While identifying overt bacterial infections in patients with atopic dermatitis is straightforward, wide variations in clinical presentation of infections in AD and features common to both can make it difficult to make a clinical diagnosis of infections.

Addressing this issue, the International Eczema Council Skin Infection Group reviewed the most current evidence on the clinical features of bacterial infections and the interaction between host and bacterial factors that affect severity and morbidity in people with atopic dermatitis (AD). Recurrent skin infections, especially from Staphylococcus aureus and occasionally from beta-hemolytic streptococci, are more common in people with AD than those who do not have AD for a variety of reasons, Helen Alexander, MD, from the unit for population-based dermatology research at St. John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, and associates wrote in the review article published in the British Journal of Dermatology.

“The reduced skin barrier, cutaneous innate and adaptive immune abnormalities and trauma from scratching all contribute to the increased risk of skin infection,” they wrote. “However, the wide variability in clinical presentation of bacterial infection in AD and the inherent features of AD – cutaneous erythema and warmth, oozing associated with edema, and regional lymphadenopathy – overlap with those of infection, making clinical diagnosis challenging.”

The clinical appearance of AD may also mask signs of the bacterial infection, they added, and providers cannot rely on positive skin swab culture from the possibly infected area since S. aureus is so common in AD. An added challenge can occur in patients of different ethnicities, in whom both AD and bacterial infection may manifest differently. For example, perifollicular accentuation often occurs with AD in dark-skinned patients with violet-colored, often muted erythema.

An estimated 70% of lesional and 39% of nonlesional AD skin is colonized with S. aureus, the authors noted, but it’s not clear how best to recognize and manage asymptomatic S. aureus colonization. Among the factors that can increase susceptibility to S. aureus colonization and infection are impaired skin barriers, type 2 inflammation and lower levels of microbial diversity in the skin microbiome.

Specific clinical features of S. aureus in patients with AD include “weeping, honey-colored crusts and pustules, both interfollicular and follicular based,” and the pustules, though not common, can involve pain and itching. By comparison, signs of beta-hemolytic streptococcal infection may include “well-defined, bright red erythema, thick-walled pustules and heavy crusting,” the authors wrote.

Fever and lymphadenopathy may occur in severe cases, as well as abscesses, particularly with methicillin-resistant S. aureus (MRSA) infection. It’s unclear whether MRSA occurs more often in people with AD since its incidence varies so widely geographically, they noted.

In the differential diagnosis, providers should consider the possibility that a patient has a concomitant viral or fungal infection. Eczema herpeticum from herpes simplex virus is a common viral infection with risk factors that include “moderate to severe AD, filaggrin loss-of-function mutation, a history of S. aureus skin infection, greater allergen sensitization and type 2 immunity,” the authors wrote.

The yeast Malassezia is implicated in inflammation in patients with dermatitis that affects the head, neck, upper chest, back, and other areas high in sebaceous glands. Some patients have greater sensitivity to Malassezia, and “cross-reactivity between Malassezia-specific IgE and Candida albicans” has occurred as well, they wrote. Current evidence favors benefit from antifungal drugs, though not conclusively.

“Although we have some understanding of how S. aureus colonizes the skin and causes inflammation in AD, many questions related to this complex relationship remain unanswered,” the authors concluded. They added that better understanding the mechanisms of S. aureus and downstream host immune mediators of inflammatory pathways involving S. aureus could potentially lead to new therapeutic targets for infection in AD patients.

The statement was funded in part by the senior author’s fellowships from the National Institutes of Health Research, and the International Eczema Council received sponsorship from AbbVie, Amgen, Asana Biosciences, Celgene, Chugai, Dermavant, Dermira, Eli Lilly, Galderma, Incyte, LEO Pharma, Kyowa Kirin, Novartis, Pierre Fabre, Pfizer, Sanofi Genzyme, Regeneron Pharmaceuticals, Sienna and Valeant. Of the 16 authors, 13 disclosed financial ties to a wide range of pharmaceutical companies, including those listed above.

SOURCE: Alexander H et al. Br J Dermatol. 2019 Nov 1. doi: 10.1111/bjd.1864319.

While identifying overt bacterial infections in patients with atopic dermatitis is straightforward, wide variations in clinical presentation of infections in AD and features common to both can make it difficult to make a clinical diagnosis of infections.

Addressing this issue, the International Eczema Council Skin Infection Group reviewed the most current evidence on the clinical features of bacterial infections and the interaction between host and bacterial factors that affect severity and morbidity in people with atopic dermatitis (AD). Recurrent skin infections, especially from Staphylococcus aureus and occasionally from beta-hemolytic streptococci, are more common in people with AD than those who do not have AD for a variety of reasons, Helen Alexander, MD, from the unit for population-based dermatology research at St. John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, and associates wrote in the review article published in the British Journal of Dermatology.

“The reduced skin barrier, cutaneous innate and adaptive immune abnormalities and trauma from scratching all contribute to the increased risk of skin infection,” they wrote. “However, the wide variability in clinical presentation of bacterial infection in AD and the inherent features of AD – cutaneous erythema and warmth, oozing associated with edema, and regional lymphadenopathy – overlap with those of infection, making clinical diagnosis challenging.”

The clinical appearance of AD may also mask signs of the bacterial infection, they added, and providers cannot rely on positive skin swab culture from the possibly infected area since S. aureus is so common in AD. An added challenge can occur in patients of different ethnicities, in whom both AD and bacterial infection may manifest differently. For example, perifollicular accentuation often occurs with AD in dark-skinned patients with violet-colored, often muted erythema.

An estimated 70% of lesional and 39% of nonlesional AD skin is colonized with S. aureus, the authors noted, but it’s not clear how best to recognize and manage asymptomatic S. aureus colonization. Among the factors that can increase susceptibility to S. aureus colonization and infection are impaired skin barriers, type 2 inflammation and lower levels of microbial diversity in the skin microbiome.

Specific clinical features of S. aureus in patients with AD include “weeping, honey-colored crusts and pustules, both interfollicular and follicular based,” and the pustules, though not common, can involve pain and itching. By comparison, signs of beta-hemolytic streptococcal infection may include “well-defined, bright red erythema, thick-walled pustules and heavy crusting,” the authors wrote.

Fever and lymphadenopathy may occur in severe cases, as well as abscesses, particularly with methicillin-resistant S. aureus (MRSA) infection. It’s unclear whether MRSA occurs more often in people with AD since its incidence varies so widely geographically, they noted.

In the differential diagnosis, providers should consider the possibility that a patient has a concomitant viral or fungal infection. Eczema herpeticum from herpes simplex virus is a common viral infection with risk factors that include “moderate to severe AD, filaggrin loss-of-function mutation, a history of S. aureus skin infection, greater allergen sensitization and type 2 immunity,” the authors wrote.

The yeast Malassezia is implicated in inflammation in patients with dermatitis that affects the head, neck, upper chest, back, and other areas high in sebaceous glands. Some patients have greater sensitivity to Malassezia, and “cross-reactivity between Malassezia-specific IgE and Candida albicans” has occurred as well, they wrote. Current evidence favors benefit from antifungal drugs, though not conclusively.

“Although we have some understanding of how S. aureus colonizes the skin and causes inflammation in AD, many questions related to this complex relationship remain unanswered,” the authors concluded. They added that better understanding the mechanisms of S. aureus and downstream host immune mediators of inflammatory pathways involving S. aureus could potentially lead to new therapeutic targets for infection in AD patients.

The statement was funded in part by the senior author’s fellowships from the National Institutes of Health Research, and the International Eczema Council received sponsorship from AbbVie, Amgen, Asana Biosciences, Celgene, Chugai, Dermavant, Dermira, Eli Lilly, Galderma, Incyte, LEO Pharma, Kyowa Kirin, Novartis, Pierre Fabre, Pfizer, Sanofi Genzyme, Regeneron Pharmaceuticals, Sienna and Valeant. Of the 16 authors, 13 disclosed financial ties to a wide range of pharmaceutical companies, including those listed above.

SOURCE: Alexander H et al. Br J Dermatol. 2019 Nov 1. doi: 10.1111/bjd.1864319.

While identifying overt bacterial infections in patients with atopic dermatitis is straightforward, wide variations in clinical presentation of infections in AD and features common to both can make it difficult to make a clinical diagnosis of infections.

Addressing this issue, the International Eczema Council Skin Infection Group reviewed the most current evidence on the clinical features of bacterial infections and the interaction between host and bacterial factors that affect severity and morbidity in people with atopic dermatitis (AD). Recurrent skin infections, especially from Staphylococcus aureus and occasionally from beta-hemolytic streptococci, are more common in people with AD than those who do not have AD for a variety of reasons, Helen Alexander, MD, from the unit for population-based dermatology research at St. John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, and associates wrote in the review article published in the British Journal of Dermatology.

“The reduced skin barrier, cutaneous innate and adaptive immune abnormalities and trauma from scratching all contribute to the increased risk of skin infection,” they wrote. “However, the wide variability in clinical presentation of bacterial infection in AD and the inherent features of AD – cutaneous erythema and warmth, oozing associated with edema, and regional lymphadenopathy – overlap with those of infection, making clinical diagnosis challenging.”

The clinical appearance of AD may also mask signs of the bacterial infection, they added, and providers cannot rely on positive skin swab culture from the possibly infected area since S. aureus is so common in AD. An added challenge can occur in patients of different ethnicities, in whom both AD and bacterial infection may manifest differently. For example, perifollicular accentuation often occurs with AD in dark-skinned patients with violet-colored, often muted erythema.

An estimated 70% of lesional and 39% of nonlesional AD skin is colonized with S. aureus, the authors noted, but it’s not clear how best to recognize and manage asymptomatic S. aureus colonization. Among the factors that can increase susceptibility to S. aureus colonization and infection are impaired skin barriers, type 2 inflammation and lower levels of microbial diversity in the skin microbiome.

Specific clinical features of S. aureus in patients with AD include “weeping, honey-colored crusts and pustules, both interfollicular and follicular based,” and the pustules, though not common, can involve pain and itching. By comparison, signs of beta-hemolytic streptococcal infection may include “well-defined, bright red erythema, thick-walled pustules and heavy crusting,” the authors wrote.

Fever and lymphadenopathy may occur in severe cases, as well as abscesses, particularly with methicillin-resistant S. aureus (MRSA) infection. It’s unclear whether MRSA occurs more often in people with AD since its incidence varies so widely geographically, they noted.

In the differential diagnosis, providers should consider the possibility that a patient has a concomitant viral or fungal infection. Eczema herpeticum from herpes simplex virus is a common viral infection with risk factors that include “moderate to severe AD, filaggrin loss-of-function mutation, a history of S. aureus skin infection, greater allergen sensitization and type 2 immunity,” the authors wrote.

The yeast Malassezia is implicated in inflammation in patients with dermatitis that affects the head, neck, upper chest, back, and other areas high in sebaceous glands. Some patients have greater sensitivity to Malassezia, and “cross-reactivity between Malassezia-specific IgE and Candida albicans” has occurred as well, they wrote. Current evidence favors benefit from antifungal drugs, though not conclusively.

“Although we have some understanding of how S. aureus colonizes the skin and causes inflammation in AD, many questions related to this complex relationship remain unanswered,” the authors concluded. They added that better understanding the mechanisms of S. aureus and downstream host immune mediators of inflammatory pathways involving S. aureus could potentially lead to new therapeutic targets for infection in AD patients.

The statement was funded in part by the senior author’s fellowships from the National Institutes of Health Research, and the International Eczema Council received sponsorship from AbbVie, Amgen, Asana Biosciences, Celgene, Chugai, Dermavant, Dermira, Eli Lilly, Galderma, Incyte, LEO Pharma, Kyowa Kirin, Novartis, Pierre Fabre, Pfizer, Sanofi Genzyme, Regeneron Pharmaceuticals, Sienna and Valeant. Of the 16 authors, 13 disclosed financial ties to a wide range of pharmaceutical companies, including those listed above.

SOURCE: Alexander H et al. Br J Dermatol. 2019 Nov 1. doi: 10.1111/bjd.1864319.

Cynodon dactylon (also known as Indian doab, Bermuda grass, Bahama grass, and several other appellations) has been used in traditional Ayurvedic medicine to treat cutaneous diseases, fevers, and rheumatism,as well as a variety of chronic inflammatory conditions.^1,2 The Ayurvedic armamentarium is thought to be the most abundant source of botanically based drugs used to treat wounds.³ Unrelated to health concerns, with the possible exception of allergic reactions, C. dactylon – which originated in Africa, is widely dispersed in Europe, and became an invasive species in locations such as Bermuda – is also used on putting greens on golf courses in subtropical and tropical climates.⁴ This grass has been shown to be safe and effective for treating induced RA in rats.^1,2 Recent findings are encouraging in the area of wound healing.

Chemical constituents

Among the numerous ingredients contained in C. dactylon are proteins, carbohydrates, minerals, terpenoids, vitamin C, palmitic acid, and alkaloids.³ Other key phytoconstituents known to impart beneficial health effects that are present in the plant include flavonoids (such as apigenin and luteolin), carotenoids (such as beta-carotene and neoxanthin), phenolics, phytosterols, glycosides, saponins, and volatile oils.³ Given such components, it should not be surprising that C. dactylon has demonstrated antioxidant activity by scavenging the 2,2-diphenyl-1-picrylhydrazyl radical.³

Wound healing

Given the reputation of C. dactylon as an effective compound used in traditional medicine for wound healing as a hemostatic agent, Biswas et al. set out in 2017 to determine if they could provide scientific validation of the botanical as a viable wound-healing option. The investigators first undertook to compare a 15% ointment of the extract with a placebo control and the standard framycetin on full-thickness punch wounds in Wistar rats. Across all parameters, results for the C. dactylon–treated group far exceeded the control group and were comparable with the framycetin group. Subsequently, in a pilot clinical study, the researchers assessed the botanical ointment in a small cohort (n = 12) of men and women aged 65-75 years (n = 12) with chronic and complicated wounds. Half were treated with a topical C. dactylon ointment and half were treated with a topical framycetin sulfate ointment. Comparable effects were seen across the groups, with significant contraction of wounds and wound area noted, along with significant development of granulation and epithelial tissues. Hematologic parameters indicating improvement were comparable between the groups. The investigators concluded that all patients treated with C. dactylon healed successfully. They added that the antioxidant activity of the constituent phenolic acids and flavonoids in C. dactylon likely play a key role in conferring potent wound-healing effects by promoting collagenesis.³

In 2018, Perumal et al. created a collagen-silica biocomposite enriched with C. dactylon extract and studied its wound-healing potential in vitro and in vivo in comparison with collagen as well as collagen-silica scaffold controls. The investigators found that the stability of the enriched product surpassed that of native collagen by virtue of the intermolecular interactions between the botanical ingredient and collagen. In a full-thickness excision wound model using Wistar rats, the biocomposite was associated with more rapid healing than wounds treated with collagen and the scaffold control.⁵

Arthritis

In 2009, Sindhu et al. orally administered C. dactylon to rats after intradermally inducing arthritis. The induction produced inflammation, and a marked rise in the levels of inflammatory mediators, C-reactive protein, myeloperoxidase, and nitrite. Resultant oxidative stress was noted with substantial declines in the activity of catalase, superoxide dismutase, and glutathione peroxidase, as well as levels of glutathione, vitamins C and E, and an increase in lipid peroxidation. Administration of C. dactylon yielded substantial changes, with mitigation of the inflammatory response and oxidative stress as well as diminution of the arthritic response nearly to the baseline condition. The investigators concluded that the botanical agent clearly demonstrates potential to protect against arthritis.²

A subsequent study in rats by Bhangale and Acharya supported the use of C. dactylon for RA, as its oral administration was found safe at all dose levels (100, 200 and 400 mg/kg), with 400 mg/kg as the most effective at ameliorating hemoglobin and red blood cell levels and C-reactive protein, as well as lowering tumor necrosis factor–alpha. The authors also noted that the ethanolic extract of C. dactylon contained alkaloids, flavonoids, and glycosides, all of which are known to confer health benefits.¹

Allergy

In 2016, López-Matas et al. studied the profiles of sensitization to C. dactylon (as well as Phragmites communis) in subjects sensitized to grasses and evaluated cross-reactivity between these grasses as well as temperate ones. Patients received skin prick tests with a grass mixture, and 24 patients (80%) were found to have had positive results for C. dactylon (and 90% to P. communis). The researchers concluded that sensitization to these species appears to be engendered by allergens other than those present in sweet grasses.⁶

Mehta et al. reported in 2018 on their investigation of common allergens in Ambala, India, using intradermal tests in patients with asthma, allergic rhinitis, and eczema. The study included 100 patients over an 8-year period, with 197 allergens (50 types of pollen, 19 fungi, 17 insects, 14 types of dust, 6 kinds of animal dander, 7 varieties of fabric and feathers, 82 foods, dust mites, and parthenium) tested. Pollens (51%) were the major allergens, followed by foods (28.9%), insects (26.9%), fungi (12.6%), and dusts (6.7%). C. dactylon (5%) was among two other species ranking fourth among pollen allergens.⁷

Also that year, Sánchez et al. investigated whether growing conditions (rural vs. urban) might influence the nasal inflammatory response to C. dactylon among patients with allergic rhinitis. They observed that the urban extract provoked larger wheals, and more patients with rhinitis experienced a positive nasal challenge test than those administered the rural extract. The skin and nasal tests did not elicit reactions in healthy controls. The researchers reached the conclusion that growth of C. dactylon in an urban setting can produce alterations in the protein extract, with potential clinical ramifications for patients who experience allergic rhinitis.⁸

Conclusion

Regular readers of this column know of my interest in botanically sourced topical products. Such ingredients with an extensive history of traditional medical use are particularly compelling. Many of these compounds are found in the modern medical and dermatologic armamentaria. C. dactylon does boast a track record of use in Ayurvedic medicine. However, there is a paucity of modern research at the present time. While there are concerns about its allergenicity, some encouraging results have been seen in relation to RA and wound healing. Much more research is needed, though, before this botanical agent can be included feasibly for standard skin care.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), as well as a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems. Write to her at dermnews@mdedge.com.

References

1. Bhangale J, Acharya S. Pers. Indian J Exp Biol. 2014 Mar;52(3):215-22.

2. Sindhu G et al. Immunopharmacol Immunotoxicol. 2009;31(4):647-53.

3. Biswas TK et al. J Ethnopharmacol. 2017 Feb 2;197:128-37.

4. Reasor EH et al. Planta. 2016 Oct;244(4):761-73.

5. Perumal RK et al. Mater Sci Eng C Mater Biol Appl. 2018 Nov 1;92:297-306.

6. López-Matas MA et al. J Investig Allergol Clin Immunol. 2016;26(5):295-303.

7. Mehta D et al. Indian J Dermatol. 2018 Jul-Aug;63(4):311-6.

8. Sánchez J et al. Allergy Rhinol (Providence). 2018 Dec 17;9:2152656718815870.

Cynodon dactylon (also known as Indian doab, Bermuda grass, Bahama grass, and several other appellations) has been used in traditional Ayurvedic medicine to treat cutaneous diseases, fevers, and rheumatism,as well as a variety of chronic inflammatory conditions.^1,2 The Ayurvedic armamentarium is thought to be the most abundant source of botanically based drugs used to treat wounds.³ Unrelated to health concerns, with the possible exception of allergic reactions, C. dactylon – which originated in Africa, is widely dispersed in Europe, and became an invasive species in locations such as Bermuda – is also used on putting greens on golf courses in subtropical and tropical climates.⁴ This grass has been shown to be safe and effective for treating induced RA in rats.^1,2 Recent findings are encouraging in the area of wound healing.

Chemical constituents

Among the numerous ingredients contained in C. dactylon are proteins, carbohydrates, minerals, terpenoids, vitamin C, palmitic acid, and alkaloids.³ Other key phytoconstituents known to impart beneficial health effects that are present in the plant include flavonoids (such as apigenin and luteolin), carotenoids (such as beta-carotene and neoxanthin), phenolics, phytosterols, glycosides, saponins, and volatile oils.³ Given such components, it should not be surprising that C. dactylon has demonstrated antioxidant activity by scavenging the 2,2-diphenyl-1-picrylhydrazyl radical.³

Wound healing

Given the reputation of C. dactylon as an effective compound used in traditional medicine for wound healing as a hemostatic agent, Biswas et al. set out in 2017 to determine if they could provide scientific validation of the botanical as a viable wound-healing option. The investigators first undertook to compare a 15% ointment of the extract with a placebo control and the standard framycetin on full-thickness punch wounds in Wistar rats. Across all parameters, results for the C. dactylon–treated group far exceeded the control group and were comparable with the framycetin group. Subsequently, in a pilot clinical study, the researchers assessed the botanical ointment in a small cohort (n = 12) of men and women aged 65-75 years (n = 12) with chronic and complicated wounds. Half were treated with a topical C. dactylon ointment and half were treated with a topical framycetin sulfate ointment. Comparable effects were seen across the groups, with significant contraction of wounds and wound area noted, along with significant development of granulation and epithelial tissues. Hematologic parameters indicating improvement were comparable between the groups. The investigators concluded that all patients treated with C. dactylon healed successfully. They added that the antioxidant activity of the constituent phenolic acids and flavonoids in C. dactylon likely play a key role in conferring potent wound-healing effects by promoting collagenesis.³

In 2018, Perumal et al. created a collagen-silica biocomposite enriched with C. dactylon extract and studied its wound-healing potential in vitro and in vivo in comparison with collagen as well as collagen-silica scaffold controls. The investigators found that the stability of the enriched product surpassed that of native collagen by virtue of the intermolecular interactions between the botanical ingredient and collagen. In a full-thickness excision wound model using Wistar rats, the biocomposite was associated with more rapid healing than wounds treated with collagen and the scaffold control.⁵

Arthritis

In 2009, Sindhu et al. orally administered C. dactylon to rats after intradermally inducing arthritis. The induction produced inflammation, and a marked rise in the levels of inflammatory mediators, C-reactive protein, myeloperoxidase, and nitrite. Resultant oxidative stress was noted with substantial declines in the activity of catalase, superoxide dismutase, and glutathione peroxidase, as well as levels of glutathione, vitamins C and E, and an increase in lipid peroxidation. Administration of C. dactylon yielded substantial changes, with mitigation of the inflammatory response and oxidative stress as well as diminution of the arthritic response nearly to the baseline condition. The investigators concluded that the botanical agent clearly demonstrates potential to protect against arthritis.²

A subsequent study in rats by Bhangale and Acharya supported the use of C. dactylon for RA, as its oral administration was found safe at all dose levels (100, 200 and 400 mg/kg), with 400 mg/kg as the most effective at ameliorating hemoglobin and red blood cell levels and C-reactive protein, as well as lowering tumor necrosis factor–alpha. The authors also noted that the ethanolic extract of C. dactylon contained alkaloids, flavonoids, and glycosides, all of which are known to confer health benefits.¹

Allergy

In 2016, López-Matas et al. studied the profiles of sensitization to C. dactylon (as well as Phragmites communis) in subjects sensitized to grasses and evaluated cross-reactivity between these grasses as well as temperate ones. Patients received skin prick tests with a grass mixture, and 24 patients (80%) were found to have had positive results for C. dactylon (and 90% to P. communis). The researchers concluded that sensitization to these species appears to be engendered by allergens other than those present in sweet grasses.⁶

Mehta et al. reported in 2018 on their investigation of common allergens in Ambala, India, using intradermal tests in patients with asthma, allergic rhinitis, and eczema. The study included 100 patients over an 8-year period, with 197 allergens (50 types of pollen, 19 fungi, 17 insects, 14 types of dust, 6 kinds of animal dander, 7 varieties of fabric and feathers, 82 foods, dust mites, and parthenium) tested. Pollens (51%) were the major allergens, followed by foods (28.9%), insects (26.9%), fungi (12.6%), and dusts (6.7%). C. dactylon (5%) was among two other species ranking fourth among pollen allergens.⁷

Also that year, Sánchez et al. investigated whether growing conditions (rural vs. urban) might influence the nasal inflammatory response to C. dactylon among patients with allergic rhinitis. They observed that the urban extract provoked larger wheals, and more patients with rhinitis experienced a positive nasal challenge test than those administered the rural extract. The skin and nasal tests did not elicit reactions in healthy controls. The researchers reached the conclusion that growth of C. dactylon in an urban setting can produce alterations in the protein extract, with potential clinical ramifications for patients who experience allergic rhinitis.⁸

Conclusion

Regular readers of this column know of my interest in botanically sourced topical products. Such ingredients with an extensive history of traditional medical use are particularly compelling. Many of these compounds are found in the modern medical and dermatologic armamentaria. C. dactylon does boast a track record of use in Ayurvedic medicine. However, there is a paucity of modern research at the present time. While there are concerns about its allergenicity, some encouraging results have been seen in relation to RA and wound healing. Much more research is needed, though, before this botanical agent can be included feasibly for standard skin care.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), as well as a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems. Write to her at dermnews@mdedge.com.

References

1. Bhangale J, Acharya S. Pers. Indian J Exp Biol. 2014 Mar;52(3):215-22.

2. Sindhu G et al. Immunopharmacol Immunotoxicol. 2009;31(4):647-53.

3. Biswas TK et al. J Ethnopharmacol. 2017 Feb 2;197:128-37.

4. Reasor EH et al. Planta. 2016 Oct;244(4):761-73.

5. Perumal RK et al. Mater Sci Eng C Mater Biol Appl. 2018 Nov 1;92:297-306.

6. López-Matas MA et al. J Investig Allergol Clin Immunol. 2016;26(5):295-303.

7. Mehta D et al. Indian J Dermatol. 2018 Jul-Aug;63(4):311-6.

8. Sánchez J et al. Allergy Rhinol (Providence). 2018 Dec 17;9:2152656718815870.

Cynodon dactylon (also known as Indian doab, Bermuda grass, Bahama grass, and several other appellations) has been used in traditional Ayurvedic medicine to treat cutaneous diseases, fevers, and rheumatism,as well as a variety of chronic inflammatory conditions.^1,2 The Ayurvedic armamentarium is thought to be the most abundant source of botanically based drugs used to treat wounds.³ Unrelated to health concerns, with the possible exception of allergic reactions, C. dactylon – which originated in Africa, is widely dispersed in Europe, and became an invasive species in locations such as Bermuda – is also used on putting greens on golf courses in subtropical and tropical climates.⁴ This grass has been shown to be safe and effective for treating induced RA in rats.^1,2 Recent findings are encouraging in the area of wound healing.

Chemical constituents

Among the numerous ingredients contained in C. dactylon are proteins, carbohydrates, minerals, terpenoids, vitamin C, palmitic acid, and alkaloids.³ Other key phytoconstituents known to impart beneficial health effects that are present in the plant include flavonoids (such as apigenin and luteolin), carotenoids (such as beta-carotene and neoxanthin), phenolics, phytosterols, glycosides, saponins, and volatile oils.³ Given such components, it should not be surprising that C. dactylon has demonstrated antioxidant activity by scavenging the 2,2-diphenyl-1-picrylhydrazyl radical.³

Wound healing

Given the reputation of C. dactylon as an effective compound used in traditional medicine for wound healing as a hemostatic agent, Biswas et al. set out in 2017 to determine if they could provide scientific validation of the botanical as a viable wound-healing option. The investigators first undertook to compare a 15% ointment of the extract with a placebo control and the standard framycetin on full-thickness punch wounds in Wistar rats. Across all parameters, results for the C. dactylon–treated group far exceeded the control group and were comparable with the framycetin group. Subsequently, in a pilot clinical study, the researchers assessed the botanical ointment in a small cohort (n = 12) of men and women aged 65-75 years (n = 12) with chronic and complicated wounds. Half were treated with a topical C. dactylon ointment and half were treated with a topical framycetin sulfate ointment. Comparable effects were seen across the groups, with significant contraction of wounds and wound area noted, along with significant development of granulation and epithelial tissues. Hematologic parameters indicating improvement were comparable between the groups. The investigators concluded that all patients treated with C. dactylon healed successfully. They added that the antioxidant activity of the constituent phenolic acids and flavonoids in C. dactylon likely play a key role in conferring potent wound-healing effects by promoting collagenesis.³

In 2018, Perumal et al. created a collagen-silica biocomposite enriched with C. dactylon extract and studied its wound-healing potential in vitro and in vivo in comparison with collagen as well as collagen-silica scaffold controls. The investigators found that the stability of the enriched product surpassed that of native collagen by virtue of the intermolecular interactions between the botanical ingredient and collagen. In a full-thickness excision wound model using Wistar rats, the biocomposite was associated with more rapid healing than wounds treated with collagen and the scaffold control.⁵

Arthritis

In 2009, Sindhu et al. orally administered C. dactylon to rats after intradermally inducing arthritis. The induction produced inflammation, and a marked rise in the levels of inflammatory mediators, C-reactive protein, myeloperoxidase, and nitrite. Resultant oxidative stress was noted with substantial declines in the activity of catalase, superoxide dismutase, and glutathione peroxidase, as well as levels of glutathione, vitamins C and E, and an increase in lipid peroxidation. Administration of C. dactylon yielded substantial changes, with mitigation of the inflammatory response and oxidative stress as well as diminution of the arthritic response nearly to the baseline condition. The investigators concluded that the botanical agent clearly demonstrates potential to protect against arthritis.²

A subsequent study in rats by Bhangale and Acharya supported the use of C. dactylon for RA, as its oral administration was found safe at all dose levels (100, 200 and 400 mg/kg), with 400 mg/kg as the most effective at ameliorating hemoglobin and red blood cell levels and C-reactive protein, as well as lowering tumor necrosis factor–alpha. The authors also noted that the ethanolic extract of C. dactylon contained alkaloids, flavonoids, and glycosides, all of which are known to confer health benefits.¹

Allergy

In 2016, López-Matas et al. studied the profiles of sensitization to C. dactylon (as well as Phragmites communis) in subjects sensitized to grasses and evaluated cross-reactivity between these grasses as well as temperate ones. Patients received skin prick tests with a grass mixture, and 24 patients (80%) were found to have had positive results for C. dactylon (and 90% to P. communis). The researchers concluded that sensitization to these species appears to be engendered by allergens other than those present in sweet grasses.⁶

Mehta et al. reported in 2018 on their investigation of common allergens in Ambala, India, using intradermal tests in patients with asthma, allergic rhinitis, and eczema. The study included 100 patients over an 8-year period, with 197 allergens (50 types of pollen, 19 fungi, 17 insects, 14 types of dust, 6 kinds of animal dander, 7 varieties of fabric and feathers, 82 foods, dust mites, and parthenium) tested. Pollens (51%) were the major allergens, followed by foods (28.9%), insects (26.9%), fungi (12.6%), and dusts (6.7%). C. dactylon (5%) was among two other species ranking fourth among pollen allergens.⁷

Also that year, Sánchez et al. investigated whether growing conditions (rural vs. urban) might influence the nasal inflammatory response to C. dactylon among patients with allergic rhinitis. They observed that the urban extract provoked larger wheals, and more patients with rhinitis experienced a positive nasal challenge test than those administered the rural extract. The skin and nasal tests did not elicit reactions in healthy controls. The researchers reached the conclusion that growth of C. dactylon in an urban setting can produce alterations in the protein extract, with potential clinical ramifications for patients who experience allergic rhinitis.⁸

Conclusion

Regular readers of this column know of my interest in botanically sourced topical products. Such ingredients with an extensive history of traditional medical use are particularly compelling. Many of these compounds are found in the modern medical and dermatologic armamentaria. C. dactylon does boast a track record of use in Ayurvedic medicine. However, there is a paucity of modern research at the present time. While there are concerns about its allergenicity, some encouraging results have been seen in relation to RA and wound healing. Much more research is needed, though, before this botanical agent can be included feasibly for standard skin care.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), as well as a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems. Write to her at dermnews@mdedge.com.

References

1. Bhangale J, Acharya S. Pers. Indian J Exp Biol. 2014 Mar;52(3):215-22.

2. Sindhu G et al. Immunopharmacol Immunotoxicol. 2009;31(4):647-53.

3. Biswas TK et al. J Ethnopharmacol. 2017 Feb 2;197:128-37.

4. Reasor EH et al. Planta. 2016 Oct;244(4):761-73.

5. Perumal RK et al. Mater Sci Eng C Mater Biol Appl. 2018 Nov 1;92:297-306.

6. López-Matas MA et al. J Investig Allergol Clin Immunol. 2016;26(5):295-303.

7. Mehta D et al. Indian J Dermatol. 2018 Jul-Aug;63(4):311-6.

8. Sánchez J et al. Allergy Rhinol (Providence). 2018 Dec 17;9:2152656718815870.

SAN ANTONIO – Adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, to neoadjuvant chemotherapy failed to significantly improve pathologic complete response (pCR) rates in women with triple-negative breast cancer in the randomized NeoTRIPaPDL1 trial.

Sharon Worcester/MDedge News

A slight improvement in pCR rates, which is a secondary study endpoint, was seen in the subgroup of PD-L1-positive women, but the difference in that group also failed to reach statistical significance, Luca Gianni, MD, said at the San Antonio Breast Cancer Symposium where he reported these initial results from the open-label multicenter trial.

“In the intent-to-treat analysis, the rate of pathological complete response was 43.5% with atezolizumab, and 40.8% without atezolizumab, for a net difference of 2.63% and an odds ratio of 1.11,” said Dr. Gianni, president of the Fondazione Michelangelo in Milan.

Among patients whose tumors tested positive for PD-L1, the pCR rates were 51.9 and 48.0% with atezolizumab versus without, but this difference was also not significant.

On multivariate analysis accounting for treatment group, PD-L1 expression, and disease stage, the only variable significantly associated with the pCR rate was PD-L1 positivity, and this association was similar in both treatment groups, he noted (odds ratio, 2.08).

“The same trend toward a numerically higher rate of clinical overall response with atezolizumab was observed on clinical grounds, but again, at 76.1% vs. 68.3% – not statistically significant,” he said.

The complete response rates with atezolizumab versus without were 29% vs. 26.1% and the partial response rates were 47.1% vs. 42.3%, respectively; 3.6% vs. 4.9% of patients in the groups had stable disease, and 5.8% vs. 8.4% had progressive disease.

The NeoTRIPaPDL1 study enrolled 280 adult women with HER2-negative, estrogen receptor– and progesterone receptor–negative early high-risk or locally advanced unilateral triple-negative breast cancer (TNBC). Participants were randomized to receive neoadjuvant carboplatin AUC 2 and intravenous abraxane at a dose of 125 mg/m² on days 1 and 8 either with or without 1,200 mg of IV atezolizumab on day 1. Both regimens were given every 3 weeks for eight cycles, followed by surgery and four cycles of an investigator-selected anthracycline regimen.

The primary study endpoint is event-free survival at 5 years after randomization of the last patient, but this initial report from the trial focused on pCR, Dr. Gianni said.

Tolerability of treatment was similar with both regimens, except for an increase in abnormal liver transaminases “that tended to be significantly more frequent with atezolizumab administration,” he said, noting that the “toxicity was very short lived and didn’t limit the possibility of administering the drug.”

“Immune-mediated adverse events and infusion reactions clustered around the atezolizumab arm, as expected, and mostly consisted of infusion reactions and hypothyroidism,” he added.

Infusion reactions occurred in 8.0% and 5.7% of patients in the atezolizumab versus no atezolizumab groups, and grade 3 or greater infusion reactions occurred in 1.4% versus 0.7%. Hypothyroidism occurred in 5.8% and 1.4%, respectively, with no grade 3 or greater events.

“All other toxicities were either mild or very rare,” he noted.

TNBC is an aggressive subtype of breast cancer with poor prognosis. Progression to distant metastases is often rapid, as is development of resistance chemotherapy, Dr. Gianni explained, adding that chemotherapy is currently the only treatment for early-stage TNBC.

Chemotherapy works in some patients, but relapse and resistance are common even after good initial responses; therefore, he and his colleagues examined the effects of immune checkpoint inhibition added to neoadjuvant chemotherapy, reasoning that the combination might boost the antitumor immune response.

Atezolizumab in combination with nab-paclitaxel is now approved by the Food and Drug Administration for the treatment of some patients with locally advanced or metastatic TNBC. The approval was based on findings from the IMpassion130 study showing a significant progression-free and overall survival benefit with atezolizumab when added to nab-paclitaxel in PD-L1-positive metastatic TNBC.

In a press statement, Dr. Gianni noted that the pCR findings he reported from the NeoTRIPaPDL1 study “may indicate that there is no therapeutic benefit to adding atezolizumab to neoadjuvant chemotherapy compared to chemotherapy alone, or may simply mean that any beneficial effects of the combination will be seen in the long term.”

“Pathologic complete response does not provide information about the quality of response, which is why we did not use it as the primary endpoint for this study. Further analyses may reveal differences in the quality of response between the treatment groups,” he added, noting that the study is limited in that reported results apply only to the initial effects of the combination treatment and do not account for effects of therapies administered after surgery.

Follow-up for the primary endpoint of event-free survival and other efficacy endpoints in the NeoTRIPaPDL1 trial is ongoing, and molecular studies are also underway, Dr. Gianni said.

Biological samples collected from patients before, during, and after neoadjuvant treatment are being examined for lymphocyte infiltration, DNA mutations, and/or levels of circulating tumor DNA, and may reveal differences between the treatment groups, he explained.

This study was sponsored by Roche and Celgene. Dr. Gianni has been an advisor and/or consultant for numerous pharmaceutical companies. He has received support for research from Daiichi Sankyo, Zymeworks, and Revolution Medicines and is a coinventor on a patent for PD-L1 expression in anti-HER2 therapy.

sworcester@mdedge.com

SOURCE: Gianni L et al. SABCS 2019. Abstract GS3-04.

SAN ANTONIO – Adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, to neoadjuvant chemotherapy failed to significantly improve pathologic complete response (pCR) rates in women with triple-negative breast cancer in the randomized NeoTRIPaPDL1 trial.

Sharon Worcester/MDedge News

A slight improvement in pCR rates, which is a secondary study endpoint, was seen in the subgroup of PD-L1-positive women, but the difference in that group also failed to reach statistical significance, Luca Gianni, MD, said at the San Antonio Breast Cancer Symposium where he reported these initial results from the open-label multicenter trial.

“In the intent-to-treat analysis, the rate of pathological complete response was 43.5% with atezolizumab, and 40.8% without atezolizumab, for a net difference of 2.63% and an odds ratio of 1.11,” said Dr. Gianni, president of the Fondazione Michelangelo in Milan.

Among patients whose tumors tested positive for PD-L1, the pCR rates were 51.9 and 48.0% with atezolizumab versus without, but this difference was also not significant.

On multivariate analysis accounting for treatment group, PD-L1 expression, and disease stage, the only variable significantly associated with the pCR rate was PD-L1 positivity, and this association was similar in both treatment groups, he noted (odds ratio, 2.08).

“The same trend toward a numerically higher rate of clinical overall response with atezolizumab was observed on clinical grounds, but again, at 76.1% vs. 68.3% – not statistically significant,” he said.

The complete response rates with atezolizumab versus without were 29% vs. 26.1% and the partial response rates were 47.1% vs. 42.3%, respectively; 3.6% vs. 4.9% of patients in the groups had stable disease, and 5.8% vs. 8.4% had progressive disease.

The NeoTRIPaPDL1 study enrolled 280 adult women with HER2-negative, estrogen receptor– and progesterone receptor–negative early high-risk or locally advanced unilateral triple-negative breast cancer (TNBC). Participants were randomized to receive neoadjuvant carboplatin AUC 2 and intravenous abraxane at a dose of 125 mg/m² on days 1 and 8 either with or without 1,200 mg of IV atezolizumab on day 1. Both regimens were given every 3 weeks for eight cycles, followed by surgery and four cycles of an investigator-selected anthracycline regimen.

The primary study endpoint is event-free survival at 5 years after randomization of the last patient, but this initial report from the trial focused on pCR, Dr. Gianni said.

Tolerability of treatment was similar with both regimens, except for an increase in abnormal liver transaminases “that tended to be significantly more frequent with atezolizumab administration,” he said, noting that the “toxicity was very short lived and didn’t limit the possibility of administering the drug.”

“Immune-mediated adverse events and infusion reactions clustered around the atezolizumab arm, as expected, and mostly consisted of infusion reactions and hypothyroidism,” he added.

Infusion reactions occurred in 8.0% and 5.7% of patients in the atezolizumab versus no atezolizumab groups, and grade 3 or greater infusion reactions occurred in 1.4% versus 0.7%. Hypothyroidism occurred in 5.8% and 1.4%, respectively, with no grade 3 or greater events.

“All other toxicities were either mild or very rare,” he noted.

TNBC is an aggressive subtype of breast cancer with poor prognosis. Progression to distant metastases is often rapid, as is development of resistance chemotherapy, Dr. Gianni explained, adding that chemotherapy is currently the only treatment for early-stage TNBC.

Chemotherapy works in some patients, but relapse and resistance are common even after good initial responses; therefore, he and his colleagues examined the effects of immune checkpoint inhibition added to neoadjuvant chemotherapy, reasoning that the combination might boost the antitumor immune response.

Atezolizumab in combination with nab-paclitaxel is now approved by the Food and Drug Administration for the treatment of some patients with locally advanced or metastatic TNBC. The approval was based on findings from the IMpassion130 study showing a significant progression-free and overall survival benefit with atezolizumab when added to nab-paclitaxel in PD-L1-positive metastatic TNBC.

In a press statement, Dr. Gianni noted that the pCR findings he reported from the NeoTRIPaPDL1 study “may indicate that there is no therapeutic benefit to adding atezolizumab to neoadjuvant chemotherapy compared to chemotherapy alone, or may simply mean that any beneficial effects of the combination will be seen in the long term.”

“Pathologic complete response does not provide information about the quality of response, which is why we did not use it as the primary endpoint for this study. Further analyses may reveal differences in the quality of response between the treatment groups,” he added, noting that the study is limited in that reported results apply only to the initial effects of the combination treatment and do not account for effects of therapies administered after surgery.

Follow-up for the primary endpoint of event-free survival and other efficacy endpoints in the NeoTRIPaPDL1 trial is ongoing, and molecular studies are also underway, Dr. Gianni said.

Biological samples collected from patients before, during, and after neoadjuvant treatment are being examined for lymphocyte infiltration, DNA mutations, and/or levels of circulating tumor DNA, and may reveal differences between the treatment groups, he explained.

This study was sponsored by Roche and Celgene. Dr. Gianni has been an advisor and/or consultant for numerous pharmaceutical companies. He has received support for research from Daiichi Sankyo, Zymeworks, and Revolution Medicines and is a coinventor on a patent for PD-L1 expression in anti-HER2 therapy.

sworcester@mdedge.com

SOURCE: Gianni L et al. SABCS 2019. Abstract GS3-04.

SAN ANTONIO – Adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, to neoadjuvant chemotherapy failed to significantly improve pathologic complete response (pCR) rates in women with triple-negative breast cancer in the randomized NeoTRIPaPDL1 trial.

Sharon Worcester/MDedge News

A slight improvement in pCR rates, which is a secondary study endpoint, was seen in the subgroup of PD-L1-positive women, but the difference in that group also failed to reach statistical significance, Luca Gianni, MD, said at the San Antonio Breast Cancer Symposium where he reported these initial results from the open-label multicenter trial.

“In the intent-to-treat analysis, the rate of pathological complete response was 43.5% with atezolizumab, and 40.8% without atezolizumab, for a net difference of 2.63% and an odds ratio of 1.11,” said Dr. Gianni, president of the Fondazione Michelangelo in Milan.

Among patients whose tumors tested positive for PD-L1, the pCR rates were 51.9 and 48.0% with atezolizumab versus without, but this difference was also not significant.

On multivariate analysis accounting for treatment group, PD-L1 expression, and disease stage, the only variable significantly associated with the pCR rate was PD-L1 positivity, and this association was similar in both treatment groups, he noted (odds ratio, 2.08).

“The same trend toward a numerically higher rate of clinical overall response with atezolizumab was observed on clinical grounds, but again, at 76.1% vs. 68.3% – not statistically significant,” he said.

The complete response rates with atezolizumab versus without were 29% vs. 26.1% and the partial response rates were 47.1% vs. 42.3%, respectively; 3.6% vs. 4.9% of patients in the groups had stable disease, and 5.8% vs. 8.4% had progressive disease.

The NeoTRIPaPDL1 study enrolled 280 adult women with HER2-negative, estrogen receptor– and progesterone receptor–negative early high-risk or locally advanced unilateral triple-negative breast cancer (TNBC). Participants were randomized to receive neoadjuvant carboplatin AUC 2 and intravenous abraxane at a dose of 125 mg/m² on days 1 and 8 either with or without 1,200 mg of IV atezolizumab on day 1. Both regimens were given every 3 weeks for eight cycles, followed by surgery and four cycles of an investigator-selected anthracycline regimen.

The primary study endpoint is event-free survival at 5 years after randomization of the last patient, but this initial report from the trial focused on pCR, Dr. Gianni said.

Tolerability of treatment was similar with both regimens, except for an increase in abnormal liver transaminases “that tended to be significantly more frequent with atezolizumab administration,” he said, noting that the “toxicity was very short lived and didn’t limit the possibility of administering the drug.”

“Immune-mediated adverse events and infusion reactions clustered around the atezolizumab arm, as expected, and mostly consisted of infusion reactions and hypothyroidism,” he added.

Infusion reactions occurred in 8.0% and 5.7% of patients in the atezolizumab versus no atezolizumab groups, and grade 3 or greater infusion reactions occurred in 1.4% versus 0.7%. Hypothyroidism occurred in 5.8% and 1.4%, respectively, with no grade 3 or greater events.

“All other toxicities were either mild or very rare,” he noted.

TNBC is an aggressive subtype of breast cancer with poor prognosis. Progression to distant metastases is often rapid, as is development of resistance chemotherapy, Dr. Gianni explained, adding that chemotherapy is currently the only treatment for early-stage TNBC.

Chemotherapy works in some patients, but relapse and resistance are common even after good initial responses; therefore, he and his colleagues examined the effects of immune checkpoint inhibition added to neoadjuvant chemotherapy, reasoning that the combination might boost the antitumor immune response.

Atezolizumab in combination with nab-paclitaxel is now approved by the Food and Drug Administration for the treatment of some patients with locally advanced or metastatic TNBC. The approval was based on findings from the IMpassion130 study showing a significant progression-free and overall survival benefit with atezolizumab when added to nab-paclitaxel in PD-L1-positive metastatic TNBC.

In a press statement, Dr. Gianni noted that the pCR findings he reported from the NeoTRIPaPDL1 study “may indicate that there is no therapeutic benefit to adding atezolizumab to neoadjuvant chemotherapy compared to chemotherapy alone, or may simply mean that any beneficial effects of the combination will be seen in the long term.”

“Pathologic complete response does not provide information about the quality of response, which is why we did not use it as the primary endpoint for this study. Further analyses may reveal differences in the quality of response between the treatment groups,” he added, noting that the study is limited in that reported results apply only to the initial effects of the combination treatment and do not account for effects of therapies administered after surgery.

Follow-up for the primary endpoint of event-free survival and other efficacy endpoints in the NeoTRIPaPDL1 trial is ongoing, and molecular studies are also underway, Dr. Gianni said.

Biological samples collected from patients before, during, and after neoadjuvant treatment are being examined for lymphocyte infiltration, DNA mutations, and/or levels of circulating tumor DNA, and may reveal differences between the treatment groups, he explained.

This study was sponsored by Roche and Celgene. Dr. Gianni has been an advisor and/or consultant for numerous pharmaceutical companies. He has received support for research from Daiichi Sankyo, Zymeworks, and Revolution Medicines and is a coinventor on a patent for PD-L1 expression in anti-HER2 therapy.

sworcester@mdedge.com

SOURCE: Gianni L et al. SABCS 2019. Abstract GS3-04.

A study using a new definition of early chronic obstructive pulmonary disease (COPD) has found that about 15% of Danish smokers under the age of 50 years meet the criteria.

The population-based cohort looked at individuals who had been exposed to at least 10 pack-years, and defined early COPD as the ratio of forced expiratory volume to forced vital capacity being less than the lower limit of normal (FEV₁/FVC less than LLN). The definition of early COPD, published in 2018 (Am J Resp and Crit Care Med. 2018;197:1540-51), also included the presence of abnormalities on a CT scan or a decline in FEV₁ (greater than 60 mL/year) that is accelerated relative to FVC, but the new population study did not include the latter two criteria.

The researchers, under corresponding author Peter Lange, MD, of the University of Copenhagen found that those with early COPD were more likely to have chronic respiratory symptoms, severe impairment of lung function, acute respirator hospitalization, and early mortality at baseline and at follow-up. The work was published in the American Journal of Respiratory and Critical Care Medicine.

“To dig through the smokers and try to figure out which smokers are more at risk than other smokers is probably the best way to summarize what they’ve done here,” said Robert Reed, MD, from the University of Maryland, Baltimore, in an interview. However, he added that he would like to see the research extended to an even younger population, as well as nonsmokers. “We don’t need all of this information to tell us that smoking is bad. I think nonsmokers would be really interesting – creating a definition of COPD that excludes patients that meet the usual definition for COPD would be of potential interest,” added Dr. Reed, who was not involved in the study.

Using a cohort of 105,630 randomly selected individuals from Danish nationwide health registries, the study identified 8,064 individuals aged under 50 years with 10 or more pack-years of tobacco exposure. In this group, 1,175 (15%) had early COPD, of whom 58% were current smokers. The cohort of smokers was followed for up to 14.4 years. Multivariate analyses found that those with early COPD, compared with smokers without COPD, were at substantially greater risk of acute obstructive lung disease hospitalization (hazard ratio, 6.42; 95% confidence interval, 3.39-12.2), acute pneumonia hospitalization (HR, 2.03; 95% CI, 1.43-2.88), and all-cause mortality (HR, 1.79; 95% CI, 1.28-2.52).

There is value in gaining a better understanding of which smokers are at greatest risk of COPD down the line, but data on younger people, even 30-year-olds, could guide therapeutic decisions when and if new drugs that can alter the state of the disease become available. Focusing more on younger, high-risk patients could also be used to create greater incentives to quit smoking, though Dr. Reed has mixed feelings even about that. “What if we identified 15% of smokers that are at risk of COPD, and the other 85% say, ‘I’ll keep smoking,’ and they fall over dead from a heart attack?” said Dr. Reed, noting that smoking has a wide range of known risks. “They should all stop,” he added.

The study also captures a wide range of patients, from some with early disease that will likely progress to COPD later in life along with some who already developed full-blown COPD in, for example, their early 40s. “Those are very different patients and to lump them together is potentially problematic,” said Dr. Reed. More granulated data could potentially inform more personalized medicine, and the discovery and verification of genetic risk factors.

Nevertheless, Dr. Reed expects the data to move the field forward. “They created a nice, rich database that I think will generate a lot more analysis and discussion.”

The study was funded by the Lundbeck Foundation. One of the authors has received support from the National Institute for Health Research Manchester (England) Biomedical Research Centre. Dr. Reed has no relevant financial disclosures.

SOURCE: Colak Y et al. Am J Resp Crit Care Med. 2019 Nov 26. doi: 10.1164/rccm.201908-1644OC

A study using a new definition of early chronic obstructive pulmonary disease (COPD) has found that about 15% of Danish smokers under the age of 50 years meet the criteria.

The population-based cohort looked at individuals who had been exposed to at least 10 pack-years, and defined early COPD as the ratio of forced expiratory volume to forced vital capacity being less than the lower limit of normal (FEV₁/FVC less than LLN). The definition of early COPD, published in 2018 (Am J Resp and Crit Care Med. 2018;197:1540-51), also included the presence of abnormalities on a CT scan or a decline in FEV₁ (greater than 60 mL/year) that is accelerated relative to FVC, but the new population study did not include the latter two criteria.

The researchers, under corresponding author Peter Lange, MD, of the University of Copenhagen found that those with early COPD were more likely to have chronic respiratory symptoms, severe impairment of lung function, acute respirator hospitalization, and early mortality at baseline and at follow-up. The work was published in the American Journal of Respiratory and Critical Care Medicine.

“To dig through the smokers and try to figure out which smokers are more at risk than other smokers is probably the best way to summarize what they’ve done here,” said Robert Reed, MD, from the University of Maryland, Baltimore, in an interview. However, he added that he would like to see the research extended to an even younger population, as well as nonsmokers. “We don’t need all of this information to tell us that smoking is bad. I think nonsmokers would be really interesting – creating a definition of COPD that excludes patients that meet the usual definition for COPD would be of potential interest,” added Dr. Reed, who was not involved in the study.

Using a cohort of 105,630 randomly selected individuals from Danish nationwide health registries, the study identified 8,064 individuals aged under 50 years with 10 or more pack-years of tobacco exposure. In this group, 1,175 (15%) had early COPD, of whom 58% were current smokers. The cohort of smokers was followed for up to 14.4 years. Multivariate analyses found that those with early COPD, compared with smokers without COPD, were at substantially greater risk of acute obstructive lung disease hospitalization (hazard ratio, 6.42; 95% confidence interval, 3.39-12.2), acute pneumonia hospitalization (HR, 2.03; 95% CI, 1.43-2.88), and all-cause mortality (HR, 1.79; 95% CI, 1.28-2.52).

There is value in gaining a better understanding of which smokers are at greatest risk of COPD down the line, but data on younger people, even 30-year-olds, could guide therapeutic decisions when and if new drugs that can alter the state of the disease become available. Focusing more on younger, high-risk patients could also be used to create greater incentives to quit smoking, though Dr. Reed has mixed feelings even about that. “What if we identified 15% of smokers that are at risk of COPD, and the other 85% say, ‘I’ll keep smoking,’ and they fall over dead from a heart attack?” said Dr. Reed, noting that smoking has a wide range of known risks. “They should all stop,” he added.

The study also captures a wide range of patients, from some with early disease that will likely progress to COPD later in life along with some who already developed full-blown COPD in, for example, their early 40s. “Those are very different patients and to lump them together is potentially problematic,” said Dr. Reed. More granulated data could potentially inform more personalized medicine, and the discovery and verification of genetic risk factors.

Nevertheless, Dr. Reed expects the data to move the field forward. “They created a nice, rich database that I think will generate a lot more analysis and discussion.”

The study was funded by the Lundbeck Foundation. One of the authors has received support from the National Institute for Health Research Manchester (England) Biomedical Research Centre. Dr. Reed has no relevant financial disclosures.

SOURCE: Colak Y et al. Am J Resp Crit Care Med. 2019 Nov 26. doi: 10.1164/rccm.201908-1644OC

A study using a new definition of early chronic obstructive pulmonary disease (COPD) has found that about 15% of Danish smokers under the age of 50 years meet the criteria.

The population-based cohort looked at individuals who had been exposed to at least 10 pack-years, and defined early COPD as the ratio of forced expiratory volume to forced vital capacity being less than the lower limit of normal (FEV₁/FVC less than LLN). The definition of early COPD, published in 2018 (Am J Resp and Crit Care Med. 2018;197:1540-51), also included the presence of abnormalities on a CT scan or a decline in FEV₁ (greater than 60 mL/year) that is accelerated relative to FVC, but the new population study did not include the latter two criteria.

The researchers, under corresponding author Peter Lange, MD, of the University of Copenhagen found that those with early COPD were more likely to have chronic respiratory symptoms, severe impairment of lung function, acute respirator hospitalization, and early mortality at baseline and at follow-up. The work was published in the American Journal of Respiratory and Critical Care Medicine.

“To dig through the smokers and try to figure out which smokers are more at risk than other smokers is probably the best way to summarize what they’ve done here,” said Robert Reed, MD, from the University of Maryland, Baltimore, in an interview. However, he added that he would like to see the research extended to an even younger population, as well as nonsmokers. “We don’t need all of this information to tell us that smoking is bad. I think nonsmokers would be really interesting – creating a definition of COPD that excludes patients that meet the usual definition for COPD would be of potential interest,” added Dr. Reed, who was not involved in the study.

Using a cohort of 105,630 randomly selected individuals from Danish nationwide health registries, the study identified 8,064 individuals aged under 50 years with 10 or more pack-years of tobacco exposure. In this group, 1,175 (15%) had early COPD, of whom 58% were current smokers. The cohort of smokers was followed for up to 14.4 years. Multivariate analyses found that those with early COPD, compared with smokers without COPD, were at substantially greater risk of acute obstructive lung disease hospitalization (hazard ratio, 6.42; 95% confidence interval, 3.39-12.2), acute pneumonia hospitalization (HR, 2.03; 95% CI, 1.43-2.88), and all-cause mortality (HR, 1.79; 95% CI, 1.28-2.52).

There is value in gaining a better understanding of which smokers are at greatest risk of COPD down the line, but data on younger people, even 30-year-olds, could guide therapeutic decisions when and if new drugs that can alter the state of the disease become available. Focusing more on younger, high-risk patients could also be used to create greater incentives to quit smoking, though Dr. Reed has mixed feelings even about that. “What if we identified 15% of smokers that are at risk of COPD, and the other 85% say, ‘I’ll keep smoking,’ and they fall over dead from a heart attack?” said Dr. Reed, noting that smoking has a wide range of known risks. “They should all stop,” he added.

The study also captures a wide range of patients, from some with early disease that will likely progress to COPD later in life along with some who already developed full-blown COPD in, for example, their early 40s. “Those are very different patients and to lump them together is potentially problematic,” said Dr. Reed. More granulated data could potentially inform more personalized medicine, and the discovery and verification of genetic risk factors.

Nevertheless, Dr. Reed expects the data to move the field forward. “They created a nice, rich database that I think will generate a lot more analysis and discussion.”

The study was funded by the Lundbeck Foundation. One of the authors has received support from the National Institute for Health Research Manchester (England) Biomedical Research Centre. Dr. Reed has no relevant financial disclosures.

SOURCE: Colak Y et al. Am J Resp Crit Care Med. 2019 Nov 26. doi: 10.1164/rccm.201908-1644OC

Physicians treating transgender patients – in particular, transgender men who were born female – are faced with a confusing process when prescribing isotretinoin for severe acne.

A research letter published in the Journal of the American Academy of Dermatology reports that half of dermatologists surveyed reported having encountered difficulties classifying a transgender patient in iPLEDGE, the risk-management registry established to prevent female patients from starting isotretinoin therapy while pregnant or from becoming pregnant while exposed to the teratogenic medication.

Nearly 90% of respondents favored changing the current gender-specific categories in iPLEDGE to gender-neutral ones, classifying patients only by whether or not they have the ability to become pregnant.

For their research, Courtney Ensslin, MD, of the department of dermatology at Johns Hopkins University, Baltimore, and colleagues, distributed an 18-point questionnaire to 385 members of the Association of Professors of Dermatology that included questions assessing clinicians’ knowledge about the reproductive potential of transgender men and women. The recipients were asked to distribute it to faculty members and residents. The survey also described three clinical scenarios in which the physician needed to decide how to register a patient in iPLEDGE. The clinicians largely opted to class transgender men as women with childbearing potential, even if the category conflicted with the patient’s self-identified and legally recognized male gender.

Of the 136 clinicians who responded, 60% were women, almost half were aged 25-34 years. About 12% of respondents said the complexities of prescribing isotretinoin to a transgender patient led them to choose alternative therapies. And the survey revealed some gaps on providers’ general literacy on transgender patients and their reproductive potential. For example, fewer than a third of respondents answered correctly as to whether testosterone treatment decreases the quality and development of an immature ovum.

The researchers wrote that the survey results, while limited by a small sample of respondents that skewed toward younger women providers, suggest that “continued education on fertility in transgender patients is needed because prescribers must fully understand each patient’s reproductive potential to safely prescribe teratogenic medications.” Additionally, they pointed out, the results support ongoing efforts to reform iPLEDGE, as the current categories “do not offer an inclusive approach to care for transgender patients.”

Earlier this year the American Academy of Dermatology issued a position statement that described a number of ongoing initiatives aimed at improving treatment for patients who are members of gender and sexual minorities. These included the “revision of the AAD position statement on isotretinoin to support a gender-neutral categorization model for [iPLEDGE] … based on child-bearing potential rather than on gender identity,” the statement said.

Dr. Ensslin and colleagues reported conflicts of interest related to their research. The study was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences of the National Institutes of Health.

SOURCE: Ensslin C et al. J Am Acad Dermatol. 2019 Dec;81(6):1426-9.

Physicians treating transgender patients – in particular, transgender men who were born female – are faced with a confusing process when prescribing isotretinoin for severe acne.

A research letter published in the Journal of the American Academy of Dermatology reports that half of dermatologists surveyed reported having encountered difficulties classifying a transgender patient in iPLEDGE, the risk-management registry established to prevent female patients from starting isotretinoin therapy while pregnant or from becoming pregnant while exposed to the teratogenic medication.

Nearly 90% of respondents favored changing the current gender-specific categories in iPLEDGE to gender-neutral ones, classifying patients only by whether or not they have the ability to become pregnant.

For their research, Courtney Ensslin, MD, of the department of dermatology at Johns Hopkins University, Baltimore, and colleagues, distributed an 18-point questionnaire to 385 members of the Association of Professors of Dermatology that included questions assessing clinicians’ knowledge about the reproductive potential of transgender men and women. The recipients were asked to distribute it to faculty members and residents. The survey also described three clinical scenarios in which the physician needed to decide how to register a patient in iPLEDGE. The clinicians largely opted to class transgender men as women with childbearing potential, even if the category conflicted with the patient’s self-identified and legally recognized male gender.

Of the 136 clinicians who responded, 60% were women, almost half were aged 25-34 years. About 12% of respondents said the complexities of prescribing isotretinoin to a transgender patient led them to choose alternative therapies. And the survey revealed some gaps on providers’ general literacy on transgender patients and their reproductive potential. For example, fewer than a third of respondents answered correctly as to whether testosterone treatment decreases the quality and development of an immature ovum.

The researchers wrote that the survey results, while limited by a small sample of respondents that skewed toward younger women providers, suggest that “continued education on fertility in transgender patients is needed because prescribers must fully understand each patient’s reproductive potential to safely prescribe teratogenic medications.” Additionally, they pointed out, the results support ongoing efforts to reform iPLEDGE, as the current categories “do not offer an inclusive approach to care for transgender patients.”

Earlier this year the American Academy of Dermatology issued a position statement that described a number of ongoing initiatives aimed at improving treatment for patients who are members of gender and sexual minorities. These included the “revision of the AAD position statement on isotretinoin to support a gender-neutral categorization model for [iPLEDGE] … based on child-bearing potential rather than on gender identity,” the statement said.

Dr. Ensslin and colleagues reported conflicts of interest related to their research. The study was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences of the National Institutes of Health.

SOURCE: Ensslin C et al. J Am Acad Dermatol. 2019 Dec;81(6):1426-9.

Physicians treating transgender patients – in particular, transgender men who were born female – are faced with a confusing process when prescribing isotretinoin for severe acne.

A research letter published in the Journal of the American Academy of Dermatology reports that half of dermatologists surveyed reported having encountered difficulties classifying a transgender patient in iPLEDGE, the risk-management registry established to prevent female patients from starting isotretinoin therapy while pregnant or from becoming pregnant while exposed to the teratogenic medication.

Nearly 90% of respondents favored changing the current gender-specific categories in iPLEDGE to gender-neutral ones, classifying patients only by whether or not they have the ability to become pregnant.

For their research, Courtney Ensslin, MD, of the department of dermatology at Johns Hopkins University, Baltimore, and colleagues, distributed an 18-point questionnaire to 385 members of the Association of Professors of Dermatology that included questions assessing clinicians’ knowledge about the reproductive potential of transgender men and women. The recipients were asked to distribute it to faculty members and residents. The survey also described three clinical scenarios in which the physician needed to decide how to register a patient in iPLEDGE. The clinicians largely opted to class transgender men as women with childbearing potential, even if the category conflicted with the patient’s self-identified and legally recognized male gender.

Of the 136 clinicians who responded, 60% were women, almost half were aged 25-34 years. About 12% of respondents said the complexities of prescribing isotretinoin to a transgender patient led them to choose alternative therapies. And the survey revealed some gaps on providers’ general literacy on transgender patients and their reproductive potential. For example, fewer than a third of respondents answered correctly as to whether testosterone treatment decreases the quality and development of an immature ovum.

The researchers wrote that the survey results, while limited by a small sample of respondents that skewed toward younger women providers, suggest that “continued education on fertility in transgender patients is needed because prescribers must fully understand each patient’s reproductive potential to safely prescribe teratogenic medications.” Additionally, they pointed out, the results support ongoing efforts to reform iPLEDGE, as the current categories “do not offer an inclusive approach to care for transgender patients.”

Earlier this year the American Academy of Dermatology issued a position statement that described a number of ongoing initiatives aimed at improving treatment for patients who are members of gender and sexual minorities. These included the “revision of the AAD position statement on isotretinoin to support a gender-neutral categorization model for [iPLEDGE] … based on child-bearing potential rather than on gender identity,” the statement said.

Dr. Ensslin and colleagues reported conflicts of interest related to their research. The study was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences of the National Institutes of Health.

SOURCE: Ensslin C et al. J Am Acad Dermatol. 2019 Dec;81(6):1426-9.

It’s best practice to not set an alarm when on vacation. The point of vacation, after all, is to escape the rock-hard constraints of the daily grind. But the melody pulling me from slumber wasn’t coming from my phone. It was the ethereal chant of Fajr, morning prayer rising from surrounding mosques. I was in the medina of Marrakesh sleeping in a hotel that was once a home, called a riad. Some parts of the building date from the medieval period. Fajr occurs at dawn, before morning light. Getting from the bed to the toilet was treacherous – you must traverse cold, uneven steps to get there. Yet I had to get dressed: Morning yoga on our riad rooftop would start with sunrise. I guess even my vacations have agendas: I was in Morocco not only to holiday, but also to improve mind, body, and spirit.

ddoorly/iStock/Getty Images Plus

Wellness vacations are a rapidly growing treatment for burnout. They are a pulse dose of burnout therapy with a potential for lasting remission. For those who can afford them, your travel is fully arranged and activities such as yoga, cooking classes, hikes, and meditation are scheduled. This was my first wellness trip and it was transformative. Many times have I tried to disconnect from the distractions of life, but there is nothing so purifying as having no phone or Internet access. When I made peace with the reality that I couldn’t access EPIC or email, it was like a ringing in the ears had lifted: I could hear silence again.

This trip took us to three locations: Marrakesh, the Atlas Mountains, and the edge of the Sahara Desert. Yoga was prescribed twice a day. Morning practice was 90 minutes of shedding layers as the sun rose and our bodies warmed to increasingly difficult sequences. This was followed by Moroccan breakfast with fellow travelers from around the world. All were professionals and I wasn’t surprised to learn that burnout is common to many. I was surprised to realize that sharing stories with strangers about the vicissitudes of life was deeply bonding. (Or perhaps it was doing yoga inversions together.)

Also surprising was how easy it is to get lost in the maze that is Marrakesh. And yet, it was rewarding. Finding our way back through the mass of people, donkeys, and motorbikes along dark, unmarked alleys – without Waze – was intensely clarifying. Few things help you be present “in the moment” as being adrift and disoriented in a foreign city.

There was relaxation too. We made Khobz, traditional Moroccan bread by mixing just the right amounts of flour, yeast, sugar, oil, water, and salt. Knead, add, knead, add, and stop when done. We then walked a half mile to give our doughy creations to a baker who, with blackened calloused hands, worked an ancient communal oven. Then we waited patiently for the sardines ahead of us to finish baking first. I’ve no idea how long it all took – I had nowhere else to be.

The next day we hiked to a village in the Ourika Valley. There we had lunch at the home of a local Berber family. They served us their best tea, vegetable couscous, and lamb tagine while their chickens and donkeys watched us curiously. It was Thanksgiving (not on the Berber calendar of course) and sharing a meal prepared by a faraway stranger who doesn’t speak English makes you feel thankful in a refreshing way. Way more alike than different we are, I learned.

We finished our trip with a little desert “glamping.” The vast expanse of desert, interrupted by swirling winds and camel bellows quiets your mind, opens you to the immensity of life. That night we sat close to a bonfire and watched the Milky Way drift across the true black sky. I woke the next morning to the best night’s sleep I’ve had all year. My last wellness activity was unplanned, but meaningful nonetheless. As it happens, there’s no hot water in the desert and a bracingly cold shower marked the end of my treatment/vacation.

If the opposite of burned out is repleted, then I am. Also grateful to have such a transformative experience, for friends new and old who love me, and for hot water. Prescribe yourself one if you can.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com.

It’s best practice to not set an alarm when on vacation. The point of vacation, after all, is to escape the rock-hard constraints of the daily grind. But the melody pulling me from slumber wasn’t coming from my phone. It was the ethereal chant of Fajr, morning prayer rising from surrounding mosques. I was in the medina of Marrakesh sleeping in a hotel that was once a home, called a riad. Some parts of the building date from the medieval period. Fajr occurs at dawn, before morning light. Getting from the bed to the toilet was treacherous – you must traverse cold, uneven steps to get there. Yet I had to get dressed: Morning yoga on our riad rooftop would start with sunrise. I guess even my vacations have agendas: I was in Morocco not only to holiday, but also to improve mind, body, and spirit.

ddoorly/iStock/Getty Images Plus

Wellness vacations are a rapidly growing treatment for burnout. They are a pulse dose of burnout therapy with a potential for lasting remission. For those who can afford them, your travel is fully arranged and activities such as yoga, cooking classes, hikes, and meditation are scheduled. This was my first wellness trip and it was transformative. Many times have I tried to disconnect from the distractions of life, but there is nothing so purifying as having no phone or Internet access. When I made peace with the reality that I couldn’t access EPIC or email, it was like a ringing in the ears had lifted: I could hear silence again.

This trip took us to three locations: Marrakesh, the Atlas Mountains, and the edge of the Sahara Desert. Yoga was prescribed twice a day. Morning practice was 90 minutes of shedding layers as the sun rose and our bodies warmed to increasingly difficult sequences. This was followed by Moroccan breakfast with fellow travelers from around the world. All were professionals and I wasn’t surprised to learn that burnout is common to many. I was surprised to realize that sharing stories with strangers about the vicissitudes of life was deeply bonding. (Or perhaps it was doing yoga inversions together.)

Also surprising was how easy it is to get lost in the maze that is Marrakesh. And yet, it was rewarding. Finding our way back through the mass of people, donkeys, and motorbikes along dark, unmarked alleys – without Waze – was intensely clarifying. Few things help you be present “in the moment” as being adrift and disoriented in a foreign city.

There was relaxation too. We made Khobz, traditional Moroccan bread by mixing just the right amounts of flour, yeast, sugar, oil, water, and salt. Knead, add, knead, add, and stop when done. We then walked a half mile to give our doughy creations to a baker who, with blackened calloused hands, worked an ancient communal oven. Then we waited patiently for the sardines ahead of us to finish baking first. I’ve no idea how long it all took – I had nowhere else to be.

The next day we hiked to a village in the Ourika Valley. There we had lunch at the home of a local Berber family. They served us their best tea, vegetable couscous, and lamb tagine while their chickens and donkeys watched us curiously. It was Thanksgiving (not on the Berber calendar of course) and sharing a meal prepared by a faraway stranger who doesn’t speak English makes you feel thankful in a refreshing way. Way more alike than different we are, I learned.

We finished our trip with a little desert “glamping.” The vast expanse of desert, interrupted by swirling winds and camel bellows quiets your mind, opens you to the immensity of life. That night we sat close to a bonfire and watched the Milky Way drift across the true black sky. I woke the next morning to the best night’s sleep I’ve had all year. My last wellness activity was unplanned, but meaningful nonetheless. As it happens, there’s no hot water in the desert and a bracingly cold shower marked the end of my treatment/vacation.

If the opposite of burned out is repleted, then I am. Also grateful to have such a transformative experience, for friends new and old who love me, and for hot water. Prescribe yourself one if you can.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com.

It’s best practice to not set an alarm when on vacation. The point of vacation, after all, is to escape the rock-hard constraints of the daily grind. But the melody pulling me from slumber wasn’t coming from my phone. It was the ethereal chant of Fajr, morning prayer rising from surrounding mosques. I was in the medina of Marrakesh sleeping in a hotel that was once a home, called a riad. Some parts of the building date from the medieval period. Fajr occurs at dawn, before morning light. Getting from the bed to the toilet was treacherous – you must traverse cold, uneven steps to get there. Yet I had to get dressed: Morning yoga on our riad rooftop would start with sunrise. I guess even my vacations have agendas: I was in Morocco not only to holiday, but also to improve mind, body, and spirit.

ddoorly/iStock/Getty Images Plus

Wellness vacations are a rapidly growing treatment for burnout. They are a pulse dose of burnout therapy with a potential for lasting remission. For those who can afford them, your travel is fully arranged and activities such as yoga, cooking classes, hikes, and meditation are scheduled. This was my first wellness trip and it was transformative. Many times have I tried to disconnect from the distractions of life, but there is nothing so purifying as having no phone or Internet access. When I made peace with the reality that I couldn’t access EPIC or email, it was like a ringing in the ears had lifted: I could hear silence again.

This trip took us to three locations: Marrakesh, the Atlas Mountains, and the edge of the Sahara Desert. Yoga was prescribed twice a day. Morning practice was 90 minutes of shedding layers as the sun rose and our bodies warmed to increasingly difficult sequences. This was followed by Moroccan breakfast with fellow travelers from around the world. All were professionals and I wasn’t surprised to learn that burnout is common to many. I was surprised to realize that sharing stories with strangers about the vicissitudes of life was deeply bonding. (Or perhaps it was doing yoga inversions together.)

Also surprising was how easy it is to get lost in the maze that is Marrakesh. And yet, it was rewarding. Finding our way back through the mass of people, donkeys, and motorbikes along dark, unmarked alleys – without Waze – was intensely clarifying. Few things help you be present “in the moment” as being adrift and disoriented in a foreign city.

There was relaxation too. We made Khobz, traditional Moroccan bread by mixing just the right amounts of flour, yeast, sugar, oil, water, and salt. Knead, add, knead, add, and stop when done. We then walked a half mile to give our doughy creations to a baker who, with blackened calloused hands, worked an ancient communal oven. Then we waited patiently for the sardines ahead of us to finish baking first. I’ve no idea how long it all took – I had nowhere else to be.

The next day we hiked to a village in the Ourika Valley. There we had lunch at the home of a local Berber family. They served us their best tea, vegetable couscous, and lamb tagine while their chickens and donkeys watched us curiously. It was Thanksgiving (not on the Berber calendar of course) and sharing a meal prepared by a faraway stranger who doesn’t speak English makes you feel thankful in a refreshing way. Way more alike than different we are, I learned.

We finished our trip with a little desert “glamping.” The vast expanse of desert, interrupted by swirling winds and camel bellows quiets your mind, opens you to the immensity of life. That night we sat close to a bonfire and watched the Milky Way drift across the true black sky. I woke the next morning to the best night’s sleep I’ve had all year. My last wellness activity was unplanned, but meaningful nonetheless. As it happens, there’s no hot water in the desert and a bracingly cold shower marked the end of my treatment/vacation.

If the opposite of burned out is repleted, then I am. Also grateful to have such a transformative experience, for friends new and old who love me, and for hot water. Prescribe yourself one if you can.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@mdedge.com.

For the last 25 years I have had the privilege of caring for a rural community, practicing full-scope family medicine including obstetrics with cesarean sections. I have had a deeply rewarding career, and delivering babies and watching them grow up has been one of the most gratifying parts of my work.

Sheri Porter/AAFP News

My concern is that, as the number of family physicians who practice maternity care has decreased, the infant and maternal mortality rate in the United States has increased, especially in rural and minority populations. Currently, 5 million women of reproductive age have no access to maternity care.

At the same time 23% of incoming family medicine residents would like to offer maternity care and are trained to do so, but few are able to find a job where this is possible.¹ This is unfortunate because family physicians have the training and expertise to provide comprehensive maternity care. Although they have lower rates of cesarean section than ob-gyns, with similar outcomes, family physicians do have surgical skills, including providing cesarean sections, that are often necessary for safe delivery.^2,3

In addition, family physicians have the internal medicine and behavioral health background to care for postpartum complications, as well as substance use disorders. Because they also care for children, they see postpartum women when they come in with their children for well-child checks. These visits offer an excellent opportunity to also check on the mother for postpartum depression and other signs of postpartum illness.

Centers for Disease Control and Prevention data reveal that maternal mortality can be divided into three nearly equal parts: pregnancy, delivery, and post partum. They define delivery as the week of delivery. The 48 hours post delivery accounted for only 12% of overall mortality. This means that even if women travel to metropolitan areas, they are likely to be home when they have fatal complications. The lack of trained and experienced physicians in the communities where women live increases their risks should they have complications. Most maternal fatalities occur when conditions are not recognized in a timely fashion. Some responses require procedural skills such as dilation and curettage (D&C).

As a member of the National Advisory Committee on Rural Health and Human Services, I visited several states to evaluate their rural health systems. We looked at infant mortality by county and found an enormous disparity between counties, largely caused by lack of prenatal services and obstetrical services.

These disparities between counties are getting worse. The United States is losing critical access hospitals at a rapid pace. We have lost 117 critical access hospitals in the last 10 years, with 40 in the last year alone. According to the National Rural Health Association, ^4,673 additional facilities – representing more than one-third of rural hospitals in the United States – are vulnerable and could close. The reasons are multiple, but the result has been an erosion of the rural safety net, especially with regard to maternity care.

These hospital closures force women to travel farther distances for maternity care, including cesarean sections, and this contributes to increased maternal and infant mortality.⁵ In a study from Canada, the complication rates increased substantially as distances increased. Women are more likely to have premature deliveries, deliver on the side of the road, or end up in inappropriate facilities.

The distance from delivery is directly related to outcomes. A study from the early 1990s showed that women did better if they received maternity care from local hospitals and physicians.⁶ From a family medicine perspective, this makes sense because traveling to a metropolitan area means isolation from family and social networks. Stress increases because pregnant women also are often the primary caregiver of other children and the primary wage earner of the family. Although we are unsure what impact stress has on pregnancy, we do know it does have an effect on greater risk of prematurity and poor outcomes.

Obstetricians provide excellent care, but they are not a panacea. Only half of U.S. counties have adequate ob.gyn. coverage. Moreover, in many of those counties, the ob.gyns. subspecialize in gynecologic surgery and infertility, but don’t provide obstetrical care. Another challenge: ob.gyns. cannot survive financially in smaller communities; our policies must include incentives to recruit and retain them in underserved areas.

Certified nurse midwives also provide excellent care and are an invaluable member of the patient-care team, but again, they cannot be the only solution. Obstetrical emergencies do occur, and mothers need a physician trained in providing on-site medical or surgical care. They also need a hospital with adequate staff to care for emergencies.

In communities large enough to support a multispecialty group, certified medical technicians, family physicians, and ob.gyns. would ideally work alongside each other. In small communities four family physicians can provide a high level of maternity care including surgical deliveries, while supporting themselves with caring for children and elders in clinics, hospitals, and EDs.

It is unconscionable that a country as wealthy as ours would accept rates of maternal and infant mortality that rival and are often worse than developing countries. Although the reasons are many, there is no excuse. Family physicians are an essential part of reversing this trend. We need policies that enable family physicians to help resolve the shortage of maternity care for underserved communities, to address the maternal and infant mortality rate, and to provide maternity care that is part of family medicine’s full scope of practice.

Dr. Cullen is board chair of the American Academy of Family Physicians and a practicing family physician in Valdez, Alaska.

References

1. Am Board Fam Med. 2017 Jul-Aug;30(4):405-6.

2. CMAJ. 2015 Oct 27;187:1125-32.

3. J Am Board Fam Med. 2013 Jul-Aug;26(4):366-72.

4. NRHA Save Rural Hospitals Action Center. www.ruralhealthweb.org/advocate/save-rural-hospitals.

5. BMC Health Serv Res. 2011 Jun 10;11:147.

6. Am J Public Health. 1990 Jul;80(7):814-8.

For the last 25 years I have had the privilege of caring for a rural community, practicing full-scope family medicine including obstetrics with cesarean sections. I have had a deeply rewarding career, and delivering babies and watching them grow up has been one of the most gratifying parts of my work.

Sheri Porter/AAFP News

My concern is that, as the number of family physicians who practice maternity care has decreased, the infant and maternal mortality rate in the United States has increased, especially in rural and minority populations. Currently, 5 million women of reproductive age have no access to maternity care.

At the same time 23% of incoming family medicine residents would like to offer maternity care and are trained to do so, but few are able to find a job where this is possible.¹ This is unfortunate because family physicians have the training and expertise to provide comprehensive maternity care. Although they have lower rates of cesarean section than ob-gyns, with similar outcomes, family physicians do have surgical skills, including providing cesarean sections, that are often necessary for safe delivery.^2,3

In addition, family physicians have the internal medicine and behavioral health background to care for postpartum complications, as well as substance use disorders. Because they also care for children, they see postpartum women when they come in with their children for well-child checks. These visits offer an excellent opportunity to also check on the mother for postpartum depression and other signs of postpartum illness.

Centers for Disease Control and Prevention data reveal that maternal mortality can be divided into three nearly equal parts: pregnancy, delivery, and post partum. They define delivery as the week of delivery. The 48 hours post delivery accounted for only 12% of overall mortality. This means that even if women travel to metropolitan areas, they are likely to be home when they have fatal complications. The lack of trained and experienced physicians in the communities where women live increases their risks should they have complications. Most maternal fatalities occur when conditions are not recognized in a timely fashion. Some responses require procedural skills such as dilation and curettage (D&C).

As a member of the National Advisory Committee on Rural Health and Human Services, I visited several states to evaluate their rural health systems. We looked at infant mortality by county and found an enormous disparity between counties, largely caused by lack of prenatal services and obstetrical services.

These disparities between counties are getting worse. The United States is losing critical access hospitals at a rapid pace. We have lost 117 critical access hospitals in the last 10 years, with 40 in the last year alone. According to the National Rural Health Association, ^4,673 additional facilities – representing more than one-third of rural hospitals in the United States – are vulnerable and could close. The reasons are multiple, but the result has been an erosion of the rural safety net, especially with regard to maternity care.

These hospital closures force women to travel farther distances for maternity care, including cesarean sections, and this contributes to increased maternal and infant mortality.⁵ In a study from Canada, the complication rates increased substantially as distances increased. Women are more likely to have premature deliveries, deliver on the side of the road, or end up in inappropriate facilities.

The distance from delivery is directly related to outcomes. A study from the early 1990s showed that women did better if they received maternity care from local hospitals and physicians.⁶ From a family medicine perspective, this makes sense because traveling to a metropolitan area means isolation from family and social networks. Stress increases because pregnant women also are often the primary caregiver of other children and the primary wage earner of the family. Although we are unsure what impact stress has on pregnancy, we do know it does have an effect on greater risk of prematurity and poor outcomes.

Obstetricians provide excellent care, but they are not a panacea. Only half of U.S. counties have adequate ob.gyn. coverage. Moreover, in many of those counties, the ob.gyns. subspecialize in gynecologic surgery and infertility, but don’t provide obstetrical care. Another challenge: ob.gyns. cannot survive financially in smaller communities; our policies must include incentives to recruit and retain them in underserved areas.

Certified nurse midwives also provide excellent care and are an invaluable member of the patient-care team, but again, they cannot be the only solution. Obstetrical emergencies do occur, and mothers need a physician trained in providing on-site medical or surgical care. They also need a hospital with adequate staff to care for emergencies.

In communities large enough to support a multispecialty group, certified medical technicians, family physicians, and ob.gyns. would ideally work alongside each other. In small communities four family physicians can provide a high level of maternity care including surgical deliveries, while supporting themselves with caring for children and elders in clinics, hospitals, and EDs.

It is unconscionable that a country as wealthy as ours would accept rates of maternal and infant mortality that rival and are often worse than developing countries. Although the reasons are many, there is no excuse. Family physicians are an essential part of reversing this trend. We need policies that enable family physicians to help resolve the shortage of maternity care for underserved communities, to address the maternal and infant mortality rate, and to provide maternity care that is part of family medicine’s full scope of practice.

Dr. Cullen is board chair of the American Academy of Family Physicians and a practicing family physician in Valdez, Alaska.

References

1. Am Board Fam Med. 2017 Jul-Aug;30(4):405-6.

2. CMAJ. 2015 Oct 27;187:1125-32.

3. J Am Board Fam Med. 2013 Jul-Aug;26(4):366-72.

4. NRHA Save Rural Hospitals Action Center. www.ruralhealthweb.org/advocate/save-rural-hospitals.

5. BMC Health Serv Res. 2011 Jun 10;11:147.

6. Am J Public Health. 1990 Jul;80(7):814-8.

For the last 25 years I have had the privilege of caring for a rural community, practicing full-scope family medicine including obstetrics with cesarean sections. I have had a deeply rewarding career, and delivering babies and watching them grow up has been one of the most gratifying parts of my work.

Sheri Porter/AAFP News

My concern is that, as the number of family physicians who practice maternity care has decreased, the infant and maternal mortality rate in the United States has increased, especially in rural and minority populations. Currently, 5 million women of reproductive age have no access to maternity care.

At the same time 23% of incoming family medicine residents would like to offer maternity care and are trained to do so, but few are able to find a job where this is possible.¹ This is unfortunate because family physicians have the training and expertise to provide comprehensive maternity care. Although they have lower rates of cesarean section than ob-gyns, with similar outcomes, family physicians do have surgical skills, including providing cesarean sections, that are often necessary for safe delivery.^2,3

In addition, family physicians have the internal medicine and behavioral health background to care for postpartum complications, as well as substance use disorders. Because they also care for children, they see postpartum women when they come in with their children for well-child checks. These visits offer an excellent opportunity to also check on the mother for postpartum depression and other signs of postpartum illness.

Centers for Disease Control and Prevention data reveal that maternal mortality can be divided into three nearly equal parts: pregnancy, delivery, and post partum. They define delivery as the week of delivery. The 48 hours post delivery accounted for only 12% of overall mortality. This means that even if women travel to metropolitan areas, they are likely to be home when they have fatal complications. The lack of trained and experienced physicians in the communities where women live increases their risks should they have complications. Most maternal fatalities occur when conditions are not recognized in a timely fashion. Some responses require procedural skills such as dilation and curettage (D&C).

As a member of the National Advisory Committee on Rural Health and Human Services, I visited several states to evaluate their rural health systems. We looked at infant mortality by county and found an enormous disparity between counties, largely caused by lack of prenatal services and obstetrical services.

These disparities between counties are getting worse. The United States is losing critical access hospitals at a rapid pace. We have lost 117 critical access hospitals in the last 10 years, with 40 in the last year alone. According to the National Rural Health Association, ^4,673 additional facilities – representing more than one-third of rural hospitals in the United States – are vulnerable and could close. The reasons are multiple, but the result has been an erosion of the rural safety net, especially with regard to maternity care.

These hospital closures force women to travel farther distances for maternity care, including cesarean sections, and this contributes to increased maternal and infant mortality.⁵ In a study from Canada, the complication rates increased substantially as distances increased. Women are more likely to have premature deliveries, deliver on the side of the road, or end up in inappropriate facilities.

The distance from delivery is directly related to outcomes. A study from the early 1990s showed that women did better if they received maternity care from local hospitals and physicians.⁶ From a family medicine perspective, this makes sense because traveling to a metropolitan area means isolation from family and social networks. Stress increases because pregnant women also are often the primary caregiver of other children and the primary wage earner of the family. Although we are unsure what impact stress has on pregnancy, we do know it does have an effect on greater risk of prematurity and poor outcomes.

Obstetricians provide excellent care, but they are not a panacea. Only half of U.S. counties have adequate ob.gyn. coverage. Moreover, in many of those counties, the ob.gyns. subspecialize in gynecologic surgery and infertility, but don’t provide obstetrical care. Another challenge: ob.gyns. cannot survive financially in smaller communities; our policies must include incentives to recruit and retain them in underserved areas.

Certified nurse midwives also provide excellent care and are an invaluable member of the patient-care team, but again, they cannot be the only solution. Obstetrical emergencies do occur, and mothers need a physician trained in providing on-site medical or surgical care. They also need a hospital with adequate staff to care for emergencies.

In communities large enough to support a multispecialty group, certified medical technicians, family physicians, and ob.gyns. would ideally work alongside each other. In small communities four family physicians can provide a high level of maternity care including surgical deliveries, while supporting themselves with caring for children and elders in clinics, hospitals, and EDs.

It is unconscionable that a country as wealthy as ours would accept rates of maternal and infant mortality that rival and are often worse than developing countries. Although the reasons are many, there is no excuse. Family physicians are an essential part of reversing this trend. We need policies that enable family physicians to help resolve the shortage of maternity care for underserved communities, to address the maternal and infant mortality rate, and to provide maternity care that is part of family medicine’s full scope of practice.

Dr. Cullen is board chair of the American Academy of Family Physicians and a practicing family physician in Valdez, Alaska.

References

1. Am Board Fam Med. 2017 Jul-Aug;30(4):405-6.

2. CMAJ. 2015 Oct 27;187:1125-32.

3. J Am Board Fam Med. 2013 Jul-Aug;26(4):366-72.

4. NRHA Save Rural Hospitals Action Center. www.ruralhealthweb.org/advocate/save-rural-hospitals.

5. BMC Health Serv Res. 2011 Jun 10;11:147.

6. Am J Public Health. 1990 Jul;80(7):814-8.

Severity of insomnia, specifically difficulty initiating sleep, was a significant predictor of major depressive disorder, a prospective study of 768 adults with a history of depression suggests.

Insomnia has been identified as a risk factor for depression, but the impact of lifetime depression history and the role of insomnia in major depressive disorder (MDD) remains unclear, wrote Tessa Blanken, MSc, of the Netherlands Institute for Neuroscience, Amsterdam, and colleagues. Studies of this relationship have been hampered by the difficulty of isolating the impact of insomnia as an independent predictor of MDD from depression and other disorders.

In a study published in Sleep, the researchers reviewed data from 768 adults aged 18-65 years who were participants in the Netherlands Study of Depression and Anxiety, a multicenter, longitudinal study that included four assessments over 6 years. The participants had no current or prior diagnosis of MDD. The average age of the participants was 41 years, and 63% were women.

The investigators used Network Outcome Analysis to study the link between insomnia and MDD. The investigators wrote, “Network modeling techniques provide a unique framework to study the interactions among symptoms and their role in the development and maintenance of psychiatric disorders. Using network analysis we can estimate the unique association between pairs of symptoms, while controlling for the state and associations of all other symptoms.”

Over 6-years’ follow-up, 141 participants (18%) were diagnosed with first-onset MDD. Overall, insomnia severity was a significant predictor of first-onset MDD (hazard ratio 1.11, 95% confidence interval). The analysis showed that the predictive effect of insomnia on first-onset MDD was driven solely by the item “Did you have trouble falling asleep” (hazard ratio, 1.33; 95% confidence interval, 1.12-1.57; observed range, 0-4). Those individuals who had trouble falling asleep 3-4 times or more than 4 times a week were 2.3 or 3.2 times, respectively, more likely to develop first-onset MDD. None of the other sleep complaints, such as nocturnal and early morning awakening, significantly increased the risk of first-onset MDD.

The study findings were limited by several factors including the full impact of short sleep duration and lack of chronotype assessment, the researchers noted. However, “the identification of ‘difficulty initiating sleep’ as a risk factor is particularly promising because a recent meta-analysis showed that cognitive behavioural therapy, the treatment of choice for insomnia, is highly effective,” the researchers wrote. The results suggest that treating problems in sleep initiation could contribute to preventing first-onset depression and reducing the overall burden of MDD, they concluded.

The study was supported by the European Research Council. The researchers had no financial conflicts to disclose.

SOURCE: Blanken TF et al. Sleep. 2019 Dec 2. doi: 10.1093/sleep/zsz288.

Severity of insomnia, specifically difficulty initiating sleep, was a significant predictor of major depressive disorder, a prospective study of 768 adults with a history of depression suggests.

Insomnia has been identified as a risk factor for depression, but the impact of lifetime depression history and the role of insomnia in major depressive disorder (MDD) remains unclear, wrote Tessa Blanken, MSc, of the Netherlands Institute for Neuroscience, Amsterdam, and colleagues. Studies of this relationship have been hampered by the difficulty of isolating the impact of insomnia as an independent predictor of MDD from depression and other disorders.

In a study published in Sleep, the researchers reviewed data from 768 adults aged 18-65 years who were participants in the Netherlands Study of Depression and Anxiety, a multicenter, longitudinal study that included four assessments over 6 years. The participants had no current or prior diagnosis of MDD. The average age of the participants was 41 years, and 63% were women.

The investigators used Network Outcome Analysis to study the link between insomnia and MDD. The investigators wrote, “Network modeling techniques provide a unique framework to study the interactions among symptoms and their role in the development and maintenance of psychiatric disorders. Using network analysis we can estimate the unique association between pairs of symptoms, while controlling for the state and associations of all other symptoms.”

Over 6-years’ follow-up, 141 participants (18%) were diagnosed with first-onset MDD. Overall, insomnia severity was a significant predictor of first-onset MDD (hazard ratio 1.11, 95% confidence interval). The analysis showed that the predictive effect of insomnia on first-onset MDD was driven solely by the item “Did you have trouble falling asleep” (hazard ratio, 1.33; 95% confidence interval, 1.12-1.57; observed range, 0-4). Those individuals who had trouble falling asleep 3-4 times or more than 4 times a week were 2.3 or 3.2 times, respectively, more likely to develop first-onset MDD. None of the other sleep complaints, such as nocturnal and early morning awakening, significantly increased the risk of first-onset MDD.

The study findings were limited by several factors including the full impact of short sleep duration and lack of chronotype assessment, the researchers noted. However, “the identification of ‘difficulty initiating sleep’ as a risk factor is particularly promising because a recent meta-analysis showed that cognitive behavioural therapy, the treatment of choice for insomnia, is highly effective,” the researchers wrote. The results suggest that treating problems in sleep initiation could contribute to preventing first-onset depression and reducing the overall burden of MDD, they concluded.

The study was supported by the European Research Council. The researchers had no financial conflicts to disclose.

SOURCE: Blanken TF et al. Sleep. 2019 Dec 2. doi: 10.1093/sleep/zsz288.

Severity of insomnia, specifically difficulty initiating sleep, was a significant predictor of major depressive disorder, a prospective study of 768 adults with a history of depression suggests.

Insomnia has been identified as a risk factor for depression, but the impact of lifetime depression history and the role of insomnia in major depressive disorder (MDD) remains unclear, wrote Tessa Blanken, MSc, of the Netherlands Institute for Neuroscience, Amsterdam, and colleagues. Studies of this relationship have been hampered by the difficulty of isolating the impact of insomnia as an independent predictor of MDD from depression and other disorders.

In a study published in Sleep, the researchers reviewed data from 768 adults aged 18-65 years who were participants in the Netherlands Study of Depression and Anxiety, a multicenter, longitudinal study that included four assessments over 6 years. The participants had no current or prior diagnosis of MDD. The average age of the participants was 41 years, and 63% were women.

The investigators used Network Outcome Analysis to study the link between insomnia and MDD. The investigators wrote, “Network modeling techniques provide a unique framework to study the interactions among symptoms and their role in the development and maintenance of psychiatric disorders. Using network analysis we can estimate the unique association between pairs of symptoms, while controlling for the state and associations of all other symptoms.”

Over 6-years’ follow-up, 141 participants (18%) were diagnosed with first-onset MDD. Overall, insomnia severity was a significant predictor of first-onset MDD (hazard ratio 1.11, 95% confidence interval). The analysis showed that the predictive effect of insomnia on first-onset MDD was driven solely by the item “Did you have trouble falling asleep” (hazard ratio, 1.33; 95% confidence interval, 1.12-1.57; observed range, 0-4). Those individuals who had trouble falling asleep 3-4 times or more than 4 times a week were 2.3 or 3.2 times, respectively, more likely to develop first-onset MDD. None of the other sleep complaints, such as nocturnal and early morning awakening, significantly increased the risk of first-onset MDD.

The study findings were limited by several factors including the full impact of short sleep duration and lack of chronotype assessment, the researchers noted. However, “the identification of ‘difficulty initiating sleep’ as a risk factor is particularly promising because a recent meta-analysis showed that cognitive behavioural therapy, the treatment of choice for insomnia, is highly effective,” the researchers wrote. The results suggest that treating problems in sleep initiation could contribute to preventing first-onset depression and reducing the overall burden of MDD, they concluded.

The study was supported by the European Research Council. The researchers had no financial conflicts to disclose.

SOURCE: Blanken TF et al. Sleep. 2019 Dec 2. doi: 10.1093/sleep/zsz288.

SAN ANTONIO – The presence of circulating tumor DNA (ctDNA) and to a lesser degree circulating tumor cells (CTCs) following neoadjuvant chemotherapy for triple-negative breast cancer (TNBC) augurs poor prognosis, but it’s still unclear how this information can inform therapy.

Neil Osterweil/MDedge News

An analysis of plasma samples from 142 women enrolled in a trial that compared outcomes of genomically directed therapy with those of physician’s choice of a regimen for treatment of TNBC showed that, at a median follow-up of 17.2 months, detection of ctDNA was significantly associated with worse distant disease-free survival and the risk of relapse was especially high for patients with both detectable ctDNA and CTCs, reported Milan Radovich, PhD, from Indiana University in Indianapolis.

“Patients with TNBC at high clinical risk of relapse due to incomplete response to neoadjuvant chemotherapy can be further risk-stratified based on the presence of [minimal residual disease] as determined by ctDNA,” he said at the San Antonio Breast Cancer Symposium.

As previously reported, the presence of detectable ctDNA after surgery for breast cancer is a significant predictor of inferior disease-free survival (DFS), but the findings, while clinically valid, are not yet applicable to clinical care, Dr. Radovich acknowledged in a briefing shortly before his presentation of the data in a general session.

As part of the BRE12-158 trial, Dr. Radovich and colleagues conducted a prospective analysis of patients with early-stage TNBC who had significant residual disease at the time of surgery, despite having undergone neoadjuvant chemotherapy. The tumors were genomically sequenced and the patients were then randomized to receive either genomocially directed therapy or the treating physician’s choice of a regimen.

Of 177 evaluable patients, a total of 142 had successful ctDNA results and 123 had successful CTC testing. The ctDNA samples were sequenced using a liquid assay for 70 oncogenes commonly mutated in cancer. CTCs were isolated from peripheral blood with a positive-selection microfluidic device. CTC-positivity was defined at detection of one or more cells.

The investigators found that ctDNA was significantly associated with distant DFS, with a median of 32.5 months for ctDNA-positive patients versus median not reached for ctDNA-negative patients. The respective 2-year distant DFS rates were 56% and 81%, respectively. The hazard ratio for worse distant DFS among ctDNA-positive patients was 2.99 (P = .0055).

Similarly, DFS was significantly inferior among ctDNA-positive patients, with a median of 22.8 months versus not reached for ctDNA-negative patients, and median 2-year DFS rates of 50% and 76%. The HR for worse survival in ctDNA-positive patients was 2.67 (P = .0069).

Overall survival (OS) was also worse for ctDNA-positive patients; although the median OS was not reached in either positive or negative patients, the 2-year OS rates were 57% among ctDNA-positive patients and 80% among negative patients. The HR for death among the ctDNA-positive patients was 4.16 (P = .0024).

CTC detection, in contrast, showed a trend toward a significant association with clinical outcomes, but neither distant DFS, DFS, nor OS measures achieved statistical significance.

However, when ctDNA and CTC were combined, the results showed significantly inferior distant DFS for patients positive for both markers, compared with that of patients who were ctDNA positive but CTC negative (median, 32.5 months vs. not reached; 2 year distant DFS, 52% vs. 89%; HR, 5.29; P = .0095).

Similarly, this group of patients had worse DFS (median, 20.8 months vs. not reached; 2-year DFS, 43% vs. 80%; HR, 3.15; P = .0370) and worse OS (median, OS not reached in either group; 2-year OS, 51% vs. 76%; HR, 8.60; P = .0074).

To take advantage of these data, the investigators are preparing to launch a phase 2 trial (BRE18-334) in which patients with residual disease are randomized by ctDNA status (positive or negative) to either genetically directed therapy or therapy with no genomic target. The patients randomized to genomically directed therapy will be treated according to mutation category.

For example, capecitabine will given plus either a PARP (poly [ADP-ribose] polymerase) inhibitor for patients with mutations in DNA repair pathways, atezolizumab (Tecentriq) for patients with mutations in the immunotherapy pathway, ipatasertib for mutations in the P13K/AKT/mTOR pathway, or a PARP inhibitor plus atezolizumab for patients with mutations in the both DNA repair immunotherapy pathways.

At the briefing, moderator Virginia Kaklamani, MD, DSc, from University of Texas Health San Antonio, commented that the results of the study can inform clinical research, but “we don’t have predictive data as to how we’re going to act on this and improve patient outcomes. What we need is exactly the trial that the investigators have designed to see whether these results can then further help us in treating our patients and improving their outcomes.”

Neil Osterweil/MDedge News

“Should we be doing this on Monday in clinic, and the answer is no,” Dr. Radovich agreed. “What we don’t know is if having this information is really going to improve outcomes.”

In an interview, senior author Bryan P. Schneider, MD from Indiana University School of Medicine put it this way: “I’ve always believed that you don’t order a test until you know what to do with it,” he said.

The study was funded by the Vera Bradley Foundation for Breast Cancer and the Indiana University Grand Challenge Precision Health Initiative. Dr. Radovich and Dr. Schneider reported no relevant disclosures. Dr. Kaklamani disclosed speakers bureau activities and consulting for multiple companies, as well as research funding from Eiasi.

SOURCE: Radovich M. SABCS 2019, Abstract GS5-02.

SAN ANTONIO – The presence of circulating tumor DNA (ctDNA) and to a lesser degree circulating tumor cells (CTCs) following neoadjuvant chemotherapy for triple-negative breast cancer (TNBC) augurs poor prognosis, but it’s still unclear how this information can inform therapy.

Neil Osterweil/MDedge News

An analysis of plasma samples from 142 women enrolled in a trial that compared outcomes of genomically directed therapy with those of physician’s choice of a regimen for treatment of TNBC showed that, at a median follow-up of 17.2 months, detection of ctDNA was significantly associated with worse distant disease-free survival and the risk of relapse was especially high for patients with both detectable ctDNA and CTCs, reported Milan Radovich, PhD, from Indiana University in Indianapolis.

“Patients with TNBC at high clinical risk of relapse due to incomplete response to neoadjuvant chemotherapy can be further risk-stratified based on the presence of [minimal residual disease] as determined by ctDNA,” he said at the San Antonio Breast Cancer Symposium.

As previously reported, the presence of detectable ctDNA after surgery for breast cancer is a significant predictor of inferior disease-free survival (DFS), but the findings, while clinically valid, are not yet applicable to clinical care, Dr. Radovich acknowledged in a briefing shortly before his presentation of the data in a general session.

As part of the BRE12-158 trial, Dr. Radovich and colleagues conducted a prospective analysis of patients with early-stage TNBC who had significant residual disease at the time of surgery, despite having undergone neoadjuvant chemotherapy. The tumors were genomically sequenced and the patients were then randomized to receive either genomocially directed therapy or the treating physician’s choice of a regimen.

Of 177 evaluable patients, a total of 142 had successful ctDNA results and 123 had successful CTC testing. The ctDNA samples were sequenced using a liquid assay for 70 oncogenes commonly mutated in cancer. CTCs were isolated from peripheral blood with a positive-selection microfluidic device. CTC-positivity was defined at detection of one or more cells.

The investigators found that ctDNA was significantly associated with distant DFS, with a median of 32.5 months for ctDNA-positive patients versus median not reached for ctDNA-negative patients. The respective 2-year distant DFS rates were 56% and 81%, respectively. The hazard ratio for worse distant DFS among ctDNA-positive patients was 2.99 (P = .0055).

Similarly, DFS was significantly inferior among ctDNA-positive patients, with a median of 22.8 months versus not reached for ctDNA-negative patients, and median 2-year DFS rates of 50% and 76%. The HR for worse survival in ctDNA-positive patients was 2.67 (P = .0069).

Overall survival (OS) was also worse for ctDNA-positive patients; although the median OS was not reached in either positive or negative patients, the 2-year OS rates were 57% among ctDNA-positive patients and 80% among negative patients. The HR for death among the ctDNA-positive patients was 4.16 (P = .0024).

CTC detection, in contrast, showed a trend toward a significant association with clinical outcomes, but neither distant DFS, DFS, nor OS measures achieved statistical significance.

However, when ctDNA and CTC were combined, the results showed significantly inferior distant DFS for patients positive for both markers, compared with that of patients who were ctDNA positive but CTC negative (median, 32.5 months vs. not reached; 2 year distant DFS, 52% vs. 89%; HR, 5.29; P = .0095).

Similarly, this group of patients had worse DFS (median, 20.8 months vs. not reached; 2-year DFS, 43% vs. 80%; HR, 3.15; P = .0370) and worse OS (median, OS not reached in either group; 2-year OS, 51% vs. 76%; HR, 8.60; P = .0074).

To take advantage of these data, the investigators are preparing to launch a phase 2 trial (BRE18-334) in which patients with residual disease are randomized by ctDNA status (positive or negative) to either genetically directed therapy or therapy with no genomic target. The patients randomized to genomically directed therapy will be treated according to mutation category.

For example, capecitabine will given plus either a PARP (poly [ADP-ribose] polymerase) inhibitor for patients with mutations in DNA repair pathways, atezolizumab (Tecentriq) for patients with mutations in the immunotherapy pathway, ipatasertib for mutations in the P13K/AKT/mTOR pathway, or a PARP inhibitor plus atezolizumab for patients with mutations in the both DNA repair immunotherapy pathways.

At the briefing, moderator Virginia Kaklamani, MD, DSc, from University of Texas Health San Antonio, commented that the results of the study can inform clinical research, but “we don’t have predictive data as to how we’re going to act on this and improve patient outcomes. What we need is exactly the trial that the investigators have designed to see whether these results can then further help us in treating our patients and improving their outcomes.”

Neil Osterweil/MDedge News

“Should we be doing this on Monday in clinic, and the answer is no,” Dr. Radovich agreed. “What we don’t know is if having this information is really going to improve outcomes.”

In an interview, senior author Bryan P. Schneider, MD from Indiana University School of Medicine put it this way: “I’ve always believed that you don’t order a test until you know what to do with it,” he said.

The study was funded by the Vera Bradley Foundation for Breast Cancer and the Indiana University Grand Challenge Precision Health Initiative. Dr. Radovich and Dr. Schneider reported no relevant disclosures. Dr. Kaklamani disclosed speakers bureau activities and consulting for multiple companies, as well as research funding from Eiasi.

SOURCE: Radovich M. SABCS 2019, Abstract GS5-02.

SAN ANTONIO – The presence of circulating tumor DNA (ctDNA) and to a lesser degree circulating tumor cells (CTCs) following neoadjuvant chemotherapy for triple-negative breast cancer (TNBC) augurs poor prognosis, but it’s still unclear how this information can inform therapy.

Neil Osterweil/MDedge News

An analysis of plasma samples from 142 women enrolled in a trial that compared outcomes of genomically directed therapy with those of physician’s choice of a regimen for treatment of TNBC showed that, at a median follow-up of 17.2 months, detection of ctDNA was significantly associated with worse distant disease-free survival and the risk of relapse was especially high for patients with both detectable ctDNA and CTCs, reported Milan Radovich, PhD, from Indiana University in Indianapolis.

“Patients with TNBC at high clinical risk of relapse due to incomplete response to neoadjuvant chemotherapy can be further risk-stratified based on the presence of [minimal residual disease] as determined by ctDNA,” he said at the San Antonio Breast Cancer Symposium.

As previously reported, the presence of detectable ctDNA after surgery for breast cancer is a significant predictor of inferior disease-free survival (DFS), but the findings, while clinically valid, are not yet applicable to clinical care, Dr. Radovich acknowledged in a briefing shortly before his presentation of the data in a general session.

As part of the BRE12-158 trial, Dr. Radovich and colleagues conducted a prospective analysis of patients with early-stage TNBC who had significant residual disease at the time of surgery, despite having undergone neoadjuvant chemotherapy. The tumors were genomically sequenced and the patients were then randomized to receive either genomocially directed therapy or the treating physician’s choice of a regimen.

Of 177 evaluable patients, a total of 142 had successful ctDNA results and 123 had successful CTC testing. The ctDNA samples were sequenced using a liquid assay for 70 oncogenes commonly mutated in cancer. CTCs were isolated from peripheral blood with a positive-selection microfluidic device. CTC-positivity was defined at detection of one or more cells.

The investigators found that ctDNA was significantly associated with distant DFS, with a median of 32.5 months for ctDNA-positive patients versus median not reached for ctDNA-negative patients. The respective 2-year distant DFS rates were 56% and 81%, respectively. The hazard ratio for worse distant DFS among ctDNA-positive patients was 2.99 (P = .0055).

Similarly, DFS was significantly inferior among ctDNA-positive patients, with a median of 22.8 months versus not reached for ctDNA-negative patients, and median 2-year DFS rates of 50% and 76%. The HR for worse survival in ctDNA-positive patients was 2.67 (P = .0069).

Overall survival (OS) was also worse for ctDNA-positive patients; although the median OS was not reached in either positive or negative patients, the 2-year OS rates were 57% among ctDNA-positive patients and 80% among negative patients. The HR for death among the ctDNA-positive patients was 4.16 (P = .0024).

CTC detection, in contrast, showed a trend toward a significant association with clinical outcomes, but neither distant DFS, DFS, nor OS measures achieved statistical significance.

However, when ctDNA and CTC were combined, the results showed significantly inferior distant DFS for patients positive for both markers, compared with that of patients who were ctDNA positive but CTC negative (median, 32.5 months vs. not reached; 2 year distant DFS, 52% vs. 89%; HR, 5.29; P = .0095).

Similarly, this group of patients had worse DFS (median, 20.8 months vs. not reached; 2-year DFS, 43% vs. 80%; HR, 3.15; P = .0370) and worse OS (median, OS not reached in either group; 2-year OS, 51% vs. 76%; HR, 8.60; P = .0074).

To take advantage of these data, the investigators are preparing to launch a phase 2 trial (BRE18-334) in which patients with residual disease are randomized by ctDNA status (positive or negative) to either genetically directed therapy or therapy with no genomic target. The patients randomized to genomically directed therapy will be treated according to mutation category.

For example, capecitabine will given plus either a PARP (poly [ADP-ribose] polymerase) inhibitor for patients with mutations in DNA repair pathways, atezolizumab (Tecentriq) for patients with mutations in the immunotherapy pathway, ipatasertib for mutations in the P13K/AKT/mTOR pathway, or a PARP inhibitor plus atezolizumab for patients with mutations in the both DNA repair immunotherapy pathways.

At the briefing, moderator Virginia Kaklamani, MD, DSc, from University of Texas Health San Antonio, commented that the results of the study can inform clinical research, but “we don’t have predictive data as to how we’re going to act on this and improve patient outcomes. What we need is exactly the trial that the investigators have designed to see whether these results can then further help us in treating our patients and improving their outcomes.”

Neil Osterweil/MDedge News

“Should we be doing this on Monday in clinic, and the answer is no,” Dr. Radovich agreed. “What we don’t know is if having this information is really going to improve outcomes.”

In an interview, senior author Bryan P. Schneider, MD from Indiana University School of Medicine put it this way: “I’ve always believed that you don’t order a test until you know what to do with it,” he said.

The study was funded by the Vera Bradley Foundation for Breast Cancer and the Indiana University Grand Challenge Precision Health Initiative. Dr. Radovich and Dr. Schneider reported no relevant disclosures. Dr. Kaklamani disclosed speakers bureau activities and consulting for multiple companies, as well as research funding from Eiasi.

SOURCE: Radovich M. SABCS 2019, Abstract GS5-02.

Researchers in Japan report that infants with atopic dermatitis who are treated early and aggressively with corticosteroids develop fewer food allergies by age 2 years.

For their research published in the Journal of Allergy and Clinical Immunology: In Practice, Yumiko Miyaji, MD, PhD, of Japan’s National Center for Child Health and Development in Tokyo and colleagues looked at 3 years’ worth of records for 177 infants younger than 1 year of age seen at a hospital allergy center for eczema. Of these infants, 89 were treated with betamethasone valerate within 4 months of disease onset, and 88 were treated after 4 months of onset. Most (142) were followed-up at 22-24 months, when all were in complete remission or near remission from eczema.

At follow-up, clinicians collected information about anaphylactic reactions to food, administered specific food challenges, and tested serum immunoglobin E levels for food allergens. Dr. Miyaji and colleagues found a significant difference in the prevalence of allergies between the early-treated and late-treated groups to chicken egg, cow’s milk, wheat, peanuts, soy, or fish (25% vs. 46%, respectively; P equal to .013). For individual food allergies, only chicken egg was associated with a statistically significant difference in prevalence (15% vs 36%, P equal to .006).

“Our present study may be the first to demonstrate that early aggressive topical corticosteroid treatment to shorten the duration of eczema in infants was significantly associated with a decrease in later development of [food allergies],” Dr. Miyaji and colleagues wrote in their analysis.

The investigators acknowledged as limitations of their study some between-group differences at baseline, with characteristics such as Staphylococcus aureus infections and some inflammatory biomarkers higher in the early treatment group.

The Japan Agency for Medical Research and Development supported the study, and the investigators disclosed no conflicts of interest related to their findings.

SOURCE: Miyaji Y et al. J Allergy Clin Immunol Pract. 2019. doi: 10.1016/j.jaip.2019.11.036

Researchers in Japan report that infants with atopic dermatitis who are treated early and aggressively with corticosteroids develop fewer food allergies by age 2 years.

For their research published in the Journal of Allergy and Clinical Immunology: In Practice, Yumiko Miyaji, MD, PhD, of Japan’s National Center for Child Health and Development in Tokyo and colleagues looked at 3 years’ worth of records for 177 infants younger than 1 year of age seen at a hospital allergy center for eczema. Of these infants, 89 were treated with betamethasone valerate within 4 months of disease onset, and 88 were treated after 4 months of onset. Most (142) were followed-up at 22-24 months, when all were in complete remission or near remission from eczema.

At follow-up, clinicians collected information about anaphylactic reactions to food, administered specific food challenges, and tested serum immunoglobin E levels for food allergens. Dr. Miyaji and colleagues found a significant difference in the prevalence of allergies between the early-treated and late-treated groups to chicken egg, cow’s milk, wheat, peanuts, soy, or fish (25% vs. 46%, respectively; P equal to .013). For individual food allergies, only chicken egg was associated with a statistically significant difference in prevalence (15% vs 36%, P equal to .006).

“Our present study may be the first to demonstrate that early aggressive topical corticosteroid treatment to shorten the duration of eczema in infants was significantly associated with a decrease in later development of [food allergies],” Dr. Miyaji and colleagues wrote in their analysis.

The investigators acknowledged as limitations of their study some between-group differences at baseline, with characteristics such as Staphylococcus aureus infections and some inflammatory biomarkers higher in the early treatment group.

The Japan Agency for Medical Research and Development supported the study, and the investigators disclosed no conflicts of interest related to their findings.

SOURCE: Miyaji Y et al. J Allergy Clin Immunol Pract. 2019. doi: 10.1016/j.jaip.2019.11.036

Researchers in Japan report that infants with atopic dermatitis who are treated early and aggressively with corticosteroids develop fewer food allergies by age 2 years.

For their research published in the Journal of Allergy and Clinical Immunology: In Practice, Yumiko Miyaji, MD, PhD, of Japan’s National Center for Child Health and Development in Tokyo and colleagues looked at 3 years’ worth of records for 177 infants younger than 1 year of age seen at a hospital allergy center for eczema. Of these infants, 89 were treated with betamethasone valerate within 4 months of disease onset, and 88 were treated after 4 months of onset. Most (142) were followed-up at 22-24 months, when all were in complete remission or near remission from eczema.

At follow-up, clinicians collected information about anaphylactic reactions to food, administered specific food challenges, and tested serum immunoglobin E levels for food allergens. Dr. Miyaji and colleagues found a significant difference in the prevalence of allergies between the early-treated and late-treated groups to chicken egg, cow’s milk, wheat, peanuts, soy, or fish (25% vs. 46%, respectively; P equal to .013). For individual food allergies, only chicken egg was associated with a statistically significant difference in prevalence (15% vs 36%, P equal to .006).

“Our present study may be the first to demonstrate that early aggressive topical corticosteroid treatment to shorten the duration of eczema in infants was significantly associated with a decrease in later development of [food allergies],” Dr. Miyaji and colleagues wrote in their analysis.

The investigators acknowledged as limitations of their study some between-group differences at baseline, with characteristics such as Staphylococcus aureus infections and some inflammatory biomarkers higher in the early treatment group.

The Japan Agency for Medical Research and Development supported the study, and the investigators disclosed no conflicts of interest related to their findings.

SOURCE: Miyaji Y et al. J Allergy Clin Immunol Pract. 2019. doi: 10.1016/j.jaip.2019.11.036