in both cases, about one-quarter of respondents either disagreed or felt neutral.

No consensus was reached on the clinical utility of these subtypes for selecting the most appropriate chemotherapy treatment – two-thirds disagreed, while 13% agreed and 17% felt neutral.

When deciding on the use of chemotherapy in the adjuvant setting in early node-negative breast cancer, 88% of respondents felt that breast cancer multigene signatures were important. Moreover, 75% considered such signatures important when deciding whether to use chemotherapy in the adjuvant setting for patients with one to three positive lymph nodes. However, no consensus was reached on the utility of signatures for deciding whether to extend endocrine therapy in either setting.

When examining the usefulness of signatures in more special settings, the authors found that the vast majority (90%) of respondents believed that multigene signatures had clinical utility for postmenopausal early breast cancer patients, and 82% did not consider signatures clinically useful in the early-stage HER2-overexpressed setting.

In addition, 74% thought that breast cancer multigene signatures were not useful in triple-negative disease or in the metastatic setting.

Respondents did not reach a consensus on the clinical utility of multigene signatures in the neoadjuvant setting – only 27% considered them useful, and almost half did not.

The “low percentage” of respondents using the signatures in the neoadjuvant setting and the “misconception regarding the predictive value of these tests on chemotherapy benefits suggest there is still room for training on results interpretation [for breast cancer multigene signatures],” the authors write.

The study was sponsored by Veracyte. Dr. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, and Veracyte. No other relevant financial relationships were disclosed.

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

This article was updated 5/9/22.

BERLIN – Some breast cancer specialists still have misconceptions about the appropriate use of multigene signatures in making prognostic and treatment decisions in early-stage disease, a European survey suggests.

The authors found, for instance, that while most specialists agreed that molecular intrinsic subtypes had clinical utility for understanding prognosis in early-stage hormone receptor (HR)–positive disease and for identifying patients for whom chemotherapy could be safely avoided, about 1 in 4 experts either disagreed or felt neutral about the use of signatures in these settings.

Similarly, almost 75% of respondents felt that these signatures were not useful in the triple-negative or metastatic setting, but a small percentage believed they were, and about 10% were neutral.

“Considering that breast cancer multigene signatures were developed in the post menopausal HR+/HER2- early breast cancer setting, the fact that some experts consider [them] useful in triple-negative, HER2+ breast cancer or in the metastatic setting corroborates a misunderstanding on how to interpret the results,” study author Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milan, and colleagues wrote.

Dr. Curigliano, who is also head of the Division of Early Drug Development at the European Institute of Oncology, presented the survey findings on May 4 at the European Society for Medical Oncology (ESMO BCC) Breast Cancer Congress.

Although several breast cancer multigene signatures are available to profile early breast cancer, little information exists on how these signatures should be used in clinical practice.

To investigate, Dr. Curigliano and colleagues convened a scientific committee of eight breast cancer experts to develop a Delphi questionnaire to examine respondents’ opinions and uses of these signatures.

The questionnaire asked about the clinical utility of multigene signatures in breast cancer and recommendations for their use in clinical practice.

In all, 133 breast cancer specialists from 11 European countries completed the questionnaire. Respondents were about 49 years old on average, and most (86.5%) worked in a teaching hospital. More than 72% were medical oncologists; 12% were pathologists.

Consensus was considered to be reached when 70% or more of the respondents were in agreement on a topic.

Participants had “extensive experience in the management of breast cancer patients and have been using breast cancer multigene signatures in clinical practice,” Dr. Curigliano said.

Almost all respondents (93.6%) reported using breast cancer multigene signatures routinely or in selected patients, and 73.4% had more than 5 years of experience with them.

Overall, more than 70% of respondents agreed that identifying tumor intrinsic subtype via gene expression profiling was important in making prognostic and treatment decisions; however, a consensus was not reached on the use of immunohistochemistry.

In addition, most respondents (76%) agreed that identifying breast cancer molecular intrinsic subtypes had clinical utility for prognosis in early-stage HR-positive disease and for identifying patients for whom chemotherapy can be safely avoided (75%). However, in both cases, about one-quarter of respondents either disagreed or felt neutral.

No consensus was reached on the clinical utility of these subtypes for selecting the most appropriate chemotherapy treatment – two-thirds disagreed, while 13% agreed and 17% felt neutral.

When deciding on the use of chemotherapy in the adjuvant setting in early node-negative breast cancer, 88% of respondents felt that breast cancer multigene signatures were important. Moreover, 75% considered such signatures important when deciding whether to use chemotherapy in the adjuvant setting for patients with one to three positive lymph nodes. However, no consensus was reached on the utility of signatures for deciding whether to extend endocrine therapy in either setting.

When examining the usefulness of signatures in more special settings, the authors found that the vast majority (90%) of respondents believed that multigene signatures had clinical utility for postmenopausal early breast cancer patients, and 82% did not consider signatures clinically useful in the early-stage HER2-overexpressed setting.

In addition, 74% thought that breast cancer multigene signatures were not useful in triple-negative disease or in the metastatic setting.

Respondents did not reach a consensus on the clinical utility of multigene signatures in the neoadjuvant setting – only 27% considered them useful, and almost half did not.

The “low percentage” of respondents using the signatures in the neoadjuvant setting and the “misconception regarding the predictive value of these tests on chemotherapy benefits suggest there is still room for training on results interpretation [for breast cancer multigene signatures],” the authors write.

The study was sponsored by Veracyte. Dr. Curigliano has relationships with Pfizer, Novartis, Lilly, Roche, Seattle Genetics, Celltrion, and Veracyte. No other relevant financial relationships were disclosed.

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

This article was updated 5/9/22.

The more boosters the better? Data from Israel show that immune protection in elderly people is strengthened even further after a fourth dose. Karl Lauterbach, MD, German minister of health, recently pleaded for a second booster for those aged 18 years and older, and he pushed for a European Union–wide recommendation. He has not been able to implement this yet.

Just as before, Germany’s Standing Committee on Vaccination (STIKO) is only recommending the second booster for people aged 70 years and older, the European Medicines Agency (EMA) is recommending the fourth vaccination for everyone aged 80 years and older, and the United States has set the general age limit at 50 years.

Specialists remain skeptical about expanding the availability of the second booster. “From an immunologic perspective, people under the age of 70 with a healthy immune system do not need this fourth vaccination,” said Christiane Falk, PhD, head of the Institute for Transplantation Immunology of the Hannover Medical School (Germany) and member of the German Federal Government COVID Expert Panel, at a Science Media Center press briefing.

After the second vaccination, young healthy people are sufficiently protected against a severe course of the disease. Dr. Falk sees the STIKO recommendation as feasible, since it can be worked with. People in nursing facilities or those with additional underlying conditions would be considered for a fourth vaccination, explained Dr. Falk.
 

Complete protection unrealistic

Achieving complete protection against infection through multiple boosters is not realistic, said Christoph Neumann-Haefelin, MD, head of the Working Group for Translational Virus Immunology at the Clinic for Internal Medicine II, University Hospital Freiburg, Germany. Therefore, this should not be pursued when discussing boosters. “The aim of the booster vaccination should be to protect different groups of people against severe courses of the disease,” said Dr. Neumann-Haefelin.

Neutralizing antibodies that are only present in high concentrations for a few weeks after infection or vaccination are sometimes able to prevent the infection on their own. The immunologic memory of B cells and T cells, which ensures long-lasting protection against severe courses of the disease, is at a high level after two doses, and a third dose increases the protection more.

While people with a weak immune system need significantly more vaccinations in a shorter period to receive the same protection, too many booster vaccinations against SARS-CoV-2 are not sensible for young healthy people.
 

Immune saturation effect

A recent study in macaques showed that an adjusted Omicron booster did not lead to higher antibody titers, compared with a usual booster. In January 2022, the EMA warned against frequent consecutive boosters that may no longer produce the desired immune response.

If someone receives a booster too early, a saturation effect can occur, warned Andreas Radbruch, PhD, scientific director of the German Rheumatism Research Center Berlin. “We know this from lots of experimental studies but also from lots of other vaccinations. For example, you cannot be vaccinated against tetanus twice at 3- or 4-week intervals. Nothing at all will happen the second time,” explained Dr. Radbruch.

If the same antigen is applied again and again at the same dose, the immune system is made so active that the antigen is directly intercepted and cannot have any new effect on the immune system. This mechanism has been known for a long time, said Dr. Radbruch.
 

‘Original antigenic sin’

Premature boosting could even be a handicap in the competition between immune response and virus, said Dr. Radbruch. This is due to the principle of “original antigenic sin.” If the immune system has already come into contact with a virus, contact with a new virus variant will cause it to form antibodies predominantly against those epitopes that were already present in the original virus. As a result of this, too many boosters can weaken protection against different variants.

“We have not actually observed this with SARS-CoV-2, however,” said Dr. Radbruch. “Immunity is always extremely broad. With a double or triple vaccination, all previously existing variants are covered by an affinity-matured immune system.”

Dr. Neumann-Haefelin confirmed this and added that all virus mutations, including Omicron, have different epitopes that affect the antibody response, but the T-cell response does not differ.

Dr. Radbruch said that the vaccine protection probably lasts for decades. Following an infection or vaccination, the antibody concentration in the bone marrow is similar to that achieved after a measles or tetanus vaccination. “The vaccination is already extremely efficient. You have protection at the same magnitude as for other infectious diseases or vaccinations, which is expected to last decades,” said Dr. Radbruch.

He clarified that the decrease in antibodies after vaccination and infection is normal and does not indicate a drop in protection. “Quantity and quality must not be confused here. There is simply less mass, but the grade of remaining antibody increases.”

In the competition around the virus antigens (referred to as affinity maturation), antibodies develop that bind 10 to 100 times better and are particularly protective against the virus. The immune system is thereby sustainably effective.
 

For whom and when?

Since the immune response is age dependent, it makes more sense to administer an additional booster to elderly people than to young people. Also included in this group, however, are people whose immune system still does not provide the same level of protection after the second or even third vaccination as that of younger, healthy people.

Dr. Radbruch noted that 4% of people older than 70 years exhibited autoantibodies against interferons. The effects are huge. “That is 20% of patients in an intensive care unit – and they all have a very poor prognosis,” said Dr. Radbruch. These people are extremely threatened by the virus. Multiple vaccinations are sensible for them.

Even people with a weak immune response benefit from multiple vaccinations, confirmed Dr. Neumann-Haefelin. “We are not seeing the antibody responses here that we see in young people with healthy immune systems until the third or fourth vaccination sometimes.”

Although for young healthy people, it is particularly important to ensure a sufficient period between vaccinations so that the affinity maturation is not impaired, those with a weak immune response can be vaccinated again as soon as after 3 months.

The “optimum minimum period of time” for people with healthy immune systems is 6 months, according to Dr. Neumann-Haefelin. “This is true for everyone in whom a proper response is expected.” The vaccine protection probably lasts significantly longer, and therefore, frequent boosting may not be necessary in the future, he said. The time separation also applies for medical personnel, for whom the Robert Koch Institute also recommends a second booster.

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

The more boosters the better? Data from Israel show that immune protection in elderly people is strengthened even further after a fourth dose. Karl Lauterbach, MD, German minister of health, recently pleaded for a second booster for those aged 18 years and older, and he pushed for a European Union–wide recommendation. He has not been able to implement this yet.

Just as before, Germany’s Standing Committee on Vaccination (STIKO) is only recommending the second booster for people aged 70 years and older, the European Medicines Agency (EMA) is recommending the fourth vaccination for everyone aged 80 years and older, and the United States has set the general age limit at 50 years.

Specialists remain skeptical about expanding the availability of the second booster. “From an immunologic perspective, people under the age of 70 with a healthy immune system do not need this fourth vaccination,” said Christiane Falk, PhD, head of the Institute for Transplantation Immunology of the Hannover Medical School (Germany) and member of the German Federal Government COVID Expert Panel, at a Science Media Center press briefing.

After the second vaccination, young healthy people are sufficiently protected against a severe course of the disease. Dr. Falk sees the STIKO recommendation as feasible, since it can be worked with. People in nursing facilities or those with additional underlying conditions would be considered for a fourth vaccination, explained Dr. Falk.
 

Complete protection unrealistic

Achieving complete protection against infection through multiple boosters is not realistic, said Christoph Neumann-Haefelin, MD, head of the Working Group for Translational Virus Immunology at the Clinic for Internal Medicine II, University Hospital Freiburg, Germany. Therefore, this should not be pursued when discussing boosters. “The aim of the booster vaccination should be to protect different groups of people against severe courses of the disease,” said Dr. Neumann-Haefelin.

Neutralizing antibodies that are only present in high concentrations for a few weeks after infection or vaccination are sometimes able to prevent the infection on their own. The immunologic memory of B cells and T cells, which ensures long-lasting protection against severe courses of the disease, is at a high level after two doses, and a third dose increases the protection more.

While people with a weak immune system need significantly more vaccinations in a shorter period to receive the same protection, too many booster vaccinations against SARS-CoV-2 are not sensible for young healthy people.
 

Immune saturation effect

A recent study in macaques showed that an adjusted Omicron booster did not lead to higher antibody titers, compared with a usual booster. In January 2022, the EMA warned against frequent consecutive boosters that may no longer produce the desired immune response.

If someone receives a booster too early, a saturation effect can occur, warned Andreas Radbruch, PhD, scientific director of the German Rheumatism Research Center Berlin. “We know this from lots of experimental studies but also from lots of other vaccinations. For example, you cannot be vaccinated against tetanus twice at 3- or 4-week intervals. Nothing at all will happen the second time,” explained Dr. Radbruch.

If the same antigen is applied again and again at the same dose, the immune system is made so active that the antigen is directly intercepted and cannot have any new effect on the immune system. This mechanism has been known for a long time, said Dr. Radbruch.
 

‘Original antigenic sin’

Premature boosting could even be a handicap in the competition between immune response and virus, said Dr. Radbruch. This is due to the principle of “original antigenic sin.” If the immune system has already come into contact with a virus, contact with a new virus variant will cause it to form antibodies predominantly against those epitopes that were already present in the original virus. As a result of this, too many boosters can weaken protection against different variants.

“We have not actually observed this with SARS-CoV-2, however,” said Dr. Radbruch. “Immunity is always extremely broad. With a double or triple vaccination, all previously existing variants are covered by an affinity-matured immune system.”

Dr. Neumann-Haefelin confirmed this and added that all virus mutations, including Omicron, have different epitopes that affect the antibody response, but the T-cell response does not differ.

Dr. Radbruch said that the vaccine protection probably lasts for decades. Following an infection or vaccination, the antibody concentration in the bone marrow is similar to that achieved after a measles or tetanus vaccination. “The vaccination is already extremely efficient. You have protection at the same magnitude as for other infectious diseases or vaccinations, which is expected to last decades,” said Dr. Radbruch.

He clarified that the decrease in antibodies after vaccination and infection is normal and does not indicate a drop in protection. “Quantity and quality must not be confused here. There is simply less mass, but the grade of remaining antibody increases.”

In the competition around the virus antigens (referred to as affinity maturation), antibodies develop that bind 10 to 100 times better and are particularly protective against the virus. The immune system is thereby sustainably effective.
 

For whom and when?

Since the immune response is age dependent, it makes more sense to administer an additional booster to elderly people than to young people. Also included in this group, however, are people whose immune system still does not provide the same level of protection after the second or even third vaccination as that of younger, healthy people.

Dr. Radbruch noted that 4% of people older than 70 years exhibited autoantibodies against interferons. The effects are huge. “That is 20% of patients in an intensive care unit – and they all have a very poor prognosis,” said Dr. Radbruch. These people are extremely threatened by the virus. Multiple vaccinations are sensible for them.

Even people with a weak immune response benefit from multiple vaccinations, confirmed Dr. Neumann-Haefelin. “We are not seeing the antibody responses here that we see in young people with healthy immune systems until the third or fourth vaccination sometimes.”

Although for young healthy people, it is particularly important to ensure a sufficient period between vaccinations so that the affinity maturation is not impaired, those with a weak immune response can be vaccinated again as soon as after 3 months.

The “optimum minimum period of time” for people with healthy immune systems is 6 months, according to Dr. Neumann-Haefelin. “This is true for everyone in whom a proper response is expected.” The vaccine protection probably lasts significantly longer, and therefore, frequent boosting may not be necessary in the future, he said. The time separation also applies for medical personnel, for whom the Robert Koch Institute also recommends a second booster.

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

The more boosters the better? Data from Israel show that immune protection in elderly people is strengthened even further after a fourth dose. Karl Lauterbach, MD, German minister of health, recently pleaded for a second booster for those aged 18 years and older, and he pushed for a European Union–wide recommendation. He has not been able to implement this yet.

Just as before, Germany’s Standing Committee on Vaccination (STIKO) is only recommending the second booster for people aged 70 years and older, the European Medicines Agency (EMA) is recommending the fourth vaccination for everyone aged 80 years and older, and the United States has set the general age limit at 50 years.

Specialists remain skeptical about expanding the availability of the second booster. “From an immunologic perspective, people under the age of 70 with a healthy immune system do not need this fourth vaccination,” said Christiane Falk, PhD, head of the Institute for Transplantation Immunology of the Hannover Medical School (Germany) and member of the German Federal Government COVID Expert Panel, at a Science Media Center press briefing.

After the second vaccination, young healthy people are sufficiently protected against a severe course of the disease. Dr. Falk sees the STIKO recommendation as feasible, since it can be worked with. People in nursing facilities or those with additional underlying conditions would be considered for a fourth vaccination, explained Dr. Falk.
 

Complete protection unrealistic

Achieving complete protection against infection through multiple boosters is not realistic, said Christoph Neumann-Haefelin, MD, head of the Working Group for Translational Virus Immunology at the Clinic for Internal Medicine II, University Hospital Freiburg, Germany. Therefore, this should not be pursued when discussing boosters. “The aim of the booster vaccination should be to protect different groups of people against severe courses of the disease,” said Dr. Neumann-Haefelin.

Neutralizing antibodies that are only present in high concentrations for a few weeks after infection or vaccination are sometimes able to prevent the infection on their own. The immunologic memory of B cells and T cells, which ensures long-lasting protection against severe courses of the disease, is at a high level after two doses, and a third dose increases the protection more.

While people with a weak immune system need significantly more vaccinations in a shorter period to receive the same protection, too many booster vaccinations against SARS-CoV-2 are not sensible for young healthy people.
 

Immune saturation effect

A recent study in macaques showed that an adjusted Omicron booster did not lead to higher antibody titers, compared with a usual booster. In January 2022, the EMA warned against frequent consecutive boosters that may no longer produce the desired immune response.

If someone receives a booster too early, a saturation effect can occur, warned Andreas Radbruch, PhD, scientific director of the German Rheumatism Research Center Berlin. “We know this from lots of experimental studies but also from lots of other vaccinations. For example, you cannot be vaccinated against tetanus twice at 3- or 4-week intervals. Nothing at all will happen the second time,” explained Dr. Radbruch.

If the same antigen is applied again and again at the same dose, the immune system is made so active that the antigen is directly intercepted and cannot have any new effect on the immune system. This mechanism has been known for a long time, said Dr. Radbruch.
 

‘Original antigenic sin’

Premature boosting could even be a handicap in the competition between immune response and virus, said Dr. Radbruch. This is due to the principle of “original antigenic sin.” If the immune system has already come into contact with a virus, contact with a new virus variant will cause it to form antibodies predominantly against those epitopes that were already present in the original virus. As a result of this, too many boosters can weaken protection against different variants.

“We have not actually observed this with SARS-CoV-2, however,” said Dr. Radbruch. “Immunity is always extremely broad. With a double or triple vaccination, all previously existing variants are covered by an affinity-matured immune system.”

Dr. Neumann-Haefelin confirmed this and added that all virus mutations, including Omicron, have different epitopes that affect the antibody response, but the T-cell response does not differ.

Dr. Radbruch said that the vaccine protection probably lasts for decades. Following an infection or vaccination, the antibody concentration in the bone marrow is similar to that achieved after a measles or tetanus vaccination. “The vaccination is already extremely efficient. You have protection at the same magnitude as for other infectious diseases or vaccinations, which is expected to last decades,” said Dr. Radbruch.

He clarified that the decrease in antibodies after vaccination and infection is normal and does not indicate a drop in protection. “Quantity and quality must not be confused here. There is simply less mass, but the grade of remaining antibody increases.”

In the competition around the virus antigens (referred to as affinity maturation), antibodies develop that bind 10 to 100 times better and are particularly protective against the virus. The immune system is thereby sustainably effective.
 

For whom and when?

Since the immune response is age dependent, it makes more sense to administer an additional booster to elderly people than to young people. Also included in this group, however, are people whose immune system still does not provide the same level of protection after the second or even third vaccination as that of younger, healthy people.

Dr. Radbruch noted that 4% of people older than 70 years exhibited autoantibodies against interferons. The effects are huge. “That is 20% of patients in an intensive care unit – and they all have a very poor prognosis,” said Dr. Radbruch. These people are extremely threatened by the virus. Multiple vaccinations are sensible for them.

Even people with a weak immune response benefit from multiple vaccinations, confirmed Dr. Neumann-Haefelin. “We are not seeing the antibody responses here that we see in young people with healthy immune systems until the third or fourth vaccination sometimes.”

Although for young healthy people, it is particularly important to ensure a sufficient period between vaccinations so that the affinity maturation is not impaired, those with a weak immune response can be vaccinated again as soon as after 3 months.

The “optimum minimum period of time” for people with healthy immune systems is 6 months, according to Dr. Neumann-Haefelin. “This is true for everyone in whom a proper response is expected.” The vaccine protection probably lasts significantly longer, and therefore, frequent boosting may not be necessary in the future, he said. The time separation also applies for medical personnel, for whom the Robert Koch Institute also recommends a second booster.

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

Standard therapies for depression are antidepressants and psychotherapy. In particularly severe cases, electroconvulsive therapy (ECT) or vagus nerve stimulation (VNS) may also be indicated. VNS is an approved, effective, well-tolerated, long-term therapy for chronic and therapy-resistant depression, wrote Christine Reif-Leonhardt, MD, and associates from the University Hospital Frankfurt am Main (Germany), in a recent journal article. In contrast to more common treatments, such as ECT, VNS is little known in the general population and among specialists. The cost of VNS is covered by health insurance funds in Germany.

Available since 1994

As the authors reported, invasive VNS was approved in the European Union in 1994 and in the United States in 1997 for the treatment of children with medicinal therapy–refractory epilepsy. Because positive and lasting effects on mood could be seen in adults after around 3 months of VNS, irrespective of the effectiveness of anticonvulsive medication, “a genuinely antidepressant effect of VNS [was] postulated,” and therefore it was further developed as an antidepressant therapy.

A VNS system first received a CE certification in 2001 in the European Union for the treatment of patients with chronic or relapsing depression who had therapy-resistant depression or who were intolerant of the current depression therapy. In 2005, VNS was approved in the United States for the treatment of patients aged 18 years or older with therapy-resistant major depression for which at least four antidepressant therapies had not helped sufficiently.
 

Few sham-controlled studies

According to Dr. Reif-Leonhardt and colleagues, there have been multiple studies and case series on VNS in patients with therapy-resistant depression in the past 20 years. Many of the studies highlighted the additional benefits of VNS as an adjuvant procedure, but they were observational studies. Sham-controlled studies are in short supply because of methodologic difficulties and ethical problems.

The largest long-term study is a registry study in which 494 patients with therapy-resistant depression received the combination of the usual antidepressant therapy and VNS. The study lasted 5 years; 301 patients served as a control group and received the usual therapy. The cumulative response to the therapy (68% vs. 41%) and the remission rate (43% vs. 26%) were significantly greater in the group that received VNS, according to the authors. Patients who underwent at least one ECT series of at least seven sessions responded particularly well to VNS. The combined therapy was also more effective in ECT nonresponders than the usual therapy alone.

To date, only one sham-controlled study of VNS treatment for therapy-resistant depression has been conducted. In it, VNS was not significantly superior to a sham stimulation over an observation period of 10 weeks. However, observational studies have provided evidence that the antidepressant effect of VNS only develops after at least 12 months of treatment. According to Dr. Reif-Leonhardt and colleagues, the data indicate that differences in response rate and therapy effect can only be observed in the longer term after 3-12 months and that as the therapy duration increases, so do the effects of VNS. From this, it can be assumed “that the VNS mechanism of action can be attributed to neuroplastic and adaptive phenomena.”

The typical, common side effects of surgery are pain and paresthesia. Through irritation of the nerve, approximately every third patient experiences postoperative hoarseness and a voice change. Serious side effects and complications, such as temporary swallowing disorders, are rare. By reducing the stimulation intensity or lowering the stimulation frequency or impulse width, the side effects associated with stimulation can be alleviated or even eliminated. A second small surgical intervention may become necessary to replace broken cables or the battery (life span, 3-8 years).
 

Criteria for VNS therapy

When should VNS be considered? The authors specified the following criteria:

• An insufficient response to at least two antidepressants from different substance classes (ideally including one tricyclic) at a sufficient dosage and duration, as well as to two augmentation agents (such as lithium and quetiapine) in combination with guideline psychotherapy
• Intolerable side effects from pharmacotherapy or contraindications to medicinal therapy
• For patients who respond to ECT, the occurrence of relapses or residual symptoms after cessation of (maintenance) ECT, intolerable ECT side effects, or the need for maintenance ECT
• Repeated or long hospital treatments because of depression

This article is a translation of an article from Univadis Germany and first appeared on Medscape.com.

Standard therapies for depression are antidepressants and psychotherapy. In particularly severe cases, electroconvulsive therapy (ECT) or vagus nerve stimulation (VNS) may also be indicated. VNS is an approved, effective, well-tolerated, long-term therapy for chronic and therapy-resistant depression, wrote Christine Reif-Leonhardt, MD, and associates from the University Hospital Frankfurt am Main (Germany), in a recent journal article. In contrast to more common treatments, such as ECT, VNS is little known in the general population and among specialists. The cost of VNS is covered by health insurance funds in Germany.

Available since 1994

As the authors reported, invasive VNS was approved in the European Union in 1994 and in the United States in 1997 for the treatment of children with medicinal therapy–refractory epilepsy. Because positive and lasting effects on mood could be seen in adults after around 3 months of VNS, irrespective of the effectiveness of anticonvulsive medication, “a genuinely antidepressant effect of VNS [was] postulated,” and therefore it was further developed as an antidepressant therapy.

A VNS system first received a CE certification in 2001 in the European Union for the treatment of patients with chronic or relapsing depression who had therapy-resistant depression or who were intolerant of the current depression therapy. In 2005, VNS was approved in the United States for the treatment of patients aged 18 years or older with therapy-resistant major depression for which at least four antidepressant therapies had not helped sufficiently.
 

Few sham-controlled studies

According to Dr. Reif-Leonhardt and colleagues, there have been multiple studies and case series on VNS in patients with therapy-resistant depression in the past 20 years. Many of the studies highlighted the additional benefits of VNS as an adjuvant procedure, but they were observational studies. Sham-controlled studies are in short supply because of methodologic difficulties and ethical problems.

The largest long-term study is a registry study in which 494 patients with therapy-resistant depression received the combination of the usual antidepressant therapy and VNS. The study lasted 5 years; 301 patients served as a control group and received the usual therapy. The cumulative response to the therapy (68% vs. 41%) and the remission rate (43% vs. 26%) were significantly greater in the group that received VNS, according to the authors. Patients who underwent at least one ECT series of at least seven sessions responded particularly well to VNS. The combined therapy was also more effective in ECT nonresponders than the usual therapy alone.

To date, only one sham-controlled study of VNS treatment for therapy-resistant depression has been conducted. In it, VNS was not significantly superior to a sham stimulation over an observation period of 10 weeks. However, observational studies have provided evidence that the antidepressant effect of VNS only develops after at least 12 months of treatment. According to Dr. Reif-Leonhardt and colleagues, the data indicate that differences in response rate and therapy effect can only be observed in the longer term after 3-12 months and that as the therapy duration increases, so do the effects of VNS. From this, it can be assumed “that the VNS mechanism of action can be attributed to neuroplastic and adaptive phenomena.”

The typical, common side effects of surgery are pain and paresthesia. Through irritation of the nerve, approximately every third patient experiences postoperative hoarseness and a voice change. Serious side effects and complications, such as temporary swallowing disorders, are rare. By reducing the stimulation intensity or lowering the stimulation frequency or impulse width, the side effects associated with stimulation can be alleviated or even eliminated. A second small surgical intervention may become necessary to replace broken cables or the battery (life span, 3-8 years).
 

Criteria for VNS therapy

When should VNS be considered? The authors specified the following criteria:

• An insufficient response to at least two antidepressants from different substance classes (ideally including one tricyclic) at a sufficient dosage and duration, as well as to two augmentation agents (such as lithium and quetiapine) in combination with guideline psychotherapy
• Intolerable side effects from pharmacotherapy or contraindications to medicinal therapy
• For patients who respond to ECT, the occurrence of relapses or residual symptoms after cessation of (maintenance) ECT, intolerable ECT side effects, or the need for maintenance ECT
• Repeated or long hospital treatments because of depression

This article is a translation of an article from Univadis Germany and first appeared on Medscape.com.

Standard therapies for depression are antidepressants and psychotherapy. In particularly severe cases, electroconvulsive therapy (ECT) or vagus nerve stimulation (VNS) may also be indicated. VNS is an approved, effective, well-tolerated, long-term therapy for chronic and therapy-resistant depression, wrote Christine Reif-Leonhardt, MD, and associates from the University Hospital Frankfurt am Main (Germany), in a recent journal article. In contrast to more common treatments, such as ECT, VNS is little known in the general population and among specialists. The cost of VNS is covered by health insurance funds in Germany.

Available since 1994

As the authors reported, invasive VNS was approved in the European Union in 1994 and in the United States in 1997 for the treatment of children with medicinal therapy–refractory epilepsy. Because positive and lasting effects on mood could be seen in adults after around 3 months of VNS, irrespective of the effectiveness of anticonvulsive medication, “a genuinely antidepressant effect of VNS [was] postulated,” and therefore it was further developed as an antidepressant therapy.

A VNS system first received a CE certification in 2001 in the European Union for the treatment of patients with chronic or relapsing depression who had therapy-resistant depression or who were intolerant of the current depression therapy. In 2005, VNS was approved in the United States for the treatment of patients aged 18 years or older with therapy-resistant major depression for which at least four antidepressant therapies had not helped sufficiently.
 

Few sham-controlled studies

According to Dr. Reif-Leonhardt and colleagues, there have been multiple studies and case series on VNS in patients with therapy-resistant depression in the past 20 years. Many of the studies highlighted the additional benefits of VNS as an adjuvant procedure, but they were observational studies. Sham-controlled studies are in short supply because of methodologic difficulties and ethical problems.

The largest long-term study is a registry study in which 494 patients with therapy-resistant depression received the combination of the usual antidepressant therapy and VNS. The study lasted 5 years; 301 patients served as a control group and received the usual therapy. The cumulative response to the therapy (68% vs. 41%) and the remission rate (43% vs. 26%) were significantly greater in the group that received VNS, according to the authors. Patients who underwent at least one ECT series of at least seven sessions responded particularly well to VNS. The combined therapy was also more effective in ECT nonresponders than the usual therapy alone.

To date, only one sham-controlled study of VNS treatment for therapy-resistant depression has been conducted. In it, VNS was not significantly superior to a sham stimulation over an observation period of 10 weeks. However, observational studies have provided evidence that the antidepressant effect of VNS only develops after at least 12 months of treatment. According to Dr. Reif-Leonhardt and colleagues, the data indicate that differences in response rate and therapy effect can only be observed in the longer term after 3-12 months and that as the therapy duration increases, so do the effects of VNS. From this, it can be assumed “that the VNS mechanism of action can be attributed to neuroplastic and adaptive phenomena.”

The typical, common side effects of surgery are pain and paresthesia. Through irritation of the nerve, approximately every third patient experiences postoperative hoarseness and a voice change. Serious side effects and complications, such as temporary swallowing disorders, are rare. By reducing the stimulation intensity or lowering the stimulation frequency or impulse width, the side effects associated with stimulation can be alleviated or even eliminated. A second small surgical intervention may become necessary to replace broken cables or the battery (life span, 3-8 years).
 

Criteria for VNS therapy

When should VNS be considered? The authors specified the following criteria:

• An insufficient response to at least two antidepressants from different substance classes (ideally including one tricyclic) at a sufficient dosage and duration, as well as to two augmentation agents (such as lithium and quetiapine) in combination with guideline psychotherapy
• Intolerable side effects from pharmacotherapy or contraindications to medicinal therapy
• For patients who respond to ECT, the occurrence of relapses or residual symptoms after cessation of (maintenance) ECT, intolerable ECT side effects, or the need for maintenance ECT
• Repeated or long hospital treatments because of depression

This article is a translation of an article from Univadis Germany and first appeared on Medscape.com.

Approximately 50% of melanomas contain BRAF mutations, which occur in a greater proportion of melanomas found on sites of intermittent sun exposure.¹BRAF-mutated melanomas have been associated with high levels of early-life ambient UV exposure, especially between ages 0 and 20 years.² In addition, studies have shown that BRAF-mutated melanomas commonly are found on the trunk and extremities.^1-3BRAF mutations also have been associated with younger age, superficial spreading subtype and low tumor thickness, absence of dermal melanocyte mitosis, low Ki-67 score, low phospho-histone H3 score, pigmented melanoma, advanced melanoma stage, and conjunctival melanoma.^4-7BRAF mutations are found more frequently in metastatic melanoma lesions than primary melanomas, suggesting that BRAF mutations may be acquired during metastasis.⁸ Studies have shown different conclusions on the effect of BRAF mutation on melanoma-related death.^5,9,10

The aim of this study was to identify trends in BRAF V600E–mutated melanoma according to age, sex, and melanoma-specific survival among Olmsted County, Minnesota, residents with a first diagnosis of melanoma at 18 to 60 years of age.

Methods

In total, 638 patients aged 18 to 60 years who resided in Olmsted County and had a first lifetime diagnosis of cutaneous melanoma between 1970 and 2009 were retrospectively identified as a part of the Rochester Epidemiology Project (REP). The REP is a health records linkage system that encompasses almost all sources of medical care available to the local population of Olmsted County.¹¹ This study was approved by the Mayo Clinic Institutional Review Board (Rochester, Minnesota).

Of the 638 individuals identified in the REP, 536 had been seen at Mayo Clinic and thus potentially had tissue blocks available for the study of BRAF mutation expression. Of these 536 patients, 156 did not have sufficient residual tissue available. As a result, 380 (60%) of the original 638 patients had available blocks with sufficient tissue for immunohistochemical analysis of BRAF expression. Only primary cutaneous melanomas were included in the present study.

All specimens were reviewed by a board-certified dermatopathologist (J.S.L.) for appropriateness of inclusion, which involved confirmation of the diagnosis of melanoma, histologic type of melanoma, and presence of sufficient residual tissue for immunohistochemical stains.

All specimens were originally diagnosed as malignant melanoma at the time of clinical care by at least 2 board-certified dermatopathologists. For the purposes of this study, all specimens were rereviewed for diagnostic accuracy. We required that specimens exhibit severe cytologic and architectural atypia as well as other features favoring melanoma, such as consumption of rete pegs, pagetosis, confluence of junctional melanocytes, evidence of regression, lack of maturation of melanocytes with descent into the dermis, or mitotic figures among the dermal melanocyte population.

The available tissue blocks were retrieved, sectioned, confirmed as melanoma, and stained with a mouse antihuman BRAF V600E monoclonal antibody (clone VE1; Spring Bioscience) to determine the presence of a BRAF V600E mutation. BRAF staining was evaluated in conjunction with a review of the associated slides stained with hematoxylin and eosin. Cytoplasmic staining of melanocytes for BRAF was graded as negative, focal or partial positive (<50% of tumor), or diffuse positive (>50% of tumor)(Figure 1). When a melanoma arose in association with a nevus, we considered only the melanoma component for BRAF staining. We categorized the histologic type as superficial spreading, nodular, or lentigo maligna, and the location as head and neck, trunk, or extremities.

Results

Clinical and Tumor Characteristics—Of the 380 tissue specimens that underwent BRAF V600E analysis, 247 had negative staining; 106 had diffuse strong staining; and 27 had focal or partial staining. In total, 133 (35%) were positive, either partially or diffusely. The median age for patients who had negative staining was 45 years; for those with positive staining, it was 41 years (P=.07).

The patients who met inclusion criteria (n=380) were compared with those who were excluded (n=258)(eTable 1). The groups were similar on the basis of sex; age; and melanoma location, stage, and histologic subtype. However, some evidence showed that patients included in the study received the diagnosis of melanoma more recently (1970-1989, 13.2%; 1990-1999, 28.7%; 2000-2009, 58.2%) than those who were excluded (1970-1989, 24.7%; 1990-1999, 23.5%; 2000-2009, 51.8%)(P=.02).

BRAF V600E expression was more commonly found in superficial spreading (37.7%) and nodular melanomas (35.0%) than in situ melanomas (17.1%)(P=.01). Other characteristics of BRAF V600E expression are described in eTable 2. Overall, invasive and advanced melanomas were significantly more likely to harbor BRAF V600E expression than noninvasive melanomas (39.6% and 37.9%, respectively, vs 17.9%; P=.003). However, advanced melanomas more commonly expressed BRAF positivity among women, and invasive melanomas more commonly expressed BRAF positivity among men (eTable 2).

Survival—Survival analyses were limited to 297 patients with confirmed invasive or advanced disease. Of these, 180 (61%) had no BRAF V600E staining; 25 (8%) had partial staining; and 92 (31%) had diffuse positive staining. In total, 117 patients (39%) had a BRAF-mutated melanoma.

Among the patients still alive, the median (interquartile range [IQR]) duration of follow-up was 10.2 (7.0-16.8) years. Thirty-nine patients with invasive or advanced disease had died of any cause at a median (IQR) of 3.0 (1.3-10.2) years after diagnosis. In total, 26 patients died of melanoma at a median (IQR) follow-up of 2.5 (1.3-7.4) years after diagnosis. Eight women and 18 men died of malignant melanoma. Five deaths occurred because of malignant melanoma among patients aged 18 to 39 years, and 21 occurred among patients aged 40 to 60 years. In the 18- to 39-year-old group, all 5 deaths were among patients with a BRAF-positive melanoma. Estimated disease-specific survival rate (95% CI; number still at risk) at 5, 10, 15, and 20 years after diagnosis was 94% (91%-97%; 243), 91% (87%-95%; 142), 89% (85%-94%; 87), and 88% (83%-93%; 45), respectively.

Comment

We found that melanomas with BRAF mutations were more likely in advanced and invasive melanoma. The frequency of BRAF mutations among melanomas that were considered advanced was higher in women than men. Although the number of deaths was limited, women with a melanoma with BRAF expression were more likely to die of melanoma, young adults with a BRAF-mutated melanoma had an almost 10-fold increased risk of dying from any cause, and middle-aged adults showed no increased risk of death. These findings suggest that young adults who are genetically prone to a BRAF-mutated melanoma could be at a disadvantage for all-cause mortality. Although this finding was significant, the 95% CI was large, and further studies would be warranted before sound conclusions could be made.

Melanoma has been increasing in incidence across all age groups in Olmsted County over the last 4 decades.^12-14 However, our results show that the percentage of BRAF-mutated melanomas in this population has been stable over time, with no statistically significant difference by age or sex. Other confounding factors may have an influence, such as increased rates of early detection and diagnosis of melanoma in contemporary times. Our data suggest that patients included in the BRAF-mutation analysis study had received the diagnosis of melanoma more recently than those who were excluded from the study, which could be due to older melanomas being less likely to have adequate tissue specimens available for immunohistochemical staining/evaluation.

Prior research has shown that BRAF-mutated melanomas typically occur on the trunk and are more likely in individuals with more than 14 nevi on the back.² In the present cohort, BRAF-positive melanomas had a predisposition toward the trunk but also were found on the head, neck, and extremities—areas that are more likely to have long-term sun damage. One suggestion is that 2 distinct pathways for melanoma development exist: one associated with a large number of melanocytic nevi (that is more prone to genetic mutations in melanocytes) and the other associated with long-term sun exposure.^15,16 The combination of these hypotheses suggests that individuals who are prone to the development of large numbers of nevi may require sun exposure for the initial insult, but the development of melanoma may be carried out by other factors after this initial sun exposure insult, whereas individuals without large numbers of nevi who may have less genetic risk may require continued long-term sun exposure for melanoma to develop.¹⁷

Our study had limitations, including the small numbers of deaths overall and cause-specific deaths of metastatic melanoma, which limited our ability to conduct more extensive multivariable modeling. Also, the retrospective nature and time frame of looking back 4 decades did not allow us to have information sufficient to categorize some patients as having dysplastic nevus syndrome or not, which would be a potentially interesting variable to include in the analysis. Because the number of deaths in the 18- to 39-year-old cohort was only 5, further statistical comparison regarding tumor type and other variables pertaining to BRAF positivity were not possible. In addition, our data were collected from patients residing in a single geographic county (Olmsted County, Minnesota), which may limit generalizability. Lastly, BRAF V600E mutations were identified through immunostaining only, not molecular data, so it is possible some patients had false-negative immunohistochemistry findings and thus were not identified.

Conclusion

BRAF-mutated melanomas were found in 35% of our cohort, with no significant change in the percentage of melanomas with BRAF V600E mutations over the last 4 decades in this population. In addition, no differences or significant trends existed according to sex and BRAF-mutated melanoma development. Women with BRAF-mutated melanomas were more likely to die of metastatic melanoma than men, and young adults with BRAF-mutated melanomas had a higher all-cause mortality risk. Further research is needed to decipher what effect BRAF-mutated melanomas have on metastasis and cause-specific death in women as well as all-cause mortality in young adults.

Acknowledgment—The authors are indebted to Scientific Publications, Mayo Clinic (Rochester, Minnesota).

Approximately 50% of melanomas contain BRAF mutations, which occur in a greater proportion of melanomas found on sites of intermittent sun exposure.¹BRAF-mutated melanomas have been associated with high levels of early-life ambient UV exposure, especially between ages 0 and 20 years.² In addition, studies have shown that BRAF-mutated melanomas commonly are found on the trunk and extremities.^1-3BRAF mutations also have been associated with younger age, superficial spreading subtype and low tumor thickness, absence of dermal melanocyte mitosis, low Ki-67 score, low phospho-histone H3 score, pigmented melanoma, advanced melanoma stage, and conjunctival melanoma.^4-7BRAF mutations are found more frequently in metastatic melanoma lesions than primary melanomas, suggesting that BRAF mutations may be acquired during metastasis.⁸ Studies have shown different conclusions on the effect of BRAF mutation on melanoma-related death.^5,9,10

The aim of this study was to identify trends in BRAF V600E–mutated melanoma according to age, sex, and melanoma-specific survival among Olmsted County, Minnesota, residents with a first diagnosis of melanoma at 18 to 60 years of age.

Methods

In total, 638 patients aged 18 to 60 years who resided in Olmsted County and had a first lifetime diagnosis of cutaneous melanoma between 1970 and 2009 were retrospectively identified as a part of the Rochester Epidemiology Project (REP). The REP is a health records linkage system that encompasses almost all sources of medical care available to the local population of Olmsted County.¹¹ This study was approved by the Mayo Clinic Institutional Review Board (Rochester, Minnesota).

Of the 638 individuals identified in the REP, 536 had been seen at Mayo Clinic and thus potentially had tissue blocks available for the study of BRAF mutation expression. Of these 536 patients, 156 did not have sufficient residual tissue available. As a result, 380 (60%) of the original 638 patients had available blocks with sufficient tissue for immunohistochemical analysis of BRAF expression. Only primary cutaneous melanomas were included in the present study.

All specimens were reviewed by a board-certified dermatopathologist (J.S.L.) for appropriateness of inclusion, which involved confirmation of the diagnosis of melanoma, histologic type of melanoma, and presence of sufficient residual tissue for immunohistochemical stains.

All specimens were originally diagnosed as malignant melanoma at the time of clinical care by at least 2 board-certified dermatopathologists. For the purposes of this study, all specimens were rereviewed for diagnostic accuracy. We required that specimens exhibit severe cytologic and architectural atypia as well as other features favoring melanoma, such as consumption of rete pegs, pagetosis, confluence of junctional melanocytes, evidence of regression, lack of maturation of melanocytes with descent into the dermis, or mitotic figures among the dermal melanocyte population.

The available tissue blocks were retrieved, sectioned, confirmed as melanoma, and stained with a mouse antihuman BRAF V600E monoclonal antibody (clone VE1; Spring Bioscience) to determine the presence of a BRAF V600E mutation. BRAF staining was evaluated in conjunction with a review of the associated slides stained with hematoxylin and eosin. Cytoplasmic staining of melanocytes for BRAF was graded as negative, focal or partial positive (<50% of tumor), or diffuse positive (>50% of tumor)(Figure 1). When a melanoma arose in association with a nevus, we considered only the melanoma component for BRAF staining. We categorized the histologic type as superficial spreading, nodular, or lentigo maligna, and the location as head and neck, trunk, or extremities.

Results

Clinical and Tumor Characteristics—Of the 380 tissue specimens that underwent BRAF V600E analysis, 247 had negative staining; 106 had diffuse strong staining; and 27 had focal or partial staining. In total, 133 (35%) were positive, either partially or diffusely. The median age for patients who had negative staining was 45 years; for those with positive staining, it was 41 years (P=.07).

The patients who met inclusion criteria (n=380) were compared with those who were excluded (n=258)(eTable 1). The groups were similar on the basis of sex; age; and melanoma location, stage, and histologic subtype. However, some evidence showed that patients included in the study received the diagnosis of melanoma more recently (1970-1989, 13.2%; 1990-1999, 28.7%; 2000-2009, 58.2%) than those who were excluded (1970-1989, 24.7%; 1990-1999, 23.5%; 2000-2009, 51.8%)(P=.02).

BRAF V600E expression was more commonly found in superficial spreading (37.7%) and nodular melanomas (35.0%) than in situ melanomas (17.1%)(P=.01). Other characteristics of BRAF V600E expression are described in eTable 2. Overall, invasive and advanced melanomas were significantly more likely to harbor BRAF V600E expression than noninvasive melanomas (39.6% and 37.9%, respectively, vs 17.9%; P=.003). However, advanced melanomas more commonly expressed BRAF positivity among women, and invasive melanomas more commonly expressed BRAF positivity among men (eTable 2).

Survival—Survival analyses were limited to 297 patients with confirmed invasive or advanced disease. Of these, 180 (61%) had no BRAF V600E staining; 25 (8%) had partial staining; and 92 (31%) had diffuse positive staining. In total, 117 patients (39%) had a BRAF-mutated melanoma.

Among the patients still alive, the median (interquartile range [IQR]) duration of follow-up was 10.2 (7.0-16.8) years. Thirty-nine patients with invasive or advanced disease had died of any cause at a median (IQR) of 3.0 (1.3-10.2) years after diagnosis. In total, 26 patients died of melanoma at a median (IQR) follow-up of 2.5 (1.3-7.4) years after diagnosis. Eight women and 18 men died of malignant melanoma. Five deaths occurred because of malignant melanoma among patients aged 18 to 39 years, and 21 occurred among patients aged 40 to 60 years. In the 18- to 39-year-old group, all 5 deaths were among patients with a BRAF-positive melanoma. Estimated disease-specific survival rate (95% CI; number still at risk) at 5, 10, 15, and 20 years after diagnosis was 94% (91%-97%; 243), 91% (87%-95%; 142), 89% (85%-94%; 87), and 88% (83%-93%; 45), respectively.

Comment

We found that melanomas with BRAF mutations were more likely in advanced and invasive melanoma. The frequency of BRAF mutations among melanomas that were considered advanced was higher in women than men. Although the number of deaths was limited, women with a melanoma with BRAF expression were more likely to die of melanoma, young adults with a BRAF-mutated melanoma had an almost 10-fold increased risk of dying from any cause, and middle-aged adults showed no increased risk of death. These findings suggest that young adults who are genetically prone to a BRAF-mutated melanoma could be at a disadvantage for all-cause mortality. Although this finding was significant, the 95% CI was large, and further studies would be warranted before sound conclusions could be made.

Melanoma has been increasing in incidence across all age groups in Olmsted County over the last 4 decades.^12-14 However, our results show that the percentage of BRAF-mutated melanomas in this population has been stable over time, with no statistically significant difference by age or sex. Other confounding factors may have an influence, such as increased rates of early detection and diagnosis of melanoma in contemporary times. Our data suggest that patients included in the BRAF-mutation analysis study had received the diagnosis of melanoma more recently than those who were excluded from the study, which could be due to older melanomas being less likely to have adequate tissue specimens available for immunohistochemical staining/evaluation.

Prior research has shown that BRAF-mutated melanomas typically occur on the trunk and are more likely in individuals with more than 14 nevi on the back.² In the present cohort, BRAF-positive melanomas had a predisposition toward the trunk but also were found on the head, neck, and extremities—areas that are more likely to have long-term sun damage. One suggestion is that 2 distinct pathways for melanoma development exist: one associated with a large number of melanocytic nevi (that is more prone to genetic mutations in melanocytes) and the other associated with long-term sun exposure.^15,16 The combination of these hypotheses suggests that individuals who are prone to the development of large numbers of nevi may require sun exposure for the initial insult, but the development of melanoma may be carried out by other factors after this initial sun exposure insult, whereas individuals without large numbers of nevi who may have less genetic risk may require continued long-term sun exposure for melanoma to develop.¹⁷

Our study had limitations, including the small numbers of deaths overall and cause-specific deaths of metastatic melanoma, which limited our ability to conduct more extensive multivariable modeling. Also, the retrospective nature and time frame of looking back 4 decades did not allow us to have information sufficient to categorize some patients as having dysplastic nevus syndrome or not, which would be a potentially interesting variable to include in the analysis. Because the number of deaths in the 18- to 39-year-old cohort was only 5, further statistical comparison regarding tumor type and other variables pertaining to BRAF positivity were not possible. In addition, our data were collected from patients residing in a single geographic county (Olmsted County, Minnesota), which may limit generalizability. Lastly, BRAF V600E mutations were identified through immunostaining only, not molecular data, so it is possible some patients had false-negative immunohistochemistry findings and thus were not identified.

Conclusion

BRAF-mutated melanomas were found in 35% of our cohort, with no significant change in the percentage of melanomas with BRAF V600E mutations over the last 4 decades in this population. In addition, no differences or significant trends existed according to sex and BRAF-mutated melanoma development. Women with BRAF-mutated melanomas were more likely to die of metastatic melanoma than men, and young adults with BRAF-mutated melanomas had a higher all-cause mortality risk. Further research is needed to decipher what effect BRAF-mutated melanomas have on metastasis and cause-specific death in women as well as all-cause mortality in young adults.

Acknowledgment—The authors are indebted to Scientific Publications, Mayo Clinic (Rochester, Minnesota).

Approximately 50% of melanomas contain BRAF mutations, which occur in a greater proportion of melanomas found on sites of intermittent sun exposure.¹BRAF-mutated melanomas have been associated with high levels of early-life ambient UV exposure, especially between ages 0 and 20 years.² In addition, studies have shown that BRAF-mutated melanomas commonly are found on the trunk and extremities.^1-3BRAF mutations also have been associated with younger age, superficial spreading subtype and low tumor thickness, absence of dermal melanocyte mitosis, low Ki-67 score, low phospho-histone H3 score, pigmented melanoma, advanced melanoma stage, and conjunctival melanoma.^4-7BRAF mutations are found more frequently in metastatic melanoma lesions than primary melanomas, suggesting that BRAF mutations may be acquired during metastasis.⁸ Studies have shown different conclusions on the effect of BRAF mutation on melanoma-related death.^5,9,10

The aim of this study was to identify trends in BRAF V600E–mutated melanoma according to age, sex, and melanoma-specific survival among Olmsted County, Minnesota, residents with a first diagnosis of melanoma at 18 to 60 years of age.

Methods

In total, 638 patients aged 18 to 60 years who resided in Olmsted County and had a first lifetime diagnosis of cutaneous melanoma between 1970 and 2009 were retrospectively identified as a part of the Rochester Epidemiology Project (REP). The REP is a health records linkage system that encompasses almost all sources of medical care available to the local population of Olmsted County.¹¹ This study was approved by the Mayo Clinic Institutional Review Board (Rochester, Minnesota).

Of the 638 individuals identified in the REP, 536 had been seen at Mayo Clinic and thus potentially had tissue blocks available for the study of BRAF mutation expression. Of these 536 patients, 156 did not have sufficient residual tissue available. As a result, 380 (60%) of the original 638 patients had available blocks with sufficient tissue for immunohistochemical analysis of BRAF expression. Only primary cutaneous melanomas were included in the present study.

All specimens were reviewed by a board-certified dermatopathologist (J.S.L.) for appropriateness of inclusion, which involved confirmation of the diagnosis of melanoma, histologic type of melanoma, and presence of sufficient residual tissue for immunohistochemical stains.

All specimens were originally diagnosed as malignant melanoma at the time of clinical care by at least 2 board-certified dermatopathologists. For the purposes of this study, all specimens were rereviewed for diagnostic accuracy. We required that specimens exhibit severe cytologic and architectural atypia as well as other features favoring melanoma, such as consumption of rete pegs, pagetosis, confluence of junctional melanocytes, evidence of regression, lack of maturation of melanocytes with descent into the dermis, or mitotic figures among the dermal melanocyte population.

The available tissue blocks were retrieved, sectioned, confirmed as melanoma, and stained with a mouse antihuman BRAF V600E monoclonal antibody (clone VE1; Spring Bioscience) to determine the presence of a BRAF V600E mutation. BRAF staining was evaluated in conjunction with a review of the associated slides stained with hematoxylin and eosin. Cytoplasmic staining of melanocytes for BRAF was graded as negative, focal or partial positive (<50% of tumor), or diffuse positive (>50% of tumor)(Figure 1). When a melanoma arose in association with a nevus, we considered only the melanoma component for BRAF staining. We categorized the histologic type as superficial spreading, nodular, or lentigo maligna, and the location as head and neck, trunk, or extremities.

Results

Clinical and Tumor Characteristics—Of the 380 tissue specimens that underwent BRAF V600E analysis, 247 had negative staining; 106 had diffuse strong staining; and 27 had focal or partial staining. In total, 133 (35%) were positive, either partially or diffusely. The median age for patients who had negative staining was 45 years; for those with positive staining, it was 41 years (P=.07).

The patients who met inclusion criteria (n=380) were compared with those who were excluded (n=258)(eTable 1). The groups were similar on the basis of sex; age; and melanoma location, stage, and histologic subtype. However, some evidence showed that patients included in the study received the diagnosis of melanoma more recently (1970-1989, 13.2%; 1990-1999, 28.7%; 2000-2009, 58.2%) than those who were excluded (1970-1989, 24.7%; 1990-1999, 23.5%; 2000-2009, 51.8%)(P=.02).

BRAF V600E expression was more commonly found in superficial spreading (37.7%) and nodular melanomas (35.0%) than in situ melanomas (17.1%)(P=.01). Other characteristics of BRAF V600E expression are described in eTable 2. Overall, invasive and advanced melanomas were significantly more likely to harbor BRAF V600E expression than noninvasive melanomas (39.6% and 37.9%, respectively, vs 17.9%; P=.003). However, advanced melanomas more commonly expressed BRAF positivity among women, and invasive melanomas more commonly expressed BRAF positivity among men (eTable 2).

Survival—Survival analyses were limited to 297 patients with confirmed invasive or advanced disease. Of these, 180 (61%) had no BRAF V600E staining; 25 (8%) had partial staining; and 92 (31%) had diffuse positive staining. In total, 117 patients (39%) had a BRAF-mutated melanoma.

Among the patients still alive, the median (interquartile range [IQR]) duration of follow-up was 10.2 (7.0-16.8) years. Thirty-nine patients with invasive or advanced disease had died of any cause at a median (IQR) of 3.0 (1.3-10.2) years after diagnosis. In total, 26 patients died of melanoma at a median (IQR) follow-up of 2.5 (1.3-7.4) years after diagnosis. Eight women and 18 men died of malignant melanoma. Five deaths occurred because of malignant melanoma among patients aged 18 to 39 years, and 21 occurred among patients aged 40 to 60 years. In the 18- to 39-year-old group, all 5 deaths were among patients with a BRAF-positive melanoma. Estimated disease-specific survival rate (95% CI; number still at risk) at 5, 10, 15, and 20 years after diagnosis was 94% (91%-97%; 243), 91% (87%-95%; 142), 89% (85%-94%; 87), and 88% (83%-93%; 45), respectively.

Comment

We found that melanomas with BRAF mutations were more likely in advanced and invasive melanoma. The frequency of BRAF mutations among melanomas that were considered advanced was higher in women than men. Although the number of deaths was limited, women with a melanoma with BRAF expression were more likely to die of melanoma, young adults with a BRAF-mutated melanoma had an almost 10-fold increased risk of dying from any cause, and middle-aged adults showed no increased risk of death. These findings suggest that young adults who are genetically prone to a BRAF-mutated melanoma could be at a disadvantage for all-cause mortality. Although this finding was significant, the 95% CI was large, and further studies would be warranted before sound conclusions could be made.

Melanoma has been increasing in incidence across all age groups in Olmsted County over the last 4 decades.^12-14 However, our results show that the percentage of BRAF-mutated melanomas in this population has been stable over time, with no statistically significant difference by age or sex. Other confounding factors may have an influence, such as increased rates of early detection and diagnosis of melanoma in contemporary times. Our data suggest that patients included in the BRAF-mutation analysis study had received the diagnosis of melanoma more recently than those who were excluded from the study, which could be due to older melanomas being less likely to have adequate tissue specimens available for immunohistochemical staining/evaluation.

Prior research has shown that BRAF-mutated melanomas typically occur on the trunk and are more likely in individuals with more than 14 nevi on the back.² In the present cohort, BRAF-positive melanomas had a predisposition toward the trunk but also were found on the head, neck, and extremities—areas that are more likely to have long-term sun damage. One suggestion is that 2 distinct pathways for melanoma development exist: one associated with a large number of melanocytic nevi (that is more prone to genetic mutations in melanocytes) and the other associated with long-term sun exposure.^15,16 The combination of these hypotheses suggests that individuals who are prone to the development of large numbers of nevi may require sun exposure for the initial insult, but the development of melanoma may be carried out by other factors after this initial sun exposure insult, whereas individuals without large numbers of nevi who may have less genetic risk may require continued long-term sun exposure for melanoma to develop.¹⁷

Our study had limitations, including the small numbers of deaths overall and cause-specific deaths of metastatic melanoma, which limited our ability to conduct more extensive multivariable modeling. Also, the retrospective nature and time frame of looking back 4 decades did not allow us to have information sufficient to categorize some patients as having dysplastic nevus syndrome or not, which would be a potentially interesting variable to include in the analysis. Because the number of deaths in the 18- to 39-year-old cohort was only 5, further statistical comparison regarding tumor type and other variables pertaining to BRAF positivity were not possible. In addition, our data were collected from patients residing in a single geographic county (Olmsted County, Minnesota), which may limit generalizability. Lastly, BRAF V600E mutations were identified through immunostaining only, not molecular data, so it is possible some patients had false-negative immunohistochemistry findings and thus were not identified.

Conclusion

BRAF-mutated melanomas were found in 35% of our cohort, with no significant change in the percentage of melanomas with BRAF V600E mutations over the last 4 decades in this population. In addition, no differences or significant trends existed according to sex and BRAF-mutated melanoma development. Women with BRAF-mutated melanomas were more likely to die of metastatic melanoma than men, and young adults with BRAF-mutated melanomas had a higher all-cause mortality risk. Further research is needed to decipher what effect BRAF-mutated melanomas have on metastasis and cause-specific death in women as well as all-cause mortality in young adults.

Acknowledgment—The authors are indebted to Scientific Publications, Mayo Clinic (Rochester, Minnesota).

The COVID-19 pandemic has brought about unprecedented changes and challenges to medical practice, including new public health measure legislation, local and national medical authority recommendations, nursing home and other ancillary health center protocols, and novel clinical decision-making considerations.^1-3 In July 2020, the American Academy of Dermatology (AAD) addressed the changing landscape in dermatologic surgery, in part, by publishing recommendations on practice protocols during the COVID-19 pandemic.⁴ The guidelines recommended deferred treatment of superficial basal cell carcinomas (BCCs) for 6 months and all other BCC subtypes for 3 to 6 months. Furthermore, the guidelines recommended deferring treatment of all actinic keratoses and squamous cell carcinomas (SCCs) in situ “for now.” Squamous cell carcinoma treatment was to be guided by prognostic variables, such as location, size, depth, differentiation, perineural or lymphovascular invasion, recurrence, and immunosuppression. The guidelines recommended melanoma in situ (MIS) treatment be deferred for 3 months and invasive melanoma with histologic clearance obtained on excisional biopsy for 3 months. Other general recommendations included triaging clinics, rebooking according to clinical priority, using telehealth where possible, screening patients for COVID-19 signs and symptoms, staggering appointment times, spacing patient chairs, limiting support persons to 1, removing possible sources of infection in the waiting room, ensuring all patients sanitized their hands on arrival, rationing personal protective equipment, considering N95 masks for periorificial surgery, and using dissolving sutures to minimize multiple presentations.⁴

The American College of Mohs Surgery (ACMS), with guidance from its sister societies and the National Comprehensive Cancer Network, also communicated COVID-19–related recommendations to its members via intermittent newsletters during the initial peak of the pandemic in March and June 2020.⁵ General social distancing and office recommendations were similar to those released by the AAD. Recommendations for skin cancer treatment included deferring all BCCs for up to 3 months, with exceptions for highly symptomatic cancers and those with potential for substantial rapid growth. Squamous cell carcinoma in situ and small, well-differentiated SCCs were deferred, with priority placed on SCCs that were rapidly enlarging, poorly differentiated, demonstrated perineural invasion, were ulcerated, or were symptomatic. Patients with major risk factors were prioritized for treatment. Melanoma in situ was deferred for 2 to 3 months.⁵

State-level guidance from the Texas Dermatological Society (TDS) communicated in April 2020 stated that skin cancers with a potential for rapid progression and metastasis, such as melanoma and SCC, may require treatment as determined by the physician.⁶ The potential risk of serious adverse medical outcomes from not treating these cancers should be carefully documented. General practice measures for preventing the spread of COVID-19 were also recommended.⁶

In the setting of emerging novel recommendations, the practice of Mohs micrographic surgery (MMS) was notably impacted by the COVID-19 pandemic. According to one survey study from the United Kingdom conducted in April and May 2020, 49% of MMS services ceased and 36% were reduced during the infancy of the COVID-19 pandemic.⁷ Mohs micrographic surgery was largely suspended because of a lack of personal protective equipment and safety concerns, according to respondents. Additionally, respondents reported 77% of departments experienced redeployment of physicians and nurses to intensive care and medical wards. Thirty-five percent reported a reduction in the proportion of flaps/grafts to primary closures performed, 74% reported a decrease in outside referrals for repair by other specialties, 81% reported increased usage of dissolvable sutures, and 29% reported an increase in prophylactic antibiotic prescriptions.⁷ Another study from Italy reported a 46.5% reduction in dermatologic surgeries performed during the initial lockdown of the COVID-19 pandemic. Patients canceled 52.9% of procedures, and 12.5% were cancelled because of confirmed or suspected COVID-19 infection.⁸ Patient perceptions of MMS have also been impacted by the COVID-19 pandemic. According to a survey study of patients in the United Kingdom undergoing MMS during the pandemic, 47% were worried the hospital would cancel their surgery, 54% were anxious about using public transportation to attend their appointment, 30% were concerned about transmitting COVID-19 to household or family members, and 19% were worried about their ability to socially distance in the hospital.⁹

Evidence is also emerging that suggests the potential negative impact of the COVID-19 pandemic on morbidity and mortality outcomes in patients with skin cancer. One European study found an increase in Breslow thickness in primary melanomas diagnosed following the initial COVID-19 lockdown (0.88-mm average thickness prelockdown vs 1.96-mm average thickness postlockdown).¹⁰ An Italian study observed similar results—an increase in median Breslow thickness during the initial COVID-19 lockdown period of 0.5 mm from 0.4 mm during the prelockdown time period.¹¹ Also providing evidence for potentially poor patient outcomes, one study modeled the impact of backlog in cutaneous melanoma referrals in the United Kingdom on patient survival and predicted 138 attributable lives lost for a 1-month delay and 1171 lives lost for a 6-month delay. The model further predicted a 3.1% to 12.5% reduction in 10-year net survival incurred from a 3-month delay in melanoma treatment, with the largest reduction seen in the patient population older than 80 years.¹²

Although the COVID-19 pandemic has been observed to impact MMS practice, patient perceptions, and clinical outcomes, it is unknown how the COVID-19 pandemic and corresponding rapidly evolving recommendations in dermatologic surgery have impacted the characteristics of cutaneous tumors treated by MMS.

Our study sought to determine the characteristics of skin cancers treated by MMS during the peak of government-mandated medical practice restrictions and business shutdowns in response to the COVID-19 pandemic and to compare them with characteristics of skin cancers treated during a prepandemic control period.

Methods

A retrospective chart review was conducted with approval from our institutional review board at the University of Texas Medical Branch (Galveston, Texas). Included in the chart review were all cutaneous malignancies treated by MMS at our outpatient, office-based surgical center from March 15, 2020, to April 30, 2020; this period corresponded to the peak of the COVID-19–related government-mandated medical and business shutdowns in our geographic region (southeast Texas). All cases performed were in compliance with national- and state-level guidance. Data were also collected for all cutaneous malignancies treated by MMS at our office from March 15, 2019, to April 30, 2019, as well as March 15, 2018, to April 30, 2018; these periods represented prepandemic control periods.

Data were collected for 516 surgeries performed on 458 patients and included patient age, preoperative clinical size, postoperative defect size, number of Mohs stages to achieve clearance, MMS appropriate use criteria (AUC) location (categorized as high-, medium-, or low-risk tumor location),¹³ and tumor type (categorized as BCC, SCC, or MIS). All variables were examined for unusual or missing values. Five patients with rare tumor types were observed and removed from the data set.

Statistical Analysis—An a priori power analysis for a power set at 0.85 determined sample sizes of 105 per group. Bivariate analyses were performed to compare variables for patients undergoing MMS during the pandemic vs prepandemic periods. Continuous outcome variables—Mohs stages, preoperative size, postoperative size, and patient age—were categorized for the analysis. Preoperative tumor size was dichotomized, with less than 2 cm² as the referent category vs 2 cm² or greater, and postoperative defect size was dichotomized with less than 3.6 cm² as the referent category vs 3.6 cm² or greater. Mohs stage was dichotomized as 1 stage (referent) vs more than 1 stage, and patient age was dichotomized as younger than 65 years (referent) vs 65 years or older.

Multivariate analyses were also performed to compare preoperative and postoperative sizes for patients undergoing MMS during the pandemic vs prepandemic periods, controlling for Mohs AUC location. Bivariate unadjusted and multivariate analyses were performed using a GENMOD logistic regression procedure in SAS (SAS Institute) to account for correlation in clustered data because a patient could be included for more than 1 surgery in the data set. Data were analyzed using SAS 9.4 for Windows. Because outcome variables tended to be skewed and not distributed normally, outcome variables were recorded as medians with interquartile ranges where possible to give a more accurate representation of the data than could be demonstrated with means with standard deviations.

Results

One hundred thirty-eight skin cancers were treated during the COVID-19 pandemic from March 15, 2020, to April 30, 2020, and 378 skin cancers were treated during the prepandemic control periods of March 15, 2019, to April 30, 2019, and March 15, 2018, to April 30, 2018. Tumor type treated during the pandemic period was more likely to be SCC or MIS (representing generally more severe tumor types) vs BCC when compared with the prepandemic periods, with an odds ratio (OR) of 1.763 (95% CI, 1.17-2.66). This outcome was statistically significant (P=.01).

Tumors treated during the pandemic period were more likely to have necessitated more than one Mohs stage for clearance compared to the prepandemic periods, though this difference was not statistically significant (OR, 1.461; 95% CI, 0.97-2.19; P=.056). Neither AUC location of treated tumors nor age were significantly different between prepandemic and pandemic periods (P=.58 and P=.84, respectively). Table 1 includes all bivariate analysis results.

Additionally, although mean preoperative and postoperative sizes were larger for each AUC location during the pandemic vs prepandemic periods, these differences did not reach statistical significance on multivariate analysis (P=.71 and P=.50, respectively)(Table 2).

Our practice has followed best practice guidelines dictated by our governing professional societies during the COVID-19 pandemic in the treatment of skin cancers by MMS, specifically highly symptomatic BCCs (in accordance with ACMS guidance), SCCs with high-risk features (in accordance with AAD, ACMS, and TDS guidance), and tumors with high risk for progression and metastasis such as melanomas (in accordance with TDS guidance). Melanoma in situ was also treated during the COVID-19 pandemic in accordance with the latter TDS guidance, particularly in light of the potential for upstaging to melanoma following resection (a phenomenon demonstrated to occur in 5%–29% of biopsied MIS lesions).¹⁴

In following best practice guidelines, our results suggested tumors treated by MMS were more severe, as evidenced by a statistically significant higher proportion of SCC and MIS tumors (representing more severe tumor types) vs BCC when compared to the prepandemic period. Supporting this conclusion, we observed larger pretreatment and posttreatment tumor sizes for all AUC locations and more tumors necessitating 2 or more stages for clearance during the pandemic vs prepandemic periods, though these differences did not reach statistical significance. We postulate these findings may be attributed to allocation of finite medical resources to the treatment of larger and more aggressive skin cancers. Additionally, these findings may be explained, in part, by limitations on patient case load imposed by social distancing measures and governing body regulations in effect during the study period, including those put forth by the AAD, ACMS, and TDS. Of note, our practice observed no hospitalizations or 911 calls during the studied period. This suggests no allocation of precious hospital resources away from patients with COVID-19 in our treatment of high-risk skin cancers.

The changing characteristics of cutaneous tumors treated by MMS during the pandemic are of clinical relevance. Larger postoperative wound sizes as observed during the pandemic, albeit not statistically significant, presumably affect reconstructive decisions. With larger wounds tending to necessitate repair by techniques higher on the reconstructive ladder, greater patient morbidity and cost are expected.¹⁵ As the cost-effectiveness of dermatology services remains a critical issue, this is an area ripe for future follow-up research. Furthermore, our observation that tumors tended to necessitate 2 or more stages for clearance during the pandemic more often than prepandemic periods, though not statistically significant, presumably affected operating times. Longer operating times during the pandemic may be of importance when making clinical decisions for patients for whom limiting health care exposure may be of particular concern. With more SCC and MIS tumors being treated relative to BCCs during the pandemic, one might expect greater size and severity of the BCCs we observe in the proceeding months to years.

As the ongoing COVID-19 pandemic continues to impact the landscape of cutaneous oncology, the need for adaptability is imperative. With 3- and 6-month skin cancer treatment deferrals lapsed, uncertainty surrounds ideal management of existing and new skin cancers arising during the pandemic. This study adds to a growing body of literature elucidating the impact of the COVID-19 pandemic on MMS practice; however, further studies and a tincture of time are needed to guide future best practice standards.

Acknowledgment—The authors acknowledge Gwen Baillargeon, MS (Galveston, Texas), who was the statistician for this article.

The COVID-19 pandemic has brought about unprecedented changes and challenges to medical practice, including new public health measure legislation, local and national medical authority recommendations, nursing home and other ancillary health center protocols, and novel clinical decision-making considerations.^1-3 In July 2020, the American Academy of Dermatology (AAD) addressed the changing landscape in dermatologic surgery, in part, by publishing recommendations on practice protocols during the COVID-19 pandemic.⁴ The guidelines recommended deferred treatment of superficial basal cell carcinomas (BCCs) for 6 months and all other BCC subtypes for 3 to 6 months. Furthermore, the guidelines recommended deferring treatment of all actinic keratoses and squamous cell carcinomas (SCCs) in situ “for now.” Squamous cell carcinoma treatment was to be guided by prognostic variables, such as location, size, depth, differentiation, perineural or lymphovascular invasion, recurrence, and immunosuppression. The guidelines recommended melanoma in situ (MIS) treatment be deferred for 3 months and invasive melanoma with histologic clearance obtained on excisional biopsy for 3 months. Other general recommendations included triaging clinics, rebooking according to clinical priority, using telehealth where possible, screening patients for COVID-19 signs and symptoms, staggering appointment times, spacing patient chairs, limiting support persons to 1, removing possible sources of infection in the waiting room, ensuring all patients sanitized their hands on arrival, rationing personal protective equipment, considering N95 masks for periorificial surgery, and using dissolving sutures to minimize multiple presentations.⁴

The American College of Mohs Surgery (ACMS), with guidance from its sister societies and the National Comprehensive Cancer Network, also communicated COVID-19–related recommendations to its members via intermittent newsletters during the initial peak of the pandemic in March and June 2020.⁵ General social distancing and office recommendations were similar to those released by the AAD. Recommendations for skin cancer treatment included deferring all BCCs for up to 3 months, with exceptions for highly symptomatic cancers and those with potential for substantial rapid growth. Squamous cell carcinoma in situ and small, well-differentiated SCCs were deferred, with priority placed on SCCs that were rapidly enlarging, poorly differentiated, demonstrated perineural invasion, were ulcerated, or were symptomatic. Patients with major risk factors were prioritized for treatment. Melanoma in situ was deferred for 2 to 3 months.⁵

State-level guidance from the Texas Dermatological Society (TDS) communicated in April 2020 stated that skin cancers with a potential for rapid progression and metastasis, such as melanoma and SCC, may require treatment as determined by the physician.⁶ The potential risk of serious adverse medical outcomes from not treating these cancers should be carefully documented. General practice measures for preventing the spread of COVID-19 were also recommended.⁶

In the setting of emerging novel recommendations, the practice of Mohs micrographic surgery (MMS) was notably impacted by the COVID-19 pandemic. According to one survey study from the United Kingdom conducted in April and May 2020, 49% of MMS services ceased and 36% were reduced during the infancy of the COVID-19 pandemic.⁷ Mohs micrographic surgery was largely suspended because of a lack of personal protective equipment and safety concerns, according to respondents. Additionally, respondents reported 77% of departments experienced redeployment of physicians and nurses to intensive care and medical wards. Thirty-five percent reported a reduction in the proportion of flaps/grafts to primary closures performed, 74% reported a decrease in outside referrals for repair by other specialties, 81% reported increased usage of dissolvable sutures, and 29% reported an increase in prophylactic antibiotic prescriptions.⁷ Another study from Italy reported a 46.5% reduction in dermatologic surgeries performed during the initial lockdown of the COVID-19 pandemic. Patients canceled 52.9% of procedures, and 12.5% were cancelled because of confirmed or suspected COVID-19 infection.⁸ Patient perceptions of MMS have also been impacted by the COVID-19 pandemic. According to a survey study of patients in the United Kingdom undergoing MMS during the pandemic, 47% were worried the hospital would cancel their surgery, 54% were anxious about using public transportation to attend their appointment, 30% were concerned about transmitting COVID-19 to household or family members, and 19% were worried about their ability to socially distance in the hospital.⁹

Evidence is also emerging that suggests the potential negative impact of the COVID-19 pandemic on morbidity and mortality outcomes in patients with skin cancer. One European study found an increase in Breslow thickness in primary melanomas diagnosed following the initial COVID-19 lockdown (0.88-mm average thickness prelockdown vs 1.96-mm average thickness postlockdown).¹⁰ An Italian study observed similar results—an increase in median Breslow thickness during the initial COVID-19 lockdown period of 0.5 mm from 0.4 mm during the prelockdown time period.¹¹ Also providing evidence for potentially poor patient outcomes, one study modeled the impact of backlog in cutaneous melanoma referrals in the United Kingdom on patient survival and predicted 138 attributable lives lost for a 1-month delay and 1171 lives lost for a 6-month delay. The model further predicted a 3.1% to 12.5% reduction in 10-year net survival incurred from a 3-month delay in melanoma treatment, with the largest reduction seen in the patient population older than 80 years.¹²

Although the COVID-19 pandemic has been observed to impact MMS practice, patient perceptions, and clinical outcomes, it is unknown how the COVID-19 pandemic and corresponding rapidly evolving recommendations in dermatologic surgery have impacted the characteristics of cutaneous tumors treated by MMS.

Our study sought to determine the characteristics of skin cancers treated by MMS during the peak of government-mandated medical practice restrictions and business shutdowns in response to the COVID-19 pandemic and to compare them with characteristics of skin cancers treated during a prepandemic control period.

Methods

A retrospective chart review was conducted with approval from our institutional review board at the University of Texas Medical Branch (Galveston, Texas). Included in the chart review were all cutaneous malignancies treated by MMS at our outpatient, office-based surgical center from March 15, 2020, to April 30, 2020; this period corresponded to the peak of the COVID-19–related government-mandated medical and business shutdowns in our geographic region (southeast Texas). All cases performed were in compliance with national- and state-level guidance. Data were also collected for all cutaneous malignancies treated by MMS at our office from March 15, 2019, to April 30, 2019, as well as March 15, 2018, to April 30, 2018; these periods represented prepandemic control periods.

Data were collected for 516 surgeries performed on 458 patients and included patient age, preoperative clinical size, postoperative defect size, number of Mohs stages to achieve clearance, MMS appropriate use criteria (AUC) location (categorized as high-, medium-, or low-risk tumor location),¹³ and tumor type (categorized as BCC, SCC, or MIS). All variables were examined for unusual or missing values. Five patients with rare tumor types were observed and removed from the data set.

Statistical Analysis—An a priori power analysis for a power set at 0.85 determined sample sizes of 105 per group. Bivariate analyses were performed to compare variables for patients undergoing MMS during the pandemic vs prepandemic periods. Continuous outcome variables—Mohs stages, preoperative size, postoperative size, and patient age—were categorized for the analysis. Preoperative tumor size was dichotomized, with less than 2 cm² as the referent category vs 2 cm² or greater, and postoperative defect size was dichotomized with less than 3.6 cm² as the referent category vs 3.6 cm² or greater. Mohs stage was dichotomized as 1 stage (referent) vs more than 1 stage, and patient age was dichotomized as younger than 65 years (referent) vs 65 years or older.

Multivariate analyses were also performed to compare preoperative and postoperative sizes for patients undergoing MMS during the pandemic vs prepandemic periods, controlling for Mohs AUC location. Bivariate unadjusted and multivariate analyses were performed using a GENMOD logistic regression procedure in SAS (SAS Institute) to account for correlation in clustered data because a patient could be included for more than 1 surgery in the data set. Data were analyzed using SAS 9.4 for Windows. Because outcome variables tended to be skewed and not distributed normally, outcome variables were recorded as medians with interquartile ranges where possible to give a more accurate representation of the data than could be demonstrated with means with standard deviations.

Results

One hundred thirty-eight skin cancers were treated during the COVID-19 pandemic from March 15, 2020, to April 30, 2020, and 378 skin cancers were treated during the prepandemic control periods of March 15, 2019, to April 30, 2019, and March 15, 2018, to April 30, 2018. Tumor type treated during the pandemic period was more likely to be SCC or MIS (representing generally more severe tumor types) vs BCC when compared with the prepandemic periods, with an odds ratio (OR) of 1.763 (95% CI, 1.17-2.66). This outcome was statistically significant (P=.01).

Tumors treated during the pandemic period were more likely to have necessitated more than one Mohs stage for clearance compared to the prepandemic periods, though this difference was not statistically significant (OR, 1.461; 95% CI, 0.97-2.19; P=.056). Neither AUC location of treated tumors nor age were significantly different between prepandemic and pandemic periods (P=.58 and P=.84, respectively). Table 1 includes all bivariate analysis results.

Additionally, although mean preoperative and postoperative sizes were larger for each AUC location during the pandemic vs prepandemic periods, these differences did not reach statistical significance on multivariate analysis (P=.71 and P=.50, respectively)(Table 2).

Our practice has followed best practice guidelines dictated by our governing professional societies during the COVID-19 pandemic in the treatment of skin cancers by MMS, specifically highly symptomatic BCCs (in accordance with ACMS guidance), SCCs with high-risk features (in accordance with AAD, ACMS, and TDS guidance), and tumors with high risk for progression and metastasis such as melanomas (in accordance with TDS guidance). Melanoma in situ was also treated during the COVID-19 pandemic in accordance with the latter TDS guidance, particularly in light of the potential for upstaging to melanoma following resection (a phenomenon demonstrated to occur in 5%–29% of biopsied MIS lesions).¹⁴

In following best practice guidelines, our results suggested tumors treated by MMS were more severe, as evidenced by a statistically significant higher proportion of SCC and MIS tumors (representing more severe tumor types) vs BCC when compared to the prepandemic period. Supporting this conclusion, we observed larger pretreatment and posttreatment tumor sizes for all AUC locations and more tumors necessitating 2 or more stages for clearance during the pandemic vs prepandemic periods, though these differences did not reach statistical significance. We postulate these findings may be attributed to allocation of finite medical resources to the treatment of larger and more aggressive skin cancers. Additionally, these findings may be explained, in part, by limitations on patient case load imposed by social distancing measures and governing body regulations in effect during the study period, including those put forth by the AAD, ACMS, and TDS. Of note, our practice observed no hospitalizations or 911 calls during the studied period. This suggests no allocation of precious hospital resources away from patients with COVID-19 in our treatment of high-risk skin cancers.

The changing characteristics of cutaneous tumors treated by MMS during the pandemic are of clinical relevance. Larger postoperative wound sizes as observed during the pandemic, albeit not statistically significant, presumably affect reconstructive decisions. With larger wounds tending to necessitate repair by techniques higher on the reconstructive ladder, greater patient morbidity and cost are expected.¹⁵ As the cost-effectiveness of dermatology services remains a critical issue, this is an area ripe for future follow-up research. Furthermore, our observation that tumors tended to necessitate 2 or more stages for clearance during the pandemic more often than prepandemic periods, though not statistically significant, presumably affected operating times. Longer operating times during the pandemic may be of importance when making clinical decisions for patients for whom limiting health care exposure may be of particular concern. With more SCC and MIS tumors being treated relative to BCCs during the pandemic, one might expect greater size and severity of the BCCs we observe in the proceeding months to years.

As the ongoing COVID-19 pandemic continues to impact the landscape of cutaneous oncology, the need for adaptability is imperative. With 3- and 6-month skin cancer treatment deferrals lapsed, uncertainty surrounds ideal management of existing and new skin cancers arising during the pandemic. This study adds to a growing body of literature elucidating the impact of the COVID-19 pandemic on MMS practice; however, further studies and a tincture of time are needed to guide future best practice standards.

Acknowledgment—The authors acknowledge Gwen Baillargeon, MS (Galveston, Texas), who was the statistician for this article.

The COVID-19 pandemic has brought about unprecedented changes and challenges to medical practice, including new public health measure legislation, local and national medical authority recommendations, nursing home and other ancillary health center protocols, and novel clinical decision-making considerations.^1-3 In July 2020, the American Academy of Dermatology (AAD) addressed the changing landscape in dermatologic surgery, in part, by publishing recommendations on practice protocols during the COVID-19 pandemic.⁴ The guidelines recommended deferred treatment of superficial basal cell carcinomas (BCCs) for 6 months and all other BCC subtypes for 3 to 6 months. Furthermore, the guidelines recommended deferring treatment of all actinic keratoses and squamous cell carcinomas (SCCs) in situ “for now.” Squamous cell carcinoma treatment was to be guided by prognostic variables, such as location, size, depth, differentiation, perineural or lymphovascular invasion, recurrence, and immunosuppression. The guidelines recommended melanoma in situ (MIS) treatment be deferred for 3 months and invasive melanoma with histologic clearance obtained on excisional biopsy for 3 months. Other general recommendations included triaging clinics, rebooking according to clinical priority, using telehealth where possible, screening patients for COVID-19 signs and symptoms, staggering appointment times, spacing patient chairs, limiting support persons to 1, removing possible sources of infection in the waiting room, ensuring all patients sanitized their hands on arrival, rationing personal protective equipment, considering N95 masks for periorificial surgery, and using dissolving sutures to minimize multiple presentations.⁴

The American College of Mohs Surgery (ACMS), with guidance from its sister societies and the National Comprehensive Cancer Network, also communicated COVID-19–related recommendations to its members via intermittent newsletters during the initial peak of the pandemic in March and June 2020.⁵ General social distancing and office recommendations were similar to those released by the AAD. Recommendations for skin cancer treatment included deferring all BCCs for up to 3 months, with exceptions for highly symptomatic cancers and those with potential for substantial rapid growth. Squamous cell carcinoma in situ and small, well-differentiated SCCs were deferred, with priority placed on SCCs that were rapidly enlarging, poorly differentiated, demonstrated perineural invasion, were ulcerated, or were symptomatic. Patients with major risk factors were prioritized for treatment. Melanoma in situ was deferred for 2 to 3 months.⁵

State-level guidance from the Texas Dermatological Society (TDS) communicated in April 2020 stated that skin cancers with a potential for rapid progression and metastasis, such as melanoma and SCC, may require treatment as determined by the physician.⁶ The potential risk of serious adverse medical outcomes from not treating these cancers should be carefully documented. General practice measures for preventing the spread of COVID-19 were also recommended.⁶

In the setting of emerging novel recommendations, the practice of Mohs micrographic surgery (MMS) was notably impacted by the COVID-19 pandemic. According to one survey study from the United Kingdom conducted in April and May 2020, 49% of MMS services ceased and 36% were reduced during the infancy of the COVID-19 pandemic.⁷ Mohs micrographic surgery was largely suspended because of a lack of personal protective equipment and safety concerns, according to respondents. Additionally, respondents reported 77% of departments experienced redeployment of physicians and nurses to intensive care and medical wards. Thirty-five percent reported a reduction in the proportion of flaps/grafts to primary closures performed, 74% reported a decrease in outside referrals for repair by other specialties, 81% reported increased usage of dissolvable sutures, and 29% reported an increase in prophylactic antibiotic prescriptions.⁷ Another study from Italy reported a 46.5% reduction in dermatologic surgeries performed during the initial lockdown of the COVID-19 pandemic. Patients canceled 52.9% of procedures, and 12.5% were cancelled because of confirmed or suspected COVID-19 infection.⁸ Patient perceptions of MMS have also been impacted by the COVID-19 pandemic. According to a survey study of patients in the United Kingdom undergoing MMS during the pandemic, 47% were worried the hospital would cancel their surgery, 54% were anxious about using public transportation to attend their appointment, 30% were concerned about transmitting COVID-19 to household or family members, and 19% were worried about their ability to socially distance in the hospital.⁹

Evidence is also emerging that suggests the potential negative impact of the COVID-19 pandemic on morbidity and mortality outcomes in patients with skin cancer. One European study found an increase in Breslow thickness in primary melanomas diagnosed following the initial COVID-19 lockdown (0.88-mm average thickness prelockdown vs 1.96-mm average thickness postlockdown).¹⁰ An Italian study observed similar results—an increase in median Breslow thickness during the initial COVID-19 lockdown period of 0.5 mm from 0.4 mm during the prelockdown time period.¹¹ Also providing evidence for potentially poor patient outcomes, one study modeled the impact of backlog in cutaneous melanoma referrals in the United Kingdom on patient survival and predicted 138 attributable lives lost for a 1-month delay and 1171 lives lost for a 6-month delay. The model further predicted a 3.1% to 12.5% reduction in 10-year net survival incurred from a 3-month delay in melanoma treatment, with the largest reduction seen in the patient population older than 80 years.¹²

Although the COVID-19 pandemic has been observed to impact MMS practice, patient perceptions, and clinical outcomes, it is unknown how the COVID-19 pandemic and corresponding rapidly evolving recommendations in dermatologic surgery have impacted the characteristics of cutaneous tumors treated by MMS.

Our study sought to determine the characteristics of skin cancers treated by MMS during the peak of government-mandated medical practice restrictions and business shutdowns in response to the COVID-19 pandemic and to compare them with characteristics of skin cancers treated during a prepandemic control period.

Methods

A retrospective chart review was conducted with approval from our institutional review board at the University of Texas Medical Branch (Galveston, Texas). Included in the chart review were all cutaneous malignancies treated by MMS at our outpatient, office-based surgical center from March 15, 2020, to April 30, 2020; this period corresponded to the peak of the COVID-19–related government-mandated medical and business shutdowns in our geographic region (southeast Texas). All cases performed were in compliance with national- and state-level guidance. Data were also collected for all cutaneous malignancies treated by MMS at our office from March 15, 2019, to April 30, 2019, as well as March 15, 2018, to April 30, 2018; these periods represented prepandemic control periods.

Data were collected for 516 surgeries performed on 458 patients and included patient age, preoperative clinical size, postoperative defect size, number of Mohs stages to achieve clearance, MMS appropriate use criteria (AUC) location (categorized as high-, medium-, or low-risk tumor location),¹³ and tumor type (categorized as BCC, SCC, or MIS). All variables were examined for unusual or missing values. Five patients with rare tumor types were observed and removed from the data set.

Statistical Analysis—An a priori power analysis for a power set at 0.85 determined sample sizes of 105 per group. Bivariate analyses were performed to compare variables for patients undergoing MMS during the pandemic vs prepandemic periods. Continuous outcome variables—Mohs stages, preoperative size, postoperative size, and patient age—were categorized for the analysis. Preoperative tumor size was dichotomized, with less than 2 cm² as the referent category vs 2 cm² or greater, and postoperative defect size was dichotomized with less than 3.6 cm² as the referent category vs 3.6 cm² or greater. Mohs stage was dichotomized as 1 stage (referent) vs more than 1 stage, and patient age was dichotomized as younger than 65 years (referent) vs 65 years or older.

Multivariate analyses were also performed to compare preoperative and postoperative sizes for patients undergoing MMS during the pandemic vs prepandemic periods, controlling for Mohs AUC location. Bivariate unadjusted and multivariate analyses were performed using a GENMOD logistic regression procedure in SAS (SAS Institute) to account for correlation in clustered data because a patient could be included for more than 1 surgery in the data set. Data were analyzed using SAS 9.4 for Windows. Because outcome variables tended to be skewed and not distributed normally, outcome variables were recorded as medians with interquartile ranges where possible to give a more accurate representation of the data than could be demonstrated with means with standard deviations.

Results

One hundred thirty-eight skin cancers were treated during the COVID-19 pandemic from March 15, 2020, to April 30, 2020, and 378 skin cancers were treated during the prepandemic control periods of March 15, 2019, to April 30, 2019, and March 15, 2018, to April 30, 2018. Tumor type treated during the pandemic period was more likely to be SCC or MIS (representing generally more severe tumor types) vs BCC when compared with the prepandemic periods, with an odds ratio (OR) of 1.763 (95% CI, 1.17-2.66). This outcome was statistically significant (P=.01).

Tumors treated during the pandemic period were more likely to have necessitated more than one Mohs stage for clearance compared to the prepandemic periods, though this difference was not statistically significant (OR, 1.461; 95% CI, 0.97-2.19; P=.056). Neither AUC location of treated tumors nor age were significantly different between prepandemic and pandemic periods (P=.58 and P=.84, respectively). Table 1 includes all bivariate analysis results.

Additionally, although mean preoperative and postoperative sizes were larger for each AUC location during the pandemic vs prepandemic periods, these differences did not reach statistical significance on multivariate analysis (P=.71 and P=.50, respectively)(Table 2).

Our practice has followed best practice guidelines dictated by our governing professional societies during the COVID-19 pandemic in the treatment of skin cancers by MMS, specifically highly symptomatic BCCs (in accordance with ACMS guidance), SCCs with high-risk features (in accordance with AAD, ACMS, and TDS guidance), and tumors with high risk for progression and metastasis such as melanomas (in accordance with TDS guidance). Melanoma in situ was also treated during the COVID-19 pandemic in accordance with the latter TDS guidance, particularly in light of the potential for upstaging to melanoma following resection (a phenomenon demonstrated to occur in 5%–29% of biopsied MIS lesions).¹⁴

In following best practice guidelines, our results suggested tumors treated by MMS were more severe, as evidenced by a statistically significant higher proportion of SCC and MIS tumors (representing more severe tumor types) vs BCC when compared to the prepandemic period. Supporting this conclusion, we observed larger pretreatment and posttreatment tumor sizes for all AUC locations and more tumors necessitating 2 or more stages for clearance during the pandemic vs prepandemic periods, though these differences did not reach statistical significance. We postulate these findings may be attributed to allocation of finite medical resources to the treatment of larger and more aggressive skin cancers. Additionally, these findings may be explained, in part, by limitations on patient case load imposed by social distancing measures and governing body regulations in effect during the study period, including those put forth by the AAD, ACMS, and TDS. Of note, our practice observed no hospitalizations or 911 calls during the studied period. This suggests no allocation of precious hospital resources away from patients with COVID-19 in our treatment of high-risk skin cancers.

The changing characteristics of cutaneous tumors treated by MMS during the pandemic are of clinical relevance. Larger postoperative wound sizes as observed during the pandemic, albeit not statistically significant, presumably affect reconstructive decisions. With larger wounds tending to necessitate repair by techniques higher on the reconstructive ladder, greater patient morbidity and cost are expected.¹⁵ As the cost-effectiveness of dermatology services remains a critical issue, this is an area ripe for future follow-up research. Furthermore, our observation that tumors tended to necessitate 2 or more stages for clearance during the pandemic more often than prepandemic periods, though not statistically significant, presumably affected operating times. Longer operating times during the pandemic may be of importance when making clinical decisions for patients for whom limiting health care exposure may be of particular concern. With more SCC and MIS tumors being treated relative to BCCs during the pandemic, one might expect greater size and severity of the BCCs we observe in the proceeding months to years.

As the ongoing COVID-19 pandemic continues to impact the landscape of cutaneous oncology, the need for adaptability is imperative. With 3- and 6-month skin cancer treatment deferrals lapsed, uncertainty surrounds ideal management of existing and new skin cancers arising during the pandemic. This study adds to a growing body of literature elucidating the impact of the COVID-19 pandemic on MMS practice; however, further studies and a tincture of time are needed to guide future best practice standards.

Acknowledgment—The authors acknowledge Gwen Baillargeon, MS (Galveston, Texas), who was the statistician for this article.

Melanomas have been designated as small melanomas or micromelanomas according to their long-axis diameter (<6 mm and ≤3 mm, respectively).^1-3 Because small-diameter melanomas also have the potential to metastasize, particularly if nodular, early diagnosis can be highly rewarding. Deep melanomas with small diameters may have the same potential for metastasis as large-diameter melanomas. In this context, dermoscopy, digital dermoscopic monitoring, and total-body photography are useful in clinical practice. However, these techniques are of limited utility for small, dermoscopic feature–poor melanomas. Conversely, less than 10% of changing lesions, which are spotted via digital dermoscopic surveillance, turn out to be melanomas; therefore, simply removing all changing lesions may result in many unnecessary excisions of benign lesions.⁴

In vivo reflectance confocal microscopy (RCM) is an advanced technique that allows recognition of the architectural and cellular details of pigmented lesions. Reflectance confocal microscopy has the potential to reduce the rate of unnecessary excisions and to diminish the risk for missing a melanoma.^5-7 In meta-analyses, RCM sensitivity was reported as 90% to 93% and specificity was reported as 78% to 82% in detecting melanoma.^8,9

We describe a case that highlights the potential role of RCM in the diagnosis of small-diameter melanomas.

Case Report

A 57-year-old man with Fitzpatrick skin type III presented to the dermato-oncology unit for evaluation of multiple nevi. He was otherwise healthy and denied a history of skin cancer. Total-body skin examination with dermoscopy was performed, and several mildly atypical lesions were identified. We decided to perform digital dermoscopic monitoring. The patient’s 6-month monitoring appointment had been scheduled, but he did not arrive for the follow-up visit until 10 months after the initial examination. A lesion on the left arm, which initially was 1.5 mm in diameter, had enlarged. It was now a dark brown–gray papule with a 2.5-mm diameter (Figure 1). Dermoscopy revealed grayish globules/dots at the center of the lesion, reticular gray-blue areas, and few milialike cysts; at the periphery, a narrow rim of brownish delicate pigment network also was seen (Figure 2). The clinical and dermoscopic differential diagnosis was either an atypical nevus or an early melanoma. For a more precise diagnosis before excision, the lesion was evaluated with RCM, which takes 10 to 15 minutes to perform.

Under RCM at the epidermis level, there was a cobblestone pattern that showed a focus with mild disarrangement and few small, roundish, nucleated cells (Figure 3). A mosaic image, akin to low-magnification microscopy that enables overview of the entire lesion, at the level of the dermoepidermal junction (DEJ) showed an overall irregular meshwork pattern. Higher-magnification optical sections showed marked and diffuse (extending >10% of lesion area) architectural disorder with confluent junctional nests that were irregular to bizarre in shape and uneven in size and spacing as well as edged and nonedged papillae. At the superficial dermal level, atypical bright nucleated cells (>5 cells/mm²) were observed (Figure 4). Bright dots and/or plump bright cells within papillae also were observed. These RCM findings were highly suggestive for melanoma.

Histopathology showed an asymmetric, junctional, lentiginous, and nested proliferation of atypical epithelioid melanocytes, with few melanocytes in a pagetoid spread. There were small nests of atypical epithelioid melanocytes at the superficial dermis extending to a depth of 0.3 mm. The atypical epithelioid melanocytes displayed angulated hyperchromatic nuclei with conspicuous nucleoli and dusty brown cytoplasm. There was notable inflammation and pigment incontinence at the dermis. There was no evidence of ulceration or mitosis at the dermal component. The diagnosis of a pT1a malignant melanoma was reported (Figure 5).

Comment

A small but enlarging dark gray papule with reticular gray-blue areas under dermoscopy in a 57-year-old man is obviously suspicious for melanoma. In daily practice, this type of small-diameter melanoma is difficult to diagnose with high confidence. We balance our aim to diagnose melanomas early with the need to reduce unnecessary excisions. Reflectance confocal microscopy may allow the clinician to arrive at the correct diagnosis and management decision with confidence before excision of the lesion.

The distinction of a small-diameter melanoma from a nevus via RCM relies on evaluation of the architectural and cellular features. Findings on RCM in small-diameter melanomas have been scarcely reported in the literature; Pupelli et al¹⁰ evaluated small melanomas with a diameter of 2 to 5 mm. Among these small-diameter melanomas, the RCM features suggestive for melanomas were the presence of cytologic atypia with cellular pleomorphism, architectural disorder with irregular nests, at least 5 pagetoid cells/mm², dendrites or tangled lines (ie, short fine lines with no visible nucleus interlacing with the adjacent keratinocytes) within the epidermis, and atypical roundish cells at the DEJ.¹⁰

The distinction between an atypical nevus and a small-diameter melanoma using RCM occasionally may be challenging.¹¹ Pellacani et al¹² reported an algorithm to distinguish melanoma from atypical nevi. According to this algorithm, when at least 1 of the architectural atypia features (irregular junctional nests, short interconnections between junctional nests, and nonhomogeneous cellularity within junctional nests) and at least 1 of the cytologic atypia features (round pagetoid cells or atypical cells at the DEJ) are observed simultaneously, the lesion is diagnosed as a dysplastic nevus or a melanoma in the first step. In the second step, the RCM diagnosis of melanoma requires at least 1 of 3 parameters: roundish pagetoid cells encompassing at least 50% of the lesional area at the spinous layer, atypical cells involving at least 50% of the lesional area at the DEJ level, and nonedged papillae involving at least 10% of the lesional area.¹² Accordingly, our case corresponded with these RCM criteria for a melanoma, given that there were irregular junctional nests, atypical cells at the DEJ, and nonedged papillae involving at least 10% of the lesion.

The current limitations of RCM are the high cost of the device (approximately $58,125–$139,400 for different models), the amount of time needed to train staff in RCM units (seminars, congresses, and special courses organized by the International Confocal Working Group), and the amount of time needed for evaluation of individual lesions (15–20 minutes). However, RCM can be valuable in the clinical diagnosis of difficult lesions, as seen in our case.

Conclusion

Our case highlights the benefit of RCM in allowing the confident diagnosis and correct management of a small-diameter melanoma that turned out to be a melanoma with 0.3-mm Breslow thickness. Even so, histopathologic evaluation remains the gold standard for the diagnosis of melanoma.

Melanomas have been designated as small melanomas or micromelanomas according to their long-axis diameter (<6 mm and ≤3 mm, respectively).^1-3 Because small-diameter melanomas also have the potential to metastasize, particularly if nodular, early diagnosis can be highly rewarding. Deep melanomas with small diameters may have the same potential for metastasis as large-diameter melanomas. In this context, dermoscopy, digital dermoscopic monitoring, and total-body photography are useful in clinical practice. However, these techniques are of limited utility for small, dermoscopic feature–poor melanomas. Conversely, less than 10% of changing lesions, which are spotted via digital dermoscopic surveillance, turn out to be melanomas; therefore, simply removing all changing lesions may result in many unnecessary excisions of benign lesions.⁴

In vivo reflectance confocal microscopy (RCM) is an advanced technique that allows recognition of the architectural and cellular details of pigmented lesions. Reflectance confocal microscopy has the potential to reduce the rate of unnecessary excisions and to diminish the risk for missing a melanoma.^5-7 In meta-analyses, RCM sensitivity was reported as 90% to 93% and specificity was reported as 78% to 82% in detecting melanoma.^8,9

We describe a case that highlights the potential role of RCM in the diagnosis of small-diameter melanomas.

Case Report

A 57-year-old man with Fitzpatrick skin type III presented to the dermato-oncology unit for evaluation of multiple nevi. He was otherwise healthy and denied a history of skin cancer. Total-body skin examination with dermoscopy was performed, and several mildly atypical lesions were identified. We decided to perform digital dermoscopic monitoring. The patient’s 6-month monitoring appointment had been scheduled, but he did not arrive for the follow-up visit until 10 months after the initial examination. A lesion on the left arm, which initially was 1.5 mm in diameter, had enlarged. It was now a dark brown–gray papule with a 2.5-mm diameter (Figure 1). Dermoscopy revealed grayish globules/dots at the center of the lesion, reticular gray-blue areas, and few milialike cysts; at the periphery, a narrow rim of brownish delicate pigment network also was seen (Figure 2). The clinical and dermoscopic differential diagnosis was either an atypical nevus or an early melanoma. For a more precise diagnosis before excision, the lesion was evaluated with RCM, which takes 10 to 15 minutes to perform.

Under RCM at the epidermis level, there was a cobblestone pattern that showed a focus with mild disarrangement and few small, roundish, nucleated cells (Figure 3). A mosaic image, akin to low-magnification microscopy that enables overview of the entire lesion, at the level of the dermoepidermal junction (DEJ) showed an overall irregular meshwork pattern. Higher-magnification optical sections showed marked and diffuse (extending >10% of lesion area) architectural disorder with confluent junctional nests that were irregular to bizarre in shape and uneven in size and spacing as well as edged and nonedged papillae. At the superficial dermal level, atypical bright nucleated cells (>5 cells/mm²) were observed (Figure 4). Bright dots and/or plump bright cells within papillae also were observed. These RCM findings were highly suggestive for melanoma.

Histopathology showed an asymmetric, junctional, lentiginous, and nested proliferation of atypical epithelioid melanocytes, with few melanocytes in a pagetoid spread. There were small nests of atypical epithelioid melanocytes at the superficial dermis extending to a depth of 0.3 mm. The atypical epithelioid melanocytes displayed angulated hyperchromatic nuclei with conspicuous nucleoli and dusty brown cytoplasm. There was notable inflammation and pigment incontinence at the dermis. There was no evidence of ulceration or mitosis at the dermal component. The diagnosis of a pT1a malignant melanoma was reported (Figure 5).

Comment

A small but enlarging dark gray papule with reticular gray-blue areas under dermoscopy in a 57-year-old man is obviously suspicious for melanoma. In daily practice, this type of small-diameter melanoma is difficult to diagnose with high confidence. We balance our aim to diagnose melanomas early with the need to reduce unnecessary excisions. Reflectance confocal microscopy may allow the clinician to arrive at the correct diagnosis and management decision with confidence before excision of the lesion.

The distinction of a small-diameter melanoma from a nevus via RCM relies on evaluation of the architectural and cellular features. Findings on RCM in small-diameter melanomas have been scarcely reported in the literature; Pupelli et al¹⁰ evaluated small melanomas with a diameter of 2 to 5 mm. Among these small-diameter melanomas, the RCM features suggestive for melanomas were the presence of cytologic atypia with cellular pleomorphism, architectural disorder with irregular nests, at least 5 pagetoid cells/mm², dendrites or tangled lines (ie, short fine lines with no visible nucleus interlacing with the adjacent keratinocytes) within the epidermis, and atypical roundish cells at the DEJ.¹⁰

The distinction between an atypical nevus and a small-diameter melanoma using RCM occasionally may be challenging.¹¹ Pellacani et al¹² reported an algorithm to distinguish melanoma from atypical nevi. According to this algorithm, when at least 1 of the architectural atypia features (irregular junctional nests, short interconnections between junctional nests, and nonhomogeneous cellularity within junctional nests) and at least 1 of the cytologic atypia features (round pagetoid cells or atypical cells at the DEJ) are observed simultaneously, the lesion is diagnosed as a dysplastic nevus or a melanoma in the first step. In the second step, the RCM diagnosis of melanoma requires at least 1 of 3 parameters: roundish pagetoid cells encompassing at least 50% of the lesional area at the spinous layer, atypical cells involving at least 50% of the lesional area at the DEJ level, and nonedged papillae involving at least 10% of the lesional area.¹² Accordingly, our case corresponded with these RCM criteria for a melanoma, given that there were irregular junctional nests, atypical cells at the DEJ, and nonedged papillae involving at least 10% of the lesion.

The current limitations of RCM are the high cost of the device (approximately $58,125–$139,400 for different models), the amount of time needed to train staff in RCM units (seminars, congresses, and special courses organized by the International Confocal Working Group), and the amount of time needed for evaluation of individual lesions (15–20 minutes). However, RCM can be valuable in the clinical diagnosis of difficult lesions, as seen in our case.

Conclusion

Our case highlights the benefit of RCM in allowing the confident diagnosis and correct management of a small-diameter melanoma that turned out to be a melanoma with 0.3-mm Breslow thickness. Even so, histopathologic evaluation remains the gold standard for the diagnosis of melanoma.

Melanomas have been designated as small melanomas or micromelanomas according to their long-axis diameter (<6 mm and ≤3 mm, respectively).^1-3 Because small-diameter melanomas also have the potential to metastasize, particularly if nodular, early diagnosis can be highly rewarding. Deep melanomas with small diameters may have the same potential for metastasis as large-diameter melanomas. In this context, dermoscopy, digital dermoscopic monitoring, and total-body photography are useful in clinical practice. However, these techniques are of limited utility for small, dermoscopic feature–poor melanomas. Conversely, less than 10% of changing lesions, which are spotted via digital dermoscopic surveillance, turn out to be melanomas; therefore, simply removing all changing lesions may result in many unnecessary excisions of benign lesions.⁴

In vivo reflectance confocal microscopy (RCM) is an advanced technique that allows recognition of the architectural and cellular details of pigmented lesions. Reflectance confocal microscopy has the potential to reduce the rate of unnecessary excisions and to diminish the risk for missing a melanoma.^5-7 In meta-analyses, RCM sensitivity was reported as 90% to 93% and specificity was reported as 78% to 82% in detecting melanoma.^8,9

We describe a case that highlights the potential role of RCM in the diagnosis of small-diameter melanomas.

Case Report

A 57-year-old man with Fitzpatrick skin type III presented to the dermato-oncology unit for evaluation of multiple nevi. He was otherwise healthy and denied a history of skin cancer. Total-body skin examination with dermoscopy was performed, and several mildly atypical lesions were identified. We decided to perform digital dermoscopic monitoring. The patient’s 6-month monitoring appointment had been scheduled, but he did not arrive for the follow-up visit until 10 months after the initial examination. A lesion on the left arm, which initially was 1.5 mm in diameter, had enlarged. It was now a dark brown–gray papule with a 2.5-mm diameter (Figure 1). Dermoscopy revealed grayish globules/dots at the center of the lesion, reticular gray-blue areas, and few milialike cysts; at the periphery, a narrow rim of brownish delicate pigment network also was seen (Figure 2). The clinical and dermoscopic differential diagnosis was either an atypical nevus or an early melanoma. For a more precise diagnosis before excision, the lesion was evaluated with RCM, which takes 10 to 15 minutes to perform.

Under RCM at the epidermis level, there was a cobblestone pattern that showed a focus with mild disarrangement and few small, roundish, nucleated cells (Figure 3). A mosaic image, akin to low-magnification microscopy that enables overview of the entire lesion, at the level of the dermoepidermal junction (DEJ) showed an overall irregular meshwork pattern. Higher-magnification optical sections showed marked and diffuse (extending >10% of lesion area) architectural disorder with confluent junctional nests that were irregular to bizarre in shape and uneven in size and spacing as well as edged and nonedged papillae. At the superficial dermal level, atypical bright nucleated cells (>5 cells/mm²) were observed (Figure 4). Bright dots and/or plump bright cells within papillae also were observed. These RCM findings were highly suggestive for melanoma.

Histopathology showed an asymmetric, junctional, lentiginous, and nested proliferation of atypical epithelioid melanocytes, with few melanocytes in a pagetoid spread. There were small nests of atypical epithelioid melanocytes at the superficial dermis extending to a depth of 0.3 mm. The atypical epithelioid melanocytes displayed angulated hyperchromatic nuclei with conspicuous nucleoli and dusty brown cytoplasm. There was notable inflammation and pigment incontinence at the dermis. There was no evidence of ulceration or mitosis at the dermal component. The diagnosis of a pT1a malignant melanoma was reported (Figure 5).

Comment

A small but enlarging dark gray papule with reticular gray-blue areas under dermoscopy in a 57-year-old man is obviously suspicious for melanoma. In daily practice, this type of small-diameter melanoma is difficult to diagnose with high confidence. We balance our aim to diagnose melanomas early with the need to reduce unnecessary excisions. Reflectance confocal microscopy may allow the clinician to arrive at the correct diagnosis and management decision with confidence before excision of the lesion.

The distinction of a small-diameter melanoma from a nevus via RCM relies on evaluation of the architectural and cellular features. Findings on RCM in small-diameter melanomas have been scarcely reported in the literature; Pupelli et al¹⁰ evaluated small melanomas with a diameter of 2 to 5 mm. Among these small-diameter melanomas, the RCM features suggestive for melanomas were the presence of cytologic atypia with cellular pleomorphism, architectural disorder with irregular nests, at least 5 pagetoid cells/mm², dendrites or tangled lines (ie, short fine lines with no visible nucleus interlacing with the adjacent keratinocytes) within the epidermis, and atypical roundish cells at the DEJ.¹⁰

The distinction between an atypical nevus and a small-diameter melanoma using RCM occasionally may be challenging.¹¹ Pellacani et al¹² reported an algorithm to distinguish melanoma from atypical nevi. According to this algorithm, when at least 1 of the architectural atypia features (irregular junctional nests, short interconnections between junctional nests, and nonhomogeneous cellularity within junctional nests) and at least 1 of the cytologic atypia features (round pagetoid cells or atypical cells at the DEJ) are observed simultaneously, the lesion is diagnosed as a dysplastic nevus or a melanoma in the first step. In the second step, the RCM diagnosis of melanoma requires at least 1 of 3 parameters: roundish pagetoid cells encompassing at least 50% of the lesional area at the spinous layer, atypical cells involving at least 50% of the lesional area at the DEJ level, and nonedged papillae involving at least 10% of the lesional area.¹² Accordingly, our case corresponded with these RCM criteria for a melanoma, given that there were irregular junctional nests, atypical cells at the DEJ, and nonedged papillae involving at least 10% of the lesion.

The current limitations of RCM are the high cost of the device (approximately $58,125–$139,400 for different models), the amount of time needed to train staff in RCM units (seminars, congresses, and special courses organized by the International Confocal Working Group), and the amount of time needed for evaluation of individual lesions (15–20 minutes). However, RCM can be valuable in the clinical diagnosis of difficult lesions, as seen in our case.

Conclusion

Our case highlights the benefit of RCM in allowing the confident diagnosis and correct management of a small-diameter melanoma that turned out to be a melanoma with 0.3-mm Breslow thickness. Even so, histopathologic evaluation remains the gold standard for the diagnosis of melanoma.

Practice Gap

An essential part of training for a micrographic surgery and dermatologic oncology fellowship and scope of practice involves planning and execution of reconstructive surgery for Mohs defects. Recently, a surgical pearl presented by Rickstrew and colleagues¹ highlighted the use of different colored surgical marking pens and their benefit in a trainee-based environment.

Delineating multiple options for reconstruction with different colored markers on live patients allows fellows in-training to participate in surgical planning but introduces more markings or drawings that need to be wiped off during or after surgery, potentially prolonging operative time. Furthermore, the Rickstrew approach has the potential to (1) cause unnecessary emotional distress for the patient during surgical planning and (2) add to the cost of surgery with the purchase of various colors of surgical markers.

Technique

To improve patient experience and trainee education, we propose fine-tuning the colored marker approach by utilizing a digital drawing program for surgical planning prior to the procedure. We recommend Snip & Sketch—a free, readily accessible digital annotating application that runs on the Microsoft Windows 10 operating system (https://www.microsoft.com/en-us/p/snip-sketch/9mz95kl8mr0l#activetab=pivot:overviewtab)—to mark up screenshot photographs of postoperative Mohs defects from the electronic medical record.

Using Snip & Sketch, the fellow in-training can then use, for example, a green “digital pen” to draw on the captured image and plan their surgical repairs (Figure 1) without input from the attending physician. Different colored pens can be used to highlight nerves, vessels, relaxed skin tension lines, and tension vectors associated with flap movement.

Subsequently, the attending physician, using a different color digital pen—say, blue—can design alternative reconstructive options (Figure 1). Suture lines also can be drawn to outline the predicted appearance of surgical scars (Figure 2).

Then, the attending physician and fellow in-training brainstorm and discuss the advantages and disadvantages of each reconstructive option to determine the optimal approach to repairing the Mohs defect.

Advantages and Disadvantages

The main advantage of using a digital drawing program is that it is time-saving and cost-efficient. Digital planning also spares the patient undue anxiety from listening to the discussion on each repair option.

The primary downside of digital surgical planning is that it is 2-dimensional, thus providing an incomplete representation of a 3-dimensional cutaneous structure. In addition, skin laxity, flap mobility, and free-margin distortion cannot be fully appreciated on a 2-dimensional image.

Despite these drawbacks, digital surgical planning provides trainees with an active learning experience through a more collaborative and comprehensive discussion of reconstructive options.

Practice Implications

Active learning using an electronic device has been validated as a beneficial addition to Mohs micrographic surgery training.² Utilizing a digitized annotating program for surgical planning increases the independence of trainees and allows immediate feedback from the attending physician. The synergy of digital technology and collaborative learning helps cultivate the next generation of confident and competent Mohs surgeons.

Practice Gap

An essential part of training for a micrographic surgery and dermatologic oncology fellowship and scope of practice involves planning and execution of reconstructive surgery for Mohs defects. Recently, a surgical pearl presented by Rickstrew and colleagues¹ highlighted the use of different colored surgical marking pens and their benefit in a trainee-based environment.

Delineating multiple options for reconstruction with different colored markers on live patients allows fellows in-training to participate in surgical planning but introduces more markings or drawings that need to be wiped off during or after surgery, potentially prolonging operative time. Furthermore, the Rickstrew approach has the potential to (1) cause unnecessary emotional distress for the patient during surgical planning and (2) add to the cost of surgery with the purchase of various colors of surgical markers.

Technique

To improve patient experience and trainee education, we propose fine-tuning the colored marker approach by utilizing a digital drawing program for surgical planning prior to the procedure. We recommend Snip & Sketch—a free, readily accessible digital annotating application that runs on the Microsoft Windows 10 operating system (https://www.microsoft.com/en-us/p/snip-sketch/9mz95kl8mr0l#activetab=pivot:overviewtab)—to mark up screenshot photographs of postoperative Mohs defects from the electronic medical record.

Using Snip & Sketch, the fellow in-training can then use, for example, a green “digital pen” to draw on the captured image and plan their surgical repairs (Figure 1) without input from the attending physician. Different colored pens can be used to highlight nerves, vessels, relaxed skin tension lines, and tension vectors associated with flap movement.

Subsequently, the attending physician, using a different color digital pen—say, blue—can design alternative reconstructive options (Figure 1). Suture lines also can be drawn to outline the predicted appearance of surgical scars (Figure 2).

Then, the attending physician and fellow in-training brainstorm and discuss the advantages and disadvantages of each reconstructive option to determine the optimal approach to repairing the Mohs defect.

Advantages and Disadvantages

The main advantage of using a digital drawing program is that it is time-saving and cost-efficient. Digital planning also spares the patient undue anxiety from listening to the discussion on each repair option.

The primary downside of digital surgical planning is that it is 2-dimensional, thus providing an incomplete representation of a 3-dimensional cutaneous structure. In addition, skin laxity, flap mobility, and free-margin distortion cannot be fully appreciated on a 2-dimensional image.

Despite these drawbacks, digital surgical planning provides trainees with an active learning experience through a more collaborative and comprehensive discussion of reconstructive options.

Practice Implications

Active learning using an electronic device has been validated as a beneficial addition to Mohs micrographic surgery training.² Utilizing a digitized annotating program for surgical planning increases the independence of trainees and allows immediate feedback from the attending physician. The synergy of digital technology and collaborative learning helps cultivate the next generation of confident and competent Mohs surgeons.

Practice Gap

An essential part of training for a micrographic surgery and dermatologic oncology fellowship and scope of practice involves planning and execution of reconstructive surgery for Mohs defects. Recently, a surgical pearl presented by Rickstrew and colleagues¹ highlighted the use of different colored surgical marking pens and their benefit in a trainee-based environment.

Delineating multiple options for reconstruction with different colored markers on live patients allows fellows in-training to participate in surgical planning but introduces more markings or drawings that need to be wiped off during or after surgery, potentially prolonging operative time. Furthermore, the Rickstrew approach has the potential to (1) cause unnecessary emotional distress for the patient during surgical planning and (2) add to the cost of surgery with the purchase of various colors of surgical markers.

Technique

To improve patient experience and trainee education, we propose fine-tuning the colored marker approach by utilizing a digital drawing program for surgical planning prior to the procedure. We recommend Snip & Sketch—a free, readily accessible digital annotating application that runs on the Microsoft Windows 10 operating system (https://www.microsoft.com/en-us/p/snip-sketch/9mz95kl8mr0l#activetab=pivot:overviewtab)—to mark up screenshot photographs of postoperative Mohs defects from the electronic medical record.

Using Snip & Sketch, the fellow in-training can then use, for example, a green “digital pen” to draw on the captured image and plan their surgical repairs (Figure 1) without input from the attending physician. Different colored pens can be used to highlight nerves, vessels, relaxed skin tension lines, and tension vectors associated with flap movement.

Subsequently, the attending physician, using a different color digital pen—say, blue—can design alternative reconstructive options (Figure 1). Suture lines also can be drawn to outline the predicted appearance of surgical scars (Figure 2).

Then, the attending physician and fellow in-training brainstorm and discuss the advantages and disadvantages of each reconstructive option to determine the optimal approach to repairing the Mohs defect.

Advantages and Disadvantages

The main advantage of using a digital drawing program is that it is time-saving and cost-efficient. Digital planning also spares the patient undue anxiety from listening to the discussion on each repair option.

The primary downside of digital surgical planning is that it is 2-dimensional, thus providing an incomplete representation of a 3-dimensional cutaneous structure. In addition, skin laxity, flap mobility, and free-margin distortion cannot be fully appreciated on a 2-dimensional image.

Despite these drawbacks, digital surgical planning provides trainees with an active learning experience through a more collaborative and comprehensive discussion of reconstructive options.

Practice Implications

Active learning using an electronic device has been validated as a beneficial addition to Mohs micrographic surgery training.² Utilizing a digitized annotating program for surgical planning increases the independence of trainees and allows immediate feedback from the attending physician. The synergy of digital technology and collaborative learning helps cultivate the next generation of confident and competent Mohs surgeons.

About 60% of physicians cite documenting information in the electronic health record and other paperwork as major contributors to burnout. Physicians have been working with a variety of ways to reduce their documentation burdens; could one of them be right for you?

Two methods involve human scribes – working either on-site or off-site. Two other methods involve digital solutions: The first is widely used speech-to-text software, which requires the doctors to manually enter the text into the EHR; the second uses artificial intelligence (AI) to not only turn speech into text but to also automatically organize it and enter it into the EHR.

These AI solutions, which are only a few years old, are widely considered to be a work in progress – but many doctors who have used these products are impressed.
 

Other people do the documenting: On-site scribes

“It’s estimated that now one in five to one in eight doctors use scribes,” said Jeffrey A. Gold, MD, an internist who has studied the phenomenon. Utilization is already very high in emergency medicine and has been surging in specialties such as orthopedic surgery; it is also growing in primary care.

Scribes work with the doctor and enter information into the EHR. Their numbers have reportedly been rising in recent years, as more doctors look for ways to cut back on their documentation, according to Dr. Gold, vice chair for quality and safety at the department of medicine at Oregon Health and Science University, Portland.

The price tag of $33,000 a year or more for an on-site scribe is a major barrier. And because the typical scribe only works for 1-1.5 years, they must be constantly hired and trained, which is done by scribing services such as Scrivas in Miami.

However, Scrivas CEO Fernando G. Mendoza, MD, said scribes typically pay for themselves because they allow physicians to see more patients. Scribes can save doctors 2-3 hours of work per day, increase reimbursement by around 20% by producing more detailed notes, and improve satisfaction for both patients and doctors, according to several studies. In one study, physician documentation time significantly decreased, averaging 3 minutes per patient and 36 minutes per session.

Despite these possible savings, many health systems resisted hiring scribes for their employed physicians until the past few years, according to Kevin Brady, president of Physicians Angels, a scribing service based in Toledo, Ohio. “They figured they’d just spent millions on EHRs and didn’t want to spend any more,” he said. “They were also waiting for the EHR vendors to simplify documentation, but that never happened.”

Mr. Brady said what finally convinced many systems to invest in scribes was the need to reduce physician turnover and improve recruitment. Newly minted physicians often look for jobs that don’t interfere with their leisure time.
 

On-site scribes

On-site scribes accompany the doctor into the exam room and type the note during the encounter. Typically, the note is completed when the encounter is over, allowing for orders to be carried out immediately.

The traditional scribe is a premed student who wants to get acquainted with medicine and is thus willing to make a fairly low income. This career trajectory is the reason scribes have a high turnover. As demand surged, the scribe pool was supplemented with students aspiring to other health care professions like nursing, and even with people who want to make a career of scribing.

Since scribes have to set aside time for studying, scribe companies provide each physician-customer with one or two backup scribes. Dr. Mendoza bills his scribes as “personal assistants” who can do some nonclinical tasks beyond filling in the EHR, such as reminding doctors about the need to order a test or check in on another patient briefly before moving on to the next exam room.

Dr. Gold, however, warned against allowing “functional creep,” where scribes are asked to carry out tasks beyond their abilities, such as interpreting medical data. He added that doctors are expected to read through and sign all scribe-generated orders.

Some practices grow their own scribes, cross-training their medical assistants (MAs) to do the work. This addresses the turnover problem and could reduce costs. MAs already know clinical terms and how the doctor works, and they may be able to get special training at a local community college. However, some MAs do not want this extra work, and in any case, the work would take them away from other duties.

How often do physicians use their scribes? “Our doctors generally use them for all of their visits, but surgeons tend to limit use to their clinic days when they’re not in surgery,” said Tony Andrulonis, MD, president of ScribeAmerica in Fort Lauderdale, Fla.
 

Virtual scribes work off-site

Virtual scribes, who operate remotely from the doctor and can cost up to $10 less per hour than on-site scribes, got a boost during the COVID-19 pandemic because they fit well with telemedicine visits. Furthermore, the growing availability of virtual scribes from abroad has made scribes even more affordable.

“When doctors could no longer work on-site due to the pandemic, they replaced their on-site scribes with virtual scribes, and to some extent this trend is still going on,” Dr. Gold said.

One downside with virtual scribes is that they cannot do many of the extra tasks that on-site scribes can do. However, they are often a necessity in rural areas where on-site scribes are not available. In addition to having an audio-video connection, they may also just be on audio in areas where internet reception is poor or the patient wants privacy, Dr. Andrulonis said.

Mr. Brady said Physicians Angels uses offshore scribes from India. The company charges $16-$18 per hour, compared with $26-$28 per hour for U.S.-based virtual scribes. He said well over half of his clients are family physicians, who appreciate the lower cost.

Another advantage of offshore scribes is slower turnover and full-time availability. Mr. Brady said his scribes usually stay with the company for 5-6 years and are always available. “This is their full-time job,” Brady said.

Mr. Brady said when large organizations arrange with his company for scribes, often the goal is that the scribes pay for themselves. “They’ll tell their doctors: ‘We’ll let you have scribes as long as you see one or two more patients a day,’ ” he said. Mr. Brady then helps the organization reach that goal, which he said is easily achievable, except when doctors have no clear incentive to see more patients. He also works with clients on other goals, such as higher quality of life or time saved.
 

Speech-to-text software

For years, doctors have been using speech-to-text software to transform their speech into notes. They speak into the microphone, calling out punctuation and referring to prep-made templates for routine tasks. As they speak, the text appears on a screen. They can correct the text if necessary, and then they must put that information into the EHR.

Speech-to-text systems are used by more physicians than those using human scribes. Nuance’s Dragon Medical One system is the most popular, with more than 1000 large healthcare organizations signed up. Competitors include Dolbey, Entrada, and nVoq.

Prices are just a fraction of the cost of a human scribe. Dolbey’s Fusion Narrate system, for example, costs about $800-$850 a year per user. Doctors should shop around for these systems, because prices can vary by 30%-50%, said Wayne Kaniewski, MD, a retired family and urgent care physician and now owner and CEO of Twin Cities EMR Consulting in Minneapolis.

As a contracted reseller of the nVoq and Dolbey systems, Dr. Kaniewski provides training and support. During 13 years in business, he said machine dictation systems have become faster, more accurate, and, thanks to cloud-based technology, easier to set up.
 

Digital assistants

AI software, also known as digital assistants, takes speech-to-text software to the next logical step – organizing and automatically entering the information into the EHR. Using ambient technology, a smartphone captures the physician-patient conversation in the exam room, extracts the needed information, and distributes it in the EHR.

The cost is about one-sixth that of a human scribe, but higher than the cost for speech-to-text software because the technology still makes errors and requires a human at the software company to guide the process.

Currently about 10 companies sell digital scribes, including Nuance’s Dragon Medical One, NoteSwift, DeepScribe, and ScribeAmerica. These systems can be connected to the major EHR systems, and in some cases EHR systems have agreements with digital scribe vendors so that their systems can be seamlessly connected.

“DAX software can understand nonlinear conversations – the way normal conversations bounce from topic to topic,” said Kenneth Harper, general manager of Nuance’s Ambient Clinical Intelligence Division. “This level of technology was not possible 5 years ago.”

Mr. Harper said DAX saves doctors 6 minutes per patient on average, and 70% of doctors using it reported less burnout and fatigue. Kansas University Medical Center has been testing DAX with physicians there. Many of them no longer need to write up their notes after hours, said Denton Shanks, DO, the medical center’s digital health medical director.

One of the things Dr. Shanks likes about DAX is that it remembers all the details of a visit. As a family physician, “there are something like 15 different problems that come up in one typical visit. Before, I had to carry those problems in my head, and when I wrote up my notes at the end of the day, I might have forgotten a few of them. Not so with DAX.”

Dr. Shanks knows he has to speak clearly and unambiguously when using DAX. “DAX can only document what it hears, so I describe what I am looking at in a physical exam or I might further explain the patient’s account so DAX can pick up on it.”
 

Are digital assistants ready for doctors?

Since a human at the software company is needed to guide the system, it takes a few hours for the digital assistant to complete entries into the EHR, but vendors are looking for ways to eliminate human guidance.

“We’re definitely moving toward digital scribes, but we’re not there yet,” Dr. Gold said, pointing to a 2018 study that found a significantly higher error rate for speech recognition software than for human scribes.

Dr. Kaniewski added that digital scribes pick up a great deal of irrelevant information, making for a bloated note. “Clinicians must then edit the note down, which is more work than just dictating a concise note,” he said.

Many doctors, however, are happy with these new systems. Steven Y. Lin, MD, a family physician who has been testing a digital scribe system with 40 fellow clinicians at Stanford (Calif.) Health Care, said 95% of clinicians who stayed with the trial are continuing to use the system, but he concedes that there was a relatively high dropout rate. “These people felt that they had lost control of the process when using the software.”

Furthermore, Dr. Lin is concerned that using a digital scribe may eliminate doctors’ crucial step of sitting down and writing the clinical note. Here “doctors bring together everything they have heard and then come up with the diagnosis and treatment.” He recognized that doctors could still take this step when reviewing the digital note, but it would be easy to skip.
 

What is the future for documentation aids?

Increasingly more doctors are finding ways to expedite documentation tasks. Speech-to-text software is still the most popular solution, but more physicians are now using human scribes, driven by the decisions of some large organizations to start paying for them.

However, these physicians are often expected to work harder in order for the scribes to pay for themselves, which is a solution that could, ironically, add to burnout rather than alleviate it.

Digital assistants answer these concerns because they are more affordable and are supposed to do all the work of human scribes. This software parses the physician-patient conversation into a clinical note and other data and deposits them directly into the EHR.

Most experts think digital assistants will eventually meet their promise, but it is widely thought that they’re not ready yet. It will be up to vendors like Nuance to convince skeptics that their products are ready for doctors.

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

About 60% of physicians cite documenting information in the electronic health record and other paperwork as major contributors to burnout. Physicians have been working with a variety of ways to reduce their documentation burdens; could one of them be right for you?

Two methods involve human scribes – working either on-site or off-site. Two other methods involve digital solutions: The first is widely used speech-to-text software, which requires the doctors to manually enter the text into the EHR; the second uses artificial intelligence (AI) to not only turn speech into text but to also automatically organize it and enter it into the EHR.

These AI solutions, which are only a few years old, are widely considered to be a work in progress – but many doctors who have used these products are impressed.
 

Other people do the documenting: On-site scribes

“It’s estimated that now one in five to one in eight doctors use scribes,” said Jeffrey A. Gold, MD, an internist who has studied the phenomenon. Utilization is already very high in emergency medicine and has been surging in specialties such as orthopedic surgery; it is also growing in primary care.

Scribes work with the doctor and enter information into the EHR. Their numbers have reportedly been rising in recent years, as more doctors look for ways to cut back on their documentation, according to Dr. Gold, vice chair for quality and safety at the department of medicine at Oregon Health and Science University, Portland.

The price tag of $33,000 a year or more for an on-site scribe is a major barrier. And because the typical scribe only works for 1-1.5 years, they must be constantly hired and trained, which is done by scribing services such as Scrivas in Miami.

However, Scrivas CEO Fernando G. Mendoza, MD, said scribes typically pay for themselves because they allow physicians to see more patients. Scribes can save doctors 2-3 hours of work per day, increase reimbursement by around 20% by producing more detailed notes, and improve satisfaction for both patients and doctors, according to several studies. In one study, physician documentation time significantly decreased, averaging 3 minutes per patient and 36 minutes per session.

Despite these possible savings, many health systems resisted hiring scribes for their employed physicians until the past few years, according to Kevin Brady, president of Physicians Angels, a scribing service based in Toledo, Ohio. “They figured they’d just spent millions on EHRs and didn’t want to spend any more,” he said. “They were also waiting for the EHR vendors to simplify documentation, but that never happened.”

Mr. Brady said what finally convinced many systems to invest in scribes was the need to reduce physician turnover and improve recruitment. Newly minted physicians often look for jobs that don’t interfere with their leisure time.
 

On-site scribes

On-site scribes accompany the doctor into the exam room and type the note during the encounter. Typically, the note is completed when the encounter is over, allowing for orders to be carried out immediately.

The traditional scribe is a premed student who wants to get acquainted with medicine and is thus willing to make a fairly low income. This career trajectory is the reason scribes have a high turnover. As demand surged, the scribe pool was supplemented with students aspiring to other health care professions like nursing, and even with people who want to make a career of scribing.

Since scribes have to set aside time for studying, scribe companies provide each physician-customer with one or two backup scribes. Dr. Mendoza bills his scribes as “personal assistants” who can do some nonclinical tasks beyond filling in the EHR, such as reminding doctors about the need to order a test or check in on another patient briefly before moving on to the next exam room.

Dr. Gold, however, warned against allowing “functional creep,” where scribes are asked to carry out tasks beyond their abilities, such as interpreting medical data. He added that doctors are expected to read through and sign all scribe-generated orders.

Some practices grow their own scribes, cross-training their medical assistants (MAs) to do the work. This addresses the turnover problem and could reduce costs. MAs already know clinical terms and how the doctor works, and they may be able to get special training at a local community college. However, some MAs do not want this extra work, and in any case, the work would take them away from other duties.

How often do physicians use their scribes? “Our doctors generally use them for all of their visits, but surgeons tend to limit use to their clinic days when they’re not in surgery,” said Tony Andrulonis, MD, president of ScribeAmerica in Fort Lauderdale, Fla.
 

Virtual scribes work off-site

Virtual scribes, who operate remotely from the doctor and can cost up to $10 less per hour than on-site scribes, got a boost during the COVID-19 pandemic because they fit well with telemedicine visits. Furthermore, the growing availability of virtual scribes from abroad has made scribes even more affordable.

“When doctors could no longer work on-site due to the pandemic, they replaced their on-site scribes with virtual scribes, and to some extent this trend is still going on,” Dr. Gold said.

One downside with virtual scribes is that they cannot do many of the extra tasks that on-site scribes can do. However, they are often a necessity in rural areas where on-site scribes are not available. In addition to having an audio-video connection, they may also just be on audio in areas where internet reception is poor or the patient wants privacy, Dr. Andrulonis said.

Mr. Brady said Physicians Angels uses offshore scribes from India. The company charges $16-$18 per hour, compared with $26-$28 per hour for U.S.-based virtual scribes. He said well over half of his clients are family physicians, who appreciate the lower cost.

Another advantage of offshore scribes is slower turnover and full-time availability. Mr. Brady said his scribes usually stay with the company for 5-6 years and are always available. “This is their full-time job,” Brady said.

Mr. Brady said when large organizations arrange with his company for scribes, often the goal is that the scribes pay for themselves. “They’ll tell their doctors: ‘We’ll let you have scribes as long as you see one or two more patients a day,’ ” he said. Mr. Brady then helps the organization reach that goal, which he said is easily achievable, except when doctors have no clear incentive to see more patients. He also works with clients on other goals, such as higher quality of life or time saved.
 

Speech-to-text software

For years, doctors have been using speech-to-text software to transform their speech into notes. They speak into the microphone, calling out punctuation and referring to prep-made templates for routine tasks. As they speak, the text appears on a screen. They can correct the text if necessary, and then they must put that information into the EHR.

Speech-to-text systems are used by more physicians than those using human scribes. Nuance’s Dragon Medical One system is the most popular, with more than 1000 large healthcare organizations signed up. Competitors include Dolbey, Entrada, and nVoq.

Prices are just a fraction of the cost of a human scribe. Dolbey’s Fusion Narrate system, for example, costs about $800-$850 a year per user. Doctors should shop around for these systems, because prices can vary by 30%-50%, said Wayne Kaniewski, MD, a retired family and urgent care physician and now owner and CEO of Twin Cities EMR Consulting in Minneapolis.

As a contracted reseller of the nVoq and Dolbey systems, Dr. Kaniewski provides training and support. During 13 years in business, he said machine dictation systems have become faster, more accurate, and, thanks to cloud-based technology, easier to set up.
 

Digital assistants

AI software, also known as digital assistants, takes speech-to-text software to the next logical step – organizing and automatically entering the information into the EHR. Using ambient technology, a smartphone captures the physician-patient conversation in the exam room, extracts the needed information, and distributes it in the EHR.

The cost is about one-sixth that of a human scribe, but higher than the cost for speech-to-text software because the technology still makes errors and requires a human at the software company to guide the process.

Currently about 10 companies sell digital scribes, including Nuance’s Dragon Medical One, NoteSwift, DeepScribe, and ScribeAmerica. These systems can be connected to the major EHR systems, and in some cases EHR systems have agreements with digital scribe vendors so that their systems can be seamlessly connected.

“DAX software can understand nonlinear conversations – the way normal conversations bounce from topic to topic,” said Kenneth Harper, general manager of Nuance’s Ambient Clinical Intelligence Division. “This level of technology was not possible 5 years ago.”

Mr. Harper said DAX saves doctors 6 minutes per patient on average, and 70% of doctors using it reported less burnout and fatigue. Kansas University Medical Center has been testing DAX with physicians there. Many of them no longer need to write up their notes after hours, said Denton Shanks, DO, the medical center’s digital health medical director.

One of the things Dr. Shanks likes about DAX is that it remembers all the details of a visit. As a family physician, “there are something like 15 different problems that come up in one typical visit. Before, I had to carry those problems in my head, and when I wrote up my notes at the end of the day, I might have forgotten a few of them. Not so with DAX.”

Dr. Shanks knows he has to speak clearly and unambiguously when using DAX. “DAX can only document what it hears, so I describe what I am looking at in a physical exam or I might further explain the patient’s account so DAX can pick up on it.”
 

Are digital assistants ready for doctors?

Since a human at the software company is needed to guide the system, it takes a few hours for the digital assistant to complete entries into the EHR, but vendors are looking for ways to eliminate human guidance.

“We’re definitely moving toward digital scribes, but we’re not there yet,” Dr. Gold said, pointing to a 2018 study that found a significantly higher error rate for speech recognition software than for human scribes.

Dr. Kaniewski added that digital scribes pick up a great deal of irrelevant information, making for a bloated note. “Clinicians must then edit the note down, which is more work than just dictating a concise note,” he said.

Many doctors, however, are happy with these new systems. Steven Y. Lin, MD, a family physician who has been testing a digital scribe system with 40 fellow clinicians at Stanford (Calif.) Health Care, said 95% of clinicians who stayed with the trial are continuing to use the system, but he concedes that there was a relatively high dropout rate. “These people felt that they had lost control of the process when using the software.”

Furthermore, Dr. Lin is concerned that using a digital scribe may eliminate doctors’ crucial step of sitting down and writing the clinical note. Here “doctors bring together everything they have heard and then come up with the diagnosis and treatment.” He recognized that doctors could still take this step when reviewing the digital note, but it would be easy to skip.
 

What is the future for documentation aids?

Increasingly more doctors are finding ways to expedite documentation tasks. Speech-to-text software is still the most popular solution, but more physicians are now using human scribes, driven by the decisions of some large organizations to start paying for them.

However, these physicians are often expected to work harder in order for the scribes to pay for themselves, which is a solution that could, ironically, add to burnout rather than alleviate it.

Digital assistants answer these concerns because they are more affordable and are supposed to do all the work of human scribes. This software parses the physician-patient conversation into a clinical note and other data and deposits them directly into the EHR.

Most experts think digital assistants will eventually meet their promise, but it is widely thought that they’re not ready yet. It will be up to vendors like Nuance to convince skeptics that their products are ready for doctors.

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

About 60% of physicians cite documenting information in the electronic health record and other paperwork as major contributors to burnout. Physicians have been working with a variety of ways to reduce their documentation burdens; could one of them be right for you?

Two methods involve human scribes – working either on-site or off-site. Two other methods involve digital solutions: The first is widely used speech-to-text software, which requires the doctors to manually enter the text into the EHR; the second uses artificial intelligence (AI) to not only turn speech into text but to also automatically organize it and enter it into the EHR.

These AI solutions, which are only a few years old, are widely considered to be a work in progress – but many doctors who have used these products are impressed.
 

Other people do the documenting: On-site scribes

“It’s estimated that now one in five to one in eight doctors use scribes,” said Jeffrey A. Gold, MD, an internist who has studied the phenomenon. Utilization is already very high in emergency medicine and has been surging in specialties such as orthopedic surgery; it is also growing in primary care.

Scribes work with the doctor and enter information into the EHR. Their numbers have reportedly been rising in recent years, as more doctors look for ways to cut back on their documentation, according to Dr. Gold, vice chair for quality and safety at the department of medicine at Oregon Health and Science University, Portland.

The price tag of $33,000 a year or more for an on-site scribe is a major barrier. And because the typical scribe only works for 1-1.5 years, they must be constantly hired and trained, which is done by scribing services such as Scrivas in Miami.

However, Scrivas CEO Fernando G. Mendoza, MD, said scribes typically pay for themselves because they allow physicians to see more patients. Scribes can save doctors 2-3 hours of work per day, increase reimbursement by around 20% by producing more detailed notes, and improve satisfaction for both patients and doctors, according to several studies. In one study, physician documentation time significantly decreased, averaging 3 minutes per patient and 36 minutes per session.

Despite these possible savings, many health systems resisted hiring scribes for their employed physicians until the past few years, according to Kevin Brady, president of Physicians Angels, a scribing service based in Toledo, Ohio. “They figured they’d just spent millions on EHRs and didn’t want to spend any more,” he said. “They were also waiting for the EHR vendors to simplify documentation, but that never happened.”

Mr. Brady said what finally convinced many systems to invest in scribes was the need to reduce physician turnover and improve recruitment. Newly minted physicians often look for jobs that don’t interfere with their leisure time.
 

On-site scribes

On-site scribes accompany the doctor into the exam room and type the note during the encounter. Typically, the note is completed when the encounter is over, allowing for orders to be carried out immediately.

The traditional scribe is a premed student who wants to get acquainted with medicine and is thus willing to make a fairly low income. This career trajectory is the reason scribes have a high turnover. As demand surged, the scribe pool was supplemented with students aspiring to other health care professions like nursing, and even with people who want to make a career of scribing.

Since scribes have to set aside time for studying, scribe companies provide each physician-customer with one or two backup scribes. Dr. Mendoza bills his scribes as “personal assistants” who can do some nonclinical tasks beyond filling in the EHR, such as reminding doctors about the need to order a test or check in on another patient briefly before moving on to the next exam room.

Dr. Gold, however, warned against allowing “functional creep,” where scribes are asked to carry out tasks beyond their abilities, such as interpreting medical data. He added that doctors are expected to read through and sign all scribe-generated orders.

Some practices grow their own scribes, cross-training their medical assistants (MAs) to do the work. This addresses the turnover problem and could reduce costs. MAs already know clinical terms and how the doctor works, and they may be able to get special training at a local community college. However, some MAs do not want this extra work, and in any case, the work would take them away from other duties.

How often do physicians use their scribes? “Our doctors generally use them for all of their visits, but surgeons tend to limit use to their clinic days when they’re not in surgery,” said Tony Andrulonis, MD, president of ScribeAmerica in Fort Lauderdale, Fla.
 

Virtual scribes work off-site

Virtual scribes, who operate remotely from the doctor and can cost up to $10 less per hour than on-site scribes, got a boost during the COVID-19 pandemic because they fit well with telemedicine visits. Furthermore, the growing availability of virtual scribes from abroad has made scribes even more affordable.

“When doctors could no longer work on-site due to the pandemic, they replaced their on-site scribes with virtual scribes, and to some extent this trend is still going on,” Dr. Gold said.

One downside with virtual scribes is that they cannot do many of the extra tasks that on-site scribes can do. However, they are often a necessity in rural areas where on-site scribes are not available. In addition to having an audio-video connection, they may also just be on audio in areas where internet reception is poor or the patient wants privacy, Dr. Andrulonis said.

Mr. Brady said Physicians Angels uses offshore scribes from India. The company charges $16-$18 per hour, compared with $26-$28 per hour for U.S.-based virtual scribes. He said well over half of his clients are family physicians, who appreciate the lower cost.

Another advantage of offshore scribes is slower turnover and full-time availability. Mr. Brady said his scribes usually stay with the company for 5-6 years and are always available. “This is their full-time job,” Brady said.

Mr. Brady said when large organizations arrange with his company for scribes, often the goal is that the scribes pay for themselves. “They’ll tell their doctors: ‘We’ll let you have scribes as long as you see one or two more patients a day,’ ” he said. Mr. Brady then helps the organization reach that goal, which he said is easily achievable, except when doctors have no clear incentive to see more patients. He also works with clients on other goals, such as higher quality of life or time saved.
 

Speech-to-text software

For years, doctors have been using speech-to-text software to transform their speech into notes. They speak into the microphone, calling out punctuation and referring to prep-made templates for routine tasks. As they speak, the text appears on a screen. They can correct the text if necessary, and then they must put that information into the EHR.

Speech-to-text systems are used by more physicians than those using human scribes. Nuance’s Dragon Medical One system is the most popular, with more than 1000 large healthcare organizations signed up. Competitors include Dolbey, Entrada, and nVoq.

Prices are just a fraction of the cost of a human scribe. Dolbey’s Fusion Narrate system, for example, costs about $800-$850 a year per user. Doctors should shop around for these systems, because prices can vary by 30%-50%, said Wayne Kaniewski, MD, a retired family and urgent care physician and now owner and CEO of Twin Cities EMR Consulting in Minneapolis.

As a contracted reseller of the nVoq and Dolbey systems, Dr. Kaniewski provides training and support. During 13 years in business, he said machine dictation systems have become faster, more accurate, and, thanks to cloud-based technology, easier to set up.
 

Digital assistants

AI software, also known as digital assistants, takes speech-to-text software to the next logical step – organizing and automatically entering the information into the EHR. Using ambient technology, a smartphone captures the physician-patient conversation in the exam room, extracts the needed information, and distributes it in the EHR.

The cost is about one-sixth that of a human scribe, but higher than the cost for speech-to-text software because the technology still makes errors and requires a human at the software company to guide the process.

Currently about 10 companies sell digital scribes, including Nuance’s Dragon Medical One, NoteSwift, DeepScribe, and ScribeAmerica. These systems can be connected to the major EHR systems, and in some cases EHR systems have agreements with digital scribe vendors so that their systems can be seamlessly connected.

“DAX software can understand nonlinear conversations – the way normal conversations bounce from topic to topic,” said Kenneth Harper, general manager of Nuance’s Ambient Clinical Intelligence Division. “This level of technology was not possible 5 years ago.”

Mr. Harper said DAX saves doctors 6 minutes per patient on average, and 70% of doctors using it reported less burnout and fatigue. Kansas University Medical Center has been testing DAX with physicians there. Many of them no longer need to write up their notes after hours, said Denton Shanks, DO, the medical center’s digital health medical director.

One of the things Dr. Shanks likes about DAX is that it remembers all the details of a visit. As a family physician, “there are something like 15 different problems that come up in one typical visit. Before, I had to carry those problems in my head, and when I wrote up my notes at the end of the day, I might have forgotten a few of them. Not so with DAX.”

Dr. Shanks knows he has to speak clearly and unambiguously when using DAX. “DAX can only document what it hears, so I describe what I am looking at in a physical exam or I might further explain the patient’s account so DAX can pick up on it.”
 

Are digital assistants ready for doctors?

Since a human at the software company is needed to guide the system, it takes a few hours for the digital assistant to complete entries into the EHR, but vendors are looking for ways to eliminate human guidance.

“We’re definitely moving toward digital scribes, but we’re not there yet,” Dr. Gold said, pointing to a 2018 study that found a significantly higher error rate for speech recognition software than for human scribes.

Dr. Kaniewski added that digital scribes pick up a great deal of irrelevant information, making for a bloated note. “Clinicians must then edit the note down, which is more work than just dictating a concise note,” he said.

Many doctors, however, are happy with these new systems. Steven Y. Lin, MD, a family physician who has been testing a digital scribe system with 40 fellow clinicians at Stanford (Calif.) Health Care, said 95% of clinicians who stayed with the trial are continuing to use the system, but he concedes that there was a relatively high dropout rate. “These people felt that they had lost control of the process when using the software.”

Furthermore, Dr. Lin is concerned that using a digital scribe may eliminate doctors’ crucial step of sitting down and writing the clinical note. Here “doctors bring together everything they have heard and then come up with the diagnosis and treatment.” He recognized that doctors could still take this step when reviewing the digital note, but it would be easy to skip.
 

What is the future for documentation aids?

Increasingly more doctors are finding ways to expedite documentation tasks. Speech-to-text software is still the most popular solution, but more physicians are now using human scribes, driven by the decisions of some large organizations to start paying for them.

However, these physicians are often expected to work harder in order for the scribes to pay for themselves, which is a solution that could, ironically, add to burnout rather than alleviate it.

Digital assistants answer these concerns because they are more affordable and are supposed to do all the work of human scribes. This software parses the physician-patient conversation into a clinical note and other data and deposits them directly into the EHR.

Most experts think digital assistants will eventually meet their promise, but it is widely thought that they’re not ready yet. It will be up to vendors like Nuance to convince skeptics that their products are ready for doctors.

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