MDedge Dermatology

Practice Gap

Terbinafine can be used safely and effectively in adult and pediatric patients to treat superficial fungal infections, including onychomycosis.¹ These superficial fungal infections have become increasingly prevalent in children and often require oral therapy²; however, children are frequently unable to swallow a pill.

Until 2016, terbinafine was available as oral granules that could be sprinkled on food, but this formulation has been discontinued.³ In addition, terbinafine tablets have a bitter taste. Therefore, the inability to swallow a pill—typical of young children and other patients with pill dysphagia—is a barrier to prescribing terbinafine.

The Technique

For patients who cannot swallow a pill, a terbinafine tablet can be crushed and mixed with food or a syrup without loss of efficacy. Terbinafine in tablet form has been shown to have relatively unchanged properties after being crushed and mixed in solution, even several weeks after preparation.⁴ Crushing and mixing a terbinafine tablet with food or a syrup therefore is an effective option for patients who cannot swallow a pill but can safely swallow food.

The food or syrup used for this purpose should have a pH of at least 5 because greater acidity reduces absorption of terbinafine. Therefore, avoid mixing it with fruit juices, applesauce, or soda. Given the bitter taste of the terbinafine tablet, mixing it with a sweet food or syrup improves taste and compliance, which makes pudding a particularly good food option for this purpose.

However, because younger patients might not finish an entire serving of pudding or other food into which the tablet has been crushed and mixed, inconsistent dosing might result. Therefore, we recommend mixing the crushed terbinafine tablet with 1 oz (30 mL) of chocolate syrup or corn syrup (Figure). This solution is sweet, easy to prepare and consume, widely available, and affordable (as low as $0.28/oz for corn syrup and as low as $0.10/oz for chocolate syrup, as priced on Amazon).

The tablet can be crushed using a pill crusher ($5–$10 at pharmacies or on Amazon) or by placing it on a piece of paper and crushing it with the back of a metal spoon. For children, the recommended dosing of terbinafine with a 250-mg tablet is based on weight: one-quarter of a tablet for a child weighing 10 to 20 kg; one-half of a tablet for a child weighing 20 to 40 kg; and a full tablet for a child weighing more than 40 kg.⁵ Because terbinafine tablets are not scored, a combined pill splitter–crusher can be used (also available at pharmacies or on Amazon; the price of this device is within the same price range as a pill crusher).

Practical Implication

Use of this method for crushing and mixing the terbinafine tablet allows patients who are unable to swallow a pill to safely and effectively use oral terbinafine.

Practice Gap

Terbinafine can be used safely and effectively in adult and pediatric patients to treat superficial fungal infections, including onychomycosis.¹ These superficial fungal infections have become increasingly prevalent in children and often require oral therapy²; however, children are frequently unable to swallow a pill.

Until 2016, terbinafine was available as oral granules that could be sprinkled on food, but this formulation has been discontinued.³ In addition, terbinafine tablets have a bitter taste. Therefore, the inability to swallow a pill—typical of young children and other patients with pill dysphagia—is a barrier to prescribing terbinafine.

The Technique

For patients who cannot swallow a pill, a terbinafine tablet can be crushed and mixed with food or a syrup without loss of efficacy. Terbinafine in tablet form has been shown to have relatively unchanged properties after being crushed and mixed in solution, even several weeks after preparation.⁴ Crushing and mixing a terbinafine tablet with food or a syrup therefore is an effective option for patients who cannot swallow a pill but can safely swallow food.

The food or syrup used for this purpose should have a pH of at least 5 because greater acidity reduces absorption of terbinafine. Therefore, avoid mixing it with fruit juices, applesauce, or soda. Given the bitter taste of the terbinafine tablet, mixing it with a sweet food or syrup improves taste and compliance, which makes pudding a particularly good food option for this purpose.

However, because younger patients might not finish an entire serving of pudding or other food into which the tablet has been crushed and mixed, inconsistent dosing might result. Therefore, we recommend mixing the crushed terbinafine tablet with 1 oz (30 mL) of chocolate syrup or corn syrup (Figure). This solution is sweet, easy to prepare and consume, widely available, and affordable (as low as $0.28/oz for corn syrup and as low as $0.10/oz for chocolate syrup, as priced on Amazon).

The tablet can be crushed using a pill crusher ($5–$10 at pharmacies or on Amazon) or by placing it on a piece of paper and crushing it with the back of a metal spoon. For children, the recommended dosing of terbinafine with a 250-mg tablet is based on weight: one-quarter of a tablet for a child weighing 10 to 20 kg; one-half of a tablet for a child weighing 20 to 40 kg; and a full tablet for a child weighing more than 40 kg.⁵ Because terbinafine tablets are not scored, a combined pill splitter–crusher can be used (also available at pharmacies or on Amazon; the price of this device is within the same price range as a pill crusher).

Practical Implication

Use of this method for crushing and mixing the terbinafine tablet allows patients who are unable to swallow a pill to safely and effectively use oral terbinafine.

Practice Gap

Terbinafine can be used safely and effectively in adult and pediatric patients to treat superficial fungal infections, including onychomycosis.¹ These superficial fungal infections have become increasingly prevalent in children and often require oral therapy²; however, children are frequently unable to swallow a pill.

Until 2016, terbinafine was available as oral granules that could be sprinkled on food, but this formulation has been discontinued.³ In addition, terbinafine tablets have a bitter taste. Therefore, the inability to swallow a pill—typical of young children and other patients with pill dysphagia—is a barrier to prescribing terbinafine.

The Technique

For patients who cannot swallow a pill, a terbinafine tablet can be crushed and mixed with food or a syrup without loss of efficacy. Terbinafine in tablet form has been shown to have relatively unchanged properties after being crushed and mixed in solution, even several weeks after preparation.⁴ Crushing and mixing a terbinafine tablet with food or a syrup therefore is an effective option for patients who cannot swallow a pill but can safely swallow food.

The food or syrup used for this purpose should have a pH of at least 5 because greater acidity reduces absorption of terbinafine. Therefore, avoid mixing it with fruit juices, applesauce, or soda. Given the bitter taste of the terbinafine tablet, mixing it with a sweet food or syrup improves taste and compliance, which makes pudding a particularly good food option for this purpose.

However, because younger patients might not finish an entire serving of pudding or other food into which the tablet has been crushed and mixed, inconsistent dosing might result. Therefore, we recommend mixing the crushed terbinafine tablet with 1 oz (30 mL) of chocolate syrup or corn syrup (Figure). This solution is sweet, easy to prepare and consume, widely available, and affordable (as low as $0.28/oz for corn syrup and as low as $0.10/oz for chocolate syrup, as priced on Amazon).

The tablet can be crushed using a pill crusher ($5–$10 at pharmacies or on Amazon) or by placing it on a piece of paper and crushing it with the back of a metal spoon. For children, the recommended dosing of terbinafine with a 250-mg tablet is based on weight: one-quarter of a tablet for a child weighing 10 to 20 kg; one-half of a tablet for a child weighing 20 to 40 kg; and a full tablet for a child weighing more than 40 kg.⁵ Because terbinafine tablets are not scored, a combined pill splitter–crusher can be used (also available at pharmacies or on Amazon; the price of this device is within the same price range as a pill crusher).

Practical Implication

Use of this method for crushing and mixing the terbinafine tablet allows patients who are unable to swallow a pill to safely and effectively use oral terbinafine.

The Diagnosis: Cutaneous Leishmaniasis

A punch biopsy of the skin showed pseudoepitheliomatous hyperplasia of the epidermis with dermal granulomatous and suppurative inflammation; tissue cultures remained sterile. Polymerase chain reaction testing of the skin revealed the presence of Leishmania guyanensis complex. Leishmaniasis is a widespread parasitic disease transmitted via sandflies that often is seen in children and young adults.¹ Although leishmaniasis is endemic to several countries within Southeast Asia, East Africa, and Latin America, an increase in international travel has brought the disease to nonendemic regions. Therefore, it is crucial to obtain a detailed history of travel and exposure to sandflies in patients who have recently returned from endemic regions.

Leishmaniasis may present in 3 forms: cutaneous, mucocutaneous, or visceral. Cutaneous clinical findings vary depending on disease stage, causative species, and host immune activation. Presentation following a sandfly bite typically includes a papule that progresses to an erythematous nodule. Cutaneous leishmaniasis commonly occurs in areas of the body that are easily accessible to sandflies, such as the face, neck, and limbs. Mucocutaneous leishmaniasis presents with nasal or oral involvement several years after the onset of cutaneous leishmaniasis; however, it can coexist with cutaneous involvement. Without treatment, mucocutaneous leishmaniasis may lead to perforation of the nasal septum, destruction of the mouth, and life-threatening airway obstruction.¹ Determining the specific species is important due to the variation in treatment options and prognosis. Because Leishmania organisms are fastidious, obtaining a positive culture often is challenging. Polymerase chain reaction can be utilized for identification, with detection rates of 97%.¹ Systemic treatment is indicated for patients with multiple or large lesions; lesions on the hands, feet, face, or joints; or immunocompromised patients. Antimonial drugs are the first-line treatment for most forms of leishmaniasis, though increasing resistance has led to a decrease in efficacy.¹ Our patient ultimately was treated with 4 weeks of miltefosine 50 mg 3 times daily. She obtained full resolution of the lesions with no further treatment indicated.

Pemphigus vegetans may present with various clinical manifestations that often can lead to a delay in diagnosis. The Hallopeau subtype typically presents as pustular lesions, while the Neumann subtype may present as large vesiculobullous erosive lesions that rupture and form verrucous, crusted, vegetative plaques. The groin, inguinal folds, axillae, thighs, and flexural areas commonly are affected, but reports of nasal, vaginal, and conjunctival involvement also exist.²

Granuloma inguinale is a sexually transmitted ulcerative disease that is caused by infection with Klebsiella granulomatis. It typically is found in tropical and subtropical climates, including Australia, Brazil, India, and South Africa. The initial presentation includes a single papule or multiple papules or nodules in the genital area that progress to a painless ulcer. It can be diagnosed via biopsies or tissue smears, which will demonstrate the presence of inclusion bodies known as Donovan bodies.³

Cutaneous tuberculosis (TB) can have variable clinical presentations and may be acquired exogenously or endogenously. Cutaneous TB can be divided into 2 categories: exogenous TB caused by inoculation and endogenous TB due to direct spread or autoinoculation. Exogenous TB subtypes include tuberculous chancre and TB verrucosa cutis, while endogenous TB includes scrofuloderma, orificial TB, and lupus vulgaris.⁴ Patches and plaques are found in patients with lupus vulgaris and TB verrucosa cutis. Scrofuloderma, tuberculous chancre, and orificial TB can present as ulcerative or erosive lesions. Cutaneous TB infection can be diagnosed through a smear, culture, or polymerase chain reaction.⁴

Deep cutaneous fungal infections most commonly present in immunocompromised individuals, particularly those who are severely neutropenic and are receiving broad-spectrum systemic antimicrobial agents. Deep cutaneous fungal infections initially present as a papule and evolve into a pustule followed by a necrotic ulcer. The lesions typically are accompanied by a fever and/or vital sign abnormalities.⁵

The Diagnosis: Cutaneous Leishmaniasis

A punch biopsy of the skin showed pseudoepitheliomatous hyperplasia of the epidermis with dermal granulomatous and suppurative inflammation; tissue cultures remained sterile. Polymerase chain reaction testing of the skin revealed the presence of Leishmania guyanensis complex. Leishmaniasis is a widespread parasitic disease transmitted via sandflies that often is seen in children and young adults.¹ Although leishmaniasis is endemic to several countries within Southeast Asia, East Africa, and Latin America, an increase in international travel has brought the disease to nonendemic regions. Therefore, it is crucial to obtain a detailed history of travel and exposure to sandflies in patients who have recently returned from endemic regions.

Leishmaniasis may present in 3 forms: cutaneous, mucocutaneous, or visceral. Cutaneous clinical findings vary depending on disease stage, causative species, and host immune activation. Presentation following a sandfly bite typically includes a papule that progresses to an erythematous nodule. Cutaneous leishmaniasis commonly occurs in areas of the body that are easily accessible to sandflies, such as the face, neck, and limbs. Mucocutaneous leishmaniasis presents with nasal or oral involvement several years after the onset of cutaneous leishmaniasis; however, it can coexist with cutaneous involvement. Without treatment, mucocutaneous leishmaniasis may lead to perforation of the nasal septum, destruction of the mouth, and life-threatening airway obstruction.¹ Determining the specific species is important due to the variation in treatment options and prognosis. Because Leishmania organisms are fastidious, obtaining a positive culture often is challenging. Polymerase chain reaction can be utilized for identification, with detection rates of 97%.¹ Systemic treatment is indicated for patients with multiple or large lesions; lesions on the hands, feet, face, or joints; or immunocompromised patients. Antimonial drugs are the first-line treatment for most forms of leishmaniasis, though increasing resistance has led to a decrease in efficacy.¹ Our patient ultimately was treated with 4 weeks of miltefosine 50 mg 3 times daily. She obtained full resolution of the lesions with no further treatment indicated.

Pemphigus vegetans may present with various clinical manifestations that often can lead to a delay in diagnosis. The Hallopeau subtype typically presents as pustular lesions, while the Neumann subtype may present as large vesiculobullous erosive lesions that rupture and form verrucous, crusted, vegetative plaques. The groin, inguinal folds, axillae, thighs, and flexural areas commonly are affected, but reports of nasal, vaginal, and conjunctival involvement also exist.²

Granuloma inguinale is a sexually transmitted ulcerative disease that is caused by infection with Klebsiella granulomatis. It typically is found in tropical and subtropical climates, including Australia, Brazil, India, and South Africa. The initial presentation includes a single papule or multiple papules or nodules in the genital area that progress to a painless ulcer. It can be diagnosed via biopsies or tissue smears, which will demonstrate the presence of inclusion bodies known as Donovan bodies.³

Cutaneous tuberculosis (TB) can have variable clinical presentations and may be acquired exogenously or endogenously. Cutaneous TB can be divided into 2 categories: exogenous TB caused by inoculation and endogenous TB due to direct spread or autoinoculation. Exogenous TB subtypes include tuberculous chancre and TB verrucosa cutis, while endogenous TB includes scrofuloderma, orificial TB, and lupus vulgaris.⁴ Patches and plaques are found in patients with lupus vulgaris and TB verrucosa cutis. Scrofuloderma, tuberculous chancre, and orificial TB can present as ulcerative or erosive lesions. Cutaneous TB infection can be diagnosed through a smear, culture, or polymerase chain reaction.⁴

Deep cutaneous fungal infections most commonly present in immunocompromised individuals, particularly those who are severely neutropenic and are receiving broad-spectrum systemic antimicrobial agents. Deep cutaneous fungal infections initially present as a papule and evolve into a pustule followed by a necrotic ulcer. The lesions typically are accompanied by a fever and/or vital sign abnormalities.⁵

The Diagnosis: Cutaneous Leishmaniasis

A punch biopsy of the skin showed pseudoepitheliomatous hyperplasia of the epidermis with dermal granulomatous and suppurative inflammation; tissue cultures remained sterile. Polymerase chain reaction testing of the skin revealed the presence of Leishmania guyanensis complex. Leishmaniasis is a widespread parasitic disease transmitted via sandflies that often is seen in children and young adults.¹ Although leishmaniasis is endemic to several countries within Southeast Asia, East Africa, and Latin America, an increase in international travel has brought the disease to nonendemic regions. Therefore, it is crucial to obtain a detailed history of travel and exposure to sandflies in patients who have recently returned from endemic regions.

Leishmaniasis may present in 3 forms: cutaneous, mucocutaneous, or visceral. Cutaneous clinical findings vary depending on disease stage, causative species, and host immune activation. Presentation following a sandfly bite typically includes a papule that progresses to an erythematous nodule. Cutaneous leishmaniasis commonly occurs in areas of the body that are easily accessible to sandflies, such as the face, neck, and limbs. Mucocutaneous leishmaniasis presents with nasal or oral involvement several years after the onset of cutaneous leishmaniasis; however, it can coexist with cutaneous involvement. Without treatment, mucocutaneous leishmaniasis may lead to perforation of the nasal septum, destruction of the mouth, and life-threatening airway obstruction.¹ Determining the specific species is important due to the variation in treatment options and prognosis. Because Leishmania organisms are fastidious, obtaining a positive culture often is challenging. Polymerase chain reaction can be utilized for identification, with detection rates of 97%.¹ Systemic treatment is indicated for patients with multiple or large lesions; lesions on the hands, feet, face, or joints; or immunocompromised patients. Antimonial drugs are the first-line treatment for most forms of leishmaniasis, though increasing resistance has led to a decrease in efficacy.¹ Our patient ultimately was treated with 4 weeks of miltefosine 50 mg 3 times daily. She obtained full resolution of the lesions with no further treatment indicated.

Pemphigus vegetans may present with various clinical manifestations that often can lead to a delay in diagnosis. The Hallopeau subtype typically presents as pustular lesions, while the Neumann subtype may present as large vesiculobullous erosive lesions that rupture and form verrucous, crusted, vegetative plaques. The groin, inguinal folds, axillae, thighs, and flexural areas commonly are affected, but reports of nasal, vaginal, and conjunctival involvement also exist.²

Granuloma inguinale is a sexually transmitted ulcerative disease that is caused by infection with Klebsiella granulomatis. It typically is found in tropical and subtropical climates, including Australia, Brazil, India, and South Africa. The initial presentation includes a single papule or multiple papules or nodules in the genital area that progress to a painless ulcer. It can be diagnosed via biopsies or tissue smears, which will demonstrate the presence of inclusion bodies known as Donovan bodies.³

Cutaneous tuberculosis (TB) can have variable clinical presentations and may be acquired exogenously or endogenously. Cutaneous TB can be divided into 2 categories: exogenous TB caused by inoculation and endogenous TB due to direct spread or autoinoculation. Exogenous TB subtypes include tuberculous chancre and TB verrucosa cutis, while endogenous TB includes scrofuloderma, orificial TB, and lupus vulgaris.⁴ Patches and plaques are found in patients with lupus vulgaris and TB verrucosa cutis. Scrofuloderma, tuberculous chancre, and orificial TB can present as ulcerative or erosive lesions. Cutaneous TB infection can be diagnosed through a smear, culture, or polymerase chain reaction.⁴

Deep cutaneous fungal infections most commonly present in immunocompromised individuals, particularly those who are severely neutropenic and are receiving broad-spectrum systemic antimicrobial agents. Deep cutaneous fungal infections initially present as a papule and evolve into a pustule followed by a necrotic ulcer. The lesions typically are accompanied by a fever and/or vital sign abnormalities.⁵

Despite the profound shift in guidelines for preventing peanut allergies in infants after the landmark LEAP study, national surveys in 2021 showed that 70% of parents and caregivers said that they hadn’t heard the new recommendations, and fewer than one-third of pediatricians were following them.

Now, in a 5-year National Institutes of Health–funded study called iREACH, researchers are testing whether a two-part intervention, which includes training videos and a clinical decision support tool, helps pediatricians follow the guidelines and ultimately reduces peanut allergy.

Early results from iREACH, presented at the American Academy of Allergy, Asthma, and Immunology 2023 annual meeting in San Antonio, showed mixed results with a sharp rise in clinician knowledge of the guidelines but only a modest increase in their real-world implementation with high-risk infants.

Raising a food-allergic child while working as a pediatrician herself, Ruchi Gupta, MD, MPH, director of the Center for Food Allergy and Asthma Research at Northwestern University, Chicago, understands the importance and challenge of translating published findings into practice.

During a typical 4- to 6-month well-child visit, pediatricians must check the baby’s growth, perform a physical exam, discuss milestones, field questions about sleep and poop and colic and – if they’re up on the latest guidelines – explain why it’s important to feed peanuts early and often.

“Pediatricians get stuff from every single specialty, and guidelines are always changing,” she told this news organization.

The current feeding guidelines, published in 2017 after the landmark LEAP study, switched from “ ‘don’t introduce peanuts until age 3’ to ‘introduce peanuts now,’ ” said Dr. Gupta.

But the recommendations aren’t entirely straightforward. They require pediatricians to make an assessment when the baby is around 4 months old. If the child is high-risk (has severe eczema or an egg allergy), they need a peanut-specific immunoglobulin E (IgE) test. If the test is negative, the pediatrician should encourage peanut introduction. If positive, they should refer the child to an allergist.

“It’s a little complicated,” Dr. Gupta said.

To boost understanding and adherence, Dr. Gupta’s team created the intervention tested in the iREACH study. It includes a set of training videos, a clinical decision support tool that embeds into the electronic health record (EHR) with pop-ups reminding the physician to discuss early introduction, menus for ordering peanut IgE tests or referring to an allergist if needed, and a caregiver handout that explains how to add peanuts to the baby’s diet. (These resources can be found here.)

The study enrolled 290 pediatric clinicians at 30 local practices, examining 18,460 babies from diverse backgrounds, about one-quarter of whom were from families on public insurance. About half of the clinicians received the intervention, whereas the other half served as the control arm.

The training videos seemed effective. Clinicians’ knowledge of the guidelines rose from 72.6% at baseline to 94.5% after the intervention, and their ability to identify severe eczema went up from 63.4% to 97.6%. This translated to 70.4% success with applying the guidelines when presented various clinical scenarios, up from 29% at baseline. These results are in press at JAMA Network Open.

The next set of analyses, preliminary and unpublished, monitored real-world adherence using natural language processing to pull EHR data from 4- and 6-month well-check visits. It was “AI [artificial intelligence] for notes,” Dr. Gupta said.

For low-risk infants, the training and EHR-embedded support tool greatly improved clinician adherence. Eighty percent of clinicians in the intervention arm followed the guidelines, compared with 26% in the control group.

In high-risk infants, the impact was much weaker. Even after the video-based training, only 17% of pediatric clinicians followed the guidelines – that is, ordered a peanut IgE test or referred to an allergist – compared with 8% in the control group.

Why such a low uptake?

Pediatricians are time-pressed. “How do you add [early introduction] to the other 10 or 15 things you want to talk to a parent about at the 4-month visit?” said Jonathan Necheles, MD, MPH, a pediatrician at Children’s Healthcare Associates in Chicago.

It can also be hard to tell if a baby’s eczema is “severe” or “mild to moderate.” The EHR-integrated support tool included a scorecard for judging eczema severity across a range of skin tones. The condition can be hard to recognize in patients of color. “You don’t get the redness in the same way,” said Dr. Necheles, who worked with Dr. Gupta to develop the iREACH intervention.

Curiously, even though the AI analysis found that less than one-fifth of pediatricians put the guidelines into action for high-risk infants, 69% of them recommended peanut introduction.

One interpretation is that busy pediatricians may be “doing the minimum” – introducing the concept of early introduction and telling parents to try it “but not giving any additional sort of guidance as far as who’s high risk, who’s low risk, who should see the allergist, who should get screened,” said Edwin Kim, MD, allergist-immunologist and director of the Food Allergy Initiative at the University of North Carolina at Chapel Hill.

The ultimate impact of iREACH has yet to be seen. “The end goal is, if pediatricians recommend, will parents follow, and will we reduce peanut allergy?” Dr. Gupta said.

Dr. Gupta consults or serves as an advisor for Genentech, Novartis, Aimmune, Allergenis, and Food Allergy Research & Education; receives research funding from Novartis, Genentech, FARE, Melchiorre Family Foundation, and Sunshine Charitable Foundation; and reports ownership interest from Yobee Care. Dr. Necheles reports no financial disclosures. Dr. Kim reports consultancy with Allergy Therapeutics, Belhaven Biopharma, Duke Clinical Research Institute, Genentech, Nutricia, and Revolo; advisory board membership with ALK, Kenota Health, and Ukko; and grant support from the National Institute of Allergy and Infectious Diseases, Immune Tolerance Network, and Food Allergy Research and Education.

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

Despite the profound shift in guidelines for preventing peanut allergies in infants after the landmark LEAP study, national surveys in 2021 showed that 70% of parents and caregivers said that they hadn’t heard the new recommendations, and fewer than one-third of pediatricians were following them.

Now, in a 5-year National Institutes of Health–funded study called iREACH, researchers are testing whether a two-part intervention, which includes training videos and a clinical decision support tool, helps pediatricians follow the guidelines and ultimately reduces peanut allergy.

Early results from iREACH, presented at the American Academy of Allergy, Asthma, and Immunology 2023 annual meeting in San Antonio, showed mixed results with a sharp rise in clinician knowledge of the guidelines but only a modest increase in their real-world implementation with high-risk infants.

Raising a food-allergic child while working as a pediatrician herself, Ruchi Gupta, MD, MPH, director of the Center for Food Allergy and Asthma Research at Northwestern University, Chicago, understands the importance and challenge of translating published findings into practice.

During a typical 4- to 6-month well-child visit, pediatricians must check the baby’s growth, perform a physical exam, discuss milestones, field questions about sleep and poop and colic and – if they’re up on the latest guidelines – explain why it’s important to feed peanuts early and often.

“Pediatricians get stuff from every single specialty, and guidelines are always changing,” she told this news organization.

The current feeding guidelines, published in 2017 after the landmark LEAP study, switched from “ ‘don’t introduce peanuts until age 3’ to ‘introduce peanuts now,’ ” said Dr. Gupta.

But the recommendations aren’t entirely straightforward. They require pediatricians to make an assessment when the baby is around 4 months old. If the child is high-risk (has severe eczema or an egg allergy), they need a peanut-specific immunoglobulin E (IgE) test. If the test is negative, the pediatrician should encourage peanut introduction. If positive, they should refer the child to an allergist.

“It’s a little complicated,” Dr. Gupta said.

To boost understanding and adherence, Dr. Gupta’s team created the intervention tested in the iREACH study. It includes a set of training videos, a clinical decision support tool that embeds into the electronic health record (EHR) with pop-ups reminding the physician to discuss early introduction, menus for ordering peanut IgE tests or referring to an allergist if needed, and a caregiver handout that explains how to add peanuts to the baby’s diet. (These resources can be found here.)

The study enrolled 290 pediatric clinicians at 30 local practices, examining 18,460 babies from diverse backgrounds, about one-quarter of whom were from families on public insurance. About half of the clinicians received the intervention, whereas the other half served as the control arm.

The training videos seemed effective. Clinicians’ knowledge of the guidelines rose from 72.6% at baseline to 94.5% after the intervention, and their ability to identify severe eczema went up from 63.4% to 97.6%. This translated to 70.4% success with applying the guidelines when presented various clinical scenarios, up from 29% at baseline. These results are in press at JAMA Network Open.

The next set of analyses, preliminary and unpublished, monitored real-world adherence using natural language processing to pull EHR data from 4- and 6-month well-check visits. It was “AI [artificial intelligence] for notes,” Dr. Gupta said.

For low-risk infants, the training and EHR-embedded support tool greatly improved clinician adherence. Eighty percent of clinicians in the intervention arm followed the guidelines, compared with 26% in the control group.

In high-risk infants, the impact was much weaker. Even after the video-based training, only 17% of pediatric clinicians followed the guidelines – that is, ordered a peanut IgE test or referred to an allergist – compared with 8% in the control group.

Why such a low uptake?

Pediatricians are time-pressed. “How do you add [early introduction] to the other 10 or 15 things you want to talk to a parent about at the 4-month visit?” said Jonathan Necheles, MD, MPH, a pediatrician at Children’s Healthcare Associates in Chicago.

It can also be hard to tell if a baby’s eczema is “severe” or “mild to moderate.” The EHR-integrated support tool included a scorecard for judging eczema severity across a range of skin tones. The condition can be hard to recognize in patients of color. “You don’t get the redness in the same way,” said Dr. Necheles, who worked with Dr. Gupta to develop the iREACH intervention.

Curiously, even though the AI analysis found that less than one-fifth of pediatricians put the guidelines into action for high-risk infants, 69% of them recommended peanut introduction.

One interpretation is that busy pediatricians may be “doing the minimum” – introducing the concept of early introduction and telling parents to try it “but not giving any additional sort of guidance as far as who’s high risk, who’s low risk, who should see the allergist, who should get screened,” said Edwin Kim, MD, allergist-immunologist and director of the Food Allergy Initiative at the University of North Carolina at Chapel Hill.

The ultimate impact of iREACH has yet to be seen. “The end goal is, if pediatricians recommend, will parents follow, and will we reduce peanut allergy?” Dr. Gupta said.

Dr. Gupta consults or serves as an advisor for Genentech, Novartis, Aimmune, Allergenis, and Food Allergy Research & Education; receives research funding from Novartis, Genentech, FARE, Melchiorre Family Foundation, and Sunshine Charitable Foundation; and reports ownership interest from Yobee Care. Dr. Necheles reports no financial disclosures. Dr. Kim reports consultancy with Allergy Therapeutics, Belhaven Biopharma, Duke Clinical Research Institute, Genentech, Nutricia, and Revolo; advisory board membership with ALK, Kenota Health, and Ukko; and grant support from the National Institute of Allergy and Infectious Diseases, Immune Tolerance Network, and Food Allergy Research and Education.

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

Despite the profound shift in guidelines for preventing peanut allergies in infants after the landmark LEAP study, national surveys in 2021 showed that 70% of parents and caregivers said that they hadn’t heard the new recommendations, and fewer than one-third of pediatricians were following them.

Now, in a 5-year National Institutes of Health–funded study called iREACH, researchers are testing whether a two-part intervention, which includes training videos and a clinical decision support tool, helps pediatricians follow the guidelines and ultimately reduces peanut allergy.

Early results from iREACH, presented at the American Academy of Allergy, Asthma, and Immunology 2023 annual meeting in San Antonio, showed mixed results with a sharp rise in clinician knowledge of the guidelines but only a modest increase in their real-world implementation with high-risk infants.

Raising a food-allergic child while working as a pediatrician herself, Ruchi Gupta, MD, MPH, director of the Center for Food Allergy and Asthma Research at Northwestern University, Chicago, understands the importance and challenge of translating published findings into practice.

During a typical 4- to 6-month well-child visit, pediatricians must check the baby’s growth, perform a physical exam, discuss milestones, field questions about sleep and poop and colic and – if they’re up on the latest guidelines – explain why it’s important to feed peanuts early and often.

“Pediatricians get stuff from every single specialty, and guidelines are always changing,” she told this news organization.

The current feeding guidelines, published in 2017 after the landmark LEAP study, switched from “ ‘don’t introduce peanuts until age 3’ to ‘introduce peanuts now,’ ” said Dr. Gupta.

But the recommendations aren’t entirely straightforward. They require pediatricians to make an assessment when the baby is around 4 months old. If the child is high-risk (has severe eczema or an egg allergy), they need a peanut-specific immunoglobulin E (IgE) test. If the test is negative, the pediatrician should encourage peanut introduction. If positive, they should refer the child to an allergist.

“It’s a little complicated,” Dr. Gupta said.

To boost understanding and adherence, Dr. Gupta’s team created the intervention tested in the iREACH study. It includes a set of training videos, a clinical decision support tool that embeds into the electronic health record (EHR) with pop-ups reminding the physician to discuss early introduction, menus for ordering peanut IgE tests or referring to an allergist if needed, and a caregiver handout that explains how to add peanuts to the baby’s diet. (These resources can be found here.)

The study enrolled 290 pediatric clinicians at 30 local practices, examining 18,460 babies from diverse backgrounds, about one-quarter of whom were from families on public insurance. About half of the clinicians received the intervention, whereas the other half served as the control arm.

The training videos seemed effective. Clinicians’ knowledge of the guidelines rose from 72.6% at baseline to 94.5% after the intervention, and their ability to identify severe eczema went up from 63.4% to 97.6%. This translated to 70.4% success with applying the guidelines when presented various clinical scenarios, up from 29% at baseline. These results are in press at JAMA Network Open.

The next set of analyses, preliminary and unpublished, monitored real-world adherence using natural language processing to pull EHR data from 4- and 6-month well-check visits. It was “AI [artificial intelligence] for notes,” Dr. Gupta said.

For low-risk infants, the training and EHR-embedded support tool greatly improved clinician adherence. Eighty percent of clinicians in the intervention arm followed the guidelines, compared with 26% in the control group.

In high-risk infants, the impact was much weaker. Even after the video-based training, only 17% of pediatric clinicians followed the guidelines – that is, ordered a peanut IgE test or referred to an allergist – compared with 8% in the control group.

Why such a low uptake?

Pediatricians are time-pressed. “How do you add [early introduction] to the other 10 or 15 things you want to talk to a parent about at the 4-month visit?” said Jonathan Necheles, MD, MPH, a pediatrician at Children’s Healthcare Associates in Chicago.

It can also be hard to tell if a baby’s eczema is “severe” or “mild to moderate.” The EHR-integrated support tool included a scorecard for judging eczema severity across a range of skin tones. The condition can be hard to recognize in patients of color. “You don’t get the redness in the same way,” said Dr. Necheles, who worked with Dr. Gupta to develop the iREACH intervention.

Curiously, even though the AI analysis found that less than one-fifth of pediatricians put the guidelines into action for high-risk infants, 69% of them recommended peanut introduction.

One interpretation is that busy pediatricians may be “doing the minimum” – introducing the concept of early introduction and telling parents to try it “but not giving any additional sort of guidance as far as who’s high risk, who’s low risk, who should see the allergist, who should get screened,” said Edwin Kim, MD, allergist-immunologist and director of the Food Allergy Initiative at the University of North Carolina at Chapel Hill.

The ultimate impact of iREACH has yet to be seen. “The end goal is, if pediatricians recommend, will parents follow, and will we reduce peanut allergy?” Dr. Gupta said.

Dr. Gupta consults or serves as an advisor for Genentech, Novartis, Aimmune, Allergenis, and Food Allergy Research & Education; receives research funding from Novartis, Genentech, FARE, Melchiorre Family Foundation, and Sunshine Charitable Foundation; and reports ownership interest from Yobee Care. Dr. Necheles reports no financial disclosures. Dr. Kim reports consultancy with Allergy Therapeutics, Belhaven Biopharma, Duke Clinical Research Institute, Genentech, Nutricia, and Revolo; advisory board membership with ALK, Kenota Health, and Ukko; and grant support from the National Institute of Allergy and Infectious Diseases, Immune Tolerance Network, and Food Allergy Research and Education.

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

SAN DIEGO – A downside of the revolutionary advances in targeted and immune therapies used to treat melanoma are their potential to trigger a wide range of skin reactions, from acneiform eruptions to Stevens-Johnson Syndrome (SJS).

“These skin reactions can cause pain, itching, and emotional and social distress that may severely impact activities of daily living,” Aleksandr Itkin, MD, a dermatologist at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. An estimated 30%-50% of patients on immune checkpoint inhibitors (ICIs) experience cutaneous adverse events, he said, which leads to dose reduction or discontinuation of ICIs in 20% of cases.

Clinicians first observed these side effects in 2011, with the Food and Drug Administration approval of ipilimumab, a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)–blocking antibody, for metastatic melanoma, followed by the programmed death receptor-1 (PD-1) inhibitors nivolumab and pembrolizumab, which were approved in 2014 for the same indication.

Courtesy Dr. Aleksandr Itkin

Since then, more ICIs showing similar adverse cutaneous reactions have been approved by the FDA. These include avelumab, atezolizumab in combination with cobimetinib and vemurafenib, and a combination of relatlimab, an anti-LAG-3 antibody, with nivolumab.

Among the targeted therapies, the BRAF inhibitors vemurafenib and dabrafenib alone or in combination with MAPK pathway inhibitors cobimetinib and trametinib, which are a first-line therapy for V600 BRAF mutated metastatic melanoma, are associated with their own set of cutaneous reactions. The oncolytic modified herpes simplex virus T-VEC (talimogene laherparepvec), approved by the FDA in 2015 for the treatment of unresectable stage IIIB-IV metastatic melanoma, also results in cutaneous reactions that have been found useful in assessing the therapeutic outcome of this agent.

According to a 2020 CME article on the dermatologic adverse events that occur after treatment initiation with ICIs, the time of onset of psoriasiform rash is within the first 3 weeks, maculopapular rash and pruritus in the first 4-6 weeks, lichenoid eruption in the first 7-12 weeks, and bullous pemphigoid in weeks 13-15. The most severe reactions – SJS, toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) – usually occur after 2-3 months of treatment.

A subsequent retrospective cohort study of patients in the United States treated with ICIs for a variety of systemic malignancies and matched controls found that the ICI-treated group had a significantly higher incidence of pruritus, mucositis, erythroderma, maculopapular eruption, vitiligo, lichen planus, bullous pemphigoid, Grover disease, rash, other nonspecific eruptions, and drug eruption or other nonspecific drug reaction. Patients with melanoma and renal cell carcinoma and those receiving combination therapy were at a higher risk of cutaneous immune-related adverse events.

Another study, a prospective trial of 617 patients with various advanced cancers (including melanoma), found that both severe and mild skin toxicities were significantly associated with improved progression-free and overall survival.

According to Dr. Itkin, erythema multiforme, SJS, and TEN have been reported with anti-PD1, anti-CTLA4, and BRAF inhibitors. In TEN induced by vemurafenib, an in vitro analysis showed cross-activation of lymphocytes with dabrafenib and with sulfamethoxazole. “This means you that may want to avoid sulfonamides in patients with serious hypersensitivity to vemurafenib, and vice versa,” he said at the meeting hosted by Scripps MD Anderson Cancer Center.
 

Acneiform eruptions

In addition, the use of MAPK inhibitors can trigger acneiform eruptions. In one study, 77% of patients on trametinib developed acneiform eruption, but only 10% of those on trametinib in combination with dabrafenib developed acneiform eruption. “Inhibition of the MAPK pathway leads to decreased proliferative markers, further leading to decreased keratinocyte replication, increased inflammatory cytokine, apoptosis, thinning and abnormal epidermal differentiation, follicular rupture, and papule/pustule formation,” he said. For these cases, “treatment options are similar to what we use for regular acne except for here, use of systemic steroids is sometimes needed, especially in more severe cases. The reaction may be so severe as to lead to dose reduction or discontinuation of antineoplastic treatment.”

Effects on nail, hair

Paronychia and onycholysis are additional potential adverse events of MEK inhibitors and BRAF inhibitors alone or in combination, Dr. Itkin continued. Onycholysis is associated with dabrafenib alone or in combination with trametinib, while vemurafenib has been shown to induce acute paronychia and brittle nails. He said that secondary infections in these cases can be treated with the options familiar to dermatologists in their daily practice: oral doxycycline, azole antifungals, vinegar soaks, topical superpotent corticosteroids under occlusion, nail avulsion, and phenol nail matrix ablation.

Dr. Itkin noted that while PD-1 and PD-L1 inhibitors can cause hair repigmentation, CTLA-4 and PD-1 inhibitors are more likely to cause vitiligo. Appearance of vitiligo is regarded as a good prognostic factor in the treatment of melanoma with various checkpoint inhibitors alone or in combination with each other or with radiation therapy. “About 5% of melanoma patients treated with ipilimumab will develop vitiligo,” he said.

ICI-induced vitiligo differs from conventional vitiligo in that there is no family or personal history of autoimmunity; it presents as a flecked pattern of lesion on photo-exposed skin, and it lacks the Koebner phenomenon. In addition, induction of squamous neoplasms can occur with BRAF inhibitors, especially in patients with a high frequency of RAS mutations.

He said that coadministration of MEK inhibitors such as trametinib and cobimetinib may prevent induction of keratinocytic neoplasms.

Dr. Itkin reported having no relevant financial disclosures.

SAN DIEGO – A downside of the revolutionary advances in targeted and immune therapies used to treat melanoma are their potential to trigger a wide range of skin reactions, from acneiform eruptions to Stevens-Johnson Syndrome (SJS).

“These skin reactions can cause pain, itching, and emotional and social distress that may severely impact activities of daily living,” Aleksandr Itkin, MD, a dermatologist at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. An estimated 30%-50% of patients on immune checkpoint inhibitors (ICIs) experience cutaneous adverse events, he said, which leads to dose reduction or discontinuation of ICIs in 20% of cases.

Clinicians first observed these side effects in 2011, with the Food and Drug Administration approval of ipilimumab, a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)–blocking antibody, for metastatic melanoma, followed by the programmed death receptor-1 (PD-1) inhibitors nivolumab and pembrolizumab, which were approved in 2014 for the same indication.

Courtesy Dr. Aleksandr Itkin

Since then, more ICIs showing similar adverse cutaneous reactions have been approved by the FDA. These include avelumab, atezolizumab in combination with cobimetinib and vemurafenib, and a combination of relatlimab, an anti-LAG-3 antibody, with nivolumab.

Among the targeted therapies, the BRAF inhibitors vemurafenib and dabrafenib alone or in combination with MAPK pathway inhibitors cobimetinib and trametinib, which are a first-line therapy for V600 BRAF mutated metastatic melanoma, are associated with their own set of cutaneous reactions. The oncolytic modified herpes simplex virus T-VEC (talimogene laherparepvec), approved by the FDA in 2015 for the treatment of unresectable stage IIIB-IV metastatic melanoma, also results in cutaneous reactions that have been found useful in assessing the therapeutic outcome of this agent.

According to a 2020 CME article on the dermatologic adverse events that occur after treatment initiation with ICIs, the time of onset of psoriasiform rash is within the first 3 weeks, maculopapular rash and pruritus in the first 4-6 weeks, lichenoid eruption in the first 7-12 weeks, and bullous pemphigoid in weeks 13-15. The most severe reactions – SJS, toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) – usually occur after 2-3 months of treatment.

A subsequent retrospective cohort study of patients in the United States treated with ICIs for a variety of systemic malignancies and matched controls found that the ICI-treated group had a significantly higher incidence of pruritus, mucositis, erythroderma, maculopapular eruption, vitiligo, lichen planus, bullous pemphigoid, Grover disease, rash, other nonspecific eruptions, and drug eruption or other nonspecific drug reaction. Patients with melanoma and renal cell carcinoma and those receiving combination therapy were at a higher risk of cutaneous immune-related adverse events.

Another study, a prospective trial of 617 patients with various advanced cancers (including melanoma), found that both severe and mild skin toxicities were significantly associated with improved progression-free and overall survival.

According to Dr. Itkin, erythema multiforme, SJS, and TEN have been reported with anti-PD1, anti-CTLA4, and BRAF inhibitors. In TEN induced by vemurafenib, an in vitro analysis showed cross-activation of lymphocytes with dabrafenib and with sulfamethoxazole. “This means you that may want to avoid sulfonamides in patients with serious hypersensitivity to vemurafenib, and vice versa,” he said at the meeting hosted by Scripps MD Anderson Cancer Center.
 

Acneiform eruptions

In addition, the use of MAPK inhibitors can trigger acneiform eruptions. In one study, 77% of patients on trametinib developed acneiform eruption, but only 10% of those on trametinib in combination with dabrafenib developed acneiform eruption. “Inhibition of the MAPK pathway leads to decreased proliferative markers, further leading to decreased keratinocyte replication, increased inflammatory cytokine, apoptosis, thinning and abnormal epidermal differentiation, follicular rupture, and papule/pustule formation,” he said. For these cases, “treatment options are similar to what we use for regular acne except for here, use of systemic steroids is sometimes needed, especially in more severe cases. The reaction may be so severe as to lead to dose reduction or discontinuation of antineoplastic treatment.”

Effects on nail, hair

Paronychia and onycholysis are additional potential adverse events of MEK inhibitors and BRAF inhibitors alone or in combination, Dr. Itkin continued. Onycholysis is associated with dabrafenib alone or in combination with trametinib, while vemurafenib has been shown to induce acute paronychia and brittle nails. He said that secondary infections in these cases can be treated with the options familiar to dermatologists in their daily practice: oral doxycycline, azole antifungals, vinegar soaks, topical superpotent corticosteroids under occlusion, nail avulsion, and phenol nail matrix ablation.

Dr. Itkin noted that while PD-1 and PD-L1 inhibitors can cause hair repigmentation, CTLA-4 and PD-1 inhibitors are more likely to cause vitiligo. Appearance of vitiligo is regarded as a good prognostic factor in the treatment of melanoma with various checkpoint inhibitors alone or in combination with each other or with radiation therapy. “About 5% of melanoma patients treated with ipilimumab will develop vitiligo,” he said.

ICI-induced vitiligo differs from conventional vitiligo in that there is no family or personal history of autoimmunity; it presents as a flecked pattern of lesion on photo-exposed skin, and it lacks the Koebner phenomenon. In addition, induction of squamous neoplasms can occur with BRAF inhibitors, especially in patients with a high frequency of RAS mutations.

He said that coadministration of MEK inhibitors such as trametinib and cobimetinib may prevent induction of keratinocytic neoplasms.

Dr. Itkin reported having no relevant financial disclosures.

SAN DIEGO – A downside of the revolutionary advances in targeted and immune therapies used to treat melanoma are their potential to trigger a wide range of skin reactions, from acneiform eruptions to Stevens-Johnson Syndrome (SJS).

“These skin reactions can cause pain, itching, and emotional and social distress that may severely impact activities of daily living,” Aleksandr Itkin, MD, a dermatologist at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. An estimated 30%-50% of patients on immune checkpoint inhibitors (ICIs) experience cutaneous adverse events, he said, which leads to dose reduction or discontinuation of ICIs in 20% of cases.

Clinicians first observed these side effects in 2011, with the Food and Drug Administration approval of ipilimumab, a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)–blocking antibody, for metastatic melanoma, followed by the programmed death receptor-1 (PD-1) inhibitors nivolumab and pembrolizumab, which were approved in 2014 for the same indication.

Courtesy Dr. Aleksandr Itkin

Since then, more ICIs showing similar adverse cutaneous reactions have been approved by the FDA. These include avelumab, atezolizumab in combination with cobimetinib and vemurafenib, and a combination of relatlimab, an anti-LAG-3 antibody, with nivolumab.

Among the targeted therapies, the BRAF inhibitors vemurafenib and dabrafenib alone or in combination with MAPK pathway inhibitors cobimetinib and trametinib, which are a first-line therapy for V600 BRAF mutated metastatic melanoma, are associated with their own set of cutaneous reactions. The oncolytic modified herpes simplex virus T-VEC (talimogene laherparepvec), approved by the FDA in 2015 for the treatment of unresectable stage IIIB-IV metastatic melanoma, also results in cutaneous reactions that have been found useful in assessing the therapeutic outcome of this agent.

According to a 2020 CME article on the dermatologic adverse events that occur after treatment initiation with ICIs, the time of onset of psoriasiform rash is within the first 3 weeks, maculopapular rash and pruritus in the first 4-6 weeks, lichenoid eruption in the first 7-12 weeks, and bullous pemphigoid in weeks 13-15. The most severe reactions – SJS, toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) – usually occur after 2-3 months of treatment.

A subsequent retrospective cohort study of patients in the United States treated with ICIs for a variety of systemic malignancies and matched controls found that the ICI-treated group had a significantly higher incidence of pruritus, mucositis, erythroderma, maculopapular eruption, vitiligo, lichen planus, bullous pemphigoid, Grover disease, rash, other nonspecific eruptions, and drug eruption or other nonspecific drug reaction. Patients with melanoma and renal cell carcinoma and those receiving combination therapy were at a higher risk of cutaneous immune-related adverse events.

Another study, a prospective trial of 617 patients with various advanced cancers (including melanoma), found that both severe and mild skin toxicities were significantly associated with improved progression-free and overall survival.

According to Dr. Itkin, erythema multiforme, SJS, and TEN have been reported with anti-PD1, anti-CTLA4, and BRAF inhibitors. In TEN induced by vemurafenib, an in vitro analysis showed cross-activation of lymphocytes with dabrafenib and with sulfamethoxazole. “This means you that may want to avoid sulfonamides in patients with serious hypersensitivity to vemurafenib, and vice versa,” he said at the meeting hosted by Scripps MD Anderson Cancer Center.
 

Acneiform eruptions

In addition, the use of MAPK inhibitors can trigger acneiform eruptions. In one study, 77% of patients on trametinib developed acneiform eruption, but only 10% of those on trametinib in combination with dabrafenib developed acneiform eruption. “Inhibition of the MAPK pathway leads to decreased proliferative markers, further leading to decreased keratinocyte replication, increased inflammatory cytokine, apoptosis, thinning and abnormal epidermal differentiation, follicular rupture, and papule/pustule formation,” he said. For these cases, “treatment options are similar to what we use for regular acne except for here, use of systemic steroids is sometimes needed, especially in more severe cases. The reaction may be so severe as to lead to dose reduction or discontinuation of antineoplastic treatment.”

Effects on nail, hair

Paronychia and onycholysis are additional potential adverse events of MEK inhibitors and BRAF inhibitors alone or in combination, Dr. Itkin continued. Onycholysis is associated with dabrafenib alone or in combination with trametinib, while vemurafenib has been shown to induce acute paronychia and brittle nails. He said that secondary infections in these cases can be treated with the options familiar to dermatologists in their daily practice: oral doxycycline, azole antifungals, vinegar soaks, topical superpotent corticosteroids under occlusion, nail avulsion, and phenol nail matrix ablation.

Dr. Itkin noted that while PD-1 and PD-L1 inhibitors can cause hair repigmentation, CTLA-4 and PD-1 inhibitors are more likely to cause vitiligo. Appearance of vitiligo is regarded as a good prognostic factor in the treatment of melanoma with various checkpoint inhibitors alone or in combination with each other or with radiation therapy. “About 5% of melanoma patients treated with ipilimumab will develop vitiligo,” he said.

ICI-induced vitiligo differs from conventional vitiligo in that there is no family or personal history of autoimmunity; it presents as a flecked pattern of lesion on photo-exposed skin, and it lacks the Koebner phenomenon. In addition, induction of squamous neoplasms can occur with BRAF inhibitors, especially in patients with a high frequency of RAS mutations.

He said that coadministration of MEK inhibitors such as trametinib and cobimetinib may prevent induction of keratinocytic neoplasms.

Dr. Itkin reported having no relevant financial disclosures.

Physician interactions with nurse practitioners (NPs) and physician assistants (PAs) are only going to increase in frequency. – The U.S. Bureau of Labor Statistics forecasts a 40% increase in the NP workforce by 2031, coupled with a 28% rise in PAs.

In recent reports on the quality of the relationships involving these health care professions, survey respondents mostly gave positive accounts of collaboration, using words such as like “comradery,” “teamwork,” “congenial,” and “cohesion.” But all was not perfect. Where and how could these important health care provider relationships improve?
 

PAs: “Competition and collaboration’ with RNs

In a Medscape survey of more than 770 PAs about their working relationships with other health care professionals; 83% of them supported the idea of PAs and NPs practicing more independently from physicians, but sometimes it’s not easy to stay in their individual lanes.

One PA respondent complained that NPs get “more opportunities and preference,” another pointed to PA-NP “turf issues,” and a third griped about NPs’ “strong unions,” which have stoked more fighting about practice abilities and available settings.

Robert Blumm, MA, PA-C, a retired surgical and emergency medicine PA who regards himself as an advocate for both PAs and NPs, describes their interaction as a “mixture of competition and collaboration.”

On one hand, the two groups typically “cooperate and do an excellent job, incurring patient errors similar to or less than physician colleagues or senior residents.” On the other hand, Mr. Blumm conceded, there is some jealousy among PAs over NPs’ advantage in staffing and hiring decisions, “since they don’t need [direct physician] supervision ... and there are limits on how many PAs can be supervised by one physician.”

Most PA-NP interactions are collaborative, although many people emphasize the relatively few conflicts, said Jennifer Orozco, DMSc, PA-C, president and chair of the American Academy of PAs.

“We see that a lot in this country,” she said. “People try to drive a wedge, but it’s often a misnomer that there’s a lot of arguing and infighting.”
 

NPs: Different backgrounds, same goal

The Medscape survey also included information from 750 NPs on working relationships; 93% of them favored nurses and PAs working more independently from doctors.

April Kapu, DNP, ARPN, has worked closely with PAs for more than 20 years. “In my experience ... they complement one another as health team members, although the education and training are somewhat different,” said Ms. Kapu, , president of the American Association of Nurse Practitioners.

Some respondents noted the different educational trajectories for NPs and PAs. “Doctors and PAs are taught using the same model, but NPs are taught under the nursing model,” wrote a family medicine PA.

In emergency departments where Mr. Blumm has worked, ICU NPs have an edge over PAs in terms of preparation, organization, and the tabulation of formulas. On the other hand, some of Mr. Blumm’s fellow PAs were also emergency medicine technicians or respiratory therapists, who had “2 years of classroom training, on par with that of medical students.”

Must these differences in training and education foment conflict between NPs and PAs? “We all bring something different to the table,” said Ms. Kapu, who also is associate dean for clinical and community partnerships at Vanderbilt University, Nashville, Tenn. “It is important to respect each person’s entry point, education, and training.”
 

Differing personalities and environments

Numerous PA respondents said that individual personalities and work environments are more likely to trigger issues with NPs than are differences in training.

“It depends on the team and situation and who the people are, not the letters behind their names,” an emergency medicine PA wrote. A surgical PA noted that “group dynamics and work culture differ from place to place,” while a third PA agreed that “it’s personality dependent, not title dependent.”

No single formula will resolve areas of NP-PA conflict, Ms. Orozco said. “What works in Chicago might not work in rural Colorado or Texas or California, but we do have to come together. The overall focus should be on greater flexibility for PAs and NPs. Patients will fare better.”
 

Joint research, publishing could help

About a decade ago, Mr. Blumm joined with another PA and an NP to form the American College of Clinicians, the first joint PA-NP national professional organization. Although it disbanded after 6 years, owing to low membership, he hopes a similar collaboration will take off in the future.

“I also recommend that PAs and NPs publish articles together, with research as an excellent place to start,” he added. “PAs and NPs should stand together and be a source of healing for all our patients. Regardless of our titles, our responsibility is to bring healing together.”

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

Physician interactions with nurse practitioners (NPs) and physician assistants (PAs) are only going to increase in frequency. – The U.S. Bureau of Labor Statistics forecasts a 40% increase in the NP workforce by 2031, coupled with a 28% rise in PAs.

In recent reports on the quality of the relationships involving these health care professions, survey respondents mostly gave positive accounts of collaboration, using words such as like “comradery,” “teamwork,” “congenial,” and “cohesion.” But all was not perfect. Where and how could these important health care provider relationships improve?
 

PAs: “Competition and collaboration’ with RNs

In a Medscape survey of more than 770 PAs about their working relationships with other health care professionals; 83% of them supported the idea of PAs and NPs practicing more independently from physicians, but sometimes it’s not easy to stay in their individual lanes.

One PA respondent complained that NPs get “more opportunities and preference,” another pointed to PA-NP “turf issues,” and a third griped about NPs’ “strong unions,” which have stoked more fighting about practice abilities and available settings.

Robert Blumm, MA, PA-C, a retired surgical and emergency medicine PA who regards himself as an advocate for both PAs and NPs, describes their interaction as a “mixture of competition and collaboration.”

On one hand, the two groups typically “cooperate and do an excellent job, incurring patient errors similar to or less than physician colleagues or senior residents.” On the other hand, Mr. Blumm conceded, there is some jealousy among PAs over NPs’ advantage in staffing and hiring decisions, “since they don’t need [direct physician] supervision ... and there are limits on how many PAs can be supervised by one physician.”

Most PA-NP interactions are collaborative, although many people emphasize the relatively few conflicts, said Jennifer Orozco, DMSc, PA-C, president and chair of the American Academy of PAs.

“We see that a lot in this country,” she said. “People try to drive a wedge, but it’s often a misnomer that there’s a lot of arguing and infighting.”
 

NPs: Different backgrounds, same goal

The Medscape survey also included information from 750 NPs on working relationships; 93% of them favored nurses and PAs working more independently from doctors.

April Kapu, DNP, ARPN, has worked closely with PAs for more than 20 years. “In my experience ... they complement one another as health team members, although the education and training are somewhat different,” said Ms. Kapu, , president of the American Association of Nurse Practitioners.

Some respondents noted the different educational trajectories for NPs and PAs. “Doctors and PAs are taught using the same model, but NPs are taught under the nursing model,” wrote a family medicine PA.

In emergency departments where Mr. Blumm has worked, ICU NPs have an edge over PAs in terms of preparation, organization, and the tabulation of formulas. On the other hand, some of Mr. Blumm’s fellow PAs were also emergency medicine technicians or respiratory therapists, who had “2 years of classroom training, on par with that of medical students.”

Must these differences in training and education foment conflict between NPs and PAs? “We all bring something different to the table,” said Ms. Kapu, who also is associate dean for clinical and community partnerships at Vanderbilt University, Nashville, Tenn. “It is important to respect each person’s entry point, education, and training.”
 

Differing personalities and environments

Numerous PA respondents said that individual personalities and work environments are more likely to trigger issues with NPs than are differences in training.

“It depends on the team and situation and who the people are, not the letters behind their names,” an emergency medicine PA wrote. A surgical PA noted that “group dynamics and work culture differ from place to place,” while a third PA agreed that “it’s personality dependent, not title dependent.”

No single formula will resolve areas of NP-PA conflict, Ms. Orozco said. “What works in Chicago might not work in rural Colorado or Texas or California, but we do have to come together. The overall focus should be on greater flexibility for PAs and NPs. Patients will fare better.”
 

Joint research, publishing could help

About a decade ago, Mr. Blumm joined with another PA and an NP to form the American College of Clinicians, the first joint PA-NP national professional organization. Although it disbanded after 6 years, owing to low membership, he hopes a similar collaboration will take off in the future.

“I also recommend that PAs and NPs publish articles together, with research as an excellent place to start,” he added. “PAs and NPs should stand together and be a source of healing for all our patients. Regardless of our titles, our responsibility is to bring healing together.”

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

Physician interactions with nurse practitioners (NPs) and physician assistants (PAs) are only going to increase in frequency. – The U.S. Bureau of Labor Statistics forecasts a 40% increase in the NP workforce by 2031, coupled with a 28% rise in PAs.

In recent reports on the quality of the relationships involving these health care professions, survey respondents mostly gave positive accounts of collaboration, using words such as like “comradery,” “teamwork,” “congenial,” and “cohesion.” But all was not perfect. Where and how could these important health care provider relationships improve?
 

PAs: “Competition and collaboration’ with RNs

In a Medscape survey of more than 770 PAs about their working relationships with other health care professionals; 83% of them supported the idea of PAs and NPs practicing more independently from physicians, but sometimes it’s not easy to stay in their individual lanes.

One PA respondent complained that NPs get “more opportunities and preference,” another pointed to PA-NP “turf issues,” and a third griped about NPs’ “strong unions,” which have stoked more fighting about practice abilities and available settings.

Robert Blumm, MA, PA-C, a retired surgical and emergency medicine PA who regards himself as an advocate for both PAs and NPs, describes their interaction as a “mixture of competition and collaboration.”

On one hand, the two groups typically “cooperate and do an excellent job, incurring patient errors similar to or less than physician colleagues or senior residents.” On the other hand, Mr. Blumm conceded, there is some jealousy among PAs over NPs’ advantage in staffing and hiring decisions, “since they don’t need [direct physician] supervision ... and there are limits on how many PAs can be supervised by one physician.”

Most PA-NP interactions are collaborative, although many people emphasize the relatively few conflicts, said Jennifer Orozco, DMSc, PA-C, president and chair of the American Academy of PAs.

“We see that a lot in this country,” she said. “People try to drive a wedge, but it’s often a misnomer that there’s a lot of arguing and infighting.”
 

NPs: Different backgrounds, same goal

The Medscape survey also included information from 750 NPs on working relationships; 93% of them favored nurses and PAs working more independently from doctors.

April Kapu, DNP, ARPN, has worked closely with PAs for more than 20 years. “In my experience ... they complement one another as health team members, although the education and training are somewhat different,” said Ms. Kapu, , president of the American Association of Nurse Practitioners.

Some respondents noted the different educational trajectories for NPs and PAs. “Doctors and PAs are taught using the same model, but NPs are taught under the nursing model,” wrote a family medicine PA.

In emergency departments where Mr. Blumm has worked, ICU NPs have an edge over PAs in terms of preparation, organization, and the tabulation of formulas. On the other hand, some of Mr. Blumm’s fellow PAs were also emergency medicine technicians or respiratory therapists, who had “2 years of classroom training, on par with that of medical students.”

Must these differences in training and education foment conflict between NPs and PAs? “We all bring something different to the table,” said Ms. Kapu, who also is associate dean for clinical and community partnerships at Vanderbilt University, Nashville, Tenn. “It is important to respect each person’s entry point, education, and training.”
 

Differing personalities and environments

Numerous PA respondents said that individual personalities and work environments are more likely to trigger issues with NPs than are differences in training.

“It depends on the team and situation and who the people are, not the letters behind their names,” an emergency medicine PA wrote. A surgical PA noted that “group dynamics and work culture differ from place to place,” while a third PA agreed that “it’s personality dependent, not title dependent.”

No single formula will resolve areas of NP-PA conflict, Ms. Orozco said. “What works in Chicago might not work in rural Colorado or Texas or California, but we do have to come together. The overall focus should be on greater flexibility for PAs and NPs. Patients will fare better.”
 

Joint research, publishing could help

About a decade ago, Mr. Blumm joined with another PA and an NP to form the American College of Clinicians, the first joint PA-NP national professional organization. Although it disbanded after 6 years, owing to low membership, he hopes a similar collaboration will take off in the future.

“I also recommend that PAs and NPs publish articles together, with research as an excellent place to start,” he added. “PAs and NPs should stand together and be a source of healing for all our patients. Regardless of our titles, our responsibility is to bring healing together.”

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

The amount of medical knowledge is said to double every 73 days, making it much tougher for physicians to identify innovative findings and newer guidelines for helping patients. Yet not keeping up with the latest information can put doctors at risk. 

“Most doctors are feeling lost about keeping up to date,” said John P.A. Ioannidis, MD, professor of medicine at Stanford (Calif.) University School of Medicine. “The vast majority of new studies are either wrong or not useful, but physicians cannot sort out which are those studies.”

The sheer number of new studies may even force some doctors to retreat from areas where they have not kept up, said Stephen A. Martin, MD, professor of family medicine and community health at the University of Massachusetts, Worcester. “When doctors don’t feel they can stay current, they may refer more cases to specialists or narrow their focus,” he said.
 

Some specialties have a greater challenge than others

Dr. Martin said the deluge of studies heavily impacts generalists because they have a wider field of information to keep up with. However, certain specialties like oncology are particularly flooded with new findings.

Specialties with the greatest number of published studies are reportedly oncology, cardiology, and neurology. A 2021 study found that the number of articles with the word “stroke” in them increased five times from 2000 to 2020. And investigative treatments targeting cancer nearly quadrupled just between 2010 and 2020.

What’s more, physicians spend a great deal of time sifting through studies that are ultimately useless. In a survey of internists by Univadis, which is part of WebMD/Medscape, 82% said that fewer than half of the studies they read actually had an impact on how they practice medicine.

“You often have to dig into an article and learn more about a finding before you now whether it’s useful,” Dr. Martin said. “And in the end, relatively few new findings are truly novel ones that are useful for patient care.”
 

So what can a physician do? First, find out what you don’t know

Looking for new findings needs to be carried out systematically, according to William B. Cutrer, MD, MEd, a pediatric intensivist who is associate dean for undergraduate medical education at Vanderbilt University School of Medicine, Nashville, Tenn.

“Before you start, you have to know what you don’t know, and that’s often not so easy,” he said. “You may get a spark about what you don’t know in an encounter with a patient or colleague or through patient outcomes data,” he said. 

Dr. Martin, on the other hand, advocates a broad approach that involves finding out at least a little about everything in one’s field. “If you have a good base, you’re not starting from zero when you encounter a new clinical situation,” he said.

“The idea is that you don’t need to memorize most things, but you do need to know how to access them,” Dr. Martin said. “I memorize the things I do all the time, such as dosing or indicated testing, but I look up things that I don’t see that often and ones that have some complexity.”
 

Updating the old ways

For generations, doctors have stayed current by going to meetings, conversing with colleagues, and reading journals, but many physicians have updated these methods through various resources on the internet.

For example, meetings went virtual during the pandemic, and now that face-to-face meetings are back, many of them retain a virtual option, said Kevin Campbell, MD, a cardiologist at Health First Medical Group, Melbourne, Fla. “I typically go to one or two conferences a year, but I also learn a lot digitally,” he said. 

As to journal reading, “assessing an article is an essential skill,” Dr. Cutrer said. “It’s important to quickly decide whether a journal article is worth reading or not. One answer to this problem is to consult summaries of important articles. But summaries are sometimes unhelpful, and it is hard to know which articles are significant. Therefore, doctors have been reaching out to others who can research the articles for them.”   

For many years, some physicians have pooled their resources in journal clubs. “You get a chance to cross-cultivate your skills with others,” Dr. Ioannidis said. “But you need someone who is well informed and dedicated to run the journal club, using evidence-based principles.”

Dr. Cutrer said physicians like to cast their net wide because they are understandably wary of changing their practice based on one study. “Unless there is one large study that is really well designed, doctors will need two or more findings to be convinced,” he said. This requires having the ability to match studies across many journals.
 

Using research summaries

In the past two decades, physicians have gained access to countless summaries of journal articles prepared by armies of clinical experts working for review services such as the New England Journal of Medicine’s “Journal Watch,” Annals of Internal Medicine’s “In the Clinic,” and BMJ’s “State of the Arts.”

In addition to summarizing findings from a wide variety of journals in plain language, reviewers may compare them to similar studies and assess the validity of the finding by assigning a level of evidence.

Some commercial ventures provide similar services. Betsy Jones, executive vice president of clinical decisions at EBSCO, said the DynaMed service is now available through an app on the physician’s smartphone or through the electronic health record.

Physicians like this approach. Many specialists have noted that reading full-length articles was not an efficient use of their time, while even more said that reviews are efficient.
 

Exchanging information online

Physicians are increasingly keeping current by using the internet, especially on social media, Dr. Cutrer said. “Young doctors in particular are more likely to keep up digitally,” he said.

Internet-based information has become so widespread that disparities in health care from region to region have somewhat abated, according to Stuart J. Fischer, MD, an orthopedic surgeon at Summit Orthopaedics and Sports Medicine, New Jersey. “One positive outcome of this plethora of information today is that geographic disparities in clinical practice are not as great as they used to be,” he said.  

Rather than chatting up colleagues in the hallway, many physicians have come to rely on internet-based discussion boards. 
 

Blogs, podcasts, and Twitter

Blogs and podcasts, often focused on a specialty, can be a great way for physicians to keep up, said UMass Chan professor Dr. Martin. “Podcasts in particular have enhanced the ability to stay current,” he said. “You want to find someone you trust.”

Internal medicine podcasts include Annals on Call, where doctors discuss articles in the Annals of Internal Medicine, and the Curbsiders, where two internists interview a guest expert.

Orthopedic surgeons can visit podcasts like Nailed it, Orthobullets, the Ortho Show, and Inside Orthopedics. Neurologists can consult Brainwaves, Neurology Podcast, Practical Neurology Podcast, and Clinical Neurology with KD. And pediatricians can drop in on Talking Pediatrics, The Cribsiders, and PedsCases.

Meanwhile, Twitter has become a particularly effective way to broadcast new findings, speeding up the transition from the bench to the bedside, said Dr. Campbell, the Florida cardiologist. 

“I visit cardio-specific resources on Twitter,” he said. “They can be real-time video chats or posted messages. They spur discussion like a journal club. Colleagues present cases and drop in and out of the discussion.”

Others are not as enthusiastic. Although Stanford’s Dr. Ioannidis is in the heart of the Silicon Valley, he is leery of some of the new digital methods. “I don’t use Twitter,” he says. “You just add more people to the process, which could only make things more confusing. I want to be able to think a lot about it.”
 

Cutting-edge knowledge at the point of care

Consulting the literature often takes place at the point of care, when a particular patient requires treatment. This can be done by using clinical decision support (CDS) and by using clinical practice guidelines (CPGs), which are typically developed by panels of doctors at specialty societies.

“It used to be that the doctor was expected to know everything,” said Ms. Jones at DynaMed. “Today there is no way to keep up with it all. Doctors often need a quick memory jog.”

Ms. Jones said the CDS result always requires the doctor’s interpretation. “It is up to the doctor to decide whether a new finding is the best choice for his or her patient,” she said.

Dr. Martin recommends going easy on point-of-care resources. “They can be used for showing a patient a differential diagnosis list or checking the cost of a procedure, but they are harder to use for novel developments that require time and context to evaluate their impact,” he said.

CPGs, meanwhile, have a high profile in the research world. In a 2018 study, Dr. Ioannidis found that 8 of the 15 most-cited articles were CPGs, disease definitions, or disease statistics.

Dr. Fischer said CPGs are typically based on thorough reviews of the literature, but they do involve experts’ interpretation of the science. “It can be difficult to obtain specific answers to some medical questions, especially for problems with complex treatments or variations,” he said.

As a result, Dr. Fischer said doctors have to use their judgment in applying CPGs to a specific patient. “For example, the orthopedic surgeon would normally recommend a total hip replacement for patients with a bad hip, but it might not be appropriate for an overweight patient.”
 

Stay skeptical

There are many novel ways for physicians to keep current, including summaries of articles, discussion boards, blogs, podcasts, Twitter, clinical decision support, and clinical practice guidelines.

Even with all these new services, though, doctors need to retain a healthy amount of skepticism about new research findings, Dr. Ioannidis said. “Ask yourself questions such as: Does it deal with a real problem? Am I getting the real information? Is it relevant to real patients? Is it offering good value for money?”

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

The amount of medical knowledge is said to double every 73 days, making it much tougher for physicians to identify innovative findings and newer guidelines for helping patients. Yet not keeping up with the latest information can put doctors at risk. 

“Most doctors are feeling lost about keeping up to date,” said John P.A. Ioannidis, MD, professor of medicine at Stanford (Calif.) University School of Medicine. “The vast majority of new studies are either wrong or not useful, but physicians cannot sort out which are those studies.”

The sheer number of new studies may even force some doctors to retreat from areas where they have not kept up, said Stephen A. Martin, MD, professor of family medicine and community health at the University of Massachusetts, Worcester. “When doctors don’t feel they can stay current, they may refer more cases to specialists or narrow their focus,” he said.
 

Some specialties have a greater challenge than others

Dr. Martin said the deluge of studies heavily impacts generalists because they have a wider field of information to keep up with. However, certain specialties like oncology are particularly flooded with new findings.

Specialties with the greatest number of published studies are reportedly oncology, cardiology, and neurology. A 2021 study found that the number of articles with the word “stroke” in them increased five times from 2000 to 2020. And investigative treatments targeting cancer nearly quadrupled just between 2010 and 2020.

What’s more, physicians spend a great deal of time sifting through studies that are ultimately useless. In a survey of internists by Univadis, which is part of WebMD/Medscape, 82% said that fewer than half of the studies they read actually had an impact on how they practice medicine.

“You often have to dig into an article and learn more about a finding before you now whether it’s useful,” Dr. Martin said. “And in the end, relatively few new findings are truly novel ones that are useful for patient care.”
 

So what can a physician do? First, find out what you don’t know

Looking for new findings needs to be carried out systematically, according to William B. Cutrer, MD, MEd, a pediatric intensivist who is associate dean for undergraduate medical education at Vanderbilt University School of Medicine, Nashville, Tenn.

“Before you start, you have to know what you don’t know, and that’s often not so easy,” he said. “You may get a spark about what you don’t know in an encounter with a patient or colleague or through patient outcomes data,” he said. 

Dr. Martin, on the other hand, advocates a broad approach that involves finding out at least a little about everything in one’s field. “If you have a good base, you’re not starting from zero when you encounter a new clinical situation,” he said.

“The idea is that you don’t need to memorize most things, but you do need to know how to access them,” Dr. Martin said. “I memorize the things I do all the time, such as dosing or indicated testing, but I look up things that I don’t see that often and ones that have some complexity.”
 

Updating the old ways

For generations, doctors have stayed current by going to meetings, conversing with colleagues, and reading journals, but many physicians have updated these methods through various resources on the internet.

For example, meetings went virtual during the pandemic, and now that face-to-face meetings are back, many of them retain a virtual option, said Kevin Campbell, MD, a cardiologist at Health First Medical Group, Melbourne, Fla. “I typically go to one or two conferences a year, but I also learn a lot digitally,” he said. 

As to journal reading, “assessing an article is an essential skill,” Dr. Cutrer said. “It’s important to quickly decide whether a journal article is worth reading or not. One answer to this problem is to consult summaries of important articles. But summaries are sometimes unhelpful, and it is hard to know which articles are significant. Therefore, doctors have been reaching out to others who can research the articles for them.”   

For many years, some physicians have pooled their resources in journal clubs. “You get a chance to cross-cultivate your skills with others,” Dr. Ioannidis said. “But you need someone who is well informed and dedicated to run the journal club, using evidence-based principles.”

Dr. Cutrer said physicians like to cast their net wide because they are understandably wary of changing their practice based on one study. “Unless there is one large study that is really well designed, doctors will need two or more findings to be convinced,” he said. This requires having the ability to match studies across many journals.
 

Using research summaries

In the past two decades, physicians have gained access to countless summaries of journal articles prepared by armies of clinical experts working for review services such as the New England Journal of Medicine’s “Journal Watch,” Annals of Internal Medicine’s “In the Clinic,” and BMJ’s “State of the Arts.”

In addition to summarizing findings from a wide variety of journals in plain language, reviewers may compare them to similar studies and assess the validity of the finding by assigning a level of evidence.

Some commercial ventures provide similar services. Betsy Jones, executive vice president of clinical decisions at EBSCO, said the DynaMed service is now available through an app on the physician’s smartphone or through the electronic health record.

Physicians like this approach. Many specialists have noted that reading full-length articles was not an efficient use of their time, while even more said that reviews are efficient.
 

Exchanging information online

Physicians are increasingly keeping current by using the internet, especially on social media, Dr. Cutrer said. “Young doctors in particular are more likely to keep up digitally,” he said.

Internet-based information has become so widespread that disparities in health care from region to region have somewhat abated, according to Stuart J. Fischer, MD, an orthopedic surgeon at Summit Orthopaedics and Sports Medicine, New Jersey. “One positive outcome of this plethora of information today is that geographic disparities in clinical practice are not as great as they used to be,” he said.  

Rather than chatting up colleagues in the hallway, many physicians have come to rely on internet-based discussion boards. 
 

Blogs, podcasts, and Twitter

Blogs and podcasts, often focused on a specialty, can be a great way for physicians to keep up, said UMass Chan professor Dr. Martin. “Podcasts in particular have enhanced the ability to stay current,” he said. “You want to find someone you trust.”

Internal medicine podcasts include Annals on Call, where doctors discuss articles in the Annals of Internal Medicine, and the Curbsiders, where two internists interview a guest expert.

Orthopedic surgeons can visit podcasts like Nailed it, Orthobullets, the Ortho Show, and Inside Orthopedics. Neurologists can consult Brainwaves, Neurology Podcast, Practical Neurology Podcast, and Clinical Neurology with KD. And pediatricians can drop in on Talking Pediatrics, The Cribsiders, and PedsCases.

Meanwhile, Twitter has become a particularly effective way to broadcast new findings, speeding up the transition from the bench to the bedside, said Dr. Campbell, the Florida cardiologist. 

“I visit cardio-specific resources on Twitter,” he said. “They can be real-time video chats or posted messages. They spur discussion like a journal club. Colleagues present cases and drop in and out of the discussion.”

Others are not as enthusiastic. Although Stanford’s Dr. Ioannidis is in the heart of the Silicon Valley, he is leery of some of the new digital methods. “I don’t use Twitter,” he says. “You just add more people to the process, which could only make things more confusing. I want to be able to think a lot about it.”
 

Cutting-edge knowledge at the point of care

Consulting the literature often takes place at the point of care, when a particular patient requires treatment. This can be done by using clinical decision support (CDS) and by using clinical practice guidelines (CPGs), which are typically developed by panels of doctors at specialty societies.

“It used to be that the doctor was expected to know everything,” said Ms. Jones at DynaMed. “Today there is no way to keep up with it all. Doctors often need a quick memory jog.”

Ms. Jones said the CDS result always requires the doctor’s interpretation. “It is up to the doctor to decide whether a new finding is the best choice for his or her patient,” she said.

Dr. Martin recommends going easy on point-of-care resources. “They can be used for showing a patient a differential diagnosis list or checking the cost of a procedure, but they are harder to use for novel developments that require time and context to evaluate their impact,” he said.

CPGs, meanwhile, have a high profile in the research world. In a 2018 study, Dr. Ioannidis found that 8 of the 15 most-cited articles were CPGs, disease definitions, or disease statistics.

Dr. Fischer said CPGs are typically based on thorough reviews of the literature, but they do involve experts’ interpretation of the science. “It can be difficult to obtain specific answers to some medical questions, especially for problems with complex treatments or variations,” he said.

As a result, Dr. Fischer said doctors have to use their judgment in applying CPGs to a specific patient. “For example, the orthopedic surgeon would normally recommend a total hip replacement for patients with a bad hip, but it might not be appropriate for an overweight patient.”
 

Stay skeptical

There are many novel ways for physicians to keep current, including summaries of articles, discussion boards, blogs, podcasts, Twitter, clinical decision support, and clinical practice guidelines.

Even with all these new services, though, doctors need to retain a healthy amount of skepticism about new research findings, Dr. Ioannidis said. “Ask yourself questions such as: Does it deal with a real problem? Am I getting the real information? Is it relevant to real patients? Is it offering good value for money?”

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

The amount of medical knowledge is said to double every 73 days, making it much tougher for physicians to identify innovative findings and newer guidelines for helping patients. Yet not keeping up with the latest information can put doctors at risk. 

“Most doctors are feeling lost about keeping up to date,” said John P.A. Ioannidis, MD, professor of medicine at Stanford (Calif.) University School of Medicine. “The vast majority of new studies are either wrong or not useful, but physicians cannot sort out which are those studies.”

The sheer number of new studies may even force some doctors to retreat from areas where they have not kept up, said Stephen A. Martin, MD, professor of family medicine and community health at the University of Massachusetts, Worcester. “When doctors don’t feel they can stay current, they may refer more cases to specialists or narrow their focus,” he said.
 

Some specialties have a greater challenge than others

Dr. Martin said the deluge of studies heavily impacts generalists because they have a wider field of information to keep up with. However, certain specialties like oncology are particularly flooded with new findings.

Specialties with the greatest number of published studies are reportedly oncology, cardiology, and neurology. A 2021 study found that the number of articles with the word “stroke” in them increased five times from 2000 to 2020. And investigative treatments targeting cancer nearly quadrupled just between 2010 and 2020.

What’s more, physicians spend a great deal of time sifting through studies that are ultimately useless. In a survey of internists by Univadis, which is part of WebMD/Medscape, 82% said that fewer than half of the studies they read actually had an impact on how they practice medicine.

“You often have to dig into an article and learn more about a finding before you now whether it’s useful,” Dr. Martin said. “And in the end, relatively few new findings are truly novel ones that are useful for patient care.”
 

So what can a physician do? First, find out what you don’t know

Looking for new findings needs to be carried out systematically, according to William B. Cutrer, MD, MEd, a pediatric intensivist who is associate dean for undergraduate medical education at Vanderbilt University School of Medicine, Nashville, Tenn.

“Before you start, you have to know what you don’t know, and that’s often not so easy,” he said. “You may get a spark about what you don’t know in an encounter with a patient or colleague or through patient outcomes data,” he said. 

Dr. Martin, on the other hand, advocates a broad approach that involves finding out at least a little about everything in one’s field. “If you have a good base, you’re not starting from zero when you encounter a new clinical situation,” he said.

“The idea is that you don’t need to memorize most things, but you do need to know how to access them,” Dr. Martin said. “I memorize the things I do all the time, such as dosing or indicated testing, but I look up things that I don’t see that often and ones that have some complexity.”
 

Updating the old ways

For generations, doctors have stayed current by going to meetings, conversing with colleagues, and reading journals, but many physicians have updated these methods through various resources on the internet.

For example, meetings went virtual during the pandemic, and now that face-to-face meetings are back, many of them retain a virtual option, said Kevin Campbell, MD, a cardiologist at Health First Medical Group, Melbourne, Fla. “I typically go to one or two conferences a year, but I also learn a lot digitally,” he said. 

As to journal reading, “assessing an article is an essential skill,” Dr. Cutrer said. “It’s important to quickly decide whether a journal article is worth reading or not. One answer to this problem is to consult summaries of important articles. But summaries are sometimes unhelpful, and it is hard to know which articles are significant. Therefore, doctors have been reaching out to others who can research the articles for them.”   

For many years, some physicians have pooled their resources in journal clubs. “You get a chance to cross-cultivate your skills with others,” Dr. Ioannidis said. “But you need someone who is well informed and dedicated to run the journal club, using evidence-based principles.”

Dr. Cutrer said physicians like to cast their net wide because they are understandably wary of changing their practice based on one study. “Unless there is one large study that is really well designed, doctors will need two or more findings to be convinced,” he said. This requires having the ability to match studies across many journals.
 

Using research summaries

In the past two decades, physicians have gained access to countless summaries of journal articles prepared by armies of clinical experts working for review services such as the New England Journal of Medicine’s “Journal Watch,” Annals of Internal Medicine’s “In the Clinic,” and BMJ’s “State of the Arts.”

In addition to summarizing findings from a wide variety of journals in plain language, reviewers may compare them to similar studies and assess the validity of the finding by assigning a level of evidence.

Some commercial ventures provide similar services. Betsy Jones, executive vice president of clinical decisions at EBSCO, said the DynaMed service is now available through an app on the physician’s smartphone or through the electronic health record.

Physicians like this approach. Many specialists have noted that reading full-length articles was not an efficient use of their time, while even more said that reviews are efficient.
 

Exchanging information online

Physicians are increasingly keeping current by using the internet, especially on social media, Dr. Cutrer said. “Young doctors in particular are more likely to keep up digitally,” he said.

Internet-based information has become so widespread that disparities in health care from region to region have somewhat abated, according to Stuart J. Fischer, MD, an orthopedic surgeon at Summit Orthopaedics and Sports Medicine, New Jersey. “One positive outcome of this plethora of information today is that geographic disparities in clinical practice are not as great as they used to be,” he said.  

Rather than chatting up colleagues in the hallway, many physicians have come to rely on internet-based discussion boards. 
 

Blogs, podcasts, and Twitter

Blogs and podcasts, often focused on a specialty, can be a great way for physicians to keep up, said UMass Chan professor Dr. Martin. “Podcasts in particular have enhanced the ability to stay current,” he said. “You want to find someone you trust.”

Internal medicine podcasts include Annals on Call, where doctors discuss articles in the Annals of Internal Medicine, and the Curbsiders, where two internists interview a guest expert.

Orthopedic surgeons can visit podcasts like Nailed it, Orthobullets, the Ortho Show, and Inside Orthopedics. Neurologists can consult Brainwaves, Neurology Podcast, Practical Neurology Podcast, and Clinical Neurology with KD. And pediatricians can drop in on Talking Pediatrics, The Cribsiders, and PedsCases.

Meanwhile, Twitter has become a particularly effective way to broadcast new findings, speeding up the transition from the bench to the bedside, said Dr. Campbell, the Florida cardiologist. 

“I visit cardio-specific resources on Twitter,” he said. “They can be real-time video chats or posted messages. They spur discussion like a journal club. Colleagues present cases and drop in and out of the discussion.”

Others are not as enthusiastic. Although Stanford’s Dr. Ioannidis is in the heart of the Silicon Valley, he is leery of some of the new digital methods. “I don’t use Twitter,” he says. “You just add more people to the process, which could only make things more confusing. I want to be able to think a lot about it.”
 

Cutting-edge knowledge at the point of care

Consulting the literature often takes place at the point of care, when a particular patient requires treatment. This can be done by using clinical decision support (CDS) and by using clinical practice guidelines (CPGs), which are typically developed by panels of doctors at specialty societies.

“It used to be that the doctor was expected to know everything,” said Ms. Jones at DynaMed. “Today there is no way to keep up with it all. Doctors often need a quick memory jog.”

Ms. Jones said the CDS result always requires the doctor’s interpretation. “It is up to the doctor to decide whether a new finding is the best choice for his or her patient,” she said.

Dr. Martin recommends going easy on point-of-care resources. “They can be used for showing a patient a differential diagnosis list or checking the cost of a procedure, but they are harder to use for novel developments that require time and context to evaluate their impact,” he said.

CPGs, meanwhile, have a high profile in the research world. In a 2018 study, Dr. Ioannidis found that 8 of the 15 most-cited articles were CPGs, disease definitions, or disease statistics.

Dr. Fischer said CPGs are typically based on thorough reviews of the literature, but they do involve experts’ interpretation of the science. “It can be difficult to obtain specific answers to some medical questions, especially for problems with complex treatments or variations,” he said.

As a result, Dr. Fischer said doctors have to use their judgment in applying CPGs to a specific patient. “For example, the orthopedic surgeon would normally recommend a total hip replacement for patients with a bad hip, but it might not be appropriate for an overweight patient.”
 

Stay skeptical

There are many novel ways for physicians to keep current, including summaries of articles, discussion boards, blogs, podcasts, Twitter, clinical decision support, and clinical practice guidelines.

Even with all these new services, though, doctors need to retain a healthy amount of skepticism about new research findings, Dr. Ioannidis said. “Ask yourself questions such as: Does it deal with a real problem? Am I getting the real information? Is it relevant to real patients? Is it offering good value for money?”

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

Verrucous carcinoma (VC) is an uncommon type of well-differentiated squamous cell carcinoma (SCC) that most commonly affects men in the fifth to sixth decades of life. ¹ The tumor grows slowly over a decade or more and does not frequently metastasize but has a high propensity for recurrence and local invasion. ²  There are 3 main subtypes of VC classified by anatomic site: oral florid papillomatosis (oral cavity), Buschke-Lowenstein tumor (anogenital region), and epithelioma cuniculatum (EC)(feet). ³ Epithelioma cuniculatum, also known as carcinoma cuniculatum or papillomatosis cutis carcinoides, most commonly presents as a solitary, warty or cauliflowerlike, exophytic mass with keratin-filled sinus tracts and malodorous discharge. ⁴ Diabetic foot ulcers and chronic inflammatory conditions are predisposing risk factors for EC, and it can result in difficulty walking/immobility, pain, and bleeding depending on anatomic involvement. ^5-9

The differential diagnosis for VC includes refractory verruca vulgaris, clavus, SCC, keratoacanthoma, deep fungal or mycobacterial infection, eccrine poroma or porocarcinoma, amelanotic melanoma, and sarcoma.^10-13 The slow-growing nature of VC, sampling error of superficial biopsies, and minimal cytological atypia on histologic examination can contribute to delayed diagnosis and appropriate treatment.¹⁴ Characteristic histologic features include hyperkeratosis, papillomatosis, marked acanthosis, broad blunt-ended rete ridges with a “bulldozing” architecture, and minimal cytologic atypia and mitoses.^5,6 In some cases, pleomorphism and glassy eosinophilic cytoplasmic changes may be more pronounced than that of a common wart though less dramatic than that of conventional SCCs.¹⁵ Antigen Ki-67 and tumor protein p53 have been proposed to help differentiate between common plantar verruca, VC, and SCC, but the histologic diagnosis remains challenging, and repeat histopathologic examination often is required.^16-19 Following diagnosis, computed tomography or magnetic resonance imaging may be necessary to determine tumor extension and assess for deep tissue and bony involvement.^20-22

Treatment of EC is particularly challenging because of the anatomic location and need for margin control while maintaining adequate function, preserving healthy tissue, and providing coverage of defects. Surgical excision of EC is the first-line treatment, most commonly by wide local excision (WLE) or amputation. Mohs micrographic surgery (MMS) also has been utilized. One review found no recurrences in 5 cases of EC treated with MMS.²³ As MMS is a tissue-sparing technique, this is a valuable modality for sites of functional importance such as the feet. Herein, we review various reported EC treatment modalities and outcomes, with an emphasis on recurrence rates for WLE and MMS.

METHODS

A systematic literature review of PubMed articles indexed for MEDLINE, as well as databases including the Cochrane Library, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL), was performed on January 14, 2020. Two authors (S.S.D. and S.V.C.) independently screened results using the search terms (plantar OR foot) AND (verrucous carcinoma OR epithelioma cuniculatum OR carcinoma cuniculatum). The search terms were chosen according to MeSH subject headings. All articles from the start date of the databases through the search date were screened, and articles pertaining to VC, EC, or carcinoma cuniculatum located on the foot were included. Of these, non–English-language articles were translated and included. Articles reporting VC on a site other than the foot (eg, the oral cavity) or benign verrucous skin lesions were excluded. The reference lists for all articles also were reviewed for additional reports that were absent from the initial search using both included and excluded articles. A full-text review was performed on 221 articles published between 1954 and 2019 per the PRISMA guidelines (Figure).

A total of 101 articles were included in the study for qualitative analysis. Nearly all articles identified were case reports, giving an evidence level of 5 by the Centre for Evidence-Based Medicine rating scale. Five articles reported data on multiple patients without individual demographic or clinical details and were excluded from analysis. Of the remaining 96 articles, information about patient characteristics, tumor size, treatment modality, and recurrence were extracted for 115 cases.

RESULTS

Of the 115 cases that were reviewed, 81 (70%) were male and 33 (29%) were female with a male-to-female ratio of 2.4:1. Ages of the patients ranged from 18 to 88 years; the mean and median age was 56 years. Nearly all reported cases of EC affected the plantar surface of one foot, with 4 reports of tumors affecting both feet.^24-27 One case affecting both feet reported known exposure to lead arsenate pesticides²⁷; all others were associated with a clinical history of chronic ulcers or warts persisting for several years to decades. Other less common sites of EC included the dorsal foot, interdigital web space, and subungual digit.^28-30 The most common location reported was the anterior ball of the foot. Tumors were reported to arise within pre-existing lesions, such as hypertrophic lichen planus or chronic foot wounds associated with diabetes mellitus or leprosy.^31-35 Tumor size ranged from 1 to 22 cm with a median of 4.5 cm.

Eight cases were reported to be associated with human papillomavirus; low-risk types 6 and 11 and high-risk types 16 and 18 were found in 6 cases.^36-41 Two cases reported association with human papillomavirus type 2.^7,42

Metastases to dermal and subdermal lymphatics, regional lymph nodes, and the lungs were reported in 3 cases, repectively.^43-45 Of these, one primary tumor had received low-dose irradiation in the form of X-ray therapy.⁴⁵

Treatment Modalities

The cases of EC that we reviewed included treatment with surgical and systemic therapies as well as other modalities such as acitretin, interferon alfa, topical imiquimod, curettage, debridement, electrodesiccation, and radiation. The Table includes a complete summary of the treatments we analyzed.

Surgical Therapy—The majority (91% [105/115]) of cases were treated surgically. The most common treatment modality was WLE (50% [58/115]), followed by amputation (37% [43/115]) and MMS (12% [14/115]).

Wide local excision was the most frequently reported treatment, with excision margins of at least 5 mm to 1 cm.⁴⁸ Incidence of recurrence was reported for 57% (33/58) of cases treated with WLE; of these, the recurrence rate was 33% (11/33). For patients with EC recurrence, the most common secondary treatment was repeat excision with wider margins (1–2 cm) or amputation (5/11).^49-52 Few postoperative complications were reported but included pain, infection, and difficulty walking, which were mostly associated with repair modality (eg, split-thickness skin grafts, rotational flaps).⁵³ 
Amputation was the second most common treatment modality, with a 67% (29/43) incidence of recurrence. Types of amputation included transmetatarsal ray amputation (7/43 [16%]), foot or forefoot amputation (2/43 [5%]), above-the-knee amputation (1/43 [2%]), and below-the-knee amputation (1/43 [2%]). Complications associated with amputation included infection and requirement of prosthetics for ambulation. Split-thickness skin grafts and rotational flaps were the most common surgical repairs performed.^52,53

Mohs micrographic surgery was the least frequently reported surgical treatment modality. Both traditional MMS on fresh tissue and “slow Mohs,” with formalin-fixed paraffin embedded tissue examination over several days, were performed for EC with horizontal en face sectioning.^54-56 Incidence of recurrence was reported for 86% (12/14) of MMS cases. Of these, recurrence was seen in 17% (2/12) that utilized a flat horizontal processing of tissue sections coupled with saucerlike excisions to enable examination of the entire undersurface and margins. In one case, the patient was treated with MMS with recurrence noted 1 month later; thus, repeat MMS was performed, and the tumor was found to be entwined around the flexor tendon.⁵⁷ The tendon was removed, and clear margins were obtained. Follow-up 3 years after the second MMS revealed no signs of recurrence.⁵⁷ In the other case, the patient had a particularly aggressive course with bilateral VC in the setting of diabetic ulcers that was treated with WLE prior to MMS and recurrence still noted after MMS.²⁶ No complications were reported with MMS.

Overall, recurrence was most frequently reported with WLE (11/33 [33%]), followed by MMS (2/12 [17%]) and amputation (3/29 [10%]). When comparing WLE and amputation, the relationship between treatment modality and recurrence was statistically significant using a χ² test of independence (χ²=4.7; P=.03). However, results were not significant with Yates correction for continuity (χ²=3.4; P=.06). The χ² test of independence showed no significant association between treatment method and recurrence when comparing WLE with MMS (χ²=1.2; P=.28). Reported follow-up times varied greatly from a few months to 10 years.

Systemic Therapy—Of the total cases, only 2 cases reported treatment with acitretin and 2 utilized interferon alfa.^58,59 In one case, treatment of EC with interferon alfa alone required more aggressive therapy (ie, amputation).⁵⁸ Neither of the 2 cases using acitretin reported recurrence.^59,60 Complications of acitretin therapy included cheilitis and transaminitis.⁶⁰

Other Treatment Modalities—Three cases utilized imiquimod, with 2 cases of imiquimod monotherapy and 1 case of imiquimod in combination with electrodesiccation and WLE.³⁷ One of the cases of EC treated with imiquimod monotherapy recurred and required WLE.⁶¹

There were reports of other treatments including curettage alone (2% [2/115]),^40,62 debridement alone (1% [1/115]),⁴⁰ electrodesiccation (1% [1/115]),³⁷ and radiation (1% [1/115]).⁴³ Recurrence was found with curettage alone and debridement alone. Electrodesiccation was reported in conjunction with WLE without recurrence. Radiation was used to treat a case of VC that had metastasized to the lymph nodes; no follow-up was described.⁴³

COMMENT

Epithelioma cuniculatum is an indolent malignancy of the plantar foot that likely is frequently underdiagnosed or misdiagnosed because of location, sampling error, and challenges in histopathologic diagnosis. Once diagnosed, surgical removal with margin control is the first-line therapy for EC. Our review found a number of surgical, systemic, and other treatment modalities that have been used to treat EC, but there remains a lack of evidence to provide clear guidelines as to which therapies are most effective. Current data on the treatment of EC largely are limited to case reports and case series. To date, there are no reports of higher-quality studies or randomized controlled trials to assess the efficacy of various treatment modalities.

Our review found that WLE is the most common treatment modality for EC, followed by amputation and MMS. Three cases^43-45 that reported metastasis to lymph nodes also were treated with fine-needle aspiration or biopsy, and it is recommended that sentinel lymph node biopsy be performed when there is a history of radiation exposure or clinically and sonographically unsuspicious lymph nodes, while dissection of regional nodes should be performed if lymph node metastasis is suspected.⁵³ Additional treatments reported included acitretin, interferon alfa, topical imiquimod, curettage, debridement, and electrodesiccation, but because of the limited number of cases and variable efficacy, no conclusions can be made on the utility of these alternative modalities.

The lowest rate of reported recurrence was found with amputation, followed by MMS and WLE. Amputation is the most aggressive treatment option, but its superiority in lower recurrence rates was not statistically significant when compared with either WLE or MMS after Yates correction. Despite treatment with radical surgery, recurrence is still possible and may be associated with factors including greater size (>2 cm) and depth (>4 mm), poor histologic differentiation, perineural involvement, failure of previous treatments, and immunosuppression.⁶³ No statistically significant difference in recurrence rates was found among surgical methods, though data trended toward lower rates of recurrence with MMS compared with WLE, as recurrence with MMS was only reported in 2 cases.^25,56

The efficacy of MMS is well documented for tumors with contiguous growth and enables maximum preservation of normal tissue structure and function with complete margin visualization. Thus, our results are in agreement with those of prior studies,^54-56,64 suggesting that MMS is associated with lower recurrence rates for EC than WLE. Future studies and reporting of MMS for EC are particularly important because of the functional importance of the plantar foot.

It is important to note that there are local and systemic risk factors that increase the likelihood of developing EC and facilitate tumor growth, including antecedent trauma to the lesion site, chronic irritation or infection, and immunosuppression (HIV related or iatrogenic medication induced). These risk factors may play a role in the treatment modality utilized (eg, more aggressive EC may be treated with amputation instead of WLE). Underlying patient comorbidities could potentially affect recurrence rates, which is a variable we could not control for in our analysis.

Our findings are limited by study design, with supporting evidence consisting of case reports and series. The review is limited by interstudy variability and heterogeneity of results. Additionally, recurrence is not reported in all cases and may be a source of sampling bias. Further complicating the generalizability of these results is the lack of follow-up to evaluate morbidity and quality of life after treatment.

CONCLUSION

This review suggests that MMS is associated with lower recurrence rates than WLE for the treatment of EC. Further investigation of MMS for EC with appropriate follow-up is necessary to identify whether MMS is associated with lower recurrence and less functional impairment. Nonsurgical treatments, including topical imiquimod, interferon alfa, and acitretin, may be useful in cases where surgical therapies are contraindicated, but there is little evidence to support these treatment modalities. Treatment guidelines for EC are not established, and appropriate treatment guidelines should be developed in the future.

Verrucous carcinoma (VC) is an uncommon type of well-differentiated squamous cell carcinoma (SCC) that most commonly affects men in the fifth to sixth decades of life. ¹ The tumor grows slowly over a decade or more and does not frequently metastasize but has a high propensity for recurrence and local invasion. ²  There are 3 main subtypes of VC classified by anatomic site: oral florid papillomatosis (oral cavity), Buschke-Lowenstein tumor (anogenital region), and epithelioma cuniculatum (EC)(feet). ³ Epithelioma cuniculatum, also known as carcinoma cuniculatum or papillomatosis cutis carcinoides, most commonly presents as a solitary, warty or cauliflowerlike, exophytic mass with keratin-filled sinus tracts and malodorous discharge. ⁴ Diabetic foot ulcers and chronic inflammatory conditions are predisposing risk factors for EC, and it can result in difficulty walking/immobility, pain, and bleeding depending on anatomic involvement. ^5-9

The differential diagnosis for VC includes refractory verruca vulgaris, clavus, SCC, keratoacanthoma, deep fungal or mycobacterial infection, eccrine poroma or porocarcinoma, amelanotic melanoma, and sarcoma.^10-13 The slow-growing nature of VC, sampling error of superficial biopsies, and minimal cytological atypia on histologic examination can contribute to delayed diagnosis and appropriate treatment.¹⁴ Characteristic histologic features include hyperkeratosis, papillomatosis, marked acanthosis, broad blunt-ended rete ridges with a “bulldozing” architecture, and minimal cytologic atypia and mitoses.^5,6 In some cases, pleomorphism and glassy eosinophilic cytoplasmic changes may be more pronounced than that of a common wart though less dramatic than that of conventional SCCs.¹⁵ Antigen Ki-67 and tumor protein p53 have been proposed to help differentiate between common plantar verruca, VC, and SCC, but the histologic diagnosis remains challenging, and repeat histopathologic examination often is required.^16-19 Following diagnosis, computed tomography or magnetic resonance imaging may be necessary to determine tumor extension and assess for deep tissue and bony involvement.^20-22

Treatment of EC is particularly challenging because of the anatomic location and need for margin control while maintaining adequate function, preserving healthy tissue, and providing coverage of defects. Surgical excision of EC is the first-line treatment, most commonly by wide local excision (WLE) or amputation. Mohs micrographic surgery (MMS) also has been utilized. One review found no recurrences in 5 cases of EC treated with MMS.²³ As MMS is a tissue-sparing technique, this is a valuable modality for sites of functional importance such as the feet. Herein, we review various reported EC treatment modalities and outcomes, with an emphasis on recurrence rates for WLE and MMS.

METHODS

A systematic literature review of PubMed articles indexed for MEDLINE, as well as databases including the Cochrane Library, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL), was performed on January 14, 2020. Two authors (S.S.D. and S.V.C.) independently screened results using the search terms (plantar OR foot) AND (verrucous carcinoma OR epithelioma cuniculatum OR carcinoma cuniculatum). The search terms were chosen according to MeSH subject headings. All articles from the start date of the databases through the search date were screened, and articles pertaining to VC, EC, or carcinoma cuniculatum located on the foot were included. Of these, non–English-language articles were translated and included. Articles reporting VC on a site other than the foot (eg, the oral cavity) or benign verrucous skin lesions were excluded. The reference lists for all articles also were reviewed for additional reports that were absent from the initial search using both included and excluded articles. A full-text review was performed on 221 articles published between 1954 and 2019 per the PRISMA guidelines (Figure).

A total of 101 articles were included in the study for qualitative analysis. Nearly all articles identified were case reports, giving an evidence level of 5 by the Centre for Evidence-Based Medicine rating scale. Five articles reported data on multiple patients without individual demographic or clinical details and were excluded from analysis. Of the remaining 96 articles, information about patient characteristics, tumor size, treatment modality, and recurrence were extracted for 115 cases.

RESULTS

Of the 115 cases that were reviewed, 81 (70%) were male and 33 (29%) were female with a male-to-female ratio of 2.4:1. Ages of the patients ranged from 18 to 88 years; the mean and median age was 56 years. Nearly all reported cases of EC affected the plantar surface of one foot, with 4 reports of tumors affecting both feet.^24-27 One case affecting both feet reported known exposure to lead arsenate pesticides²⁷; all others were associated with a clinical history of chronic ulcers or warts persisting for several years to decades. Other less common sites of EC included the dorsal foot, interdigital web space, and subungual digit.^28-30 The most common location reported was the anterior ball of the foot. Tumors were reported to arise within pre-existing lesions, such as hypertrophic lichen planus or chronic foot wounds associated with diabetes mellitus or leprosy.^31-35 Tumor size ranged from 1 to 22 cm with a median of 4.5 cm.

Eight cases were reported to be associated with human papillomavirus; low-risk types 6 and 11 and high-risk types 16 and 18 were found in 6 cases.^36-41 Two cases reported association with human papillomavirus type 2.^7,42

Metastases to dermal and subdermal lymphatics, regional lymph nodes, and the lungs were reported in 3 cases, repectively.^43-45 Of these, one primary tumor had received low-dose irradiation in the form of X-ray therapy.⁴⁵

Treatment Modalities

The cases of EC that we reviewed included treatment with surgical and systemic therapies as well as other modalities such as acitretin, interferon alfa, topical imiquimod, curettage, debridement, electrodesiccation, and radiation. The Table includes a complete summary of the treatments we analyzed.

Surgical Therapy—The majority (91% [105/115]) of cases were treated surgically. The most common treatment modality was WLE (50% [58/115]), followed by amputation (37% [43/115]) and MMS (12% [14/115]).

Wide local excision was the most frequently reported treatment, with excision margins of at least 5 mm to 1 cm.⁴⁸ Incidence of recurrence was reported for 57% (33/58) of cases treated with WLE; of these, the recurrence rate was 33% (11/33). For patients with EC recurrence, the most common secondary treatment was repeat excision with wider margins (1–2 cm) or amputation (5/11).^49-52 Few postoperative complications were reported but included pain, infection, and difficulty walking, which were mostly associated with repair modality (eg, split-thickness skin grafts, rotational flaps).⁵³ 
Amputation was the second most common treatment modality, with a 67% (29/43) incidence of recurrence. Types of amputation included transmetatarsal ray amputation (7/43 [16%]), foot or forefoot amputation (2/43 [5%]), above-the-knee amputation (1/43 [2%]), and below-the-knee amputation (1/43 [2%]). Complications associated with amputation included infection and requirement of prosthetics for ambulation. Split-thickness skin grafts and rotational flaps were the most common surgical repairs performed.^52,53

Mohs micrographic surgery was the least frequently reported surgical treatment modality. Both traditional MMS on fresh tissue and “slow Mohs,” with formalin-fixed paraffin embedded tissue examination over several days, were performed for EC with horizontal en face sectioning.^54-56 Incidence of recurrence was reported for 86% (12/14) of MMS cases. Of these, recurrence was seen in 17% (2/12) that utilized a flat horizontal processing of tissue sections coupled with saucerlike excisions to enable examination of the entire undersurface and margins. In one case, the patient was treated with MMS with recurrence noted 1 month later; thus, repeat MMS was performed, and the tumor was found to be entwined around the flexor tendon.⁵⁷ The tendon was removed, and clear margins were obtained. Follow-up 3 years after the second MMS revealed no signs of recurrence.⁵⁷ In the other case, the patient had a particularly aggressive course with bilateral VC in the setting of diabetic ulcers that was treated with WLE prior to MMS and recurrence still noted after MMS.²⁶ No complications were reported with MMS.

Overall, recurrence was most frequently reported with WLE (11/33 [33%]), followed by MMS (2/12 [17%]) and amputation (3/29 [10%]). When comparing WLE and amputation, the relationship between treatment modality and recurrence was statistically significant using a χ² test of independence (χ²=4.7; P=.03). However, results were not significant with Yates correction for continuity (χ²=3.4; P=.06). The χ² test of independence showed no significant association between treatment method and recurrence when comparing WLE with MMS (χ²=1.2; P=.28). Reported follow-up times varied greatly from a few months to 10 years.

Systemic Therapy—Of the total cases, only 2 cases reported treatment with acitretin and 2 utilized interferon alfa.^58,59 In one case, treatment of EC with interferon alfa alone required more aggressive therapy (ie, amputation).⁵⁸ Neither of the 2 cases using acitretin reported recurrence.^59,60 Complications of acitretin therapy included cheilitis and transaminitis.⁶⁰

Other Treatment Modalities—Three cases utilized imiquimod, with 2 cases of imiquimod monotherapy and 1 case of imiquimod in combination with electrodesiccation and WLE.³⁷ One of the cases of EC treated with imiquimod monotherapy recurred and required WLE.⁶¹

There were reports of other treatments including curettage alone (2% [2/115]),^40,62 debridement alone (1% [1/115]),⁴⁰ electrodesiccation (1% [1/115]),³⁷ and radiation (1% [1/115]).⁴³ Recurrence was found with curettage alone and debridement alone. Electrodesiccation was reported in conjunction with WLE without recurrence. Radiation was used to treat a case of VC that had metastasized to the lymph nodes; no follow-up was described.⁴³

COMMENT

Epithelioma cuniculatum is an indolent malignancy of the plantar foot that likely is frequently underdiagnosed or misdiagnosed because of location, sampling error, and challenges in histopathologic diagnosis. Once diagnosed, surgical removal with margin control is the first-line therapy for EC. Our review found a number of surgical, systemic, and other treatment modalities that have been used to treat EC, but there remains a lack of evidence to provide clear guidelines as to which therapies are most effective. Current data on the treatment of EC largely are limited to case reports and case series. To date, there are no reports of higher-quality studies or randomized controlled trials to assess the efficacy of various treatment modalities.

Our review found that WLE is the most common treatment modality for EC, followed by amputation and MMS. Three cases^43-45 that reported metastasis to lymph nodes also were treated with fine-needle aspiration or biopsy, and it is recommended that sentinel lymph node biopsy be performed when there is a history of radiation exposure or clinically and sonographically unsuspicious lymph nodes, while dissection of regional nodes should be performed if lymph node metastasis is suspected.⁵³ Additional treatments reported included acitretin, interferon alfa, topical imiquimod, curettage, debridement, and electrodesiccation, but because of the limited number of cases and variable efficacy, no conclusions can be made on the utility of these alternative modalities.

The lowest rate of reported recurrence was found with amputation, followed by MMS and WLE. Amputation is the most aggressive treatment option, but its superiority in lower recurrence rates was not statistically significant when compared with either WLE or MMS after Yates correction. Despite treatment with radical surgery, recurrence is still possible and may be associated with factors including greater size (>2 cm) and depth (>4 mm), poor histologic differentiation, perineural involvement, failure of previous treatments, and immunosuppression.⁶³ No statistically significant difference in recurrence rates was found among surgical methods, though data trended toward lower rates of recurrence with MMS compared with WLE, as recurrence with MMS was only reported in 2 cases.^25,56

The efficacy of MMS is well documented for tumors with contiguous growth and enables maximum preservation of normal tissue structure and function with complete margin visualization. Thus, our results are in agreement with those of prior studies,^54-56,64 suggesting that MMS is associated with lower recurrence rates for EC than WLE. Future studies and reporting of MMS for EC are particularly important because of the functional importance of the plantar foot.

It is important to note that there are local and systemic risk factors that increase the likelihood of developing EC and facilitate tumor growth, including antecedent trauma to the lesion site, chronic irritation or infection, and immunosuppression (HIV related or iatrogenic medication induced). These risk factors may play a role in the treatment modality utilized (eg, more aggressive EC may be treated with amputation instead of WLE). Underlying patient comorbidities could potentially affect recurrence rates, which is a variable we could not control for in our analysis.

Our findings are limited by study design, with supporting evidence consisting of case reports and series. The review is limited by interstudy variability and heterogeneity of results. Additionally, recurrence is not reported in all cases and may be a source of sampling bias. Further complicating the generalizability of these results is the lack of follow-up to evaluate morbidity and quality of life after treatment.

CONCLUSION

This review suggests that MMS is associated with lower recurrence rates than WLE for the treatment of EC. Further investigation of MMS for EC with appropriate follow-up is necessary to identify whether MMS is associated with lower recurrence and less functional impairment. Nonsurgical treatments, including topical imiquimod, interferon alfa, and acitretin, may be useful in cases where surgical therapies are contraindicated, but there is little evidence to support these treatment modalities. Treatment guidelines for EC are not established, and appropriate treatment guidelines should be developed in the future.

Verrucous carcinoma (VC) is an uncommon type of well-differentiated squamous cell carcinoma (SCC) that most commonly affects men in the fifth to sixth decades of life. ¹ The tumor grows slowly over a decade or more and does not frequently metastasize but has a high propensity for recurrence and local invasion. ²  There are 3 main subtypes of VC classified by anatomic site: oral florid papillomatosis (oral cavity), Buschke-Lowenstein tumor (anogenital region), and epithelioma cuniculatum (EC)(feet). ³ Epithelioma cuniculatum, also known as carcinoma cuniculatum or papillomatosis cutis carcinoides, most commonly presents as a solitary, warty or cauliflowerlike, exophytic mass with keratin-filled sinus tracts and malodorous discharge. ⁴ Diabetic foot ulcers and chronic inflammatory conditions are predisposing risk factors for EC, and it can result in difficulty walking/immobility, pain, and bleeding depending on anatomic involvement. ^5-9

The differential diagnosis for VC includes refractory verruca vulgaris, clavus, SCC, keratoacanthoma, deep fungal or mycobacterial infection, eccrine poroma or porocarcinoma, amelanotic melanoma, and sarcoma.^10-13 The slow-growing nature of VC, sampling error of superficial biopsies, and minimal cytological atypia on histologic examination can contribute to delayed diagnosis and appropriate treatment.¹⁴ Characteristic histologic features include hyperkeratosis, papillomatosis, marked acanthosis, broad blunt-ended rete ridges with a “bulldozing” architecture, and minimal cytologic atypia and mitoses.^5,6 In some cases, pleomorphism and glassy eosinophilic cytoplasmic changes may be more pronounced than that of a common wart though less dramatic than that of conventional SCCs.¹⁵ Antigen Ki-67 and tumor protein p53 have been proposed to help differentiate between common plantar verruca, VC, and SCC, but the histologic diagnosis remains challenging, and repeat histopathologic examination often is required.^16-19 Following diagnosis, computed tomography or magnetic resonance imaging may be necessary to determine tumor extension and assess for deep tissue and bony involvement.^20-22

Treatment of EC is particularly challenging because of the anatomic location and need for margin control while maintaining adequate function, preserving healthy tissue, and providing coverage of defects. Surgical excision of EC is the first-line treatment, most commonly by wide local excision (WLE) or amputation. Mohs micrographic surgery (MMS) also has been utilized. One review found no recurrences in 5 cases of EC treated with MMS.²³ As MMS is a tissue-sparing technique, this is a valuable modality for sites of functional importance such as the feet. Herein, we review various reported EC treatment modalities and outcomes, with an emphasis on recurrence rates for WLE and MMS.

METHODS

A systematic literature review of PubMed articles indexed for MEDLINE, as well as databases including the Cochrane Library, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL), was performed on January 14, 2020. Two authors (S.S.D. and S.V.C.) independently screened results using the search terms (plantar OR foot) AND (verrucous carcinoma OR epithelioma cuniculatum OR carcinoma cuniculatum). The search terms were chosen according to MeSH subject headings. All articles from the start date of the databases through the search date were screened, and articles pertaining to VC, EC, or carcinoma cuniculatum located on the foot were included. Of these, non–English-language articles were translated and included. Articles reporting VC on a site other than the foot (eg, the oral cavity) or benign verrucous skin lesions were excluded. The reference lists for all articles also were reviewed for additional reports that were absent from the initial search using both included and excluded articles. A full-text review was performed on 221 articles published between 1954 and 2019 per the PRISMA guidelines (Figure).

A total of 101 articles were included in the study for qualitative analysis. Nearly all articles identified were case reports, giving an evidence level of 5 by the Centre for Evidence-Based Medicine rating scale. Five articles reported data on multiple patients without individual demographic or clinical details and were excluded from analysis. Of the remaining 96 articles, information about patient characteristics, tumor size, treatment modality, and recurrence were extracted for 115 cases.

RESULTS

Of the 115 cases that were reviewed, 81 (70%) were male and 33 (29%) were female with a male-to-female ratio of 2.4:1. Ages of the patients ranged from 18 to 88 years; the mean and median age was 56 years. Nearly all reported cases of EC affected the plantar surface of one foot, with 4 reports of tumors affecting both feet.^24-27 One case affecting both feet reported known exposure to lead arsenate pesticides²⁷; all others were associated with a clinical history of chronic ulcers or warts persisting for several years to decades. Other less common sites of EC included the dorsal foot, interdigital web space, and subungual digit.^28-30 The most common location reported was the anterior ball of the foot. Tumors were reported to arise within pre-existing lesions, such as hypertrophic lichen planus or chronic foot wounds associated with diabetes mellitus or leprosy.^31-35 Tumor size ranged from 1 to 22 cm with a median of 4.5 cm.

Eight cases were reported to be associated with human papillomavirus; low-risk types 6 and 11 and high-risk types 16 and 18 were found in 6 cases.^36-41 Two cases reported association with human papillomavirus type 2.^7,42

Metastases to dermal and subdermal lymphatics, regional lymph nodes, and the lungs were reported in 3 cases, repectively.^43-45 Of these, one primary tumor had received low-dose irradiation in the form of X-ray therapy.⁴⁵

Treatment Modalities

The cases of EC that we reviewed included treatment with surgical and systemic therapies as well as other modalities such as acitretin, interferon alfa, topical imiquimod, curettage, debridement, electrodesiccation, and radiation. The Table includes a complete summary of the treatments we analyzed.

Surgical Therapy—The majority (91% [105/115]) of cases were treated surgically. The most common treatment modality was WLE (50% [58/115]), followed by amputation (37% [43/115]) and MMS (12% [14/115]).

Wide local excision was the most frequently reported treatment, with excision margins of at least 5 mm to 1 cm.⁴⁸ Incidence of recurrence was reported for 57% (33/58) of cases treated with WLE; of these, the recurrence rate was 33% (11/33). For patients with EC recurrence, the most common secondary treatment was repeat excision with wider margins (1–2 cm) or amputation (5/11).^49-52 Few postoperative complications were reported but included pain, infection, and difficulty walking, which were mostly associated with repair modality (eg, split-thickness skin grafts, rotational flaps).⁵³ 
Amputation was the second most common treatment modality, with a 67% (29/43) incidence of recurrence. Types of amputation included transmetatarsal ray amputation (7/43 [16%]), foot or forefoot amputation (2/43 [5%]), above-the-knee amputation (1/43 [2%]), and below-the-knee amputation (1/43 [2%]). Complications associated with amputation included infection and requirement of prosthetics for ambulation. Split-thickness skin grafts and rotational flaps were the most common surgical repairs performed.^52,53

Mohs micrographic surgery was the least frequently reported surgical treatment modality. Both traditional MMS on fresh tissue and “slow Mohs,” with formalin-fixed paraffin embedded tissue examination over several days, were performed for EC with horizontal en face sectioning.^54-56 Incidence of recurrence was reported for 86% (12/14) of MMS cases. Of these, recurrence was seen in 17% (2/12) that utilized a flat horizontal processing of tissue sections coupled with saucerlike excisions to enable examination of the entire undersurface and margins. In one case, the patient was treated with MMS with recurrence noted 1 month later; thus, repeat MMS was performed, and the tumor was found to be entwined around the flexor tendon.⁵⁷ The tendon was removed, and clear margins were obtained. Follow-up 3 years after the second MMS revealed no signs of recurrence.⁵⁷ In the other case, the patient had a particularly aggressive course with bilateral VC in the setting of diabetic ulcers that was treated with WLE prior to MMS and recurrence still noted after MMS.²⁶ No complications were reported with MMS.

Overall, recurrence was most frequently reported with WLE (11/33 [33%]), followed by MMS (2/12 [17%]) and amputation (3/29 [10%]). When comparing WLE and amputation, the relationship between treatment modality and recurrence was statistically significant using a χ² test of independence (χ²=4.7; P=.03). However, results were not significant with Yates correction for continuity (χ²=3.4; P=.06). The χ² test of independence showed no significant association between treatment method and recurrence when comparing WLE with MMS (χ²=1.2; P=.28). Reported follow-up times varied greatly from a few months to 10 years.

Systemic Therapy—Of the total cases, only 2 cases reported treatment with acitretin and 2 utilized interferon alfa.^58,59 In one case, treatment of EC with interferon alfa alone required more aggressive therapy (ie, amputation).⁵⁸ Neither of the 2 cases using acitretin reported recurrence.^59,60 Complications of acitretin therapy included cheilitis and transaminitis.⁶⁰

Other Treatment Modalities—Three cases utilized imiquimod, with 2 cases of imiquimod monotherapy and 1 case of imiquimod in combination with electrodesiccation and WLE.³⁷ One of the cases of EC treated with imiquimod monotherapy recurred and required WLE.⁶¹

There were reports of other treatments including curettage alone (2% [2/115]),^40,62 debridement alone (1% [1/115]),⁴⁰ electrodesiccation (1% [1/115]),³⁷ and radiation (1% [1/115]).⁴³ Recurrence was found with curettage alone and debridement alone. Electrodesiccation was reported in conjunction with WLE without recurrence. Radiation was used to treat a case of VC that had metastasized to the lymph nodes; no follow-up was described.⁴³

COMMENT

Epithelioma cuniculatum is an indolent malignancy of the plantar foot that likely is frequently underdiagnosed or misdiagnosed because of location, sampling error, and challenges in histopathologic diagnosis. Once diagnosed, surgical removal with margin control is the first-line therapy for EC. Our review found a number of surgical, systemic, and other treatment modalities that have been used to treat EC, but there remains a lack of evidence to provide clear guidelines as to which therapies are most effective. Current data on the treatment of EC largely are limited to case reports and case series. To date, there are no reports of higher-quality studies or randomized controlled trials to assess the efficacy of various treatment modalities.

Our review found that WLE is the most common treatment modality for EC, followed by amputation and MMS. Three cases^43-45 that reported metastasis to lymph nodes also were treated with fine-needle aspiration or biopsy, and it is recommended that sentinel lymph node biopsy be performed when there is a history of radiation exposure or clinically and sonographically unsuspicious lymph nodes, while dissection of regional nodes should be performed if lymph node metastasis is suspected.⁵³ Additional treatments reported included acitretin, interferon alfa, topical imiquimod, curettage, debridement, and electrodesiccation, but because of the limited number of cases and variable efficacy, no conclusions can be made on the utility of these alternative modalities.

The lowest rate of reported recurrence was found with amputation, followed by MMS and WLE. Amputation is the most aggressive treatment option, but its superiority in lower recurrence rates was not statistically significant when compared with either WLE or MMS after Yates correction. Despite treatment with radical surgery, recurrence is still possible and may be associated with factors including greater size (>2 cm) and depth (>4 mm), poor histologic differentiation, perineural involvement, failure of previous treatments, and immunosuppression.⁶³ No statistically significant difference in recurrence rates was found among surgical methods, though data trended toward lower rates of recurrence with MMS compared with WLE, as recurrence with MMS was only reported in 2 cases.^25,56

The efficacy of MMS is well documented for tumors with contiguous growth and enables maximum preservation of normal tissue structure and function with complete margin visualization. Thus, our results are in agreement with those of prior studies,^54-56,64 suggesting that MMS is associated with lower recurrence rates for EC than WLE. Future studies and reporting of MMS for EC are particularly important because of the functional importance of the plantar foot.

It is important to note that there are local and systemic risk factors that increase the likelihood of developing EC and facilitate tumor growth, including antecedent trauma to the lesion site, chronic irritation or infection, and immunosuppression (HIV related or iatrogenic medication induced). These risk factors may play a role in the treatment modality utilized (eg, more aggressive EC may be treated with amputation instead of WLE). Underlying patient comorbidities could potentially affect recurrence rates, which is a variable we could not control for in our analysis.

Our findings are limited by study design, with supporting evidence consisting of case reports and series. The review is limited by interstudy variability and heterogeneity of results. Additionally, recurrence is not reported in all cases and may be a source of sampling bias. Further complicating the generalizability of these results is the lack of follow-up to evaluate morbidity and quality of life after treatment.

CONCLUSION

This review suggests that MMS is associated with lower recurrence rates than WLE for the treatment of EC. Further investigation of MMS for EC with appropriate follow-up is necessary to identify whether MMS is associated with lower recurrence and less functional impairment. Nonsurgical treatments, including topical imiquimod, interferon alfa, and acitretin, may be useful in cases where surgical therapies are contraindicated, but there is little evidence to support these treatment modalities. Treatment guidelines for EC are not established, and appropriate treatment guidelines should be developed in the future.

Technologies that allow people to monitor blood sugar and automate the administration of insulin have radically transformed the lives of patients – and children in particular – with type 1 diabetes. But the devices often come with a cost: Insulin pumps and continuous glucose monitors can irritate the skin at the points of contact, causing some people to stop using their pumps or monitors altogether.

Regular use of lipid-rich skin creams can reduce eczema in children who use insulin pumps and continuous glucose monitors to manage type 1 diabetes, Danish researchers reported last month. The article is currently undergoing peer review at The Lancet Diabetes and Endocrinology, and the authors said they hope their approach will deter more children from abandoning diabetes technology.

“A simple thing can actually change a lot,” said Anna Korsgaard Berg, MD, a pediatrician who specializes in diabetes care at Copenhagen University Hospital’s Steno Diabetes Center in Herlev, Denmark, and a coauthor of the new study. “Not all skin reactions can be solved by the skin care program, but it can help improve the issue.”

More than 1.5 million children and adolescents worldwide live with type 1 diabetes, a condition that requires continuous insulin infusion. Insulin pumps meet this need in many wealthier countries, and are often used in combination with sensors that measure a child’s glucose level. Both the American Diabetes Association and the International Society for Adolescent and Pediatric Diabetes recommend insulin pumps and continuous glucose monitors as core treatment tools.

Dr. Berg and colleagues, who have previously shown that as many as 90% of children who use these devices experience some kind of skin reaction, want to minimize the rate of such discomfort in hopes that fewer children stop using the devices. According to a 2014 study, 18% of people with type 1 diabetes who stopped using continuous glucose monitors did so because of skin irritation.
 

Lather on that lipid-rich lotion

Dr. Berg and colleagues studied 170 children and adolescents with type 1 diabetes (average age, 11 years) who use insulin pumps, continuous glucose monitors, or both. From March 2020 to July 2021, 112 children (55 girls) employed a skin care program developed for the study, while the other 58 (34 girls) did not receive any skin care advice.

The skin care group received instructions about how to gently insert and remove their insulin pumps or glucose monitors, to minimize skin damage. They also were told to avoid disinfectants such as alcohol, which can irritate skin. The children in this group used a cream containing 70% lipids to help rehydrate their skin, applying the salve each day a device was not inserted into their skin.

Eczema can be a real problem for kids who use insulin pumps and continuous glucose monitors to manage type 1 diabetes. Researchers found that regular use of lipid-rich skin creams can reduce its incidence.

Although insulin pumps and glucose monitors are kept in place for longer periods of time than they once were, Dr. Berg and colleagues noted, users do periodically remove them when bathing or when undergoing medical tests that involve x-rays. On days when the devices were not in place for a period of time, children in the skin care group were encouraged to follow the protocol.
 

Study results

One-third of children in the skin care group developed eczema or experienced a wound, compared with almost half of the children in the control group, according to the researchers. The absolute difference in developing eczema or wounds between the two groups was 12.9 % (95% confidence interval, –28.7% to 2.9%).

Children in the skin care group were much less likely to develop wounds, the researchers found, when they focused only on wounds and not eczema (odds ratio, 0.29, 95% CI, 0.12-0.68).

Dr. Berg said she would like to explore whether other techniques, such as a combination of patches, adhesives, or other lotions, yield even better results.

“Anything that can help people use technology more consistently is better for both quality of life and diabetes outcomes,” said Priya Prahalad, MD, a specialist in pediatric endocrinology and diabetes at Stanford Medicine Children’s Health in Palo Alto and Sunnyvale, Calif. 

Dr. Prahalad, who was not involved in the Danish study, said that although the sample sizes in the trial were relatively small, the data are “headed in the right direction.”

Pediatricians already recommend using moisturizing creams at the sites where pumps or glucose monitors are inserted into the skin, she noted. But the new study simply employed an especially moisturizing cream to mitigate skin damage.

Although one reason for skin irritation may be the repeated insertion and removal of devices, Dr. Berg and Dr. Prahalad stressed that the medical devices themselves may contain allergy-causing components. Device makers are not required to disclose what’s inside the boxes.

“I do not understand why the full content of a device is not by law mandatory to declare, when declaration by law is mandatory for many other products and drugs but not for medical devices,” Dr. Berg said.

Dr. Berg reports receiving lipid cream from Teva Pharmaceuticals and research support from Medtronic. Dr. Prahalad reports no relevant financial relationships.

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

Technologies that allow people to monitor blood sugar and automate the administration of insulin have radically transformed the lives of patients – and children in particular – with type 1 diabetes. But the devices often come with a cost: Insulin pumps and continuous glucose monitors can irritate the skin at the points of contact, causing some people to stop using their pumps or monitors altogether.

Regular use of lipid-rich skin creams can reduce eczema in children who use insulin pumps and continuous glucose monitors to manage type 1 diabetes, Danish researchers reported last month. The article is currently undergoing peer review at The Lancet Diabetes and Endocrinology, and the authors said they hope their approach will deter more children from abandoning diabetes technology.

“A simple thing can actually change a lot,” said Anna Korsgaard Berg, MD, a pediatrician who specializes in diabetes care at Copenhagen University Hospital’s Steno Diabetes Center in Herlev, Denmark, and a coauthor of the new study. “Not all skin reactions can be solved by the skin care program, but it can help improve the issue.”

More than 1.5 million children and adolescents worldwide live with type 1 diabetes, a condition that requires continuous insulin infusion. Insulin pumps meet this need in many wealthier countries, and are often used in combination with sensors that measure a child’s glucose level. Both the American Diabetes Association and the International Society for Adolescent and Pediatric Diabetes recommend insulin pumps and continuous glucose monitors as core treatment tools.

Dr. Berg and colleagues, who have previously shown that as many as 90% of children who use these devices experience some kind of skin reaction, want to minimize the rate of such discomfort in hopes that fewer children stop using the devices. According to a 2014 study, 18% of people with type 1 diabetes who stopped using continuous glucose monitors did so because of skin irritation.
 

Lather on that lipid-rich lotion

Dr. Berg and colleagues studied 170 children and adolescents with type 1 diabetes (average age, 11 years) who use insulin pumps, continuous glucose monitors, or both. From March 2020 to July 2021, 112 children (55 girls) employed a skin care program developed for the study, while the other 58 (34 girls) did not receive any skin care advice.

The skin care group received instructions about how to gently insert and remove their insulin pumps or glucose monitors, to minimize skin damage. They also were told to avoid disinfectants such as alcohol, which can irritate skin. The children in this group used a cream containing 70% lipids to help rehydrate their skin, applying the salve each day a device was not inserted into their skin.

Eczema can be a real problem for kids who use insulin pumps and continuous glucose monitors to manage type 1 diabetes. Researchers found that regular use of lipid-rich skin creams can reduce its incidence.

Although insulin pumps and glucose monitors are kept in place for longer periods of time than they once were, Dr. Berg and colleagues noted, users do periodically remove them when bathing or when undergoing medical tests that involve x-rays. On days when the devices were not in place for a period of time, children in the skin care group were encouraged to follow the protocol.
 

Study results

One-third of children in the skin care group developed eczema or experienced a wound, compared with almost half of the children in the control group, according to the researchers. The absolute difference in developing eczema or wounds between the two groups was 12.9 % (95% confidence interval, –28.7% to 2.9%).

Children in the skin care group were much less likely to develop wounds, the researchers found, when they focused only on wounds and not eczema (odds ratio, 0.29, 95% CI, 0.12-0.68).

Dr. Berg said she would like to explore whether other techniques, such as a combination of patches, adhesives, or other lotions, yield even better results.

“Anything that can help people use technology more consistently is better for both quality of life and diabetes outcomes,” said Priya Prahalad, MD, a specialist in pediatric endocrinology and diabetes at Stanford Medicine Children’s Health in Palo Alto and Sunnyvale, Calif. 

Dr. Prahalad, who was not involved in the Danish study, said that although the sample sizes in the trial were relatively small, the data are “headed in the right direction.”

Pediatricians already recommend using moisturizing creams at the sites where pumps or glucose monitors are inserted into the skin, she noted. But the new study simply employed an especially moisturizing cream to mitigate skin damage.

Although one reason for skin irritation may be the repeated insertion and removal of devices, Dr. Berg and Dr. Prahalad stressed that the medical devices themselves may contain allergy-causing components. Device makers are not required to disclose what’s inside the boxes.

“I do not understand why the full content of a device is not by law mandatory to declare, when declaration by law is mandatory for many other products and drugs but not for medical devices,” Dr. Berg said.

Dr. Berg reports receiving lipid cream from Teva Pharmaceuticals and research support from Medtronic. Dr. Prahalad reports no relevant financial relationships.

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

Technologies that allow people to monitor blood sugar and automate the administration of insulin have radically transformed the lives of patients – and children in particular – with type 1 diabetes. But the devices often come with a cost: Insulin pumps and continuous glucose monitors can irritate the skin at the points of contact, causing some people to stop using their pumps or monitors altogether.

Regular use of lipid-rich skin creams can reduce eczema in children who use insulin pumps and continuous glucose monitors to manage type 1 diabetes, Danish researchers reported last month. The article is currently undergoing peer review at The Lancet Diabetes and Endocrinology, and the authors said they hope their approach will deter more children from abandoning diabetes technology.

“A simple thing can actually change a lot,” said Anna Korsgaard Berg, MD, a pediatrician who specializes in diabetes care at Copenhagen University Hospital’s Steno Diabetes Center in Herlev, Denmark, and a coauthor of the new study. “Not all skin reactions can be solved by the skin care program, but it can help improve the issue.”

More than 1.5 million children and adolescents worldwide live with type 1 diabetes, a condition that requires continuous insulin infusion. Insulin pumps meet this need in many wealthier countries, and are often used in combination with sensors that measure a child’s glucose level. Both the American Diabetes Association and the International Society for Adolescent and Pediatric Diabetes recommend insulin pumps and continuous glucose monitors as core treatment tools.

Dr. Berg and colleagues, who have previously shown that as many as 90% of children who use these devices experience some kind of skin reaction, want to minimize the rate of such discomfort in hopes that fewer children stop using the devices. According to a 2014 study, 18% of people with type 1 diabetes who stopped using continuous glucose monitors did so because of skin irritation.
 

Lather on that lipid-rich lotion

Dr. Berg and colleagues studied 170 children and adolescents with type 1 diabetes (average age, 11 years) who use insulin pumps, continuous glucose monitors, or both. From March 2020 to July 2021, 112 children (55 girls) employed a skin care program developed for the study, while the other 58 (34 girls) did not receive any skin care advice.

The skin care group received instructions about how to gently insert and remove their insulin pumps or glucose monitors, to minimize skin damage. They also were told to avoid disinfectants such as alcohol, which can irritate skin. The children in this group used a cream containing 70% lipids to help rehydrate their skin, applying the salve each day a device was not inserted into their skin.

Eczema can be a real problem for kids who use insulin pumps and continuous glucose monitors to manage type 1 diabetes. Researchers found that regular use of lipid-rich skin creams can reduce its incidence.

Although insulin pumps and glucose monitors are kept in place for longer periods of time than they once were, Dr. Berg and colleagues noted, users do periodically remove them when bathing or when undergoing medical tests that involve x-rays. On days when the devices were not in place for a period of time, children in the skin care group were encouraged to follow the protocol.
 

Study results

One-third of children in the skin care group developed eczema or experienced a wound, compared with almost half of the children in the control group, according to the researchers. The absolute difference in developing eczema or wounds between the two groups was 12.9 % (95% confidence interval, –28.7% to 2.9%).

Children in the skin care group were much less likely to develop wounds, the researchers found, when they focused only on wounds and not eczema (odds ratio, 0.29, 95% CI, 0.12-0.68).

Dr. Berg said she would like to explore whether other techniques, such as a combination of patches, adhesives, or other lotions, yield even better results.

“Anything that can help people use technology more consistently is better for both quality of life and diabetes outcomes,” said Priya Prahalad, MD, a specialist in pediatric endocrinology and diabetes at Stanford Medicine Children’s Health in Palo Alto and Sunnyvale, Calif. 

Dr. Prahalad, who was not involved in the Danish study, said that although the sample sizes in the trial were relatively small, the data are “headed in the right direction.”

Pediatricians already recommend using moisturizing creams at the sites where pumps or glucose monitors are inserted into the skin, she noted. But the new study simply employed an especially moisturizing cream to mitigate skin damage.

Although one reason for skin irritation may be the repeated insertion and removal of devices, Dr. Berg and Dr. Prahalad stressed that the medical devices themselves may contain allergy-causing components. Device makers are not required to disclose what’s inside the boxes.

“I do not understand why the full content of a device is not by law mandatory to declare, when declaration by law is mandatory for many other products and drugs but not for medical devices,” Dr. Berg said.

Dr. Berg reports receiving lipid cream from Teva Pharmaceuticals and research support from Medtronic. Dr. Prahalad reports no relevant financial relationships.

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

Hair loss is an exceedingly common chief concern in outpatient dermatology clinics. An estimated 50% of males and females will experience androgenetic alopecia.¹ Approximately 2% of new dermatology outpatient visits in the United States and the United Kingdom are for alopecia areata, the second most common type of hair loss.² As access to dermatology appointments remains an issue with some studies citing wait times ranging from 2 to 25 days for a dermatologic consultation, the ease of accessibility of medical information on social media continues to grow,³ which leaves many of our patients turning to social media as a first-line source of information. As dermatology resident physicians, it is essential to be aware of popular dermatologic therapies on social media so that we may provide evidence-based opinions to our patients.

Remedies for Hair Loss on Social Media

Many trends on hair loss therapies found on TikTok focus on natural remedies that are produced by ingredients accessible to patients at home and over the counter, which may increase the appeal due to ease of treatment.

Rosemary Oil—The top trends in hair loss remedies I have come across are rosemary oil and rosemary water. Rosemary (Rosmarinus officinalis) has been known to possess antimicrobial and antioxidant properties but also has shown enhancement of microcapillary perfusion, which could explain its role in the prevention of hair loss and aiding hair growth in a similar mechanism to minoxidil.^4,5 Unlike many other natural hair loss remedies, there are randomized controlled trials that assess the efficacy of rosemary oil for the treatment of hair loss. In a 2015 study of 100 patients with androgenetic alopecia, there was no statistically significant difference in mean hair count measured by microphotographic assessment after 6 months of treatment in 2 groups treated with either minoxidil solution 2% or rosemary oil, and both groups experienced a significant increase in hair count at 6 months (P<.05) compared with baseline and 3 months.⁶ Additionally, essential oils, including a mixture of thyme, rosemary, lavender, and cedarwood oils for alopecia were superior to placebo carrier oils in a posttreatment photographic assessment of their efficacy.⁷

Rice Water—The use of rice water and rice bran extract is a common hair care practice in Asia. Rice bran extract preparations have been shown in vivo to increase the number of anagen hair follicles as well as the number of anagen-related molecules in the dermal papillae.^8,9 However, there are limited clinical data to support the use of rice water for hair growth.¹⁰

Onion Juice—Sharquie and Al-Obaidi¹¹ conducted a study comparing crude onion juice to tap water in 38 patients with alopecia areata. They found that onion juice produced hair regrowth in significantly more patients than tap water (P<.0001).¹¹ The mechanism of crude onion juice in hair growth is unknown; however, the induction of irritant or allergic contact dermatitis to components in crude onion juice may stimulate antigenic competition.¹²

Garlic Gel—Garlic gel, which is in the genus Allium, produces organosulfur compounds that provide antimicrobial and anti-inflammatory benefits.¹² Additionally, in a double-blind randomized controlled trial, garlic powder was shown to increase cutaneous capillary perfusion.⁵ One study in 40 patients with alopecia areata demonstrated garlic gel 5% added to betamethasone valerate cream 0.1% was statistically superior to betamethasone alone in stimulating terminal hair growth (P=.001).¹³

Limitations and Downsides to Hair Loss Remedies on Social Media

Social media continues to be a prominent source of medical information for our patients, but most sources of hair content on social media are not board-certified dermatologists. A recent review of alopecia-related content found only 4% and 10% of posts were created by medical professionals on Instagram and TikTok, respectively, making misinformation extremely likely.¹⁴ Natural hair loss remedies contrived by TikTok have little clinical evidence to support their claims. Few data are available that compare these treatments to gold-standard hair loss therapies. Additionally, while some of these agents may be beneficial, the lack of standardized dosing may counteract these benefits. For example, videos on rosemary water advise the viewer to boil fresh rosemary sprigs in water and apply the solution to the hair daily with a spray bottle or apply cloves of garlic directly to the scalp, as opposed to a measured and standardized percentage. Some preparations may even induce harm to patients. Over-the-counter oils with added fragrances and natural compounds in onion and garlic may cause contact dermatitis. Finally, by using these products, patients may delay consultation with a board-certified dermatologist, leading to delays in applying evidence-based therapies targeted to specific hair loss subtypes while also incurring unnecessary expenses for these preparations.

Final Thoughts

Hair loss affects a notable portion of the population and is a common chief concern in dermatology clinics. Misinformation on social media continues to grow in prevalence. It is important to be aware of the hair loss remedies that are commonly touted to patients online and the evidence behind them.

Hair loss is an exceedingly common chief concern in outpatient dermatology clinics. An estimated 50% of males and females will experience androgenetic alopecia.¹ Approximately 2% of new dermatology outpatient visits in the United States and the United Kingdom are for alopecia areata, the second most common type of hair loss.² As access to dermatology appointments remains an issue with some studies citing wait times ranging from 2 to 25 days for a dermatologic consultation, the ease of accessibility of medical information on social media continues to grow,³ which leaves many of our patients turning to social media as a first-line source of information. As dermatology resident physicians, it is essential to be aware of popular dermatologic therapies on social media so that we may provide evidence-based opinions to our patients.

Remedies for Hair Loss on Social Media

Many trends on hair loss therapies found on TikTok focus on natural remedies that are produced by ingredients accessible to patients at home and over the counter, which may increase the appeal due to ease of treatment.

Rosemary Oil—The top trends in hair loss remedies I have come across are rosemary oil and rosemary water. Rosemary (Rosmarinus officinalis) has been known to possess antimicrobial and antioxidant properties but also has shown enhancement of microcapillary perfusion, which could explain its role in the prevention of hair loss and aiding hair growth in a similar mechanism to minoxidil.^4,5 Unlike many other natural hair loss remedies, there are randomized controlled trials that assess the efficacy of rosemary oil for the treatment of hair loss. In a 2015 study of 100 patients with androgenetic alopecia, there was no statistically significant difference in mean hair count measured by microphotographic assessment after 6 months of treatment in 2 groups treated with either minoxidil solution 2% or rosemary oil, and both groups experienced a significant increase in hair count at 6 months (P<.05) compared with baseline and 3 months.⁶ Additionally, essential oils, including a mixture of thyme, rosemary, lavender, and cedarwood oils for alopecia were superior to placebo carrier oils in a posttreatment photographic assessment of their efficacy.⁷

Rice Water—The use of rice water and rice bran extract is a common hair care practice in Asia. Rice bran extract preparations have been shown in vivo to increase the number of anagen hair follicles as well as the number of anagen-related molecules in the dermal papillae.^8,9 However, there are limited clinical data to support the use of rice water for hair growth.¹⁰

Onion Juice—Sharquie and Al-Obaidi¹¹ conducted a study comparing crude onion juice to tap water in 38 patients with alopecia areata. They found that onion juice produced hair regrowth in significantly more patients than tap water (P<.0001).¹¹ The mechanism of crude onion juice in hair growth is unknown; however, the induction of irritant or allergic contact dermatitis to components in crude onion juice may stimulate antigenic competition.¹²

Garlic Gel—Garlic gel, which is in the genus Allium, produces organosulfur compounds that provide antimicrobial and anti-inflammatory benefits.¹² Additionally, in a double-blind randomized controlled trial, garlic powder was shown to increase cutaneous capillary perfusion.⁵ One study in 40 patients with alopecia areata demonstrated garlic gel 5% added to betamethasone valerate cream 0.1% was statistically superior to betamethasone alone in stimulating terminal hair growth (P=.001).¹³

Limitations and Downsides to Hair Loss Remedies on Social Media

Social media continues to be a prominent source of medical information for our patients, but most sources of hair content on social media are not board-certified dermatologists. A recent review of alopecia-related content found only 4% and 10% of posts were created by medical professionals on Instagram and TikTok, respectively, making misinformation extremely likely.¹⁴ Natural hair loss remedies contrived by TikTok have little clinical evidence to support their claims. Few data are available that compare these treatments to gold-standard hair loss therapies. Additionally, while some of these agents may be beneficial, the lack of standardized dosing may counteract these benefits. For example, videos on rosemary water advise the viewer to boil fresh rosemary sprigs in water and apply the solution to the hair daily with a spray bottle or apply cloves of garlic directly to the scalp, as opposed to a measured and standardized percentage. Some preparations may even induce harm to patients. Over-the-counter oils with added fragrances and natural compounds in onion and garlic may cause contact dermatitis. Finally, by using these products, patients may delay consultation with a board-certified dermatologist, leading to delays in applying evidence-based therapies targeted to specific hair loss subtypes while also incurring unnecessary expenses for these preparations.

Final Thoughts

Hair loss affects a notable portion of the population and is a common chief concern in dermatology clinics. Misinformation on social media continues to grow in prevalence. It is important to be aware of the hair loss remedies that are commonly touted to patients online and the evidence behind them.

Hair loss is an exceedingly common chief concern in outpatient dermatology clinics. An estimated 50% of males and females will experience androgenetic alopecia.¹ Approximately 2% of new dermatology outpatient visits in the United States and the United Kingdom are for alopecia areata, the second most common type of hair loss.² As access to dermatology appointments remains an issue with some studies citing wait times ranging from 2 to 25 days for a dermatologic consultation, the ease of accessibility of medical information on social media continues to grow,³ which leaves many of our patients turning to social media as a first-line source of information. As dermatology resident physicians, it is essential to be aware of popular dermatologic therapies on social media so that we may provide evidence-based opinions to our patients.

Remedies for Hair Loss on Social Media

Many trends on hair loss therapies found on TikTok focus on natural remedies that are produced by ingredients accessible to patients at home and over the counter, which may increase the appeal due to ease of treatment.

Rosemary Oil—The top trends in hair loss remedies I have come across are rosemary oil and rosemary water. Rosemary (Rosmarinus officinalis) has been known to possess antimicrobial and antioxidant properties but also has shown enhancement of microcapillary perfusion, which could explain its role in the prevention of hair loss and aiding hair growth in a similar mechanism to minoxidil.^4,5 Unlike many other natural hair loss remedies, there are randomized controlled trials that assess the efficacy of rosemary oil for the treatment of hair loss. In a 2015 study of 100 patients with androgenetic alopecia, there was no statistically significant difference in mean hair count measured by microphotographic assessment after 6 months of treatment in 2 groups treated with either minoxidil solution 2% or rosemary oil, and both groups experienced a significant increase in hair count at 6 months (P<.05) compared with baseline and 3 months.⁶ Additionally, essential oils, including a mixture of thyme, rosemary, lavender, and cedarwood oils for alopecia were superior to placebo carrier oils in a posttreatment photographic assessment of their efficacy.⁷

Rice Water—The use of rice water and rice bran extract is a common hair care practice in Asia. Rice bran extract preparations have been shown in vivo to increase the number of anagen hair follicles as well as the number of anagen-related molecules in the dermal papillae.^8,9 However, there are limited clinical data to support the use of rice water for hair growth.¹⁰

Onion Juice—Sharquie and Al-Obaidi¹¹ conducted a study comparing crude onion juice to tap water in 38 patients with alopecia areata. They found that onion juice produced hair regrowth in significantly more patients than tap water (P<.0001).¹¹ The mechanism of crude onion juice in hair growth is unknown; however, the induction of irritant or allergic contact dermatitis to components in crude onion juice may stimulate antigenic competition.¹²

Garlic Gel—Garlic gel, which is in the genus Allium, produces organosulfur compounds that provide antimicrobial and anti-inflammatory benefits.¹² Additionally, in a double-blind randomized controlled trial, garlic powder was shown to increase cutaneous capillary perfusion.⁵ One study in 40 patients with alopecia areata demonstrated garlic gel 5% added to betamethasone valerate cream 0.1% was statistically superior to betamethasone alone in stimulating terminal hair growth (P=.001).¹³

Limitations and Downsides to Hair Loss Remedies on Social Media

Social media continues to be a prominent source of medical information for our patients, but most sources of hair content on social media are not board-certified dermatologists. A recent review of alopecia-related content found only 4% and 10% of posts were created by medical professionals on Instagram and TikTok, respectively, making misinformation extremely likely.¹⁴ Natural hair loss remedies contrived by TikTok have little clinical evidence to support their claims. Few data are available that compare these treatments to gold-standard hair loss therapies. Additionally, while some of these agents may be beneficial, the lack of standardized dosing may counteract these benefits. For example, videos on rosemary water advise the viewer to boil fresh rosemary sprigs in water and apply the solution to the hair daily with a spray bottle or apply cloves of garlic directly to the scalp, as opposed to a measured and standardized percentage. Some preparations may even induce harm to patients. Over-the-counter oils with added fragrances and natural compounds in onion and garlic may cause contact dermatitis. Finally, by using these products, patients may delay consultation with a board-certified dermatologist, leading to delays in applying evidence-based therapies targeted to specific hair loss subtypes while also incurring unnecessary expenses for these preparations.

Final Thoughts

Hair loss affects a notable portion of the population and is a common chief concern in dermatology clinics. Misinformation on social media continues to grow in prevalence. It is important to be aware of the hair loss remedies that are commonly touted to patients online and the evidence behind them.

To the Editor:

Epidermodysplasia verruciformis (EDV) is a rare generalized form of epidermal dysplasia that is linked to certain subtypes of human papillomavirus (HPV) infection and inherited or acquired states of immunodeficiency.^1-3 The inherited form most commonly manifests via autosomal-recessive inactivation of the EVER1 and EVER2 genes that encode integral membrane proteins in the endoplasmic reticulum, though cases of autosomal-dominant and X-linked inheritance have been reported.^1-3 Acquired cases have been reported in patients lacking immunocompetency, including transplant recipients and patients living with HIV.^4-11 We present the case of a patient with HIV-associated EDV who was treated successfully with intralesional Candida albicans antigen, oral acitretin, and cryotherapy.

A 56-year-old man presented for evaluation of several cutaneous lesions that had developed over several months on the neck and over many years on the hands and feet. He had a 16-year history of HIV, Castleman disease, and primary effusion lymphoma in remission that was treated with rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride 10 or more years ago. The patient denied pruritus or pain associated with the skin lesions. He was intermittently taking immunosuppressants and antiretrovirals including dolutegravir and emtricitabine-tenofovir for 3 years. Prior treatments of the lesions included cryotherapy and over-the-counter 17% salicylic acid. Physical examination revealed the presence of innumerable, clustered, verrucous, scaly papules on the dorsal and palmoplantar regions of the hands (Figure 1), as well as hypopigmented macules clustered on the neck that morphologically resembled tinea versicolor (Figure 2). The physical examination was otherwise unremarkable.

Complete blood cell counts as well as lipid, liver, and renal function panel results were unremarkable. Laboratory examination also revealed a CD4 cell count of 373/µL (reference range, 320–1900/µL) and an undetectable HIV copy number (<40 copies/mL). A punch biopsy of a hypopigmented macule on the left side of the neck revealed epidermal acanthosis, hypergranulosis, and hyperkeratosis, with blue-gray cytoplasm observed in the keratinocytes (Figure 3). Koilocytes with perinuclear clearing associated with keratinocytes in the upper epidermis were noted. Based on the clinical and histopathologic correlation, acquired EDV was diagnosed.

Given that HIV-associated EDV often is recalcitrant and there is a lack of consistent and effective treatment, the patient initially was prescribed oral acitretin 25 mg/d with intralesional C albicans antigen injected once per month into the lesions along with concurrent cryotherapy. At subsequent monthly follow-ups, the involved areas were notably thinner and flat. The patient reported no remarkable side effects from the systemic retinoid treatment such as abdominal pain, photosensitivity, or headaches, though he did experience mild xerosis. Complete resolution of EDV occurred with multimodal therapy—acitretin, cryotherapy, and intralesional Candida antigen. Palmar verrucae were much improved, and he is currently continuing therapy.

Epidermodysplasia verruciformis is a rare genodermatosis associated with an abnormal susceptibility to cutaneous HPV and can be acquired in immunocompromised patients. Patients with EDV present with a clinically heterogeneous disease that can manifest as hypopigmented, red-brown macules with scaling on the trunk, neck, and extremities, which are morphologically similar to tinea versicolor, or patients can present with flat wartlike papules that are most commonly found on the face, hands, and feet.^2,3 Epidermodysplasia verruciformis can be distinguished from EDV-like eruptions and other generalized verrucoses by its characteristic histologic appearance and by the demonstration of HPV within the lesions, typically subtypes HPV-5 and HPV-8.^1-3 Classic EDV histopathologic findings include mild to moderate acanthosis and hyperkeratosis with enlarged keratinocytes featuring blue-gray cytoplasm and perinuclear halos.¹

The histologic differential diagnosis of EDV is quite broad and includes common verrucae, which may be distinguished by the absence of blue-gray discoloration of the cytoplasm among the individual keratinocytes.¹ Verruca plana and condylomata also may mimic EDV, and patients may present with minimal papillomatosis of the surface epidermis.² Squamous cell carcinoma in situ (SCC-IS) and particularly bowenoid papulosis also may share similar histologic features.² However, in SCC-IS, there typically is full-thickness dysplasia of the epidermis, which is not present in EDV. Nonetheless, EDV is equivalent to SCC-IS in its clinical behavior. Bowenoid papulosis shares similar findings, but lesions generally are located in the genital areas and linked to HPV-16 and HPV-18.² Additional histologic features of EDV have been described in the entity of EDV acanthoma, specifically incidental findings present in association with other cutaneous neoplasms including acantholytic acanthomas, condylomas, intradermal nevi, and seborrheic keratoses.¹²

The pathophysiology of EDV is thought to be specifically associated with patients with immunocompromised conditions. Particular attention has been paid to the association between EDV and HIV. Anselmo et al¹³ reported a case of HIV-associated acquired EDV with preexisting lesions that were spread along the distribution of the patient’s tattoo, suggesting potential autoinoculation. In individuals living with HIV, the cutaneous features of EDV are not associated with immune status.¹⁴

Acquired EDV also may be associated with other conditions including renal transplantation, IgM deficiency, severe combined immunodeficiency, common variable immunodeficiency, systemic lupus erythematosus, and myasthenia gravis.² Hematologic malignancies such as Hodgkin disease,⁴ natural killer/T-cell lymphoma,⁵ cutaneous T-cell lymphoma,⁶ adult T-cell leukemia,⁷ intestinal diffuse large B-cell lymphoma,^8,9 transformed acute myelogenous lymphoma,¹⁰ and chronic myelogenous leukemia¹¹ also may be associated with EDV. In the inherited form, integral membrane proteins of the endoplasmic reticulum encoded by the genes EVER1 and EVER2 on chromosome 17 are thought to act as restriction factors for certain types of HPV.^2,3 Inactivating mutations in EVER1 and EVER2 result in defects in cell-mediated immunity, rendering patients susceptible to both benign and oncogenic verrucous infections.^2,3 Currently, it is believed that immunosuppressed states may result in defects in cell-mediated immunity that make patients similarly susceptible to these virulent strains of HPV, resulting in an acquired form of EDV.³ Interestingly, the clinical and histologic presentation is identical for acquired EDV and genetic EDV.

Due to the general resistance of EDV to treatment, a variety of options for acquired EDV have been explored including topical and systemic retinoids, cryotherapy, interferon alfa‐2a, zidovudine, ketoconazole, corticosteroids, podophyllotoxin, imiquimod, cidofovir, electrosurgery, 5‐fluorouracil, glycolic acid, temporized diathermy, and methyl aminolevulinate photodynamic therapy.³ Highly active antiretroviral therapy has been proposed as a potential treatment modality for HIV-associated cases; however, acquired EDV has been reported to develop as an immune reconstitution inflammatory syndrome after the initiation of highly active antiretroviral therapy.¹⁵

Combination therapy consisting of a systemic retinoid, immunotherapy, and cryotherapy was initiated for our patient. Human papillomavirus infection is marked by epithelial hyperplasia, and retinoids induce antiproliferation through the control of epithelial cell differentiation.¹⁶ The specific mechanism of action of retinoids in EDV treatment is unknown; however, the beneficial effects may result from the modification of terminal differentiation, a direct antiviral action, or the enhancement of killer T cells.¹⁷ Immunotherapy with C albicans antigen initiates an inflammatory reaction that leads to an immune response directed against the virus, thus reducing the number of warts.² Cryotherapy aims to destroy the lesion but not the virus.² The combination of systemic retinoids, immunotherapy, and destruction may target EDV via multiple potentially synergistic mechanisms. Thus, a multimodal approach can be beneficial in patients with recalcitrant acquired EDV.

The occurrence of EDV is rare, and data on treatment are limited in number resulting in general uncertainty about the efficacy of therapies. Elucidation of the specific mechanism of immunosuppression and its effects on T lymphocytes in acquired EDV may shed light on the most effective treatments. We present this novel case of a patient with HIV-associated acquired EDV who responded favorably to a combination treatment of acitretin, intralesional C albicans antigen, and cryotherapy.

To the Editor:

Epidermodysplasia verruciformis (EDV) is a rare generalized form of epidermal dysplasia that is linked to certain subtypes of human papillomavirus (HPV) infection and inherited or acquired states of immunodeficiency.^1-3 The inherited form most commonly manifests via autosomal-recessive inactivation of the EVER1 and EVER2 genes that encode integral membrane proteins in the endoplasmic reticulum, though cases of autosomal-dominant and X-linked inheritance have been reported.^1-3 Acquired cases have been reported in patients lacking immunocompetency, including transplant recipients and patients living with HIV.^4-11 We present the case of a patient with HIV-associated EDV who was treated successfully with intralesional Candida albicans antigen, oral acitretin, and cryotherapy.

A 56-year-old man presented for evaluation of several cutaneous lesions that had developed over several months on the neck and over many years on the hands and feet. He had a 16-year history of HIV, Castleman disease, and primary effusion lymphoma in remission that was treated with rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride 10 or more years ago. The patient denied pruritus or pain associated with the skin lesions. He was intermittently taking immunosuppressants and antiretrovirals including dolutegravir and emtricitabine-tenofovir for 3 years. Prior treatments of the lesions included cryotherapy and over-the-counter 17% salicylic acid. Physical examination revealed the presence of innumerable, clustered, verrucous, scaly papules on the dorsal and palmoplantar regions of the hands (Figure 1), as well as hypopigmented macules clustered on the neck that morphologically resembled tinea versicolor (Figure 2). The physical examination was otherwise unremarkable.

Complete blood cell counts as well as lipid, liver, and renal function panel results were unremarkable. Laboratory examination also revealed a CD4 cell count of 373/µL (reference range, 320–1900/µL) and an undetectable HIV copy number (<40 copies/mL). A punch biopsy of a hypopigmented macule on the left side of the neck revealed epidermal acanthosis, hypergranulosis, and hyperkeratosis, with blue-gray cytoplasm observed in the keratinocytes (Figure 3). Koilocytes with perinuclear clearing associated with keratinocytes in the upper epidermis were noted. Based on the clinical and histopathologic correlation, acquired EDV was diagnosed.

Given that HIV-associated EDV often is recalcitrant and there is a lack of consistent and effective treatment, the patient initially was prescribed oral acitretin 25 mg/d with intralesional C albicans antigen injected once per month into the lesions along with concurrent cryotherapy. At subsequent monthly follow-ups, the involved areas were notably thinner and flat. The patient reported no remarkable side effects from the systemic retinoid treatment such as abdominal pain, photosensitivity, or headaches, though he did experience mild xerosis. Complete resolution of EDV occurred with multimodal therapy—acitretin, cryotherapy, and intralesional Candida antigen. Palmar verrucae were much improved, and he is currently continuing therapy.

Epidermodysplasia verruciformis is a rare genodermatosis associated with an abnormal susceptibility to cutaneous HPV and can be acquired in immunocompromised patients. Patients with EDV present with a clinically heterogeneous disease that can manifest as hypopigmented, red-brown macules with scaling on the trunk, neck, and extremities, which are morphologically similar to tinea versicolor, or patients can present with flat wartlike papules that are most commonly found on the face, hands, and feet.^2,3 Epidermodysplasia verruciformis can be distinguished from EDV-like eruptions and other generalized verrucoses by its characteristic histologic appearance and by the demonstration of HPV within the lesions, typically subtypes HPV-5 and HPV-8.^1-3 Classic EDV histopathologic findings include mild to moderate acanthosis and hyperkeratosis with enlarged keratinocytes featuring blue-gray cytoplasm and perinuclear halos.¹

The histologic differential diagnosis of EDV is quite broad and includes common verrucae, which may be distinguished by the absence of blue-gray discoloration of the cytoplasm among the individual keratinocytes.¹ Verruca plana and condylomata also may mimic EDV, and patients may present with minimal papillomatosis of the surface epidermis.² Squamous cell carcinoma in situ (SCC-IS) and particularly bowenoid papulosis also may share similar histologic features.² However, in SCC-IS, there typically is full-thickness dysplasia of the epidermis, which is not present in EDV. Nonetheless, EDV is equivalent to SCC-IS in its clinical behavior. Bowenoid papulosis shares similar findings, but lesions generally are located in the genital areas and linked to HPV-16 and HPV-18.² Additional histologic features of EDV have been described in the entity of EDV acanthoma, specifically incidental findings present in association with other cutaneous neoplasms including acantholytic acanthomas, condylomas, intradermal nevi, and seborrheic keratoses.¹²

The pathophysiology of EDV is thought to be specifically associated with patients with immunocompromised conditions. Particular attention has been paid to the association between EDV and HIV. Anselmo et al¹³ reported a case of HIV-associated acquired EDV with preexisting lesions that were spread along the distribution of the patient’s tattoo, suggesting potential autoinoculation. In individuals living with HIV, the cutaneous features of EDV are not associated with immune status.¹⁴

Acquired EDV also may be associated with other conditions including renal transplantation, IgM deficiency, severe combined immunodeficiency, common variable immunodeficiency, systemic lupus erythematosus, and myasthenia gravis.² Hematologic malignancies such as Hodgkin disease,⁴ natural killer/T-cell lymphoma,⁵ cutaneous T-cell lymphoma,⁶ adult T-cell leukemia,⁷ intestinal diffuse large B-cell lymphoma,^8,9 transformed acute myelogenous lymphoma,¹⁰ and chronic myelogenous leukemia¹¹ also may be associated with EDV. In the inherited form, integral membrane proteins of the endoplasmic reticulum encoded by the genes EVER1 and EVER2 on chromosome 17 are thought to act as restriction factors for certain types of HPV.^2,3 Inactivating mutations in EVER1 and EVER2 result in defects in cell-mediated immunity, rendering patients susceptible to both benign and oncogenic verrucous infections.^2,3 Currently, it is believed that immunosuppressed states may result in defects in cell-mediated immunity that make patients similarly susceptible to these virulent strains of HPV, resulting in an acquired form of EDV.³ Interestingly, the clinical and histologic presentation is identical for acquired EDV and genetic EDV.

Due to the general resistance of EDV to treatment, a variety of options for acquired EDV have been explored including topical and systemic retinoids, cryotherapy, interferon alfa‐2a, zidovudine, ketoconazole, corticosteroids, podophyllotoxin, imiquimod, cidofovir, electrosurgery, 5‐fluorouracil, glycolic acid, temporized diathermy, and methyl aminolevulinate photodynamic therapy.³ Highly active antiretroviral therapy has been proposed as a potential treatment modality for HIV-associated cases; however, acquired EDV has been reported to develop as an immune reconstitution inflammatory syndrome after the initiation of highly active antiretroviral therapy.¹⁵

Combination therapy consisting of a systemic retinoid, immunotherapy, and cryotherapy was initiated for our patient. Human papillomavirus infection is marked by epithelial hyperplasia, and retinoids induce antiproliferation through the control of epithelial cell differentiation.¹⁶ The specific mechanism of action of retinoids in EDV treatment is unknown; however, the beneficial effects may result from the modification of terminal differentiation, a direct antiviral action, or the enhancement of killer T cells.¹⁷ Immunotherapy with C albicans antigen initiates an inflammatory reaction that leads to an immune response directed against the virus, thus reducing the number of warts.² Cryotherapy aims to destroy the lesion but not the virus.² The combination of systemic retinoids, immunotherapy, and destruction may target EDV via multiple potentially synergistic mechanisms. Thus, a multimodal approach can be beneficial in patients with recalcitrant acquired EDV.

The occurrence of EDV is rare, and data on treatment are limited in number resulting in general uncertainty about the efficacy of therapies. Elucidation of the specific mechanism of immunosuppression and its effects on T lymphocytes in acquired EDV may shed light on the most effective treatments. We present this novel case of a patient with HIV-associated acquired EDV who responded favorably to a combination treatment of acitretin, intralesional C albicans antigen, and cryotherapy.

To the Editor:

Epidermodysplasia verruciformis (EDV) is a rare generalized form of epidermal dysplasia that is linked to certain subtypes of human papillomavirus (HPV) infection and inherited or acquired states of immunodeficiency.^1-3 The inherited form most commonly manifests via autosomal-recessive inactivation of the EVER1 and EVER2 genes that encode integral membrane proteins in the endoplasmic reticulum, though cases of autosomal-dominant and X-linked inheritance have been reported.^1-3 Acquired cases have been reported in patients lacking immunocompetency, including transplant recipients and patients living with HIV.^4-11 We present the case of a patient with HIV-associated EDV who was treated successfully with intralesional Candida albicans antigen, oral acitretin, and cryotherapy.

A 56-year-old man presented for evaluation of several cutaneous lesions that had developed over several months on the neck and over many years on the hands and feet. He had a 16-year history of HIV, Castleman disease, and primary effusion lymphoma in remission that was treated with rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride 10 or more years ago. The patient denied pruritus or pain associated with the skin lesions. He was intermittently taking immunosuppressants and antiretrovirals including dolutegravir and emtricitabine-tenofovir for 3 years. Prior treatments of the lesions included cryotherapy and over-the-counter 17% salicylic acid. Physical examination revealed the presence of innumerable, clustered, verrucous, scaly papules on the dorsal and palmoplantar regions of the hands (Figure 1), as well as hypopigmented macules clustered on the neck that morphologically resembled tinea versicolor (Figure 2). The physical examination was otherwise unremarkable.

Complete blood cell counts as well as lipid, liver, and renal function panel results were unremarkable. Laboratory examination also revealed a CD4 cell count of 373/µL (reference range, 320–1900/µL) and an undetectable HIV copy number (<40 copies/mL). A punch biopsy of a hypopigmented macule on the left side of the neck revealed epidermal acanthosis, hypergranulosis, and hyperkeratosis, with blue-gray cytoplasm observed in the keratinocytes (Figure 3). Koilocytes with perinuclear clearing associated with keratinocytes in the upper epidermis were noted. Based on the clinical and histopathologic correlation, acquired EDV was diagnosed.

Given that HIV-associated EDV often is recalcitrant and there is a lack of consistent and effective treatment, the patient initially was prescribed oral acitretin 25 mg/d with intralesional C albicans antigen injected once per month into the lesions along with concurrent cryotherapy. At subsequent monthly follow-ups, the involved areas were notably thinner and flat. The patient reported no remarkable side effects from the systemic retinoid treatment such as abdominal pain, photosensitivity, or headaches, though he did experience mild xerosis. Complete resolution of EDV occurred with multimodal therapy—acitretin, cryotherapy, and intralesional Candida antigen. Palmar verrucae were much improved, and he is currently continuing therapy.

Epidermodysplasia verruciformis is a rare genodermatosis associated with an abnormal susceptibility to cutaneous HPV and can be acquired in immunocompromised patients. Patients with EDV present with a clinically heterogeneous disease that can manifest as hypopigmented, red-brown macules with scaling on the trunk, neck, and extremities, which are morphologically similar to tinea versicolor, or patients can present with flat wartlike papules that are most commonly found on the face, hands, and feet.^2,3 Epidermodysplasia verruciformis can be distinguished from EDV-like eruptions and other generalized verrucoses by its characteristic histologic appearance and by the demonstration of HPV within the lesions, typically subtypes HPV-5 and HPV-8.^1-3 Classic EDV histopathologic findings include mild to moderate acanthosis and hyperkeratosis with enlarged keratinocytes featuring blue-gray cytoplasm and perinuclear halos.¹

The histologic differential diagnosis of EDV is quite broad and includes common verrucae, which may be distinguished by the absence of blue-gray discoloration of the cytoplasm among the individual keratinocytes.¹ Verruca plana and condylomata also may mimic EDV, and patients may present with minimal papillomatosis of the surface epidermis.² Squamous cell carcinoma in situ (SCC-IS) and particularly bowenoid papulosis also may share similar histologic features.² However, in SCC-IS, there typically is full-thickness dysplasia of the epidermis, which is not present in EDV. Nonetheless, EDV is equivalent to SCC-IS in its clinical behavior. Bowenoid papulosis shares similar findings, but lesions generally are located in the genital areas and linked to HPV-16 and HPV-18.² Additional histologic features of EDV have been described in the entity of EDV acanthoma, specifically incidental findings present in association with other cutaneous neoplasms including acantholytic acanthomas, condylomas, intradermal nevi, and seborrheic keratoses.¹²

The pathophysiology of EDV is thought to be specifically associated with patients with immunocompromised conditions. Particular attention has been paid to the association between EDV and HIV. Anselmo et al¹³ reported a case of HIV-associated acquired EDV with preexisting lesions that were spread along the distribution of the patient’s tattoo, suggesting potential autoinoculation. In individuals living with HIV, the cutaneous features of EDV are not associated with immune status.¹⁴

Acquired EDV also may be associated with other conditions including renal transplantation, IgM deficiency, severe combined immunodeficiency, common variable immunodeficiency, systemic lupus erythematosus, and myasthenia gravis.² Hematologic malignancies such as Hodgkin disease,⁴ natural killer/T-cell lymphoma,⁵ cutaneous T-cell lymphoma,⁶ adult T-cell leukemia,⁷ intestinal diffuse large B-cell lymphoma,^8,9 transformed acute myelogenous lymphoma,¹⁰ and chronic myelogenous leukemia¹¹ also may be associated with EDV. In the inherited form, integral membrane proteins of the endoplasmic reticulum encoded by the genes EVER1 and EVER2 on chromosome 17 are thought to act as restriction factors for certain types of HPV.^2,3 Inactivating mutations in EVER1 and EVER2 result in defects in cell-mediated immunity, rendering patients susceptible to both benign and oncogenic verrucous infections.^2,3 Currently, it is believed that immunosuppressed states may result in defects in cell-mediated immunity that make patients similarly susceptible to these virulent strains of HPV, resulting in an acquired form of EDV.³ Interestingly, the clinical and histologic presentation is identical for acquired EDV and genetic EDV.

Due to the general resistance of EDV to treatment, a variety of options for acquired EDV have been explored including topical and systemic retinoids, cryotherapy, interferon alfa‐2a, zidovudine, ketoconazole, corticosteroids, podophyllotoxin, imiquimod, cidofovir, electrosurgery, 5‐fluorouracil, glycolic acid, temporized diathermy, and methyl aminolevulinate photodynamic therapy.³ Highly active antiretroviral therapy has been proposed as a potential treatment modality for HIV-associated cases; however, acquired EDV has been reported to develop as an immune reconstitution inflammatory syndrome after the initiation of highly active antiretroviral therapy.¹⁵

Combination therapy consisting of a systemic retinoid, immunotherapy, and cryotherapy was initiated for our patient. Human papillomavirus infection is marked by epithelial hyperplasia, and retinoids induce antiproliferation through the control of epithelial cell differentiation.¹⁶ The specific mechanism of action of retinoids in EDV treatment is unknown; however, the beneficial effects may result from the modification of terminal differentiation, a direct antiviral action, or the enhancement of killer T cells.¹⁷ Immunotherapy with C albicans antigen initiates an inflammatory reaction that leads to an immune response directed against the virus, thus reducing the number of warts.² Cryotherapy aims to destroy the lesion but not the virus.² The combination of systemic retinoids, immunotherapy, and destruction may target EDV via multiple potentially synergistic mechanisms. Thus, a multimodal approach can be beneficial in patients with recalcitrant acquired EDV.

The occurrence of EDV is rare, and data on treatment are limited in number resulting in general uncertainty about the efficacy of therapies. Elucidation of the specific mechanism of immunosuppression and its effects on T lymphocytes in acquired EDV may shed light on the most effective treatments. We present this novel case of a patient with HIV-associated acquired EDV who responded favorably to a combination treatment of acitretin, intralesional C albicans antigen, and cryotherapy.